WO2025166077A1 - Compositions comprising progranulin and uses thereof - Google Patents

Abstract

Provided here are complexes comprising an antigen-binding domain that binds to human transferrin receptor or human CD98 heavy chain linked to a Progranulin polypeptide. Also provided herein are isolated Progranulin mutant polypeptides. Methods of using and making such complexes and isolated polypeptides are provided herein.

Description

735022004340 COMPOSITIONS COMPRISING PROGRANULIN AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Patent Application No. 63/627,682, filed January 31, 2024; U.S. Provisional Patent Application No.63/660,926, filed June 17, 2024; and U.S. Provisional Patent Application No.63/744,150, filed January 10, 2025; the disclosures of each of which are incorporated herein by reference in their entirety. REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY [0002] The contents of the electronic sequence listing (735022004340SEQLIST.xml; Size: 497,495 bytes; and Date of Creation: January 21, 2025) is herein incorporated by reference in its entirety. FIELD OF THE PRESENT DISCLOSURE [0003] The present disclosure relates to complexes comprising antigen-binding domain linked to a Progranulin (PGRN) polypeptide. The antigen-binding domain can bind specifically to human transferrin receptor (TfR) or human CD98 heavy chain (CD98hc) to facilitate the transport of the PGRN polypeptide across the blood brain barrier (BBB). BACKGROUND [0004] Passive transfer of substances from blood to brain is restricted by the blood brain barrier (BBB). The BBB provides precise control of central nervous system (CNS) homeostasis allowing for proper neuronal function and also protecting neural tissue from toxins and pathogens. Alterations of the BBB are an important component of pathology and progression of different neurological diseases. However, the BBB poses a problem with regard to delivering therapeutics to the CNS. While recombinant proteins and antibody therapeutics have shown much success outside the CNS, such biologics do not cross the BBB efficiently. As a result, delivery of some therapeutics to the CNS has relied on injection of the therapeutic directly into the CNS. However, such injections are invasive procedures that have efficacy but are limited by the rapid export of cerebral spinal fluid (CSF) containing the therapeutic from the brain to the blood. Alternatively, a therapeutic intended for the CNS may be administered systemically at a high dose to allow for sufficient penetration of the BBB by the therapeutic. However, in some^ny-2871899 735022004340 cases, this approach may result in unintended effects due to the high dose in the periphery or increased manufacturing and formulation burdens to achieve the high dose. [0005] Progranulin (PGRN) is a secreted, growth factor-like, trophic, and anti-inflammatory protein, which also plays a role as an adipokine involved in diet-induced obesity and insulin resistance (Nguyen DA et al., (2013). Trends in Endocrinology and Metabolism, 24, 597- 606). Progranulin deficiency accounts for roughly 25% of all heritable forms of frontotemporal dementia (FTD), an early-onset neurodegenerative disease. Patients with heterozygous loss-of- function mutations in PGRN have ~50% reduced extracellular levels of the protein and they will invariably develop FTD, making PGRN a causal gene for the disease (Baker, M et al., (2006) Nature 442, 916-919; Carecchio M et al., (2011) J Alzheimers Dis 27, 781-790; Cruts, M et al., (2008) Trends Genet 24, 186-194; Galimberti, D et al., (2010) J Alzheimers Dis 19, 171-177). In addition, PGRN mutant alleles have been identified in Alzheimer’s disease patients (Seelaar, H et al., (2011). Journal of neurology, neurosurgery, and psychiatry 82, 476-486). Importantly, PGRN acts protectively in several disease models with increased PGRN levels, accelerating behavioral recovery from ischemia (Tao, J et al., (2012) Brain Res 1436, 130-136; Egashira, Y. et al., (2013). J Neuroinflammation 10, 105), suppressing locomotor deficits in a Parkinson’s disease model (Van Kampen, J.M et al. (2014). PLoS One 9, e97032), attenuating pathology in a model of amyotrophic lateral sclerosis (Laird, A.S et al., (2010). PLoS One 5, e13368.) and arthritis (Tang, W et al., (2011). Science 332, 478-484) and preventing memory deficits in an Alzheimer’s disease model (Minami, S.S et al., (2014). Nat Med 20, 1157-1164). [0006] Accordingly, improved products and methods for delivering Progranulin therapeutics across the BBB are needed. SUMMARY OF THE PRESENT DISCLOSURE [0007] Provided herein are complexes comprising an antigen-binding domain linked to a Progranulin (PGRN) polypeptide, and methods of making and using the same. The antigen- binding domain can bind specifically to human transferrin receptor (TfR) or human CD98 heavy chain (CD98hc) to facilitate the transport of the PGRN polypeptide across the blood brain barrier (BBB). [0008] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a Progranulin (PGRN) polypeptide, wherein the antigen-binding domain specifically^ny-2871899 735022004340 binds to human transferrin receptor (TfR), and wherein the PGRN polypeptide comprises a C- terminal amino acid sequence defined by X1X2X3X4, wherein X1 is any amino acid, and wherein X2, X3, and X4 are not PIL, PFL, PPL, PYL, QRL or QHL. [0009] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a Progranulin (PGRN) polypeptide, wherein the antigen-binding domain specifically binds to human transferrin receptor (TfR) and is not within an Fc domain of the complex. [0010] In some embodiments, the antigen-binding domain comprises a heavy chain variable region (VH) comprising a VH CDR1, VH CDR2, and VH CDR3 and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: SEQ ID NOs: 8, 11, 24, 40, 55, and 61, respectively; SEQ ID NOs: 8, 11, 25, 41, 55, and 61, respectively; SEQ ID NOs: 8, 12, 26, 42, 55, and 61, respectively; SEQ ID NOs: 8, 12, 27, 42, 55, and 61, respectively; SEQ ID NOs: 8, 13, 25, 42, 55, and 61, respectively; SEQ ID NOs: 8, 14, 25, 42, 55, and 61, respectively; SEQ ID NOs: 8, 15, 25, 43, 55, and 61, respectively; SEQ ID NOs: 8, 16, 25, 42, 55, and 61, respectively; SEQ ID NOs: 8, 17, 25, 44, 55, and 61, respectively; SEQ ID NOs: 9, 18, 28, 45, 56, and 62, respectively; SEQ ID NOs: 9, 19, 28, 45, 56, and 62, respectively; SEQ ID NOs: 9, 20, 28, 46, 57, and 62, respectively; SEQ ID NOs: 9, 20, 28, 46, 58, and 62, respectively; SEQ ID NOs: 9, 20, 28, 47, 59, and 62, respectively; SEQ ID NOs: 9, 21, 28, 46, 57, and 62, respectively; SEQ ID NOs: 9, 21, 28, 47, 59, and 62, respectively; SEQ ID NOs: 9, 22, 28, 46, 57, and 62, respectively; SEQ ID NOs: 9, 22, 28, 46, 58, and 62, respectively; SEQ ID NOs: 9, 22, 28, 47, 59, and 62, respectively; SEQ ID NOs: 10, 22, 28, 46, 58, and 62, respectively; SEQ ID NOs: 10, 22, 30, 46, 58, and 62, respectively; SEQ ID NOs: 10, 22, 31, 46, 58, and 62, respectively; SEQ ID NOs: 10, 22, 32, 46, 58, and 62, respectively; SEQ ID NOs: 10, 22, 33, 46, 58, and 62, respectively; SEQ ID NOs: 10, 22, 34, 46, 58, and 62, respectively; SEQ ID NOs: 10, 22, 35, 46, 58, and 62, respectively; SEQ ID NOs: 10, 22, 36, 46, 58, and 62, respectively; SEQ ID NOs: 10, 22, 37, 46, 58, and 62, respectively; SEQ ID NOs: 10, 22, 38, 46, 58, and 62, respectively; SEQ ID NOs: 10, 22, 39, 46, 58, and 62, respectively; SEQ ID NOs: 10, 22, 28, 49, 58, and 62, respectively; SEQ ID NOs: 10, 22, 28, 50, 58, and 62, respectively; SEQ ID NOs: 10, 22, 28, 51, 58, and 62, respectively; SEQ ID NOs: 10, 22, 28, 52, 58, and 62, respectively; SEQ ID NOs: 10, 22, 28, 53, 58, and 62, respectively; or SEQ ID NOs: 10, 22, 28, 54, 58, and 62, respectively.^ny-2871899 735022004340 [0011] In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, or 127. [0012] In some embodiments, the VL comprises the amino acid sequence of SEQ ID NO: 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 173, 174, 175, 176, 177, or 178. [0013] In some embodiments, the VH and the VL comprise the amino acid sequences of: SEQ ID NOs: 64 and 129, respectively; SEQ ID NOs: 65 and 130, respectively; SEQ ID NOs: 66 and 131, respectively; SEQ ID NOs: 67 and 130, respectively; SEQ ID NOs: 68 and 131, respectively; SEQ ID NOs: 69 and 130, respectively; SEQ ID NOs: 70 and 131, respectively; SEQ ID NOs: 71 and 130, respectively; SEQ ID NOs: 72 and 131, respectively; SEQ ID NOs: 73 and 130, respectively; SEQ ID NOs: 74 and 131, respectively; SEQ ID NOs: 75 and 132, respectively; SEQ ID NOs: 76 and 131, respectively; SEQ ID NOs: 77 and 132, respectively; SEQ ID NOs: 77 and 133, respectively; SEQ ID NOs: 78 and 134, respectively; SEQ ID NOs: 77 and 135, respectively; SEQ ID NOs: 77 and 136, respectively; SEQ ID NOs: 77 and 137, respectively; SEQ ID NOs: 77 and 138, respectively; SEQ ID NOs: 79 and 131, respectively; SEQ ID NOs: 77 and 139, respectively; SEQ ID NOs: 77 and 131, respectively; SEQ ID NOs: 80 and 140, respectively; SEQ ID NOs: 81 and 141, respectively; SEQ ID NOs: 82 and 131, respectively; SEQ ID NOs: 83 and 142, respectively; SEQ ID NOs: 77 and 143, respectively; SEQ ID NOs: 75 and 131, respectively; SEQ ID NOs: 75 and 144, respectively; SEQ ID NOs: 77 and 145, respectively; SEQ ID NOs: 84 and 131, respectively; SEQ ID NOs: 75 and 146, respectively; SEQ ID NOs: 85 and 131, respectively; SEQ ID NOs: 86 and 138, respectively; SEQ ID NOs: 79 and 139, respectively; SEQ ID NOs: 77 and 147, respectively; SEQ ID NOs: 75 and 148, respectively; SEQ ID NOs: 87 and 131, respectively; SEQ ID NOs: 88 and 131, respectively; SEQ ID NOs: 75 and 149, respectively; SEQ ID NOs: 89 and 150, respectively; SEQ ID NOs: 90 and 151, respectively; SEQ ID NOs: 77 and 152, respectively; SEQ ID NOs: 79 and 153, respectively; SEQ ID NOs: 91 and 131, respectively; SEQ ID NOs: 92 and 131, respectively; SEQ ID NOs: 79 and 154, respectively; SEQ ID NOs: 93 and 155, respectively; SEQ ID NOs: 80 and 131, respectively; SEQ ID NOs: 94 and 131, respectively; SEQ ID NOs:^ny-2871899 735022004340 95 and 131, respectively; SEQ ID NOs: 66 and 156, respectively; SEQ ID NOs: 97 and 138, respectively; SEQ ID NOs: 95 and 156, respectively; SEQ ID NOs: 98 and 157, respectively; SEQ ID NOs: 99 and 157, respectively; SEQ ID NOs: 100 and 157, respectively; SEQ ID NOs: 101 and 157, respectively; SEQ ID NOs: 102 and 158, respectively; SEQ ID NOs: 103 and 157, respectively; SEQ ID NOs: 104 and 159, respectively; SEQ ID NOs: 105 and 160, respectively; SEQ ID NOs: 106 and 161, respectively; SEQ ID NOs: 107 and 162, respectively; SEQ ID NOs: 106 and 163, respectively; SEQ ID NOs: 108 and 164, respectively; SEQ ID NOs: 106 and 165, respectively; SEQ ID NOs: 108 and 166, respectively; SEQ ID NOs: 109 and 165, respectively; SEQ ID NOs: 110 and 167, respectively; SEQ ID NOs: 111 and 168, respectively; SEQ ID NOs: 112 and 160, respectively; SEQ ID NOs: 113 and 169, respectively; SEQ ID NOs: 113 and 170, respectively; SEQ ID NOs: 113 and 171, respectively; SEQ ID NOs: 114 and 169, respectively; SEQ ID NOs: 114 and 171, respectively; SEQ ID NOs: 115 and 169, respectively; SEQ ID NOs: 115 and 170, respectively; SEQ ID NOs: 115 and 171, respectively; SEQ ID NOs: 116 and 169, respectively; SEQ ID NOs: 116 and 170, respectively; SEQ ID NOs: 116 and 171, respectively; SEQ ID NOs: 117 and 170, respectively; SEQ ID NOs: 118 and 170, respectively; SEQ ID NOs: 119 and 170, respectively; SEQ ID NOs: 120 and 170, respectively; SEQ ID NOs: 121 and 170, respectively; SEQ ID NOs: 122 and 170, respectively; SEQ ID NOs: 123 and 170, respectively; SEQ ID NOs: 124 and 170, respectively; SEQ ID NOs: 125 and 170, respectively; SEQ ID NOs: 126 and 170, respectively; SEQ ID NOs: 127 and 170, respectively; SEQ ID NOs: 117 and 173, respectively; SEQ ID NOs: 117 and 174, respectively; SEQ ID NOs: 117 and 175, respectively; SEQ ID NOs: 117 and 176, respectively; SEQ ID NOs: 117 and 177, respectively; SEQ ID NOs: 117 and 178, respectively; or SEQ ID NOs: 117 and 173, respectively. [0014] In some embodiments, the antigen-binding domain is a VHH comprising: (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: SEQ ID NOs: 8, 11, and 24, respectively; SEQ ID NOs: 8, 11, and 25, respectively; SEQ ID NOs: 8, 12, and 26, respectively; SEQ ID NOs: 8, 12, and 27, respectively; SEQ ID NOs: 8, 13, and 25, respectively; SEQ ID NOs: 8, 14, and 25, respectively; SEQ ID NOs: 8, 15, and 25, respectively; SEQ ID NOs: 8, 16, and 25, respectively; SEQ ID NOs: 8, 17, and 25, respectively; SEQ ID NOs: 9, 18, and 28, respectively; SEQ ID NOs: 9, 19, and 28, respectively; SEQ ID NOs: 9, 20, and 28, respectively; SEQ ID NOs: 9, 21, and 28, respectively; SEQ ID NOs: 9, 22, and 28, respectively; SEQ ID NOs: 10, 22, and 28, respectively; SEQ ID NOs: 10, 22, and 30, respectively; SEQ ID^ny-2871899 735022004340 NOs: 10, 22, and 31, respectively; SEQ ID NOs: 10, 22, and 32, respectively; SEQ ID NOs: 10, 22, and 33, respectively; SEQ ID NOs: 10, 22, and 34, respectively; SEQ ID NOs: 10, 22, and 35, respectively; SEQ ID NOs: 10, 22, and 36, respectively; SEQ ID NOs: 10, 22, and 37, respectively; SEQ ID NOs: 10, 22, and 38, respectively; or SEQ ID NOs: 10, 22, and 39, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, or 127. [0015] In some embodiments, the antigen-binding domain comprises a VH and a VL on a single polypeptide chain. In some embodiments, the antigen-binding domain comprises a single- chain fragment variable (scFv). In some embodiments, the scFv is in the orientation VH-linker- VL. In some embodiments, the scFv is in the orientation VL-linker-VH. In some embodiments, the linker (i) is about 5 to about 25 amino acids, is about 5 to about 20 amino acids, is about 10 to about 25 amino acids, or is about 10 to about 20 amino acids and/or (ii) comprises the amino acid sequence of GGSEGKSSGSGSESKSTGGS (SEQ ID NO: 6) or GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 7). [0016] In some embodiments, the antigen-binding domain comprises a VH on a first polypeptide and a VL on a second polypeptide. [0017] In some embodiments, the antigen-binding domain is a murine, chimeric, humanized, or human antigen-binding domain, optionally wherein the antigen-binding domain is a humanized antigen-binding domain. [0018] In some embodiments, the complex further comprises an Fc region, wherein the Fc region comprises a first and second polypeptide chain. In some embodiments, the Fc region is capable of binding FcRn. [0019] In some embodiments, the complex further comprises an Fc domain. In some embodiments, the Fc domain is capable of binding FcRn. [0020] In some embodiments, the complex comprises: (i) a single scFv or VHH or Fab antigen-binding domain that binds to human TfR and (ii) and two copies of the PGRN polypeptide. In some embodiments, the single scFv, Fab or VHH antigen-binding domain that binds to human TfR is linked to the C-terminus of one of the two copies of the PGRN polypeptide. In some embodiments, one of the two copies of the PGRN polypeptide is linked to^ny-2871899 735022004340 the N-terminus of the first polypeptide chain of the Fc region, and the other copy of the PGRN polypeptide is linked to the N-terminus of the second polypeptide chain of the Fc region. In some embodiments, the single scFv, Fab, or VHH antigen-binding domain that binds to human TfR is linked to the N-terminus of the first or second polypeptide chain of the Fc region. In some embodiments, one of the two copies of the PGRN polypeptide is linked to the C-terminus of the first polypeptide chain of the Fc region, and the other copy of the PGRN polypeptide is linked to the C-terminus of the second polypeptide chain of the Fc region. In some embodiments, the complex comprises: (i) an antibody that binds to human TfR, wherein the antibody comprises two heavy chains and two light chains; and (ii) two copies of the PGRN polypeptide, wherein each copy of the PGRN polypeptide is linked to the C-termini of one of the two antibody heavy chains. In some embodiments, the complex comprises (i) two scFv, Fab, or VHH antigen- binding domains that bind to human TfR, (ii) an Fc region; and (iii) two copies of the PGRN polypeptide, wherein one of the two scFv, Fab, or VHH antigen-binding domains that binds to human TfR is linked to the C-terminus of the first polypeptide chain of the Fc region, wherein the other scFv, Fab, or VHH antigen-binding domains that binds to human TfR is linked to the C-terminus of the second polypeptide chain of the Fc region, wherein one of the two copies of the PGRN polypeptide is linked to the N-terminus of the first polypeptide chain of the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the N-terminus of the second polypeptide chain of the Fc region. [0021] In some embodiments, the complex comprises: (i) a single scFv, VHH, or Fab antigen- binding domain that binds to human TfR, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the C-terminus of the first or second polypeptide chain of the Fc region and the PGRN polypeptide is linked to N-terminus of the first or second polypeptide chain of the Fc region. In some embodiments, the complex comprises: (i) a single scFv, VHH, or Fab antigen- binding domain that binds to human TfR, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the C-terminus of the Fc domain and the PGRN polypeptide is linked to N- terminus of the Fc domain. In some embodiments, the complex comprises: (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human TfR, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding^ny-2871899 735022004340 domain that binds to human TfR is linked to the N-terminus of the first or second polypeptide chain of the Fc region and the PGRN polypeptide is linked to the C-terminus of the first or second polypeptide chain of the Fc region. In some embodiments, the complex comprises: (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human TfR, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen- binding domain that binds to human TfR is linked to the N-terminus of the Fc domain and the PGRN polypeptide is linked to the C-terminus of the Fc domain. In some embodiments, the complex comprises: (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human TfR, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the N-terminus of one of the two polypeptide chains of the Fc region, and wherein the PGRN polypeptide is linked to the N-terminus of the other polypeptide chain of the Fc region. [0022] In some embodiments, the Fc region is a heterodimeric Fc region, optionally comprising knob and hole mutations. In some embodiments, the Fc region is a modified Fc region with a modification listed in Table 8 or Table 9. In some embodiments, the Fc region is a human IgG1 Fc region, wherein the human IgG1 Fc region comprises a mutation that reduces effector function, optionally wherein the mutation that reduces effector function comprises: (i) L234A, L235A, and/or P331S; (ii) N325S and/or L328F; (iii) L234A, L235A, and/or P329G; or (iv) L234A, L235A, and/or P329S. In some embodiments, the wherein the Fc domain is a single chain monovalent Fc domain. In some embodiments, the Fc domain is a modified Fc domain with a modification listed in Table 8. In some embodiments, the Fc domain is a human IgG1 Fc domain, wherein the human IgG1 Fc domain comprises a mutation that reduces effector function, optionally wherein the mutation that reduces effector function comprises: (i) L234A, L235A, and/or P331S; (ii) N325S and/or L328F; (iii) L234A, L235A, and/or P329G; or (iv) L234A, L235A, and/or P329S. [0023] In some embodiments, the PGRN polypeptide comprises the amino acid sequence of SEQ ID NO: 330, and wherein: (a) X1 is an amino acid selected from the group consisting of R, I, V, Q, T, P, and D; (b) X2 is an amino acid selected from the group consisting of Q and P; (c) X3 is absent or is an amino acid selected from the group consisting of L, P, C, G, T, D, Y, R, S, Q, V, A, I, H, K, and N; and/or (d) X₄ is absent or is an amino acid selected from the group consisting of L, E, G, P, R, D, S, H, N, V, T, I, and A. In some embodiments, the PGRN^ny-2871899 735022004340 polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 259, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. [0024] In some aspects, provided herein is a complex comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a PGRN polypeptide; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2 and a CH3; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR. In some embodiments, the PGRN polypeptide comprises the amino acid sequence of SEQ ID NO: 330, and wherein: (a) X₁ is an amino acid selected from the group consisting of R, I, V, Q, T, P, and D; (b) X₂ is an amino acid selected from the group consisting of Q and P; (c) X₃ is absent or is an amino acid selected from the group consisting of L, P, C, G, T, D, Y, R, S, Q, V, A, I, H, K, and N; and/or (d) X4 is absent or is an amino acid selected from the group consisting of L, E, G, P, R, D, S, H, N, V, T, I, and A. In some embodiments, the PGRN polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 259, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. In some embodiments, (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 319; (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 320; and (iii) the third polypeptide comprises the amino acid sequence of SEQ ID NO: 321.^ny-2871899 735022004340 [0025] In some aspects, provided herein is a complex comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, and a CH3; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a PGRN polypeptide; and (iii) a third polypeptide comprising, from the N- terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR. In some embodiments, the PGRN polypeptide comprises the amino acid sequence of SEQ ID NO: 330, and wherein: (a) X₁ is an amino acid selected from the group consisting of R, I, V, Q, T, P, and D; (b) X₂ is an amino acid selected from the group consisting of Q and P; (c) X₃ is absent or is an amino acid selected from the group consisting of L, P, C, G, T, D, Y, R, S, Q, V, A, I, H, K, and N; and/or (d) X4 is absent or is an amino acid selected from the group consisting of L, E, G, P, R, D, S, H, N, V, T, I, and A. In some embodiments, the PGRN polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 259, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. In some embodiments, (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 322; (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 323; and (iii) the third polypeptide comprises the amino acid sequence of SEQ ID NO: 321. [0026] In some aspects, provided herein is a complex comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a PGRN polypeptide; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a PGRN polypeptide; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR. In some embodiments, the PGRN polypeptide comprises the amino acid sequence of SEQ ID NO: 330, and wherein: (a) X1 is an amino acid selected from the group consisting of R, I, V, Q, T, P, and D; (b) X₂ is an amino acid selected from the group consisting of Q and P; (c) X₃ is absent or is an amino acid selected^ny-2871899 735022004340 from the group consisting of L, P, C, G, T, D, Y, R, S, Q, V, A, I, H, K, and N; and/or (d) X₄ is absent or is an amino acid selected from the group consisting of L, E, G, P, R, D, S, H, N, V, T, I, and A. In some embodiments, the PGRN polypeptide of the first polypeptide and the second polypeptide each comprise an amino acid sequence selected from the group consisting of SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 259, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. In some embodiments, (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 319; (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 323; and (iii) the third polypeptide comprises the amino acid sequence of SEQ ID NO: 321. [0027] In some aspects, provided herein is a complex comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a PGRN polypeptide; and (ii) a second polypeptide comprising, from the N- terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR. In some embodiments, the PGRN polypeptide comprises the amino acid sequence of SEQ ID NO: 330, and wherein: (a) X1 is an amino acid selected from the group consisting of R, I, V, Q, T, P, and D; (b) X2 is an amino acid selected from the group consisting of Q and P; (c) X₃ is absent or is an amino acid selected from the group consisting of L, P, C, G, T, D, Y, R, S, Q, V, A, I, H, K, and N; and/or (d) X₄ is absent or is an amino acid selected from the group consisting of L, E, G, P, R, D, S, H, N, V, T, I, and A. In some embodiments, the PGRN polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 259, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ^ny-2871899 735022004340 ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. In some embodiments, (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 332; and (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 321. [0028] In some embodiments, (i) the VH comprises a VH CDR1, VH CDR2, and VH CDR3; wherein the VH CDR1 comprises the amino acid sequence of SEQ ID NO: 8; wherein the VH CDR2 comprises the amino acid sequence of SEQ ID NO: 15; and wherein the VH CDR3 comprises the amino acid sequence of SEQ ID NO: 25; and/or (ii) the VL comprises a VL CDR1, VL CDR2, and VL CDR3; wherein the VL CDR1 comprises the amino acid sequence of SEQ ID NO: 43; wherein the VL CDR2 comprises the amino acid sequence of SEQ ID NO: 55; and wherein the VL CDR3 comprises the amino acid sequence of SEQ ID NO: 61. In some embodiments, (i) the VH comprises the amino acid sequence of SEQ ID NO: 102; and/or (ii) the VL comprises the amino acid sequence of SEQ ID NO: 158. [0029] In some embodiments, the complex binds human Sortilin with a dissociation constant (K_D) that ranges from about 5 nM to about 400 nM. In some embodiments, the complex binds human Sortilin with a K_D that ranges from about 50 nM to about 350 nM. In some embodiments, the complex binds human Sortilin with a K_D that ranges from about 100 nM to about 300 nM. In some embodiments, the complex increases cellular GCase activity greater than the PGRN polypeptide alone. In some embodiments, the complex increases cellular GCase activity at least about 0.5-fold, at least about 1-fold, or at least about 2-fold greater than the PGRN polypeptide alone. In some embodiments, the complex is linked to an imaging agent. [0030] In some aspects, provided herein is a polynucleotide encoding the complex of any one of the embodiments. In some aspects, provided herein is a vector comprising the polynucleotide of the preceding embodiment. In some aspects, provided herein is a host cell comprising the vector of the preceding embodiment. In some aspects, provided herein is a method of producing a complex comprising culturing the host cell of the preceding embodiment so that the complex is produced, optionally wherein the method further comprises isolating the complex from the culture. In some aspects, provided herein is an isolated complex thereof produced by the method of the preceding embodiment. In some aspects, provided herein is a pharmaceutical composition comprising the complex of any one of the embodiments. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.^ny-2871899 735022004340 [0031] In some aspects, provided herein is a method of treating a neurological disease or disorder in a subject comprising administering the complex of any one of the embodiments or the pharmaceutical composition of any one of the embodiments to the subject. In some embodiments, the neurological disease or disorder is selected from a neuropathy disorder, a neurodegenerative disease, an ocular disease disorder, a seizure disorder, a lysosomal storage disease, ischemia, a behavioral disorder, and CNS inflammation. In some embodiments, the neurological disease or disorder is selected from Alzheimer's disease (AD), Huntington’s disease, dystonia, ataxia, stroke, dementia, Lewy body dementia, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson's disease, Pick's disease, encephalitis, traumatic brain injury, and limbic-predominant age-related TDP-43 encephalopathy (LATE). In some embodiments, the dementia is frontotemporal dementia (FTD). In some embodiments, the neurological disease or disorder is Alzheimer’s disease. In some embodiments, the Alzheimer's disease is early onset Alzheimer’s disease, prodromal Alzheimer’s disease, mild Alzheimer’s disease, or late onset Alzheimer’s disease. In some embodiments, the neurological disease or disorder is Parkinson’s disease. In some embodiments, the neurological disease or disorder is frontal temporal epilepsy. [0032] In some aspects, provided herein is a method of treating a lysosomal storage disease in a subject comprising administering the complex of any one of the embodiments or the pharmaceutical composition of any one of the embodiments to the subject. In some embodiments, the lysosomal storage disease is selected from Gaucher disease, Ceroid lipofuscinosis (Batten disease), Mucopolysaccharidosis (MPS) Type I, MPS Type II and MPS Type III. [0033] In some aspects, provided herein is a method of transporting a complex across the BBB of a subject, comprising administering the complex of any one of the embodiments or the pharmaceutical composition of any one of the embodiments to the subject. [0034] In some aspects, provided herein is a method of increasing the concentration of PGRN in the cerebral spinal fluid (CSF) of a subject, comprising administering the complex of any one of the embodiments or the pharmaceutical composition of any one of the embodiments to the subject, wherein the concentration of PGRN is increased as compared to administering the PGRN polypeptide alone to the subject.^ny-2871899 735022004340 [0035] In some aspects, provided herein is a method of imaging PGRN within a subject, comprising administering to the subject the complex of any one of the embodiments and locating the imaging agent within the subject. In some aspects, provided herein is a method of detecting PGRN in vitro, comprising contacting an in vitro sample with the complex of any one of the embodiments and locating the imaging agent within the sample. [0036] In some aspects, provided herein is use of the complex of any one of the embodiments or the pharmaceutical composition of any one of the embodiments in the method of any one of the embodiments. In some aspects, provided herein is a complex of any one of the embodiments or the pharmaceutical composition of any one of the embodiments for use in the method of any one of the embodiments. [0037] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a PGRN polypeptide, wherein the antigen-binding domain specifically binds to human CD98 heavy chain (CD98hc). In some embodiments, the antigen-binding domain comprises a VH comprising a VH CDR1, VH CDR2, and VH CDR3, and a VL comprising a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences comprise the amino acid sequences of: SEQ ID NOs: 181, 185, 191, 194, 198, and 201, respectively; SEQ ID NOs: 182, 186, 191, 195, 199, and 202, respectively; SEQ ID NOs: 183, 187, 192, 196, 200, and 203, respectively; SEQ ID NOs: 9, 188, 192, 196, 200, and 203, respectively; SEQ ID NOs: 184, 189, 193, 197, 198, and 204, respectively; SEQ ID NOs: 184, 190, 193, 197, 198, and 204, respectively; SEQ ID NOs: 184, 324, 193, 197, 198, and 204, respectively; SEQ ID NOs: 184, 325, 193, 197, 198, and 204, respectively; or SEQ ID NOs: 184, 326, 193, 197, 198, and 204, respectively. [0038] In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 205, 206, 207, 208, 209, 210, 327, 328, or 329. In some embodiments, the VL comprises the amino acid sequence of SEQ ID NO: 211, 212, 213, 214, 215, or 216. In some embodiments, the VH and the VL comprise the amino acid sequences of: SEQ ID NOs: 205 and 211, respectively; SEQ ID NOs: 206 and 212, respectively; SEQ ID NOs: 207 and 213, respectively; SEQ ID NOs: 208 and 214, respectively; SEQ ID NOs: 209 and 215, respectively; SEQ ID NOs: 210 and 216, respectively; SEQ ID NOs: 327 and 216, respectively; SEQ ID NOs: 328 and 216, respectively; or SEQ ID NOs: 329 and 216, respectively.^ny-2871899 735022004340 [0039] In some embodiments, the antigen-binding domain is a VHH comprising: (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: SEQ ID NOs: 181, 185, and 191, respectively; SEQ ID NOs: 182, 186, and 191, respectively; SEQ ID NOs: 183, 187, and 192, respectively; SEQ ID NOs: 9, 188, and 192, respectively; SEQ ID NOs: 184, 189, and 193, respectively; SEQ ID NOs: 184, 190, and 193, respectively; SEQ ID NOs: 184, 324, and 193, respectively; SEQ ID NOs: 184, 325, and 193, respectively; or SEQ ID NOs: 184, 326, and 193, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 205, 206, 207, 208, 209, 210, 327, 328, or 329. [0040] In some embodiments, the antigen-binding domain comprises a VH and a VL on a single polypeptide chain. In some embodiments, the antigen-binding domain comprises a single- chain fragment variable (scFv). In some embodiments, the scFv is in the orientation VH-linker- VL. In some embodiments, the scFv is in the orientation VL-linker-VH. In some embodiments, the linker is about 5 to about 25 amino acids, is about 5 to about 20 amino acids, is about 10 to about 25 amino acids, or is about 10 to about 20 amino acids. In some embodiments, the linker comprises the amino acid sequence of GGSEGKSSGSGSESKSTGGS (SEQ ID NO: 6) or GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 7). [0041] In some embodiments, the antigen-binding domain comprises a VH on a first polypeptide and a VL on a second polypeptide. [0042] In some embodiments, the antigen-binding domain is a murine, chimeric, humanized, or human antigen-binding domain, optionally wherein the antigen-binding domain is a humanized antigen-binding domain. In some embodiments, the complex further comprises an Fc region, wherein the Fc region comprises a first and second polypeptide chain. In some embodiments, the Fc region is capable of binding FcRn. [0043] In some embodiments, the complex further comprises an Fc domain. In some embodiments, the Fc domain is capable of binding FcRn. [0044] In some embodiments, the complex further comprises (i) a single scFv or VHH or Fab antigen-binding domain that binds to human CD98hc and (ii) and two copies of the PGRN polypeptide. In some embodiments, the single scFv, Fab or VHH antigen-binding domain that binds to human CD98hc is linked to the C-terminus of one of the two copies of the PGRN polypeptide. In some embodiments, one of the two copies of the PGRN polypeptide is linked to^ny-2871899 735022004340 the N-terminus of the first polypeptide chain of the Fc region, and the other copy of the PGRN polypeptide is linked to the N-terminus of the second polypeptide chain of the Fc region. In some embodiments, the single scFv, Fab, or VHH antigen-binding domain that binds to human CD98hc is linked to the N-terminus of the first or second polypeptide chain of the Fc region. In some embodiments, one of the two copies of the PGRN polypeptide is linked to the C-terminus of the first polypeptide chain of the Fc region, and the other copy of the PGRN polypeptide is linked to the C-terminus of the second polypeptide chain of the Fc region. [0045] In some embodiments, the complex further comprises (i) an antibody that binds to human CD98hc, wherein the antibody comprises two heavy chains and two light chains; and (ii) two copies of the PGRN polypeptide, wherein each copy of the PGRN polypeptide is linked to the C-termini of one of the two antibody heavy chains. In some embodiments, the complex further comprises (i) two scFv, Fab, or VHH antigen-binding domains that bind to human CD98hc, (ii) an Fc region; and (iii) two copies of the PGRN polypeptide, wherein one of the two scFv, Fab, or VHH antigen-binding domains that binds to human CD98hc is linked to the C- terminus of the first polypeptide chain of the Fc region, wherein the other scFv, Fab, or VHH antigen-binding domains that binds to human CD98hc is linked to the C-terminus of the second polypeptide chain of the Fc region, wherein one of the two copies of the PGRN polypeptide is linked to the N-terminus of the first polypeptide chain of the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the N-terminus of the second polypeptide chain of the Fc region. [0046] In some embodiments, the complex further comprises: (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the C-terminus of the first or second polypeptide chain of the Fc region and the PGRN polypeptide is linked to N-terminus of the first or second polypeptide chain of the Fc region. In some embodiments, the complex further comprises: (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the C-terminus of the Fc domain and the PGRN polypeptide is linked to N-terminus of the Fc domain. In some embodiments, the complex further comprises: (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc,^ny-2871899 735022004340 (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the N-terminus of the first or second polypeptide chain of the Fc region and the PGRN polypeptide is linked to the C-terminus of the first or second polypeptide chain of the Fc region. In some embodiments, the complex further comprises: (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the N-terminus of the Fc domain and the PGRN polypeptide is linked to the C-terminus of the Fc domain. In some embodiments, the complex further comprises: (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the N-terminus of one of the two polypeptide chains of the Fc region, and wherein the PGRN polypeptide is linked to the N-terminus of the other polypeptide chain of the Fc region. [0047] In some embodiments, the Fc region is a heterodimeric Fc region, optionally comprising knob and hole mutations. In some embodiments, the Fc region is a modified Fc region with a modification listed in Table 8 or Table 9. In some embodiments, the Fc region is a human IgG1 Fc region, wherein the human IgG1 Fc region comprises a mutation that reduces effector function, optionally wherein the mutation that reduces effector function comprises: (i) L234A, L235A, and/or P331S; (ii) N325S and/or L328F; (iii) L234A, L235A, and/or P329G; or (iv) L234A, L235A, and/or P329S. [0048] In some embodiments, the Fc domain is a single chain monovalent Fc domain. In some embodiments, the Fc domain is a modified Fc domain with a modification listed in Table 8. In some embodiments, the Fc domain is a human IgG1 Fc domain, wherein the human IgG1 Fc domain comprises a mutation that reduces effector function, optionally wherein the mutation that reduces effector function comprises: (i) L234A, L235A, and/or P331S; (ii) N325S and/or L328F; (iii) L234A, L235A, and/or P329G; or (iv) L234A, L235A, and/or P329S. [0049] In some embodiments, the PGRN polypeptide comprises the amino acid sequence of SEQ ID NO: 330, wherein: (a) X1 is an amino acid selected from the group consisting of R, I, V, Q, T, P, and D; (b) X₂ is an amino acid selected from the group consisting of Q and P; (c) X₃ is absent or is an amino acid selected from the group consisting of L, P, C, G, T, D, Y, R, S, Q, V,^ny-2871899 735022004340 A, I, H, K, and N; and/or (d) X₄ is absent or is an amino acid selected from the group consisting of L, E, G, P, R, D, S, H, N, V, T, I, and A. In some embodiments, the PGRN polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 247, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 260, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. [0050] In some embodiments, the complex is linked to an imaging agent. [0051] In some aspects, provided herein is a polynucleotide encoding the complex of any one of the embodiments. In some aspects, provided herein is a vector comprising the polynucleotide of any one of the embodiments. In some aspects, provided herein is a host cell comprising the vector of any one of the embodiments. In some aspects, provided herein is a method of producing a complex comprising culturing the host cell of any one of the embodiments so that the complex is produced, optionally wherein the method further comprises isolating the complex from the culture. In some aspects, provided herein is an isolated complex thereof produced by the method of any one of the embodiments. In some aspects, provided herein is a pharmaceutical composition comprising the complex of any one of the embodiments. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. [0052] In some aspects, provided herein is a method of treating a neurological disease or disorder in a subject comprising administering the complex of any one of the embodiments or the pharmaceutical composition of any one of the embodiments to the subject. In some embodiments, the neurological disease or disorder is selected from a neuropathy disorder, a neurodegenerative disease, an ocular disease disorder, a seizure disorder, a lysosomal storage disease, ischemia, a behavioral disorder, and CNS inflammation. In some embodiments, the neurological disease or disorder is selected from Alzheimer's disease (AD), Huntington’s disease, dystonia, ataxia, stroke, dementia, Lewy body dementia, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson's disease, Pick's disease, encephalitis, traumatic brain injury, and limbic-predominant age-related TDP-43 encephalopathy (LATE). In some^ny-2871899 735022004340 embodiments, the dementia is frontotemporal dementia (FTD). In some embodiments, the neurological disease or disorder is Alzheimer’s disease. In some embodiments, the Alzheimer's disease is early onset Alzheimer’s disease, prodromal Alzheimer’s disease, mild Alzheimer’s disease, or late onset Alzheimer’s disease. In some embodiments, the neurological disease or disorder is Parkinson’s disease. In some embodiments, the neurological disease or disorder is frontal temporal epilepsy. [0053] In some aspects, provided herein is a method of treating a lysosomal storage disease in a subject comprising administering the complex of any one of the embodiments or the pharmaceutical composition of any one of the embodiments to the subject. In some embodiments, the lysosomal storage disease is selected from Gaucher disease, Ceroid lipofuscinosis (Batten disease), Mucopolysaccharidosis (MPS) Type I, MPS Type II and MPS Type III. [0054] In some aspects, provided herein is a method of transporting a complex across the BBB of a subject, comprising administering the complex of any one of the embodiments or the pharmaceutical composition of any one of the embodiments to the subject. In some aspects, provided herein is a method of increasing the concentration of PGRN in the CSF of a subject, comprising administering the complex of any one of the embodiments or the pharmaceutical composition of any one of the embodiments to the subject, wherein the concentration of PGRN is increased as compared to administering the PGRN polypeptide alone to the subject. In some aspects, provided herein is a method of imaging PGRN within a subject, comprising administering to the subject the complex of any one of the embodiments and locating the imaging agent within the subject. In some aspects, provided herein is a method of detecting PGRN in vitro, comprising contacting an in vitro sample with the complex of any one of the embodiments and locating the imaging agent within the sample. [0055] In some aspects, provided herein is use of the complex of any one of the embodiments or the pharmaceutical composition of any one of the embodiments in the method of any one of the embodiments. In some aspects, provided herein is a complex of any one of the embodiments or the pharmaceutical composition of any one of the embodiments for use in the method of any one of the embodiments. [0056] In some aspects, provided herein is an isolated PGRN polypeptide, wherein: (i) the isolated PGRN polypeptide comprises a C-terminal amino acid sequence defined by X₁X₂X₃X₄,^ny-2871899 735022004340 and wherein: (a) X₁ is an amino acid selected from the group consisting of R, D, E, I, P, or Q; (b) X2 is an amino acid selected from the group consisting of Q and P; (c) X3 is an amino acid selected from the group consisting of L, A, C, D, F, G, H, I, K, M, N, P, Q, R, S, T, V, or Y; and/or (d) X4 is absent or is an amino acid selected from the group consisting of L, R, or V; and (ii) X2, X3, and X4 are not PIL, PFL, PPL, PYL, QRL, or QHL. In some embodiments, the isolated PGRN polypeptide comprises the amino acid sequence of SEQ ID NO: 330. In some embodiments, the amino acid sequence is selected from the group consisting of SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 259, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. In some embodiments, the amino acid sequence is SEQ ID NO: 231. In some embodiments, the amino acid sequence is SEQ ID NO: 232. In some embodiments, the amino acid sequence is SEQ ID NO: 233. In some embodiments, the amino acid sequence is SEQ ID NO: 234. In some embodiments, the amino acid sequence is SEQ ID NO: 235. In some embodiments, the amino acid sequence is SEQ ID NO: 236. In some embodiments, the amino acid sequence is SEQ ID NO: 237. In some embodiments, the amino acid sequence is SEQ ID NO: 238. In some embodiments, the amino acid sequence is SEQ ID NO: 239. In some embodiments, the amino acid sequence is SEQ ID NO: 240. In some embodiments, the amino acid sequence is SEQ ID NO: 241. In some embodiments, the amino acid sequence is SEQ ID NO: 242. In some embodiments, the amino acid sequence is SEQ ID NO: 243. In some embodiments, the amino acid sequence is SEQ ID NO: 244. In some embodiments, the amino acid sequence is SEQ ID NO: 245. In some embodiments, the amino acid sequence is SEQ ID NO: 246. In some embodiments, the amino acid sequence is SEQ ID NO: 248. In some embodiments, the amino acid sequence is SEQ ID NO: 249. In some embodiments, the amino acid sequence is SEQ ID NO: 250. In some embodiments, the amino acid sequence is SEQ ID NO: 251. In some embodiments, the amino acid sequence is SEQ ID NO: 252. In some embodiments, the amino acid sequence is SEQ ID NO: 253. In some embodiments, the amino acid sequence is SEQ ID NO: 254. In some embodiments, the amino acid sequence is SEQ ID^ny-2871899 735022004340 NO: 255. In some embodiments, the amino acid sequence is SEQ ID NO: 256. In some embodiments, the amino acid sequence is SEQ ID NO: 257. In some embodiments, the amino acid sequence is SEQ ID NO: 259. In some embodiments, the amino acid sequence is SEQ ID NO: 261. In some embodiments, the amino acid sequence is SEQ ID NO: 262. In some embodiments, the amino acid sequence is SEQ ID NO: 263. In some embodiments, the amino acid sequence is SEQ ID NO: 264. In some embodiments, the amino acid sequence is SEQ ID NO: 265. In some embodiments, the amino acid sequence is SEQ ID NO: 266. [0057] In some aspects, provided herein is an isolated nucleic acid encoding the isolated PGRN polypeptide of any one of the embodiments. In some aspects, provided herein is a vector comprising the nucleic acid of any one of the embodiments. In some aspects, provided herein is a host cell comprising the vector of any one of the embodiments. In some aspects, provided herein is a method of producing an isolated PGRN polypeptide comprising culturing the host cell of any one of the embodiments so that the isolated PGRN polypeptide is produced, optionally wherein the method further comprises isolating the isolated PGRN polypeptide from the culture. In some aspects, provided herein is an isolated PGRN polypeptide produced by the method of any one of the embodiments. In some aspects, provided herein is a pharmaceutical composition comprising the isolated PGRN polypeptide of any one of the embodiments. [0058] In some aspects, provided herein is a method of treating a neurological disease or disorder in a subject comprising administering the isolated PGRN polypeptide of any one of any one of the embodiments or the pharmaceutical composition of any one of the embodiments to the subject. In some embodiments, the neurological disease or disorder is selected from a neuropathy disorder, a neurodegenerative disease, an ocular disease disorder, a seizure disorder, a lysosomal storage disease, ischemia, a behavioral disorder, and CNS inflammation. [0059] In some embodiments, the neurological disease or disorder is selected from Alzheimer's disease (AD), Huntington’s disease, dystonia, ataxia, stroke, dementia, Lewy body dementia, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson's disease, Pick's disease, encephalitis, traumatic brain injury, and limbic-predominant age-related TDP-43 encephalopathy (LATE). In some embodiments, the dementia is frontotemporal dementia (FTD). In some embodiments, the neurological disease or disorder is Alzheimer’s disease. In some embodiments, the Alzheimer's disease is early onset Alzheimer’s disease, prodromal Alzheimer’s disease, mild Alzheimer’s disease, or late onset Alzheimer’s disease. In some embodiments, the neurological^ny-2871899 735022004340 disease or disorder is Parkinson’s disease. In some embodiments, the neurological disease or disorder is frontal temporal epilepsy. [0060] In some aspects, provided herein is a method of treating a lysosomal storage disease in a subject comprising administering the isolated PGRN polypeptide of any one of the embodiments or the pharmaceutical composition of any one of the embodiments to the subject. In some embodiments, the lysosomal storage disease is selected from Gaucher disease, Ceroid lipofuscinosis (Batten disease), Mucopolysaccharidosis (MPS) Type I, MPS Type II and MPS Type III. [0061] In some aspects, provided herein is a complex comprising (a) an antigen-binding domain that specifically binds to human transferrin receptor (TfR) and (b) a Progranulin (PGRN) polypeptide. [0062] In some aspects, provided herein is a complex comprising (a) an affinity-tuned antigen- binding domain that specifically binds to human TfR, wherein the antigen-binding domain binds to human TfR with an affinity of 0.01 nM to 50 nM, and (b) a PGRN polypeptide. [0063] In some aspects, provided herein is a complex comprising (a) an affinity-tuned antigen- binding domain that specifically binds to human TfR, wherein the antigen-binding domain binds to human TfR with an affinity of 51 nM to 750 nM, and (b) a PGRN polypeptide. In some embodiments, the antigen-binding domain binds to human TfR with an affinity of 600 nM to 650 nM. In some embodiments, the antigen-binding domain binds to human TfR with an affinity of 160 nM to 200 nM. [0064] In some aspects, provided herein is a complex comprising (a) an affinity-tuned antigen- binding domain that specifically binds to human TfR, wherein the antigen-binding domain binds to human TfR with an affinity of 751 nM to 10,000 nM, and (b) a PGRN polypeptide. [0065] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a Progranulin (PGRN) polypeptide, wherein the antigen-binding domain specifically binds to human transferrin receptor (TfR), wherein the antigen-binding domain comprises a heavy chain variable region (VH) comprising a VH CDR1, VH CDR2, and VH CDR3 and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3, and wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; 22^ny-2871899 735022004340 (ii) SEQ ID NOs: 8, 15, 25, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 50, 58, and 62, respectively; (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 341, 55, and 61, respectively. [0066] In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 101, 102, 342, 117, 343, or 118. In some embodiments, the VL comprises the amino acid sequence of SEQ ID NO: 154, 344, 345, 174, 346, 347, 348, 349, or 350. In some embodiments, the VH and the VL comprise the amino acid sequences of: (i) SEQ ID NOs: 101 and 154, respectively; (ii) SEQ ID NOs: 102 and 344, respectively; (iii) SEQ ID NOs: 102 and 345, respectively; (iv) SEQ ID NOs: 342 and 174, respectively; (v) SEQ ID NOs: 117 and 346, respectively; (vi) SEQ ID NOs: 117 and 347, respectively; (vii) SEQ ID NOs: 117 and 348, respectively; (viii) SEQ ID NOs: 117 and 349, respectively; (ix) SEQ ID NOs: 343 and 174, respectively; (x) SEQ ID NOs: 118 and 174, respectively; or (xi) SEQ ID NOs: 101 and 350, respectively. [0067] In some embodiments, a complex comprising an antigen-binding domain linked to a PGRN polypeptide, wherein the antigen-binding domain specifically binds to human TfR, and wherein the antigen-binding domain is a VHH comprising: (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 8, 14, and 25, respectively; (ii) SEQ ID NOs: 8, 15, and 25, respectively;^ny-2871899 735022004340 (iv) SEQ ID NOs: 10, 22, and 333, respectively; (v) SEQ ID NOs: 10, 22, and 28, respectively; (ix) SEQ ID NOs: 10, 22, and 334, respectively; or (x) SEQ ID NOs: 10, 22, and 30, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 101, 102, 342, 117, 343, or 118. [0068] In some embodiments, the antigen-binding domain comprises a VH and a VL on a single polypeptide chain. In some embodiments, the antigen-binding domain comprises a single- chain fragment variable (scFv). In some embodiments, the scFv is in the orientation VH-linker- VL. In some embodiments, the scFv is in the orientation VL-linker-VH. In some embodiments, the linker (i) is about 5 to about 25 amino acids, is about 5 to about 20 amino acids, is about 10 to about 25 amino acids, or is about 10 to about 20 amino acids and/or (ii) comprises the amino acid sequence of GGSEGKSSGSGSESKSTGGS (SEQ ID NO: 6) or GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 7). [0069] In some embodiments, the antigen-binding domain comprises a VH on a first polypeptide and a VL on a second polypeptide. In some embodiments, the antigen-binding domain is a murine, chimeric, humanized, or human antigen-binding domain, optionally wherein the antigen-binding domain is a humanized antigen-binding domain. [0070] In some embodiments, the complex further comprises an Fc region, wherein the Fc region comprises a first and second polypeptide chain. In some embodiments, the Fc region is capable of binding FcRn. In some embodiments, the complex further comprises an Fc domain. In some embodiments, the Fc domain is capable of binding FcRn. [0071] In some embodiments, the complex comprises (i) a single scFv or VHH or Fab antigen- binding domain that binds to human TfR and (ii) and two copies of the PGRN polypeptide. In some embodiments, the single scFv, Fab or VHH antigen-binding domain that binds to human TfR is linked to the C-terminus of one of the two copies of the PGRN polypeptide. In some embodiments, one of the two copies of the PGRN polypeptide is linked to the N-terminus of the first polypeptide chain of the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the N-terminus of the second polypeptide chain of the Fc region. In some embodiments, the single scFv, Fab, or VHH antigen-binding domain that binds to human TfR is linked to the N-terminus of the first or second polypeptide chain of the Fc region. In some embodiments, one^ny-2871899 735022004340 of the two copies of the PGRN polypeptide is linked to the C-terminus of the first polypeptide chain of the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the C- terminus of the second polypeptide chain of the Fc region. [0072] In some embodiments, the complex comprises (i) an antibody that binds to human TfR, wherein the antibody comprises two heavy chains and two light chains; and (ii) two copies of the PGRN polypeptide, wherein each copy of the PGRN polypeptide is linked to the C-termini of one of the two antibody heavy chains. [0073] In some embodiments, the complex comprises (i) two scFv, Fab, or VHH antigen- binding domains that bind to human TfR, (ii) an Fc region; and (iii) two copies of the PGRN polypeptide, wherein one of the two scFv, Fab, or VHH antigen-binding domains that binds to human TfR is linked to the C-terminus of the first polypeptide chain of the Fc region, wherein the other scFv, Fab, or VHH antigen-binding domains that binds to human TfR is linked to the C-terminus of the second polypeptide chain of the Fc region, wherein one of the two copies of the PGRN polypeptide is linked to the N-terminus of the first polypeptide chain of the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the N-terminus of the second polypeptide chain of the Fc region. [0074] In some embodiments, the complex comprises (i) a single scFv, VHH, or Fab antigen- binding domain that binds to human TfR, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the C-terminus of the first or second polypeptide chain of the Fc region and the PGRN polypeptide is linked to N-terminus of the first or second polypeptide chain of the Fc region. [0075] In some embodiments, the complex comprises (i) a single scFv, VHH, or Fab antigen- binding domain that binds to human TfR, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the C-terminus of the Fc domain and the PGRN polypeptide is linked to N- terminus of the Fc domain. [0076] In some embodiments, the complex comprises (i) a single scFv, VHH, or Fab antigen- binding domain that binds to human TfR, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the N-terminus of the first or second polypeptide chain of the Fc region and the^ny-2871899 735022004340 PGRN polypeptide is linked to the C-terminus of the first or second polypeptide chain of the Fc region. [0077] In some embodiments, the complex comprises (i) a single scFv, VHH, or Fab antigen- binding domain that binds to human TfR, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the N-terminus of the Fc domain and the PGRN polypeptide is linked to the C- terminus of the Fc domain. [0078] In some embodiments, the complex comprises (i) a single scFv, VHH, or Fab antigen- binding domain that binds to human TfR, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the N-terminus of one of the two polypeptide chains of the Fc region, and wherein the PGRN polypeptide is linked to the N-terminus of the other polypeptide chain of the Fc region. [0079] In some embodiments, the Fc region is a heterodimeric Fc region, optionally comprising knob and hole mutations. In some embodiments, the Fc domain is a single chain monovalent Fc domain. In some embodiments, the Fc region is a modified Fc region with a modification listed in Table 8 or Table 9. In some embodiments, the Fc region is a human IgG1 Fc region, wherein the human IgG1 Fc region comprises a mutation that reduces effector function, optionally wherein the mutation that reduces effector function comprises: (i) L234A, L235A, and/or P331S; (ii) N325S and/or L328F; (iii) L234A, L235A, and/or P329G; or (iv) L234A, L235A, and/or P329S. [0080] In some embodiments, the Fc domain is a modified Fc domain with a modification listed in Table 8. In some embodiments, the Fc domain is a human IgG1 Fc domain, wherein the human IgG1 Fc domain comprises a mutation that reduces effector function, optionally wherein the mutation that reduces effector function comprises: (i) L234A, L235A, and/or P331S; (ii) N325S and/or L328F; (iii) L234A, L235A, and/or P329G; or (iv) L234A, L235A, and/or P329S. [0081] In some embodiments, the PGRN polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 230, SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 247, SEQ ID NO:^ny-2871899 735022004340 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 260, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. [0082] In some aspects, provided herein is a complex comprising: (a) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a PGRN polypeptide; (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2 and a CH3; and (c) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 15, 25, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 50, 58, and 62, respectively; (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 341, 55, and 61, respectively. [0083] In some aspects, provided herein is a complex comprising: (a) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, and a CH3; (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a PGRN polypeptide; and (c) a third polypeptide comprising, from the N- terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises a VL CDR1, VL CDR2, and VL CDR3, wherein^ny-2871899 735022004340 the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 15, 25, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 50, 58, and 62, respectively; (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 341, 55, and 61, respectively. [0084] In some aspects, provided herein is a complex comprising: (a) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a PGRN polypeptide; (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a PGRN polypeptide; and (c) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 15, 25, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 50, 58, and 62, respectively;^ny-2871899 735022004340 (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 341, 55, and 61, respectively. [0085] In some aspects, provided herein is a complex comprising: (a) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a PGRN polypeptide; and (b) a second polypeptide comprising, from the N- terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 15, 25, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 50, 58, and 62, respectively; (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 341, 55, and 61, respectively. [0086] In some aspects, provided herein is a complex comprising: (a) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, and a CH3; (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a PGRN polypeptide, a linker, a CH2, and a CH3; and (c) a third polypeptide comprising, from the N- terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively;^ny-2871899 735022004340 (ii) SEQ ID NOs: 8, 15, 25, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 50, 58, and 62, respectively; (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 341, 55, and 61, respectively. [0087] In some embodiments, the PGRN polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 230, SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 247, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 260, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. [0088] In some embodiments, the VH and the VL comprise the amino acid sequences of: (i) SEQ ID NOs: 101 and 154, respectively; (ii) SEQ ID NOs: 102 and 344, respectively; (iii) SEQ ID NOs: 102 and 345, respectively; (iv) SEQ ID NOs: 342 and 174, respectively; (v) SEQ ID NOs: 117 and 346, respectively; (vi) SEQ ID NOs: 117 and 347, respectively; (vii) SEQ ID NOs: 117 and 348, respectively; (viii) SEQ ID NOs: 117 and 349, respectively; (ix) SEQ ID NOs: 343 and 174, respectively; (x) SEQ ID NOs: 118 and 174, respectively; or (xi) SEQ ID NOs: 101 and 350, respectively.