WO2025074337A1

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Publication number: WO2025074337A1
Application number: PCT/IB2024/059756
Authority: WO
Inventors: Thomas Arnhold; Kristell MARZIN; Ghazal MONTASERI; Klas PETERSSON; Bryan RUDOLPH; Peng Sun
Original assignee: Boehringer Ingelheim International GmbH; OSE Immunotherapeutics SA
Current assignee: Boehringer Ingelheim International GmbH; OSE Immunotherapeutics SA
Priority date: 2023-10-06
Filing date: 2024-10-04
Publication date: 2025-04-10
Anticipated expiration: 2026-04-06

Abstract

The present disclosure relates to the treatment of a SIRPα (signal regulatory protein alpha) pathway disease or disorder, such as a liver disease or disorder, by administering an anti-SIRPα antibody or antigen-binding fragment thereof to a subject in need thereof.

Description

USE OF ANTI-SIRP-ALPHA ANTIBODIES TO TREAT A LIVER DISEASE OR DISORDER

SEQUENCE LISTING

[0001] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on September 25, 2024, is named 105218-03-5014-01 -WO_Sequence Listing .xml and is 291 ,384 bytes in size.

RELATED APPLICATION DISCLOSURE

[0002] The subject application claims the benefit of U.S. Provisional Application No. 63/542,986 filed October 6, 2023, and U.S. Provisional Application No. 63/654,791 , filed May 31 , 2024, each of which is incorporated by reference in its entirety.

FIELD

[0003] The present disclosure relates to the treatment of a SIRPa (signal regulatory protein alpha) pathway disease or disorder, such as a liver disease or disorder, by using an anti-SIRPa antibody or antigen-binding fragment thereof.

BACKGROUND

[0004] SIRPa is an inhibitory receptor expressed on myeloid cells such as macrophages, neutrophils and subsets of dendritic cells. SIRPa contains three Ig-like domains, a single transmembrane domain, and a cytoplasmic tail with four tyrosine residues which form two typical immunoreceptor tyrosine based inhibitory motifs (ITIMs). The natural ligand for SIRPa is CD47, expressed on many cells including erythrocytes and platelets. Binding of SIRPa to CD47 leads to the phosphorylation of the tyrosine residues in SIRPa intracellular ITIM domain and subsequent recruitment and activation SHP-1 and SHP-2 phosphatases at the cell membrane which can then, by dephosphorylation of downstream targets, regulate cellular functions including phagocytosis or antigen presentation.

[0005] The development of an effective SIRPa antagonist is complicated by polymorphisms within the CD47 binding domain. It has been reported that there may be up to ten allelic variants in the general population (Takenaka 2007; Nat Immunol 2007 Dec;8(12):1313-23) and recent studies (Treffers, 2018, Eur J Immunol. 2018 Feb;48(2):344- 354; MAbs Aug/Sep 2019;11 (6):1036-1052) highlight that two SIRPa variants, V1 and V2, constitute the most prevalent allelic groups: homozygous V1/V1 , homozygous V2/V2, and heterozygous