^ny-2871899 735022004340 [0089] In some embodiments, the complex is linked to an imaging agent. [0090] In some aspects, provided herein is a polynucleotide encoding the complex of any one of the preceding embodiments. In some aspects, provided herein is a vector comprising the polynucleotide of the preceding embodiment. In some aspects, provided herein is a host cell comprising the vector of the preceding embodiment. In some aspects, provided herein is a method of producing a complex comprising culturing the host cell of the preceding embodiment so that the complex is produced, optionally wherein the method further comprises isolating the complex from the culture. In some aspects, provided herein is an isolated complex thereof produced by the method of the preceding embodiment. In some aspects, provided herein is a pharmaceutical composition comprising the complex of any one of the preceding embodiments. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. [0091] In some aspects, provided herein is a method of treating a neurological disease or disorder in a subject comprising administering the complex of any one of the preceding embodiments or the pharmaceutical composition of any one of the preceding embodiments to the subject. In some embodiments, the neurological disease or disorder is selected from a neuropathy disorder, a neurodegenerative disease, an ocular disease disorder, a seizure disorder, a lysosomal storage disease, ischemia, a behavioral disorder, and CNS inflammation. In some embodiments, the neurological disease or disorder is selected from Alzheimer's disease (AD), Huntington’s disease, dystonia, ataxia, stroke, dementia, Lewy body dementia, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson's disease, Pick's disease, encephalitis, traumatic brain injury, and limbic-predominant age-related TDP-43 encephalopathy (LATE). In some embodiments, the dementia is frontotemporal dementia (FTD). In some embodiments, the neurological disease or disorder is Alzheimer’s disease. In some embodiments, the Alzheimer's disease is early onset Alzheimer’s disease, prodromal Alzheimer’s disease, mild Alzheimer’s disease, or late onset Alzheimer’s disease. In some embodiments, the neurological disease or disorder is Parkinson’s disease. In some embodiments, the neurological disease or disorder is frontal temporal epilepsy. [0092] In some aspects, provided herein is a method of treating a lysosomal storage disease in a subject comprising administering the complex of any one of the preceding embodiments or the pharmaceutical composition of any one of the preceding embodiments to the subject. In some^ny-2871899 735022004340 embodiments, the lysosomal storage disease is selected from Gaucher disease, Ceroid lipofuscinosis (Batten disease), Mucopolysaccharidosis (MPS) Type I, MPS Type II and MPS Type III. [0093] In some aspects, provided herein a method of transporting a complex across the BBB of a subject, comprising administering the complex of any one of the preceding embodiments or the pharmaceutical composition of any one of the preceding embodiments to the subject. [0094] In some aspects, provided herein is a method of increasing the concentration of PGRN in the cerebral spinal fluid (CSF) of a subject, comprising administering the complex of any one of the preceding embodiments or the pharmaceutical composition of any one of the preceding embodiments to the subject, wherein the concentration of PGRN is increased as compared to administering the PGRN polypeptide alone to the subject. [0095] In some aspects, provided herein is a method of imaging PGRN within a subject, comprising administering to the subject the complex of any one of the preceding embodiments and locating the imaging agent within the subject. [0096] In some aspects, provided herein is a method of detecting PGRN in vitro, comprising contacting an in vitro sample with the complex of any one of the preceding embodiments and locating the imaging agent within the sample. [0097] In some aspects, provided herein is a use of the complex of any one of the preceding embodiments or the pharmaceutical composition of any one of the preceding embodiments in the method of any one of the preceding embodiments. [0098] In some aspects, provided herein is the complex of any one of the preceding embodiments or the pharmaceutical composition of any one of the preceding embodiments for use in the method of any one of the preceding embodiments. [0099] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a PGRN polypeptide, wherein the antigen-binding domain specifically binds to human CD98 heavy chain (CD98hc), and wherein the antigen-binding domain comprises a VH comprising a VH CDR1, VH CDR2, and VH CDR3, and a VL comprising a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences comprise the amino acid sequences of: (i) SEQ ID NOs: 184, 352, 193, 197, 198, and 204, respectively; (ii) SEQ ID NOs: 184, 353, 193, 197, 198, and 204, respectively;^ny-2871899 735022004340 (iii) SEQ ID NOs: 184, 354, 193, 197, 198, and 204, respectively; (iv) SEQ ID NOs: 184, 355, 193, 197, 198, and 204, respectively; (v) SEQ ID NOs: 184, 356, 193, 197, 198, and 204, respectively; (vi) SEQ ID NOs: 184, 357, 193, 197, 198, and 204, respectively; (vii) SEQ ID NOs: 184, 358, 193, 197, 198, and 204, respectively; (viii) SEQ ID NOs: 184, 190, 193, 369, 198, and 204, respectively; (ix) SEQ ID NOs: 184, 190, 193, 370, 198, and 204, respectively; (x) SEQ ID NOs: 184, 190, 193, 371, 198, and 204, respectively; (xi) SEQ ID NOs: 184, 190, 193, 372, 198, and 204, respectively; (xii) SEQ ID NOs: 184, 190, 193, 373, 198, and 204, respectively; (xiii) SEQ ID NOs: 184, 190, 193, 374, 198, and 204, respectively; (xiv) SEQ ID NOs: 184, 190, 193, 375, 198, and 204, respectively; (xv) SEQ ID NOs: 184, 354, 193, 371, 198, and 204, respectively; (xvi) SEQ ID NOs: 184, 359, 193, 197, 198, and 204, respectively; (xvii) SEQ ID NOs: 184, 190, 360, 197, 198, and 204, respectively; (xviii) SEQ ID NOs: 184, 190, 361, 197, 198, and 204, respectively; (xix) SEQ ID NOs: 184, 190, 362, 197, 198, and 204, respectively; (xx) SEQ ID NOs: 184, 190, 363, 197, 198, and 204, respectively; (xxi) SEQ ID NOs: 184, 190, 364, 197, 198, and 204, respectively; (xxii) SEQ ID NOs: 184, 190, 365, 197, 198, and 204, respectively; (xxiii) SEQ ID NOs: 184, 190, 366, 197, 198, and 204, respectively; (xxiv) SEQ ID NOs: 184, 190, 367, 197, 198, and 204, respectively; (xxv) SEQ ID NOs: 184, 190, 368, 197, 198, and 204, respectively; (xxvi) SEQ ID NOs: 184, 190, 193, 376, 198, and 204, respectively; (xxvii) SEQ ID NOs: 184, 190, 193, 377, 198, and 204, respectively; (xxviii) SEQ ID NOs: 184, 190, 193, 378, 198, and 204, respectively; (xxix) SEQ ID NOs: 184, 190, 193, 379, 198, and 204, respectively; (xxx) SEQ ID NOs: 184, 190, 193, 380, 198, and 204, respectively; (xxxi) SEQ ID NOs: 184, 190, 193, 381, 198, and 204, respectively; (xxxii) SEQ ID NOs: 184, 190, 193, 197, 198, and 382, respectively; (xxxiii) SEQ ID NOs: 184, 190, 193, 197, 198, and 383, respectively;^ny-2871899 735022004340 (xxxiv) SEQ ID NOs: 184, 190, 193, 197, 198, and 384, respectively; (xxxv) SEQ ID NOs: 184, 190, 193, 197, 198, and 385, respectively; (xxxvi) SEQ ID NOs: 184, 190, 193, 197, 198, and 386, respectively; (xxxvii) SEQ ID NOs: 184, 190, 193, 197, 198, and 387, respectively; (xxxviii) SEQ ID NOs: 184, 190, 193, 197, 198, and 388, respectively; (xxxix) SEQ ID NOs: 184, 190, 193, 197, 198, and 389, respectively; (xl) SEQ ID NOs: 184, 190, 193, 197, 198, and 390, respectively; (xli) SEQ ID NOs: 184, 190, 193, 197, 198, and 391, respectively; (xlii) SEQ ID NOs: 351, 190, 193, 197, 198, and 204, respectively; or (xliii) SEQ ID NOs: 351, 190, 193, 197, 198, and 391, respectively. [0100] In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 210, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, or 409. In some embodiments, the VL comprises the amino acid sequence of SEQ ID NO: 215, 216, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, or 432. In some embodiments, the VH and the VL comprise the amino acid sequences of: (i) SEQ ID NOs: 392 and 216, respectively; (ii) SEQ ID NOs: 393 and 216, respectively; (iii) SEQ ID NOs: 394 and 216, respectively; (iv) SEQ ID NOs: 395 and 216, respectively; (v) SEQ ID NOs: 396 and 216, respectively; (vi) SEQ ID NOs: 397 and 216, respectively; (vii) SEQ ID NOs: 398 and 216, respectively; (viii) SEQ ID NOs: 210 and 410, respectively; (ix) SEQ ID NOs: 210 and 411, respectively; (x) SEQ ID NOs: 210 and 412, respectively; (xi) SEQ ID NOs: 210 and 413, respectively; (xii) SEQ ID NOs: 210 and 414, respectively; (xiii) SEQ ID NOs: 210 and 415, respectively; (xiv) SEQ ID NOs: 210 and 416, respectively; (xv) SEQ ID NOs: 394 and 412, respectively;^ny-2871899 735022004340 (xvi) SEQ ID NOs: 399 and 216, respectively; (xvii) SEQ ID NOs: 400 and 216, respectively; (xviii) SEQ ID NOs: 401 and 216, respectively; (xix) SEQ ID NOs: 402 and 216, respectively; (xx) SEQ ID NOs: 403 and 216, respectively; (xxi) SEQ ID NOs: 404 and 216, respectively; (xxii) SEQ ID NOs: 405 and 216, respectively; (xxiii) SEQ ID NOs: 406 and 216, respectively; (xxiv) SEQ ID NOs: 407 and 216, respectively; (xxv) SEQ ID NOs: 408 and 216, respectively; (xxvi) SEQ ID NOs: 210 and 417, respectively; (xxvii) SEQ ID NOs: 210 and 418, respectively; (xxviii) SEQ ID NOs: 210 and 419, respectively; (xxix) SEQ ID NOs: 210 and 420, respectively; (xxx) SEQ ID NOs: 210 and 421, respectively; (xxxi) SEQ ID NOs: 210 and 422, respectively; (xxxii) SEQ ID NOs: 210 and 423, respectively; (xxxiii) SEQ ID NOs: 210 and 424, respectively; (xxxiv) SEQ ID NOs: 210 and 425, respectively; (xxxv) SEQ ID NOs: 210 and 426, respectively; (xxxvi) SEQ ID NOs: 210 and 427, respectively; (xxxvii) SEQ ID NOs: 210 and 428, respectively; (xxxviii) SEQ ID NOs: 210 and 429, respectively; (xxxix) SEQ ID NOs: 210 and 430, respectively; (xl) SEQ ID NOs: 210 and 431, respectively; (xli) SEQ ID NOs: 210 and 432, respectively; (xlii) SEQ ID NOs: 409 and 215, respectively; or (xliii) SEQ ID NOs: 409 and 432, respectively. [0101] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a PGRN polypeptide, wherein the antigen-binding domain specifically binds to human CD98 heavy chain (CD98hc), and wherein the antigen-binding domain is a VHH comprising:^ny-2871899 735022004340 (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 184, 352, and 193, respectively; (ii) SEQ ID NOs: 184, 353, and 193, respectively; (iii) SEQ ID NOs: 184, 354, and 193, respectively; (iv) SEQ ID NOs: 184, 355, and 193, respectively; (v) SEQ ID NOs: 184, 356, and 193, respectively; (vi) SEQ ID NOs: 184, 357, and 193, respectively; (vii) SEQ ID NOs: 184, 358, and 193, respectively; (viii) SEQ ID NOs: 184, 190, and 193, respectively; (ix) SEQ ID NOs: 184, 359, and 193, respectively; (x) SEQ ID NOs: 184, 190, and 360, respectively; (xi) SEQ ID NOs: 184, 190, and 361, respectively; (xii) SEQ ID NOs: 184, 190, and 362, respectively; (xiii) SEQ ID NOs: 184, 190, and 363, respectively; (xiv) SEQ ID NOs: 184, 190, and 364, respectively; (xv) SEQ ID NOs: 184, 190, and 365, respectively; (xvi) SEQ ID NOs: 184, 190, and 366, respectively; (xvii) SEQ ID NOs: 184, 190, and 367, respectively; (xviii) SEQ ID NOs: 184, 190, and 368, respectively; or (xix) SEQ ID NOs: 351, 190, and 193, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 210, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, or 409. [0102] In some embodiments, the antigen-binding domain comprises a VH and a VL on a single polypeptide chain. In some embodiments, the antigen-binding domain comprises a single- chain fragment variable (scFv). In some embodiments, the scFv is in the orientation VH-linker- VL. In some embodiments, the scFv is in the orientation VL-linker-VH. In some embodiments, the linker is about 5 to about 25 amino acids, is about 5 to about 20 amino acids, is about 10 to about 25 amino acids, or is about 10 to about 20 amino acids. In some embodiments, the linker comprises the amino acid sequence of GGSEGKSSGSGSESKSTGGS (SEQ ID NO: 6) or GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 7).^ny-2871899 735022004340 [0103] In some embodiments, the antigen-binding domain comprises a VH on a first polypeptide and a VL on a second polypeptide. In some embodiments, the antigen-binding domain is a murine, chimeric, humanized, or human antigen-binding domain, optionally wherein the antigen-binding domain is a humanized antigen-binding domain. [0104] In some embodiments, the complex further comprises an Fc region, wherein the Fc region comprises a first and second polypeptide chain. In some embodiments, the Fc region is capable of binding FcRn. In some embodiments, the complex further comprises an Fc domain. In some embodiments, the Fc domain is capable of binding FcRn. [0105] In some embodiments, the complex comprises (i) a single scFv or VHH or Fab antigen- binding domain that binds to human CD98hc and (ii) and two copies of the PGRN polypeptide. In some embodiments, the single scFv, Fab or VHH antigen-binding domain that binds to human CD98hc is linked to the C-terminus of one of the two copies of the PGRN polypeptide. In some embodiments, one of the two copies of the PGRN polypeptide is linked to the N-terminus of the first polypeptide chain of the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the N-terminus of the second polypeptide chain of the Fc region. In some embodiments, the single scFv, Fab, or VHH antigen-binding domain that binds to human CD98hc is linked to the N-terminus of the first or second polypeptide chain of the Fc region. In some embodiments, one of the two copies of the PGRN polypeptide is linked to the C-terminus of the first polypeptide chain of the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the C-terminus of the second polypeptide chain of the Fc region. [0106] In some embodiments, the complex comprises (i) an antibody that binds to human CD98hc, wherein the antibody comprises two heavy chains and two light chains; and (ii) two copies of the PGRN polypeptide, wherein each copy of the PGRN polypeptide is linked to the C- termini of one of the two antibody heavy chains. [0107] In some embodiments, the complex comprises (i) two scFv, Fab, or VHH antigen- binding domains that bind to human CD98hc, (ii) an Fc region; and (iii) two copies of the PGRN polypeptide, wherein one of the two scFv, Fab, or VHH antigen-binding domains that binds to human CD98hc is linked to the C-terminus of the first polypeptide chain of the Fc region, wherein the other scFv, Fab, or VHH antigen-binding domains that binds to human CD98hc is linked to the C-terminus of the second polypeptide chain of the Fc region, wherein one of the two copies of the PGRN polypeptide is linked to the N-terminus of the first polypeptide chain of 37^ny-2871899 735022004340 the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the N-terminus of the second polypeptide chain of the Fc region. In some embodiments, the complex comprises (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the C-terminus of the first or second polypeptide chain of the Fc region and the PGRN polypeptide is linked to N-terminus of the first or second polypeptide chain of the Fc region. [0108] In some embodiments, the complex comprises (i) a single scFv, VHH, or Fab antigen- binding domain that binds to human CD98hc, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the C-terminus of the Fc domain and the PGRN polypeptide is linked to N-terminus of the Fc domain. [0109] In some embodiments, the complex comprises (i) a single scFv, VHH, or Fab antigen- binding domain that binds to human CD98hc, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the N-terminus of the first or second polypeptide chain of the Fc region and the PGRN polypeptide is linked to the C-terminus of the first or second polypeptide chain of the Fc region. [0110] In some embodiments, the complex comprises (i) a single scFv, VHH, or Fab antigen- binding domain that binds to human CD98hc, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the N-terminus of the Fc domain and the PGRN polypeptide is linked to the C-terminus of the Fc domain. [0111] In some embodiments, the complex comprises (i) a single scFv, VHH, or Fab antigen- binding domain that binds to human CD98hc, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the N-terminus of one of the two polypeptide chains of the Fc region, and wherein the PGRN polypeptide is linked to the N-terminus of the other polypeptide chain of the Fc region. [0112] In some embodiments, the Fc region is a heterodimeric Fc region, optionally comprising knob and hole mutations. In some embodiments, the Fc domain is a single chain^ny-2871899 735022004340 monovalent Fc domain. In some embodiments, the Fc region is a modified Fc region with a modification listed in Table 8 or Table 9. In some embodiments, the Fc region is a human IgG1 Fc region, wherein the human IgG1 Fc region comprises a mutation that reduces effector function, optionally wherein the mutation that reduces effector function comprises: (i) L234A, L235A, and/or P331S; (ii) N325S and/or L328F; (iii) L234A, L235A, and/or P329G; or (iv) L234A, L235A, and/or P329S. [0113] In some embodiments, the Fc domain is a modified Fc domain with a modification listed in Table 8. In some embodiments, the Fc domain is a human IgG1 Fc domain, wherein the human IgG1 Fc domain comprises a mutation that reduces effector function, optionally wherein the mutation that reduces effector function comprises: (i) L234A, L235A, and/or P331S; (ii) N325S and/or L328F; (iii) L234A, L235A, and/or P329G; or (iv) L234A, L235A, and/or P329S. [0114] In some embodiments, the PGRN polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 230, SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 247, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 260, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. [0115] In some embodiments, the complex is linked to an imaging agent. [0116] In some aspects, provided herein is a polynucleotide encoding the complex of any one of the preceding embodiments. In some aspects, provided herein is a vector comprising the polynucleotide of the preceding embodiment. In some aspects, provided herein is a host cell comprising the vector of the preceding embodiment. In some aspects, provided herein is a method of producing a complex comprising culturing the host cell of the preceding embodiment so that the complex is produced, optionally wherein the method further comprises isolating the complex from the culture. In some aspects, provided herein is an isolated complex thereof produced by the method of the preceding embodiment. In some aspects, provided herein is a pharmaceutical composition comprising the complex of the preceding embodiment. In some^ny-2871899 735022004340 embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. [0117] In some aspects, provided herein is a method of treating a neurological disease or disorder in a subject comprising administering the complex of any one of the preceding embodiments or the pharmaceutical composition of any one of the preceding embodiments to the subject. In some embodiments, the neurological disease or disorder is selected from a neuropathy disorder, a neurodegenerative disease, an ocular disease disorder, a seizure disorder, a lysosomal storage disease, ischemia, a behavioral disorder, and CNS inflammation. In some embodiments, the neurological disease or disorder is selected from Alzheimer's disease (AD), Huntington’s disease, dystonia, ataxia, stroke, dementia, Lewy body dementia, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson's disease, Pick's disease, encephalitis, traumatic brain injury, and limbic-predominant age-related TDP-43 encephalopathy (LATE). In some embodiments, the dementia is frontotemporal dementia (FTD). In some embodiments, the neurological disease or disorder is Alzheimer’s disease. In some embodiments, the Alzheimer's disease is early onset Alzheimer’s disease, prodromal Alzheimer’s disease, mild Alzheimer’s disease, or late onset Alzheimer’s disease. In some embodiments, the neurological disease or disorder is Parkinson’s disease. In some embodiments, the neurological disease or disorder is frontal temporal epilepsy. [0118] In some aspects, provided herein is a method of treating a lysosomal storage disease in a subject comprising administering the complex of any one of the preceding embodiments or the pharmaceutical composition of any one of the preceding embodiments to the subject. In some embodiments, the lysosomal storage disease is selected from Gaucher disease, Ceroid lipofuscinosis (Batten disease), Mucopolysaccharidosis (MPS) Type I, MPS Type II and MPS Type III. [0119] In some aspects, provided herein is a method of transporting a complex across the BBB of a subject, comprising administering the complex of any one of the preceding embodiments or the pharmaceutical composition of any one of the preceding embodiments to the subject. [0120] In some aspects, provided herein is a method of increasing the concentration of PGRN in the CSF of a subject, comprising administering the complex of any one of the preceding embodiments or the pharmaceutical composition of any one of the preceding embodiments to the^ny-2871899 735022004340 subject, wherein the concentration of PGRN is increased as compared to administering the PGRN polypeptide alone to the subject. [0121] In some aspects, provided herein is a method of imaging PGRN within a subject, comprising administering to the subject the complex of any one of the preceding embodiments and locating the imaging agent within the subject. [0122] In some aspects, provided herein is a method of detecting PGRN in vitro, comprising contacting an in vitro sample with the complex of any one of the preceding embodiments and locating the imaging agent within the sample. [0123] In some aspects, provided herein is a use of the complex of any one of the preceding embodiments or the pharmaceutical composition of any one of the preceding embodiments in the method of any one of the preceding embodiments. [0124] In some aspects, provided herein is the complex of any one of the preceding embodiments or the pharmaceutical composition of any one of the preceding embodiments for use in the method of any one of the preceding embodiments. [0125] In some aspects, provided herein is a method of increasing PGRN in a subject, the method comprising administering the isolated PGRN mutant polypeptide of any one of the preceding embodiments or the pharmaceutical composition of any one of the preceding embodiments to the subject. [0126] It is to be understood that one, some, or all of the properties of the various embodiments described herein may be combined to form other embodiments of the present invention. These and other aspects of the invention will become apparent to one of skill in the art. These and other embodiments of the invention are further described by the detailed description that follows. BRIEF DESCRIPTION OF THE DRAWINGS [0127] The present application can be understood by reference to the following description taken in conjunction with the accompanying figures. [0128] FIGS. 1A-1J show example formats of complexes. [0129] FIGS. 2A-2D show example formats of anti-TfR-PGRN complexes. PGRN comprises a half granulin domain, “paragranulin” (P), followed by 7 granulin domains (G-F-B-A-C-D-E).^ny-2871899 735022004340 [0130] FIGS. 3A-3C show representative sensor gram data using the PGRN Capture method on Carterra LSA. Shown are example sensor gram data for PGRN mutants in HEK293 and CHO cells: mvFc-PGRN_16 (QYL C-term mutation; SEQ ID NO: 462) (FIG.3A) and mvFc- PGRN_31 (“QKL” C-term mutation; SEQ ID NO: 447) (FIG. 3B). FIG. 3C shows sensor gram data for wild-type PGRN in HEK293 and CHO cells (“APLRDPALRQLL” C-term; SEQ ID NO: 451). In FIGS.3A-3C, each curve represents an Sortilin analyte concentration (4.9 nM, 14.8 nM, 44.4 nM, 133.3 nM, and 400nM Sortilin). The measured response (RU) was proportional to the analyte concentration used (e.g., highest curve = 400 nM Sortilin and lowest curve = 4.9 nM Sortilin). [0131] FIG. 4 shows progranulin proteins containing a mouse transferrin antigen-binding domain induce greater -Glucocerebrosidase (GCase) activity in RAW 264.7 mouse macrophage cells. Legend: mTfR1 = mouse anti-TfR1 Fab domains; mvFc = monovalent Fc; Iso = isotype; Wt = wildtype; cis = HC1 (Fab-Fc-knob-PGRN) and HC2 (Fc-hole) and LC; trans = HC1 (Fab- Fc-hole) and HC2 (Fc-knob-PGRN) and LC; and 1+2 = HC1 (mTfR1 Fab-Fc-knob-PGRN) and HC2 (Fc-hole-PGRN) and LC. N = 2 combined experiments. [0132] FIG. 5 shows the extent of uptake of anti-TfR-PGRN complexes in a mouse brain endothelial cell line bEND.3 at 2 hours. Higher uptake is observed as compared to progranulin proteins with an isotype control domain. Images displayed are for human Fc detection using an anti-HuIgG antibody conjugated to Alexa Fluor-647. Nuclei were labeled with DAPI. [0133] FIGS. 6A-6B show the quantification of the cell uptake experiment in FIG.5 and demonstrates that bEND.3 cells endocytose anti-TfR-PGRN complexes to a greater extent after 2 hours than those containing an isotype control domain. Shown is cellular uptake of PGRN measured by human Fc detection (FIG.6A) and human PGRN detection (FIG. 6B). Legend: mTfR1 = mouse anti-TfR1 Fab domains; mvFc = monovalent Fc; Iso = isotype; Wt = wildtype; cis = HC1 (Fab-Fc-knob-PGRN) and HC2 (Fc-hole) and LC; trans = HC1 (Fab-Fc-hole) and HC2 (Fc-knob-PGRN) and LC; and 1+2 = HC1 (mTfR1 Fab-Fc-knob-PGRN) and HC2 (Fc- hole-PGRN) and LC. [0134] FIGS. 7A-7B show nonspecific binding (BVP score) of affinity-tuned anti-TfR antibodies to baculovirus particles (BVP). Shown are BVP scores for TfR.15.WH8.1.24A.42Q (24A_42Q), TfR.15.WH8.1.42Q.H6-4 (H6-4), TfR.15.WH8.1.42Q.L7-2 (L7-2), TfR.15.WH8.1.42Q.L10-1 (L10-1), TfR.15.WH8.1.42Q.L10-8 (L10-8),^ny-2871899 735022004340 TfR.15.WH8.1.42Q.L10-16 (L10-16), TfR.15.WH8.1.42Q.H3-7 (H3-7), TfR.9.1B.39.27.L-35 (L-35), TfR.9.1B.39.38.L-21 (L-21), TfR.9.1B.39.38.L-6 (L-6), and TfR.9.1B.39.27.L-19 (L-19) antibodies. Control antibodies (isotype, negative and positive control) were tested. Parental antibodies – TfR.15.WH8.1.24A (24A), TfR.9.1B.39.38 (39.38), and TfR.15.WH8.1.42Q (42Q) – served as additional controls. [0135] FIGS. 8A-8B show nonspecific binding (OD 450 nm) of affinity-tuned anti-TfR antibodies to dsDNA. Shown are absorbance values for 24A_42Q, H6-4, L7-2, L10-1, L10-8, L10-16, H3-7, L-35, L-21, L-6, and L-19 antibodies. Control antibodies (isotype, negative and positive control) were tested. Parental antibodies – 24A, 39.38, and 42Q – served as additional controls. [0136] FIG. 9 shows the extent of cell uptake of affinity-tuned anti-TfR antibodies in a brain microvascular endothelial cell line (hCMEC/D3) at 2 hours. Shown is cell uptake for 24A.42Q, H6-4, L7-2, L10-1, L10-8, L10-16, H3-7, and L-35 antibodies. Isotype (Iso mvFc-Iso scFv) and parental antibodies – 24A and 42Q – served as controls. Images displayed are for human Fc detection using an anti-HuIgG fluorescent antibody. [0137] FIGS. 10A-10B show brain uptake of antibody in huTfR KI mice dosed with 5 mg/kg of H6-4, L7-2, L10-1, L10-8, L-35, L10-16, H3-7, or 24A_42Q variant antibodies after 24 hours. Isotype (Iso) and parental antibodies – 24A and 42Q – served as controls. FIG.10A shows antibody concentration (ng/mg tissue) in vessel-depleted brain after 24 hrs. FIG. 10B shows the fold change over the matched isotype control in vessel-depleted brain. [0138] FIG. 11 shows the ratio of antibody concentration in vessel-depleted brain to whole brain of huTfR KI mice dosed with 5 mg/kg of H6-4, L7-2, L10-1, L10-8, L-35, L10-16, H3-7, or 24A_42Q variant antibodies. Isotype (Iso) and parental antibodies – 24A and 42Q – served as controls. [0139] FIG. 12 shows the effect of affinity-tuned anti-TfR antibodies on levels of circulating reticulocytes in mice. Mice were dosed with 5 mg/kg of H6-4, L7-2, L10-1, L10-8, L-35, L10- 16, H3-7, or 24A_42Q variant antibodies and assessed after 24 hours. Isotype (Iso) and parental antibodies – 24A and 42Q – served as controls. Levels of circulating reticulocytes are shown as absolute reticulocyte (K/ul) (left of dotted line) and percent reticulocytes (right of dotted line). [0140] FIG. 13 shows the levels of TfR in whole brain lysates isolated from mice dosed with L-21, L-6, and L-35 variant antibodies. Isotype (Iso-Fab) and parental antibodies – 24A, 39.38,^ny-2871899 735022004340 and 42Q – served as controls. Shown are TfR levels normalized to levels of GAPDH for each sample and the isotype control mean. [0141] FIGS. 14A-14B set forth data showing increased brain uptake in mice of anti- CD98hc.04.048.WH1 antibody variants of the present disclosure, presented as ng of antibody per mg total protein (FIG.14A) and fold-change compared to isotype control antibody (FIG. 14B). [0142] FIG. 15 sets forth data showing no decrease in amino acid uptake in cells treated with anti-CD98hc.04.048.WH1 antibody variants of the present disclosure. [0143] FIG. 16 shows the binding curves assessed by ELISA for msTfR-msPgrn test articles used in aged Grn-KO mice for a proof-of-concept efficacy study. Both msTfR-msPgrn fusion protein affinity variants for msTfR demonstrate binding to mouse sortilin with similar EC50 values. [0144] FIG. 17 shows the protein format for the msTfR-msPgrn fusion proteins used in an aged Grn-KO proof-of-concept efficacy study. The timeline for dosing is also shown along with mouse genotype, test article, dose level, and sample size. The affinities of 8D3v33-msPgrn and 8D3v12-msPgrn for apical mouse TfR are specified as the equilibrium dissociation constant (K_D). Abbreviations: F = female; M = male. [0145] FIG. 18 shows the serum pharmacokinetic profile of dosed msTfR-msPgrn fusion proteins in aged Grn KO mice over the course of 8 days, where mice were dosed once on Day 0 and once on Day 7 (as indicated by arrows on horizontal axis). Fusion proteins containing msTfR binders 8D3v12 and 8D3v33 display faster clearance profiles, which correlate with their affinity for msTfR. [0146] FIG. 19 shows the levels of msTfR-msPgrn fusion proteins detected in aged Grn-KO vessel-depleted brain lysates 24 hrs post-second dose (previous dose was administered seven days prior). Animals receiving 8D3v12-msPgrn displayed the highest levels of test article, about seven-fold higher than the levels of isotype-control-msPgrn. Triangles: female mice; circles: male mice. [0147] FIG. 20 shows the extent of reduction in the accumulation of glucosylsphingosine (GlcSph) in the brains of aged Grn-KO mice after two doses of 8D3v12-msPgrn and 8D3v33- msPgrn. The pharmacodynamic readout of GlcSph may reflect the level of lysosomal dysfunction induced by Grn deficiency and age in the mouse model.^ny-2871899 735022004340 [0148] FIG. 21 shows the evaluation of Gpnmb levels in aged Grn-KO whole mouse brain lysates after dosing with saline, 8D3v12-msPgrn, 8D3v33-msPgrn or isotype-control-msPgrn. Increased Gpnmb was observed in saline-dosed aged Grn-KO mouse brains, and this was partially reduced in the brains of mice dosed with 8D3v12-msPgrn. Triangles: female mice; circles: male mice. One way ANOVA with Dunnett’s multiple comparisons test. **** p < 0.0001; **: p < 0.005; ns: not significant. [0149] FIG. 22 shows the assessment of huTfR-huPGRN variants for binding to human sortilin using an ELISA. No differences were detected in human sortilin binding for all huTfR- huPGRN variants and binding affinities are represented as EC₅₀ for all proteins. [0150] FIG. 23 shows the evaluation of hematological parameters in huTfR-KI mice 24 hrs after administration of huTfR-huPGRN fusion proteins at various doses. Blood reticulocyte and red blood cell (RBC) counts were assessed by flow cytometry and no differences were observed between treatment groups. [0151] FIG. 24 shows the assessment of surface huTfR levels on blood reticulocytes in huTfR- KI mice 24 hrs after dosing with huTfR-huPGRN variants or isotype-control-huPGRN. No differences were observed between treatment groups. [0152] FIG. 25 shows the brain levels of huTfR-huPGRN or isotype-control-huPGRN detected in vessel-depleted brain lysates from huTfR-KI mice dosed once at various dose levels and collected 6 hrs or 24 hrs post-dose. A dose-dependent increase in huTfR10-16-huPGRN was observed, as expected. Similar fusion protein brain levels were observed at 6 hrs for animals dosed at 10 mg/kg huTfR10-16-huPGRN and 3 mg/kg huTfR10-8-huPGRN. [0153] FIG. 26 shows TfR levels in whole brain lysates of mice dosed with huTfR-huPGRN fusion proteins. Tissues were collected at 6 hours or 24 hours post-dosing and analyzed by quantitative immunoblotting. No differences were observed between treatment groups, suggesting no effect on total brain TfR levels after a single dose of huTfR-huPGRN at these time points. [0154] FIG. 27 shows the assessment of huCD98-huPGRN fusion protein variants for binding to human sortilin by ELISA. No differences were detected in binding to human sortilin for all huCD98-huPGRN variants and binding affinities are represented as EC50 for all fusion proteins. [0155] FIG. 28 shows the brain levels of huCD98-huPGRN or isotype-control-huPGRN detected 72 hrs post-dose in vessel-depleted brain lysates from huCD98-KI mice dosed once.^ny-2871899 735022004340 [0156] FIG. 29 shows analytical hydrophobic interaction chromatography (aHIC) profile of indicated PGRN fusion proteins. [0157] FIGs. 30A and 30B show levels of brain uptake of various anti-CD98hc.04.048.WH1 monovalent Fab variants of the present disclosure presented as ng binding domain/mg total protein and fold-change over control, respectively. [0158] FIG. 31A shows serum clearance of antibodies containing an anti- CD98hc.04.048.WH1 binding domain following 3 weekly doses in mice. [0159] FIG. 31B shows increased levels of antibodies containing an anti-CD98hc.04.048.WH1 binding domain in vessel-depleted mouse brain fractions compared to that observed with an isotype control antibody. [0160] FIGs. 32A and 32B show serum PK measurements of various anti- CD98hc.04.048.WH1 antibody variants in mice dosed with 20 mg/kg and 3 mg/kg, respectively. [0161] FIGs. 32C and 32D show antibody concentrations in vessel-depleted brain samples from mice following administration of various anti-CD98hc.04.048.WH1 antibody variants at 20 mg/kg and 3 mg/kg, respectively. DETAILED DESCRIPTION OF THE PRESENT DISCLOSURE [0162] The present disclosure relates to complexes comprising an antigen-binding domain linked to a Progranulin (PGRN) polypeptide, where the antigen-binding domain can bind specifically to human transferrin receptor (TfR) or human CD98 heavy chain (CD98hc). Complexes of the present disclosure provide compositions with an increased capacity to facilitate the transport of PGRN polypeptides across the blood brain barrier, thereby meeting the need in the art for improved compositions and methods for treating patients with diseases involving PGRN deficiency. [0163] Certain techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodology by those skilled in the art, such as, for example, the widely utilized methodologies such as those described in Sambrook et al. Molecular Cloning: A Laboratory Manual 3d edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Current Protocols in Molecular Biology (F.M. Ausubel, et al. eds., (2003); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000).^ny-2871899 735022004340 Definitions [0164] The terms “central nervous system” or “CNS” refer to the complex of nerve tissues that control bodily function and includes the brain and spinal cord. [0165] The terms “blood brain barrier” or “BBB” refer to a network of brain capillary endothelial cells that are closely sealed by tight junctions. [0166] A “central nervous system antigen” or “CNS antigen” is an antigen expressed in the CNS, including the brain. [0167] A “brain antigen” is a CNS antigen expressed in the brain. [0168] A “neurological disorder” as used herein refers to a disease or disorder which affects the CNS and/or which has an etiology in the CNS. Exemplary CNS diseases or disorders include, but are not limited to, neuropathy, amyloidosis, cancer, an ocular disease or disorder, viral or microbial infection, inflammation, ischemia, neurodegenerative disease, seizure, behavioral disorders, and a lysosomal storage disease. [0169] A “lysosomal storage disorder” or “LSD” as used herein refers to an inherited metabolic disease characterized by the accumulation of substrates, such as undigested or partially digested macromolecules, in excess in various cells of organs, which ultimately results in cellular dysfunction and clinical abnormalities. LSDs have been defined as deficiencies in lysosomal function generally classified by the accumulated substrate and include sphingolipidoses, oligosaccharidoses, mucolipidoses, mucopolysaccharidoses, lipoprotein storage disorders, neuronal ceroid lipofuscinoses, and others. LSDs may also include other deficiencies or defects in proteins that result in accumulation of macromolecules, such as proteins necessary for normal post-translational modification of lysosomal enzymes, or proteins important for proper lysosomal trafficking. LSDs are diseases caused by defects in single genes. Enzyme defects cause nearly seventy percent of the LSDs, and the rest are defects in enzyme activator or associated proteins. [0170] “Protein replacement therapy” or “PRT” refers to a medical treatment or therapy that supplements or replaces a protein in an individual in whom that particular protein is deficient, non-functional, or absent. [0171] As used herein, a “mutant Progranulin polypeptide” or “Progranulin mutant polypeptide” refers to a mutated polypeptide of a wild-type Progranulin polypeptide. A Progranulin mutant polypeptide may comprise an amino acid sequence containing one or more substitutions (e.g., conservative substitutions, insertions, or deletions) relative to an amino acid^ny-2871899 735022004340 sequence of the wild-type Progranulin polypeptide (e.g., relative to SEQ ID NO: 230). A Progranulin mutant polypeptide can have similar or substantially the same functions as those of a wild-type Progranulin polypeptide. For instance, a Progranulin mutant polypeptide may bind Sortilin or prosaposin, regulate the activity and levels of various lysosomal proteins (e.g., cathepsins), promote neurite outgrowth and neuronal survival, and/or any other function described herein. [0172] As used herein, a “complex” refers to one or more proteins comprising connected parts. The parts can be connected e.g., via a peptide bond (e.g., in a fusion protein), a linker (e.g., a peptide linker), or via noncovalent protein-protein interactions such as disulfide bonds (e.g., in an antibody). Exemplary parts that can be included in a complex include a PGRN mutant polypeptide, an antigen-binding domain than specifically binds to CD98hc or TfR, an Fc region, and/or an Fc domain. Accordingly, non-limiting examples of a “complex” comprising an antigen-binding domain and a PGRN mutant polypeptide include (a) a fusion protein comprising an antigen-binding domain, an Fc domain, and a PGRN mutant polypeptide in a single polypeptide chain (e.g., as shown in FIG. 1A), and (b) three proteins connected via noncovalent protein-protein interactions, wherein the first protein contains a PGRN mutant polypeptide and an Fc domain, the second protein contains a heavy chain of an antigen-binding domain, and the third protein contains a light chain of an antigen-binding domain (e.g., as shown in FIG. 2B). Formats of other exemplary complexes are provided in FIGs.1 and 2. [0173] The terms “Transferrin receptor,” “TfR,” “TfR polypeptide,” and “TfR protein” are used interchangeably herein to refer to any native TfR from any vertebrate source, including mammals such as primates (e.g., humans and cynomolgus monkeys (cynos)) and rodents (e.g., mice and rats), unless otherwise indicated. TfR is also referred to as transferrin receptor protein 1, TR, tfR1, Trfr, T9, and p90. In some embodiments, the term encompasses both wild-type sequences and naturally occurring variant sequences, e.g., splice variants or allelic variants. In some embodiments, the term encompasses “full-length,” unprocessed TfR, as well as any form of TfR that results from processing in the cell. Full-length transferrin receptor protein includes a short N-terminal intracellular region, a transmembrane region, and a large extracellular domain. The extracellular domain is characterized by three domains: a protease-like domain, a helical domain, and an apical domain. In some embodiments, the TfR is human TfR. As used herein, the term “human TfR” refers to a polypeptide with the following amino acid sequence:^ny-2871899 735022004340 MMDQARSAFSNLFGGEPLSYTRFSLARQVDGDNSHVEMKLAVDEEENADNNTKANVT KPKRCSGSICYGTIAVIVFFLIGFMIGYLGYCKGVEPKTECERLAGTESPVREEPGEDFPA ARRLYWDDLKRKLSEKLDSTDFTGTIKLLNENSYVPREAGSQKDENLALYVENQFREFK LSKVWRDQHFVKIQVKDSAQNSVIIVDKNGRLVYLVENPGGYVAYSKAATVTGKLVH ANFGTKKDFEDLYTPVNGSIVIVRAGKITFAEKVANAESLNAIGVLIYMDQTKFPIVNAE LSFFGHAHLGTGDPYTPGFPSFNHTQFPPSRSSGLPNIPVQTISRAAAEKLFGNMEGDCPS DWKTDSTCRMVTSESKNVKLTVSNVLKEIKILNIFGVIKGFVEPDHYVVVGAQRDAWG PGAAKSGVGTALLLKLAQMFSDMVLKDGFQPSRSIIFASWSAGDFGSVGATEWLEGYL SSLHLKAFTYINLDKAVLGTSNFKVSASPLLYTLIEKTMQNVKHPVTGQFLYQDSNWAS KVEKLTLDNAAFPFLAYSGIPAVSFCFCEDTDYPYLGTTMDTYKELIERIPELNKVARAA AEVAGQFVIKLTHDVELNLDYERYNSQLLSFVRDLNQYRADIKEMGLSLQWLYSARGD FFRATSRLTTDFGNAEKTDRFVMKKLNDRVMRVEYHFLSPYVSPKESPFRHVFWGSGS HTLPALLENLKLRKQNNGAFNETLFRNQLALATWTIQGAANALSGDVWDIDNEF (SEQ ID NO: 1). [0174] As used herein, the terms “CD98hc,” “CD98hc polypeptide,” and “CD98hc protein” are used interchangeably herein to refer to any native CD98hc from any vertebrate source, including mammals such as primates (e.g., humans and cynomolgus monkeys (cynos)) and rodents (e.g., mice and rats), unless otherwise indicated. CD98hc is also referred to as 4F2 cell- surface antigen heavy chain, 4F2hc, 4F2 heavy chain antigen, lymphocyte activation antigen 4F2 large subunit, solute carrier family 3 member 2, and CD98. CD98hc protein is encoded by the SLC3A2 gene and is part of the large amino acid transporter (LAT) complex. In some embodiments, the term encompasses both wild-type sequences and naturally occurring variant sequences, e.g., splice variants or allelic variants. In some embodiments, the term encompasses “full-length,” unprocessed CD98hc, as well as any form of CD98hc that results from processing in the cell. In some embodiments, the CD98hc is human CD98hc. As used herein, the term “human CD98hc” refers to a polypeptide with the following amino acid sequence: MELQPPEASIAVVSIPRQLPGSHSEAGVQGLSAGDDSELGSHCVAQTGLELLASGDPLPS ASQNAEMIETGSDCVTQAGLQLLASSDPPALASKNAEVTGTMSQDTEVDMKEVELNEL EPEKQPMNAASGAAMSLAGAEKNGLVKIKVAEDEAEAAAAAKFTGLSKEELLKVAGSP GWVRTRWALLLLFWLGWLGMLAGAVVIIVRAPRCRELPAQKWWHTGALYRIGDLQAF QGHGAGNLAGLKGRLDYLSSLKVKGLVLGPIHKNQKDDVAQTDLLQIDPNFGSKEDFD^ny-2871899 735022004340 SLLQSAKKKSIRVILDLTPNYRGENSWFSTQVDTVATKVKDALEFWLQAGVDGFQVRDI ENLKDASSFLAEWQNITKGFSEDRLLIAGTNSSDLQQILSLLESNKDLLLTSSYLSDSGST GEHTKSLVTQYLNATGNRWCSWSLSQARLLTSFLPAQLLRLYQLMLFTLPGTPVFSYGD EIGLDAAALPGQPMEAPVMLWDESSFPDIPGAVSANMTVKGQSEDPGSLLSLFRRLSDQ RSKERSLLHGDFHAFSAGPGLFSYIRHWDQNERFLVVLNFGDVGLSAGLQASDLPASAS LPAKADLLLSTQPGREEGSPLELERLKLEPHEGLLLRFPYAA (SEQ ID NO: 2). [0175] As used herein, the terms “antibody” and “immunoglobulin” are used interchangeably and refer to an antibody molecule that recognizes and specifically binds to a target, such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or combinations of the foregoing (e.g., a glycoprotein), through at least one antigen recognition site within the variable region of the immunoglobulin molecule. The term “antibody” encompasses monoclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, multi-specific (e.g., bi- specific) antibodies, and any other immunoglobulin molecule so long as the antibodies exhibit the desired biological activity. An antibody can be of any the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or subclasses (isotypes) thereof (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), based on the identity of their heavy-chain constant regions referred to as alpha, delta, epsilon, gamma, and mu, respectively. The different classes of antibodies have different and well-known subunit structures and three-dimensional configurations. For the structure and properties of the different classes of antibodies, see, e.g., Basic and Clinical Immunology, 8th Ed., Daniel P. Stites, Abba I. Terr and Tristram G. Parslow (eds.), Appleton & Lange, Norwalk, CT, 1994, page 71 and Chapter 6. [0176] The terms “anti-TfR antibody,” “antibody that binds to TfR,” and “antibody that specifically binds TfR” refer to an antibody that is capable of binding TfR with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting TfR. In some embodiments, the anti-TfR antibody is capable of transporting another diagnostic and/or therapeutic agent into the brain. In certain embodiments, an anti-TfR antibody binds to an epitope of TfR that is conserved among TfR from different species. [0177] The terms "anti-CD98hc antibody," "antibody that binds to CD98hc," and "antibody that specifically binds CD98hc" refer to an antibody that is capable of binding CD98hc with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting CD98hc. In some embodiments, the anti-CD98hc antibody is capable of transporting^ny-2871899 735022004340 another diagnostic and/or therapeutic agent into the brain. In certain embodiments, an anti- CD98hc antibody binds to an epitope of CD98hc that is conserved among CD98hc from different species. [0178] An “antigen-binding domain” or “antigen-binding region” refers to a monovalent portion of an antibody that binds to an antigen. An “antigen-binding domain” can comprise the antigenic determining regions of an antibody (e.g., the complementarity determining regions (CDRs)). An antibody or antigen-binding fragment thereof (including mono-specific and multi- specific (e.g., bi-specific) antibodies or antigen-binding fragments thereof can comprise an antigen-binding domain. In some embodiments, an antigen-binding domain is not present in the context of an antibody. [0179] The terms “anti-TfR antigen-binding domain,” “antigen-binding domain that binds to TfR,” “anti-TfR antigen-binding region,” “antigen-binding region that binds to TfR,” and “TfR binding domain” refer to an antigen-binding domain that binds to TfR with sufficient affinity such that the antigen-binding domain is useful as a diagnostic and/or therapeutic agent in targeting TfR. In one aspect, the extent of binding of an anti-TfR antigen-binding domain to an unrelated, non-TfR polypeptide is less than about 10% of the binding of the antigen-binding domain to TfR as measured, e.g., by a radioimmunoassay (RIA). In certain embodiments, an antibody that binds to TfR has a dissociation constant (KD) of about 0.01 nM to about 50 nM, about 51 nM to about 750 nM, about 751 nM to about 10,000 nM, less than about 20 μM, less than about 15 μM, less than about 12 μM, less than about 10 μM, less than about 7.5 μM, less than about 5 μM, less than about 2.5 μM, less than about 1 , less than about 100 nM, less than about 10 nM, less than about 1 nM, less than about 0.1 nM, less than about 0.01 nM, or less than about 0.001 nM (e.g., 10^-8 M or less, e.g., from 10^-8 M to 10^-13 M, e.g., from 10^-9 M to 10^-13 M). In certain embodiments, an anti-TfR antigen-binding domain binds to an epitope of TfR that is conserved among TfR from different species. [0180] The terms “anti-CD98hc antigen-binding domain,” “antigen-binding domain that binds to CD98hc,” “anti-CD98hc antigen-binding region,” “antigen-binding region that binds to CD98hc,” and “CD98hc binding domain” refer to an antigen-binding domain that binds to CD98hc with sufficient affinity such that the antigen-binding domain is useful for targeting CD98hc and/or useful as a diagnostic agent, a therapeutic agent, or for transporting a molecule or compound across the BBB. In one aspect, the extent of binding of an anti-CD98hc antigen-^ny-2871899 735022004340 binding domain to an unrelated, non-CD98hc polypeptide is less than about 10% of the binding of the antigen-binding domain to CD98hc as measured, e.g., by a radioimmunoassay (RIA). In certain embodiments, an antibody that binds to CD98hc has a dissociation constant (KD) of about 10 nM to about 1500 nM, about 500 nM to about 10 μM, about 100 nM to about 500 nM, less than about 0.1 , less than about 1 , less than about 10 M, less than about 100 nM, less than about 10 nM, less than about 1 nM, less than about 0.1 nM, less than about 0.01 nM, or less than about 0.001 nM (e.g., 10^-8 M or less, e.g., from 10^-8 M to 10^-13 M, e.g., from 10^-9 M to 10^-13 M). In certain embodiments, an anti-CD98hc antigen-binding domain binds to an epitope of CD98hc that is conserved among CD98hc from different species. [0181] The terms “full-length antibody,” “intact antibody” or “whole antibody” are used interchangeably to refer to an antibody in its substantially intact form, as opposed to an antibody fragment. Specifically, whole antibodies include those with heavy and light chains including an Fc region. The constant regions can be native sequence constant regions (e.g., human native sequence constant regions) or amino acid sequence variants thereof. In some cases, the intact antibody can have one or more effector functions. [0182] The term “native IgG antibodies” refers to heterotetrameric glycoproteins of about 150,000 Daltons, composed of two identical light (“L”) chains and two identical heavy (“H”) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies among the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intra-chain disulfide bridges. Each heavy chain has at one end a variable domain (VH) followed by a number of constant domains. Each light chain has a variable domain at one end (V_L) and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain. Particular amino acid residues are believed to form an interface between the light chain and heavy chain variable domains. [0183] The terms “VH” and “VH domain” are used interchangeably to refer to the heavy chain variable region of an antibody. [0184] As used herein, the term “heavy chain” when used in reference to an antibody can refer_{to any distinct type, e.g., alpha ( ), delta ( ), epsilon ( ), gamma ( ), and mu (μ), based on the} amino acid sequence of the constant region, which give rise to IgA, IgD, IgE, IgG, and IgM^ny-2871899 735022004340 classes of antibodies, respectively, including subclasses of IgG, e.g., IgG₁, IgG₂, IgG₃, and IgG₄. Heavy chain amino acid sequences are well known in the art. In some embodiments, the heavy chain is a human heavy chain. [0185] The terms “VL” and “VL domain” are used interchangeably to refer to the light chain variable region of an antibody. [0186] As used herein, the term “light chain” when used in reference to an antibody can refer_{to any distinct type, e.g., kappa ( ) or lambda ( ) based on the amino acid sequence of the} constant regions. Light chain amino acid sequences are well known in the art. In some embodiments, the light chain is a human light chain. [0187] The terms “variable region” or “variable domain” refers to the amino-terminal domains of the heavy or light chain of the antibody. The variable domains of the heavy chain and light chain may be referred to as “VH” and “VL”, respectively. These domains are generally the most variable parts of the antibody (relative to other antibodies of the same class) and contain the antigen binding sites. Generally, the variable region or variable domain is typically about the amino-terminal 110 to 120 amino acids or 110 to 125 amino acids in the mature heavy chain and about 90 to 115 amino acids in the mature light chain. [0188] The term “Fv” or “variable fragment” refers to the minimum antibody fragment which comprises a complete antigen-binding site and consists of a dimer of one heavy-chain variable region (VH) and one light-chain variable region (VL). From the folding of these two domains emanate six hypervariable loops (3 loops each from the H and L chain) that contribute the amino acid residues for antigen binding and confer antigen binding specificity to the antibody. [0189] As used herein, the term “constant region” is a region of an antibody that is not the variable region of the antibody, e.g., a carboxyl terminal portion of a light and/or heavy chain which is not directly involved in binding of an antibody to antigen, but which can exhibit various effector functions, such as interaction with the Fc receptor. The constant region of an immunoglobulin molecule generally has a more conserved amino acid sequence relative to an immunoglobulin variable domain. In certain embodiments, an antibody or antigen-binding fragment comprises a constant region or portion thereof that is sufficient for antibody-dependent cell-mediated cytotoxicity (ADCC).^ny-2871899 735022004340 [0190] A “constant domain” means a domain within a constant region that is capable of forming an immunoglobulin fold. Constant domains include the CH1, CH2, CH3, and CL domains. [0191] The term “antibody fragment” refers to a portion of an antibody. An “antigen-binding fragment” of an antibody refers to a portion of an antibody that binds to an antigen. An antigen- binding fragment of an antibody can comprise the antigenic determining regions of an antibody (e.g., the complementarity determining regions (CDRs)). Examples of antigen-binding fragments of antibodies include, but are not limited to Fab, Fab’, F(ab’)2, and Fv fragments, linear antibodies, and single chain antibodies. An antigen-binding fragment of an antibody can be monovalent or multi-valent (e.g., bi-valent). An antigen-binding fragment of an antibody can be monospecific or multi-specific (e.g., bi-specific.) An antigen-binding fragment of an antibody can be derived from any animal species, such as rodents (e.g., mouse, rat, or hamster) and humans or can be artificially produced. [0192] The term “Fab” or “fragment antigen-binding region” refers to a region on an antibody that binds to antigens. It is composed of one constant domain, one variable domain of the heavy chain and one variable domain of the light chain. Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen-binding site. [0193] The term “F(ab’)2 fragment” refers to antibody fragments that are generated by pepsin digestion of whole IgG antibodies to remove most of the Fc region while leaving intact some of the hinge region. F(ab’)2 fragments have two antigen-binding F(ab) portions linked together by disulfide bonds, and therefore are divalent with a molecular weight of about 110 kDa. Fab’ fragments differ from Fab fragments by having a few additional residues at the carboxy termin’s of the C_H1 domain including one or more cysteines from the antibody hinge region. Fab’-SH is the designation herein for Fab’ in which the cysteine residue(s) of the constant domains bear a free thiol group. [0194] As used herein, a “Fc fragment,” “fragment crystallizable region,” or “Fc region” is composed of two or more polypeptides, each being an antibody heavy chain fragment and each containing at least one (e.g., two or three) heavy chain constant domains. In some embodiments, an Fc region is composed of two heavy chain fragments, each containing a CH2 domain and a CH3 domain. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy-chain Fc region is usually defined to stretch from an amino^ny-2871899 735022004340 acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof. The C- terminal lysine (residue 447 according to the EU numbering system) of the Fc region can be removed, for example, during production or purification of the antibody, or by recombinantly engineering the nucleic acid encoding a heavy chain of the antibody. Accordingly, an Fc region may not contain any K447 residues, may contain at least one polypeptide containing a K447 residue and at least one polypeptide that does not contain a K447 residue, or may only contain polypeptides that include a K447 residue. Suitable native-sequence Fc regions for use in the present disclosure include human IgG1, IgG2, IgG3 and IgG4. In a native antibody, an Fc region refers to the region of an antibody that interacts with cell surface receptors called Fc receptors and some proteins of the complement system. However, as used herein, an Fc region can be modified to increase, decrease, or eliminate interaction with Fc receptors and/or proteins of the complement system. In native IgG, IgA and IgD antibody isotypes, the Fc region is composed of two identical protein fragments, derived from the second and third constant domains of the antibody’s two heavy chains. However, as used herein, the two or more polypeptides in an “Fc region” do not need to have identical sequences. In some embodiments, an “Fc region” comprises a first polypeptide comprising an Fc domain (e.g., IgG1 Fc domain) with a knob mutation and a second polypeptide comprising an Fc domain (e.g., IgG1 Fc domain) with a hole mutation. In native IgM and IgE antibody isotypes, the Fc region contains three heavy chain constant domains (CH domains 2–4) in each polypeptide chain. [0195] A “native sequence Fc region” comprises an amino acid sequence identical to the amino acid sequence of an Fc region found in nature. Native sequence human Fc regions include a native sequence human IgG1 Fc region (non-A and A allotypes); native sequence human IgG2 Fc region; native sequence human IgG3 Fc region; and native sequence human IgG4 Fc region. [0196] A “variant Fc region” comprises an amino acid sequence which differs from that of a native sequence Fc region by virtue of at least one amino acid modification, in some embodiments, two or more amino acid substitution(s). In some embodiments, the variant Fc region has at least one amino acid substitution compared to a native sequence Fc region or to the Fc region of a parent polypeptide, e.g. from about one to about ten amino acid substitutions, and in some embodiments, from about one to about five amino acid substitutions in a native sequence Fc region or in the Fc region of the parent polypeptide. In some embodiments, the variant Fc region possesses at least 80% homology with a native sequence Fc region and/or with an Fc^ny-2871899 735022004340 region of a parent polypeptide, at least 90% homology therewith, or at least 95% homology therewith. [0197] The term “Fc domain” refers to one or more domains within an Fc region, such as a CH2 or CH3 domain, in a single polypeptide. In some aspects, the Fc domain includes at least one amino acid deletion, addition, or substitution as compared to the amino acid sequence of a native Fc domain, such as by including a set of “knob-into-hole” deletions, additions, or substitutions or including amino acid deletions, additions, or substitutions to effect electrostatic steering of the Fc domain to favor attractive interactions among different polypeptide chains. In some aspects, the Fc domain is in a "knob" format. In some aspects, the Fc domain is in a "hole" format. [0198] The term “single-chain Fv”, also abbreviated as “sFv” or “scFv”, refers to antibody fragments that comprise the VH and VL antibody domains that form a single polypeptide chain. In some embodiments, the scFv polypeptide comprises a polypeptide linker between the VH and V_L domains, which enables the scFv to form the desired structure for antigen binding. [0199] The term “diabodies” refers to small antibody fragments prepared by constructing scFv fragments with short linkers (about 5-10 residues) between the V_H and V_L domains, such that inter-chain but not intra-chain pairing of the variable domains is achieved, thereby resulting in a bivalent fragment (i.e., a fragment having two antigen-binding sites). Bispecific diabodies are heterodimers of two “crossover” scFv fragments in which the VH and VL domains of the two antibodies are present on different polypeptide chains. [0200] The term “CDR” or “complementarity determining region” refers to hypervariable regions (“HVRs”) in the variable region of an immunoglobulin that determine antibody diversity and antigen specificity. [0201] The term “Kabat numbering” and like terms are recognized in the art and refer to a system of numbering amino acid residues in the heavy and light chain variable regions of an antibody or an antigen-binding fragment thereof. In certain embodiments, CDRs can be determined according to the Kabat numbering system (see, e.g., Kabat EA & Wu TT (1971) Ann NY Acad Sci 190: 382-391 and Kabat EA et al., (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No.91- 3242). Using the Kabat numbering system, CDRs within an antibody heavy chain molecule are typically present at amino acid positions 31 to 35, which optionally can include one or two^ny-2871899 735022004340 additional amino acids, following 35 (referred to in the Kabat numbering scheme as 35A and 35B) (CDRH1), amino acid positions 50 to 65 (CDRH2), and amino acid positions 95 to 102 (CDRH3). Using the Kabat numbering system, CDRs within an antibody light chain molecule are typically present at amino acid positions 24 to 34 (CDRL1), amino acid positions 50 to 56 (CDRL2), and amino acid positions 89 to 97 (CDRL3). [0202] The term “Chothia” refers to the location of the structural loops (see, e.g., Chothia C & Lesk AM, (1987), J Mol Biol 196: 901-917; Al-Lazikani B et al., (1997) J Mol Biol 273: 927- 948; Chothia C et al., (1992) J Mol Biol 227: 799-817; Tramontano A et al., (1990) J Mol Biol 215(1): 175-82; and U.S. Patent No. 7,709,226). In some embodiments, the Chothia residues are numbered as shown in the table below. In some embodiments, the CDRs are Chothia CDRs. [0203] The AbM hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops and are used by Oxford Molecular’s AbM antibody modeling software. In some embodiments, the CDRs are AbM CDRs. [0204] In some embodiments, the CDRs can be “contact” CDRs. The “contact” CDRs are based on an analysis of the available complex crystal structures. In some embodiments, the CDRs are “contact” CDRs. [0205] The residues from each of these CDRs are noted below. Loop Kabat AbM Chothia Contact L1 L24-L34 L24-L34 L26-L32 L30-L36 L2 L50-L56 L50-L56 L50-L52 L46-L55 L3 L89-L97 L89-L97 L91-L96 L89-L96 H1 H31-H35B H26-H35B H26-H32 H30-H35B (Kabat numbering) H1 H31-H35 H26-H35 H26-H32 H30-H35 (Chothia numbering) H2 H50-H65 H50-H58 H52-H56 H47-H58 H3 H95-H102 H95-H102 H96-H101 H93-H101 [0206] CDRs can comprise “extended CDRs” as follows: 24-36 or 24-34 (L1), 46-56 or 50-56 (L2), and 89-97 or 89-96 (L3) in the VL, and 26-35 (H1), 50-65 or 49-65 (H2), and 93-102, 94- 102, or 95-102 (H3) in the VH. The variable-domain residues are numbered according to Kabat et al., supra, for each of these extended-CDR definitions. [0207] CDRs can also be identified according to the IMGT numbering system as described in Lefranc M-P, (1999) The Immunologist 7: 132-136 and Lefranc M-P et al., (1999) Nucleic Acids^ny-2871899 735022004340 Res 27: 209-212. According to the IMGT numbering scheme, VH-CDR1 is at positions 26 to 35, VH-CDR2 is at positions 51 to 57, VH-CDR3 is at positions 93 to 102, VL-CDR1 is at positions 27 to 32, VL-CDR2 is at positions 50 to 52, and VL-CDR3 is at positions 89 to 97. [0208] The term “monoclonal” when referring to an antibody or antigen-binding fragment thereof refers to a homogeneous antibody or antigen-binding fragment population involved in the highly specific recognition and binding of a single antigenic determinant, or epitope. This is in contrast to polyclonal antibodies that typically include different antibodies directed against different antigenic determinants. The term “monoclonal” antibody or antigen-binding fragment thereof encompasses both intact and full-length monoclonal antibodies as well as antibody fragments (such as Fab, Fab’, F(ab’)2, Fv), single chain (scFv) mutants, fusion proteins comprising an antibody or antibody portion, and any other modified immunoglobulin molecule comprising an antigen recognition site. Furthermore, a “monoclonal” antibody or antigen- binding fragment thereof refers to such antibodies and antigen-binding fragments thereof made in any number of manners including but not limited to by hybridoma, phage selection, recombinant expression, and transgenic animals. [0209] The term “chimeric” antibodies or antigen-binding fragments thereof refers to antibodies or antigen-binding fragments thereof wherein the amino acid sequence is derived from two or more species. Typically, the variable region of both light and heavy chains corresponds to the variable region of antibodies or antigen-binding fragments thereof derived from one species of mammals (e.g., mouse, rat, rabbit, etc.) with the desired specificity, affinity, and capability, while the constant regions are homologous to the sequences in antibodies or antigen-binding fragments thereof derived from another (usually human) to avoid eliciting an immune response in that species. [0210] The term “humanized” antibody or antigen-binding fragment thereof refers to forms of non-human (e.g., murine) antibodies or antigen-binding fragments that are specific immunoglobulin chains, chimeric immunoglobulins, or fragments thereof that contain minimal non-human (e.g., murine) sequences. Typically, humanized antibodies or antigen-binding fragments thereof are human immunoglobulins in which residues from the complementarity determining regions (CDRs) are replaced by residues from the CDRs of a molecule originating from a non-human species (e.g. mouse, rat, rabbit, hamster) that have the desired specificity, affinity, and capability (“CDR grafted”) (Jones et al., Nature 321:522-525 (1986); Riechmann et^ny-2871899 735022004340 al., Nature 332:323-327 (1988); Verhoeyen et al., Science 239:1534-1536 (1988)). The humanized antibody or antigen-binding fragment thereof can be further modified by the substitution of additional residues either in the Fv framework region and/or within the replaced non-human residues to refine and optimize the specificity, affinity, and/or capability of the antibody or antigen-binding fragment thereof. In general, the humanized antibody or antigen- binding fragment thereof will comprise VH and VL that comprise substantially all of at least one, and typically two or three, of the CDR regions that correspond to the non-human immunoglobulin, whereas all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. The humanized antibody or antigen-binding fragment thereof can also comprise at least a portion of an immunoglobulin constant region or Fc region, typically that of a human immunoglobulin. Examples of methods used to generate humanized antibodies are described in U.S. Pat.5,225,539; Roguska et al., Proc. Natl. Acad. Sci., USA, 91(3):969-973 (1994), and Roguska et al., Protein Eng.9(10):895-904 (1996). In some embodiments, a “humanized antibody” is a resurfaced antibody. [0211] The term “human” antibody or antigen-binding fragment thereof means an antibody or antigen-binding fragment thereof having an amino acid sequence derived from a human immunoglobulin gene locus, where such antibody or antigen-binding fragment is made using any technique known in the art. This definition of a human antibody or antigen-binding fragment thereof includes intact or full-length antibodies and fragments thereof. [0212] “Framework” or “FR” residues are those variable-domain residues other than the CDR residues as herein defined. [0213] An “acceptor human framework” as used herein is a framework comprising the amino acid sequence of a V_L or V_H framework derived from a human immunoglobulin framework or a human consensus framework. An acceptor human framework “derived from” a human immunoglobulin framework or a human consensus framework can comprise the same amino acid sequence thereof, or it can comprise pre-existing amino acid sequence changes. In some embodiments, the number of pre-existing amino acid changes are 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. Where pre-existing amino acid changes are present in a VH, in some embodiments those changes occur at only three, two, or one of positions 71H, 73H and 78H; for instance, the amino acid residues at those positions can by 71A, 73T and/or 78A. In some embodiments, the VL acceptor human framework is identical^ny-2871899 735022004340 in sequence to the V_L human immunoglobulin framework sequence or human consensus framework sequence. [0214] A “human consensus framework” is a framework that represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest, 5^th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991). Examples include for the V_L, the subgroup can be subgroup kappa I, kappa II, kappa III or kappa IV as in Kabat et al., supra. Additionally, for the VH, the subgroup can be subgroup I, subgroup II, or subgroup III as in Kabat et al., supra. [0215] An “amino-acid modification” at a specified position, e.g., of an antibody of the present disclosure, refers to the substitution or deletion of the specified residue, or the insertion of at least one amino acid residue adjacent the specified residue. Insertion “adjacent” to a specified residue means insertion within one to two residues thereof. The insertion can be N-terminal or C- terminal to the specified residue. In some embodiments, an amino acid modification is a substitution. [0216] Antibody “effector functions” refer to those biological activities attributable to the Fc region (a native sequence Fc region or amino acid sequence variant Fc region) of an antibody and vary with the antibody isotype. [0217] “Fc receptor” or “FcR” describes a receptor that binds to the Fc region of an antibody. In some embodiments, an FcR is a native sequence human FcR. In some embodiments, an FcR is_{one which binds an IgG antibody (a gamma receptor) and includes receptors of the Fc RI,Fc RII, and Fc RIII subclasses, including allelic variants and alternatively spliced forms of thesereceptors, Fc RII receptors include Fc RIIA (an “activating receptor”) and Fc RIIB (an} “inhibiting receptor”), which have similar amino acid sequences that differ primarily in the_{cytoplasmic domains thereof. Activating receptor Fc RIIA contains an immunoreceptor tyrosine-based activation motif (“ITAM”) in its cytoplasmic domain. Inhibiting receptor Fc RIIB} contains an immunoreceptor tyrosine-based inhibition motif (“ITIM”) in its cytoplasmic domain. Other FcRs, including those to be identified in the future, are encompassed by the term “FcR” herein. FcRs can also increase the serum half-life of antibodies.^ny-2871899 735022004340 [0218] “Binding affinity” generally refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody or antigen-binding fragment thereof) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity which reflects a 1:1 interaction between members of a binding pair (e.g., antibody or antigen-binding fragment thereof and antigen). The affinity of a molecule X for its partner Y can generally be represented by the equilibrium dissociation constant (K_D). Affinity can be measured and/or expressed in a number of ways known in the art, including, but not limited to, equilibrium dissociation constant (K_D), and equilibrium association constant (K_A). The K_D is calculated from the quotient of k_off/k_on, whereas KA is calculated from the quotient of kon/koff. kon refers to the association rate constant of, e.g., an antibody or antigen-binding fragment thereof to an antigen, and koff refers to the dissociation rate constant of, e.g., an antibody or antigen-binding fragment thereof from an antigen. The kon and koff can be determined by techniques known to one of ordinary skill in the art, such as BIAcore^® or KinExA. Dissociation constants may also be determined through any analytical technique, including any biochemical or biophysical technique such as ELISA, surface plasmon resonance (SPR), bio-layer interferometry (see, e.g., Octet System by ForteBio), isothermal titration calorimetry (ITC), differential scanning calorimetry (DSC), circular dichroism (CD), stopped-flow analysis, and colorimetric or fluorescent protein melting analyses. (See, e.g., Estep et al, (2013) MAbs 5(2):270-8.) [0219] With regard to the binding of an antibody to a target molecule, the term “specific binding” or “specifically binds” or is “specific for” a particular polypeptide or an epitope on a particular polypeptide target means binding that is measurably different from a non-specific interaction. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule. For example, specific binding can be determined by competition with a control molecule that is similar to the target, for example, an excess of non-labeled target. In this case, specific binding is indicated if the binding of the labeled target to a probe is competitively inhibited by excess unlabeled target. The term “specific binding” or “specifically binds” or is “specific for” a particular polypeptide or an epitope on a particular polypeptide target as used herein can be exhibited, for example, by a molecule having a KD for the target of about any of 10^-4 M or lower, 10^-5 M or lower, 10^-6 M or lower, 10^-7 M or lower, 10^-8 M or lower, 10^-9 M or lower, 10^-10 M or lower, 10^-11 M or lower, 10^-12 M or lower or^ny-2871899 735022004340 a KD in the range of 10^-4 M to 10^-6 M or 10^-6 M to 10^-10 M or 10^-7 M to 10^-9 M. As will be appreciated by the skilled artisan, affinity and KD values are inversely related. A high affinity for an antigen is measured by a low KD value. In some embodiments, the term “specific binding” refers to binding where a molecule binds to a particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope. [0220] The term “linker” or “linked” refers to the covalent linkage between two polypeptides or two heterologous molecules. In some embodiments, a linker is a chemical linker. In some embodiments, the linker comprises a peptide bond, and the two polypeptides or two heterologous molecules are linked to each other either directly to or via one or more additional amino acids. A glycine linker is one that comprises one or more glycines, but no other amino acids, e.g., GGGG (SEQ ID NO: 3). A glycine-rich linker is one that comprises one or more glycines and can contain other amino acids as long as glycine is the predominant species in the linker e.g., GGGNGG (SEQ ID NO: 4), wherein N is any amino acid. A glycine-serine linker is one which contains both glycine and serine in any proportion, e.g., GGGS (SEQ ID NO: 5). Similarly, a proline linker is one that comprises one or more prolines but no other amino acids. A proline-rich linker is one that comprises one or more prolines and can contain other amino acids so long as proline is the predominant species in the linker. [0221] As used herein, “percent (%) amino acid sequence identity” and “homology” with respect to a peptide, polypeptide or antibody sequence refers to the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as identical matches. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGN^TM (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms known in the art needed to achieve maximal alignment over the full-length of the sequences being compared. [0222] A polypeptide, antibody, polynucleotide, vector, cell, or composition which is “isolated” is a polypeptide, antibody, polynucleotide, vector, cell, or composition which is in a^ny-2871899 735022004340 form not found in nature. Isolated polypeptides, antibodies, polynucleotides, vectors, cells or compositions include those which have been purified to a degree that they are no longer in a form in which they are found in nature. In some embodiments, an antibody, polynucleotide, vector, cell, or composition which is isolated is substantially pure. [0223] As used herein, “substantially pure” refers to material which is at least 50% pure (i.e., free from contaminants), at least 90% pure, at least 95% pure, at least 98% pure, or at least 99% pure. [0224] The term “expression system” refers to one or more nucleic acid molecules comprising coding sequence and control sequence(s) in operable linkage, along with a host cell and/or other in vitro transcription and translation machinery, such that one or more proteins encoded by the nucleic acid molecule(s) are capable of being produced. [0225] The term “vector,” as used herein, is intended to refer to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a “plasmid,” which refers to a circular double stranded DNA into which additional DNA segments can be ligated. Another type of vector is a phage vector. Another type of vector is a viral vector, wherein additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operatively linked. Such vectors are referred to herein as “recombinant expression vectors,” or simply, “expression vectors.” In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. In the present specification, “plasmid” and “vector” can be used interchangeably as the plasmid is the most commonly used form of vector. [0226] “Polynucleotide,” or “nucleic acid,” as used interchangeably herein, refer to polymers of nucleotides of any length, and include DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and/or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase or by a synthetic reaction.^ny-2871899 735022004340 [0227] A “host cell” includes an individual cell or cell culture that can be or has been a recipient for vector(s) for incorporation of polynucleotide inserts. Host cells include progeny of a single host cell, and the progeny may not necessarily be completely identical (in morphology or in genomic DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation. A host cell includes cells transfected in vivo with a polynucleotide(s) of this disclosure. In some aspects, the host cell is an isolated host cell. [0228] “Carriers” as used herein include pharmaceutically acceptable carriers, excipients, or stabilizers that are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. [0229] As used herein, the term “treatment” refers to clinical intervention designed to alter the natural course of the individual being treated during the course of clinical pathology. Desirable effects of treatment include decreasing the rate of progression, ameliorating or palliating the pathological state, and remission or improved prognosis of a particular disease, disorder, or condition. An individual is successfully “treated”, for example, if one or more symptoms associated with a particular disease, disorder, or condition are mitigated or eliminated. [0230] The terms “administer,” “administering,” “administration,” and the like, as used herein, refer to methods that can be used to deliver a drug, e.g., an anti-human antibody or antigen- binding fragment thereof, to the desired site of biological action. [0231] An “effective amount” refers to at least an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. An effective amount can be provided in one or more administrations. An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects. For therapeutic use, beneficial or desired results include clinical results such as decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and/or prolonging survival. An effective amount of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an “effective amount” can be considered in the context of^ny-2871899 735022004340 administering one or more therapeutic agents, and a single agent can be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result can be or is achieved. [0232] As used herein, the terms “subject” and “patient” are used interchangeably. The subject can be a mammal such as a non-human animal (e.g., cow, pig, horse, cat, dog, rat, mouse, monkey or other primate, etc.). In some embodiments, the subject is a cynomolgus monkey. In some embodiments, the subject is a human. [0233] As used herein, administration “in conjunction” or “in combination” with another compound or composition includes simultaneous administration and/or administration at different times. Administration in conjunction also encompasses administration as a co- formulation or administration as separate compositions, including at different dosing frequencies or intervals, and using the same route of administration or different routes of administration. In some embodiments, administration in conjunction is administration as a part of the same treatment regimen. [0234] As used herein, the terms “about” and “approximately,” when used to modify a numeric value or numeric range, indicate that deviations of up to 10% above and down to 10% below the value or range remain within the intended meaning of the recited value or range. It is understood that wherever aspects are described herein with the language “about” or “approximately” a numeric value or range, otherwise analogous aspects referring to the specific numeric value or range are also provided. [0235] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly indicates otherwise. For example, reference to an “antibody” is a reference to from one to many antibodies, such as molar amounts, and includes equivalents thereof known to those skilled in the art, and so forth. [0236] It is understood that wherever aspects are described herein with the language “comprising,” otherwise analogous aspects described in terms of “consisting of” and/or “consisting essentially of” are also provided. In this disclosure, “comprises,” “comprising,” “containing” and “having” and the like can mean “includes,” “including,” and the like; “consisting essentially of” or “consists essentially of” are open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited is not changed by the presence of more than that which is recited, but excludes prior art aspects.^ny-2871899 735022004340 I. Complexes Comprising Progranulin Polypeptides [0237] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a Progranulin (PGRN) polypeptide, wherein the antigen-binding domain specifically binds to human transferrin receptor (TfR). [0238] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a Progranulin (PGRN) polypeptide, wherein the antigen-binding domain specifically binds to human transferrin receptor (TfR), wherein the PGRN polypeptide comprises a C- terminal amino acid sequence defined by X₁X₂X₃X₄, wherein X₁ is any amino acid, and wherein X2, X3, and X4 are not PIL, PFL, PPL, PYL, QRL or QHL. [0239] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a Progranulin (PGRN) polypeptide, wherein the antigen-binding domain specifically binds to human transferrin receptor (TfR) and is not within an Fc domain of the complex. [0240] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a PGRN polypeptide, wherein the antigen-binding domain specifically binds to human CD98 heavy chain (CD98hc). [0241] In some aspects, a “1+1 format” of a complex comprising an anti-TfR antigen-binding domain refers to a format comprising (i) an antigen-binding domain that binds to human TfR; and (ii) a Progranulin (PGRN) polypeptide, and (iii) optionally an Fc domain or Fc region. In some aspects, a “1+1 format” of a complex comprising an anti-CD98hc antigen-binding domain refers to a format comprising (i) an antigen-binding domain that binds to human CD98hc; and (ii) a Progranulin (PGRN) polypeptide, and (iii) optionally an Fc domain or Fc region. For example, see FIG. 1A-1D, 1I and 1H. In some embodiments, the Fc domain is a monovalent Fc (see FIG. 1A, 1B). [0242] In some aspects, a “2+1 format” of a complex comprising an anti-TfR antigen-binding domain refers to a format comprising (i) an antigen-binding domain that binds to human TfR and (ii) two Progranulin (PGRN) polypeptides, and (iii) optionally an Fc domain or Fc region. As used herein, a “2+1 format” of a complex comprising an anti-CD98hc antigen-binding domain refers to a format comprising (i) an antigen-binding domain that binds to human CD98hc, (ii) two Progranulin (PGRN) polypeptides, and (iii) optionally an Fc domain or Fc region. For example, see FIG. 1E-1F.^ny-2871899 735022004340 [0243] In some aspects, a “1+2 format” of a complex comprising an anti-TfR antigen-binding domain refers to a format comprising (i) two antigen-binding domains that bind to human TfR and (ii) a Progranulin (PGRN) polypeptide, and (iii) optionally an Fc domain or Fc region. As used herein, a “1+2 format” of a complex comprising an anti-CD98hc antigen-binding domain refers to a format comprising (i) two antigen-binding domains that binds to human CD98hc, (ii) a Progranulin (PGRN) polypeptide, and (iii) optionally an Fc domain or Fc region. For example, see FIG.1E-1F. [0244] In some aspects, a “2+2 format” of a complex comprising an anti-TfR antigen-binding domain refers to a format comprising (i) two antigen-binding domains that bind to human TfR and (ii) two Progranulin (PGRN) polypeptides, and (iii) optionally an Fc domain or Fc region. In some aspects, a “2+2 format” of a complex comprising an anti-CD98hc antigen-binding domain refers to a format comprising (i) two antigen-binding domains that bind to human TfR and (ii) two Progranulin (PGRN) polypeptides, and (iii) optionally an Fc domain or Fc region. For example, see FIG.1G-1H. [0245] In some aspects, provided herein is a complex comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a PGRN polypeptide; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2 and a CH3; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR. For example, see FIG.2C. [0246] In some aspects, provided herein is a complex comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, and a CH3; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a PGRN polypeptide; and (iii) a third polypeptide comprising, from the N- terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR. For example, see FIG. 2B. [0247] In some aspects, provided herein is a complex comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a PGRN polypeptide; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a PGRN polypeptide; and (iii) a third polypeptide^ny-2871899 735022004340 comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR. For example, see FIG.2D. [0248] In some aspects, provided herein is a complex comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a PGRN polypeptide; and (ii) a second polypeptide comprising, from the N- terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR. For example, see FIG.2A. II. Progranulin (PGRN) Polypeptides [0249] Provided herein are complexes comprising an antigen-binding domain linked to a Progranulin (PGRN) polypeptide. The antigen-binding domain can bind specifically to human transferrin receptor (TfR) or human CD98 heavy chain (CD98hc) to facilitate the transport of the PGRN polypeptide across the blood brain barrier (BBB). Also provided herein are isolated PGRN polypeptides. [0250] Progranulin is variously referred to as PGRN, proepithelin, granulin-epithelin precursor, PC (prostate cancer) cell-derived growth factor (PCDGF), and acrogranin. Progranulin is a 593 amino acid protein that encodes a 68.5 kD a secreted glycoprotein that has 7.5 repeats of smaller granulin (epithelin) motifs, ranging from 6-25 kDa, which can be proteolytically cleaved from the precursor PGRN. Examples of Progranulin cleavage products include, without limitation, granulin A / Epithelins 1, granulin B / Epithelins 2, granulin C, granulins D, granulin E, granulin F, granulin G and any other known peptide products derived from Progranulin. [0251] Progranulin is widely expressed, and in non-neuronal cells has been associated with a variety of events, such as cell cycle regulation and cell motility, wound repair, inflammation, induction of growth factors such as vascular endothelial growth factor (VEGF), and tumorigenesis. Progranulin is also widely expressed in early neural development but becomes restricted in later development to defined neuronal populations, such as cortical neurons, hippocampal pyramidal neurons, and Purkinje cells. However, the role of Progranulin in neuronal cells was unclear until patients suffering from frontotemporal dementia (FTD) were shown to carry mutations in the Progranulin gene on chromosome 17. Subsequently, Progranulin has been shown to promote neuronal survival and enhance neurite outgrowth in cortical and motor neurons. Thus, although Progranulin is not a neurotrophin, or a member of the^ny-2871899 735022004340 neurotrophin family, it has been referred to as a neurotrophic factor because of its ability to promote neuronal survival. [0252] Further, it has been shown that haploinsufficiency of Progranulin (which include over 70 different mutations, such as loss-of-function mutations) is associated with frontotemporal dementia (FTD) with TDP-43 pathology. Furthermore, Progranulin levels in plasma are reduced with patients with FTD mutations. Progranulin mutations account for 25% of familial FTD. Additionally, low levels of Progranulin are seen in some FTD patients without Progranulin mutations, and Progranulin levels are altered in Alzheimer’s disease and ALS. Thus, it is believed that Progranulin may be generally involved in degenerative diseases. [0253] It has also been shown that complete loss of Progranulin leads to a Neuronal Lipoid Fuscinosis (NPL) phenotype. Accordingly, it is believed that individuals with various lysosomal storage disorders may respond to increased levels of Progranulin. Progranulin is widely expressed, and in the central nervous system is produced by neurons and microglia. Progranulin is also generally thought to have an anti-inflammatory role in macrophages and microglia, and a pro-survival role in neurons. [0254] Accordingly, the complexes and isolated PGRN mutant polypeptides provided herein that increase Progranulin levels would be beneficial for preventing, lowering the risk of, or treating conditions and/or diseases associated with decreased levels of Progranulin expression and/or activity, cell death (e.g., neuronal cell death), frontotemporal dementia, Alzheimer’s disease, vascular dementia, seizures, retinal dystrophy, a traumatic brain injury, a spinal cord injury, long-term depression, atherosclerotic vascular diseases, undesirable symptoms of normal aging, dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington’s disease, taupathy disease, stroke, acute trauma, chronic trauma, lupus, acute and chronic colitis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, malaria, essential tremor, central nervous system lupus, Behcet's disease, Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, intervertebral disc degeneration, Shy-Drager syndrome, progressive supranuclear palsy, cortical basal ganglionic degeneration, acute disseminated encephalomyelitis, granulomartous disorders, Sarcoidosis, diseases of aging, age related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infection, sepsis, eye infection, systemic infection, inflammatory disorders, arthritis, multiple sclerosis, metabolic disorder, obesity, insulin resistance, type 2^ny-2871899 735022004340 diabetes, tissue or vascular damage, an injury, and/or one or more undesirable symptoms of normal aging. [0255] In some embodiments, the present disclosure provides complexes and isolated PGRN mutant polypeptides that increase Progranulin levels, increase the stability of PGRN, maintain similar binding affinity to Sortilin compared to the binding affinity of wild-type PGRN, and exhibit GCase activity. In some embodiments, the complex binds human Sortilin with a dissociation constant (K_D) that ranges from about 5 nM to about 400 nM, wherein the K_D is determined by a capture kinetics assay (see, e.g., Example 6). In some embodiments, the capture kinetics assay is performed on Carterra LSA. In some embodiments, the complex binds human Sortilin with a KD that ranges from about 50 nM to about 350 nM. In some embodiments, the complex binds human Sortilin with a KD that ranges from about 100 nM to about 300 nM. [0256] In some embodiments, the complex increases cellular GCase activity greater than the PGRN mutant polypeptide alone, wherein GCase activity is determined by an in-vitro GCase activity assay (see, e.g., Example 7). In some embodiments, GCase activity assay is measured by flow cytometry. In some embodiments, the complex increases cellular GCase activity at least about 0.5-fold, at least about 1-fold, or at least about 2-fold greater than the PGRN mutant polypeptide alone. A. Complexes Comprising Progranulin Polypeptides [0257] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a Progranulin (PGRN) polypeptide, wherein the antigen-binding domain specifically binds to human transferrin receptor (TfR). In some embodiments, the PGRN polypeptide is a PGRN mutant polypeptide, wherein the PGRN polypeptide comprises a C-terminal amino acid sequence defined by X₁X₂X₃X₄, wherein X₁ is any amino acid, and wherein X₂, X₃, and X₄ are not PIL, PFL, PPL, PYL, QRL or QHL. In some embodiments, the PGRN polypeptide comprises the amino acid sequence of SEQ ID NO: 330, and wherein: (a) X₁ is an amino acid selected from the group consisting of R, I, V, Q, T, P, and D; (b) X₂ is an amino acid selected from the group consisting of Q and P; (c) X3 is absent or is an amino acid selected from the group consisting of L, P, C, G, T, D, Y, R, S, Q, V, A, I, H, K, and N; and/or (d) X4 is absent or is an amino acid selected from the group consisting of L, E, G, P, R, D, S, H, N, V, T, I, and A. [0258] In some embodiments, the complex comprises an antigen-binding domain that specifically binds to human TfR and a PGRN polypeptide selected from PGRN (wt), PGRN_1,^ny-2871899 735022004340 PGRN_2, PGRN_3, PGRN_4, PGRN_5, PGRN_6, PGRN_7, PGRN_8, PGRN_9, PGRN_10, PGRN_11, PGRN_12, PGRN_13, PGRN_14, PGRN_15, PGRN_16, PGRN_17, PGRN_18, PGRN_19, PGRN_20, PGRN_21, PGRN_22, PGRN_23, PGRN_24, PGRN_25, PGRN_26, PGRN_27, PGRN_28, PGRN_29, PGRN_30, PGRN_31, PGRN_32, PGRN_33, PGRN_34, PGRN_35, or PGRN_36 (e.g., as shown in Table 1). [0259] In some embodiments, the complex comprises an antigen-binding domain that specifically binds to human TfR and a PGRN polypeptide, wherein the PGRN polypeptide comprises an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to an amino acid sequence of SEQ ID NO: 230. In some embodiments, the PGRN polypeptide comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence of SEQ ID NO: 230), but retains the ability to bind to Sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids been substituted, inserted, and/or deleted in the PGRN polypeptide amino acid sequence of SEQ ID NO: 230. [0260] In some embodiments, the complex comprises an antigen-binding domain that specifically binds to human TfR and a PGRN polypeptide, wherein the PGRN polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 230, SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 247, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 260, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. [0261] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a Progranulin (PGRN) polypeptide, wherein the antigen-binding domain specifically binds to human CD98 heavy chain (CD98hc). In some embodiments, the PGRN polypeptide is a PGRN mutant polypeptide. In some embodiments, the PGRN polypeptide comprises the amino acid sequence of SEQ ID NO: 330, and wherein: (a) X₁ is an amino acid selected from the group consisting of R, I, V, Q, T, P, and D; (b) X₂ is an amino acid selected from the group consisting^ny-2871899 735022004340 of Q and P; (c) X₃ is absent or is an amino acid selected from the group consisting of L, P, C, G, T, D, Y, R, S, Q, V, A, I, H, K, and N; and/or (d) X4 is absent or is an amino acid selected from the group consisting of L, E, G, P, R, D, S, H, N, V, T, I, and A. [0262] In some embodiments, the complex comprises an antigen-binding domain that specifically binds to human CD98hc and a PGRN polypeptide selected from PGRN (wt), PGRN_1, PGRN_2, PGRN_3, PGRN_4, PGRN_5, PGRN_6, PGRN_7, PGRN_8, PGRN_9, PGRN_10, PGRN_11, PGRN_12, PGRN_13, PGRN_14, PGRN_15, PGRN_16, PGRN_17, PGRN_18, PGRN_19, PGRN_20, PGRN_21, PGRN_22, PGRN_23, PGRN_24, PGRN_25, PGRN_26, PGRN_27, PGRN_28, PGRN_29, PGRN_30, PGRN_31, PGRN_32, PGRN_33, PGRN_34, PGRN_35, or PGRN_36 (e.g., as shown in Table 1). [0263] In some embodiments, the complex comprises an antigen-binding domain that specifically binds to human CD98hc and a PGRN polypeptide, wherein the PGRN polypeptide comprises an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity to an amino acid sequence of SEQ ID NO: 230. In some embodiments, the PGRN polypeptide comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence of SEQ ID NO: 230), but retains the ability to bind to Sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids been substituted, inserted, and/or deleted in the PGRN polypeptide amino acid sequence of SEQ ID NO: 230. [0264] In some embodiments, the complex comprises an antigen-binding domain that specifically binds to human CD98hc and a PGRN polypeptide, wherein the PGRN polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 230, SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 247, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 260, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266.^ny-2871899 735022004340 B. Isolated PGRN Mutant Polypeptides [0265] In some aspects, provided herein is an isolated PGRN mutant polypeptide, wherein: (i) the isolated PGRN mutant polypeptide comprises a C-terminal amino acid sequence defined by X1X2X3X4, and wherein: (a) X1 is an amino acid selected from the group consisting of R, D, E, I, P, or Q; (b) X₂ is an amino acid selected from the group consisting of Q and P; (c) X₃ is an amino acid selected from the group consisting of L, A, C, D, F, G, H, I, K, M, N, P, Q, R, S, T, V, or Y; and/or (d) X₄ is absent or is an amino acid selected from the group consisting of L, R, or V; and (ii) X₂, X₃, and X₄ are not PIL, PFL, PPL, PYL, QRL, or QHL. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 330. [0266] In some embodiments, the isolated PGRN mutant polypeptide is an isolated PGRN mutant polypeptide selected from PGRN_1, PGRN_2, PGRN_3, PGRN_4, PGRN_5, PGRN_6, PGRN_7, PGRN_8, PGRN_9, PGRN_10, PGRN_11, PGRN_12, PGRN_13, PGRN_14, PGRN_15, PGRN_16, PGRN_18, PGRN_19, PGRN_20, PGRN_21, PGRN_22, PGRN_23, PGRN_24, PGRN_25, PGRN_26, PGRN_27, PGRN_29, PGRN_31, PGRN_32, PGRN_33, PGRN_34, PGRN_35, or PGRN_36 (e.g., as shown in Table 1). [0267] In some embodiments, the isolated PGRN mutant polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 259, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. [0268] In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 231. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 232. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 233. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 234. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 235. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 236. In some embodiments, the 73^ny-2871899 735022004340 isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 237. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 238. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 239. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 240. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 241. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 242. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 243. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 244. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 245. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 246. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 248. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 249. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 250. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 251. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 252. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 253. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 254. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 255. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 256. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 257. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 259. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 261. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 262. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 263. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 264. In^ny-2871899 735022004340 some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 265. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 266. [0269] Table 1 shows exemplary PGRN mutant polypeptides. In Table 1, C-terminal mutations relative to wild-type (RQLL; SEQ ID NO: 230) are bold and underlined. A PGRN mutant polypeptide of a complex can comprise the amino acid sequence of SEQ ID NO: 330, wherein X is absent or any amino acid. Table 1. PGRN Mutant Polypeptide Sequences^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340 III. Compositions that Bind to Blood-Brain Barrier Receptors or Proteins [0270] Provided herein are complexes, and compositions thereof, comprising an antigen- binding domain linked to a PGRN polypeptide. The antigen-binding domain can specifically bind to human receptors or proteins of the blood-brain barrier. Such complexes are capable of crossing the blood brain barrier (BBB) and capable of transporting the PGRN polypeptide across the BBB. Exemplary human receptors or proteins of the blood-brain barrier are transferrin receptor (TfR) and CD98 heavy chain (CD98hc).^ny-2871899 735022004340 [0271] In some embodiments, the antigen-binding domain is a TfR antigen-binding domain. In some embodiments, the antigen-binding domain is a CD98hc antigen-binding domain. A. Antigen-Binding Domains That Bind to TfR [0272] In some embodiments, the antigen-binding domain specifically bind to human TfR. The anti-TfR antigen-binding domain is capable of crossing the blood brain barrier (BBB) and thus transporting the PGRN polypeptide linked to the antigen-binding domain across the BBB. Accordingly, in some embodiments, provided herein are complexes comprising an antigen- binding domain linked to a PGRN polypeptide, wherein the antigen-binding domain specifically binds to human TfR and is capable of being internalized in BBB epithelial cells. [0273] In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises the six CDRs of an antibody listed in Table 2 and Table 3 below (i.e. the three VH CDRs of the antibody listed in Table 2 and the three VL CDRs of the same antibody listed in Table 3). In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises the six CDRs of an antibody listed in Table 2, Table 3, or Table 4 below. In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises the six CDRs of an antibody listed in Table 2, Table 3, or Table 4 as determined by Kabat numbering. In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises the six Chothia CDRs of an antibody listed in Table 2, Table 3, or Table 4. [0274] In some embodiments, the CDRs of an antigen-binding domain that specifically binds to human TfR can be determined according to MacCallum RM et al., (1996) J Mol Biol 262: 732-745. See also, e.g., Martin A. “Protein Sequence and Structure Analysis of Antibody Variable Domains,” in Antibody Engineering, Kontermann and Dübel, eds., Chapter 31, pp.422- 439, Springer-Verlag, Berlin (2001). In some embodiments, provided herein are antigen-binding domains that specifically bind to human TfR and comprise VH and VL CDRs of an antibody listed in Table 2, Table 3, or Table 4 as determined by the method in MacCallum RM et al. [0275] In some embodiments, the CDRs of an antigen-binding domain that specifically binds to human TfR can be determined according to the AbM numbering scheme, which refers to AbM hypervariable regions, which represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular's AbM antibody modeling software (Oxford Molecular Group, Inc.). In some embodiments, provided herein are antigen-binding domains that^ny-2871899 735022004340 specifically bind to human TfR and comprise VH and VL CDRs of an antibody listed in Table 2, Table 3, or Table 4 as determined by the AbM numbering scheme. [0276] In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises the six IMGT CDRs of an antibody listed in listed in Table 2, Table 3, or Table 4 according to the IMGT numbering system as described in Lefranc M-P, (1999) The Immunologist 7: 132-136 and Lefranc M-P et al., (1999) Nucleic Acids Res 27: 209-212. According to the IMGT numbering scheme, VH-CDR1 is at positions 26 to 35, VH-CDR2 is at positions 51 to 57, VH-CDR3 is at positions 93 to 102, VL-CDR1 is at positions 27 to 32, VL- CDR2 is at positions 50 to 52, and VL-CDR3 is at positions 89 to 97. [0277] In some embodiments, an antigen-binding domain that specifically binds to human TfR provided herein is described by its VL domain alone, or its VH domain alone, or by its 3 VL CDRs alone, or its 3 VH CDRs alone. See, for example, Rader C et al., (1998) PNAS 95: 8910- 8915, which is incorporated herein by reference in its entirety, describing the humanization of_{the mouse anti- v 3 antibody by identifying a complementing light chain or heavy chain,} respectively, from a human light chain or heavy chain library, resulting in humanized antibody variants having affinities as high or higher than the affinity of the original antibody. See also Clackson T et al., (1991) Nature 352: 624-628, which is incorporated herein by reference in its entirety, describing methods of producing antibodies that bind a specific antigen by using a specific VL domain (or VH domain) and screening a library for the complementary variable domains. The screen produced 14 new partners for a specific VH domain and 13 new partners for a specific VL domain, which were strong binders, as determined by ELISA. See also Kim SJ & Hong HJ, (2007) J Microbiol 45: 572-577, which is incorporated herein by reference in its entirety, describing methods of producing antibodies that bind a specific antigen by using a specific VH domain and screening a library (e.g., human VL library) for complementary VL domains; the selected VL domains in turn could be used to guide selection of additional complementary (e.g., human) VH domains. [0278] In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises the VH of an antibody listed in Table 4. [0279] In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises the VL of antibody listed in Table 4.^ny-2871899 735022004340 [0280] In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises the VH and the VL of an antibody listed in Table 4 (i.e., the VH of the antibody listed in Table 4 and the VL of the same antibody listed in Table 4. [0281] In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises (i) a VH comprising an amino acid sequence that is at least 80% identical to a VH amino acid sequence of an antibody listed in Table 4 and (ii) a VL comprising an amino acid sequence that is at least 80% identical to the VL amino acid sequence of the same antibody in Table 4. In some embodiments, the antigen-binding domain that specifically binds to human TfR also comprises the CDRs of the antibody in Table 2 and Table 3 (e.g., the non-identical amino acids in the VH and/or VL are outside of the CDRs). In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises (i) a VH comprising an amino acid sequence that is at least 85% identical to a VH amino acid sequence of an antibody in Table 4 and (ii) a VL comprising an amino acid sequence that is at least 85% identical to the VL amino acid sequence of the same antibody in Table 4. [0282] In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises (i) a VH comprising an amino acid sequence that is at least 90% identical to a VH amino acid sequence of an antibody in Table 4, and (ii) a VL comprising an amino acid sequence that is at least 90% identical to the VL amino acid sequence of the same antibody in Table 4. In some embodiments, the antigen-binding domain that specifically binds to human TfR also comprises the CDRs of an antibody in listed in Table 2 and Table 3 (e.g., the non-identical amino acids in the VH and/or VL are outside of the CDRs). [0283] In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises (i) a VH comprising an amino acid sequence that is at least 95% identical to a VH amino acid sequence of an antibody in Table 4 and (ii) a VL comprising an amino acid sequence that is at least 95% identical to the VL amino acid sequence of the same antibody in Table 4. In some embodiments, the antigen-binding domain that specifically binds to human TfR also comprises the CDRs of the antibody in Table 2 and Table 3 (e.g., the non-identical amino acids in the VH and/or VL are outside of the CDRs). [0284] In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises (i) a VH comprising an amino acid sequence that is at least 96% identical to a VH amino acid sequence of an antibody in Table 4 and (ii) a VL comprising an amino acid sequence^ny-2871899 735022004340 that is at least 96% identical to the VL amino acid sequence of the same antibody in Table 4. In some embodiments, the antigen-binding domain that specifically binds to human TfR also comprises the CDRs of the antibody in Table 2 and Table 3 (e.g., the non-identical amino acids in the VH and/or VL are outside of the CDRs). [0285] In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises (i) a VH comprising an amino acid sequence that is at least 97% identical to a VH amino acid sequence of an antibody in Table 4 and (ii) a VL comprising an amino acid sequence that is at least 97% identical to the VL amino acid sequence of the same antibody in Table 4. In some embodiments, the antigen-binding domain that specifically binds to human TfR also comprises the CDRs of the antibody in Table 2 and Table 3 (e.g., the non-identical amino acids in the VH and/or VL are outside of the CDRs). [0286] In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises (i) a VH comprising an amino acid sequence that is at least 98% identical to a VH amino acid sequence of an antibody in Table 4 and (ii) a VL comprising an amino acid sequence that is at least 98% identical to the VL amino acid sequence of the same antibody in Table 4. In some embodiments, the antigen-binding domain that specifically binds to human TfR also comprises the CDRs of the antibody in Table 2 and Table 3 (e.g., the non-identical amino acids in the VH and/or VL are outside of the CDRs). [0287] In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises (i) a VH comprising an amino acid sequence that is at least 99% identical to a VH amino acid sequence of an antibody in Table 4 and (ii) a VL comprising an amino acid sequence that is at least 99% identical to the VL amino acid sequence of the same antibody in Tables 3 and 4. In some embodiments, the antigen-binding domain that specifically binds to human TfR also comprises the CDRs of the antibody in Table 2 and Table 3 (e.g., the non-identical amino acids in the VH and/or VL are outside of the CDRs). [0288] In some embodiments, provided herein is an antigen-binding domain that competitively inhibits binding to TfR of as an antibody comprising a VH amino acid sequence of an antibody in Table 4 and a VL amino acid sequence of the same antibody in Table 4. [0289] In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises a VH and a VL on a single polypeptide chain (e.g., a VH and VL in Table 4).^ny-2871899 735022004340 [0290] In some embodiments, the antigen-binding domain comprises an scFv. In some embodiments, an scFv comprises a VH and a VL of an antibody listed in Table 4. The scFv can comprise a VH that is N-terminal to a VL or a VL that is N-terminal to a VH. The scFv can comprise a linker, e.g., between a VH and a VL. Accordingly, the scFv can be in the orientation VH-linker-VL or VL-linker-VH. Such a linker can be about 5 to about 25 amino acids in length. Such a linker can be about 5 to about 20 amino acids in length. Such a linker can be about 10 to about 25 amino acids in length. Such a linker can be about 10 to about 20 amino acids in length. Such a linker can be, e.g., a glycine linker, a glycine-rich linker, or a glycine-serine linker. Such a linker can comprise the amino acid sequence of GGSEGKSSGSGSESKSTGGS (SEQ ID NO: 6). Such a linker can comprise the amino acid sequence of GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 7). [0291] In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises a VH on a first polypeptide and a VL on a second polypeptide (e.g., a Fab). The Fab comprises one constant domain, one VH, and one VL. In some embodiments, the antigen- binding domain comprises a Fab comprising a constant domain, a VH of an antibody listed in Table 4 and a VL of the same antibody in Table 4. In some embodiments, the antigen-binding domain that comprises a Fab comprises the CDRs of the antibody in Table 2 and Table 3 (e.g., the non-identical amino acids in the VH and/or VL are outside of the CDRs). [0292] In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises the antigen-binding fragment of a heavy chain only antibody (e.g., a VHH or nanobody). In some embodiments, an antigen-binding domain comprises a VHH comprising the VH of an antibody listed in Table 4. In other embodiments, the antigen-binding domain comprises a VHH comprises the heavy chain CDRs of an antibody listed in Table 2. [0293] In some embodiments, an antigen-binding domain that specifically binds to human TfR is a murine antigen-binding domain. In some embodiments, an antigen-binding domain that specifically binds to human TfR is a chimeric antigen-binding domain. In some embodiments, an antigen-binding domain that specifically binds to human TfR is a humanized antigen-binding domain. In some embodiments, an antigen-binding domain that specifically binds to human TfR is a human antigen-binding domain. [0294] In some embodiments, an antigen-binding domain provided herein that specifically binds to human TfR also binds to cynomolgus monkey TfR.^ny-2871899 735022004340 [0295] In some embodiments, an antigen-binding domain provided herein binds to human TfR with “low” affinity. In some embodiments, the antigen-binding domain binds human TfR with an affinity between 500 nM and 10 uM. In some embodiments, an antigen-binding domain provided herein specifically binds to human TfR with an affinity from about 751 nM to about 10,000 nM, such as about 751 nM to about 2,500 nM, about 751 nM to about 5,000 nM, about 2,500 nM to about 5,000 nM, about 2,500 nM to about 10,000 nM, about 5,000 nM to about 10,000 nM, and values and ranges therebetween. In some embodiments, the antigen-binding domain binds human TfR with an affinity between 2 μM and 5 μM. In some embodiments, the antigen-binding domain binds human TfR with an affinity between 1 μM and 5 μM. In some embodiments, the antigen-binding domain binds human TfR with an affinity between 2 μM and 8 μM. In some embodiments, the antigen-binding domain binds human TfR with an affinity between 750 nM and 2 μM. [0296] In some embodiments, an antigen-binding domain provided herein binds to human TfR with “medium” affinity. In some embodiments, the antigen-binding domain binds human TfR with an affinity between 10 nM and 500 nM. In some embodiments, an antigen-binding domain provided herein specifically binds to human TfR with an affinity from about 51 nM to about 750 nM, such as about 51 nM to about 100 nM, about 51 nM to about 250 nM, about 51 nM to about 500 nM, about 100 nM to about 250 nM, about 100 nM to about 500 nM, about 100 nM to about 750 nM, about 250 nM to about 500 nM, about 250 nM to about 750 nM, about 500 nM to about 750 nM, and values and ranges therebetween. In some embodiments, the antigen-binding domain binds human TfR with an affinity between 50 nM and 500 nM. In some embodiments, the antigen-binding domain binds human TfR with an affinity between 100 nM and 250 nM. In some embodiments, the antigen-binding domain binds human TfR with an affinity between 10 nM and 100 nM. In some embodiments, the antigen-binding domain binds human TfR with an affinity between 250 nM and 500 nM. [0297] In some embodiments, an antigen-binding domain provided herein binds to human TfR with “high” affinity. In some embodiments, the antigen-binding domain binds human TfR with an affinity less than 10 nM. In some embodiments, the antigen-binding domain binds human TfR with an affinity between 0.01 nM and 10 nM. In some embodiments, the antigen-binding domain provided herein specifically binds to human TfR with an affinity from about 0.01 nM to about 50 nM, such as about 0.01 nM to about 1 nM, about 0.01 nM to about 5 nM, about 0.01 nM to about^ny-2871899 735022004340 25 nM, about 1 nM to about 5 nM, about 1 nM to about 25 nM, about 1 nM to about 50 nM, about 5 nM to about 25 nM, about 5 nM to about 50 nM, about 10 nM to about 25 nM, about 10 nM to about 50 nM, about 25 nM to about 50 nM, and values and ranges therebetween. In some embodiments, the antigen-binding domain binds human TfR with an affinity between 0.1 nM and 10 nM. In some embodiments, the antigen-binding domain binds human TfR with an affinity between 0.01 nM and 1 nM. [0298] In some embodiments, the antigen binding domain binds provided herein binds to human TfR with an affinity of 150 nM to 700 nM. In some embodiments, the antigen-binding domain binds to human TfR with an affinity of 250 nM to 700 nM, 350 nM to 700 nM, 450 nM to 700 nM, or 550 nM to 700 nM. In some embodiments, the antigen-binding domain binds to human TfR with an affinity of 575 nM to 675 nM. In some embodiments, the antigen-binding domain binds to human TfR with an affinity of 600 nM to 650 nM. In some embodiments, the antigen-binding domain binds to human TfR with an affinity of 630 nM to 650 nM. In some embodiments, the antigen-binding domain binds to human TfR with an affinity of about 635 nM, about 636 nM, about 637 nM, about 638 nM, about 639 nM, about 640 nM, about 641 nM, about 642 nM, about 643 nM, about 644 nM or about 645 nM. In some embodiments, the antigen- binding domain binds to human TfR with an affinity of about 639 nM. In some embodiments, the antigen-binding domain binds to human TfR with an affinity of 639 nM. [0299] In some embodiments, the antigen binding domain binds provided herein binds to human TfR with an affinity of 150 nM to 700 nM. In some embodiments, the antigen-binding domain binds to human TfR with an affinity of 150 nM to 650 nM, 150 nM to 550 nM, 150 nM to 450 nM, 150 nM to 350 nM, or 150 nM to 250 nM. In some embodiments, the antigen-binding domain binds to human TfR with an affinity of 160 nM to 200 nM. In some embodiments, the antigen-binding domain binds to human TfR with an affinity of 170 nM to 190 nM. In some embodiments, the antigen-binding domain binds to human TfR with an affinity of 175 nM to 185 nM. In some embodiments, the antigen-binding domain binds to human TfR with an affinity of about 175 nM, about 176 nM, about 177 nM, about 178 nM, about 179 nM, about 180 nM, about 181 nM, about 182 nM, about 183 nM, or about 184 nM. In some embodiments, the antigen- binding domain binds to human TfR with an affinity of about 182 nM. In some embodiments, the antigen-binding domain binds to human TfR with an affinity of 182 nM.^ny-2871899 735022004340 [0300] In some embodiments, an antigen-binding domain provided herein specifically binds to human TfR with an affinity measured using surface plasmon resonance, such as a BIACORE™ SPR system. In some embodiments, the affinity between the antigen-binding domain and TfR is measured using the Carterra LSA platform. In some embodiments, an antigen-binding domain provided herein that specifically binds to human TfR binds to human TfR as measured by, for example, radioimmunoassay (RIA), Western blot, or ELISA OD₄₅₀. [0301] In some embodiments, binding of an antigen-binding domain provided herein to human TfR is measured using surface plasmon resonance. In some embodiments, affinity measured using the Carterra LSA platform. [0302] In some embodiments, an antigen-binding domain provided herein that specifically binds to human TfR reduces cell surface expression by more than 40%, 60%, or 80% relative to cell surface expression of TfR on HCMEC/D3 cells treated with an isotype control. Cell surface expression can be measured, e.g., using Western blot or FACS. [0303] In some embodiments, an antigen-binding domain provided herein that specifically binds to human TfR does not significantly increase cell surface expression of TfR on HCMED/D3 cells relative to cell surface expression of TfR on HCMEC/D3 cells treated with an isotype control. Cell surface expression can be measured, e.g., using Western blot or FACS. [0304] In some embodiments, an antigen-binding domain provided herein that specifically binds to human TfR does not significantly increase cell surface expression of TfR on HCMED/D3 cells relative to cell surface expression of TfR on HCMEC/D3 cells treated with an isotype control. Cell surface expression can be measured, e.g., using Western blot or FACS. [0305] In some embodiments, an antigen-binding domain provided herein that specifically binds to human TfR accumulates at least 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40 or 50-fold more than an isotype control after peripheral injection. In some embodiments, an antigen-binding domain provided herein that specifically binds to human TfR at least 5-fold more than binding to an irrelevant protein and/or specifically binds to cynomolgus TfR at least 5-fold more than binding to an irrelevant protein. [0306] Also provided herein are antigen-binding domains that bind to the same epitope of TfR as a TfR antigen-binding domain provided herein. Also provided herein are antigen-binding domains that competitively inhibit binding to TfR of a TfR antigen-binding domain provided herein.^ny-2871899 735022004340 [0307] As provided herein, antigen-binding domains provided herein are capable of crossing the BBB. In some embodiments, antigen-binding domains provided herein are internalized in blood-brain barrier epithelial cells greater than 5-fold, or 10-fold, as compared to internalization by an isotype control. The blood-brain barrier endothelial cells can be, e.g., HCMEC/D3 cells. [0308] In some embodiments, antigen-binding domains provided herein do not reduce cell- surface expression of TfR on HCMEC/D3 cells by more than 20%, 40%, or 60% relative to cell- surface expression of TfR on HCMEC/D3 cells treated with an isotype control. Cell surface expression can be measured, e.g., using Western blot or FACS. In some embodiments, antigen- binding domains provided herein do not significantly increase cell-surface expression of TfR on HCMEC/D3 cells relative to cell-surface expression of TfR on HCMEC/D3 cells treated with an isotype control. Cell surface expression can be measured, e.g., using Western blot or FACS. [0309] In some embodiments, antigen-binding domains provided herein accumulate at least 4- fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 40-fold or 50-fold or more than an isotype control in vessel-depleted mouse brain. Table 2: Heavy Chain CDR Sequences of Anti-TfR Antibodies^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340 Table 3: Light Chain CDR Sequences of Anti-TfR Antibodies^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340 Table 4: VH and VL Sequences of Anti-TfR Antibodies^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340 B. Antigen-Binding Domains That Bind to CD98hc [0310] In some embodiments, the antigen-binding domain specifically bind to human CD98hc. The anti-CD98hc antigen-binding domain is capable of crossing the blood brain barrier (BBB) and thus transporting the PGRN polypeptide linked to the antigen-binding domain across the BBB. Accordingly, in some embodiments, provided herein are complexes comprising an antigen-binding domain linked to a PGRN polypeptide, wherein the antigen-binding domain specifically binds to human CD98hc and is capable of being internalized in BBB epithelial cells. [0311] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises the six CDRs of an antibody listed in Table 5 and Table 6 (i.e. the three VH CDRs of the antibody listed in Table 5 and the three VL CDRs of the same antibody listed in Table 6). In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises the six CDRs of an antibody listed in Table 5 and Table 6 as determined by Kabat numbering. In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises the six Chothia CDRs of an antibody listed in Table 5 and Table 6. [0312] In some embodiments, the CDRs of an antigen-binding domain that specifically binds to human CD98hc can be determined according to MacCallum RM et al., (1996) J Mol Biol 262: 732-745. See also, e.g., Martin A. “Protein Sequence and Structure Analysis of Antibody Variable Domains,” in Antibody Engineering, Kontermann and Dübel, eds., Chapter 31, pp.422- 439, Springer-Verlag, Berlin (2001). In some embodiments, provided herein are antigen-binding domains that specifically bind to human CD98hc and comprise VH and VL CDRs of an antibody listed in Table 5 and Table 6 as determined by the method in MacCallum RM et al. [0313] In some embodiments, the CDRs of an antigen-binding domain that specifically binds to human CD98hc can be determined according to the AbM numbering scheme (as described above). In some embodiments, provided herein are antigen-binding domains that specifically bind to human CD98hc and comprise VH and VL CDRs of an antibody listed in Table 5 and Table 6 as determined by the AbM numbering scheme. [0314] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises the six IMGT CDRs of an antibody listed in Table 5 and Table 6 according to the IMGT numbering system as described above.^ny-2871899 735022004340 [0315] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc provided herein is described by its VL domain alone, or its VH domain alone, or by its 3 VL CDRs alone, or its 3 VH CDRs alone. [0316] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises the VH of an antibody listed in Table 7. [0317] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises the VL of antibody listed in Table 7. [0318] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises the VH and the VL of an antibody listed in Table 7 (i.e., the VH of the antibody listed in Table 7 and the VL of the same antibody listed in Table 7. [0319] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises (i) a VH comprising an amino acid sequence that is at least 80% identical to a VH amino acid sequence of an antibody in Table 7 and (ii) a VL comprising an amino acid sequence that is at least 80% identical to the VL amino acid sequence of the same antibody in Table 7. In some embodiments, the antigen-binding domain that specifically binds to human CD98hc also comprises the CDRs of the antibody in Table 5 and Table 6 (e.g., the non- identical amino acids in the VH and/or VL are outside of the CDRs). In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises (i) a VH comprising an amino acid sequence that is at least 85% identical to a VH amino acid sequence of an antibody in Table 7 and (ii) a VL comprising an amino acid sequence that is at least 85% identical to the VL amino acid sequence of the same antibody in Table 7. [0320] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises (i) a VH comprising an amino acid sequence that is at least 90% identical to a VH amino acid sequence of an antibody in Table 7 and (ii) a VL comprising an amino acid sequence that is at least 90% identical to the VL amino acid sequence of the same antibody in Table 7. In some embodiments, the antigen-binding domain that specifically binds to human CD98hc also comprises the CDRs of the antibody in Table 5 and Table 6 (e.g., the non- identical amino acids in the VH and/or VL are outside of the CDRs). [0321] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises (i) a VH comprising an amino acid sequence that is at least 95% identical to a VH amino acid sequence of an antibody in Table 7 and (ii) a VL comprising an amino acid^ny-2871899 735022004340 sequence that is at least 95% identical to the VL amino acid sequence of the same antibody in Table 7. In some embodiments, the antigen-binding domain that specifically binds to human CD98hc also comprises the CDRs of the antibody in Table 5 and Table 6 (e.g., the non- identical amino acids in the VH and/or VL are outside of the CDRs). [0322] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises (i) a VH comprising an amino acid sequence that is at least 96% identical to a VH amino acid sequence of an antibody in Table 7 and (ii) a VL comprising an amino acid sequence that is at least 96% identical to the VL amino acid sequence of the same antibody in Table 7. In some embodiments, the antigen-binding domain that specifically binds to human CD98hc also comprises the CDRs of the antibody in Table 5 and Table 6 (e.g., the non- identical amino acids in the VH and/or VL are outside of the CDRs). [0323] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises (i) a VH comprising an amino acid sequence that is at least 97% identical to a VH amino acid sequence of an antibody in Table 7 and (ii) a VL comprising an amino acid sequence that is at least 97% identical to the VL amino acid sequence of the same antibody in Table 7. In some embodiments, the antigen-binding domain that specifically binds to human CD98hc also comprises the CDRs of the antibody in Table 5 and Table 6 (e.g., the non- identical amino acids in the VH and/or VL are outside of the CDRs). [0324] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises (i) a VH comprising an amino acid sequence that is at least 98% identical to a VH amino acid sequence of an antibody in Table 7 and (ii) a VL comprising an amino acid sequence that is at least 98% identical to the VL amino acid sequence of the same antibody in Table 7. In some embodiments, the antigen-binding domain that specifically binds to human CD98hc also comprises the CDRs of the antibody in Table 5 and Table 6 (e.g., the non- identical amino acids in the VH and/or VL are outside of the CDRs). [0325] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises (i) a VH comprising an amino acid sequence that is at least 99% identical to a VH amino acid sequence of an antibody in Table 7 and (ii) a VL comprising an amino acid sequence that is at least 99% identical to the VL amino acid sequence of the same antibody in Table 7. In some embodiments, the antigen-binding domain that specifically binds to human^ny-2871899 735022004340 CD98hc also comprises the CDRs of the antibody in Table 5 and Table 6 (e.g., the non- identical amino acids in the VH and/or VL are outside of the CDRs). [0326] In some embodiments, provided herein is an antigen-binding domain that competitively inhibits binding to CD98hc of as an antibody comprising a VH amino acid sequence of an antibody in Table 7 and a VL amino acid sequence of the same antibody in Table 7. [0327] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises a VH and a VL on a single polypeptide chain (e.g., a VH and VL in Table 7). In some embodiments, the antigen-binding domain comprises an scFv. The scFv can comprise a VH that is N-terminal to a VL or a VL that is N-terminal to a VH. The scFv can comprise a linker, e.g., between a VH and a VL. Accordingly, the scFv can be in the orientation VH-linker- VL or VL-linker-VH. Such a linker can be about 5 to about 25 amino acids in length. Such a linker can be about 5 to about 20 amino acids in length. Such a linker can be about 10 to about 25 amino acids in length. Such a linker can be about 10 to about 20 amino acids in length. Such a linker can be, e.g., a glycine linker, a glycine-rich linker, or a glycine-serine linker. Such a linker can comprise the amino acid sequence of GGSEGKSSGSGSESKSTGGS (SEQ ID NO: 6). Such a linker can comprise the amino acid sequence of GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 7). [0328] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises a VH on a first polypeptide and a VL on a second polypeptide (e.g., a Fab). [0329] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises the antigen-binding fragment of a heavy chain only antibody (e.g., a VHH or nanobody). [0330] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc is a murine antigen-binding domain. In some embodiments, an antigen-binding domain that specifically binds to human CD98hc is a chimeric antigen-binding domain. In some embodiments, an antigen-binding domain that specifically binds to human CD98hc is a humanized antigen-binding domain. In some embodiments, an antigen-binding domain that specifically binds to human CD98hc is a human antigen-binding domain. [0331] In some embodiments, an antigen-binding domain provided herein that specifically binds to human CD98hc also binds to cynomolgus monkey CD98hc.^ny-2871899 735022004340 [0332] In some embodiments, an antigen-binding domain provided herein binds to human CD98hc with “low” affinity. In some embodiments, the antigen-binding domain binds human CD98hc with an affinity between about 500 nM and about 10 uM, such as about 500 nM to about 2.5 μM, about 500 nM to about 5 μM, about 1 μM to about 2.5 μM, about 1 μM to about 5 μM, about 1 μM to about 10 μM, about 2.5 μM to about 5 μM, about 2.5 μM to about 10 μM, about 5 μM to about 10 μM, and values and ranges therebetween. In some embodiments, the antigen-binding domain binds human CD98hc with an affinity between 2 μM and 5 μM. In some embodiments, the antigen-binding domain binds human CD98hc with an affinity between 1 μM and 5 μM. In some embodiments, the antigen-binding domain binds human CD98hc with an affinity between 2 μM and 8 μM. In some embodiments, the antigen-binding domain binds human CD98hc with an affinity between 750 nM and 2 μM. [0333] In some embodiments, an antigen-binding domain provided herein binds to human CD98hc with “medium” affinity. In some embodiments, the antigen-binding domain binds human CD98hc with an affinity between about 100 nM and about 500 nM, such as about 100 nM to about 250 nM, about 250 nM to about 500 nM, and values and ranges therebetween. In some aspects, the antigen-binding domain binds human CD98hc with an affinity between about 200 nM and about 300 nM. In some embodiments, the antigen-binding domain binds human CD98hc with an affinity between 50 nM and 500 nM. In some embodiments, the antigen-binding domain binds human CD98hc with an affinity between 100 nM and 250 nM. In some embodiments, the antigen-binding domain binds human CD98hc with an affinity between 10 nM and 100 nM. In some embodiments, the antigen-binding domain binds human CD98hc with an affinity between 250 nM and 500 nM. [0334] In some embodiments, an antigen-binding domain provided herein binds to human CD98hc with “high” affinity. In some embodiments, the antigen-binding domain binds human CD98hc with an affinity less than about 100 nM, such as less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM. In some embodiments, the antigen-binding domain binds human CD98hc with an affinity between about 0.1 nM to about 100 nM, such as about 0.1 nM to about 10 nM, about 0.1 nM to about 25 nM, about 1 nM to about 25 nM, about 1 nM to about 50 nM, about 25 nM to about 50 nM, about 25 nM to about 100 nM, about 50 nM to about 100 nM, and values and ranges therebetween. In some^ny-2871899 735022004340 embodiments, the antigen-binding domain binds human CD98hc with an affinity between 0.01 nM and 10 nM. In some embodiments, the antigen-binding domain binds human CD98hc with an affinity between 0.1 nM and 10 nM. In some embodiments, the antigen-binding domain binds human CD98hc with an affinity between 0.01 nM and 1 nM. [0335] In some embodiments, an antigen-binding domain provided herein that specifically binds to human CD98hc binds to human CD98hc is measured using surface plasmon resonance. In some embodiments, affinity is measured using the Carterra LSA platform. In some embodiments, an antigen-binding domain provided herein that specifically binds to human CD98hc binds to human CD98hc as measured by, for example, radioimmunoassay (RIA), Western blot, or ELISA OD450. [0336] In some embodiments, an antigen-binding domain provided herein that specifically binds to human CD98hc does not reduce cell surface expression of CD98hc on HCMED/D3 cells by more than 20% relative to cell surface expression of CD98hc on HCMEC/D3 cells treated with an isotype control. Cell surface expression can be measured, e.g., using Western blot or FACS. [0337] In some embodiments, an antigen-binding domain provided herein that specifically binds to human CD98hc does not increase cell surface expression of CD98hc on HCMED/D3 cells by more than 50% relative to cell surface expression of CD98hc on HCMEC/D3 cells treated with an isotype control. Cell surface expression can be measured, e.g., using Western blot or FACS. [0338] In some embodiments, an antigen-binding domain provided herein that specifically binds to human CD98hc does not reduce cell surface expression of CD98hc on HCMED/D3 cells by more than 20% relative to cell surface expression of CD98hc on HCMEC/D3 cells treated with an isotype control and does not increase cell surface expression of CD98hc on HCMED/D3 cells by more than 50% relative to cell surface expression of CD98hc on HCMEC/D3 cells treated with an isotype control. Cell surface expression can be measured, e.g., using Western Blot or FACS. [0339] In some embodiments, an antigen-binding domain provided herein that specifically binds to human CD98hc accumulates at least 1.5-fold more than an isotype control in vessel- depleted human CD98hc knock-in mouse brain after peripheral injection. In some embodiments,^ny-2871899 735022004340 an antigen-binding domain provided herein that specifically binds to human CD98hc accumulates at least 1-fold more than an isotype control in vessel-depleted mouse brain. [0340] In some embodiments, an antigen-binding domain provided herein that specifically binds to human CD98hc has at least a 5-fold increase in brain:serum concentration ratio over an isotype control 24 hours after administration to a mouse. [0341] Also provided herein are antigen-binding domains that bind to the same epitope of CD98hc as a CD98hc antigen-binding domain provided herein. Also provided herein are antigen-binding domains that competitively inhibit binding to CD98hc of CD98hc antigen- binding domain provided herein. Table 5: Heavy Chain CDR Sequences of Anti-CD98hc Antibodies^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340 Table 6: Light Chain CDR Sequences of Anti-CD98hc Antibodies^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340 Table 7: VH and VL Sequences of Anti-CD98hc Antibodies^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340 IV. Antigen-Binding Domains and Compositions Comprising Antigen-Binding Domains [0342] In some aspects, provided herein are complexes, and compositions thereof, comprising an antigen-binding domain linked to a Progranulin (PGRN) polypeptide. The antigen-binding domain can bind specifically to human transferrin receptor (TfR) or human CD98 heavy chain (CD98hc) to facilitate the transport of the PGRN polypeptide across the blood brain barrier (BBB). [0343] In some embodiments, the antigen-binding domain is an antigen-binding fragment. Antigen-binding fragments of antibodies include, but are not limited to, Fab, Fab’, Fab’-SH, F(ab’)2, Fv, and scFv fragments, and other fragments described below. For a review of certain antibody fragments, see Hudson et al. Nat. Med.9:129-134 (2003). For a review of scFv^ny-2871899 735022004340 fragments, see, e.g., WO 93/16185; and U.S. Patent Nos.5,571,894 and 5,587,458. For discussion of Fab and F(ab’)2 fragments comprising salvage receptor binding epitope residues and having increased in vivo half-life, see U.S. Patent No.5,869,046. [0344] Diabodies are antibody fragments with two antigen-binding sites that can be bivalent and/or bispecific. See, for example, EP404097; WO 1993/01161; Hudson et al. Nat. Med.9:129- 134 (2003). Triabodies and tetrabodies are also described in Hudson et al. Nat. Med.9:129-134 (2003). Single-domain antibodies are antibody fragments comprising all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody. In some embodiments, a single-domain antibody is a human single-domain antibody (see, e.g., U.S. Patent No.6,248,516). [0345] Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells (e.g., E. coli or phage), as described herein. [0346] In some embodiments, the antigen-binding domain is chimeric. Certain chimeric antibodies are described, e.g., in U.S. Patent No.4,816,567. In one example, a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate, such as a monkey) and a human constant region. In a further example, a chimeric antibody is a “class switched” antibody in which the class or subclass has been changed from that of the parent antibody. [0347] In some embodiments, the antigen-binding domain is humanized. Typically, a non- human antibody is humanized to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody. In some embodiments, a humanized antibody is substantially non-immunogenic in humans. In some embodiments, a humanized antibody has substantially the same affinity for a target as an antibody from another species from which the humanized antibody is derived. See, e.g., U.S. Pat. No. 5,530,101; 5,693,761; 5,693,762; and 5,585,089. In some embodiments, amino acids of an antibody variable domain that can be modified without diminishing the native affinity of the antigen-binding domain while reducing its immunogenicity are identified. See, e.g., U.S. Pat. Nos. 5,766,886 and 5,869,619. Generally, a humanized antibody comprises one or more variable domains in which CDRs (or portions thereof) are derived from a non-human antibody, and framework regions (FRs) (or portions thereof) are derived from human antibody sequences. A humanized antibody can^ny-2871899 735022004340 comprise at least a portion of a human constant region. In some embodiments, some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the CDR residues are derived), for example, to restore or improve antibody specificity or affinity. [0348] Humanized antibodies and methods of making them are reviewed, for example, in Almagro et al. Front. Biosci.13:1619-1633 (2008), and are further described, e.g., in U.S. Patent Nos.5,821,337; 7,527,791; 6,982,321; and 7087409. Human framework regions that can be used for humanization include but are not limited to: framework regions selected using the “best- fit” method (see, e.g., Sims et al. J. Immunol.151:2296 (1993)); framework regions derived from the consensus sequence of human antibodies of a particular subgroup of light or heavy chain variable regions (see, e.g., Carter et al. Proc. Natl. Acad. Sci. USA 89:4285 (1992); and Presta et al., J. Immunol.151 :2623 (1993)); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson Front. Biosci. 13:1619-1633 (2008)); and framework regions derived from screening FR libraries (see, e.g., Baca et al. J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al. J. Biol. Chem. 271:22611-22618 (1996)). [0349] In some embodiments, the antigen-binding domain is human. Human antibodies can be produced using various techniques known in the art. Human antibodies are described generally in van Dijk et al. Curr. Opin. Pharmacol.5:368-74 (2001) and Lonberg Curr. Opin. Immunol. 20:450-459 (2008). [0350] Human antibodies can be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge. One can engineer mouse strains deficient in mouse antibody production with large fragments of the human Ig loci in anticipation that such mice would produce human antibodies in the absence of mouse antibodies. Large human Ig fragments can preserve the large variable gene diversity as well as the proper regulation of antibody production and expression. By exploiting the mouse machinery for antibody diversification and selection and the lack of immunological tolerance to human proteins, the reproduced human antibody repertoire in these mouse strains can yield high affinity fully human antibodies against any antigen of interest, including human antigens. Using the hybridoma technology, antigen-specific human Mabs with the desired specificity can be^ny-2871899 735022004340 produced and selected. Certain exemplary methods are described in U.S. Pat. No.5,545,807, EP546073, and EP546073. See also, for example, U.S. Patent Nos.6,075,181 and 6,150,584 describing XENOMOUSE™ technology; U.S. Patent No.5,770,429 describing HUMAB® technology; U.S. Patent No.7,041,870 describing K-M MOUSE® technology, and U.S. Patent Application Publication No. US 2007/0061900, describing VELOCIMOUSE® technology. Human variable regions from intact antibodies generated by such animals can be further modified, e.g., by combining with a different human constant region. [0351] Human antibodies can also be made by hybridoma-based methods. Human myeloma and mouse-human heteromyeloma cell lines for the production of human monoclonal antibodies have been described. (See, e.g., Kozbor J. Immunol. 133:3001 (1984) and Boerner et al. J. Immunol. 147:86 (1991)). Human antibodies generated via human B-cell hybridoma technology are also described in Li et al. Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006). Additional methods include those described, for example, in U.S. Patent No.7,189,826 (describing production of monoclonal human IgM antibodies from hybridoma cell lines). Human hybridoma technology (Trioma technology) is also described in Vollmers et al. Histology and Histopathology 20(3) :927-937 (2005) and Vollmers et al. Methods and Findings in Experimental and Clinical Pharmacology 27(3):185-91 (2005). Human antibodies can also be generated by isolating Fv clone variable domain sequences selected from human-derived phage display libraries. Such variable domain sequences can then be combined with a desired human constant domain. Techniques for selecting human antibodies from antibody libraries are described below. [0352] In some embodiments, the antigen-binding domain is an antibody, wherein the antibody is a human antibody isolated by in vitro methods and/or screening combinatorial libraries for antibodies with the desired activity or activities. Suitable examples include but are not limited to phage display (CAT, Morphosys, Dyax, Biosite/Medarex, Xoma, Symphogen, Alexion (formerly Proliferon), Affimed) ribosome display (CAT), yeast display (Adimab), and the like. In certain phage display methods, repertoires of VH and VL genes are separately cloned by polymerase chain reaction (PCR) and recombined randomly in phage libraries, which can then be screened for antigen-binding phage as described in Winter et al. Ann. Rev. Immunol.12: 433-455 (1994). For example, a variety of methods are known in the art for generating phage display libraries and screening such libraries for antibodies possessing the desired binding characteristics. See also^ny-2871899 735022004340 Sidhu et al. J. Mol. Biol. 338(2): 299-310, 2004; Lee et al. J. Mol. Biol. 340(5): 1073-1093, 2004; Fellouse Proc. Natl. Acad. Sci. USA 101(34):12467-12472 (2004); and Lee et al. J. Immunol. Methods 284( -2):119-132 (2004). Phage typically display antibody fragments, either as single-chain Fv (scFv) fragments or as Fab fragments. Libraries from immunized sources provide high-affinity antibodies to the immunogen without the requirement of constructing hybridomas. Alternatively, the naive repertoire can be cloned (e.g., from human) to provide a single source of antibodies to a wide range of non-self and also self-antigens without any immunization as described by Griffiths et al. EMBO J.12: 725-734 (1993). Finally, naive libraries can also be made synthetically by cloning unrearranged V-gene segments from stem cells, and using PCR primers comprising random sequence to encode the highly variable CDR3 regions and to accomplish rearrangement in vitro, as described by Hoogenboom et al. J. Mol. Biol., 227: 381-388, 1992. Patent publications describing human antibody phage libraries include, for example: U.S. Patent No.5,750,373, and U.S. Patent Publication Nos.2007/0292936 and 2009/0002360. Antibodies isolated from human antibody libraries are considered human antibodies or human antibody fragments herein. V. Fc Domains [0353] In some embodiments, a complex provided herein comprises an Fc domain or fragment thereof. In some embodiments, an Fc domain is of IgG class, the IgM class, or the IgA class. In some embodiments, an Fc domain or fragment thereof is an IgG Fc domain or fragment thereof. In some embodiments, an Fc domain or fragment thereof is a human IgG Fc domain or fragment thereof. In some embodiments, an Fc domain or fragment thereof is a human IgG1 Fc domain or fragment thereof. In some embodiments, an Fc domain or fragment thereof is a human IgG2 Fc domain or fragment thereof. In some embodiments, an Fc domain or fragment thereof is a human IgG4 Fc domain or fragment thereof. In some embodiments, an Fc domain or fragment thereof is a monovalent Fc. In some embodiments, the Fc domain or fragment thereof is a modified Fc domain or fragment thereof comprising one or more modifications relative to the corresponding wild-type Fc domain. In some embodiments, the one or more modifications reduce effector function. [0354] In some embodiments, the Fc domain is a modified Fc domain or fragment thereof. In some embodiments, the modified Fc domain or fragment thereof is a modified IgG1 Fc comprising one or more modifications. For example, in some embodiments, the IgG1 modified^ny-2871899 735022004340 Fc comprises one or more amino acid substitutions (e.g., relative to a wild-type Fc domain of the same isotype). In some embodiments, the modified Fc domain or fragment thereof is a modified IgG2 Fc domain. In some embodiments, the modified Fc domain or fragment thereof is a modified IgG2 Fc domain comprising one or more modifications relative to a wild-type IgG2, such as one or more modifications that reduce effector function. In some embodiments, the modified Fc domain or fragment thereof is a modified IgG4 Fc domain relative to a wild-type IgG4. In some embodiments, the modified Fc domain or fragment thereof is a modified IgG4 Fc domain comprising one or more modifications relative to a wild-type IgG4, such as one or more modifications that reduce effector function. In some embodiments, the modified Fc domain or fragment thereof is a modified IgG4 Fc domain comprising one or more amino acid substitutions selected from IgG4-S228P or IgG4-S228P/L235E, wherein the amino acid position is according to the EU numbering convention. In some embodiments, the one or more amino acid substitutions are selected from N297A (Bolt S et al. (1993) Eur J Immunol 23:403-411), D265A (Shields et al. (2001) R. J. Biol. Chem.276, 6591–6604), L234A, L235A (Hutchins et al. (1995) Proc Natl Acad Sci USA, 92:11980-11984; Alegre et al., (1994) Transplantation 57:1537-1543. 31; Xu et al., (2000) Cell Immunol, 200:16-26), G237A (Alegre et al. (1994) Transplantation 57:1537-1543.31; Xu et al. (2000) Cell Immunol, 200:16-26), C226S, C229S, E233P, L234V, L234F, L235E (McEarchern et al., (2007) Blood, 109:1185-1192), P331S (Sazinsky et al., (2008) Proc Natl Acad Sci USA 2008, 105:20167-20172), K322A (Hezareh et al. (2001) J Virol. 75(24) 12161-12168), S267E, L328F, A330L, M252Y, S254T, E430G, and/or T256E, where the amino acid position is according to the EU numbering convention. In some embodiments, the Fc domain comprises the amino acid substitutions L234A, L235A, and P331S (LALAPS) according to EU numbering. In some embodiments, the Fc domain comprises N325S and L328F mutations according to EU numbering. In some embodiments, the Fc domain comprises L234A, L235A, and P329G mutations according to EU numbering. In some embodiments, the Fc domain comprises L234A, L235A, and P329S mutations according to EU numbering. In some embodiments, the Fc domain comprises K322A according to EU numbering. In some embodiments, the Fc domain comprises S228P according to EU numbering. In some embodiments, the Fc domain comprises L235E according to EU numbering. In some embodiments, the Fc domain comprises S228P and L235E according to EU numbering. In some^ny-2871899 735022004340 embodiments, the modified Fc domain or fragment thereof is a modified IgG4 and comprises S228P and L235E according to EU numbering. [0355] Any suitable Fc domain or fragment thereof is contemplated in the multi-specific proteins described herein, and exemplary Fc domains are provided in Table 8 below. Table 8: Exemplary Fc Domains^ny-2871899 735022004340^ny-2871899 735022004340 [0356] In some embodiments provided herein, a complex provided herein comprises one or more mutations to promote heterodimerization of Fc domains. In some embodiments, a dimerized Fc domain of a bispecific provided herein is formed by Fc domains that contain amino acid mutations, substitutions, additions, or deletions to promote heterodimerization in which different polypeptides comprising different Fc domains can dimerize to yield a heterodimer configuration. In some embodiments, a bispecific of the present disclosure comprises a first Fc sequence comprising a first CH3 region, and a second Fc sequence comprising a second CH3 region, wherein the sequences of the first and second CH3 regions are different and are such that the heterodimeric interaction between said first and second CH3 regions is stronger than each of the homodimeric interactions of said first and second CH3 regions. [0357] Methods to promote heterodimerization of Fc domains include amino acid deletions, additions, or substitutions of the amino acid sequence of the Fc domain, such as by including a set of “knob-into-hole” deletions, additions, or substitutions or including amino acid deletions, additions, or substitutions to effect electrostatic steering of the Fc to favor attractive interactions among different polypeptide chains. Methods for promoting heterodimerization of complementary Fc polypeptides have been previously described in, for example, Ridgway et al, 1996, Protein Eng, 9:617-621; Merchant et al, 1998, Nature Biotechnol, 16:677-681; Moore et al, 2011, MAbs, 3:546-557; Von Kreudenstein et al, 2013, 5:646-654; Gunasekaran et al, 2010, J Biol Chem, 285:19637-19464; Leaver-Fay et al, 2016, Structure, 24:641-651; Ha et al, 2016, Frontiers in Immunology, 7:1; Davis et al, 2010, Protein Eng Des Sel, 23:195-202; PCT Pub. Nos. WO1996/027011; WO1998/050431; WO2006/028936; WO2009/089004; WO2011/143545; WO2014/067011; WO2012/058768; WO2018/027025; US Pub. Nos. US2014/0363426; US2015/0307628; US2018/0016354; US2015/0239991; US2017/0058054; U.S. Pat. Nos.5,731,168; 7,183,076; 9,701,759; 9,605,084; 9,650,446; 8,216,805; 8,765,412; and 8,258,268. [0358] In some embodiments, complementary Fc polypeptides of an Fc heterodimer include a mutation to alter charge polarity across the Fc dimer interface such that co-expression of electrostatically matched Fc domains support favorable attractive interactions, thereby promoting desired Fc heterodimer formation; whereas unfavorable repulsive charge interactions suppress unwanted Fc homodimer formation (Guneskaran et al, 2010, J Biol Chem, 285:19637-19646).^ny-2871899 735022004340 When co-expressed in a cell, association between the polypeptide chains is possible but the chains do not substantially self-associate due to charge repulsion. [0359] “Knob-hole” or “knob-into-hole” configurations are complementary Fc polypeptides of an Fc heterodimer that promote heterodimerization of two Fc polypeptides. “Knob-into-hole” technology is described in U.S. Pat. Nos.5,731,168; 7,695,936; 8,216,805; 8,765,412; Ridgway et al., Prot Eng 9, 617-621 (1996); and Carter, J Immunol Meth 248, 7-15 (2001). Generally, the method involves introducing a protuberance (“knob”) at the interface of a first polypeptide and a corresponding cavity (“hole”) in the interface of a second polypeptide, such that the protuberance can be positioned in the cavity so as to promote heterodimer formation and hinder homodimer formation. Protuberances are constructed by replacing small amino acid side chains from the interface of the first polypeptide with larger side chains (e.g., tyrosine or tryptophan). Compensatory cavities of identical or similar size to the protuberances are created in the interface of the second polypeptide by replacing large amino acid side chains with smaller ones (e.g., alanine or threonine). The protuberance and cavity can be made by altering the nucleic acid encoding the polypeptides, e.g., by site-specific mutagenesis, or by peptide synthesis. [0360] In some embodiments, a complex provided herein comprises an Fc dimer comprising a “knob” mutation in one Fc domain and a “hole” mutation in the other Fc domain. In some embodiments, the “knob” mutation comprises the amino acid substitution T366W according to EU numbering. In some embodiments, the “hole” mutation comprises the amino acids substitutions T366S, L368A, and Y407V according to EU numbering. In some embodiments, the “knob” mutation comprises the amino acid substitution T366W in one of the two subunits of the Fc dimer, and the “hole” mutation comprises the amino acid substitutions T366S, L368A and Y407V in the other subunit of the Fc dimer. In some embodiments, the subunit of the Fc dimer comprising the “knob” mutation additionally comprises the amino acid substitution S354C, and the subunit of the Fc dimer comprising the “hole” mutation additionally comprises the amino acid substitution Y349C. Introduction of these two cysteine residues results in the formation of a disulfide bridge between the two subunits of the Fc dimer, thus further stabilizing the dimer (Carter, J Immunol Methods 248, 7-15 (2001)). Thus, in such configurations, a first Fc polypeptide comprises amino acid modifications to form the “knob” and a second Fc polypeptide comprises amino acid modifications to form the “hole” thus forming an Fc heterodimer comprising complementary Fc polypeptides.^ny-2871899 735022004340 [0361] Exemplary paired amino acid modifications of complementary Fc polypeptides of an Fc heterodimeric configuration are set forth below in Table 9 (EU numbering). Table 9: Exemplary paired Fc modifications for heterodimeric Fc domains VI. Complexes that Bind to Blood-Brain Barrier Receptors or Proteins [0362] Provided herein are complexes, and compositions thereof, comprising an antigen- binding domain linked to a PGRN polypeptide. The antigen-binding domain can bind specifically to human transferrin receptor (TfR) or human CD98 heavy chain (CD98hc) to facilitate the transport of the PGRN polypeptide across the blood brain barrier (BBB). A. Complexes Comprising Anti-TfR Antigen-Binding Domains [0363] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a Progranulin (PGRN) polypeptide, wherein the antigen-binding domain specifically binds to human transferrin receptor (TfR). In some embodiments, the PGRN polypeptide is a PGRN mutant polypeptide. In some embodiments, the PGRN polypeptide comprises a C- terminal amino acid sequence defined by X₁X₂X₃X₄, wherein X₁ is any amino acid, and wherein X2, X3, and X4 are not PIL, PFL, PPL, PYL, QRL or QHL.^ny-2871899 735022004340 [0364] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a Progranulin (PGRN) polypeptide, wherein the antigen-binding domain specifically binds to human transferrin receptor (TfR), wherein the antigen-binding domain comprises a heavy chain variable region (VH) comprising a VH CDR1, VH CDR2, and VH CDR3 and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3, and wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 15, 25, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 50, 58, and 62, respectively; (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 341, 55, and 61, respectively. [0365] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a PGRN polypeptide, wherein the antigen-binding domain specifically binds to human TfR, and wherein the antigen-binding domain is a VHH comprising: (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 8, 14, and 25, respectively; (ii) SEQ ID NOs: 8, 15, and 25, respectively; (iv) SEQ ID NOs: 10, 22, and 333, respectively; (v) SEQ ID NOs: 10, 22, and 28, respectively; (ix) SEQ ID NOs: 10, 22, and 334, respectively; or (x) SEQ ID NOs: 10, 22, and 30, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 101, 102, 342, 117, 343, or 118. [0366] In some aspects, provided herein is a complex comprising: (a) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a PGRN polypeptide; (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2 and a CH3; and (c) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 15,^ny-2871899 735022004340 25, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 50, 58, and 62, respectively; (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 341, 55, and 61, respectively. [0367] In some aspects, provided herein is a complex comprising: (a) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, and a CH3; (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a PGRN polypeptide; and (c) a third polypeptide comprising, from the N- terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 15, 25, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 50, 58, and 62, respectively; (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 341, 55, and 61, respectively. [0368] In some aspects, provided herein is a complex comprising: (a) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a PGRN polypeptide; (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a PGRN polypeptide; and (c) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61,^ny-2871899 735022004340 respectively; (ii) SEQ ID NOs: 8, 15, 25, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 50, 58, and 62, respectively; (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 341, 55, and 61, respectively. [0369] In some aspects, provided herein is a complex comprising: (a) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a PGRN polypeptide; and (b) a second polypeptide comprising, from the N- terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 15, 25, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 50, 58, and 62, respectively; (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 341, 55, and 61, respectively. [0370] In some aspects, provided herein is a complex comprising: (a) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, and a CH3; (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a PGRN polypeptide, a linker, a CH2, and a CH3; and (c) a third polypeptide comprising, from the N- terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; (ii) SEQ ID NOs: 8,^ny-2871899 735022004340 15, 25, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 50, 58, and 62, respectively; (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 341, 55, and 61, respectively. [0371] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a Progranulin (PGRN) polypeptide, wherein the antigen-binding domain specifically binds to human transferrin receptor (TfR) and is not within an Fc domain of the complex. [0372] In the complexes provided herein, the PGRN polypeptide may be any PGRN polypeptide disclosed herein. [0373] Exemplary formats for a complex as disclosed herein are depicted in FIGs.1A-1J. [0374] In some embodiments, the PGRN polypeptide in the complex is N-terminal to the antigen-binding domain that specifically binds to human TfR. [0375] In some embodiments, the PGRN polypeptide in the complex is C-terminal to the antigen-binding domain that specifically binds to human TfR. [0376] In some embodiments, the PGRN polypeptide and the antigen-binding domain that specifically binds to human TfR are directly connected via a peptide bond. In some embodiments, the PGRN polypeptide and the antigen-binding domain that specifically binds to human TfR are connected via a linker, e.g., a peptide linker. In some embodiments, the complex does not comprise an Fc portion. [0377] In some embodiments, the complex comprises an antigen-binding domain that specifically binds to human TfR, a PGRN polypeptide, and an Fc portion. In some embodiments, the antigen-binding domain that specifically binds to human TfR and the PGRN polypeptide are linked to the N-terminus of the Fc portion of the complex. [0378] In some embodiments, the antigen-binding domain that specifically binds to human TfR and the PGRN polypeptide are both linked to the C-terminus of the Fc portion of the complex. In other embodiments, the antigen-binding domain that specifically binds to human TfR is linked to the N-terminus of the Fc portion and the PGRN polypeptide is linked to the C- terminus of the Fc portion of the complex. In other embodiments, the PGRN polypeptide is^ny-2871899 735022004340 linked to the N-terminus of the Fc portion of the complex and the antigen-binding domain that specifically binds to human TfR is linked to the C-terminus of the Fc portion. [0379] In some embodiments, disclosed herein is a complex comprising (i) a single scFv, or VHH, or Fab antigen-binding domain that specifically binds to human TfR and (ii) a PGRN polypeptide, wherein the complex comprises two copies of the PGRN polypeptide. In some embodiments, the complex comprises an Fc domain. The Fc may be a heterodimeric Fc, comprising a first Fc polypeptide with a knob mutation and a second Fc polypeptide with a hole mutation (a “knob-hole” or “knob-into-hole” or “knob-hole Fc”, as described herein). In some embodiments, the single scFv, Fab or VHH antigen-binding domain that binds to human TfR is linked to the C-terminus of the Fc domain (i.e., to one of the two heavy chains of the Fc domain) while the two copies of the PGRN polypeptide are linked to the N-terminus of the Fc. An example of this 2+1 format is shown in FIG.1F. [0380] In some embodiments, the single scFv, Fab or VHH antigen-binding domain that specifically binds to human TfR is linked to the N-terminus of the Fc domain (i.e., to one of the two heavy chains of the Fc domain) while the two copies of the PGRN polypeptide are linked to the C-terminus of the Fc domain. An example of this 2+1 format is shown in FIG.1E. [0381] In FIG. 2D, an example of a “2+1” format is shown, which comprises (1) a first heavy chain comprising a Fab, an Fc domain with a knob mutation, a PGRN polypeptide linked to the C-term of the Fc domain, (2) a second heavy chain comprising an Fc domain with a hole mutation and a second PGRN polypeptide linked to the C term of the Fc domain, and (3) a light chain. The “2+1” refers to one Fab domain targeting the BBB and two PGRN polypeptides. [0382] In some embodiments, disclosed herein is a complex comprising (i) an antibody that specifically binds to human TfR, wherein the antibody comprises two heavy chains and two light chains; and (ii) two copies of a PGRN polypeptide linked to the C-terminus of the two antibody heavy chains. An example of this 2+2 format is shown in FIG.1G. [0383] In some embodiments, the complex comprises (i) two scFv, Fab, or VHH antigen- binding domains that specifically bind to human TfR linked to the C-terminus of the heavy chain and (ii) two copies of a PGRN polypeptide linked to the N-terminus of the Fc domain. An example of this 2+2 format is shown in FIG.1H. In some embodiments, the complex comprises (i) two scFv, Fab, or VHH antigen-binding domains that specifically bind to human TfR linked^ny-2871899 735022004340 to the N-terminus of the heavy chain and (ii) two copies of a PGRN polypeptide linked to the C- terminus of the Fc domain. [0384] In some embodiments, disclosed herein is a complex comprising (i) a single scFv, VHH, or Fab antigen-binding domain that specifically binds to human TfR, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen- binding domain that binds to human TfR is linked to the C-terminus of the Fc domain and the PGRN polypeptide is linked to N-terminus of the Fc domain. In some embodiments, the Fc domain is a single chain, engineered monovalent Fc domain. An example of this single chain 1+1 format of a complex is shown in FIG.1A, 1I, and 1J. [0385] In some embodiments, disclosed herein is a complex comprising (i) a single scFv, VHH, or Fab antigen-binding domain that specifically binds to human TfR, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen- binding domain that binds to human TfR is linked to the N-terminus of the Fc domain and the PGRN polypeptide linked to C-terminus of the Fc domain. In some embodiments, the Fc is a single chain, engineered monovalent Fc. Examples of this 1+1 format of a complex are shown in FIGs.1B and 1C. [0386] In FIG. 2A, an example “mcFv” format is shown for an anti-TfR-PGRN complex. The “mcFv” format comprises (1) a heavy chain comprising a Fab domain, a single Fc domain, and a PGRN polypeptide linked to the C terminus of the Fc domain and (2) a light chain. [0387] In FIG. 2B, an example “trans” format is shown, which comprises (1) a first heavy chain comprising a Fab domain and an Fc with a hole mutation, (2) a second heavy chain comprising an Fc domain with a knob mutation linked to a PGRN polypeptide, and (3) a light chain. In some embodiments the first heavy chain can have an Fc with a knob mutation and the second heavy chain can have an Fc domain with a hole mutation. [0388] In FIG. 2C, an example of a “cis” format is shown, which comprises (1) a first heavy chain comprising a Fab, Fc with a knob mutation, and a PGRN polypeptide linked to the C term of the Fc-knob, (2) a second heavy chain comprising an Fc with a hole mutation, and a (3) light chain. The “1+1” refers to one Fab domain targeting the BBB and one PGRN polypeptide. [0389] In some embodiments, disclosed herein is a complex comprising (i) a single scFv, VHH, or Fab antigen-binding domain that specifically binds to human TfR, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-^ny-2871899 735022004340 binding domain that specifically binds to human TfR and the PGRN polypeptide are both linked to the N-terminus of the Fc domain. An example of this 1+1 format of a complex is shown in FIG.1D. In some embodiments, disclosed herein is a complex comprising (i) a single scFv, VHH, or Fab antigen-binding domain that specifically binds to human TfR, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen- binding domain that specifically binds to human TfR and the PGRN polypeptide are both linked to the C-terminus of the Fc domain. [0390] In some aspects, provided herein is a complex comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a PGRN polypeptide; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2 and a CH3; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR. In some embodiments, the PGRN polypeptide is PGRN mutant polypeptide. In some embodiments, the PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 330, and wherein: (a) X₁ is an amino acid selected from the group consisting of R, I, V, Q, T, P, and D; (b) X₂ is an amino acid selected from the group consisting of Q and P; (c) X₃ is absent or is an amino acid selected from the group consisting of L, P, C, G, T, D, Y, R, S, Q, V, A, I, H, K, and N; and/or (d) X4 is absent or is an amino acid selected from the group consisting of L, E, G, P, R, D, S, H, N, V, T, I, and A. In some embodiments, the PGRN polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 230, SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 247, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 260, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. In some embodiments, the first polypeptide comprises the amino acid sequence of SEQ ID NO: 319; the second polypeptide comprises the amino acid sequence of SEQ ID NO: 320; and the third polypeptide comprises the amino acid sequence of SEQ ID NO: 321. In some embodiments, the VH comprises a VH CDR1, VH CDR2, and VH CDR3; wherein the VH^ny-2871899 735022004340 CDR1 comprises the amino acid sequence of SEQ ID NO: 8; wherein the VH CDR2 comprises the amino acid sequence of SEQ ID NO: 15; and wherein the VH CDR3 comprises the amino acid sequence of SEQ ID NO: 25; and/or the VL comprises a VL CDR1, VL CDR2, and VL CDR3; wherein the VL CDR1 comprises the amino acid sequence of SEQ ID NO: 43; wherein the VL CDR2 comprises the amino acid sequence of SEQ ID NO: 55; and wherein the VL CDR3 comprises the amino acid sequence of SEQ ID NO: 61. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 102; and/or the VL comprises the amino acid sequence of SEQ ID NO: 158. [0391] In some aspects, provided herein is a complex comprising: a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, and a CH3; a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a PGRN polypeptide; and a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR. In some embodiments, the PGRN polypeptide is a PGRN mutant polypeptide. In some embodiments, the PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 330, and wherein: (a) X₁ is an amino acid selected from the group consisting of R, I, V, Q, T, P, and D; (b) X₂ is an amino acid selected from the group consisting of Q and P; (c) X3 is absent or is an amino acid selected from the group consisting of L, P, C, G, T, D, Y, R, S, Q, V, A, I, H, K, and N; and/or (d) X4 is absent or is an amino acid selected from the group consisting of L, E, G, P, R, D, S, H, N, V, T, I, and A. In some embodiments, the PGRN polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 230, SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 247, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 260, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. In some embodiments, the first polypeptide comprises the amino acid sequence of SEQ ID NO: 322; the second polypeptide comprises the amino acid sequence of SEQ ID NO: 323; and the third polypeptide comprises the amino acid sequence of SEQ ID NO: 321. In some^ny-2871899 735022004340 embodiments, the VH comprises a VH CDR1, VH CDR2, and VH CDR3; wherein the VH CDR1 comprises the amino acid sequence of SEQ ID NO: 8; wherein the VH CDR2 comprises the amino acid sequence of SEQ ID NO: 15; and wherein the VH CDR3 comprises the amino acid sequence of SEQ ID NO: 25; and/or the VL comprises a VL CDR1, VL CDR2, and VL CDR3; wherein the VL CDR1 comprises the amino acid sequence of SEQ ID NO: 43; wherein the VL CDR2 comprises the amino acid sequence of SEQ ID NO: 55; and wherein the VL CDR3 comprises the amino acid sequence of SEQ ID NO: 61. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 102; and/or the VL comprises the amino acid sequence of SEQ ID NO: 158. [0392] In some aspects, provided herein is a complex comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a PGRN polypeptide; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a PGRN polypeptide; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR. In some embodiments, the PGRN polypeptide is a PGRN mutant polypeptide. In some embodiments, the PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 330, and wherein: (a) X₁ is an amino acid selected from the group consisting of R, I, V, Q, T, P, and D; (b) X2 is an amino acid selected from the group consisting of Q and P; (c) X3 is absent or is an amino acid selected from the group consisting of L, P, C, G, T, D, Y, R, S, Q, V, A, I, H, K, and N; and/or (d) X4 is absent or is an amino acid selected from the group consisting of L, E, G, P, R, D, S, H, N, V, T, I, and A. In some embodiments, the PGRN polypeptide of the first polypeptide and the second polypeptide each comprise an amino acid sequence selected from the group consisting of SEQ ID NO: 230, SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 247, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 260, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. In some embodiments, the first polypeptide comprises the amino acid sequence of SEQ ID^ny-2871899 735022004340 NO: 319; the second polypeptide comprises the amino acid sequence of SEQ ID NO: 323; and the third polypeptide comprises the amino acid sequence of SEQ ID NO: 321. In some embodiments, the VH comprises a VH CDR1, VH CDR2, and VH CDR3; wherein the VH CDR1 comprises the amino acid sequence of SEQ ID NO: 8; wherein the VH CDR2 comprises the amino acid sequence of SEQ ID NO: 15; and wherein the VH CDR3 comprises the amino acid sequence of SEQ ID NO: 25; and/or the VL comprises a VL CDR1, VL CDR2, and VL CDR3; wherein the VL CDR1 comprises the amino acid sequence of SEQ ID NO: 43; wherein the VL CDR2 comprises the amino acid sequence of SEQ ID NO: 55; and wherein the VL CDR3 comprises the amino acid sequence of SEQ ID NO: 61. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 102; and/or the VL comprises the amino acid sequence of SEQ ID NO: 158. [0393] In some aspects, provided herein is a complex comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a PGRN polypeptide; and (ii) a second polypeptide comprising, from the N- terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR. In some embodiments, the PGRN polypeptide is a PGRN mutant polypeptide. In some embodiments, the PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 330, and wherein: (a) X1 is an amino acid selected from the group consisting of R, I, V, Q, T, P, and D; (b) X2 is an amino acid selected from the group consisting of Q and P; (c) X3 is absent or is an amino acid selected from the group consisting of L, P, C, G, T, D, Y, R, S, Q, V, A, I, H, K, and N; and/or (d) X4 is absent or is an amino acid selected from the group consisting of L, E, G, P, R, D, S, H, N, V, T, I, and A. In some embodiments, the PGRN polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 230, SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 247, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 260, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. In some embodiments, the first polypeptide comprises the amino^ny-2871899 735022004340 acid sequence of SEQ ID NO: 332; and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 321. In some embodiments, the VH comprises a VH CDR1, VH CDR2, and VH CDR3; wherein the VH CDR1 comprises the amino acid sequence of SEQ ID NO: 8; wherein the VH CDR2 comprises the amino acid sequence of SEQ ID NO: 15; and wherein the VH CDR3 comprises the amino acid sequence of SEQ ID NO: 25; and/or the VL comprises a VL CDR1, VL CDR2, and VL CDR3; wherein the VL CDR1 comprises the amino acid sequence of SEQ ID NO: 43; wherein the VL CDR2 comprises the amino acid sequence of SEQ ID NO: 55; and wherein the VL CDR3 comprises the amino acid sequence of SEQ ID NO: 61. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 102; and/or the VL comprises the amino acid sequence of SEQ ID NO: 158.. [0394] In some embodiments, the complex comprises an antigen-binding domain linked to a PGRN polypeptide, wherein the antigen-binding domain is any antigen-binding domain that specifically binds to human TfR described herein, and wherein the PGRN polypeptide is any PGRN polypeptide described herein. [0395] Table 10 to Table 12 show exemplary complex sequences. Amino acid linkers are bold and underlined. Table 10: “1+1 Cis” TfR9.1B.39.38-PGRN Complex Sequences (Format 1: 1+1 CIS = HC1 (Fab-Fc-knob-PGRN) and HC2 (Fc-hole) and LC)^ny-2871899 735022004340 Table 11: “1+1 Trans” TfR9.1B.39.38-PGRN Complex Sequences (Format 2: 1+1 TRANS = HC1 (Fab-FcKnob) and HC2 (Fchole-PGRN) and LC)^ny-2871899 735022004340 Table 12: “1+2” TfR9.1B.39.38-PGRN Complex Sequences (Format 3: 1+2 = HC1 (Fab- FcKnob-PGRN) and HC2 (Fc-hole-PGRN2) and LC)^ny-2871899 735022004340^ny-2871899 735022004340 Table 13: “1+1” 39.38mvFc-PGRN Complex Sequences^ny-2871899 735022004340 B. Complexes Comprising CD98hc binding domains [0396] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a PGRN polypeptide, wherein the antigen-binding domain specifically binds to human CD98 heavy chain (CD98hc). [0397] In some embodiments, the PGRN polypeptide is a PGRN mutant polypeptide. In some embodiments, the PGRN mutant polypeptide comprises a C-terminal amino acid sequence defined by X1X2X3X4, wherein X1 is any amino acid, and wherein X2, X3, and X4 are not PIL, PFL, PPL, PYL, QRL or QHL. [0398] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a PGRN polypeptide, wherein the antigen-binding domain specifically binds to human CD98 heavy chain (CD98hc), and wherein the antigen-binding domain comprises a VH comprising a VH CDR1, VH CDR2, and VH CDR3, and a VL comprising a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences comprise the amino acid sequences of: (i) SEQ ID NOs: 184, 352, 193, 197, 198, and 204, respectively; (ii) SEQ ID NOs: 184, 353, 193, 197, 198, and 204, respectively; (iii) SEQ ID NOs: 184, 354, 193, 197, 198, and 204, respectively; (iv) SEQ ID NOs: 184, 355, 193, 197, 198, and 204, respectively; (v) SEQ ID NOs: 184, 356, 193, 197, 198, and 204, respectively; (vi) SEQ ID NOs: 184, 357, 193, 197, 198, and 204, respectively; (vii)^ny-2871899 735022004340 SEQ ID NOs: 184, 358, 193, 197, 198, and 204, respectively; (viii) SEQ ID NOs: 184, 190, 193, 369, 198, and 204, respectively; (ix) SEQ ID NOs: 184, 190, 193, 370, 198, and 204, respectively; (x) SEQ ID NOs: 184, 190, 193, 371, 198, and 204, respectively; (xi) SEQ ID NOs: 184, 190, 193, 372, 198, and 204, respectively; (xii) SEQ ID NOs: 184, 190, 193, 373, 198, and 204, respectively; (xiii) SEQ ID NOs: 184, 190, 193, 374, 198, and 204, respectively; (xiv) SEQ ID NOs: 184, 190, 193, 375, 198, and 204, respectively; (xv) SEQ ID NOs: 184, 354, 193, 371, 198, and 204, respectively; (xvi) SEQ ID NOs: 184, 359, 193, 197, 198, and 204, respectively; (xvii) SEQ ID NOs: 184, 190, 360, 197, 198, and 204, respectively; (xviii) SEQ ID NOs: 184, 190, 361, 197, 198, and 204, respectively; (xix) SEQ ID NOs: 184, 190, 362, 197, 198, and 204, respectively; (xx) SEQ ID NOs: 184, 190, 363, 197, 198, and 204, respectively; (xxi) SEQ ID NOs: 184, 190, 364, 197, 198, and 204, respectively; (xxii) SEQ ID NOs: 184, 190, 365, 197, 198, and 204, respectively; (xxiii) SEQ ID NOs: 184, 190, 366, 197, 198, and 204, respectively; (xxiv) SEQ ID NOs: 184, 190, 367, 197, 198, and 204, respectively; (xxv) SEQ ID NOs: 184, 190, 368, 197, 198, and 204, respectively; (xxvi) SEQ ID NOs: 184, 190, 193, 376, 198, and 204, respectively; (xxvii) SEQ ID NOs: 184, 190, 193, 377, 198, and 204, respectively; (xxviii) SEQ ID NOs: 184, 190, 193, 378, 198, and 204, respectively; (xxix) SEQ ID NOs: 184, 190, 193, 379, 198, and 204, respectively; (xxx) SEQ ID NOs: 184, 190, 193, 380, 198, and 204, respectively; (xxxi) SEQ ID NOs: 184, 190, 193, 381, 198, and 204, respectively; (xxxii) SEQ ID NOs: 184, 190, 193, 197, 198, and 382, respectively; (xxxiii) SEQ ID NOs: 184, 190, 193, 197, 198, and 383, respectively; (xxxiv) SEQ ID NOs: 184, 190, 193, 197, 198, and 384, respectively; (xxxv) SEQ ID NOs: 184, 190, 193, 197, 198, and 385, respectively; (xxxvi) SEQ ID NOs: 184, 190, 193, 197, 198, and 386, respectively; (xxxvii) SEQ ID NOs: 184, 190, 193, 197, 198, and 387, respectively; (xxxviii) SEQ ID NOs: 184, 190, 193, 197, 198, and 388, respectively; (xxxix) SEQ ID NOs: 184, 190, 193, 197, 198, and 389, respectively; (xl) SEQ ID NOs: 184, 190, 193, 197, 198, and 390, respectively; (xli) SEQ ID NOs: 184, 190, 193, 197, 198, and 391, respectively; (xlii) SEQ ID NOs: 351, 190, 193, 197, 198, and 204, respectively; or SEQ ID NOs: 351, 190, 193, 197, 198, and 391, respectively. [0399] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a PGRN polypeptide, wherein the antigen-binding domain specifically binds to human CD98 heavy chain (CD98hc), and wherein the antigen-binding domain is a VHH comprising: (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: (i) SEQ ID^ny-2871899 735022004340 NOs: 184, 352, and 193, respectively; (ii) SEQ ID NOs: 184, 353, and 193, respectively; (iii) SEQ ID NOs: 184, 354, and 193, respectively; (iv) SEQ ID NOs: 184, 355, and 193, respectively; (v) SEQ ID NOs: 184, 356, and 193, respectively; (vi) SEQ ID NOs: 184, 357, and 193, respectively; (vii) SEQ ID NOs: 184, 358, and 193, respectively; (viii) SEQ ID NOs: 184, 190, and 193, respectively; (ix) SEQ ID NOs: 184, 359, and 193, respectively; (x) SEQ ID NOs: 184, 190, and 360, respectively; (xi) SEQ ID NOs: 184, 190, and 361, respectively; (xii) SEQ ID NOs: 184, 190, and 362, respectively; (xiii) SEQ ID NOs: 184, 190, and 363, respectively; (xiv) SEQ ID NOs: 184, 190, and 364, respectively; (xv) SEQ ID NOs: 184, 190, and 365, respectively; (xvi) SEQ ID NOs: 184, 190, and 366, respectively; (xvii) SEQ ID NOs: 184, 190, and 367, respectively; (xviii) SEQ ID NOs: 184, 190, and 368, respectively; or (xix) SEQ ID NOs: 351, 190, and 193, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 210, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, or 409. [0400] Exemplary formats for a complex as disclosed herein are depicted in FIGs.1A-1J. [0401] In some embodiments, the PGRN polypeptide in the complex is N-terminal to the antigen-binding domain that specifically binds to human CD98hc. [0402] In some embodiments, the PGRN polypeptide in the complex is C-terminal to the antigen-binding domain that specifically binds to human CD98hc. [0403] In some embodiments, the PGRN polypeptide and the antigen-binding domain that specifically binds to human CD98hc are directly connected via a peptide bond. In some embodiments, the PGRN polypeptide and the antigen-binding domain that specifically binds to human CD98hc are connected via a linker, e.g., a peptide linker. [0404] In some embodiments, the complex comprises an antigen-binding domain that specifically binds to human CD98hc, a PGRN polypeptide, and an Fc portion. In some embodiments, the antigen-binding domain that specifically binds to human CD98hc and the PGRN polypeptide are linked to the N-terminus of the Fc portion of the complex. [0405] In some embodiments, the antigen-binding domain that specifically binds to human CD98hc and the PGRN polypeptide are both linked to the C-terminus of the Fc portion of the complex. In other embodiments, the antigen-binding domain that specifically binds to human CD98hc is linked to the N-terminus of the Fc portion and the PGRN polypeptide is linked to the C-terminus of the Fc portion of the complex. In other embodiments, the PGRN polypeptide is^ny-2871899 735022004340 linked to the N-terminus of the Fc portion of the complex and the antigen-binding domain that specifically binds to human CD98hc is linked to the C-terminus of the Fc portion. [0406] In some embodiments, disclosed herein is a complex comprising (i) a single scFv, or VHH, or Fab antigen-binding domain that specifically binds to human CD98hc and (ii) a PGRN polypeptide, wherein the complex comprises two copies of the PGRN polypeptide. In some embodiments, the complex comprises an Fc domain. The Fc may be a heterodimeric Fc, comprising a first Fc polypeptide with a knob mutation and a second Fc polypeptide with a hole mutation (a “knob-hole”, “knob-into-hole”, “knob-hole Fc”, as described herein). In some embodiments, the single scFv, Fab or VHH antigen-binding domain that binds to human CD98hc is linked to the C-terminus of the Fc domain (i.e., to one of the two heavy chains of the Fc domain) while the two copies of the PGRN polypeptide are linked to the N-terminus of the Fc. An example of this 2+1 format is shown in FIG. 1F. [0407] In some embodiments, the single scFv, Fab or VHH antigen-binding domain that specifically binds to human CD98hc is linked to the N-terminus of the Fc domain (i.e., to one of the two heavy chains of the Fc domain) while the two copies of the PGRN polypeptide are linked to the C-terminus of the Fc domain. An example of this 2+1 format is shown in FIG.1E. [0408] In some embodiments, disclosed herein is a complex comprising (i) an antibody that specifically binds to human CD98hc, wherein the antibody comprises two heavy chains and two light chains; and (ii) two copies of a PGRN polypeptide linked to the C-terminus of the two antibody heavy chains. An example of this 2+2 format is shown in FIG. 1G. [0409] In some embodiments, the complex comprises (i) two scFv, Fab, or VHH antigen- binding domains that specifically bind to human CD98hc linked to the C-terminus of the heavy chain and (ii) two copies of a PGRN polypeptide linked to the N-terminus of the Fc domain. An example of this format is shown in FIG.1H. In some embodiments, the complex comprises (i) two scFv, Fab, or VHH antigen-binding domains that specifically bind to human CD98hc linked to the N-terminus of the heavy chain and (ii) two copies of a PGRN polypeptide linked to the C- terminus of the Fc domain. [0410] In some embodiments, disclosed herein is a complex comprising (i) a single scFv, VHH, or Fab antigen-binding domain that specifically binds to human CD98hc, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the C-terminus of the Fc^ny-2871899 735022004340 domain and the PGRN polypeptide is linked to N-terminus of the Fc domain. In some embodiments, the Fc is a single chain, engineered monovalent Fc domain. An example of this single chain 1+1 format of a complex is shown in FIG. 1A, 1I, and 1J. [0411] In some embodiments, disclosed herein is a complex comprising (i) a single scFv, VHH, or Fab antigen-binding domain that specifically binds to human CD98hc, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the N-terminus of the Fc domain and the PGRN polypeptide linked to C-terminus of the Fc domain. In some embodiments, the Fc is a single chain, engineered monovalent Fc. An example of this 1+1 format of a complex is shown in FIG.1B and 1C. [0412] In some aspects, disclosed herein is a complex comprising (i) a single scFv, VHH, or Fab antigen-binding domain that specifically binds to human CD98hc, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen- binding domain that specifically binds to human CD98hc and the PGRN polypeptide are both linked to the N-terminus of the Fc domain. An example of this 1+1 format of a complex is shown in FIG. 1D. [0413] In some aspects, disclosed herein is a complex comprising (i) a single scFv, VHH, or Fab antigen-binding domain that specifically binds to human CD98hc, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen- binding domain that specifically binds to human CD98hc and the PGRN polypeptide are both linked to the C-terminus of the Fc domain. [0414] In some embodiments, the complex comprises an antigen-binding domain linked to a PGRN polypeptide, wherein the antigen-binding domain is any antigen-binding domain that specifically binds to human CD98hc described herein, and wherein the PGRN polypeptide is any PGRN polypeptide described herein. VII. Polynucleotides and Methods of Making the Same [0415] In some aspects, provided herein is a nucleotide sequence encoding a complex comprising an antigen-binding domain linked to a PGRN polypeptide, wherein the antigen- binding domain specifically binds to a human BBB protein or receptor. In some embodiments, the human BBB protein or receptor is TfR. In some embodiments, the human BBB protein is CD98hc.^ny-2871899 735022004340 [0416] Also provided herein are polynucleotides encoding an isolated PGRN mutant polypeptide. [0417] Provided herein are polynucleotides comprising a nucleotide sequence encoding the complex or isolated PGRN mutant polypeptide described herein, that are optimized, e.g., by codon/RNA optimization, replacement with heterologous signal sequences, and/or elimination of mRNA instability elements. Methods to generate optimized nucleic acids for recombinant expression by introducing codon changes (e.g., a codon change that encodes the same amino acid due to the degeneracy of the genetic code) and/or eliminating inhibitory regions in the mRNA can be carried out by adapting the optimization methods described in, e.g., U.S. Patent Nos. 5,965,726; 6,174,666; 6,291,664; 6,414,132; and 6,794,498, accordingly. [0418] A polynucleotide comprising a nucleotide sequence encoding the complex or isolated PGRN mutant polypeptide described herein, can be generated from nucleic acid from a suitable source (e.g., a hybridoma) using methods well known in the art (e.g., PCR and other molecular cloning methods). For example, PCR amplification using synthetic primers hybridizable to the 3’ and 5’ ends of a known sequence can be performed using genomic DNA obtained from hybridoma cells producing the antibody of interest. Such PCR amplification methods can be used to obtain nucleic acids comprising, e.g., the sequence encoding the light chain and/or heavy chain of an antigen-binding domain, antibody, or antigen-binding fragment thereof. The amplified nucleic acids can be cloned into vectors for expression in host cells and for further cloning, for example, to generate a complex or isolated PGRN mutant polypeptide described herein. [0419] Polynucleotides provided herein can be in the form of RNA or in the form of DNA. DNA includes cDNA, genomic DNA, and synthetic DNA, and DNA can be double-stranded or single-stranded. If single stranded, DNA can be the coding strand or non-coding (anti-sense) strand. In some embodiments, the polynucleotide is a cDNA or a DNA lacking one more endogenous introns. In some embodiments, a polynucleotide is a non-naturally occurring polynucleotide. In some embodiments, a polynucleotide is recombinantly produced. In some embodiments, the polynucleotides are isolated. In some embodiments, the polynucleotides are substantially pure. [0420] In some embodiments, polynucleotides provided herein are in the form of RNA. In some embodiments, polynucleotides provided herein are in the form of RNA encoding a^ny-2871899 735022004340 complex or isolated PGRN mutant polypeptide provided herein. In some embodiments, a polynucleotide provided herein is a synthetic messenger RNA (mRNA). In some embodiments, the synthetic mRNA has at least one nucleoside modification. In some embodiments, the at least one nucleoside modification is selected from the group consisting of pyridin-4-one ribonucleoside, 5-aza-uridine, 2-thio-5-aza-uridine, 2-thiouridine, 4-thio-pseudouridine, 2-thio- pseudouridine, 5-hydroxyuridine, 3-methyluridine, 5-carboxymethyl-uridine, 1-carboxymethyl- pseudouridine, 5-propynyl-uridine, 1-propynyl-pseudouridine, 5-taurinomethyluridine, 1- taurinomethyl-pseudouridine, 5-taurinomethyl-2-thio-uridine, 1-taurinomethyl-4-thio-uridine, 5- methyl-uridine, 1-methyl-pseudouridine, 4-thio-1-methyl-pseudouridine, 2-thio-1-methyl- pseudouridine, 1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-1-deaza-pseudouridine, dihydrouridine, dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-dihydropseudouridine, 2- methoxyuridine, 2-methoxy-4-thio-uridine, 4-methoxy-pseudouridine, 4-methoxy-2-thio- pseudouridine, 5-aza-cytidine, pseudoisocytidine, 3-methyl-cytidine, N4-acetylcytidine, 5- formylcytidine, N4-methylcytidine, 5-hydroxymethylcytidine, 1-methyl-pseudoisocytidine, pyrrolo-cytidine, pyrrolo-pseudoisocytidine, 2-thio-cytidine, 2-thio-5-methyl-cytidine, 4-thio- pseudoisocytidine, 4-thio-1-methyl-pseudoisocytidine, 4-thio-1-methyl-1-deaza- pseudoisocytidine, 1-methyl-1-deaza-pseudoisocytidine, zebularine, 5-aza-zebularine, 5-methyl- zebularine, 5-aza-2-thio-zebularine, 2-thio-zebularine, 2-methoxy-cytidine, 2-methoxy-5-methyl- cytidine, 4-methoxy-pseudoisocytidine, 4-methoxy-1-methyl-pseudoisocytidine, 2-aminopurine, 2,6-diaminopurine, 7-deaza-adenine, 7-deaza-8-aza-adenine, 7-deaza-2-aminopurine, 7-deaza-8- aza-2-aminopurine, 7-deaza-2,6-diaminopurine, 7-deaza-8-aza-2,6-diaminopurine, 1- methyladenosine, N6-methyladenosine, N6-isopentenyladenosine, N6-(cis- hydroxyisopentenyl)adenosine, 2-methylthio-N6-(cis-hydroxyisopentenyl) adenosine, N6- glycinylcarbamoyladenosine, N6-threonylcarbamoyladenosine, 2-methylthio-N6-threonyl carbamoyladenosine, N6,N6-dimethyladenosine, 7-methyladenine, 2-methylthio-adenine, 2- methoxy-adenine, inosine, 1-methyl-inosine, wyosine, wybutosine, 7-deaza-guanosine, 7-deaza- 8-aza-guanosine, 6-thio-guanosine, 6-thio-7-deaza-guanosine, 6-thio-7-deaza-8-aza-guanosine, 7-methyl-guanosine, 6-thio-7-methyl-guanosine, 7-methylinosine, 6-methoxy-guanosine, 1- methylguanosine, N2-methylguanosine, N2,N2-dimethylguanosine, 8-oxo-guanosine, 7-methyl- 8-oxo-guanosine, 1-methyl-6-thio-guanosine, N2-methyl-6-thio-guanosine, and N2,N2-dimethyl- 6-thio-guanosine.^ny-2871899 735022004340 [0421] In certain aspects, provided herein are vectors (e.g., expression vectors) comprising polynucleotides comprising nucleotide sequences encoding the complex or isolated PGRN mutant polypeptide described herein, for recombinant expression in a host cell, e.g., in a mammalian host cell or in an E. coli cell. A vector for the production of the complex or isolated PGRN mutant polypeptide described herein, can be produced, e.g., by recombinant DNA technology using techniques well known in the art. These methods include, for example, in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. Also provided are replicable vectors comprising a nucleotide sequence encoding the complex or isolated PGRN mutant polypeptide described herein, operably linked to a promoter. Such vectors can, for example, include the nucleotide sequence encoding the constant region of an antigen- binding domain, antibody or antigen-binding fragment thereof (see, e.g., International Publication Nos. WO 86/05807 and WO 89/01036; and U.S. Patent No. 5,122,464), and variable domains of the antigen-binding domain, antibody or antigen-binding fragment thereof can be cloned into such a vector for expression of the entire heavy, the entire light chain, or both the entire heavy and light chains. In some embodiments, the vector is gene therapy vector (e.g., an AAV or lentiviral vector). [0422] In certain aspects, provided herein are expression systems comprising polynucleotides comprising nucleotide sequences encoding the complex or isolated PGRN mutant polypeptide described herein. An expression system can be included on a vector. An expression system can also be integrated into a host cell chromosome. In some embodiments, an expression system is a cell free expression system. In some embodiments, an expressions system comprises a host cell comprising a polynucleotide and/or vector provided herein. [0423] Accordingly, also provided herein are cells, e.g. host cells, comprising polynucleotides and/or vectors for recombinantly expressing the complex or isolated PGRN mutant polypeptide described herein. In some embodiments, for the expression of double-chained antigen-binding proteins, vectors encoding both the heavy and light chains, individually, can be co-expressed in the host cell for expression of the entire immunoglobulin. In some embodiments, a host cell contains two different vectors, a first vector comprising a polynucleotide encoding a heavy chain of an antigen-binding protein and a PGRN polypeptide described herein, and a second vector comprising a polynucleotide encoding a light chain of the antigen-binding protein. In some embodiments, a first host cell comprises a first vector comprising a polynucleotide encoding a^ny-2871899 735022004340 heavy chain and a PGRN polypeptide, and a second host cell comprises a second vector comprising a polynucleotide encoding a light chain. In some embodiments, provided herein is a population of host cells comprising such first host cell and such second host cell. [0424] In some aspects, provided herein are methods for producing the complex or isolated PGRN mutant polypeptide described herein in a host cell. [0425] An expression vector can be transferred to a cell (e.g., host cell) by conventional techniques, and the resulting cells can then be cultured by conventional techniques to produce the complex or isolated PGRN mutant polypeptide described herein. [0426] A variety of host-expression vector systems can be utilized for the complex or isolated PGRN mutant polypeptide described herein (see, e.g., U.S. Patent No. 5,807,715). Such host- expression systems represent vehicles by which the coding sequences of interest can be produced and subsequently purified, but also represent cells which can, when transformed or transfected with the appropriate nucleotide coding sequences, express the compositions described herein, or a domain thereof described herein in situ. These include but are not limited to microorganisms such as bacteria (e.g., E. coli and B. subtilis) transformed with recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vectors containing antibody coding sequences; yeast (e.g., Saccharomyces Pichia) transformed with recombinant yeast expression vectors containing antibody coding sequences; insect cell systems infected with recombinant virus expression vectors (e.g., baculovirus) containing antibody coding sequences; plant cell systems (e.g., green algae such as Chlamydomonas reinhardtii) infected with recombinant virus expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with recombinant plasmid expression vectors (e.g., Ti plasmid) containing coding sequences; or mammalian cell systems (e.g., COS (e.g., COS1 or COS), CHO, BHK, MDCK, HEK 293, NS0, PER.C6, VERO, CRL7O3O, HsS78Bst, HeLa, and NIH3T3, HEK-293T, HepG2, SP210, R1.1, B-W, L-M, BSC1, BSC40, YB/20 and BMT10 cells) harboring recombinant expression constructs containing promoters derived from the genome of mammalian cells (e.g., metallothionein promoter) or from mammalian viruses (e.g., the adenovirus late promoter; the vaccinia virus 7.5K promoter). In some embodiments, cells for expressing the complex or isolated PGRN mutant polypeptide described herein are CHO cells, for example CHO cells from the CHO GS System™ (Lonza). In some embodiments, cells for expressing the complex or isolated PGRN mutant polypeptide described herein are human cells, e.g., human cell lines. In^ny-2871899 735022004340 some embodiments, a mammalian expression vector is pOptiVEC™ or pcDNA3.3. In some embodiments, bacterial cells, such as Escherichia coli, or eukaryotic cells (e.g., mammalian cells) are used for the expression of the complex or isolated PGRN mutant polypeptide described herein. For example, mammalian cells such as Chinese hamster ovary (CHO) cells in conjunction with a vector such as the major intermediate early gene promoter element from human cytomegalovirus is an effective expression system for antibodies (Foecking MK & Hofstetter H (1986) Gene 45: 101-105; and Cockett MI et al., (1990) Biotechnology 8: 662-667). In some embodiments, the complex or isolated PGRN mutant polypeptide described herein is produced by CHO cells or NS0 cells. [0427] In addition, a host cell strain can be chosen which modulates the expression of the inserted sequences, or modifies and processes the gene product in the specific fashion desired. Such modifications (e.g., glycosylation) and processing (e.g., cleavage) of protein products can contribute to the function of the protein. To this end, eukaryotic host cells which possess the cellular machinery for proper processing of the primary transcript, glycosylation, and phosphorylation of the gene product can be used. Such mammalian host cells include but are not limited to CHO, VERO, BHK, Hela, MDCK, HEK 293, NIH 3T3, W138, BT483, Hs578T, HTB2, BT2O and T47D, NS0 (a murine myeloma cell line that does not endogenously produce any immunoglobulin chains), CRL7O3O, COS (e.g., COS1 or COS), PER.C6, VERO, HsS78Bst, HEK-293T, HepG2, SP210, R1.1, B-W, L-M, BSC1, BSC40, YB/20, BMT10 and HsS78Bst cells. [0428] Once a complex or isolated PGRN mutant polypeptide described herein has been produced by recombinant expression, it can be purified by any method known in the art for purification, for example, by chromatography (e.g., ion exchange, affinity, particularly by affinity for the specific antigen after Protein A, and sizing column chromatography), centrifugation, differential solubility, or by any other standard technique for the purification of proteins. Further, the complex or isolated PGRN mutant polypeptide described herein can be fused to heterologous polypeptide sequences to facilitate purification. [0429] In some embodiments, the complex or isolated PGRN mutant polypeptide described herein are isolated or purified. Generally, an isolated or purified complex or isolated PGRN mutant polypeptide described herein is one that is substantially free of other proteins. For^ny-2871899 735022004340 example, in some embodiments, a preparation of the complex or isolated PGRN mutant polypeptide described herein is substantially free of cellular material and/or chemical precursors. A. Polynucleotides Encoding Complexes that Bind TfR [0430] In some aspects, provided herein are polynucleotides comprising a nucleotide sequence encoding a complex comprising an antigen-binding domain linked to a PGRN polypeptide. The antigen-binding domain can bind specifically to human transferrin receptor (TfR) to facilitate the transport of the PGRN polypeptide across the blood brain barrier (BBB). In some embodiments, the polynucleotide is DNA. In some embodiments, the polynucleotide is RNA or mRNA. [0431] In some embodiments, a polynucleotide provided herein comprises a nucleic acid molecule encoding the heavy chain of an antigen-binding domain that specifically binds to human TfR provided herein. In some embodiments, a polynucleotide provided herein comprises a nucleic acid molecule encoding the light chain of an antigen-binding domain that specifically binds to human TfR provided herein. In some embodiments, a polynucleotide provided herein comprises a nucleic acid molecule encoding the heavy chain of an antigen-binding domain that specifically binds to human TfR provided herein and a nucleic acid molecule encoding the light chain of an antigen-binding domain that specifically binds to human TfR provided herein. [0432] In some embodiments, a polynucleotide provided herein comprises a nucleic acid molecule encoding the PGRN polypeptide as provided herein. In some embodiments, a polynucleotide provided herein comprises a nucleic acid molecule encoding a domain of the PGRN polypeptide as provided herein. In some embodiments, a polynucleotide provided herein comprises a nucleic acid molecule encoding one or more domains of the PGRN polypeptide as provided herein. [0433] In some embodiments, disclosed herein are polynucleotides encoding a complex disclosed herein comprising an antigen-binding domain linked to a PGRN polypeptide, wherein the antigen-binding domain specifically binds to human TfR. In some embodiments, provided herein is a polynucleotide that encodes a PGRN polypeptide, an Fc domain, a linker, and an antigen-binding domain that specifically binds to human TfR provided herein. In some embodiments, a combination or composition comprises a first polynucleotide and a second polynucleotide, wherein the first polynucleotide encodes a PGRN polypeptide, a linker, and a heavy chain of an antigen-binding domain that binds to human TfR provided herein, and wherein the second polynucleotide encodes a light chain of the antigen-binding domain that bind to^ny-2871899 735022004340 human TfR provided herein. In some embodiments, the polynucleotide is DNA. In some embodiments, the polynucleotide is RNA or mRNA. [0434] In certain embodiments, provided herein are vectors (e.g., expression vectors) comprising polynucleotides comprising nucleotide sequences encoding a complex described herein for recombinant expression in a host cell, e.g., in a mammalian host cell. [0435] In certain embodiments, provided herein are expression systems comprising polynucleotides comprising nucleotide sequences encoding the complex described herein. [0436] Accordingly, also provided herein are cells, e.g. host cells, comprising polynucleotides and/or vectors for recombinantly expressing a complex described herein. [0437] In some embodiments, provided herein are methods for producing a complex described herein in a host cell. [0438] In some embodiments, provided herein are methods for producing a single chain antigen-binding domain that specifically binds to human TfR, an Fc domain, a linker, and a PGRN polypeptide. [0439] In some embodiments, a complex that binds to human TfR as described herein is isolated or purified (e.g., is one that is substantially free of other proteins, and/or is substantially free of cellular material and/or chemical precursors). B. Polynucleotides Encoding Complexes that Bind CD98hc [0440] In some aspects, provided herein are polynucleotides comprising a nucleotide sequence encoding a complexes comprising an antigen-binding domain linked to a PGRN polypeptide. The antigen-binding domain can bind specifically to human CD98 heavy chain (CD98hc) to facilitate the transport of the PGRN polypeptide across the blood brain barrier (BBB). In some embodiments, the polynucleotide is DNA. In some embodiments, the polynucleotide is RNA or mRNA. In some embodiments, the polynucleotide is DNA. In some embodiments, the polynucleotide is RNA or mRNA. [0441] In some embodiments, provided herein are polynucleotides comprising a nucleotide sequence encoding compositions that specifically bind to human CD98hc described herein or a domain thereof described herein. [0442] In some embodiments, a polynucleotide provided herein comprises a nucleic acid molecule encoding the heavy chain of an antigen-binding domain that specifically binds to human CD98hc provided herein. In some embodiments, a polynucleotide provided herein^ny-2871899 735022004340 comprises a nucleic acid molecule encoding the light chain of an antigen-binding domain that specifically binds to human CD98hc provided herein. In some embodiments, a polynucleotide provided herein comprises a nucleic acid molecule encoding the heavy chain of an antigen- binding domain that specifically binds to human CD98hc provided herein and a nucleic acid molecule encoding the light chain of an antigen-binding domain that specifically binds to human CD98hc provided herein. [0443] In some embodiments, a polynucleotide provided herein comprises a nucleic acid molecule encoding the PGRN polypeptide as provided herein. In some embodiments, a polynucleotide provided herein comprises a nucleic acid molecule encoding a domain of the PGRN polypeptide as provided herein. In some embodiments, a polynucleotide provided herein comprises a nucleic acid molecule encoding one or more domains of the PGRN polypeptide as provided herein. [0444] In some embodiments, disclosed herein are polynucleotides encoding a complex disclosed herein comprising an antigen-binding domain linked to a PGRN polypeptide, wherein the antigen-binding domain specifically binds to human CD98hc. In some embodiments, provided herein is a polynucleotide that encodes a PGRN polypeptide, an Fc domain, a linker, and an antigen-binding domain that specifically binds to human CD98hc provided herein. In some embodiments, a combination or composition comprises a first polynucleotide and a second polynucleotide, wherein the first polynucleotide encodes a PGRN polypeptide, a linker, and a heavy chain of an antigen-binding domain that bind to human CD98hc provided herein, and wherein the second polynucleotide encodes a light chain of the antigen-binding domain that bind to human CD98hc provided herein. In some embodiments, the polynucleotide is DNA. In some embodiments, the polynucleotide is RNA or mRNA. [0445] In certain embodiments, provided herein are vectors (e.g., expression vectors) comprising polynucleotides comprising a complex described herein for recombinant expression in a host cell, e.g., in a mammalian host cell. [0446] In certain embodiments, provided herein are expression systems comprising polynucleotides comprising nucleotide sequences encoding the complex described herein. [0447] Accordingly, also provided herein are cells, e.g. host cells, comprising polynucleotides and/or vectors for recombinantly expressing the complex described herein.^ny-2871899 735022004340 [0448] In some embodiments, provided herein are methods for producing a complex described herein in a host cell. [0449] In some embodiments, provided herein are methods for producing a single chain antigen-binding domain that specifically binds to human CD98hc, an Fc domain, a linker, and a PGRN polypeptide. [0450] A variety of host-expression vector systems and host cells are described herein. [0451] In some embodiments, a complex that binds to human CD98hc as described herein is isolated or purified (e.g., is one that is substantially free of other proteins, and/or is substantially free of cellular material and/or chemical precursors). VIII. Pharmaceutical Compositions [0452] Provided herein are pharmaceutical compositions comprising a complex or isolated PGRN mutant polypeptide as described herein and a pharmaceutically acceptable carrier, excipient or stabilizer (Remington’s Pharmaceutical Sciences (1990) Mack Publishing Co., Easton, PA). Also provided herein are pharmaceutical compositions comprising a complex or isolated PGRN mutant polypeptide as described herein and a pharmaceutically acceptable carrier, excipient or stabilizer. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed. Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can comprise antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. [0453] In some embodiments, a pharmaceutical composition comprises a complex or isolated PGRN mutant polypeptide as described herein and a pharmaceutically acceptable carrier (see, e.g., Gennaro, Remington: The Science and Practice of Pharmacy with Facts and Comparisons: Drugfacts Plus, 20th ed. (2003); Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed., Lippencott Williams and Wilkins (2004); Kibbe et al., Handbook of Pharmaceutical Excipients, 3rd ed., Pharmaceutical Press (2000)). In some embodiments, a pharmaceutical composition comprises a complex or isolated PGRN mutant polypeptide as described herein and a pharmaceutically acceptable carrier. Pharmaceutical compositions described herein are, in some embodiments, for use as a medicament. The compositions to be^ny-2871899 735022004340 used for in vivo administration can be sterile. This is readily accomplished by filtration through, e.g., sterile filtration membranes. [0454] In some embodiments, provided herein are pharmaceutical compositions comprising a polynucleotide encoding a complex or isolated PGRN mutant polypeptide as described herein. Also provided herein are pharmaceutical compositions comprising a polynucleotide encoding a complex or isolated PGRN mutant polypeptide as described herein. In some embodiments, the polynucleotide is RNA. In some embodiments, the polynucleotide is a synthetic mRNA. In some embodiments, the polynucleotide is a modified mRNA. In some embodiments, the pharmaceutical composition comprising a polynucleotide further comprises a lipid-based transfection reagent. [0455] A pharmaceutical composition described herein can be used to exert a biological effect(s) in vivo or in vitro. For example, a pharmaceutical composition described herein can be used to cross a blood brain barrier, e.g., in a subject. [0456] In some embodiments, a pharmaceutical composition provided herein is used to treat diseases or conditions such as a neuropathy disorder, a neurodegenerative disease, cancer, an ocular disease disorder, a seizure disorder, a lysosomal storage disease, amyloidosis, a viral or microbial disease, ischemia, a behavioral disorder, and CNS inflammation. In some embodiments, a pharmaceutical composition provided herein is used to treat diseases or conditions such as Alzheimer's disease (AD), stroke, dementia , muscular dystrophy (MD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), cystic fibrosis, Angelman's syndrome, Liddle syndrome, Parkinson's disease, Pick's disease, Paget's disease, cancer, and traumatic brain injury. In some embodiments, a pharmaceutical composition provided herein is used to treat frontotemporal dementia. [0457] In some embodiments, a pharmaceutical composition provided herein is formulated for intravenous administration. In some embodiments, a pharmaceutical composition provided herein is formulated for subcutaneous administration. IX. Methods of Using Complexes and Isolated PGRN Mutant Polypeptides [0458] Provided herein is a complex, or composition thereof, comprising an antigen-binding domain linked to a PGRN polypeptide. The antigen-binding domain can bind specifically to human transferrin receptor (TfR) or human CD98 heavy chain (CD98hc) to facilitate the transport of the PGRN polypeptide across the blood brain barrier (BBB).^ny-2871899 735022004340 [0459] Accordingly, provided herein are methods of administering or transporting a PGRN polypeptide across the blood brain barrier (BBB) of a subject, comprising administering a complex as described herein to the subject. Also provided herein are methods for increasing the concentration of PGRN in the cerebral spinal fluid (CSF) of a subject, comprising administering a complex as provided herein, wherein the concentration of PGRN is increased as compared to administering the PGRN polypeptide alone to the subject. [0460] In view of the ability of the complexes provided herein to specifically bind to human TfR or human CD98hc and be transported across a blood brain barrier, these complexes can be used to treat a neurological disease or disorder. In some embodiments, a method of treating a neurological disease or disorder in a subject comprises administering to the subject a complex as described herein. Other aspects of the present disclosure relate to the use of a complex as described herein in the manufacture of a medicament for treating a neurological disease or disorder in a subject. Other aspects of the present disclosure relate to a complex as described herein for use in treating a neurological disease or disorder in a subject. [0461] The neurological disease or disorder can be, for example, a neuropathy disorder, a neurodegenerative disease, cancer, an ocular disease disorder, a seizure disorder, a lysosomal storage disease, amyloidosis, a viral or microbial disease, ischemia, a behavioral disorder, or CNS inflammation. The neurological disease or disorder can be, for example, a neurodegenerative disease (such as Lewy body disease, postpoliomyelitis syndrome, Shy- Draeger syndrome, olivopontocerebellar atrophy, Parkinson's disease, Gaucher disease, multiple system atrophy, striatonigral degeneration, spinocerebellar ataxia, spinal muscular atrophy), a tauopathy (such as Alzheimer disease and supranuclear palsy), a prion disease (such as bovine spongiform encephalopathy, scrapie, Creutz-feldt-Jakob syndrome, kuru, Gerstmann-Straussler- Scheinker disease, chronic wasting disease, and fatal familial insomnia), bulbar palsy, motor neuron disease, a nervous system heterodegenerative disorders (such as Canavan disease, Huntington's disease, neuronal ceroid-lipofuscinosis, Alexander's disease, Tourette's syndrome, Menkes kinky hair syndrome, Cockayne syndrome, Halervorden-Spatz syndrome, lafora disease, Rett syndrome, hepatolenticular degeneration, Lesch-Nyhan syndrome, and Unverricht- Lundborg syndrome), dementia (such as Pick's disease, and spinocerebellar ataxia), cancer of the CNS and/or brain (such as glioblastoma or brain metastases resulting from cancer elsewhere in the body), Alzheimer's disease (AD), stroke, dementia, muscular dystrophy (MD), multiple^ny-2871899 735022004340 sclerosis (MS), amyotrophic lateral sclerosis (ALS), limbic-predominant age-related TDP-43 encephalopathy (LATE), cystic fibrosis, Angelman's syndrome, Liddle syndrome, Parkinson's disease, Pick's disease, Paget's disease, cancer, or traumatic brain injury. In some embodiments, the neurological disease or disorder is dementia. In some embodiments, the neurological disease or disorder is frontotemporal dementia. In some embodiments, the neurological disease or disorder is Alzheimer’s disease. In some embodiments, the neurological disease or disorder is Parkinson’s disease. In some embodiments, the neurological disease or disorder is frontal temporal epilepsy. In some embodiments, the neurological disease or disorder is autism. In some embodiments, the neurological disease or disorder is lissencephaly. [0462] Pharmaceutical compositions containing a complex of the present disclosure may be administered to an individual in need of treatment with the complex in accordance with known methods, such as intravenous administration as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intracerobrospinal, intracranial, intraspinal, subcutaneous, intra-articular, intrasynovial, intrathecal, oral, topical, or inhalation routes. [0463] Dosages and desired drug concentration of pharmaceutical compositions of the present disclosure may vary depending on the particular use envisioned. The determination of the appropriate dosage or route of administration is well within the skill of an ordinary artisan. Animal experiments provide reliable guidance for the determination of effective doses for human therapy. Interspecies scaling of effective doses can be performed following the principles described in Mordenti, J. and Chappell, W. “The Use of Interspecies Scaling in Toxicokinetics,” In Toxicokinetics and New Drug Development, Yacobi et al., Eds, Pergamon Press, New York 1989, pp.42-46. [0464] In some embodiments, provided herein is a method of treating a lysosomal storage disease with a complex disclosed herein. Other aspects of the present disclosure relate to the use of a complex as described herein in the manufacture of a medicament for treating a lysosomal storage disease in a subject. Other aspects of the present disclosure relate to a complex as described herein for use in treating a lysosomal storage disease in a subject. In some embodiments, the lysosomal storage disease is selected from Gaucher disease, Ceroid lipofuscinosis (Batten disease), Mucopolysaccharidosis (MPS) Type I, MPS Type II and MPS Type III.).^ny-2871899 735022004340 [0465] Complexes provided herein can be used to detect PGRN. In some embodiments, the complexes provided herein can be labeled (e.g., with an imaging agent). Exemplary labels include, for example, radioisotopes (e.g.,⁶⁴CU) and fluorescent labels. Accordingly, methods of detecting PGRN as described herein are provided. In some embodiments, a method of detecting PGRN in the CNS (e.g., brain) of a subject comprises administering the complex provided herein in the CNS (e.g., brain). Such methods can further comprise, e.g., performing Positron emission tomography (PET) imaging on the subject. In some embodiments, disclosed herein is a method of detecting PGRN in vitro, comprising contacting an in vitro sample with a complex disclosed herein and locating the imaging agent within the sample. [0466] Complexes provided herein can be used for prognostic, diagnostic, monitoring, and/or screening applications, including in vivo applications well known and standard to the skilled artisan and based on the present description. In some embodiments, provided herein is a complex for use as a diagnostic. In some embodiments, the complexes provided herein comprise a detectable label. [0467] Also provided herein are isolated PGRN mutant polypeptides. Accordingly, provided herein are methods of treating a disease or disorder comprising administering an isolated PGRN mutant polypeptide as described herein to the subject. [0468] In some embodiments, the isolated PGRN mutant polypeptide described herein can be used to treat a neurological disease or disorder. In some embodiments, a method of treating a neurological disease or disorder in a subject comprises administering to the subject an isolated PGRN mutant polypeptide as described herein. Other aspects of the present disclosure relate to the use of an isolated PGRN mutant polypeptide as described herein in the manufacture of a medicament for treating a neurological disease or disorder in a subject. Other aspects of the present disclosure relate to an isolated PGRN mutant polypeptide as described herein for use in treating a neurological disease or disorder in a subject. [0469] The neurological disease or disorder can be, for example, a neuropathy disorder, a neurodegenerative disease, cancer, an ocular disease disorder, a seizure disorder, a lysosomal storage disease, amyloidosis, a viral or microbial disease, ischemia, a behavioral disorder, or CNS inflammation. The neurological disease or disorder can be, for example, a neurodegenerative disease (such as Lewy body disease, postpoliomyelitis syndrome, Shy- Draeger syndrome, olivopontocerebellar atrophy, Parkinson's disease, Gaucher disease, multiple^ny-2871899 735022004340 system atrophy, striatonigral degeneration, spinocerebellar ataxia, spinal muscular atrophy), a tauopathy (such as Alzheimer disease and supranuclear palsy), a prion disease (such as bovine spongiform encephalopathy, scrapie, Creutz-feldt-Jakob syndrome, kuru, Gerstmann-Straussler- Scheinker disease, chronic wasting disease, and fatal familial insomnia), bulbar palsy, motor neuron disease, a nervous system heterodegenerative disorders (such as Canavan disease, Huntington's disease, neuronal ceroid-lipofuscinosis, Alexander's disease, Tourette's syndrome, Menkes kinky hair syndrome, Cockayne syndrome, Halervorden-Spatz syndrome, lafora disease, Rett syndrome, hepatolenticular degeneration, Lesch-Nyhan syndrome, and Unverricht- Lundborg syndrome), dementia (such as Pick's disease, and spinocerebellar ataxia), cancer of the CNS and/or brain (such as glioblastoma or brain metastases resulting from cancer elsewhere in the body), Alzheimer's disease (AD), stroke, dementia, muscular dystrophy (MD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), limbic-predominant age-related TDP-43 encephalopathy (LATE), cystic fibrosis, Angelman's syndrome, Liddle syndrome, Parkinson's disease, Pick's disease, Paget's disease, cancer, or traumatic brain injury. In some embodiments, the neurological disease or disorder is dementia. In some embodiments, the neurological disease or disorder is frontotemporal dementia. In some embodiments, the neurological disease or disorder is Alzheimer’s disease. In some embodiments, the neurological disease or disorder is Parkinson’s disease. In some embodiments, the neurological disease or disorder is frontal temporal epilepsy. In some embodiments, the neurological disease or disorder is autism. In some embodiments, the neurological disease or disorder is lissencephaly. [0470] Pharmaceutical compositions containing an isolated PGRN mutant polypeptide of the present disclosure may be administered to an individual in need of treatment with the isolated PGRN mutant polypeptide in accord with known methods, such as intravenous administration as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intracerobrospinal, intracranial, intraspinal, subcutaneous, intra-articular, intrasynovial, intrathecal, oral, topical, or inhalation routes. Dosages and desired drug concentration of pharmaceutical compositions of the present disclosure may vary depending on the particular use envisioned. The determination of the appropriate dosage or route of administration is well within the skill of an ordinary artisan. Animal experiments provide reliable guidance for the determination of effective doses for human therapy. Interspecies scaling of effective doses can be performed following the principles described in Mordenti, J. and Chappell, W. “The Use of^ny-2871899 735022004340 Interspecies Scaling in Toxicokinetics,” In Toxicokinetics and New Drug Development, Yacobi et al., Eds, Pergamon Press, New York 1989, pp.42-46. [0471] In some embodiments, provided herein is a method of treating a lysosomal storage disease with an isolated PGRN mutant polypeptide disclosed herein. Other aspects of the present disclosure relate to the use of an isolated PGRN mutant polypeptide as described herein in the manufacture of a medicament for treating a lysosomal storage disease in a subject. Other aspects of the present disclosure relate to an isolated PGRN mutant polypeptide as described herein for use in treating a lysosomal storage disease in a subject. In some embodiments, the lysosomal storage disease is selected from Gaucher disease, Ceroid lipofuscinosis (Batten disease), Mucopolysaccharidosis (MPS) Type I, MPS Type II and MPS Type III.). [0472] All references cited herein, including patent applications and publications, are hereby incorporated by reference in their entirety. [0473] The present disclosure will be more fully understood by reference to the following Examples. They should not, however, be construed as limiting the scope of the present disclosure. X. Exemplary Embodiments [0474] Among the provided embodiments are: Embodiment 1. A complex comprising (a) an antigen-binding domain that specifically binds to human transferrin receptor (TfR) and (b) a Progranulin (PGRN) polypeptide. Embodiment 2. A complex comprising (a) an affinity-tuned antigen-binding domain that specifically binds to human TfR, wherein the antigen-binding domain binds to human TfR with an affinity of 0.01 nM to 50 nM, and (b) a PGRN polypeptide. Embodiment 3. A complex comprising (a) an affinity-tuned antigen-binding domain that specifically binds to human TfR, wherein the antigen-binding domain binds to human TfR with an affinity of 51 nM to 750 nM, and (b) a PGRN polypeptide. Embodiment 4. The complex of embodiment 3, wherein the antigen-binding domain binds to human TfR with an affinity of 600 nM to 650 nM. Embodiment 5. The complex of embodiment 3, wherein the antigen-binding domain binds to human TfR with an affinity of 160 nM to 200 nM.^ny-2871899 735022004340 Embodiment 6. A complex comprising (a) an affinity-tuned antigen-binding domain that specifically binds to human TfR, wherein the antigen-binding domain binds to human TfR with an affinity of 751 nM to 10,000 nM, and (b) a PGRN polypeptide. Embodiment 7. The complex of any one of embodiments 1-6, further comprising an Fc domain. Embodiment 8. The complex of embodiment 7, wherein the antigen-binding domain that specifically binds to human transferrin receptor (TfR) is not within the Fc domain of the complex. Embodiment 9. The complex of any one of embodiments 1-8, wherein the antigen-binding domain comprises a VH and a VL on separate polypeptides. Embodiment 10. The complex of any one of embodiments 1-9, wherein the complex comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and the PGRN polypeptide; and (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form the antigen-binding domain that specifically binds to human TfR. Embodiment 11. The complex of embodiment 10, further comprising (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a CH2 and a CH3. Embodiment 12. The complex of embodiment 10, further comprising (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a second PGRN polypeptide. Embodiment 13. The complex of embodiment 10, further comprising: (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a second VH, a second CH1, a second hinge region, a second CH2, a second CH3, a second linker, and a second PGRN polypeptide; (iv) a fourth polypeptide comprising, from the N-terminus to the C-terminus, a second VL and a second CL; wherein the second VH and the second VL form a second antigen-binding domain that specifically binds to human TfR.^ny-2871899 735022004340 Embodiment 14. The complex of any one of embodiments 1-8, comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, and a CH3; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and the PGRN polypeptide; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form the antigen-binding domain that specifically binds to human TfR. Embodiment 15. The complex of any one of embodiments 1-8, wherein the antigen-binding domain comprises a VH and VL on a single polypeptide chain. Embodiment 16. The complex of any one of embodiments 1-8 and 15, wherein the antigen- binding domain comprises a single-chain fragment variable (scFv). Embodiment 17. The complex of embodiment 16, wherein the scFv is in the orientation VH-linker-VL. Embodiment 18. The complex of embodiment 16, wherein the scFv is in the orientation VL-linker-VH. Embodiment 19. The complex of embodiment 17 or embodiment 18, wherein the linker (A) is about 5 to about 25 amino acids, is about 5 to about 20 amino acids, is about 10 to about 25 amino acids, or is about 10 to about 20 amino acids and/or (B) comprises the amino acid sequence of GGSEGKSSGSGSESKSTGGS (SEQ ID NO: 6) or GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 7). Embodiment 20. The complex of any one of embodiments 1-8 and 15-19, comprising (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the PGRN polypeptide, a first Fc domain, and the antigen-binding domain and (ii) a second polypeptide comprising a second Fc domain. Embodiment 21. The complex of any one of embodiments 1-8 comprising (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the PGRN polypeptide and a first Fc domain and (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a second Fc domain and the antigen-binding domain. Embodiment 22. The complex of any one of embodiments 1-9 comprising:^ny-2871899 735022004340 (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the PGRN polypeptide and a first Fc domain, (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, and a second Fc domain, and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form the antigen-binding domain that specifically binds to human TfR. Embodiment 23. The complex of any one of embodiments 1-8 and 15, comprising (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the PGRN polypeptide, a first Fc domain, and the antigen-binding domain and (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a second PGRN polypeptide and a second Fc domain. Embodiment 24. The complex of embodiment 23, wherein the second polypeptide comprises, from the N-terminus to the C-terminus, the second PGRN polypeptide, the second Fc domain, and a second antigen-binding domain that specifically binds TfR. Embodiment 25. The complex of any one of embodiments 1-24, wherein the antigen- binding domain is a murine, chimeric, humanized, or human antigen-binding domain, optionally wherein the antigen-binding domain is a humanized antigen-binding domain. Embodiment 26. The complex of any one of embodiments 7-25, wherein the Fc domain is capable of binding FcRn. Embodiment 27. The complex of any one of embodiments 1-6, further comprising an Fc region, wherein the Fc region comprises a first and second polypeptide chain. Embodiment 28. The complex of embodiment 27, wherein the Fc region is capable of binding FcRn. Embodiment 29. The complex of embodiment 27 or embodiment 28, comprising (i) a single scFv or VHH or Fab antigen-binding domain that binds to human TfR and (ii) and two copies of the PGRN polypeptide. Embodiment 30. The complex of embodiment 29, wherein the single scFv, Fab or VHH antigen-binding domain that binds to human TfR is linked to the C-terminus of one of the two copies of the PGRN polypeptide.^ny-2871899 735022004340 Embodiment 31. The complex of embodiment 29, wherein one of the two copies of the PGRN polypeptide is linked to the N-terminus of the first polypeptide chain of the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the N-terminus of the second polypeptide chain of the Fc region. Embodiment 32. The complex of embodiment 29, wherein the single scFv, Fab, or VHH antigen-binding domain that binds to human TfR is linked to the N-terminus of the first or second polypeptide chain of the Fc region. Embodiment 33. The complex of embodiment 29, wherein one of the two copies of the PGRN polypeptide is linked to the C-terminus of the first polypeptide chain of the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the C-terminus of the second polypeptide chain of the Fc region. Embodiment 34. The complex of embodiment 27 or embodiment 28, comprising (i) an antibody that binds to human TfR, wherein the antibody comprises two heavy chains and two light chains; and (ii) two copies of the PGRN polypeptide, wherein each copy of the PGRN polypeptide is linked to the C-termini of one of the two antibody heavy chains. Embodiment 35. The complex of embodiment 27 or embodiment 28, comprising (i) two scFv, Fab, or VHH antigen-binding domains that bind to human TfR, (ii) the Fc region; and (iii) two copies of the PGRN polypeptide, wherein one of the two scFv, Fab, or VHH antigen-binding domains that binds to human TfR is linked to the C-terminus of the first polypeptide chain of the Fc region, wherein the other scFv, Fab, or VHH antigen-binding domains that binds to human TfR is linked to the C-terminus of the second polypeptide chain of the Fc region, wherein one of the two copies of the PGRN polypeptide is linked to the N-terminus of the first polypeptide chain of the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the N- terminus of the second polypeptide chain of the Fc region. Embodiment 36. The complex of embodiment 27 or embodiment 28, comprising (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human TfR, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the C-terminus of the first or second polypeptide chain of the Fc region and the PGRN polypeptide is linked to N-terminus of the first or second polypeptide chain of the Fc region.^ny-2871899 735022004340 Embodiment 37. The complex of embodiment 7, comprising (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human TfR, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the C-terminus of the Fc domain and the PGRN polypeptide is linked to N-terminus of the Fc domain. Embodiment 38. The complex of embodiment 27 or embodiment 28, comprising (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human TfR, (ii) the Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the N-terminus of the first or second polypeptide chain of the Fc region and the PGRN polypeptide is linked to the C-terminus of the first or second polypeptide chain of the Fc region. Embodiment 39. The complex of embodiment 7, comprising (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human TfR, (ii) the Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the N-terminus of the Fc domain and the PGRN polypeptide is linked to the C-terminus of the Fc domain. Embodiment 40. The complex of embodiment 27 or embodiment 28, comprising (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human TfR, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the N-terminus of one of the two polypeptide chains of the Fc region, and wherein the PGRN polypeptide is linked to the N-terminus of the other polypeptide chain of the Fc region. Embodiment 41. The complex of any one of embodiments 27-36, 38, and 40, wherein the Fc region is a heterodimeric Fc region, optionally comprising knob and hole mutations. Embodiment 42. The complex of any one of embodiments 7, 37, and 39, wherein the Fc domain is a single chain monovalent Fc domain. Embodiment 43. The complex of any one of embodiments 27-36, 38, and 40-41, wherein the Fc region is a modified Fc region with a modification listed in Table 8 or Table 9. Embodiment 44. The complex of any one of embodiments 27-36, 38, 40-41, and 43, wherein the Fc region is a human IgG1 Fc region, wherein the human IgG1 Fc region comprises a mutation that reduces effector function, optionally wherein the mutation that reduces effector^ny-2871899 735022004340 function comprises: (i) L234A, L235A, and/or P331S; (ii) N325S and/or L328F; (iii) L234A, L235A, and/or P329G; or (iv) L234A, L235A, and/or P329S. Embodiment 45. The complex of any one of embodiments 7, 37, 39, and 42, wherein the Fc domain is a modified Fc domain with a modification listed in Table 8. Embodiment 46. The complex of any one of embodiments 7, 37, 39, 42, and 45, wherein the Fc domain is a human IgG1 Fc domain, wherein the human IgG1 Fc domain comprises a mutation that reduces effector function, optionally wherein the mutation that reduces effector function comprises: (i) L234A, L235A, and/or P331S; (ii) N325S and/or L328F; (iii) L234A, L235A, and/or P329G; or (iv) L234A, L235A, and/or P329S. Embodiment 47. The complex of any one of embodiments 1 and 7-46, wherein the antigen- binding domain comprises a heavy chain variable region (VH) comprising a VH CDR1, VH CDR2, and VH CDR3 and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: (i) SEQ ID NOs: 8, 16, 25, 42, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 11, 24, 40, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 11, 25, 41, 55, and 61, respectively; (iv) SEQ ID NOs: 8, 12, 26, 42, 55, and 61, respectively; (v) SEQ ID NOs: 8, 12, 27, 42, 55, and 61, respectively; (vi) SEQ ID NOs: 8, 13, 25, 42, 55, and 61, respectively; (vii) SEQ ID NOs: 8, 14, 25, 42, 55, and 61, respectively; (viii) SEQ ID NOs: 8, 15, 25, 43, 55, and 61, respectively; (ix) SEQ ID NOs: 8, 17, 25, 44, 55, and 61, respectively; (x) SEQ ID NOs: 9, 18, 28, 45, 56, and 62, respectively; (xi) SEQ ID NOs: 9, 19, 28, 45, 56, and 62, respectively; (xii) SEQ ID NOs: 9, 20, 28, 46, 57, and 62, respectively; (xiii) SEQ ID NOs: 9, 20, 28, 46, 58, and 62, respectively; (xiv) SEQ ID NOs: 9, 20, 28, 47, 59, and 62, respectively; (xv) SEQ ID NOs: 9, 21, 28, 46, 57, and 62, respectively; (xvi) SEQ ID NOs: 9, 21, 28, 47, 59, and 62, respectively; (xvii) SEQ ID NOs: 9, 22, 28, 46, 57, and 62, respectively;^ny-2871899 735022004340 (xviii) SEQ ID NOs: 9, 22, 28, 46, 58, and 62, respectively; (xix) SEQ ID NOs: 9, 22, 28, 47, 59, and 62, respectively; (xx) SEQ ID NOs: 10, 22, 28, 46, 58, and 62, respectively; (xxi) SEQ ID NOs: 10, 22, 30, 46, 58, and 62, respectively; (xxii) SEQ ID NOs: 10, 22, 31, 46, 58, and 62, respectively; (xxiii) SEQ ID NOs: 10, 22, 32, 46, 58, and 62, respectively; (xxiv) SEQ ID NOs: 10, 22, 33, 46, 58, and 62, respectively; (xxv) SEQ ID NOs: 10, 22, 34, 46, 58, and 62, respectively; (xxvi) SEQ ID NOs: 10, 22, 35, 46, 58, and 62, respectively; (xxvii) SEQ ID NOs: 10, 22, 36, 46, 58, and 62, respectively; (xxviii) SEQ ID NOs: 10, 22, 37, 46, 58, and 62, respectively; (xxix) SEQ ID NOs: 10, 22, 38, 46, 58, and 62, respectively; (xxx) SEQ ID NOs: 10, 22, 39, 46, 58, and 62, respectively; (xxxi) SEQ ID NOs: 10, 22, 28, 49, 58, and 62, respectively; (xxxii) SEQ ID NOs: 10, 22, 28, 50, 58, and 62, respectively; (xxxiii) SEQ ID NOs: 10, 22, 28, 51, 58, and 62, respectively; (xxxiv) SEQ ID NOs: 10, 22, 28, 52, 58, and 62, respectively; (xxxv) SEQ ID NOs: 10, 22, 28, 53, 58, and 62, respectively; or (xxxvi) SEQ ID NOs: 10, 22, 28, 54, 58, and 62, respectively. Embodiment 48. The complex of embodiment 47, wherein the VH comprises the amino acid sequence of SEQ ID NO: 103, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 97, 98, 99, 100, 101, 102, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, or 127. Embodiment 49. The complex of embodiment 47 or embodiment 48, wherein the VL comprises the amino acid sequence of SEQ ID NO: 157, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 173, 174, 175, 176, 177, or 178. Embodiment 50. The complex of embodiment 48 or embodiment 49, wherein the VH and the VL comprise the amino acid sequences of:^ny-2871899 735022004340 (i) SEQ ID NOs: 103 and 157, respectively; (ii) SEQ ID NOs: 64 and 129, respectively; (iii) SEQ ID NOs: 65 and 130, respectively; (iv) SEQ ID NOs: 66 and 131, respectively; (v) SEQ ID NOs: 67 and 130, respectively; (vi) SEQ ID NOs: 68 and 131, respectively; (vii) SEQ ID NOs: 69 and 130, respectively; (viii) SEQ ID NOs: 70 and 131, respectively; (ix) SEQ ID NOs: 71 and 130, respectively; (x) SEQ ID NOs: 72 and 131, respectively; (xi) SEQ ID NOs: 73 and 130, respectively; (xii) SEQ ID NOs: 74 and 131, respectively; (xiii) SEQ ID NOs: 75 and 132, respectively; (xiv) SEQ ID NOs: 76 and 131, respectively; (xv) SEQ ID NOs: 77 and 132, respectively; (xvi) SEQ ID NOs: 77 and 133, respectively; (xvii) SEQ ID NOs: 78 and 134, respectively; (xviii) SEQ ID NOs: 77 and 135, respectively; (xix) SEQ ID NOs: 77 and 136, respectively; (xx) SEQ ID NOs: 77 and 137, respectively; (xxi) SEQ ID NOs: 77 and 138, respectively; (xxii) SEQ ID NOs: 79 and 131, respectively; (xxiii) SEQ ID NOs: 77 and 139, respectively; (xxiv) SEQ ID NOs: 77 and 131, respectively; (xxv) SEQ ID NOs: 80 and 140, respectively; (xxvi) SEQ ID NOs: 81 and 141, respectively; (xxvii) SEQ ID NOs: 82 and 131, respectively; (xxviii) SEQ ID NOs: 83 and 142, respectively; (xxix) SEQ ID NOs: 77 and 143, respectively; (xxx) SEQ ID NOs: 75 and 131, respectively; (xxxi) SEQ ID NOs: 75 and 144, respectively;^ny-2871899 735022004340 (xxxii) SEQ ID NOs: 77 and 145, respectively; (xxxiii) SEQ ID NOs: 84 and 131, respectively; (xxxiv) SEQ ID NOs: 75 and 146, respectively; (xxxv) SEQ ID NOs: 85 and 131, respectively; (xxxvi) SEQ ID NOs: 86 and 138, respectively; (xxxvii) SEQ ID NOs: 79 and 139, respectively; (xxxviii) SEQ ID NOs: 77 and 147, respectively; (xxxix) SEQ ID NOs: 75 and 148, respectively; (xl) SEQ ID NOs: 87 and 131, respectively; (xli) SEQ ID NOs: 88 and 131, respectively; (xlii) SEQ ID NOs: 75 and 149, respectively; (xliii) SEQ ID NOs: 89 and 150, respectively; (xliv) SEQ ID NOs: 90 and 151, respectively; (xlv) SEQ ID NOs: 77 and 152, respectively; (xlvi) SEQ ID NOs: 79 and 153, respectively; (xlvii) SEQ ID NOs: 91 and 131, respectively; (xlviii) SEQ ID NOs: 92 and 131, respectively; (xlix) SEQ ID NOs: 79 and 154, respectively; (l) SEQ ID NOs: 93 and 155, respectively; (li) SEQ ID NOs: 80 and 131, respectively; (lii) SEQ ID NOs: 94 and 131, respectively; (liii) SEQ ID NOs: 95 and 131, respectively; (liv) SEQ ID NOs: 66 and 156, respectively; (lv) SEQ ID NOs: 97 and 138, respectively; (lvi) SEQ ID NOs: 95 and 156, respectively; (lvii) SEQ ID NOs: 98 and 157, respectively; (lviii) SEQ ID NOs: 99 and 157, respectively; (lix) SEQ ID NOs: 100 and 157, respectively; (lx) SEQ ID NOs: 101 and 157, respectively; (lxi) SEQ ID NOs: 102 and 158, respectively; (lxii) SEQ ID NOs: 104 and 159, respectively;^ny-2871899 735022004340 (lxiii) SEQ ID NOs: 105 and 160, respectively; (lxiv) SEQ ID NOs: 106 and 161, respectively; (lxv) SEQ ID NOs: 107 and 162, respectively; (lxvi) SEQ ID NOs: 106 and 163, respectively; (lxvii) SEQ ID NOs: 108 and 164, respectively; (lxviii) SEQ ID NOs: 106 and 165, respectively; (lxix) SEQ ID NOs: 108 and 166, respectively; (lxx) SEQ ID NOs: 109 and 165, respectively; (lxxi) SEQ ID NOs: 110 and 167, respectively; (lxxii) SEQ ID NOs: 111 and 168, respectively; (lxxiii) SEQ ID NOs: 112 and 160, respectively; (lxxiv) SEQ ID NOs: 113 and 169, respectively; (lxxv) SEQ ID NOs: 113 and 170, respectively; (lxxvi) SEQ ID NOs: 113 and 171, respectively; (lxxvii) SEQ ID NOs: 114 and 169, respectively; (lxxviii) SEQ ID NOs: 114 and 171, respectively; (lxxix) SEQ ID NOs: 115 and 169, respectively; (lxxx) SEQ ID NOs: 115 and 170, respectively; (lxxxi) SEQ ID NOs: 115 and 171, respectively; (lxxxii) SEQ ID NOs: 116 and 169, respectively; (lxxxiii) SEQ ID NOs: 116 and 170, respectively; (lxxxiv) SEQ ID NOs: 116 and 171, respectively; (lxxxv) SEQ ID NOs: 117 and 170, respectively; (lxxxvi) SEQ ID NOs: 118 and 170, respectively; (lxxxvii) SEQ ID NOs: 119 and 170, respectively; (lxxxviii) SEQ ID NOs: 120 and 170, respectively; (lxxxix) SEQ ID NOs: 121 and 170, respectively; (xc) SEQ ID NOs: 122 and 170, respectively; (xci) SEQ ID NOs: 123 and 170, respectively; (xcii) SEQ ID NOs: 124 and 170, respectively; (xciii) SEQ ID NOs: 125 and 170, respectively;^ny-2871899 735022004340 (xciv) SEQ ID NOs: 126 and 170, respectively; (xcv) SEQ ID NOs: 127 and 170, respectively; (xcvi) SEQ ID NOs: 117 and 173, respectively; (xcvii) SEQ ID NOs: 117 and 174, respectively; (xcviii) SEQ ID NOs: 117 and 175, respectively; (xcix) SEQ ID NOs: 117 and 176, respectively; (c) SEQ ID NOs: 117 and 177, respectively; or (ci) SEQ ID NOs: 117 and 178, respectively. Embodiment 51. The complex of any one of embodiments 1 and 7-46, wherein the antigen- binding domain is a VHH comprising: (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 8, 16, and 25, respectively; (ii) SEQ ID NOs: 8, 11, and 24, respectively; (iii) SEQ ID NOs: 8, 11, and 25, respectively; (iv) SEQ ID NOs: 8, 12, and 26, respectively; (v) SEQ ID NOs: 8, 12, and 27, respectively; (vi) SEQ ID NOs: 8, 13, and 25, respectively; (vii) SEQ ID NOs: 8, 14, and 25, respectively; (viii) SEQ ID NOs: 8, 15, and 25, respectively; (ix) SEQ ID NOs: 8, 17, and 25, respectively; (x) SEQ ID NOs: 9, 18, and 28, respectively; (xi) SEQ ID NOs: 9, 19, and 28, respectively; (xii) SEQ ID NOs: 9, 20, and 28, respectively; (xiii) SEQ ID NOs: 9, 21, and 28, respectively; (xiv) SEQ ID NOs: 9, 22, and 28, respectively; (xv) SEQ ID NOs: 10, 22, and 28, respectively; (xvi) SEQ ID NOs: 10, 22, and 30, respectively; (xvii) SEQ ID NOs: 10, 22, and 31, respectively; (xviii) SEQ ID NOs: 10, 22, and 32, respectively; (xix) SEQ ID NOs: 10, 22, and 33, respectively; (xx) SEQ ID NOs: 10, 22, and 34, respectively;^ny-2871899 735022004340 (xxi) SEQ ID NOs: 10, 22, and 35, respectively; (xxii) SEQ ID NOs: 10, 22, and 36, respectively; (xxiii) SEQ ID NOs: 10, 22, and 37, respectively; (xxiv) SEQ ID NOs: 10, 22, and 38, respectively; or (xxv) SEQ ID NOs: 10, 22, and 39, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 103, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 97, 98, 99, 100, 101, 102, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, or 127. Embodiment 52. The complex of any one of embodiments 1-46, wherein the antigen- binding domain comprises a heavy chain variable region (VH) comprising a VH CDR1, VH CDR2, and VH CDR3 and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3, and wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 15, 25, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 50, 58, and 62, respectively; (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 341, 55, and 61, respectively. Embodiment 53. The complex of embodiment 52, wherein the VH comprises the amino acid sequence of SEQ ID NO: 101, 102, 342, 117, 343, or 118. Embodiment 54. The complex of embodiment 52 or embodiment 53, wherein the VL comprises the amino acid sequence of SEQ ID NO: 154, 344, 345, 174, 346, 347, 348, 349, or 350.^ny-2871899 735022004340 Embodiment 55. The complex of embodiment 53 or embodiment 54, wherein the VH and the VL comprise the amino acid sequences of: (i) SEQ ID NOs: 101 and 154, respectively; (ii) SEQ ID NOs: 102 and 344, respectively; (iii) SEQ ID NOs: 102 and 345, respectively; (iv) SEQ ID NOs: 342 and 174, respectively; (v) SEQ ID NOs: 117 and 346, respectively; (vi) SEQ ID NOs: 117 and 347, respectively; (vii) SEQ ID NOs: 117 and 348, respectively; (viii) SEQ ID NOs: 117 and 349, respectively; (ix) SEQ ID NOs: 343 and 174, respectively; (x) SEQ ID NOs: 118 and 174, respectively; or (xi) SEQ ID NOs: 101 and 350, respectively. Embodiment 56. The complex of any one of embodiments 1-46, wherein antigen-binding domain specifically binds to human TfR, and wherein the antigen-binding domain is a VHH comprising: (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 8, 14, and 25, respectively; (ii) SEQ ID NOs: 8, 15, and 25, respectively; (iv) SEQ ID NOs: 10, 22, and 333, respectively; (v) SEQ ID NOs: 10, 22, and 28, respectively; (ix) SEQ ID NOs: 10, 22, and 334, respectively; or (x) SEQ ID NOs: 10, 22, and 30, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 101, 102, 342, 117, 343, or 118. Embodiment 57. The complex of any one of the preceding embodiments, wherein the PGRN polypeptide comprises an amino acid sequence set forth in SEQ ID NO:230. Embodiment 58. The complex of any one of embodiments 1-56, wherein the PGRN polypeptide is a mutant PGRN polypeptide comprising a C-terminal amino acid sequence defined by X1X2X3X4, wherein X1 is any amino acid, and wherein X2, X3, and X4 are not PIL, PFL, PPL, PYL, QRL, or QHL.^ny-2871899 735022004340 Embodiment 59. The complex of embodiment 58, wherein the PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 330, and wherein: (a) X1 is an amino acid selected from the group consisting of R, I, V, Q, T, P, and D; (b) X2 is an amino acid selected from the group consisting of Q and P; (c) X3 is absent or is an amino acid selected from the group consisting of L, P, C, G, T, D, Y, R, S, Q, V, A, I, H, K, and N; and/or (d) X4 is absent or is an amino acid selected from the group consisting of L, E, G, P, R, D, S, H, N, V, T, I, and A. Embodiment 60. The complex of any one of embodiments 1-56 and 58-59, wherein the PGRN mutant polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 259, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. Embodiment 61. The complex of any one of embodiments 2-56, wherein the PGRN mutant polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 247, SEQ ID NO: 258, and SEQ ID NO: 260. Embodiment 62. The complex of embodiment 11, wherein: (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO:319; (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO:321; and (iii) the third polypeptide comprises the amino acid sequence of SEQ ID NO:320. Embodiment 63. The complex of embodiment 14, wherein: (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO:322; (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO:323; and (iii) the third polypeptide comprises the amino acid sequence of SEQ ID NO:321. Embodiment 64. The complex of embodiment 12, wherein: (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO:319; (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO:321; and^ny-2871899 735022004340 (iii) the third polypeptide comprises the amino acid sequence of SEQ ID NO:323. Embodiment 65. The complex of embodiment 10, wherein: (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO:332, and (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO:321. Embodiment 66. A complex comprising: (a) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a PGRN polypeptide; (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2 and a CH3; and (c) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 15, 25, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 50, 58, and 62, respectively; (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 341, 55, and 61, respectively. Embodiment 67. A complex comprising: (a) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, and a CH3;^ny-2871899 735022004340 (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a PGRN polypeptide; and (c) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 15, 25, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 50, 58, and 62, respectively; (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 341, 55, and 61, respectively. Embodiment 68. A complex comprising: (a) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a PGRN polypeptide; (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a PGRN polypeptide; and (c) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and^ny-2871899 735022004340 wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 15, 25, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 50, 58, and 62, respectively; (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 341, 55, and 61, respectively. Embodiment 69. A complex comprising: (a) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a PGRN polypeptide; and (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 15, 25, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively;^ny-2871899 735022004340 (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 50, 58, and 62, respectively; (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 341, 55, and 61, respectively. Embodiment 70. The complex of any one of embodiments 66-69, wherein the VH and the VL comprise the amino acid sequences of: (i) SEQ ID NOs: 101 and 154, respectively; (ii) SEQ ID NOs: 102 and 344, respectively; (iii) SEQ ID NOs: 102 and 345, respectively; (iv) SEQ ID NOs: 342 and 174, respectively; (v) SEQ ID NOs: 117 and 346, respectively; (vi) SEQ ID NOs: 117 and 347, respectively; (vii) SEQ ID NOs: 117 and 348, respectively; (viii) SEQ ID NOs: 117 and 349, respectively; (ix) SEQ ID NOs: 343 and 174, respectively; (x) SEQ ID NOs: 118 and 174, respectively; or (xi) SEQ ID NOs: 101 and 350, respectively. Embodiment 71. The complex of any one of embodiments 66-70, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively. Embodiment 72. The complex of embodiment 71, wherein the VH and the VL comprise the amino acid sequences of 117 and 349, respectively. Embodiment 73. The complex of any one of embodiments 66-70, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively. Embodiment 74. The complex of embodiment 73, wherein the VH and the VL comprise the amino acid sequences of 117 and 348, respectively. Embodiment 75. The complex of any one of embodiments 66-74, wherein the PGRN polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 230, SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240,^ny-2871899 735022004340 SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 247, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 260, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. Embodiment 76. The complex of any one of embodiments 1-75, wherein the complex binds human Sortilin with a dissociation constant (KD) that ranges from about 5 nM to about 400 nM. Embodiment 77. The complex of any one of embodiments 1-76, wherein the complex binds human Sortilin with a KD that ranges from about 50 nM to about 350 nM. Embodiment 78. The complex of any one of embodiments 1-77, wherein the complex binds human Sortilin with a KD that ranges from about 100 nM to about 300 nM. Embodiment 79. The complex of any one of embodiments 1-78, wherein the complex increases cellular GCase activity greater than the PGRN polypeptide alone. Embodiment 80. The complex of any one of embodiments 1-79, wherein the complex increases cellular GCase activity at least about 0.5-fold, at least about 1-fold, or at least about 2- fold greater than the PGRN polypeptide alone. Embodiment 81. The complex of any one of embodiments 1-80, wherein the complex is linked to an imaging agent. Embodiment 82. A polynucleotide encoding the complex of any one of embodiments 1-81. Embodiment 83. A vector comprising the polynucleotide of embodiment 82. Embodiment 84. A host cell comprising the vector of embodiment 83. Embodiment 85. A method of producing a complex comprising culturing the host cell of embodiment 84 so that the complex is produced, optionally wherein the method further comprises isolating the complex from the culture. Embodiment 86. An isolated complex thereof produced by the method of embodiment 85. Embodiment 87. A pharmaceutical composition comprising the complex of any one of embodiments 1-81. Embodiment 88. The pharmaceutical composition of embodiment 87, further comprising a pharmaceutically acceptable carrier.^ny-2871899 735022004340 Embodiment 89. A method of treating a neurological disease or disorder in a subject comprising administering the complex of any one of embodiments 1-81 or the pharmaceutical composition of embodiment 87 or 88 to the subject. Embodiment 90. The method of embodiment 89, wherein the neurological disease or disorder is selected from a neuropathy disorder, a neurodegenerative disease, an ocular disease disorder, a seizure disorder, a lysosomal storage disease, ischemia, a behavioral disorder, and CNS inflammation. Embodiment 91. The method of embodiment 90, wherein the neurological disease or disorder is selected from Alzheimer's disease (AD), Huntington’s disease, dystonia, ataxia, stroke, dementia, Lewy body dementia, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson's disease, Pick's disease, encephalitis, traumatic brain injury, and limbic- predominant age-related TDP-43 encephalopathy (LATE). Embodiment 92. The method of embodiment 91, wherein the dementia is frontotemporal dementia (FTD). Embodiment 93. The method of embodiment 91, wherein the neurological disease or disorder is Alzheimer’s disease. Embodiment 94. The method of embodiment 93, wherein the Alzheimer's disease is early onset Alzheimer’s disease, prodromal Alzheimer’s disease, mild Alzheimer’s disease, or late onset Alzheimer’s disease. Embodiment 95. The method of embodiment 91, wherein the neurological disease or disorder is Parkinson’s disease. Embodiment 96. The method of embodiment 91, wherein the neurological disease or disorder is frontal temporal epilepsy. Embodiment 97. A method of treating a lysosomal storage disease in a subject comprising administering the complex of any one of embodiments 1-81 or the pharmaceutical composition of embodiment 87 or 88 to the subject. Embodiment 98. The method of embodiment 97, wherein the lysosomal storage disease is selected from Gaucher disease, Ceroid lipofuscinosis (Batten disease), Mucopolysaccharidosis (MPS) Type I, MPS Type II and MPS Type III.^ny-2871899 735022004340 Embodiment 99. A method of transporting a complex across the BBB of a subject, comprising administering the complex of any one of embodiments 1-81 or the pharmaceutical composition of embodiment 87 or 88 to the subject. Embodiment 100. A method of increasing the concentration of PGRN in the cerebral spinal fluid (CSF) of a subject, comprising administering the complex of any one of embodiments 1-81 or the pharmaceutical composition of embodiment 87 or 88 to the subject, wherein the concentration of PGRN is increased as compared to administering the PGRN polypeptide alone to the subject. Embodiment 101. A method of imaging PGRN within a subject, comprising administering to the subject the complex of embodiment 81 and locating the imaging agent within the subject. Embodiment 102. A method of detecting PGRN in vitro, comprising contacting an in vitro sample with the complex of embodiment 81 and locating the imaging agent within the sample. Embodiment 103. Use of the complex of any one of embodiments 1-81 or the pharmaceutical composition of embodiment 87 or 88 in the method of any one of embodiments 89-102. Embodiment 104. The complex of any one of embodiments 1-81 or the pharmaceutical composition of embodiment 87 or 88 for use in the method of any one of embodiments 89-102. Embodiment 105. A complex comprising (a) an antigen-binding domain that specifically binds to human CD98 heavy chain (CD98hc) and (b) a Progranulin (PGRN) polypeptide. Embodiment 106. The complex of embodiment 105, further comprising an Fc domain. Embodiment 107. The complex of embodiment 105 or 106, wherein the antigen-binding domain comprises a VH and a VL on separate polypeptides. Embodiment 108. The complex of any one of embodiments 105-107, wherein the complex comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and the PGRN polypeptide; and (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form the antigen-binding domain that specifically binds to human CD98hc. Embodiment 109. The complex of embodiment 108, further comprising (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a CH2 and a CH3.^ny-2871899 735022004340 Embodiment 110. The complex of embodiment 108, further comprising (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a second PGRN polypeptide. Embodiment 111. The complex of embodiment 108, further comprising: (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a second VH, a second CH1, a second hinge region, a second CH2, a second CH3, a second linker, and a second PGRN polypeptide; (iv) a fourth polypeptide comprising, from the N-terminus to the C-terminus, a second VL and a second CL; wherein the second VH and the second VL form a second antigen-binding domain that specifically binds to human CD98hc. Embodiment 112. The complex of embodiment 105, comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, and a CH3; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and the PGRN polypeptide; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form the antigen-binding domain that specifically binds to human CD98hc. Embodiment 113. The complex of embodiment 105 or 106, wherein the antigen-binding domain comprises a VH and VL on a single polypeptide chain. Embodiment 114. The complex of any one of embodiments 105, 106 and 113, wherein the antigen-binding domain comprises a single-chain fragment variable (scFv). Embodiment 115. The complex of embodiment 114, wherein the scFv is in the orientation VH-linker-VL. Embodiment 116. The complex of embodiment 114, wherein the scFv is in the orientation VL-linker-VH. Embodiment 117. The complex of embodiment 115 or embodiment 116, wherein the linker (A) is about 5 to about 25 amino acids, is about 5 to about 20 amino acids, is about 10 to about 25 amino acids, or is about 10 to about 20 amino acids and/or (B) comprises the amino acid^ny-2871899 735022004340 sequence of GGSEGKSSGSGSESKSTGGS (SEQ ID NO: 6) or GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 7). Embodiment 118. The complex of any one of embodiments 105, 106, and 113-117, comprising (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the PGRN polypeptide, a first Fc domain, and the antigen-binding domain and (ii) a second polypeptide comprising a second Fc domain. Embodiment 119. The complex of embodiment 105 or 106 comprising (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the PGRN polypeptide and a first Fc domain and (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a second Fc domain and the antigen-binding domain. Embodiment 120. The complex of any one of embodiments 105-107, comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the PGRN polypeptide and a first Fc domain, (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, and a second Fc domain, and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form the antigen-binding domain that specifically binds to human CD98hc. Embodiment 121. The complex of any one of embodiments 105, 106, and 113, comprising (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the PGRN polypeptide, a first Fc domain, and the antigen-binding domain and (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a second PGRN polypeptide and a second Fc domain. Embodiment 122. The complex of embodiment 121, wherein the second polypeptide comprises, from the N-terminus to the C-terminus, the second PGRN polypeptide, the second Fc domain, and a second antigen-binding domain that specifically binds CD98hc. Embodiment 123. The complex of any one of embodiments 105-122, wherein the antigen- binding domain is a murine, chimeric, humanized, or human antigen-binding domain, optionally wherein the antigen-binding domain is a humanized antigen-binding domain.^ny-2871899 735022004340 Embodiment 124. The complex of any one of embodiments 105-123, wherein the Fc domain is capable of binding FcRn. Embodiment 125. The complex of embodiment 105, further comprising an Fc region, wherein the Fc region comprises a first and second polypeptide chain. Embodiment 126. The complex of embodiment 125, wherein the Fc region is capable of binding FcRn. Embodiment 127. The complex of embodiment 125 or embodiment 126, comprising (i) a single scFv or VHH or Fab antigen-binding domain that binds to human CD98hc and (ii) and two copies of the PGRN polypeptide. Embodiment 128. The complex of embodiment 127, wherein the single scFv, Fab or VHH antigen-binding domain that binds to human CD98hc is linked to the C-terminus of one of the two copies of the PGRN polypeptide. Embodiment 129. The complex of embodiment 127, wherein one of the two copies of the PGRN polypeptide is linked to the N-terminus of the first polypeptide chain of the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the N-terminus of the second polypeptide chain of the Fc region. Embodiment 130. The complex of embodiment 127, wherein the single scFv, Fab, or VHH antigen-binding domain that binds to human CD98hc is linked to the N-terminus of the first or second polypeptide chain of the Fc region. Embodiment 131. The complex of embodiment 127, wherein one of the two copies of the PGRN polypeptide is linked to the C-terminus of the first polypeptide chain of the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the C-terminus of the second polypeptide chain of the Fc region. Embodiment 132. The complex of embodiment 125 or embodiment 126, comprising (i) an antibody that binds to human CD98hc, wherein the antibody comprises two heavy chains and two light chains; and (ii) two copies of the PGRN polypeptide, wherein each copy of the PGRN polypeptide is linked to the C-termini of one of the two antibody heavy chains. Embodiment 133. The complex of embodiment 125 or embodiment 126, comprising (i) two scFv, Fab, or VHH antigen-binding domains that bind to human CD98hc, (ii) the Fc region; and (iii) two copies of the PGRN polypeptide, wherein one of the two scFv, Fab, or VHH antigen- binding domains that binds to human CD98hc is linked to the C-terminus of the first polypeptide^ny-2871899 735022004340 chain of the Fc region, wherein the other scFv, Fab, or VHH antigen-binding domains that binds to human CD98hc is linked to the C-terminus of the second polypeptide chain of the Fc region, wherein one of the two copies of the PGRN polypeptide is linked to the N-terminus of the first polypeptide chain of the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the N-terminus of the second polypeptide chain of the Fc region. Embodiment 134. The complex of embodiment 125 or embodiment 126, comprising (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the C-terminus of the first or second polypeptide chain of the Fc region and the PGRN polypeptide is linked to N-terminus of the first or second polypeptide chain of the Fc region. Embodiment 135. The complex of embodiment 106, comprising (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the C-terminus of the Fc domain and the PGRN polypeptide is linked to N-terminus of the Fc domain. Embodiment 136. The complex of embodiment 125 or embodiment 126, comprising (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc, (ii) the Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the N-terminus of the first or second polypeptide chain of the Fc region and the PGRN polypeptide is linked to the C-terminus of the first or second polypeptide chain of the Fc region. Embodiment 137. The complex of embodiment 106, comprising (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc, (ii) the Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the N-terminus of the Fc domain and the PGRN polypeptide is linked to the C-terminus of the Fc domain. Embodiment 138. The complex of embodiment 125 or embodiment 126, comprising (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the N-terminus of one of the^ny-2871899 735022004340 two polypeptide chains of the Fc region, and wherein the PGRN polypeptide is linked to the N- terminus of the other polypeptide chain of the Fc region. Embodiment 139. The complex of any one of embodiments 125-134, 136, and 138, wherein the Fc region is a heterodimeric Fc region, optionally comprising knob and hole mutations. Embodiment 140. The complex of any one of embodiments 106, 135, and 137, wherein the Fc domain is a single chain monovalent Fc domain. Embodiment 141. The complex of any one of embodiments 125-134, 136, and 138-139, wherein the Fc region is a modified Fc region with a modification listed in Table 8 or Table 9. Embodiment 142. The complex of any one of embodiments 125-134, 136, 138-139, and 141, wherein the Fc region is a human IgG1 Fc region, wherein the human IgG1 Fc region comprises a mutation that reduces effector function, optionally wherein the mutation that reduces effector function comprises: (i) L234A, L235A, and/or P331S; (ii) N325S and/or L328F; (iii) L234A, L235A, and/or P329G; or (iv) L234A, L235A, and/or P329S. Embodiment 143. The complex of any one of embodiments 106, 135, 137, and 140, wherein the Fc domain is a modified Fc domain with a modification listed in Table 8. Embodiment 144. The complex of any one of embodiments 106, 135, 137, 140, and 143, wherein the Fc domain is a human IgG1 Fc domain, wherein the human IgG1 Fc domain comprises a mutation that reduces effector function, optionally wherein the mutation that reduces effector function comprises: (i) L234A, L235A, and/or P331S; (ii) N325S and/or L328F; (iii) L234A, L235A, and/or P329G; or (iv) L234A, L235A, and/or P329S. Embodiment 145. The complex of any one of embodiments 105-144, wherein the antigen- binding domain comprises a VH comprising a VH CDR1, VH CDR2, and VH CDR3, and a VL comprising a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences comprise the amino acid sequences of: (i) SEQ ID NOs: 181, 185, 191, 194, 198, and 201, respectively; (ii) SEQ ID NOs: 182, 186, 191, 195, 199, and 202, respectively; (iii) SEQ ID NOs: 183, 187, 192, 196, 200, and 203, respectively; (iv) SEQ ID NOs: 9, 188, 192, 196, 200, and 203, respectively; (v) SEQ ID NOs: 184, 189, 193, 197, 198, and 204, respectively; (vi) SEQ ID NOs: 184, 190, 193, 197, 198, and 204, respectively; (vii) SEQ ID NOs: 184, 324, 193, 197, 198, and 204, respectively;^ny-2871899 735022004340 (viii) SEQ ID NOs: 184, 325, 193, 197, 198, and 204, respectively; or (ix) SEQ ID NOs: 184, 326, 193, 197, 198, and 204, respectively. Embodiment 146. The complex of embodiment 145, wherein the VH comprises the amino acid sequence of SEQ ID NO: 205, 206, 207, 208, 209, 210, 327, 328, or 329. Embodiment 147. The complex of embodiment 145 or 146, wherein the VL comprises the amino acid sequence of SEQ ID NO: 211, 212, 213, 214, 215, or 216. Embodiment 148. The complex of embodiment 146 or 147, wherein the VH and the VL comprise the amino acid sequences of: (i) SEQ ID NOs: 205 and 211, respectively; (ii) SEQ ID NOs: 206 and 212, respectively; (iii) SEQ ID NOs: 207 and 213, respectively; (iv) SEQ ID NOs: 208 and 214, respectively; (i) SEQ ID NOs: 209 and 215, respectively; (ii) SEQ ID NOs: 210 and 216, respectively; (iii) SEQ ID NOs: 327 and 216, respectively; (iv) SEQ ID NOs: 328 and 216, respectively; or (v) SEQ ID NOs: 329 and 216, respectively. Embodiment 149. The complex of any one of embodiments 105-144, wherein the antigen- binding domain is a VHH comprising: (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 181, 185, and 191, respectively; (ii) SEQ ID NOs: 182, 186, and 191, respectively; (iii) SEQ ID NOs: 183, 187, and 192, respectively; (iv) SEQ ID NOs: 9, 188, and 192, respectively; (v) SEQ ID NOs: 184, 189, and 193, respectively; (vi) SEQ ID NOs: 184, 190, and 193, respectively; (vii) SEQ ID NOs: 184, 324, and 193, respectively; (viii) SEQ ID NOs: 184, 325, and 193, respectively; or (ix) SEQ ID NOs: 184, 326, and 193, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 205, 206, 207, 208, 209, 210, 327, 328, or 329.^ny-2871899 735022004340 Embodiment 150. The complex of any one of embodiments 105-144, wherein the antigen- binding domain comprises a VH comprising a VH CDR1, VH CDR2, and VH CDR3, and a VL comprising a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences comprise the amino acid sequences of: (i) SEQ ID NOs: 184, 352, 193, 197, 198, and 204, respectively; (ii) SEQ ID NOs: 184, 353, 193, 197, 198, and 204, respectively; (iii) SEQ ID NOs: 184, 354, 193, 197, 198, and 204, respectively; (iv) SEQ ID NOs: 184, 355, 193, 197, 198, and 204, respectively; (v) SEQ ID NOs: 184, 356, 193, 197, 198, and 204, respectively; (vi) SEQ ID NOs: 184, 357, 193, 197, 198, and 204, respectively; (vii) SEQ ID NOs: 184, 358, 193, 197, 198, and 204, respectively; (viii) SEQ ID NOs: 184, 190, 193, 369, 198, and 204, respectively; (ix) SEQ ID NOs: 184, 190, 193, 370, 198, and 204, respectively; (x) SEQ ID NOs: 184, 190, 193, 371, 198, and 204, respectively; (xi) SEQ ID NOs: 184, 190, 193, 372, 198, and 204, respectively; (xii) SEQ ID NOs: 184, 190, 193, 373, 198, and 204, respectively; (xiii) SEQ ID NOs: 184, 190, 193, 374, 198, and 204, respectively; (xiv) SEQ ID NOs: 184, 190, 193, 375, 198, and 204, respectively; (xv) SEQ ID NOs: 184, 354, 193, 371, 198, and 204, respectively; (xvi) SEQ ID NOs: 184, 359, 193, 197, 198, and 204, respectively; (xvii) SEQ ID NOs: 184, 190, 360, 197, 198, and 204, respectively; (xviii) SEQ ID NOs: 184, 190, 361, 197, 198, and 204, respectively; (xix) SEQ ID NOs: 184, 190, 362, 197, 198, and 204, respectively; (xx) SEQ ID NOs: 184, 190, 363, 197, 198, and 204, respectively; (xxi) SEQ ID NOs: 184, 190, 364, 197, 198, and 204, respectively; (xxii) SEQ ID NOs: 184, 190, 365, 197, 198, and 204, respectively; (xxiii) SEQ ID NOs: 184, 190, 366, 197, 198, and 204, respectively; (xxiv) SEQ ID NOs: 184, 190, 367, 197, 198, and 204, respectively; (xxv) SEQ ID NOs: 184, 190, 368, 197, 198, and 204, respectively; (xxvi) SEQ ID NOs: 184, 190, 193, 376, 198, and 204, respectively; (xxvii) SEQ ID NOs: 184, 190, 193, 377, 198, and 204, respectively;^ny-2871899 735022004340 (xxviii) SEQ ID NOs: 184, 190, 193, 378, 198, and 204, respectively; (xxix) SEQ ID NOs: 184, 190, 193, 379, 198, and 204, respectively; (xxx) SEQ ID NOs: 184, 190, 193, 380, 198, and 204, respectively; (xxxi) SEQ ID NOs: 184, 190, 193, 381, 198, and 204, respectively; (xxxii) SEQ ID NOs: 184, 190, 193, 197, 198, and 382, respectively; (xxxiii) SEQ ID NOs: 184, 190, 193, 197, 198, and 383, respectively; (xxxiv) SEQ ID NOs: 184, 190, 193, 197, 198, and 384, respectively; (xxxv) SEQ ID NOs: 184, 190, 193, 197, 198, and 385, respectively; (xxxvi) SEQ ID NOs: 184, 190, 193, 197, 198, and 386, respectively; (xxxvii) SEQ ID NOs: 184, 190, 193, 197, 198, and 387, respectively; (xxxviii) SEQ ID NOs: 184, 190, 193, 197, 198, and 388, respectively; (xxxix) SEQ ID NOs: 184, 190, 193, 197, 198, and 389, respectively; (xl) SEQ ID NOs: 184, 190, 193, 197, 198, and 390, respectively; (xli) SEQ ID NOs: 184, 190, 193, 197, 198, and 391, respectively; (xlii) SEQ ID NOs: 351, 190, 193, 197, 198, and 204, respectively; or (xliii) SEQ ID NOs: 351, 190, 193, 197, 198, and 391, respectively. Embodiment 151. The complex of embodiment 150, wherein the VH comprises the amino acid sequence of SEQ ID NO: 210, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, or 409. Embodiment 152. The complex of embodiment 150 or 151, wherein the VL comprises the amino acid sequence of SEQ ID NO: 215, 216, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, or 432. Embodiment 153. The complex of embodiment 151 or 152, wherein the VH and the VL comprise the amino acid sequences of: (i) SEQ ID NOs: 392 and 216, respectively; (ii) SEQ ID NOs: 393 and 216, respectively; (iii) SEQ ID NOs: 394 and 216, respectively; (iv) SEQ ID NOs: 395 and 216, respectively; (v) SEQ ID NOs: 396 and 216, respectively; (vi) SEQ ID NOs: 397 and 216, respectively; (vii) SEQ ID NOs: 398 and 216, respectively;^ny-2871899 735022004340 (viii) SEQ ID NOs: 210 and 410, respectively; (ix) SEQ ID NOs: 210 and 411, respectively; (x) SEQ ID NOs: 210 and 412, respectively; (xi) SEQ ID NOs: 210 and 413, respectively; (xii) SEQ ID NOs: 210 and 414, respectively; (xiii) SEQ ID NOs: 210 and 415, respectively; (xiv) SEQ ID NOs: 210 and 416, respectively; (xv) SEQ ID NOs: 394 and 412, respectively; (xvi) SEQ ID NOs: 399 and 216, respectively; (xvii) SEQ ID NOs: 400 and 216, respectively; (xviii) SEQ ID NOs: 401 and 216, respectively; (xix) SEQ ID NOs: 402 and 216, respectively; (xx) SEQ ID NOs: 403 and 216, respectively; (xxi) SEQ ID NOs: 404 and 216, respectively; (xxii) SEQ ID NOs: 405 and 216, respectively; (xxiii) SEQ ID NOs: 406 and 216, respectively; (xxiv) SEQ ID NOs: 407 and 216, respectively; (xxv) SEQ ID NOs: 408 and 216, respectively; (xxvi) SEQ ID NOs: 210 and 417, respectively; (xxvii) SEQ ID NOs: 210 and 418, respectively; (xxviii) SEQ ID NOs: 210 and 419, respectively; (xxix) SEQ ID NOs: 210 and 420, respectively; (xxx) SEQ ID NOs: 210 and 421, respectively; (xxxi) SEQ ID NOs: 210 and 422, respectively; (xxxii) SEQ ID NOs: 210 and 423, respectively; (xxxiii) SEQ ID NOs: 210 and 424, respectively; (xxxiv) SEQ ID NOs: 210 and 425, respectively; (xxxv) SEQ ID NOs: 210 and 426, respectively; (xxxvi) SEQ ID NOs: 210 and 427, respectively; (xxxvii) SEQ ID NOs: 210 and 428, respectively; (xxxviii) SEQ ID NOs: 210 and 429, respectively;^ny-2871899 735022004340 (xxxix) SEQ ID NOs: 210 and 430, respectively; (xl) SEQ ID NOs: 210 and 431, respectively; (xli) SEQ ID NOs: 210 and 432, respectively; (xlii) SEQ ID NOs: 409 and 215, respectively; or (xliii) SEQ ID NOs: 409 and 432, respectively. Embodiment 154. The complex of any one of embodiments 105-144, wherein the antigen- binding domain specifically binds to human CD98 heavy chain (CD98hc), and wherein the antigen-binding domain is a VHH comprising: (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 184, 352, and 193, respectively; (ii) SEQ ID NOs: 184, 353, and 193, respectively; (iii) SEQ ID NOs: 184, 354, and 193, respectively; (iv) SEQ ID NOs: 184, 355, and 193, respectively; (v) SEQ ID NOs: 184, 356, and 193, respectively; (vi) SEQ ID NOs: 184, 357, and 193, respectively; (vii) SEQ ID NOs: 184, 358, and 193, respectively; (viii) SEQ ID NOs: 184, 190, and 193, respectively; (ix) SEQ ID NOs: 184, 359, and 193, respectively; (x) SEQ ID NOs: 184, 190, and 360, respectively; (xi) SEQ ID NOs: 184, 190, and 361, respectively; (xii) SEQ ID NOs: 184, 190, and 362, respectively; (xiii) SEQ ID NOs: 184, 190, and 363, respectively; (xiv) SEQ ID NOs: 184, 190, and 364, respectively; (xv) SEQ ID NOs: 184, 190, and 365, respectively; (xvi) SEQ ID NOs: 184, 190, and 366, respectively; (xvii) SEQ ID NOs: 184, 190, and 367, respectively; (xviii) SEQ ID NOs: 184, 190, and 368, respectively; or (xix) SEQ ID NOs: 351, 190, and 193, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 210, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, or 409.^ny-2871899 735022004340 Embodiment 155. The complex of any one of the preceding embodiments, wherein the PGRN polypeptide comprises an amino acid sequence set forth in SEQ ID NO:230. Embodiment 156. The complex of any one of embodiments 105-154, wherein the PGRN mutant polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 247, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 260, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. Embodiment 157. The complex of any one of embodiments 105-156, wherein the complex is linked to an imaging agent. Embodiment 158. A polynucleotide encoding the complex of any one of embodiments 105- 157. Embodiment 159. A vector comprising the polynucleotide of embodiment 158. Embodiment 160. A host cell comprising the vector of embodiment 159. Embodiment 161. A method of producing a complex comprising culturing the host cell of embodiment 160 so that the complex is produced, optionally wherein the method further comprises isolating the complex from the culture. Embodiment 162. An isolated complex thereof produced by the method of embodiment 161. Embodiment 163. A pharmaceutical composition comprising the complex of any one of embodiments 105-157. Embodiment 164. The pharmaceutical composition of embodiment 163, further comprising a pharmaceutically acceptable carrier. Embodiment 165. A method of treating a neurological disease or disorder in a subject comprising administering the complex of any one of embodiments 105-157 or the pharmaceutical composition of embodiment 163 or 164 to the subject. Embodiment 166. The method of embodiment 165, wherein the neurological disease or disorder is selected from a neuropathy disorder, a neurodegenerative disease, an ocular disease^ny-2871899 735022004340 disorder, a seizure disorder, a lysosomal storage disease, ischemia, a behavioral disorder, and CNS inflammation. Embodiment 167. The method of embodiment 166, wherein the neurological disease or disorder is selected from Alzheimer's disease (AD), Huntington’s disease, dystonia, ataxia, stroke, dementia, Lewy body dementia, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson's disease, Pick's disease, encephalitis, traumatic brain injury, and limbic- predominant age-related TDP-43 encephalopathy (LATE). Embodiment 168. The method of embodiment 167, wherein the dementia is frontotemporal dementia (FTD). Embodiment 169. The method of embodiment 167, wherein the neurological disease or disorder is Alzheimer’s disease. Embodiment 170. The method of embodiment 169, wherein the Alzheimer's disease is early onset Alzheimer’s disease, prodromal Alzheimer’s disease, mild Alzheimer’s disease, or late onset Alzheimer’s disease. Embodiment 171. The method of embodiment 167, wherein the neurological disease or disorder is Parkinson’s disease. Embodiment 172. The method of embodiment 165, wherein the neurological disease or disorder is frontal temporal epilepsy. Embodiment 173. A method of treating a lysosomal storage disease in a subject comprising administering the complex of any one of embodiments 105-157 or the pharmaceutical composition of embodiment 163 or 164 to the subject. Embodiment 174. The method of embodiment 173, wherein the lysosomal storage disease is selected from Gaucher disease, Ceroid lipofuscinosis (Batten disease), Mucopolysaccharidosis (MPS) Type I, MPS Type II and MPS Type III. Embodiment 175. A method of transporting a complex across the BBB of a subject, comprising administering the complex of any one of embodiments 105-157 or the pharmaceutical composition of embodiment 163 or 164 to the subject. Embodiment 176. A method of increasing the concentration of PGRN in the cerebral spinal fluid (CSF) of a subject, comprising administering the complex of any one of embodiments 105- 157 or the pharmaceutical composition of embodiment 163 or 164 to the subject, wherein the^ny-2871899 735022004340 concentration of PGRN is increased as compared to administering the PGRN polypeptide alone to the subject. Embodiment 177. A method of imaging PGRN within a subject, comprising administering to the subject the complex of embodiment 157 and locating the imaging agent within the subject. Embodiment 178. A method of detecting PGRN in vitro, comprising contacting an in vitro sample with the complex of embodiment 157 and locating the imaging agent within the sample. Embodiment 179. Use of the complex of any one of embodiments 105-157 or the pharmaceutical composition of embodiment 163 or 164 in the method of any one of embodiments 165-178. Embodiment 180. The complex of any one of embodiments 105-157 or the pharmaceutical composition of embodiment 163 or 164 for use in the method of any one of embodiments 165- 178. Embodiment 181. An isolated PGRN mutant polypeptide, wherein: (i) the isolated PGRN mutant polypeptide comprises a C-terminal amino acid sequence defined by X1X2X3X4, and wherein: (a) X1 is an amino acid selected from the group consisting of R, D, E, I, P, or Q; (b) X2 is an amino acid selected from the group consisting of Q and P; (c) X3 is an amino acid selected from the group consisting of L, A, C, D, F, G, H, I, K, M, N, P, Q, R, S, T, V, or Y; and/or (d) X4 is absent or is an amino acid selected from the group consisting of L, R, or V; and (ii) X2, X3, and X4 are not PIL, PFL, PPL, PYL, QRL, or QHL. Embodiment 182. The isolated PGRN mutant polypeptide of embodiment 181, wherein the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 330. Embodiment 183. The isolated PGRN mutant polypeptide of embodiment 182, wherein the amino acid sequence is selected from the group consisting of SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 259, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266.^ny-2871899 735022004340 Embodiment 184. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 231. Embodiment 185. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 232. Embodiment 186. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 233. Embodiment 187. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 234. Embodiment 188. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 235. Embodiment 189. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 236. Embodiment 190. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 237. Embodiment 191. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 238. Embodiment 192. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 239. Embodiment 193. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 240. Embodiment 194. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 241. Embodiment 195. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 242. Embodiment 196. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 243. Embodiment 197. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 244. Embodiment 198. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 245.^ny-2871899 735022004340 Embodiment 199. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 246. Embodiment 200. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 248. Embodiment 201. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 249. Embodiment 202. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 250. Embodiment 203. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 251. Embodiment 204. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 252. Embodiment 205. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 253. Embodiment 206. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 254. Embodiment 207. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 255. Embodiment 208. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 256. Embodiment 209. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 257. Embodiment 210. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 259. Embodiment 211. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 261. Embodiment 212. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 262. Embodiment 213. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 263.^ny-2871899 735022004340 Embodiment 214. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 264. Embodiment 215. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 265. Embodiment 216. The isolated PGRN mutant polypeptide of embodiment 183, wherein the amino acid sequence is SEQ ID NO: 266. Embodiment 217. An isolated nucleic acid encoding the isolated PGRN mutant polypeptide of any one of embodiments 181-216. Embodiment 218. A vector comprising the nucleic acid of embodiment 217. Embodiment 219. A host cell comprising the vector of embodiment 218. Embodiment 220. A method of producing an isolated PGRN mutant polypeptide comprising culturing the host cell of embodiment 219 so that the isolated PGRN mutant polypeptide is produced, optionally wherein the method further comprises isolating the isolated PGRN mutant polypeptide from the culture. Embodiment 221. An isolated PGRN mutant polypeptide produced by the method of embodiment 220. Embodiment 222. A pharmaceutical composition comprising the isolated PGRN mutant polypeptide of any one of embodiments 181-216 and 221. Embodiment 223. A method of treating a neurological disease or disorder in a subject comprising administering the isolated PGRN mutant polypeptide of any one of embodiments 181-216 and 221 or the pharmaceutical composition of embodiment 222 to the subject. Embodiment 224. The method of embodiment 223, wherein the neurological disease or disorder is selected from a neuropathy disorder, a neurodegenerative disease, an ocular disease disorder, a seizure disorder, a lysosomal storage disease, ischemia, a behavioral disorder, and CNS inflammation. Embodiment 225. The method of embodiment 224, wherein the neurological disease or disorder is selected from Alzheimer's disease (AD), Huntington’s disease, dystonia, ataxia, stroke, dementia, Lewy body dementia, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson's disease, Pick's disease, encephalitis, traumatic brain injury, and limbic- predominant age-related TDP-43 encephalopathy (LATE).^ny-2871899 735022004340 Embodiment 226. The method of embodiment 225, wherein the dementia is frontotemporal dementia (FTD). Embodiment 227. The method of embodiment 225, wherein the neurological disease or disorder is Alzheimer’s disease. Embodiment 228. The method of embodiment 227, wherein the Alzheimer's disease is early onset Alzheimer’s disease, prodromal Alzheimer’s disease, mild Alzheimer’s disease, or late onset Alzheimer’s disease. Embodiment 229. The method of embodiment 225, wherein the neurological disease or disorder is Parkinson’s disease. Embodiment 230. The method of embodiment 223, wherein the neurological disease or disorder is frontal temporal epilepsy. Embodiment 231. A method of treating a lysosomal storage disease in a subject comprising administering the isolated PGRN mutant polypeptide of any one of embodiments 181-216 and 221 or the pharmaceutical composition of embodiment 222 to the subject. Embodiment 232. The method of embodiment 231, wherein the lysosomal storage disease is selected from Gaucher disease, Ceroid lipofuscinosis (Batten disease), Mucopolysaccharidosis (MPS) Type I, MPS Type II and MPS Type III. Embodiment 233. A method of increasing PGRN in a subject, the method comprising administering the isolated PGRN mutant polypeptide of any one of embodiments 181-216 and 221 or the pharmaceutical composition of embodiment 222 to the subject. EXAMPLES Example 1: Engineering of Antigen-Binding Domains against Human Transferrin Receptor [0475] Mammalian expression of human, cynomolgus macaque (cyno) and mouse variants of Transferrin Receptor antigens (SEQ ID NOs: 218-224) was performed by cloning synthetic genes based on cDNA into mammalian expression vectors, followed by transient transfection and expression in Expi293 cells and purified by Ni-NTA agarose (QIAGEN 30230) using the manufacturer’s protocol. See Example 1 of WO2024026472.^ny-2871899 735022004340 Table 14: Avi-His tagged variants of TfR^ny-2871899 735022004340 [0476] Plasmid constructs each expressing full length human TfR and mouse TfR (SEQ ID NOs: 1 and 225, respectively) were used to generate CHO cells stably expressing human TfR and mouse TfR. The resulting CHO cells stably expressing human TfR and mouse TfR were analyzed for cell surface expression by flow cytometry. See Example 2 of WO2024026472.^ny-2871899 735022004340 Table 15. Full-length TfR sequences [0477] Mouse lines were generated at Taconic Biosciences GmbH (Germany) to humanize the extracellular domains of TfR. CRISPR was used to replace the mouse ECD with the human^ny-2871899 735022004340 version, while retaining the mouse intracellular and transmembrane portions under the control of the mouse promotor. Brain slices from these mice were evaluated by IHC and/or Western Blot to confirm expression and localization of the human ECD in vivo (data not shown). See Example 3 of WO2024026472. [0478] Hybridomas to obtain antibodies against TfR were generated by immunizing BALB/c mice or Sprague Dawley rats with purified extracellular domain polypeptides of human/ cyno and/or mouse TfR. Lymph nodes were harvested from the mice or rats for hybridoma cell line generation. Sera from the animals were analyzed for reactivity to TfR and lymphocytes from animals whose sera demonstrated strong binding were used to generate hybridoma libraries. See Example 4 of WO2024026472. [0479] A total of 1536 anti-TfR hybridoma supernatants were screened via FACS for their ability to differentially bind CHO cells overexpressing human or mouse TfR compared to CHO parental cells. A total of 189 mouse hybridoma and 115 rat hybridoma clones displayed greater than 3-fold difference in binding (as determined by MFI) to CHO cells stably overexpressing human TfR compared to isotype control. See Example 5 of WO2024026472. [0480] Hybridoma culture supernatants from 319 hybridomas obtained as described above were screened for their ability to bind Avi-His-tagged huTfR ECD, huTfR apical domain, and muTfR ECD) as compared to binding to an irrelevant Avi-His-tagged control protein. From this hybridoma supernatant screen, a total of 112 anti-TfR hybridoma clones were identified that displayed greater than 5-fold difference in binding to recombinant huTfR Avi-His over background, and 86 of these anti-TfR hybridoma clones also bound to the huTfR apical domain. See Example 6 of WO2024026472. [0481] Anti-TfR hybridoma antibodies were purified and screened for their ability to internalize into a blood-brain barrier endothelial cell line (hCMEC/D3). Internalization into endothelial cells at the blood-brain barrier is the first stage of transcytosis across the BBB and into the brain. To identify anti-TfR antibodies with internalization ability, HCMEC/D3 cells were seeded and treated with anti-TfR antibodies. A human IgG isotype and an anti-TfR antibody with known internalization ability were included in the assay as negative and positive controls, respectively. Antibodies (TfR1-32) were found to have a fold change of internalization over an irrelevant mouse IgG antibodies in a range from 1-2 fold to 714.7 fold. See Example 7 of WO2024026472.^ny-2871899 735022004340 [0482] Anti-TfR antibodies from hybridomas were then cloned and out of 72 apical domain positive anti-TfR hybridoma clones, a total 32 unique sequences were identified. Out of 24 apical domain positive anti-TfR hybridoma clones from rats, an additional 21 unique sequences were identified. See Example 8 of WO2024026472. [0483] Example anti-TfR antibody sequences are shown in Table 2, Table 3, and Table 4 above. [0484] Anti-TfR antibodies were then reformatted into a 2 +1 bispecific antibody format. Antibodies were selected for reformatting based on various criteria: 1) the antibodies covered a broad range of affinities based on ELISA and FACS binding assays, 2) the antibodies covered a broad range of internalization activity, 3) no outstanding high-risk modification sites were identified in the CDRs, and 4) the antibodies were phylogenetically diverse from each other within the hybridoma sequences obtained. An IgG isotype antibody with no target specificity (“inert isotype control antibody”) with knob-hole mutations in the constant domains of the heavy chains was used for formatting into a 2+1 bispecific antibody. An example structure of a 2+1 bispecific antibody comprised the following components: 1) Isotype control hIgG1 wildtype antibody with a knob ((T366W) mutation and a hole mutation (T366S_L368A_Y407V) in the constant regions, 2) a (G4S)x3 linker (SEQ ID NO: 179) between the “hole side” of the hIgG1 antibody and a scFv, 3) a VH sequence of the scFv, 4) a 20 amino acid linker sequence between the VH and VL of the scFv, and 5) a VL sequence of the scFv. See Example 9 of WO2024026472. [0485] Once converted into a 2 +1 antibody format, anti-TfR hybridoma antibodies were confirmed to retain TfR binding via ELISA and FACs. In total, 28 out of 32 reformatted antibodies retained binding affinity against TfR in the 2+1 format. Importantly, only 6 of the 32 antibodies (TfR6, TfR9, TfR12, TfR15, TfR19, TfR27) showed strong cyno cross-reactivity. See Example 10 of WO2024026472. [0486] Certain 2 +1 anti-TfR bispecific antibodies were tested for their ability to be internalized into the hCMEC/D3 cell line. The 2+1 anti-TfR bispecific antibodies showed a wide range of internalization capability with many showing significantly higher internalization than an anti-TfR control antibody. See Example 11 of WO2024026472. [0487] The scFv portion of certain anti-TfR antibodies were then chosen for their cross- reactivity, function, functional stability and sequence diversity for humanization. Structure-based^ny-2871899 735022004340 antibody modeling was applied in the process of humanizing anti-TfR mouse monoclonal antibodies (mAbs) utilizing the BioMOE module of MOE (Molecular Operating Environment, Chemical Computing Group, Montreal, Canada). After the BIoMOE module of MOE was used to visualize and classify potential residues for back mutation, the back potential back mutations were classified based on amino acid type difference, interaction potential with CDR residues, impact potential for VL / VH pairing, and potential change in hydrophobic and charged surface area in and near the CDRs. Mutations that were near the CDRs or the VL/VH interface, have a significant charge difference or contain strong H-bond interactions were individually evaluated and the significantly disrupting mutations were reverted back to the original query residues. As a result, humanized sequences may contain up to five back mutations. See Example 12 of WO2024026472. Certain humanized anti-TfR antibody sequences for TfR9, TfR12, and TfR15 are shown in Table 2, Table 3, and Table 4 above. [0488] To determine whether the antibodies will transport efficiently into the brain without affecting the expression level or localization of the target receptor, the effect of the 2+1 anti-TfR bispecific antibodies on recycling of the transferrin receptor in HCMEC/D3 cells were tested by both FACS and Western blot methods. To define effects of the 2+1 anti-TfR bispecific antibodies on TfR recycling, the Mean Fluorescence Intensity (MFI) for cells treated with each individual 2+1 anti-TfR bispecific antibody was normalized against that obtained for human IgG isotype. Treatment of HCMEC/D3 cells with the 2+1 anti-TfR bispecific antibodies resulted in 40-80% reduction in cell-surface expression of TfR via FACs. Antibodies named TfR9 and TfR12, were selected for further engineering and a panel of humanized antibodies were generated, some of which displayed no adverse effect on receptor recycling (i.e., TfR9.1B and TfR9.5B). In contrast, all the clones generated from TfR12 strongly impaired receptor recycling. A panel of humanized antibodies based on TfR15 were generated (see Example 15 of WO2024026472), and another antibody clone, TfR15.WH8, was identified that showed no detrimental effects on TfR recycling. See Example 13 of WO2024026472. [0489] To validate the FACS data, the total amount of TfR protein in the cell lysates obtained from HCMEC/D3 following antibody treatment was quantified by Western blot. Similar to the FACS data, treatment of HCMEC/D3 cells with 2+1 anti-TfR bispecific antibodies had either minor or no effects on the total amount of TfR protein via Western blot, with TfR9.1B in particular having no effect on total protein levels. In contrast, the total TfR protein in^ny-2871899 735022004340 HCMEC/D3 was strongly reduced upon exposure to humanized antibodies generated from TfR12. See Example 13 of WO2024026472. [0490] Humanized TfR9.1B was selected for further affinity optimization. TfR9.1B scFv was subjected to overlap extension PCR mutagenesis to generate randomized VH and VL libraries, which were packaged into bacteriophages each expressing a unique VH/VL combination and subsequently screened for TfR binding ability.46 of the 9.1B scFv variants were selected to clone into a 2 +1 bispecific format and were expressed and purified for further characterization. Clone TfR9.1B.39 was chosen as the template for an additional round of random mutagenesis to remove two potential isomerization sites (D34 in VL and D62 in VH). Using biotinylated human and cyno TfR Avi-His protein as bait for panning and ELISA for screening, seven mutants with both potential isomerization sites fixed were selected to clone 2+1 bispecific antibody vector and used for further characterization. See Example 14 of WO2024026472. [0491] Engineering of humanized TfR.15.WH8.1 variants was carried out to optimize target affinity. See Example 16 of WO2024026472. [0492] Binding kinetics of 2+2 TfR.15.WH8.1 variants (Isotype IgG with 2 anti-TfR scFvs) to Avi-His tagged human and cynomolgus TfR apical domains were evaluated. The results illustrated that these 2+2 anti-TfR bispecific antibodies exhibit a range of affinities from approximately 3 nM to >2.5 μM for TfR apical domain binding. In particular, the affinity of 2+2 anti-TfR bispecific antibodies for binding to human TfR Avi-His ranged from 6 nM to >2.5 μM; and affinity of anti-TfR antibodies of the present disclosure for binding to cynomolgus TfR Avi- His ranged from 3 nM to >2.5 μM. See Example 17 of WO2024026472. [0493] Binding kinetics of certain humanized 2+1 anti-TfR bispecific antibodies to human and cyno TfR Avi-His were evaluated. The equilibrium dissociation constants (KD) were calculated from the fitted association and dissociation rate constants (k-on and k-off) for anti-TfR Avi-His antibodies of the present disclosure. The values were combined, means and standard deviation calculated. Some antibodies displayed heterogeneous binding profiles that do not fit to a 1:1 binding model, thus their rate constants could not be determined.^ny-2871899 735022004340 Table 16. Equilibrium dissociation constants (K_D) for anti-TfR 2+1 bispecific antibodies^ny-2871899 735022004340 N=number of determinations; NT=not tested; NA=not applicable; LB=low binding (below limit of measurement); NB=no binding detected [0494] The results of these studies illustrated that these 2+1 anti-TfR bispecific antibodies exhibit a range of affinities from approximately 6 nM to 900 nM for TfR Avi-His. In particular, affinity of these 2+1 anti-TfR bispecific antibodies for binding to huTfR Avi-His ranged from 6.7 nM to 340 nM, and affinity of these anti-TfR antibodies for binding to cyno TfR Avi-His ranged from 18 nM to 870 nM. See Example 18 of WO2024026472. Example 2: Further studies of 2 +1 anti-TfR bispecific Antibodies [0495] To establish in vivo proof of concept for brain penetration of 2+1 anti-TfR bispecific antibodies, a heterozygous knock-in (KI) mouse was generated in which the ectodomain region of mouse TfR was replaced with that of human in one of the two alleles. This was because the 2+1 anti-TfR bispecific antibodies specifically bind to primate but not mouse TfR. A group of WT and hu-TfRmu/hu mice were dosed with 10 mg/kg of either isotype IgG or 2+1 anti-TfR bispecific antibodies at day 1 and 14 and blood samples were collected from antibody treated animals at different timepoints. By measuring antibody concentrations in the vessel depleted mice brains, levels of 2+1 anti-TfR bispecific antibodies were 4-5 fold higher than isotype IgG in hu-TfRmu/hu mice. In contrast, brain uptake of 2+1 anti-TfR bispecific antibodies in WT animals, which do not express target receptor, was similar to that observed for isotype IgG. These results indicated that the 2+1 anti-TfR bispecific antibodies have enhanced ability for brain entry mediated by the transferrin receptor. See Example 19 of WO2024026472. [0496] To determine if 2+1 anti-TfR bispecific antibodies dysregulate receptor recycling in target cells in vivo, the total amount of TfR protein was quantified in the vessel portion of brain tissues, collected from antibody treated animals. Using quantitative analysis, no significant differences in TfR band densities were observed between samples obtained from hu-TfR+/- KI^ny-2871899 735022004340 mice that were injected with anti-TfR antibodies (i.e., TfR-9.1B.39 and TfR-15.WH8) compared to those from isotype treated animals, which indicated that 2+1 anti-TfR bispecific antibodies do not alter TfR recycling at the blood brain barrier (BBB) in vivo. See Example 20 of WO2024026472. [0497] Anti-TfR antibodies are known to induce cell death in reticulocyte cell population in vivo. To examine this, a group of WT and hu-TfR+/- KI mice were injected with either 2+1 anti- TfR bispecific antibodies (TfR-9.1B.39 and TfR-15.WH8), a human IgG1 isotype or the previously published anti-ms TfR antibody 8D3 (Boado et al, Biotechnol Bioeng.2009 Mar 1; 102(4): 1251–1258; also referred to herein as mTfR1), which is known to drive strong depletion of reticulocytes in mice. As expected, injection of 8D3 antibody resulted in a complete loss of reticulocytes in WT animals, whereas this cell population was not altered in isotype treated animals, regardless of genotype. Similarly, no changes in reticulocytes numbers were observed in WT mice receiving anti-TfR 2+1 bispecific antibodies. In contrast, the hu-TfR+/- KI mice treated with TfR-9.1B.39 and TfR-15.WH8 displayed ~ 80% to 90% reduction in reticulocytes numbers, respectively. See Example 21 of WO2024026472. [0498] To investigate the mechanism of reticulocyte depletion seen in 2+1 anti-TfR bispecific antibodies, the ability of these same antibodies was evaluated to elicit in vitro effector responses, such as complement dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). Given that anti-TfR antibodies on wt huIgG1 backbone have been shown to elicit ADCC responses, alternative Fc formats were tested, such as N325S/L328F (NSLF) and L234A/L235A/P331S (LALAPS), which have strongly decreased binding to activating FcgRs (in particular, FcgRIIIa which is the key driver of ADCC). Two of the 2+1 anti-TfR bispecific antibodies, which elicited ADCC signal (TfR9.1B.39 and TfR15.WH8) were re-expressed in a variety of Fc formats, including wildtype hIgG1, hIgG1 NSLF and hIgG1 LALAPS and tested in the ADCC assay. In this assay, both NSLF and LALAPS were able to reduce the ADCC signal significantly, with NSLF showing >90% reduction of signal at the highest concentration tested for both 2+1 anti-Tfr bispecific antibodies tested. See Example 22 of WO2024026472. [0499] Binding kinetics of 2+1 anti-TfR bispecific antibodies to human TfR Avi-His were evaluated using a GatorBio BLI instrument (GatorBio, Palo Alto, CA). The equilibrium dissociation constants (KD) were calculated from the fitted association and dissociation rate constants (k-on and k-off) for 2+1 anti-Tfr bispecific antibodies. The values were combined,^ny-2871899 735022004340 means and standard deviation calculated, and graphs prepared using GraphPad Prism. Some antibodies, as indicated in Table 17, displayed heterogeneous binding profiles that do not fit to a 1:1 binding model, thus their rate constants could not be determined. The KD values are summarized in Table 17 below. Table 17. Equilibrium dissociation constants (K_D) for anti-TfR 2+1 antibodies N=number of determinations; NT=not tested; NA=not applicable; LB=low binding (below limit of measurement); NB=no binding detected. [0500] These results illustrate that 2+1 anti-TfR bispecific antibodies exhibit a range of affinities from approximately 30 nM to 4 μM for TfR Avi-His. Affinity of 2+1 anti-TfR bispecific antibodies for binding to human TfR Avi-His ranged from 65 nM to 3.5 μM; affinity of 2+1 anti-TfR bispecific antibodies for binding to cyno TfR Avi-His ranged from 38 nM to 2.3 μM. See Example 23 of WO2024026472. [0501] In order to evaluate the pharmacokinetics and pharmacodynamics of 2+1 anti-TfR antibodies, a 2+1 anti-TfR bi-specific antibody was generated with: (i) TfR9.1B.39.38 scFv; and (ii) a monoclonal antibody specific for human MS4A4A (referred to as “TD1”) in a 2+1 (hole) format (referred to as “TD1-TfR”). To confirm that TD1-TfR retains the function of the parental TD1 (anti-human MS4A4A) antibody, a soluble TREM2 (sTREM2) assay was conducted using human monocyte-derived macrophages. TD1-TfR showed activity by increasing sTREM2 levels^ny-2871899 735022004340 in an in vitro assay, as compared to hIgG1 and Iso-TfR. This data indicates that addition of the anti-TfR scFv to the TD1 antibody did not impair function of TD1. See Example 24 of WO2024026472. Example 3: NHP Studies for Antigen-Binding Domains against Human Transferrin Receptor [0502] A PK/PD study was conducted in naïve male cynomolgus monkeys (n=12) following intravenous (iv) dosing of 20 mg/kg of each of: Iso-TfR, TD1-TfR, TD1 and huIgG1 (isotype control) on Day 1 and 29 (total of 2 administrations). At pre-dose and following dose administration on days 3, 8, 15, 28, and 31, blood samples (~2mL) for hematology were collected from the femoral vein. Overall, no notable changes were observed in any hematology parameters, and no consistent reduction in reticulocytes was observed over the course of the study. See Examples 25 and 26 of WO2024026472. [0503] Cerebrospinal fluid (CSF) and serum were collected from the NHPs at various times following the first and second administrations and tested for antibody levels. An increased CSF Cmax was seen with TD1-TfR, when compared to TD1. An increased CSF Cmax was also seen with Iso-TfR when compared to isotype control. Further, TD1-TfR demonstrated faster serum clearance in NHPs as compared to either Iso-TfR or TD1 alone. See Example 27 of WO2024026472. [0504] Antibody levels were also assessed directly in multiple NHP brain regions (frontal cortex, entorhinal cortex and hippocampus) using vessel-depleted brain lysates. The TfR BBB targeting arm was able to increase brain uptake of (i) TD1-TfR compared to TD1 in all 3 brain regions tested (ranging from a 2- to 11-fold increase) and (ii) Iso-TfR compared to isotype parental antibody in all 3 brain regions tested (ranging from an 8 to 64 fold increase). See Example 28 of WO2024026472. [0505] CSF and serum from NHP test subjects and NHP brain lysates were further tested for downstream biomarkers of TD1 function, including sTREM2 and CSF1R. Serum levels of soluble TREM2 (sTREM2) were increased in NHPs treated with TD1-TfR as compared to TD1 alone, Iso-TfR or hIgG1 following administration of the first and the second dose. CSF-1 levels were increased in CSF from NHPs treated with TD1-TfR as compared to TD1 alone, Iso-Tfr or hIgG1. These data showed that the enhanced brain penetration also led to a stronger pharmacodynamic response. See Example 29 of WO2024026472.^ny-2871899 735022004340 [0506] Anti-TfR antibodies have been shown to be able to degrade the receptor (Niewoehner et al, Neuron 20148:49-60), which is an undesirable side effect of a BBB-penetrating anti-TfR molecule. In order to test for this effect brain tissue samples were collected from the non-human primates dosed with 2+1 anti-TfR and control antibodies and total TfR levels were quantified by an MSD method. Quantitative data analysis revealed a slight decline in TfR expression levels in the brain tissues of animals treated with 2+1 anti-TfR bispecific antibodies compared to those injected with either hIgG1 Isotype control antibody or TD1 antibody alone that was not statistically significant. These results show that 2+1 anti-TfR bispecific antibodies disclosed herein do not have a significant impact on TfR expression in vivo. See Example 30 of WO2024026472. Example 4: Engineering of Antigen-Binding Domains against human CD98 Heavy Chain [0507] Avi-His tagged variants of the extra-cellular domain (ECD) of human, cynomolgus macaque (cyno), and mouse CD98 heavy chain (CD98hc) were used were used to produce CHO cells stably expressing human CD98hc and mouse CD98hc, whose cell surface expression was confirmed by FACS. See Examples 1 and 2 of PCT/US2023/071238. Table 18. Avi-His tagged variants of CD98hc ECD^ny-2871899 735022004340 Table 19. Full Length CD98hc Sequences^ny-2871899 735022004340 [0508] Humanized mouse lines expressing human extracellular domains of CD98hc were generated (Taconic Biosciences GmbH (Germany)). CRISPR was used to replace the mouse ECD with the human version, while retaining the mouse intracellular and transmembrane portions under the control of the mouse promotor. See Example 3 of PCT/US2023/071238. [0509] To obtain antibodies against CD98hc, BALB/c mice or Sprague Dawley rats were immunized with purified ECD polypeptides of human, cyno and/or mouse CD98hc. Sera from the animals were analyzed for reactivity to CD98hc (human, mouse or cyno), and lymphocytes from animals whose sera demonstrated strong CD98hc binding were isolated and fused with myeloma fusion partners to produce hybridoma cell lines. See Example 4 of PCT/US2023/071238. [0510] From four hybridoma campaigns, 121 hybridoma clones displaying an MFI ratio greater than 2-fold for binding to CHO cells overexpressing human CD98hc, 120 out of the 121 anti-CD98hc hybridoma clones were found to bind to human and cyno CD98hc with OD450 values greater than 0.45. One hybridoma clone, CD98HC.02.020, bound to mouse CD98hc. See Examples 5 and 6 of PCT/US2023/071238. [0511] Anti-CD98hc antibodies were then tested for their ability to internalize into a blood- brain barrier endothelial cell line (hCMEC/D3) (see Example 7 of PCT/US2023/071238), and subsequently cloned (see Example 8 of PCT/US2023/071238). Certain anti-CD98hc antibodies were formatted into a 2 + 1 bispecific format. See Example 9 of PCT/US2023/071238. [0512] CD98hc binding retention of the 2 +1 bispecific antibodies was tested and cross reactivity to mouse CD98hc and cyno CD98hc was also tested, along with ability to internalize into the hCMEC/D3 cell line. Examples 11-13 of PCT/US2023/071238. [0513] Binding kinetics of the 2 +1 anti-CD98hc bispecific antibodies were tested and they were found to exhibit a range of affinities from approximately 3 nM to 200nM for CD98hc Avi-^ny-2871899 735022004340 His binding. In particular, affinity of 2+1 anti-CD98hc bispecific antibodies for binding to human CD98hc Avi-His ranged from 3.1nM to 210nM; affinity of anti-CD98hc antibodies of the present disclosure for binding to cyno CD98hc Avi-His ranged from 3.2nM to 145nM. See Example 15 of PCT/US2023/071238. [0514] The 2+ 1 anti-CD98hc bispecific antibodies were then tested for whether they affect any dysregulation of cell surface CD98hc expression and no reduction in cell-surface expression of CD98hc was found. However, certain antibodies were found to result in increased CD98hc cell surface expression and those antibodies were excluded from further development. See Example 16 of PCT/US2023/071238. [0515] Studies in mice with the anti-CD98hc bispecific antibodies showed that after antibody administration, antibody concentrations in vessel depleted brains, levels of 2+1 anti-CD98hc bispecific antibodies were determined to be up to 2-fold higher than isotype IgG in HET huCD98hc KI mice and three of the 2+1 anti-CD98hc bispecific antibodies (CD98hc.04.062, CD98hc.04.063, CD98hc.04.064) tested showed a significant (5-17) fold change in brain/serum ratio at the 24 hour timepoint tested. See Example 17 of PCT/US2023/071238. [0516] CD98hc.04.064 was humanized and further optimized to remove liabilities and optimize affinity, resulting in a 4.064 humanized panel that bound human CD98hc at a range of about 18 nM to 35 nM and cynomolgus CD98hc at a range of about 340 nM to 1.5 μM. Examples 18-21 of PCT/US2023/071238. [0517] Certain exemplary anti-CD98hc antibody sequences are shown in Table 5, Table 6, and Table 7 above._{[0518] One member of the CD98hc.04.064 humanized panel ( ) was} formatted into a bi-specific antibody with an antibody specific for human MSA4A (TD1), in a 2+1 (hole) format (TD1-CD98hc), which was intravenously injected into naïve male cynomolgus monkeys, along with a TD1 control and human IgG1, where no notable changed were observed in hematology parameters, including no consistent reduction in reticulocytes. See Examples 25 and 26 of PCT/US2023/071238. [0519] The CD98hc BBB targeting arm was further seen to be able to increase brain uptake of the TD1-CD98hc compared to TD1 alone up to 3-fold in the frontal cortex, and up to 4-fold in the entorhinal cortex, with no significant increase seen in the hippocampus, and was further able to increase serum levels of soluble TREM2. See Examples 27-29 of PCT/US2023/071238.^ny-2871899 735022004340 Example 5: Generation of PGRN mutants and anti-TfR-PGRN complexes [0520] The goal of this example was to generate PGRN mutants that possess similar biological activity to wild-type PGRN but with better stability. Better stability can be useful for the manufacturing processes using CHO cell lines. An antigen expression vector using a pcDNA plasmid to construct the PGRN mutants with a monovalent Fc (mvFc) tag and a His tag. To create a base vector, wild-type PGRN (UniProt ID: P28799) was synthesized and cloned into the pcDNA vector via infusion cloning methods (Clontech). [0521] PGRN C-terminal mutants were generated from the base vector by amplifying PGRN inserts using a forward primer for wild-type PGRN and a set of reverse primers carrying a Proline mutation or additional mutations in the C-terminal end. The resulting expression vector contained an ORF encoding PGRN (C-terminal mutants). The PGRN mutants generated are shown in Table 1. [0522] Expression vectors carrying various PGRN mutants were transfected into Expi293 and ExpiCHO cells and PGRN mutants were purified via Protein A chromatography. The purified material was used in the Carterra LSA assays (described below). [0523] Anti-TfR-PGRN mutants were generated in a similar method as described above, and transfected with both this vector and the light chain plasmid to generate the anti-TfR-PGRN constructs. Example 6: Carterra LSA kinetics measurements [0524] To determine the binding kinetics of PGRN wildtype and mutants to human sortilin protein, a kinetics assay was performed. [0525] After priming with running buffer (HBS-EP+, Teknova) with 0.5mg/ml BSA (Sigma), a HC200M Sensor Chip (Carterra, 4287) immobilized with goat anti-human IgG Fc specific antibody (Jackson ImmunoResearch) was used for capturing mvFc-tagged PGRN and mvFc- tagged PGRN mutants. A standard capture kinetics assay using huSortilin (Acrobiosystems SON-H52H5-100ug) was performed on Carterra LSA. FIGs.3A and 3B show example sensor gram data for certain PGRN mutants in HEK293 and CHO cells: mvFc-PGRN_16 (QYL C-term mutation; SEQ ID NO: 462) and mvFc-PGRN_31 (“QKL” C-term mutation; SEQ ID NO: 447). The data from the CHO cells illustrate that binding was maintained. FIG. 3C shows sensor gram data for wild-type PGRN in HEK293 and CHO cells (“APLRDPALRQLL” C-term; SEQ ID NO: 451).^ny-2871899 735022004340 [0526] Estimates of affinity were generated by injecting each analyte over the entire antibody array using the single channel flow cell. Sortilin analytes were diluted to 4.9 nM, 14.8 nM, 44.4 nM, 133.3 nM, and 400nM in running buffer, and injected serially from lowest to highest concentration with regeneration. Data were processed and analyzed using Kinetics™ high- throughput kinetics analysis software (Carterra). The results suggest that the terminal residue Leucine is important for sortilin binding whereas the -2, -3 and upstream positions are more permissive for mutation while maintaining wildtype-like sortilin binding affinity. Results are shown in Table 20. Table 20. Binding kinetics of PGRN wildtype and C-terminal mutants to human sortilin protein^ny-2871899 735022004340 Example 7: GCase Activity of Anti-TfR-PGRN Complexes using RAW 264.7 cells [0527] PGRN deficiency or loss-of-function has been shown to be associated with reduced GCase activity. To determine whether anti-TfR-PGRN complexes exhibit GCase activity, an in- vitro GCase activity assay was performed. [0528] Anti-TfR-PGRN complexes were generated with a Fab domain from a mouse anti-TfR antibody (called mTfR1) linked to a PGRN wildtype or PGRN mutant through a human Fc. Sequences for mTfR1 are found in Table 21. Table 22 shows the light chain sequence of the mTfR1-PGRN complexes. Table 23 shows the heavy chain-PGRN fusion sequences of the mTfR1-PGRN complexes. Table 24 to Table 26 show exemplary mTfR1-PGRN complex sequences. Amino acid linkers are bold and underlined. Table 21. mTfR1 Antibody Sequences^ny-2871899 735022004340 Table 22. Light Chain Sequence of mTfR1-PGRN Complexes^ny-2871899 735022004340 Table 23. Heavy Chain-PGRN Fusion Sequence of mTfR1-PGRN Complexes^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340 Table 24. “1+2” mTfR2-PGRN Complex Sequences^ny-2871899 735022004340^ny-2871899 735022004340 Table 25. “1+1 Trans” mTfR2-PGRN Complex Sequences^ny-2871899 735022004340^ny-2871899 735022004340 Table 26. “1+1 Cis” mTfR2-PGRN Complex Sequences^ny-2871899 735022004340 [0529] Purified PGRN-isotype and anti-TfR-PGRN complexes (wild type and PGRN mutants) were assayed for activity using a mouse macrophage cell line RAW 264.7 (ATCC) and the GCase substrate PFB-FDglu (Thermofisher). Cells were seeded onto 96-well microtiter plates and treated 24 hours post plating with various anti-TfR-PGRN complexes at 50nM for 48 h. Cells were then lifted with Cell Stripper and transferred to untreated U-bottom 96 well microtiter plates. Conduritol B epoxide (CBE) was used to inhibit GCase activity in negative control wells._{5-(Pentafluorobenzoylamino)Fluorescein Di- -D-Glucopyranoside (PFB-FDglu) was added to} the cells for 1 hr and then washed once before analysis on a Canto Flow Cytometer (BD) using FITC excitation. Data were analyzed using FlowJo software and plotted using GraphPad Prism. [0530] FIG. 4 shows GCase activity for various anti-TfR-PGRN complexes and controls. The anti-TfR-PGRN complexes generally induced greater GCase activity than isotype-mvFc-PGRN or PGRN alone in RAW 264.7 mouse macrophage cells.^ny-2871899 735022004340 Example 8: Cellular uptake of anti-TfR-PGRN complexes into bEND.3 cells [0531] To determine the extent of cellular uptake of anti-TfR-PGRN complexes into brain endothelial-like cells, an acute cell trafficking assay was performed. Mouse brain endothelioma cell line bEND.3 was seeded onto 96 well microtiter plates and after 24hrs, the cells were incubated with various anti-TfR-PGRN complexes diluted into fresh media. After the 2 hr incubation, the cells were washed once in PBS, fixed in paraformaldehyde, and blocked in 1% BSA, 0.2% saponin diluted into PBS for 1 hr. Anti-huPGRN antibodies (R&D) were added overnight and detected with anti-goat secondary labeled with Alexa-Fluor-647 and anti-hu IgG antibody labeled with Alexa-Fluor-594. Nuclei were labeled with DAPI. Images were obtained using the Operetta CLS (Revvity) and spot areas were quantified to compare extent of complex uptake. [0532] FIG. 5 shows images from the cellular uptake assay using the following: mTfR1- PGRN as a monovalent Fc (mvFc) format, an isotype IgG-PGRN (mvFc format), a mTfR1- PGRN (cis format), an iso-PGRN (cis format), mTfR1-PGRN in a trans format, an iso-PGRN (trans format), an iso-PGRN (1+2) format, a mTfR1-PGRN (1+2 format), a His-tagged PGRN control and untreated control. The images show higher cellular uptake for anti-TfR PGRN complexes, as visualized with an anti-huFc secondary antibody. [0533] FIGs. 6A-6B show quantification of the cellular uptake of anti-TfR-PGRN complexes in bEND.3 cells. Two doses of anti-TfR-PGRN complexes were administered to the cells (50 nM or 150 nM). In FIG.6A, cellular uptake of PGRN measured by human Fc detection was greater for proteins fused to mTfR1 (either in mvFc, cis, trans, or 1+2 formats) than complexes without mTfR (iso-PGRN in mvFc, cis, trans or 1+2 formats) or PGRN alone. In FIG.6B, detection of endocytosed PGRN complexes were with anti-human PGRN. Similar to FIG. 6A, greater uptake is observed for proteins fused to mTfR1 (either in mvFc, cis, trans, or 1+2 formats) than complexes without mTfR (iso-PGRN in mvFc, cis, trans or 1+2 formats) or PGRN alone. A greater dose-range effect is observed with anti-huFc detection and quantification. Example 9: In vivo mouse studies with anti-TfR-PGRN complexes [0534] To assess peripheral clearance and effects on various endpoint readouts, a single dose acute study will be conducted following an i.v. dose of anti-TfR-PGRN complexes into Grn knock-out (KO) mice. The Grn KO mice will have endogenous mouse TfR and anti-TfR-PGRN complexes with msTfR binding properties will be administered. At 24 hrs post dosing, the 278^ny-2871899 735022004340 serum, brains, spleens, and livers will be harvested and snap frozen for subsequent analysis of BMP species, glucosylsphingosine, and levels of anti-TfR-PGRN complexes. A single dose, 2- week durability study will also be conducted to assess effects of anti-TfR-PGRN complexes on Grn KO readouts. [0535] Additional multi-dose studies including a once weekly dose for 6 to 12 weeks or biweekly dosing will be tested. The readouts in these longer-term studies will include analysis of BMP species, glucosylsphingosine, and levels of anti-TfR-PGRN complexes in the brain, liver, spleen. In addition, one hemibrain will be processed for immunofluorescence labeling and assessed for levels of GFAP, Iba1, and C1q. CSF will be collected and analyzed for levels of NfL. Trem2 and cytokine levels will be assessed in the brain lysates. Anti-CD4 antibody will be co-administered to suppress a T-cell response and prevent the production of anti-drug antibodies (ADA). Example 10: Generation of Affinity-Tuned Anti-TfR Antibodies [0536] To generate affinity-tuned TfR antibodies, humanized anti-TfR antibodies TfR.9.1B.39.38, TfR.15.WH8.1.24A, and TfR.15.WH8.1.42Q were selected for further affinity tuning. The generation of humanized antibodies TfR.9.1B.39.38, TfR.15.WH8.1.24A and TfR.15.WH8.1.42Q was described in International Publication No. WO2024/026472. Amino acid substitutions at selected positions in the CDRs were performed to generate affinity variants. The variants were expressed in Expi293 culture and either supernatant or purified protein was used for screening. [0537] The antibody sequences of the affinity-tuned anti-TfR antibodies (or “affinity variants”) are provided in Table 27 to Table 29 below. Table 27. Heavy Chain CDR Sequences of Anti-TfR Antibodies^ny-2871899 735022004340 Table 28. Light Chain CDR Sequences of Anti-TfR Antibodies^ny-2871899 735022004340 Table 29. VH and VL Sequences of Anti-TfR Antibodies^ny-2871899 735022004340^ny-2871899 735022004340 Example 11: Assessment of Affinity of Anti-TfR Antibodies [0538] To assess the affinity of anti-TfR antibodies, a Biacore T200 instrument was used to evaluate the binding kinetics (Global Life Sciences Solutions USA LLC, Marlborough, MA). The anti-TfR antibodies were formatted as scFvs with a monovalent format. Anti-TfR antibodies were prepared by dilution in running buffer HBS-EP+ (Teknova) with BSA (MP Biomedicals) and captured by an anti-Fab antibody (Cat. 28958325, Cytiva) immobilized on a CM4 Sensor S Series sensor chip surface (Cytiva) that was prepared according to the manufacturer’s recommendations. A fixed concentration of molecules was captured on flow cell. A concentration series of human or cyno apical TfR analyte was then injected over all four flow cells, followed by dissociation. Blank injections were performed and used for double- referencing. All surfaces were regenerated with 10 mM glycine pH 2.1 buffer (Cytiva) at the end of each injection cycle. Data were processed and analyzed using Biacore T200 BiaEvaluation software (Cytiva). Results for the various anti-TfR antibodies are shown in Table 30. Table 30: Affinities of anti-TfR antibodies (in Fab format)^ny-2871899 735022004340 Example 12: Nonspecific binding assay (BVP and dsDNA) [0539] To assess nonspecific binding of the anti-TfR with varying affinities (“affinity variants”), an ELISA assay was performed to assess binding to baculovirus particles (BVP), and double stranded DNA (dsDNA). BVP particles derived from insect cells contain phospholipid, carbohydrate, glycoproteins, extracellular matrix, nucleic acids, viral capsid, allowing for detection of electrostatic and hydrophobic interactions (Hotzel et al., mAbs, 2012). dsDNA is one of the agents used in ELISA assay to study polyreactivity in natural antibody repertoires during B-cell maturation. Majority of the antibodies expressed from early immature B cells showed ELISA binding to dsDNA, ssDNA, insulin, and LPS (Wardemann et al., 2003). [0540] An ELISA plate was coated with either BVP particles or dsDNA, washed and incubated with blocking buffer, washed and incubated with the samples, followed by detection with anti-human IgG HRP antibody. A BVP score was calculated from the OD450 value of the sample wells to the background (no protein) wells. [0541] Anti-TfR affinity variants in Table 31 were tested for nonspecific binding to BVP and dsDNA. In the BVP binding assay, the following concentrations of each antibody were tested: 1 μM, 0.33 μM, 0.11 μM or 0.037 μM. Control antibodies (isotype, negative and positive control) were also tested at these concentrations. In the dsDNA binding assay, antibodies were tested at 10 μg/mL. Table 31. Anti-TfR Antibodies Tested for Non-specific Binding to BVP and dsDNA^ny-2871899 735022004340 [0542] As shown in FIGs. 7A and 7B, all anti-TfR affinity variants showed low BVP scores. As shown in FIGs.8A and 8B, all anti-TfR affinity variants showed low dsDNA binding. Example 13: Developability Assessment of Anti-TfR Affinity Variants [0543] The physiochemical and biochemical properties of a protein can impact protein stability and can pose potential manufacturability risks. In this study, a developability assessment was conducted by testing selected anti-TfR antibodies in IgG format, in order to determine and identify these characteristics. Several analytical techniques were utilized as shown in Table 32 below, demonstrating that the properties of those selected anti-TfR antibodies met the criteria for developability. Table 32: Developability Overview for Selected Anti-TfR Affinity Variants^ny-2871899 735022004340 Example 14: In-vitro Cell Uptake of Anti-TfR Affinity Variants [0544] Anti-human TfR affinity variant antibodies were assessed for extent of cell uptake using hCMEC/D3 cells in an acute 2-hour incubation assay. Anti-TfR affinity variants were fused to an N-terminus of a monovalent Fc (mvFc), with an isotype control scFv fused to the C- terminus of the mvFc (“anti-TfR Fab-mvFc-Iso-scFv”) and were assessed by a 2-point titration at 500 nM and 100 nM concentration. The following anti-TfR antibodies were tested: H6-4, H3-7, 24A, L7-2, L10-16, 24A.42Q, L10-1, L-35, L10-8, 42Q and an isotype control. FIG.9 shows the detection of the anti-TfR antibodies at 500 nM concentration. Cell uptake was observed for anti- TfR antibodies but not for the isotype control antibody (in an Iso Fab-mvFc – Iso scFv format). Generally, the extent of cell uptake correlated with the affinity of the antibodies (see FIG.9). The cell uptake was proportionally weaker when incubated at the lower dose of 100 nM (data not shown). Example 15: Brain Uptake of Anti-TfR Affinity Variants [0545] In vivo studies were conducted to determine the brain penetration of a panel of anti-TfR antibodies with varying affinities to human transferrin receptor (TfR) apical domain ranging from double digit nM to single digit uM (see Table 30). huTfR KI mice were injected with a single dose of antibody in a monovalent format to determine the brain uptake at the 24-hour time^ny-2871899 735022004340 point. Brain uptake was determined from both vessel-depleted and whole brain fractions to assess whether the higher affinity anti-TfR antibodies were retained in the brain vasculature. [0546] To produce vessel depleted brain fractions, brain tissues were minced and homogenized in HBSS buffer (MilliporeSigma #55037C) containing 10 mM HEPES (#15630130, Gibco) using a hand-operated tissue grinder. Subsequently, samples were centrifuged to separate the vessel portion from the parenchymal portion, lysed in RIPA with protease inhibitors, and total protein concentration in the lysates was determined by BCA Assay (Pierce #23225). Lysates were subsequently frozen on dry ice and stored at 80°C until analysis. [0547] Antibody concentrations in the brain were measured using an MSD (Meso Scale Discovery) assay. Antibody concentrations were normalized to the total protein concentration in the lysate and then graphed as either antibody concentration (ng antibody/mg total protein), or fold-change over the format matched isotype control antibody. [0548] At 24-hour post i.v. injection, an increase in brain uptake in vessel depleted brain was observed for all anti-TfR antibodies as compared to the format-matched isotype control (FIGs. 10A and 10B). FIG.10A shows brain uptake of various anti-TfR affinity variants (administered at 5 mg/kg) after 24 hrs in vessel-depleted brain. FIG.10B shows the fold change over the matched isotype control in vessel-depleted brain. [0549] In addition, whole brain antibody concentration was determined, and a ratio of vessel depleted to whole brain antibody concentration was calculated (FIG. 11). The data indicates that some fraction of the higher affinity anti-TfR antibodies remained in the vessels at the 24hr timepoint, while the lower affinity TfR-antibodies (such as H3-7) had equivalent antibody levels in vessel depleted or whole brain, indicating that there was not a significant retention in the blood vessels. A similar trend was also observed in another in vivo study with other anti-TfR affinity variants (data not shown). [0550] Overall, this study showed that the anti-TfR antibodies can drive brain uptake even at a low dose. Example 16: Analysis of Blood Reticulocyte Levels_{[0551] To assess the safety of higher affinity TfR antibodies, the population of reticulocytes in wholeblood samples at 24 h was assessed. Whole blood samples from animals dosed with anti-TfR} affinity variants or isotype control antibodies were drawn from the animals prior to perfusion, collected into K2EDTA tubes, and hematological analysis was performed (Idexx Laboratories^ny-2871899 735022004340 (Fremont CA)). A fully automated diagnostic instrument SYSMEX XT-V was used for routine hematology testing. The complete blood count (CBC) and reticulocyte count were measured by flow cytometry. [0552] As shown in FIG.12, no significant effect on blood reticulocyte levels was observed among groups in this experiment at the time point sampled. Although some variability is observed, there were no substantial decreases in reticulocyte levels or associated acute clinical symptoms. Example 17: Assessment of TfR Degradation by Anti-TfR Affinity Variants [0553] High-affinity TfR binders have been reported to drive TfR to the lysosome and induce TfR degradation (Bien-Ly, N. et al., J. Exp. Med. 2014 Feb 10;211(2):233-44.), which is undesirable as it may impact the capacity of TfR to transport its natural ligand and any cargo attached to the anti-TfR antibody. To determine whether the anti-TfR affinity variants led to TfR degradation, the whole brain lysate from the in vivo study described above in Example 8 were prepared in RIPA buffer with protease and phosphatase inhibitors. Total protein concentration in the lysates were determined by BCA assay (Pierce #23225) and 40 μg of each sample were separated by SDS-PAGE and the gels were transferred to nitrocellulose membranes for immunoblot. An anti-TfR antibody detecting both human and mouse TfR (Thermo #13-6800) and mouse anti-GAPDH (Millipore MAB374) were incubated overnight. Images were captured using a Biorad ChemiDoc system and analyzed with Image Lab 6.1 software. Band intensities for TfR were normalized to levels of GAPDH for each sample and the isotype control mean. [0554] FIG. 13 shows that TfR levels in animals treated with anti-TfR antibodies L-21, L-6, and L-35 were reduced in comparison to the isotype controls; however, this difference was not statistically significant. The TfR levels in anti-TfR antibodies 42Q, 24A, and 39.38 also did not decrease significantly. Overall, these results suggest that the anti-TfR antibodies tested did not robustly degrade TfR, with a subset of the anti-TfR antibodies slightly reducing TfR levels at the 24 h timepoint and 5 mg/kg dose. Example 18: Affinity Engineering of Anti-CD98hc Antibody CD98hc.04.048.WH1 [0555] Affinity variants of anti-CD98hc antibody CD98hc.04.048.WH1 were generated as follows. Amino acid substitutions within the variable heavy chains and variable light chains were introduced at various selected positions within or near the CDR regions of anti-CD98hc antibody CD98hc.04.048.WH1 using standard methodologies. The antibody variants were expressed in^ny-2871899 735022004340 Expi293 or ExpiCHO cell cultures and either supernatants or purified antibodies of these variants were subsequently used to evaluate binding and cell uptake. [0556] Following binding and cell uptake evaluation, a subset of these variants were generated in monovalent scFv and Fab antibody formats for further characterization, as described below. [0557] The antibody sequences of the affinity-tuned anti-CD98hc antibodies are provided in Table 33 to Table 35 below. Table 33: Heavy Chain CDR Sequences of Anti-CD98hc Antibodies^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340 Table 34: Light Chain CDR Sequences of Anti-CD98hc Antibodies^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340 Table 35: VH and VL Sequences of Anti-CD98hc Antibodies^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340^ny-2871899 735022004340 Example 19: Binding Kinetics of Anti-CD98hc.04.048.WH1 Antibody Variants [0558] Binding kinetics of anti-CD98hc.04.048.WH1 affinity engineered antibody variants to human and cynomolgus CD98hc were evaluated using Biacore T200 (Cytiva). Antibodies were tested in both Fab and scFv monovalent formats. Briefly, anti-CD98hc.04.048.WH1 antibody variants were diluted and captured using a Cytiva Anti-Fab (Cytiva, # 28958325) surface on a CM4 chip that was prepared by amine coupling according to the instrument manufacturer’s recommendations. The captured antibodies were tested for their ability to bind human and cynomolgus CD98hc recombinant proteins as follows. [0559] The human and cynomolgus CD98hc recombinant protein analytes were diluted in running buffer to a concentration of 1 M, and then diluted 3-fold serially. Each sample injection^ny-2871899 735022004340 was followed by three 30-second injections of 10 mM glycine pH 2.1 to regenerate the chip. Fresh antibody was captured at the beginning of each cycle. [0560] Data were analyzed using Biacore evaluation software to generate kinetic constants. The equilibrium dissociation constants (KD) were calculated from the fitted association and dissociation rate constants (k-on and k-off) for each of the anti-CD98hc.04.048.WH1 antibody variants. The K_D values for antibodies in monovalent Fab format are summarized in Table 36 below, and the K_D values for antibodies in monovalent scFv format are summarized in Table 37 below. Table 36: Kinetic Rate Constants for Anti-CD98hc.04.048.WH1 Affinity Variants in Monovalent Fab Format for Binding to Human and Cynomolgus CD98hc^ny-2871899 735022004340 Table 37: Kinetic Rate Constants for Anti-CD98hc.04.048.WH1 Affinity Variants in Monovalent scFv Format for Binding to Human and Cynomolgus CD98hc^ny-2871899 735022004340^ny-2871899 735022004340 Example 20: Brain Uptake of Engineered Affinity Panel Variants [0561] Test To examine brain uptake of affinity-engineered anti-CD98hc.04.048.WH1 antibody variants of the present disclosure, a subset of them were injected into huCD98hc ECD^+/+ knock-in homozygous mice in the C57Bl/6 background at 7-9 weeks of age. Animals were administered anti-CD98hc.04.048.WH1 antibody variants at 20 mg/kg via intravenous injection of the tail vein. Animals were sacrificed 48 hours following antibody administration, terminally bled, perfused, and whole brains were harvested. Homogenized brain tissue samples were centrifuged to separate the vessel portion from the parenchyma portion and were frozen on dry ice and stored at 80 °C until analysis. Total protein concentration in the lysates was determined by BCA Assay (Pierce #23225). The validity of this method to remove blood vessels was confirmed using western blot analysis, in which markers of brain endothelial cells were absent in the parenchymal portions used in these studies. [0562] Antibody concentrations in the brain and serum samples were measured using an MSD (Meso Scale Discovery) assay as described above. Antibody concentrations were normalized to the total protein concentration in the lysate and then graphed as fold-change over the format- matched control antibody. [0563] Brain uptake measurements obtained for the anti-CD98hc.04.048.WH1 antibody variants are shown in FIG.14A (ng antibody/mg total protein) and FIG. 14B (fold-change over control). In these studies, all anti-CD98hc.04/048.WH1 antibody variants tested showed increased brain uptake at the 48 hr timepoint and showed a 3.5-fold to 8-fold enrichment in brain uptake as compared to a format-matched antibody isotype control. Example 21: Effect of Anti-CD98hc.04.048.WH1 Antibody Affinity Variants on Amino Acid Uptake [0564] The ability of affinity-tuned variants of 04.048.WH1 antibodies to affect amino acid uptake was evaluated using a commercially available bioluminescent assay (Promega JE9400). Briefly, hCMEC/D3 cells were seeded into clear tissue culture treated 96-well plates and allowed^ny-2871899 735022004340 to adhere for an additional 24 hours. Anti-CD98hc antibodies were then added at varying dilutions in serum-free DMEM and the cells were incubated at 37°C overnight. The following day, the cells were processed according to assay manufacturer instructions and luminescence was recorded with an integration time of 1 second per well (Molecular Devices SpectraMax M5). [0565] As shown in FIG.15, none of the anti-CD98hc.04.048.WH1 antibody variants tested in this assay decreased amino acid uptake. These results indicated that use of anti- CD98hc.04.048.WH1 antibody variants of the present disclosure to transport molecules across the blood brain barrier would not interfere with amino acid transport. Example 22: Binding affinities of anti-mouse TfR-mouse progranulin fusion proteins for mouse sortilin [0566] To assess the binding of msTfR-msPgrn (8D3v12-msPgrn or 8D3v33-msPgrn) or isotype-control-msPgrn fusion proteins to mouse sortilin, binding affinities were determined by ELISA (FIG.16). A 96-well ELISA plate (Thermo, 446612) was coated with 2 μg/mL of recombinant mouse sortilin protein (R&D Systems, 2934-ST) in phosphate buffered saline (PBS) for 24 hours at 4 °C and subsequently blocked using 10% bovine serum albumin (BSA) in PBS for 1 hour. The fusion proteins were diluted three-fold from a highest concentration of 300 nM to a lowest concentration of 0.0017 nM, added to the plate, and incubated for 1 hour at room temperature (RT). Then, the plate was washed four times with PBS with 0.05% Tween-20 (PBST). Horseradish peroxidase (HRP)-conjugated anti-mouse Fc secondary antibodies were added to the plate for 30 min at room temperature, followed by washing. The plate was developed using TMB (Surmodics, TMBS-1000-01) and quenched using 2N H2SO4. Optical density at 450 nm was measured using a microplate reader. Binding affinities were determined based on EC50, with 8D3v33-msPgrn, 8D3v12-msPgrn, and isotype-control-msPgrn showing similar affinities for mouse sortilin, ranging from about 26 to about 47 nM. [0567] 8D3v12 VL sequence: DIQMTQSPASLSASLEEIVTITCQASQDIGNWLAWYQQKPGKSPQLLIYGATSLADGVPS RFSGSRSGTQFSLKISRVQVEDIGIYYCLQAYNTPWTFGGGTKLELK (SEQ ID NO:267). [0568] 8D3v12 VH sequence: EVQLVESGGGLVQPGNSLTLSCVASGFTFSNYGMHWIRQAPKKGLEWIAAIYYDSSKM NYADTVKGRFTISRDNSKNTLYLEMNSLRSEDTAMYYCAVPTSHYVVDVWGQGVSVT VSS (SEQ ID NO:470).^ny-2871899 735022004340 [0569] 8d3v33 VL sequence: DIQMTQSPASLSASLEEIVTITCQASQDIGNWLAWYQQKPGKSPQLLIYGATSLADGVPS RFSGSRSGTQFSLKISRVQVEDIGIYYCLQAYNTPWTFGGGTKLELK (SEQ ID NO:267). [0570] 8D3v33 VH sequence: EVQLVESGGGLVQPGNSLTLSCVASGFTFSNYGMHWIRQAPKKGLEWIAMIYYDSSKM NYADTVKGRFTISRDNSKNTLYLEMNSLRSEDTAMYYCAVPTSHYAVDVWGQGVSVT VSS (SEQ ID NO:471). Example 23: Two dose anti-mouse TfR-mouse progranulin fusion protein pharmacokinetic and proof-of-concept efficacy study in aged Grn knockout mice [0571] Literature reports have demonstrated that antibodies modified with TfR binding further enable sustained brain uptake (Couch et al., Sci Transl Med.2013 May 1;5(183):183ra57, 1-12. doi: 10.1126/scitranslmed.3005338; Kariolis et al. Sci Transl Med. 2020 May 27;12(545):eaay1359. doi: 10.1126/scitranslmed.aay1359). A pharmacokinetic (PK), brain uptake, and proof-of-concept efficacy study was conducted to test msTfR-msPgrn in ten-month- old Grn knockout (KO) mice of mixed sex (three females and three males per group; Taconic). Mice were group-housed and maintained on a 12 hour/12 hour light/dark cycle with room temperature maintained at 22±2 °C at approximately 50% humidity. Mice received standard rodent chow TestDiet PicoLab Rodent Diet 20 and Inovive water bottles ad libitum. On Day 0 and Day 7, mice were weighed using a Mettler Toledo precision balance and dosed via intravenous injection (i.v.) of the tail vein with 10 mg/kg isotype-msPgrn-msIgG2a-LALAPG (i.e., L234A/L235A/P329G), 8D3v33-msPgrn-msIgG2a-LALAPG, or 8D3v12-msPgrn- msIgG2a-LALAPG. In parallel, age-, sex-, and strain-matched wildtype (WT) and Grn-KO mice were dosed with saline as controls (FIG.17). Animals were bled by sub-mandibular vein without anesthesia pre-dosing and at 1 hour, 4 hours, 24 hours, 3 days, and 6 days post-dose-one, as well as 24 hours post-dose-two, to determine serum PK profiles (FIG. 18). Brains were collected 24 hours post-dose-two to determine brain fusion protein levels (FIG.19) and assess pharmacodynamic (PD) readouts, specifically levels of glucosylsphingosine (GlcSph; FIG. 20) and glycoprotein (transmembrane) nmb (Gpnmb; FIG.21). During tissue collection, blood was collected via cardiac puncture and all mice then underwent transcardial perfusion with PBS. After perfusion, brains were collected and snap frozen on dry ice.^ny-2871899 735022004340 [0572] Mice were dosed with Fab-msFc-msPgrn fusion proteins generated on a mouse IgG2a backbone, with the anti-mouse TfR or isotype control moieties within the Fab region and the Fc_{region mutated to LALAP329G to attenuate Fc receptor binding and thus effector functions.} The N-terminus of mature mouse progranulin was fused to the C-terminus of the mouse IgG2a backbone to attenuate potential interference with progranulin binding to sortilin via its C- terminus. The integrity of the fusion protein C-termini was evaluated by mass spectrometry. [0573] Binding affinities of msTfR-msPgrn fusion proteins for mouse apical TfR were determined by bio-layer interferometry (BLI) and equilibrium dissociation constants (K_D) were reported.8D3v33-msPgrn-msIgG2a-LALAPG binds to mouse TfR with approximately two-fold higher affinity compared to 8D3v12-msPgrn-msIgG2a-LALAPG. [0574] Serum PK profiles were analyzed using a modified Mesoscale Discovery (MSD) electrochemiluminescence assay (ECLA) that captures the mouse IgG2a backbone and detects mouse progranulin (mIgG2a-mPgrn) (FIG.18). Briefly, a 384-well streptavidin-coated MSD plate (MSD, L21SA-1) was coated with 0.5 μg/mL of in-house biotinylated goat anti-mouse IgG2a (Southern Biotech, SA5-10265) in Tris-buffered saline assay buffer (TAB; 0.1% BSA in Tris-buffered saline with 0.05% Tween-20) for 1 hour at room temperature, shaking at 600 rpm (Heidolph, Titramax 1000). After three washes with PBST, standards, quality controls (QCs), and samples were added to the plate and incubated for 2 hours at room temperature, shaking at 600 rpm. After three washes, 0.5 μg/mL in-house ruthenylated sheep anti-mouse progranulin (R&D Systems, AF2557) diluted in TAB was added to the plate and incubated for 1 hour at room temperature, shaking at 600 rpm while protected from light. After three washes with PBST, 2x MSD Read Buffer T with surfactant (MSD, R92TC) was added to the plate and it was read immediately using a MSD Sector S600 plate reader. For all serum PK assays each fusion protein was included as a standard, and sample and QC concentrations were interpolated based on the respective fusion protein standard curve. Isotype-control-msPgrn showed relatively slow serum clearance, while msTfR-msPgrn fusion proteins showed msTfR affinity-dependent clearance, with 8D3v33-msPgrn clearing more quickly than 8D3v12-msPgrn (FIG.18). [0575] Brain fusion protein levels were assessed 24 hours post-second-dose in vessel-depleted brain lysates using the mIgG2a-mPgrn assay described above (FIG. 19). Analyses were performed using vessel-depleted brain lysates to measure brain fusion protein levels in the brain parenchyma. To generate vessel-depleted brain lysates, brain tissues were minced using a single-^ny-2871899 735022004340 edged razor blade, then homogenized in HBSS buffer (MilliporeSigma, 55037C) containing 10 mM HEPES (Gibco, 15630130) using a hand-operated tissue grinder. Subsequently, samples were centrifuged to separate the vessel-containing fraction from the parenchymal fraction. The parenchymal fraction was collected, lysed using RIPA buffer (MilliporeSigma, 20-188) with protease and phosphatase inhibitors (Thermo, 78446), and stored at –80 °C until analysis. The total protein concentration of parenchymal lysates was determined using a bicinchoninic acid (BCA) assay (Thermo, 23225). The validity of the vessel depletion method has previously been confirmed by immunoblotting, where brain endothelial brain cell markers are absent in the parenchymal fraction (data not shown). For all brain uptake assays, each fusion protein was included as a standard, and sample and QC concentrations were interpolated based on the respective fusion protein standard curve. Brain fusion protein levels were normalized to total protein concentration for each sample. [0576] msTfR-msPgrn fusion protein brain levels were higher compared to isotype-control- msPgrn levels (FIG.19).8D3v12-msPgrn and 8D3v33-msPgrn brain levels were seven- and four-fold higher, respectively, than isotype-control-msPgrn. Of note, the lower affinity msTfR (8D3v12) fusion protein, showed higher brain levels 24 hours post-second-dose compared to the higher affinity msTfR (8D3v33) fusion protein. [0577] Aged Grn KO mice, which represent a lysosomal storage disorder (LSD) model, exhibit brain accumulation of GlcSph relative to WT mice. Brain GlcSph levels were analyzed to assess the efficacy of two doses of msTfR-msPgrn fusion proteins (FIG.20). Brain GlcSph levels were detected by LC/ESI-MS/MS. A specific sample amount was spiked with a mixture of 10 ng of deuterated internal standards consisting of 1-ß-D-Glucosylsphingosine-d5 (d18:1) (Cayman Chemical, Ann Arbor, USA). A Folch extraction was performed, followed by an evaporation and reconstitution in ethanol. The clear solutions were analyzed using an Agilent 1290 HPLC system with binary pump, multisampler and column thermostat with a Halo 90A HILIC, 3.0 x 150 mm, 2.7μm column using a gradient solvent system of acetonitrile/methanol/formic acid and aqueous formic acid/ammonium formate. The flow rate was set at 0.5 mL/min, the injection volume was 1 μL. The HPLC was coupled with an Agilent 6495 Triplequad mass spectrometer (Agilent Technologies, Santa Clara, USA) with electrospray ionisation source. Analysis was performed with Multiple Reaction Monitoring in positive mode,^ny-2871899 735022004340 with at least two mass transitions for each compound. Quantification was done using individual calibration curves for each compound. [0578] A partial, but significant, reduction in elevated brain GlcSph levels was observed with two 10 mg/kg doses of either msTfR-msPgrn construct, but not with isotype-control-msPgrn (FIG. 20). [0579] As an additional measure of msTfR-msPgrn fusion protein efficacy in aged Grn KO mice, brain Gpnmb levels were evaluated. Elevated Gpnmb levels are thought to reflect myeloid cell lysosomal stress, and elevated brain Gpnmb have been reported in aged Grn KO mice as well as in the brain and cerebrospinal fluid (CSF) of FTD-Grn patients (Huang et al., 2020). Cleared whole brain lysates were generated from PBS-perfused brain tissue using N-PER lysis buffer (Thermo, 87792) with Halt protease and phosphatase inhibitors (Thermo, 78466), Qiagen TissueLyser II with 5 mm stainless steel beads (Qiagen), and centrifugation. Gpnmb levels were evaluated using a modified MSD ECLA. A 96-well streptavidin-coated plate (MSD, L15SA-1) was blocked for 1-2 hours at room temperature (Thermo, 37515). After washes with PBST, 100 nM biotinylated Nano-CaptureLigand nanobodies against mouse IgG2a (Proteintech, smsG2aB- 1-100) was added in assay buffer (1% BSA and 0.05% Tween-20 in PBS) and incubated for 1 hour, shaking at 350 rpm. After washes with PBST, the plate was coated with 1 μg/mL of an anti-Gpnmb antibody A (Alector) overnight at 4 °C, shaking at 350 rpm. The next day, samples, QCs, and standards were mixed 1:1 with 20 μg/mL of an anti-Gpnmb antibody B (Alector) and 20 μg/mL of an anti-Gpnmb antibody C (Alector) in assay buffer for 1 hour at room temperature, shaking at 500 rpm. The coated plate was washed. Pre-treated samples, standards, and QCs were added to the plate and incubated for 3 hours at room temperature, shaking at 350 rpm. After washes, 0.1 μg/mL a ruthenylated anti-Gpnmb antibody D (Alector) was added and the plate was incubated for 2 hours at room temperature, shaking at 350 rpm. Finally, the plate was washed, 2x MSD Read Buffer T with surfactant (MSD, R92TC) was added, and the plate was read immediately using an MSD Sector S600 plate reader. Total protein concentration of whole brain lysates was determined using a BCA assay (Thermo, 23225). Gpnmb levels were normalized to total protein concentration for each sample. [0580] A statistically significant partial reduction in elevated brain Gpnmb levels was observed with two 10 mg/kg doses of 8D3v12-msPgrn in aged Grn KO mice (FIG.21).^ny-2871899 735022004340 Example 24: Binding affinities of anti-human TfR-human progranulin fusion proteins for human sortilin [0581] To assess the binding of huTfR-huPGRN (L10-16.hIgG1LALAPS.hPGRN, L10- 8.hIgG1LALAPS.hPGRN, 24A.hIgG1LALAPS.hPGRN, 39.38hIgG1LALAPS.hPGRN or isotype-control-hIgG1LALAPS.hPGRN) fusion constructs to human sortilin, ELISAs were performed (FIG.22). A pre-blocked streptavidin-coated plate (Thermo, 15125) was coated with 1 μg/mL of biotinylated recombinant human sortilin (Acrobiosystems, SON-H82E9) in PBS for 24 hours at 4 °C. The fusion proteins were diluted three-fold from a highest concentration of 300 nM to a lowest concentration of 0.0017 nM and incubated for 1 hour at room temperature. Then, the plate was washed four times with PBST. HRP-conjugated anti-human Fc secondary antibodies were added to the plate for 30 minutes at room temperature, followed by washing. The plate was developed using TMB (Surmodics, TMBS-1000-01) and quenched using 2N H2SO4. Optical density at 450 nm was measured using a microplate reader. [0582] Binding affinities were determined based on EC50, with L10-8-huPGRN, L10-16- huPGRN, and isotype-control-huPGRN showing similar affinities for human sortilin ranging from about 0.4 to about 1.2 nM (FIG.22, left). In a separate experiment, 39.38-huPGRN displayed an affinity of about 4 nM for human sortilin (FIG.22, right). Example 25: Brain uptake of huTfR-huPGRN anti-huTfR affinity variants in huTfR KI mice after a single dose [0583] An in vivo study was performed in human TfR knock-in (hu TfR KI) mice to determine the extent of brain uptake of human PGRN constructs with various human TfR binding sequences displaying different affinities for human TfR. [0584] Seven- to nine-week-old female homozygous huTfR KI mice, on a C57Bl/6 background, were used for all studies (Taconic). Mice were maintained and identified as described in Example 23, above. On the day of treatment, the mice were weighed and dosed via intravenous injection of the tail vein. Mice were dosed with anti-huTfR-huPGRN variants of known differing anti-huTfR affinity: L10-16-huPGRN (3, 10, or 30 mg/kg), 10 mg/kg L10-8- huPGRN, 10 mg/kg 39.38-huPGRN, or 10 mg/kg isotype-control-huPGRN (six mice per group). Three mice from each group were taken down 6 hours post-dose and the three remaining mice from each group were taken down 24 hours post-dose. During tissue collection, blood was^ny-2871899 735022004340 collected via cardiac puncture and all mice then underwent transcardial perfusion with PBS. After perfusion, brains were collected and snap frozen on dry ice. Whole blood samples from animals administered huTfR-huPGRN and isotype-control-huPGRN were obtained from the animals prior to perfusion for hematology analysis (performed at Idexx Laboratories, Fremont CA) using a fully automated diagnostic instrument SYSMEX XT-V. The complete blood count (CBC, data not shown) and reticulocyte count were measured by flow cytometry. [0585] Mice were dosed with Fab-huFc-huPgrn fusion proteins generated on a human IgG1 backbone, with the anti-human TfR or isotype control moieties within the Fab region and the Fc_{region mutated to LALAPS to attenuate Fc receptor binding and thus effector functions. The N-} terminus of mature mouse progranulin was fused to the C-terminus of the human IgG1 backbone to attenuate potential interference with progranulin binding to sortilin via its C-terminus. The intactness of the fusion protein C-termini was evaluated by mass spectrometry. [0586] As shown in FIG.23, no major changes in red blood cell count (RBC, a key hematological parameter) were observed in mice administered huTfR-huPGRN or isotype- control-huPGRN fusion proteins. In addition, blood reticulocyte counts did not differ between treatment groups. Surface TfR levels on blood reticulocytes were analyzed by in-house FACS of whole blood (FIG. 24). No significant differences were observed between the treatment groups. [0587] Brain fusion protein levels were analyzed using a modified MSD ECLA (FIG.25). Analyses were performed using vessel-depleted brain lysates to measure brain fusion protein levels in the brain parenchyma. Vessel-depleted brain lysates were generated and the total protein concentrations were measured as described in Example 23, above. Briefly, a 384- or 96- well streptavidin-coated plate (MSD, L21SA-1 or L15SA-1) was incubated with 0.1 μg/mL of biotinylated goat anti-human IgG (SouthernBiotech, 2049-08) in TAB (0.1% BSA and 0.05% Tween-20 in Tris-buffered saline) for 1 hour at room temperature, shaking at 600 rpm or 350 rpm (for 384- and 96-well plates, respectively). After washing with PBST, standards, QCs, and samples were added to the plate and incubated for 2 hours at room temperature with shaking. During this time, the detection antibody was prepared by incubating 0.25 μg/mL of ruthenylated goat anti-human IgG with 0.1% mouse serum in TAB for 1 hour at room temperature while rotating. After washing the plate with PBST, the detection antibody was added and incubated for 1 hour at room temperature with shaking. After washing with PBST, 2X MSD Read Buffer T with surfactant (MSD, R92TC) was added to the plate and it was read immediately using an^ny-2871899 735022004340 MSD Sector S600 plate reader. For all brain uptake assays, each fusion protein was included as a standard, and sample and QC concentrations were interpolated based on the respective fusion protein standard curve. Antibody concentrations were normalized to the total protein concentration in the lysate for each sample. [0588] FIG. 25 shows brain levels of anti-huTfR-huPGRN fusion proteins 6 hours and 24 hours after a single dose in huTfR-KI mice. While isotype-control-huPGRN levels were relatively low, mice dosed with L10-16-huPGRN showed a dose-dependent increase in brain levels. At 6 hours post-dose, 3 mg/kg L10-8-huPGRN group reached brain levels that were similar to those of the 10 mg/kg L10-16-huPGRN group. Overall, higher huTfR affinity correlated with increased brain fusion protein levels at 6 hours and 24 hours post-dose. [0589] As shown in FIG.26, TfR levels in whole brain lysates were assessed to determine whether the blood-brain barrier (BBB) target showed an affinity-dependent decrease. Cleared whole brain lysates were generated from PBS-perfused brain tissue using N-PER lysis buffer (Thermo, 87792) with Halt protease and phosphatase inhibitors (Thermo, 78466), Qiagen TissueLyser II with 5 mm stainless steel beads (Qiagen), and centrifugation. Brain TfR levels were determined by quantitative immunoblotting. No differences were observed in brain TfR levels as a function of treatment group at 6 hours or 24 hours post-dose. Example 26: Binding affinities of anti-human CD98hc-human progranulin fusion proteins for human sortilin [0590] The ELISA method was performed as described in Example 24, above. As shown in FIG.27, binding affinities of isotype-control-huPGRN, WH1.208-huPGRN, and WH1-huPGRN for human sortilin were similar, ranging from about 1.4 to about 2.7 nM. In a separate experiment, the binding affinity of WH1.133-huPGRN for human sortilin was about 6 nM. Example 27: Brain fusion protein levels with single injection of huCD98hc-huPGRN fusion proteins [0591] Young adult female homozygous huCD98hc-KI mice, on a C57Bl/6 background, were used for all studies (Taconic). Mice were maintained and identified as described in Example 23, above. On the day of treatment, the mice were weighed and dosed via intravenous injection of the tail vein. Mice were dosed with 10 mg/kg isotype-control-huPGRN, 10 mg/kg WH1v133- huPGRN, or 10 mg/kg WH1-huPGRN (four mice per group). In other experiments, it was^ny-2871899 735022004340 determined that anti-CD98hc test articles reach brain C_max 72 hours post-dose (data not shown). All subjects were taken down 72 hours post-dose. During tissue collection, all mice underwent transcardial perfusion with PBS. After perfusion, brains were collected and snap frozen on dry ice. [0592] Mice were dosed with Fab-huFc-huPgrn fusion proteins generated on a human IgG1 backbone, with the anti-human CD98hc or isotype control moieties within the Fab region and the_{Fc region mutated to LALAPS to attenuate Fc receptor binding and thus effector functions. The} N-terminus of mature mouse progranulin was fused to the C-terminus of the human IgG1 backbone to attenuate potential interference with progranulin binding to sortilin via its C- terminus. The intactness of the fusion protein C-termini was evaluated by mass spectrometry. [0593] To determine brain levels of huCD98hc-huPGRN in mice dosed once, a modified MSD ECLA (hIgG capture/hIgG detect) was performed as described in Example 25, above, and brain fusion protein levels in vessel-depleted brain lysates were measured (FIG.28). Mice dosed with isotype-control-huPGRN showed relatively low brain fusion protein levels relative to mice dosed with huCD98hc-huPGRN fusion proteins. Mice dosed with the lower affinity anti-huCD98hc fusion protein WH1v133-huPGRN showed two-fold higher uptake compared to mice dosed with the higher affinity anti-huCD98hc protein WH1-huPGRN. Example 28: Developability Properties of Human and Mouse PGRN fusion Proteins [0594] Surface hydrophobicity. Surface hydrophobicity is a parameter investigated as a part of developability characterization of biotherapeutics (see, e.g., Mieczkowski et al., 2023, Blueprint for antibody biologics developability; MABS2023, VOL.15, NO.1, 2185924, https://doi.org/10.1080/19420862.2023.2185924). Surface hydrophobicity of biologics can contribute to their aggregation, self-interaction, and nonspecific binding. Therefore, we determined the Retention time (Rt) of PGRN-antibody fusion proteins on a ProPac HIC-10 (Thermo Scientific, USA) analytical hydrophobic interaction chromatography (aHIC) column mounted on an Agilent 1260 Infinity II HPLC following standard procedures. [0595] Both iso-huIgG1LALAPS-huPGRN and 8D3v33-msPGRN-msIgG2a-LALAPG constructs show homogeneous and largely symmetric aHIC profile as shown in FIG. 29. aHIC R_t are 17.0 and 17.8 minutes for iso-hIgG1-huPGRN and 8D3v33-msPGRN-msIgG2a fusion proteins, respectively. These values are comparable to that of the reference antibody NISTmAb (https://www.nist.gov/programs-projects/nist-monoclonal-antibody-reference-material-8671),^ny-2871899 735022004340 which shows a R_t of 16.7 minute. These results indicate PGRN-antibody fusion proteins are expected to have good developability and manufacturability profiles. [0596] Thermal stability. The melting temperature (Tm) and temperature at which protein begin to unfold (T_onset) of purified Iso-huIgG1-huPGRN and 8D3v33-msPGRN-msIgG2a were measured in 20mM histidine pH 6.0, 150mM sodium chloride, 7.5% sucrose, with tween-80 buffer using the UNCLE (Unchained Labs, USA) instrument that facilitates simultaneous monitoring of fluorescence and static-light scattering along with dynamic-light scattering at the beginning and end of temperature ramping. A temperature from 25 °C to 95 °C was used with a ramping rate of 0.5 °C per minute. Data were analyzed using Lunatic analysis software. [0597] The T_m and T_onset values of Iso-hIgG1-huPGRN and 8D3v33-msPGRN-mIgG2a are_{reported in Table 38. Iso-hIgG1-huPGRN shows Tm and Tonset of 66.6 °C and 59.5 °C,respectively. Similarly, Tm and Tonset values for 8D3v33-msPGRN-mIgG2a are 69.4 °C and 63.1} °C, respectively. These values are higher than the accepted Tm of 55.0 °C for Protein or Enzyme Replacement Therapeutics (PRT or ERT). Thus, human and mouse PGRN-antibody fusion proteins show excellent thermal stability. Table 38. T_m and T_onset for human and mouse PGRN-antibody fusion proteins [0598] Forced degradation. Purified Iso-hIgG1-huPGRN and 8D3v33-msPGRN-msIgG2a fusion proteins were dialyzed against HSS (20 mM histidine pH 6.0, 150 mM sodium chloride, and 7.5% sucrose) and PBS pH 7.4 at 4 °C overnight with at least one additional buffer exchange using slide-A-lyzer 10 kD MWCO (0.5 mL cups). Concentrations of dialyzed proteins were measured using Lunatic (Unchained labs). About 125 μL of PGRN-antibody fusion proteins in HSS pH 6.0 and PBS pH 7.4 were incubated at 40 °C for 14 days. Samples were frozen at various time points and analyzed on an ACQUITY UPLC Protein BEH SEC, 200 Å (Waters, USA) column mounted on an Agilent 1260 Infinity II HPLC using 2x PBS, 10% ethanol as the mobile phase. Area under the PGRN-antibody fusion proteins corresponding to its monomeric conformation was used to monitor the aggregation level during the forced degradation.^ny-2871899 735022004340 [0599] Changes in the HMWs (high molecular weight species), monomer, and LMWs (low molecular weight species) content before T=0 and after T=2 weeks forced degradation of Iso- hIgG1-huPGRN and 8D3v33-msPGRN-mIgG2a fusion proteins are shown in percentage (%) in Table 39 (changes in HMWs (high molecular weight species), monomer, and LMWs (low molecular weight species) before T=0 and after T=2 weeks are shown in percentage (%)). Analytical SEC (aSEC) profiles of both proteins show high monomeric content of 97% or 98% indicating high purity and homogeneity. These samples have 2% or 3% of HMWs and do not contain any detectable levels of LMWs suggesting an absence of any degradation. After 2 weeks at 40 °C in both HSS and PBS buffers, the amount of HMWs remained largely unchanged revealing that Iso-hIgG1-huPGRN and 8D3v33-msPGRN-mIgG2a fusion proteins do not undergo aggregation under the tested conditions. All four samples show some tendency to degrade upon force degradation. However, the total amount of LMWs remained very low at ~4%, leaving most of the protein, 92% to 94%, as monomer. Thus, both Iso-hIgG1-huPGRN and 8D3v33-msPGRN-msIgG2a fusion proteins show excellent forced degradation stability and therefore human-PGRN-antibody fusion proteins are expected to be good candidates for further development as biotherapeutics. Table 39. Forced Degradation (at 40 °C for 14-days) human and mouse PGRN-antibody fusion proteins Example 29: Brain Uptake of Affinity-Engineered Anti-CD98hc.04.048.WH1 Monovalent Fab Antibody Variants [0600] Brain uptake of various affinity-engineered anti-CD98hc.04.048.WH1 monovalent Fab antibody variants of the present disclosure was assayed in huCD98hc ECD+/+ KI (knock-in) mice using methods as described in Example 20, above. These affinity-engineered anti- CD98hc.04.048.WH1 monovalent Fab antibody variants included: anti-^ny-2871899 735022004340 CD98hc.04.048.WH1.Fab.Iso scFv; anti-CD98hc.04.048.WH1.222.Fab.Iso scFv; anti- CD98hc.04.048.WH1.083.Fab.Iso scFv; anti-CD98hc.04.048.WH1.218.Fab.Iso scFv; anti- CD98hc.04.048.WH1.269.Fab.Iso scFv; anti-CD98hc.04.048.WH1.208.Fab.Iso scFv; anti- CD98hc.04.048.WH1.253.Fab.Iso scFv; anti-CD98hc.04.048.WH1.283.Fab.Iso scFv; anti- CD98hc.04.048.WH1.271.Fab.Iso scFv; and Iso.Fab.Iso scFv isotype control. Antibody concentrations in vessel depleted brain and serum samples were measured using an MSD (Meso Scale Discovery) assay as described above. Antibody concentrations were normalized to the total protein concentration in the lysate and then graphed as either antibody concentration (ng antibody/mg total protein) or fold-change over the format-matched control antibody. [0601] Brain uptake measurements obtained for the various anti-CD98hc.04.048.WH1 monovalent Fab affinity-engineered antibody variants are shown in FIG.30A (ng binding domain/mg total protein) and FIG.30B (fold-change over control). All anti- CD98hc.04.048.WH1 monovalent Fab affinity-engineered antibody variants tested in these studies displayed increased brain uptake in hCD98hc ECD+/+ KI mice at 48 hours after antibody administration, showing a 4-fold to 10-fold enrichment in brain uptake as compared to that observed with a format-matched antibody isotype control. Example 33: Binding Kinetics of CD98hc.04.048.WH1 with Isotype Control Antibody in 2+1 Format [0602] The kinetics of multi-specific 2+1 antibodies disclosed herein with either isotype control antibody and CD98hc.04.048.WH1 scFv binding to human CD98hc were evaluated using a Biacore T200 instrument (Cytiva). In these studies, an isotype control antibody was formatted to include anti-CD98hc-04.048.WH1 Fab in a 2+1 format. [0603] Briefly, anti-human Fab capture reagent (Cytiva, Cat 28958325) was immobilized on all 4 flow cells of a CM4 sensor chip via amine coupling using sulfo-NHS (Cytiva Cat BR100050)/EDC (Cytiva Cat BR100050) and remaining capture surfaces blocked with 1M Ethanolamine (Carterra, 3628). Antibodies were captured onto flow cells 2, 3, and 4, while flow cell 1 was used for reference subtraction. Four serially-diluted concentrations of human CD98hc (22 – 600 nM) were injected over all captured antibodies for two minutes of association, followed by 5 minutes of dissociation, with regeneration performed using 10mM glycine-HCl pH 2.1. Results were processed and analyzed using Biacore T200 Evaluation kinetics analysis software (Cytiva). The equilibrium dissociation constants (KD) were calculated from the fitted^ny-2871899 735022004340 association and dissociation rate constants. The K_D values are summarized in Table 40 below. The anti-CD98hc 04.048.WH1 scFv affinity to human CD98hc was similar across all antibodies at approximately 50 nM. The hIgG1 Fc mutations did not affect the Fab or scFv binding to their respective targets. Table 40. Kinetic Rate Constants for Isotype Control Fab-04.048.WH1 scFv 2+1 Bispecific Antibodies Binding to Human CD98hc. Example 34: Multi-specific binding proteins comprising anti-CD98hc antibodies show enhanced brain penetration and accumulation with multiple doses in mice [0604] Human CD98hc ECD+/+ KI mice were injected intravenously with 3 weekly doses of 50 mg/kg of isotype-control/CD98hc.04.048.WH1 with hIgG1 WT, cis-LALAP331S/WT, or LALAP331S Fc. Forty-eight hours after the 3^rd injection, the mice were sacrificed and antibody levels in the serum and vessel-depleted mouse brain fractions were determined. [0605] Antibody concentrations in serum were measured using a custom Gyrolab assay. As shown in FIG.31A, faster serum clearance was observed with antibodies containing an anti- CD98hc.04.048.WH1 binding domain. Additional serum PK measurements also showed an enhancement of serum clearance with antibodies containing anti-CD98hc binding domains. [0606] Antibody concentrations in vessel-depleted brain samples were measured using an MSD method. Briefly, biotinylated goat anti-human IgG was added to streptavidin coated MSD plates and incubated for 1hr at room temperature. Plates were then washed 3x with wash buffer, followed by incubation with blocking buffer. Subsequently, diluted brain samples were added in duplicates. Each of the antibody test articles with a known concentration was included in the assay to generate a standard curve. Plates were washed 3x with wash buffer, followed by the addition of Sulfo-Tag goat anti-human Ab (Alector) in assay buffer (1x Tris, 0.05% Tween-20, 0.01% BSA, 0.1% mouse serum) and incubated for 1 hour.2x READ buffer (R92PC-2, Meso^ny-2871899 735022004340 Scale Discovery) was added to the plates before reading on a Sector Imager S600 instrument. Antibody concentrations were normalized to the total protein concentration in the lysate and then graphed as antibody concentration (ng antibody/mg total protein). [0607] Antibody brain uptake results from these studies are shown in FIG.31B. Antibodies with an anti-CD98hc.04.048.WH1 binding moiety showed significantly increased levels in vessel-depleted brain fraction as compared to that observed with isotype control antibody. Additionally, antibody brain concentrations measured following the multi-dose regimen of these studies were significantly higher than that previously observed with single-dose studies, demonstrating that multiple injections of 2+1 format antibodies with anti-CD98hc.04.048.WH1 binding domain resulted in antibody accumulation in the brain parenchyma. Example 35: Binding Kinetics of anti-CD98hc.04.048.WH1 affinity variants in a 2+1 format [0608] Selected CD98hc.04.048.WH1 affinity variants, as described above, were reformatted into a 2+1 format and their binding kinetics to human and cynomolgus CD98hc were evaluated using a Biacore T200 instrument (Cytiva) as described above. Anti-CD98hc 2+1 antibodies were captured and four serially-diluted concentrations of human and cynomolgus CD98hc (22 – 600 nM) were injected over all captured antibodies. The K_D values are summarized in Table 41 below. Binding affinities to human CD98hc ranged from approximately 50 nM to 600 nM; binding affinities to cynomolgus CD98hc ranged from approximately 50 nM to 900 nM. There was general agreement in the affinities to CD98 from both species for each antibody, with the affinity ranking order maintained. Table 41. Binding Affinities of Selected Anti-CD98hc.04.048.WH1 Affinity Variants in 2+1 format to Human and Cynomolgus CD98hc.^ny-2871899 735022004340 Example 36: Brain Uptake of anti-CD98hc.04.048.WH1 affinity variants in 2+1 format [0609] Brain uptake of affinity-engineered anti-CD98hc.04.048.WH1 antibody variants in 2+1 format was assayed in hCD98hc ECD+/+ KI mice using methods as described above. The animals were administered a single injection of either 3 mg/kg or 20 mg/kg via intravenous injection of the tail vein. [0610] Antibody concentrations in the serum samples were measured at 48, 96, and 144 hours post injection using a custom Gyrolab assay; antibody concentrations in the brain samples were measured using an MSD assay as described above. The serum PK for the 20 mg/kg dose and 3 mg/kg dose are shown in FIGs. 32A and 32B, respectively. Antibodies with the anti-CD98hc binding domain showed faster clearance compared to that observed with an isotype control antibody, with the clearance from serum seemingly being driven in an affinity-dependent manner. [0611] Antibody concentrations in vessel-depleted brain samples from these mice were measured using an MSD method as described above. Antibody concentrations were normalized to the total protein concentration in the lysate and then graphed as antibody concentration (ng antibody/mg total protein). The brain uptake results for the 20 mg/kg and 3 mg/kg doses are shown in FIGs.32C and 32D, respectively. All 2+1-format antibodies containing anti-CD98hc binding domains showed significantly increased brain uptake at both doses tested in these studies relative to that observed with an isotype control antibody. The parental anti- CD98hc.04.048.WH1 antibody, which has the highest affinity to CD98hc compared to other anti-CD98hc antibody variants of the present disclosure tested herein, showed the greatest level of brain uptake. Specifically, anti-CD98hc.04.048.WH1 antibody had 24-fold and 30-fold greater^ny-2871899 735022004340 brain uptake compared to that observed with an isotype control antibody at 20 mg/kg and 3 mg/kg, respectively.^ny-2871899

Claims

735022004340 WHAT IS CLAIMED IS: 1. A complex comprising (a) an antigen-binding domain that specifically binds to human transferrin receptor (TfR) and (b) a Progranulin (PGRN) polypeptide. 2. A complex comprising (a) an affinity-tuned antigen-binding domain that specifically binds to human TfR, wherein the antigen-binding domain binds to human TfR with an affinity of 0.01 nM to 50 nM, and (b) a PGRN polypeptide. 3. A complex comprising (a) an affinity-tuned antigen-binding domain that specifically binds to human TfR, wherein the antigen-binding domain binds to human TfR with an affinity of 51 nM to 750 nM, and (b) a PGRN polypeptide. 4. The complex of claim 3, wherein the antigen-binding domain binds to human TfR with an affinity of 600 nM to 650 nM. 5. The complex of claim 3, wherein the antigen-binding domain binds to human TfR with an affinity of 160 nM to 200 nM. 6. A complex comprising (a) an affinity-tuned antigen-binding domain that specifically binds to human TfR, wherein the antigen-binding domain binds to human TfR with an affinity of 751 nM to 10,000 nM, and (b) a PGRN polypeptide. 7. The complex of any one of claims 1-6, further comprising an Fc domain. 8. The complex of claim 7, wherein the antigen-binding domain that specifically binds to human transferrin receptor (TfR) is not within the Fc domain of the complex. 9. The complex of any one of claims 1-8, wherein the antigen-binding domain comprises a VH and a VL on separate polypeptides. 10. The complex of any one of claims 1-9, wherein the complex comprises:^ny-2871899 735022004340 (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and the PGRN polypeptide; and (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form the antigen-binding domain that specifically binds to human TfR. 11. The complex of claim 10, further comprising (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a CH2 and a CH3. 12. The complex of claim 10, further comprising (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a second PGRN polypeptide. 13. The complex of claim 10, further comprising: (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a second VH, a second CH1, a second hinge region, a second CH2, a second CH3, a second linker, and a second PGRN polypeptide; (iv) a fourth polypeptide comprising, from the N-terminus to the C-terminus, a second VL and a second CL; wherein the second VH and the second VL form a second antigen-binding domain that specifically binds to human TfR. 14. The complex of any one of claims 1-8, comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, and a CH3; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and the PGRN polypeptide; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form the antigen-binding domain that specifically binds to human TfR.^ny-2871899 735022004340 15. The complex of any one of claims 1-8, wherein the antigen-binding domain comprises a VH and VL on a single polypeptide chain. 16. The complex of any one of claims 1-8 and 15, wherein the antigen-binding domain comprises a single-chain fragment variable (scFv). 17. The complex of claim 16, wherein the scFv is in the orientation VH-linker-VL. 18. The complex of claim 16, wherein the scFv is in the orientation VL-linker-VH. 19. The complex of claim 17 or claim 18, wherein the linker (A) is about 5 to about 25 amino acids, is about 5 to about 20 amino acids, is about 10 to about 25 amino acids, or is about 10 to about 20 amino acids and/or (B) comprises the amino acid sequence of GGSEGKSSGSGSESKSTGGS (SEQ ID NO: 6) or GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 7). 20. The complex of any one of claims 1-8 and 15-19, comprising (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the PGRN polypeptide, a first Fc domain, and the antigen-binding domain and (ii) a second polypeptide comprising a second Fc domain. 21. The complex of any one of claims 1-8 comprising (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the PGRN polypeptide and a first Fc domain and (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a second Fc domain and the antigen-binding domain. 22. The complex of any one of claims 1-9 comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the PGRN polypeptide and a first Fc domain, (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, and a second Fc domain, and^ny-2871899 735022004340 (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form the antigen-binding domain that specifically binds to human TfR. 23. The complex of any one of claims 1-8 and 15, comprising (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the PGRN polypeptide, a first Fc domain, and the antigen-binding domain and (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a second PGRN polypeptide and a second Fc domain. 24. The complex of claim 23, wherein the second polypeptide comprises, from the N- terminus to the C-terminus, the second PGRN polypeptide, the second Fc domain, and a second antigen-binding domain that specifically binds TfR. 25. The complex of any one of claims 1-24, wherein the antigen-binding domain is a murine, chimeric, humanized, or human antigen-binding domain, optionally wherein the antigen-binding domain is a humanized antigen-binding domain. 26. The complex of any one of claims 7-25, wherein the Fc domain is capable of binding FcRn. 27. The complex of any one of claims 1-6, further comprising an Fc region, wherein the Fc region comprises a first and second polypeptide chain. 28. The complex of claim 27, wherein the Fc region is capable of binding FcRn. 29. The complex of claim 27 or claim 28, comprising (i) a single scFv or VHH or Fab antigen-binding domain that binds to human TfR and (ii) and two copies of the PGRN polypeptide.^ny-2871899 735022004340 30. The complex of claim 29, wherein the single scFv, Fab or VHH antigen-binding domain that binds to human TfR is linked to the C-terminus of one of the two copies of the PGRN polypeptide. 31. The complex of claim 29, wherein one of the two copies of the PGRN polypeptide is linked to the N-terminus of the first polypeptide chain of the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the N-terminus of the second polypeptide chain of the Fc region. 32. The complex of claim 29, wherein the single scFv, Fab, or VHH antigen-binding domain that binds to human TfR is linked to the N-terminus of the first or second polypeptide chain of the Fc region. 33. The complex of claim 29, wherein one of the two copies of the PGRN polypeptide is linked to the C-terminus of the first polypeptide chain of the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the C-terminus of the second polypeptide chain of the Fc region. 34. The complex of claim 27 or claim 28, comprising (i) an antibody that binds to human TfR, wherein the antibody comprises two heavy chains and two light chains; and (ii) two copies of the PGRN polypeptide, wherein each copy of the PGRN polypeptide is linked to the C-termini of one of the two antibody heavy chains. 35. The complex of claim 27 or claim 28, comprising (i) two scFv, Fab, or VHH antigen- binding domains that bind to human TfR, (ii) the Fc region; and (iii) two copies of the PGRN polypeptide, wherein one of the two scFv, Fab, or VHH antigen-binding domains that binds to human TfR is linked to the C-terminus of the first polypeptide chain of the Fc region, wherein the other scFv, Fab, or VHH antigen-binding domains that binds to human TfR is linked to the C-terminus of the second polypeptide chain of the Fc region, wherein one of the two copies of the PGRN polypeptide is linked to the N-terminus of the first polypeptide chain of the Fc region,^ny-2871899 735022004340 and wherein the other copy of the PGRN polypeptide is linked to the N-terminus of the second polypeptide chain of the Fc region. 36. The complex of claim 27 or claim 28, comprising (i) a single scFv, VHH, or Fab antigen- binding domain that binds to human TfR, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the C-terminus of the first or second polypeptide chain of the Fc region and the PGRN polypeptide is linked to N-terminus of the first or second polypeptide chain of the Fc region. 37. The complex of claim 7, comprising (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human TfR, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the C-terminus of the Fc domain and the PGRN polypeptide is linked to N- terminus of the Fc domain. 38. The complex of claim 27 or claim 28, comprising (i) a single scFv, VHH, or Fab antigen- binding domain that binds to human TfR, (ii) the Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the N-terminus of the first or second polypeptide chain of the Fc region and the PGRN polypeptide is linked to the C-terminus of the first or second polypeptide chain of the Fc region. 39. The complex of claim 7, comprising (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human TfR, (ii) the Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the N-terminus of the Fc domain and the PGRN polypeptide is linked to the C- terminus of the Fc domain. 40. The complex of claim 27 or claim 28, comprising (i) a single scFv, VHH, or Fab antigen- binding domain that binds to human TfR, (ii) an Fc region, and (iii) a single copy of the PGRN^ny-2871899 735022004340 polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the N-terminus of one of the two polypeptide chains of the Fc region, and wherein the PGRN polypeptide is linked to the N-terminus of the other polypeptide chain of the Fc region. 41. The complex of any one of claims 27-36, 38, and 40, wherein the Fc region is a heterodimeric Fc region, optionally comprising knob and hole mutations. 42. The complex of any one of claims 7, 37, and 39, wherein the Fc domain is a single chain monovalent Fc domain. 43. The complex of any one of claims 27-36, 38, and 40-41, wherein the Fc region is a modified Fc region with a modification listed in Table 8 or Table 9. 44. The complex of any one of claims 27-36, 38, 40-41, and 43, wherein the Fc region is a human IgG1 Fc region, wherein the human IgG1 Fc region comprises a mutation that reduces effector function, optionally wherein the mutation that reduces effector function comprises: (i) L234A, L235A, and/or P331S; (ii) N325S and/or L328F; (iii) L234A, L235A, and/or P329G; or (iv) L234A, L235A, and/or P329S. 45. The complex of any one of claims 7, 37, 39, and 42, wherein the Fc domain is a modified Fc domain with a modification listed in Table 8. 46. The complex of any one of claims 7, 37, 39, 42, and 45, wherein the Fc domain is a human IgG1 Fc domain, wherein the human IgG1 Fc domain comprises a mutation that reduces effector function, optionally wherein the mutation that reduces effector function comprises: (i) L234A, L235A, and/or P331S; (ii) N325S and/or L328F; (iii) L234A, L235A, and/or P329G; or (iv) L234A, L235A, and/or P329S. 47. The complex of any one of claims 1 and 7-46, wherein the antigen-binding domain comprises a heavy chain variable region (VH) comprising a VH CDR1, VH CDR2, and VH^ny-2871899 735022004340 CDR3 and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: (i) SEQ ID NOs: 8, 16, 25, 42, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 11, 24, 40, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 11, 25, 41, 55, and 61, respectively; (iv) SEQ ID NOs: 8, 12, 26, 42, 55, and 61, respectively; (v) SEQ ID NOs: 8, 12, 27, 42, 55, and 61, respectively; (vi) SEQ ID NOs: 8, 13, 25, 42, 55, and 61, respectively; (vii) SEQ ID NOs: 8, 14, 25, 42, 55, and 61, respectively; (viii) SEQ ID NOs: 8, 15, 25, 43, 55, and 61, respectively; (ix) SEQ ID NOs: 8, 17, 25, 44, 55, and 61, respectively; (x) SEQ ID NOs: 9, 18, 28, 45, 56, and 62, respectively; (xi) SEQ ID NOs: 9, 19, 28, 45, 56, and 62, respectively; (xii) SEQ ID NOs: 9, 20, 28, 46, 57, and 62, respectively; (xiii) SEQ ID NOs: 9, 20, 28, 46, 58, and 62, respectively; (xiv) SEQ ID NOs: 9, 20, 28, 47, 59, and 62, respectively; (xv) SEQ ID NOs: 9, 21, 28, 46, 57, and 62, respectively; (xvi) SEQ ID NOs: 9, 21, 28, 47, 59, and 62, respectively; (xvii) SEQ ID NOs: 9, 22, 28, 46, 57, and 62, respectively; (xviii) SEQ ID NOs: 9, 22, 28, 46, 58, and 62, respectively; (xix) SEQ ID NOs: 9, 22, 28, 47, 59, and 62, respectively; (xx) SEQ ID NOs: 10, 22, 28, 46, 58, and 62, respectively; (xxi) SEQ ID NOs: 10, 22, 30, 46, 58, and 62, respectively; (xxii) SEQ ID NOs: 10, 22, 31, 46, 58, and 62, respectively; (xxiii) SEQ ID NOs: 10, 22, 32, 46, 58, and 62, respectively; (xxiv) SEQ ID NOs: 10, 22, 33, 46, 58, and 62, respectively; (xxv) SEQ ID NOs: 10, 22, 34, 46, 58, and 62, respectively; (xxvi) SEQ ID NOs: 10, 22, 35, 46, 58, and 62, respectively; (xxvii) SEQ ID NOs: 10, 22, 36, 46, 58, and 62, respectively; (xxviii) SEQ ID NOs: 10, 22, 37, 46, 58, and 62, respectively;^ny-2871899 735022004340 (xxix) SEQ ID NOs: 10, 22, 38, 46, 58, and 62, respectively; (xxx) SEQ ID NOs: 10, 22, 39, 46, 58, and 62, respectively; (xxxi) SEQ ID NOs: 10, 22, 28, 49, 58, and 62, respectively; (xxxii) SEQ ID NOs: 10, 22, 28, 50, 58, and 62, respectively; (xxxiii) SEQ ID NOs: 10, 22, 28, 51, 58, and 62, respectively; (xxxiv) SEQ ID NOs: 10, 22, 28, 52, 58, and 62, respectively; (xxxv) SEQ ID NOs: 10, 22, 28, 53, 58, and 62, respectively; or (xxxvi) SEQ ID NOs: 10, 22, 28, 54, 58, and 62, respectively. 48. The complex of claim 47, wherein the VH comprises the amino acid sequence of SEQ ID NO: 103, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 97, 98, 99, 100, 101, 102, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, or 127. 49. The complex of claim 47 or claim 48, wherein the VL comprises the amino acid sequence of SEQ ID NO: 157, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 173, 174, 175, 176, 177, or 178. 50. The complex of claim 48 or claim 49, wherein the VH and the VL comprise the amino acid sequences of: (i) SEQ ID NOs: 103 and 157, respectively; (ii) SEQ ID NOs: 64 and 129, respectively; (iii) SEQ ID NOs: 65 and 130, respectively; (iv) SEQ ID NOs: 66 and 131, respectively; (v) SEQ ID NOs: 67 and 130, respectively; (vi) SEQ ID NOs: 68 and 131, respectively; (vii) SEQ ID NOs: 69 and 130, respectively; (viii) SEQ ID NOs: 70 and 131, respectively; (ix) SEQ ID NOs: 71 and 130, respectively; (x) SEQ ID NOs: 72 and 131, respectively;^ny-2871899 735022004340 (xi) SEQ ID NOs: 73 and 130, respectively; (xii) SEQ ID NOs: 74 and 131, respectively; (xiii) SEQ ID NOs: 75 and 132, respectively; (xiv) SEQ ID NOs: 76 and 131, respectively; (xv) SEQ ID NOs: 77 and 132, respectively; (xvi) SEQ ID NOs: 77 and 133, respectively; (xvii) SEQ ID NOs: 78 and 134, respectively; (xviii) SEQ ID NOs: 77 and 135, respectively; (xix) SEQ ID NOs: 77 and 136, respectively; (xx) SEQ ID NOs: 77 and 137, respectively; (xxi) SEQ ID NOs: 77 and 138, respectively; (xxii) SEQ ID NOs: 79 and 131, respectively; (xxiii) SEQ ID NOs: 77 and 139, respectively; (xxiv) SEQ ID NOs: 77 and 131, respectively; (xxv) SEQ ID NOs: 80 and 140, respectively; (xxvi) SEQ ID NOs: 81 and 141, respectively; (xxvii) SEQ ID NOs: 82 and 131, respectively; (xxviii) SEQ ID NOs: 83 and 142, respectively; (xxix) SEQ ID NOs: 77 and 143, respectively; (xxx) SEQ ID NOs: 75 and 131, respectively; (xxxi) SEQ ID NOs: 75 and 144, respectively; (xxxii) SEQ ID NOs: 77 and 145, respectively; (xxxiii) SEQ ID NOs: 84 and 131, respectively; (xxxiv) SEQ ID NOs: 75 and 146, respectively; (xxxv) SEQ ID NOs: 85 and 131, respectively; (xxxvi) SEQ ID NOs: 86 and 138, respectively; (xxxvii) SEQ ID NOs: 79 and 139, respectively; (xxxviii) SEQ ID NOs: 77 and 147, respectively; (xxxix) SEQ ID NOs: 75 and 148, respectively; (xl) SEQ ID NOs: 87 and 131, respectively; (xli) SEQ ID NOs: 88 and 131, respectively;^ny-2871899 735022004340 (xlii) SEQ ID NOs: 75 and 149, respectively; (xliii) SEQ ID NOs: 89 and 150, respectively; (xliv) SEQ ID NOs: 90 and 151, respectively; (xlv) SEQ ID NOs: 77 and 152, respectively; (xlvi) SEQ ID NOs: 79 and 153, respectively; (xlvii) SEQ ID NOs: 91 and 131, respectively; (xlviii) SEQ ID NOs: 92 and 131, respectively; (xlix) SEQ ID NOs: 79 and 154, respectively; (l) SEQ ID NOs: 93 and 155, respectively; (li) SEQ ID NOs: 80 and 131, respectively; (lii) SEQ ID NOs: 94 and 131, respectively; (liii) SEQ ID NOs: 95 and 131, respectively; (liv) SEQ ID NOs: 66 and 156, respectively; (lv) SEQ ID NOs: 97 and 138, respectively; (lvi) SEQ ID NOs: 95 and 156, respectively; (lvii) SEQ ID NOs: 98 and 157, respectively; (lviii) SEQ ID NOs: 99 and 157, respectively; (lix) SEQ ID NOs: 100 and 157, respectively; (lx) SEQ ID NOs: 101 and 157, respectively; (lxi) SEQ ID NOs: 102 and 158, respectively; (lxii) SEQ ID NOs: 104 and 159, respectively; (lxiii) SEQ ID NOs: 105 and 160, respectively; (lxiv) SEQ ID NOs: 106 and 161, respectively; (lxv) SEQ ID NOs: 107 and 162, respectively; (lxvi) SEQ ID NOs: 106 and 163, respectively; (lxvii) SEQ ID NOs: 108 and 164, respectively; (lxviii) SEQ ID NOs: 106 and 165, respectively; (lxix) SEQ ID NOs: 108 and 166, respectively; (lxx) SEQ ID NOs: 109 and 165, respectively; (lxxi) SEQ ID NOs: 110 and 167, respectively; (lxxii) SEQ ID NOs: 111 and 168, respectively;^ny-2871899 735022004340 (lxxiii) SEQ ID NOs: 112 and 160, respectively; (lxxiv) SEQ ID NOs: 113 and 169, respectively; (lxxv) SEQ ID NOs: 113 and 170, respectively; (lxxvi) SEQ ID NOs: 113 and 171, respectively; (lxxvii) SEQ ID NOs: 114 and 169, respectively; (lxxviii) SEQ ID NOs: 114 and 171, respectively; (lxxix) SEQ ID NOs: 115 and 169, respectively; (lxxx) SEQ ID NOs: 115 and 170, respectively; (lxxxi) SEQ ID NOs: 115 and 171, respectively; (lxxxii) SEQ ID NOs: 116 and 169, respectively; (lxxxiii) SEQ ID NOs: 116 and 170, respectively; (lxxxiv) SEQ ID NOs: 116 and 171, respectively; (lxxxv) SEQ ID NOs: 117 and 170, respectively; (lxxxvi) SEQ ID NOs: 118 and 170, respectively; (lxxxvii) SEQ ID NOs: 119 and 170, respectively; (lxxxviii) SEQ ID NOs: 120 and 170, respectively; (lxxxix) SEQ ID NOs: 121 and 170, respectively; (xc) SEQ ID NOs: 122 and 170, respectively; (xci) SEQ ID NOs: 123 and 170, respectively; (xcii) SEQ ID NOs: 124 and 170, respectively; (xciii) SEQ ID NOs: 125 and 170, respectively; (xciv) SEQ ID NOs: 126 and 170, respectively; (xcv) SEQ ID NOs: 127 and 170, respectively; (xcvi) SEQ ID NOs: 117 and 173, respectively; (xcvii) SEQ ID NOs: 117 and 174, respectively; (xcviii) SEQ ID NOs: 117 and 175, respectively; (xcix) SEQ ID NOs: 117 and 176, respectively; (c) SEQ ID NOs: 117 and 177, respectively; or (ci) SEQ ID NOs: 117 and 178, respectively.^ny-2871899 735022004340 51. The complex of any one of claims 1 and 7-46, wherein the antigen-binding domain is a VHH comprising: (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 8, 16, and 25, respectively; (ii) SEQ ID NOs: 8, 11, and 24, respectively; (iii) SEQ ID NOs: 8, 11, and 25, respectively; (iv) SEQ ID NOs: 8, 12, and 26, respectively; (v) SEQ ID NOs: 8, 12, and 27, respectively; (vi) SEQ ID NOs: 8, 13, and 25, respectively; (vii) SEQ ID NOs: 8, 14, and 25, respectively; (viii) SEQ ID NOs: 8, 15, and 25, respectively; (ix) SEQ ID NOs: 8, 17, and 25, respectively; (x) SEQ ID NOs: 9, 18, and 28, respectively; (xi) SEQ ID NOs: 9, 19, and 28, respectively; (xii) SEQ ID NOs: 9, 20, and 28, respectively; (xiii) SEQ ID NOs: 9, 21, and 28, respectively; (xiv) SEQ ID NOs: 9, 22, and 28, respectively; (xv) SEQ ID NOs: 10, 22, and 28, respectively; (xvi) SEQ ID NOs: 10, 22, and 30, respectively; (xvii) SEQ ID NOs: 10, 22, and 31, respectively; (xviii) SEQ ID NOs: 10, 22, and 32, respectively; (xix) SEQ ID NOs: 10, 22, and 33, respectively; (xx) SEQ ID NOs: 10, 22, and 34, respectively; (xxi) SEQ ID NOs: 10, 22, and 35, respectively; (xxii) SEQ ID NOs: 10, 22, and 36, respectively; (xxiii) SEQ ID NOs: 10, 22, and 37, respectively; (xxiv) SEQ ID NOs: 10, 22, and 38, respectively; or (xxv) SEQ ID NOs: 10, 22, and 39, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 103, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 97, 98,^ny-2871899 735022004340 99, 100, 101, 102, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, or 127. 52. The complex of any one of claims 1-46, wherein the antigen-binding domain comprises a heavy chain variable region (VH) comprising a VH CDR1, VH CDR2, and VH CDR3 and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3, and wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 15, 25, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 50, 58, and 62, respectively; (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 341, 55, and 61, respectively. 53. The complex of claim 52, wherein the VH comprises the amino acid sequence of SEQ ID NO: 101, 102, 342, 117, 343, or 118. 54. The complex of claim 52 or claim 53, wherein the VL comprises the amino acid sequence of SEQ ID NO: 154, 344, 345, 174, 346, 347, 348, 349, or 350. 55. The complex of claim 53 or claim 54, wherein the VH and the VL comprise the amino acid sequences of: (i) SEQ ID NOs: 101 and 154, respectively; (ii) SEQ ID NOs: 102 and 344, respectively; (iii) SEQ ID NOs: 102 and 345, respectively;^ny-2871899 735022004340 (iv) SEQ ID NOs: 342 and 174, respectively; (v) SEQ ID NOs: 117 and 346, respectively; (vi) SEQ ID NOs: 117 and 347, respectively; (vii) SEQ ID NOs: 117 and 348, respectively; (viii) SEQ ID NOs: 117 and 349, respectively; (ix) SEQ ID NOs: 343 and 174, respectively; (x) SEQ ID NOs: 118 and 174, respectively; or (xi) SEQ ID NOs: 101 and 350, respectively. 56. The complex of any one of claims 1-46, wherein antigen-binding domain specifically binds to human TfR, and wherein the antigen-binding domain is a VHH comprising: (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 8, 14, and 25, respectively; (ii) SEQ ID NOs: 8, 15, and 25, respectively; (iv) SEQ ID NOs: 10, 22, and 333, respectively; (v) SEQ ID NOs: 10, 22, and 28, respectively; (ix) SEQ ID NOs: 10, 22, and 334, respectively; or (x) SEQ ID NOs: 10, 22, and 30, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 101, 102, 342, 117, 343, or 118. 57. The complex of any one of the preceding claims, wherein the PGRN polypeptide comprises an amino acid sequence set forth in SEQ ID NO:230. 58. The complex of any one of claims 1-56, wherein the PGRN polypeptide is a mutant PGRN polypeptide comprising a C-terminal amino acid sequence defined by X1X2X3X4, wherein X1 is any amino acid, and wherein X2, X3, and X4 are not PIL, PFL, PPL, PYL, QRL, or QHL. 59. The complex of claim 58, wherein the PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 330, and wherein:^ny-2871899 735022004340 (a) X1 is an amino acid selected from the group consisting of R, I, V, Q, T, P, and D; (b) X2 is an amino acid selected from the group consisting of Q and P; (c) X3 is absent or is an amino acid selected from the group consisting of L, P, C, G, T, D, Y, R, S, Q, V, A, I, H, K, and N; and/or (d) X4 is absent or is an amino acid selected from the group consisting of L, E, G, P, R, D, S, H, N, V, T, I, and A. 60. The complex of any one of claims 1-56 and 58-59, wherein the PGRN mutant polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 259, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. 61. The complex of any one of claims 2-56, wherein the PGRN mutant polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 247, SEQ ID NO: 258, and SEQ ID NO: 260. 62. The complex of claim 11, wherein: (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO:319; (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO:321; and (iii) the third polypeptide comprises the amino acid sequence of SEQ ID NO:320. 63. The complex of claim 14, wherein: (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO:322;^ny-2871899 735022004340 (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO:323; and (iii) the third polypeptide comprises the amino acid sequence of SEQ ID NO:321. 64. The complex of claim 12, wherein: (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO:319; (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO:321; and (iii) the third polypeptide comprises the amino acid sequence of SEQ ID NO:323. 65. The complex of claim 10, wherein: (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO:332, and (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO:321. 66. A complex comprising: (a) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a PGRN polypeptide; (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2 and a CH3; and (c) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 15, 25, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively;^ny-2871899 735022004340 (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 50, 58, and 62, respectively; (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 341, 55, and 61, respectively. 67. A complex comprising: (a) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, and a CH3; (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a PGRN polypeptide; and (c) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 15, 25, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 50, 58, and 62, respectively; (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 341, 55, and 61, respectively. 68. A complex comprising:^ny-2871899 735022004340 (a) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a PGRN polypeptide; (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a PGRN polypeptide; and (c) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 15, 25, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 50, 58, and 62, respectively; (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 341, 55, and 61, respectively. 69. A complex comprising: (a) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a PGRN polypeptide; and (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and^ny-2871899 735022004340 wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 15, 25, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 50, 58, and 62, respectively; (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 341, 55, and 61, respectively. 70. The complex of any one of claims 66-69, wherein the VH and the VL comprise the amino acid sequences of: (i) SEQ ID NOs: 101 and 154, respectively; (ii) SEQ ID NOs: 102 and 344, respectively; (iii) SEQ ID NOs: 102 and 345, respectively; (iv) SEQ ID NOs: 342 and 174, respectively; (v) SEQ ID NOs: 117 and 346, respectively; (vi) SEQ ID NOs: 117 and 347, respectively; (vii) SEQ ID NOs: 117 and 348, respectively; (viii) SEQ ID NOs: 117 and 349, respectively; (ix) SEQ ID NOs: 343 and 174, respectively; (x) SEQ ID NOs: 118 and 174, respectively; or (xi) SEQ ID NOs: 101 and 350, respectively.^ny-2871899 735022004340 71. The complex of any one of claims 66-70, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively. 72. The complex of claim 71, wherein the VH and the VL comprise the amino acid sequences of 117 and 349, respectively. 73. The complex of any one of claims 66-70, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively. 74. The complex of claim 73, wherein the VH and the VL comprise the amino acid sequences of 117 and 348, respectively. 75. The complex of any one of claims 66-74, wherein the PGRN polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 230, SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 247, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 260, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. 76. The complex of any one of claims 1-75, wherein the complex binds human Sortilin with a dissociation constant (KD) that ranges from about 5 nM to about 400 nM. 77. The complex of any one of claims 1-76, wherein the complex binds human Sortilin with a KD that ranges from about 50 nM to about 350 nM.^ny-2871899 735022004340 78. The complex of any one of claims 1-77, wherein the complex binds human Sortilin with a KD that ranges from about 100 nM to about 300 nM. 79. The complex of any one of claims 1-78, wherein the complex increases cellular GCase activity greater than the PGRN polypeptide alone. 80. The complex of any one of claims 1-79, wherein the complex increases cellular GCase activity at least about 0.5-fold, at least about 1-fold, or at least about 2-fold greater than the PGRN polypeptide alone. 81. The complex of any one of claims 1-80, wherein the complex is linked to an imaging agent. 82. A polynucleotide encoding the complex of any one of claims 1-81. 83. A vector comprising the polynucleotide of claim 82. 84. A host cell comprising the vector of claim 83. 85. A method of producing a complex comprising culturing the host cell of claim 84 so that the complex is produced, optionally wherein the method further comprises isolating the complex from the culture. 86. An isolated complex thereof produced by the method of claim 85. 87. A pharmaceutical composition comprising the complex of any one of claims 1-81. 88. The pharmaceutical composition of claim 87, further comprising a pharmaceutically acceptable carrier.^ny-2871899 735022004340 89. A method of treating a neurological disease or disorder in a subject comprising administering the complex of any one of claims 1-81 or the pharmaceutical composition of claim 87 or 88 to the subject. 90. The method of claim 89, wherein the neurological disease or disorder is selected from a neuropathy disorder, a neurodegenerative disease, an ocular disease disorder, a seizure disorder, a lysosomal storage disease, ischemia, a behavioral disorder, and CNS inflammation. 91. The method of claim 90, wherein the neurological disease or disorder is selected from Alzheimer's disease (AD), Huntington’s disease, dystonia, ataxia, stroke, dementia, Lewy body dementia, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson's disease, Pick's disease, encephalitis, traumatic brain injury, and limbic-predominant age-related TDP-43 encephalopathy (LATE). 92. The method of claim 91, wherein the dementia is frontotemporal dementia (FTD). 93. The method of claim 91, wherein the neurological disease or disorder is Alzheimer’s disease. 94. The method of claim 93, wherein the Alzheimer's disease is early onset Alzheimer’s disease, prodromal Alzheimer’s disease, mild Alzheimer’s disease, or late onset Alzheimer’s disease. 95. The method of claim 91, wherein the neurological disease or disorder is Parkinson’s disease. 96. The method of claim 91, wherein the neurological disease or disorder is frontal temporal epilepsy.^ny-2871899 735022004340 97. A method of treating a lysosomal storage disease in a subject comprising administering the complex of any one of claims 1-81 or the pharmaceutical composition of claim 87 or 88 to the subject. 98. The method of claim 97, wherein the lysosomal storage disease is selected from Gaucher disease, Ceroid lipofuscinosis (Batten disease), Mucopolysaccharidosis (MPS) Type I, MPS Type II and MPS Type III. 99. A method of transporting a complex across the BBB of a subject, comprising administering the complex of any one of claims 1-81 or the pharmaceutical composition of claim 87 or 88 to the subject. 100. A method of increasing the concentration of PGRN in the cerebral spinal fluid (CSF) of a subject, comprising administering the complex of any one of claims 1-81 or the pharmaceutical composition of claim 87 or 88 to the subject, wherein the concentration of PGRN is increased as compared to administering the PGRN polypeptide alone to the subject. 101. A method of imaging PGRN within a subject, comprising administering to the subject the complex of claim 81 and locating the imaging agent within the subject. 102. A method of detecting PGRN in vitro, comprising contacting an in vitro sample with the complex of claim 81 and locating the imaging agent within the sample. 103. Use of the complex of any one of claims 1-81 or the pharmaceutical composition of claim 87 or 88 in the method of any one of claims 89-102. 104. The complex of any one of claims 1-81 or the pharmaceutical composition of claim 87 or 88 for use in the method of any one of claims 89-102. 105. A complex comprising (a) an antigen-binding domain that specifically binds to human CD98 heavy chain (CD98hc) and (b) a Progranulin (PGRN) polypeptide.^ny-2871899 735022004340 106. The complex of claim 105, further comprising an Fc domain. 107. The complex of claim 105 or 106, wherein the antigen-binding domain comprises a VH and a VL on separate polypeptides. 108. The complex of any one of claims 105-107, wherein the complex comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and the PGRN polypeptide; and (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form the antigen-binding domain that specifically binds to human CD98hc. 109. The complex of claim 108, further comprising (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a CH2 and a CH3. 110. The complex of claim 108, further comprising (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a second PGRN polypeptide. 111. The complex of claim 108, further comprising: (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a second VH, a second CH1, a second hinge region, a second CH2, a second CH3, a second linker, and a second PGRN polypeptide; (iv) a fourth polypeptide comprising, from the N-terminus to the C-terminus, a second VL and a second CL; wherein the second VH and the second VL form a second antigen-binding domain that specifically binds to human CD98hc. 112. The complex of claim 105, comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, and a CH3;^ny-2871899 735022004340 (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and the PGRN polypeptide; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form the antigen-binding domain that specifically binds to human CD98hc. 113. The complex of claim 105 or 106, wherein the antigen-binding domain comprises a VH and VL on a single polypeptide chain. 114. The complex of any one of claims 105, 106 and 113, wherein the antigen-binding domain comprises a single-chain fragment variable (scFv). 115. The complex of claim 114, wherein the scFv is in the orientation VH-linker-VL. 116. The complex of claim 114, wherein the scFv is in the orientation VL-linker-VH. 117. The complex of claim 115 or claim 116, wherein the linker (A) is about 5 to about 25 amino acids, is about 5 to about 20 amino acids, is about 10 to about 25 amino acids, or is about 10 to about 20 amino acids and/or (B) comprises the amino acid sequence of GGSEGKSSGSGSESKSTGGS (SEQ ID NO: 6) or GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 7). 118. The complex of any one of claims 105, 106, and 113-117, comprising (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the PGRN polypeptide, a first Fc domain, and the antigen-binding domain and (ii) a second polypeptide comprising a second Fc domain. 119. The complex of claim 105 or 106 comprising (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the PGRN polypeptide and a first Fc domain and (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a second Fc domain and the antigen-binding domain.^ny-2871899 735022004340 120. The complex of any one of claims 105-107, comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the PGRN polypeptide and a first Fc domain, (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, and a second Fc domain, and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form the antigen-binding domain that specifically binds to human CD98hc. 121. The complex of any one of claims 105, 106, and 113, comprising (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the PGRN polypeptide, a first Fc domain, and the antigen-binding domain and (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a second PGRN polypeptide and a second Fc domain. 122. The complex of claim 121, wherein the second polypeptide comprises, from the N- terminus to the C-terminus, the second PGRN polypeptide, the second Fc domain, and a second antigen-binding domain that specifically binds CD98hc. 123. The complex of any one of claims 105-122, wherein the antigen-binding domain is a murine, chimeric, humanized, or human antigen-binding domain, optionally wherein the antigen- binding domain is a humanized antigen-binding domain. 124. The complex of any one of claims 105-123, wherein the Fc domain is capable of binding FcRn. 125. The complex of claim 105, further comprising an Fc region, wherein the Fc region comprises a first and second polypeptide chain. 126. The complex of claim 125, wherein the Fc region is capable of binding FcRn.^ny-2871899 735022004340 127. The complex of claim 125 or claim 126, comprising (i) a single scFv or VHH or Fab antigen-binding domain that binds to human CD98hc and (ii) and two copies of the PGRN polypeptide. 128. The complex of claim 127, wherein the single scFv, Fab or VHH antigen-binding domain that binds to human CD98hc is linked to the C-terminus of one of the two copies of the PGRN polypeptide. 129. The complex of claim 127, wherein one of the two copies of the PGRN polypeptide is linked to the N-terminus of the first polypeptide chain of the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the N-terminus of the second polypeptide chain of the Fc region. 130. The complex of claim 127, wherein the single scFv, Fab, or VHH antigen-binding domain that binds to human CD98hc is linked to the N-terminus of the first or second polypeptide chain of the Fc region. 131. The complex of claim 127, wherein one of the two copies of the PGRN polypeptide is linked to the C-terminus of the first polypeptide chain of the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the C-terminus of the second polypeptide chain of the Fc region. 132. The complex of claim 125 or claim 126, comprising (i) an antibody that binds to human CD98hc, wherein the antibody comprises two heavy chains and two light chains; and (ii) two copies of the PGRN polypeptide, wherein each copy of the PGRN polypeptide is linked to the C- termini of one of the two antibody heavy chains. 133. The complex of claim 125 or claim 126, comprising (i) two scFv, Fab, or VHH antigen- binding domains that bind to human CD98hc, (ii) the Fc region; and (iii) two copies of the PGRN polypeptide, wherein one of the two scFv, Fab, or VHH antigen-binding domains that^ny-2871899 735022004340 binds to human CD98hc is linked to the C-terminus of the first polypeptide chain of the Fc region, wherein the other scFv, Fab, or VHH antigen-binding domains that binds to human CD98hc is linked to the C-terminus of the second polypeptide chain of the Fc region, wherein one of the two copies of the PGRN polypeptide is linked to the N-terminus of the first polypeptide chain of the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the N-terminus of the second polypeptide chain of the Fc region. 134. The complex of claim 125 or claim 126, comprising (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the C-terminus of the first or second polypeptide chain of the Fc region and the PGRN polypeptide is linked to N-terminus of the first or second polypeptide chain of the Fc region. 135. The complex of claim 106, comprising (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the C-terminus of the Fc domain and the PGRN polypeptide is linked to N- terminus of the Fc domain. 136. The complex of claim 125 or claim 126, comprising (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc, (ii) the Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the N-terminus of the first or second polypeptide chain of the Fc region and the PGRN polypeptide is linked to the C-terminus of the first or second polypeptide chain of the Fc region. 137. The complex of claim 106, comprising (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc, (ii) the Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human^ny-2871899 735022004340 CD98hc is linked to the N-terminus of the Fc domain and the PGRN polypeptide is linked to the C-terminus of the Fc domain. 138. The complex of claim 125 or claim 126, comprising (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the N-terminus of one of the two polypeptide chains of the Fc region, and wherein the PGRN polypeptide is linked to the N-terminus of the other polypeptide chain of the Fc region. 139. The complex of any one of claims 125-134, 136, and 138, wherein the Fc region is a heterodimeric Fc region, optionally comprising knob and hole mutations. 140. The complex of any one of claims 106, 135, and 137, wherein the Fc domain is a single chain monovalent Fc domain. 141. The complex of any one of claims 125-134, 136, and 138-139, wherein the Fc region is a modified Fc region with a modification listed in Table 8 or Table 9. 142. The complex of any one of claims 125-134, 136, 138-139, and 141, wherein the Fc region is a human IgG1 Fc region, wherein the human IgG1 Fc region comprises a mutation that reduces effector function, optionally wherein the mutation that reduces effector function comprises: (i) L234A, L235A, and/or P331S; (ii) N325S and/or L328F; (iii) L234A, L235A, and/or P329G; or (iv) L234A, L235A, and/or P329S. 143. The complex of any one of claims 106, 135, 137, and 140, wherein the Fc domain is a modified Fc domain with a modification listed in Table 8. 144. The complex of any one of claims 106, 135, 137, 140, and 143, wherein the Fc domain is a human IgG1 Fc domain, wherein the human IgG1 Fc domain comprises a mutation that reduces effector function, optionally wherein the mutation that reduces effector function^ny-2871899 735022004340 comprises: (i) L234A, L235A, and/or P331S; (ii) N325S and/or L328F; (iii) L234A, L235A, and/or P329G; or (iv) L234A, L235A, and/or P329S. 145. The complex of any one of claims 105-144, wherein the antigen-binding domain comprises a VH comprising a VH CDR1, VH CDR2, and VH CDR3, and a VL comprising a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences comprise the amino acid sequences of: (i) SEQ ID NOs: 181, 185, 191, 194, 198, and 201, respectively; (ii) SEQ ID NOs: 182, 186, 191, 195, 199, and 202, respectively; (iii) SEQ ID NOs: 183, 187, 192, 196, 200, and 203, respectively; (iv) SEQ ID NOs: 9, 188, 192, 196, 200, and 203, respectively; (v) SEQ ID NOs: 184, 189, 193, 197, 198, and 204, respectively; (vi) SEQ ID NOs: 184, 190, 193, 197, 198, and 204, respectively; (vii) SEQ ID NOs: 184, 324, 193, 197, 198, and 204, respectively; (viii) SEQ ID NOs: 184, 325, 193, 197, 198, and 204, respectively; or (ix) SEQ ID NOs: 184, 326, 193, 197, 198, and 204, respectively. 146. The complex of claim 145, wherein the VH comprises the amino acid sequence of SEQ ID NO: 205, 206, 207, 208, 209, 210, 327, 328, or 329. 147. The complex of claim 145 or 146, wherein the VL comprises the amino acid sequence of SEQ ID NO: 211, 212, 213, 214, 215, or 216. 148. The complex of claim 146 or 147, wherein the VH and the VL comprise the amino acid sequences of: (i) SEQ ID NOs: 205 and 211, respectively; (ii) SEQ ID NOs: 206 and 212, respectively; (iii) SEQ ID NOs: 207 and 213, respectively; (iv) SEQ ID NOs: 208 and 214, respectively; (i) SEQ ID NOs: 209 and 215, respectively; (ii) SEQ ID NOs: 210 and 216, respectively;^ny-2871899 735022004340 (iii) SEQ ID NOs: 327 and 216, respectively; (iv) SEQ ID NOs: 328 and 216, respectively; or (v) SEQ ID NOs: 329 and 216, respectively. 149. The complex of any one of claims 105-144, wherein the antigen-binding domain is a VHH comprising: (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 181, 185, and 191, respectively; (ii) SEQ ID NOs: 182, 186, and 191, respectively; (iii) SEQ ID NOs: 183, 187, and 192, respectively; (iv) SEQ ID NOs: 9, 188, and 192, respectively; (v) SEQ ID NOs: 184, 189, and 193, respectively; (vi) SEQ ID NOs: 184, 190, and 193, respectively; (vii) SEQ ID NOs: 184, 324, and 193, respectively; (viii) SEQ ID NOs: 184, 325, and 193, respectively; or (ix) SEQ ID NOs: 184, 326, and 193, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 205, 206, 207, 208, 209, 210, 327, 328, or 329. 150. The complex of any one of claims 105-144, wherein the antigen-binding domain comprises a VH comprising a VH CDR1, VH CDR2, and VH CDR3, and a VL comprising a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences comprise the amino acid sequences of: (i) SEQ ID NOs: 184, 352, 193, 197, 198, and 204, respectively; (ii) SEQ ID NOs: 184, 353, 193, 197, 198, and 204, respectively; (iii) SEQ ID NOs: 184, 354, 193, 197, 198, and 204, respectively; (iv) SEQ ID NOs: 184, 355, 193, 197, 198, and 204, respectively; (v) SEQ ID NOs: 184, 356, 193, 197, 198, and 204, respectively; (vi) SEQ ID NOs: 184, 357, 193, 197, 198, and 204, respectively; (vii) SEQ ID NOs: 184, 358, 193, 197, 198, and 204, respectively; (viii) SEQ ID NOs: 184, 190, 193, 369, 198, and 204, respectively;^ny-2871899 735022004340 (ix) SEQ ID NOs: 184, 190, 193, 370, 198, and 204, respectively; (x) SEQ ID NOs: 184, 190, 193, 371, 198, and 204, respectively; (xi) SEQ ID NOs: 184, 190, 193, 372, 198, and 204, respectively; (xii) SEQ ID NOs: 184, 190, 193, 373, 198, and 204, respectively; (xiii) SEQ ID NOs: 184, 190, 193, 374, 198, and 204, respectively; (xiv) SEQ ID NOs: 184, 190, 193, 375, 198, and 204, respectively; (xv) SEQ ID NOs: 184, 354, 193, 371, 198, and 204, respectively; (xvi) SEQ ID NOs: 184, 359, 193, 197, 198, and 204, respectively; (xvii) SEQ ID NOs: 184, 190, 360, 197, 198, and 204, respectively; (xviii) SEQ ID NOs: 184, 190, 361, 197, 198, and 204, respectively; (xix) SEQ ID NOs: 184, 190, 362, 197, 198, and 204, respectively; (xx) SEQ ID NOs: 184, 190, 363, 197, 198, and 204, respectively; (xxi) SEQ ID NOs: 184, 190, 364, 197, 198, and 204, respectively; (xxii) SEQ ID NOs: 184, 190, 365, 197, 198, and 204, respectively; (xxiii) SEQ ID NOs: 184, 190, 366, 197, 198, and 204, respectively; (xxiv) SEQ ID NOs: 184, 190, 367, 197, 198, and 204, respectively; (xxv) SEQ ID NOs: 184, 190, 368, 197, 198, and 204, respectively; (xxvi) SEQ ID NOs: 184, 190, 193, 376, 198, and 204, respectively; (xxvii) SEQ ID NOs: 184, 190, 193, 377, 198, and 204, respectively; (xxviii) SEQ ID NOs: 184, 190, 193, 378, 198, and 204, respectively; (xxix) SEQ ID NOs: 184, 190, 193, 379, 198, and 204, respectively; (xxx) SEQ ID NOs: 184, 190, 193, 380, 198, and 204, respectively; (xxxi) SEQ ID NOs: 184, 190, 193, 381, 198, and 204, respectively; (xxxii) SEQ ID NOs: 184, 190, 193, 197, 198, and 382, respectively; (xxxiii) SEQ ID NOs: 184, 190, 193, 197, 198, and 383, respectively; (xxxiv) SEQ ID NOs: 184, 190, 193, 197, 198, and 384, respectively; (xxxv) SEQ ID NOs: 184, 190, 193, 197, 198, and 385, respectively; (xxxvi) SEQ ID NOs: 184, 190, 193, 197, 198, and 386, respectively; (xxxvii) SEQ ID NOs: 184, 190, 193, 197, 198, and 387, respectively; (xxxviii) SEQ ID NOs: 184, 190, 193, 197, 198, and 388, respectively; (xxxix) SEQ ID NOs: 184, 190, 193, 197, 198, and 389, respectively;^ny-2871899 735022004340 (xl) SEQ ID NOs: 184, 190, 193, 197, 198, and 390, respectively; (xli) SEQ ID NOs: 184, 190, 193, 197, 198, and 391, respectively; (xlii) SEQ ID NOs: 351, 190, 193, 197, 198, and 204, respectively; or (xliii) SEQ ID NOs: 351, 190, 193, 197, 198, and 391, respectively. 151. The complex of claim 150, wherein the VH comprises the amino acid sequence of SEQ ID NO: 210, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, or 409. 152. The complex of claim 150 or 151, wherein the VL comprises the amino acid sequence of SEQ ID NO: 215, 216, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, or 432. 153. The complex of claim 151 or 152, wherein the VH and the VL comprise the amino acid sequences of: (i) SEQ ID NOs: 392 and 216, respectively; (ii) SEQ ID NOs: 393 and 216, respectively; (iii) SEQ ID NOs: 394 and 216, respectively; (iv) SEQ ID NOs: 395 and 216, respectively; (v) SEQ ID NOs: 396 and 216, respectively; (vi) SEQ ID NOs: 397 and 216, respectively; (vii) SEQ ID NOs: 398 and 216, respectively; (viii) SEQ ID NOs: 210 and 410, respectively; (ix) SEQ ID NOs: 210 and 411, respectively; (x) SEQ ID NOs: 210 and 412, respectively; (xi) SEQ ID NOs: 210 and 413, respectively; (xii) SEQ ID NOs: 210 and 414, respectively; (xiii) SEQ ID NOs: 210 and 415, respectively; (xiv) SEQ ID NOs: 210 and 416, respectively; (xv) SEQ ID NOs: 394 and 412, respectively; (xvi) SEQ ID NOs: 399 and 216, respectively;^ny-2871899 735022004340 (xvii) SEQ ID NOs: 400 and 216, respectively; (xviii) SEQ ID NOs: 401 and 216, respectively; (xix) SEQ ID NOs: 402 and 216, respectively; (xx) SEQ ID NOs: 403 and 216, respectively; (xxi) SEQ ID NOs: 404 and 216, respectively; (xxii) SEQ ID NOs: 405 and 216, respectively; (xxiii) SEQ ID NOs: 406 and 216, respectively; (xxiv) SEQ ID NOs: 407 and 216, respectively; (xxv) SEQ ID NOs: 408 and 216, respectively; (xxvi) SEQ ID NOs: 210 and 417, respectively; (xxvii) SEQ ID NOs: 210 and 418, respectively; (xxviii) SEQ ID NOs: 210 and 419, respectively; (xxix) SEQ ID NOs: 210 and 420, respectively; (xxx) SEQ ID NOs: 210 and 421, respectively; (xxxi) SEQ ID NOs: 210 and 422, respectively; (xxxii) SEQ ID NOs: 210 and 423, respectively; (xxxiii) SEQ ID NOs: 210 and 424, respectively; (xxxiv) SEQ ID NOs: 210 and 425, respectively; (xxxv) SEQ ID NOs: 210 and 426, respectively; (xxxvi) SEQ ID NOs: 210 and 427, respectively; (xxxvii) SEQ ID NOs: 210 and 428, respectively; (xxxviii) SEQ ID NOs: 210 and 429, respectively; (xxxix) SEQ ID NOs: 210 and 430, respectively; (xl) SEQ ID NOs: 210 and 431, respectively; (xli) SEQ ID NOs: 210 and 432, respectively; (xlii) SEQ ID NOs: 409 and 215, respectively; or (xliii) SEQ ID NOs: 409 and 432, respectively. 154. The complex of any one of claims 105-144, wherein the antigen-binding domain specifically binds to human CD98 heavy chain (CD98hc), and wherein the antigen-binding domain is a VHH comprising:^ny-2871899 735022004340 (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 184, 352, and 193, respectively; (ii) SEQ ID NOs: 184, 353, and 193, respectively; (iii) SEQ ID NOs: 184, 354, and 193, respectively; (iv) SEQ ID NOs: 184, 355, and 193, respectively; (v) SEQ ID NOs: 184, 356, and 193, respectively; (vi) SEQ ID NOs: 184, 357, and 193, respectively; (vii) SEQ ID NOs: 184, 358, and 193, respectively; (viii) SEQ ID NOs: 184, 190, and 193, respectively; (ix) SEQ ID NOs: 184, 359, and 193, respectively; (x) SEQ ID NOs: 184, 190, and 360, respectively; (xi) SEQ ID NOs: 184, 190, and 361, respectively; (xii) SEQ ID NOs: 184, 190, and 362, respectively; (xiii) SEQ ID NOs: 184, 190, and 363, respectively; (xiv) SEQ ID NOs: 184, 190, and 364, respectively; (xv) SEQ ID NOs: 184, 190, and 365, respectively; (xvi) SEQ ID NOs: 184, 190, and 366, respectively; (xvii) SEQ ID NOs: 184, 190, and 367, respectively; (xviii) SEQ ID NOs: 184, 190, and 368, respectively; or (xix) SEQ ID NOs: 351, 190, and 193, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 210, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, or 409. 155. The complex of any one of the preceding claims, wherein the PGRN polypeptide comprises an amino acid sequence set forth in SEQ ID NO:230. 156. The complex of any one of claims 105-154, wherein the PGRN mutant polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 247,^ny-2871899 735022004340 SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 260, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. 157. The complex of any one of claims 105-156, wherein the complex is linked to an imaging agent. 158. A polynucleotide encoding the complex of any one of claims 105-157. 159. A vector comprising the polynucleotide of claim 158. 160. A host cell comprising the vector of claim 159. 161. A method of producing a complex comprising culturing the host cell of claim 160 so that the complex is produced, optionally wherein the method further comprises isolating the complex from the culture. 162. An isolated complex thereof produced by the method of claim 161. 163. A pharmaceutical composition comprising the complex of any one of claims 105-157. 164. The pharmaceutical composition of claim 163, further comprising a pharmaceutically acceptable carrier. 165. A method of treating a neurological disease or disorder in a subject comprising administering the complex of any one of claims 105-157 or the pharmaceutical composition of claim 163 or 164 to the subject. 166. The method of claim 165, wherein the neurological disease or disorder is selected from a neuropathy disorder, a neurodegenerative disease, an ocular disease disorder, a seizure disorder, a lysosomal storage disease, ischemia, a behavioral disorder, and CNS inflammation.^ny-2871899 735022004340 167. The method of claim 166, wherein the neurological disease or disorder is selected from Alzheimer's disease (AD), Huntington’s disease, dystonia, ataxia, stroke, dementia, Lewy body dementia, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson's disease, Pick's disease, encephalitis, traumatic brain injury, and limbic-predominant age-related TDP-43 encephalopathy (LATE). 168. The method of claim 167, wherein the dementia is frontotemporal dementia (FTD). 169. The method of claim 167, wherein the neurological disease or disorder is Alzheimer’s disease. 170. The method of claim 169, wherein the Alzheimer's disease is early onset Alzheimer’s disease, prodromal Alzheimer’s disease, mild Alzheimer’s disease, or late onset Alzheimer’s disease. 171. The method of claim 167, wherein the neurological disease or disorder is Parkinson’s disease. 172. The method of claim 165, wherein the neurological disease or disorder is frontal temporal epilepsy. 173. A method of treating a lysosomal storage disease in a subject comprising administering the complex of any one of claims 105-157 or the pharmaceutical composition of claim 163 or 164 to the subject. 174. The method of claim 173, wherein the lysosomal storage disease is selected from Gaucher disease, Ceroid lipofuscinosis (Batten disease), Mucopolysaccharidosis (MPS) Type I, MPS Type II and MPS Type III. 175. A method of transporting a complex across the BBB of a subject, comprising administering the complex of any one of claims 105-157 or the pharmaceutical composition of claim 163 or 164 to the subject.^ny-2871899 735022004340 176. A method of increasing the concentration of PGRN in the cerebral spinal fluid (CSF) of a subject, comprising administering the complex of any one of claims 105-157 or the pharmaceutical composition of claim 163 or 164 to the subject, wherein the concentration of PGRN is increased as compared to administering the PGRN polypeptide alone to the subject. 177. A method of imaging PGRN within a subject, comprising administering to the subject the complex of claim 157 and locating the imaging agent within the subject. 178. A method of detecting PGRN in vitro, comprising contacting an in vitro sample with the complex of claim 157 and locating the imaging agent within the sample. 179. Use of the complex of any one of claims 105-157 or the pharmaceutical composition of claim 163 or 164 in the method of any one of claims 165-178. 180. The complex of any one of claims 105-157 or the pharmaceutical composition of claim 163 or 164 for use in the method of any one of claims 165-178. 181. An isolated PGRN mutant polypeptide, wherein: (i) the isolated PGRN mutant polypeptide comprises a C-terminal amino acid sequence defined by X1X2X3X4, and wherein: (a) X1 is an amino acid selected from the group consisting of R, D, E, I, P, or Q; (b) X2 is an amino acid selected from the group consisting of Q and P; (c) X3 is an amino acid selected from the group consisting of L, A, C, D, F, G, H, I, K, M, N, P, Q, R, S, T, V, or Y; and/or (d) X4 is absent or is an amino acid selected from the group consisting of L, R, or V; and (ii) X2, X3, and X4 are not PIL, PFL, PPL, PYL, QRL, or QHL. 182. The isolated PGRN mutant polypeptide of claim 181, wherein the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 330. 183. The isolated PGRN mutant polypeptide of claim 182, wherein the amino acid sequence is selected from the group consisting of SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ^ny-2871899 735022004340 ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 259, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. 184. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 231. 185. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 232. 186. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 233. 187. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 234. 188. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 235. 189. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 236. 190. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 237. 191. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 238. 192. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 239.^ny-2871899 735022004340 193. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 240. 194. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 241. 195. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 242. 196. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 243. 197. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 244. 198. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 245. 199. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 246. 200. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 248. 201. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 249. 202. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 250. 203. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 251. 204. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 252.^ny-2871899 735022004340 205. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 253. 206. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 254. 207. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 255. 208. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 256. 209. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 257. 210. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 259. 211. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 261. 212. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 262. 213. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 263. 214. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 264. 215. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 265.^ny-2871899 735022004340 216. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 266. 217. An isolated nucleic acid encoding the isolated PGRN mutant polypeptide of any one of claims 181-216. 218. A vector comprising the nucleic acid of claim 217. 219. A host cell comprising the vector of claim 218. 220. A method of producing an isolated PGRN mutant polypeptide comprising culturing the host cell of claim 219 so that the isolated PGRN mutant polypeptide is produced, optionally wherein the method further comprises isolating the isolated PGRN mutant polypeptide from the culture. 221. An isolated PGRN mutant polypeptide produced by the method of claim 220. 222. A pharmaceutical composition comprising the isolated PGRN mutant polypeptide of any one of claims 181-216 and 221. 223. A method of treating a neurological disease or disorder in a subject comprising administering the isolated PGRN mutant polypeptide of any one of claims 181-216 and 221 or the pharmaceutical composition of claim 222 to the subject. 224. The method of claim 223, wherein the neurological disease or disorder is selected from a neuropathy disorder, a neurodegenerative disease, an ocular disease disorder, a seizure disorder, a lysosomal storage disease, ischemia, a behavioral disorder, and CNS inflammation. 225. The method of claim 224, wherein the neurological disease or disorder is selected from Alzheimer's disease (AD), Huntington’s disease, dystonia, ataxia, stroke, dementia, Lewy body dementia, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson's disease, Pick's disease, encephalitis, traumatic brain injury, and limbic-predominant age-related TDP-43 encephalopathy (LATE).^ny-2871899 735022004340 226. The method of claim 225, wherein the dementia is frontotemporal dementia (FTD). 227. The method of claim 225, wherein the neurological disease or disorder is Alzheimer’s disease. 228. The method of claim 227, wherein the Alzheimer's disease is early onset Alzheimer’s disease, prodromal Alzheimer’s disease, mild Alzheimer’s disease, or late onset Alzheimer’s disease. 229. The method of claim 225, wherein the neurological disease or disorder is Parkinson’s disease. 230. The method of claim 223, wherein the neurological disease or disorder is frontal temporal epilepsy. 231. A method of treating a lysosomal storage disease in a subject comprising administering the isolated PGRN mutant polypeptide of any one of claims 181-216 and 221 or the pharmaceutical composition of claim 222 to the subject. 232. The method of claim 231, wherein the lysosomal storage disease is selected from Gaucher disease, Ceroid lipofuscinosis (Batten disease), Mucopolysaccharidosis (MPS) Type I, MPS Type II and MPS Type III. 233. A method of increasing PGRN in a subject, the method comprising administering the isolated PGRN mutant polypeptide of any one of claims 181-216 and 221 or the pharmaceutical composition of claim 222 to the subject.^ny-2871899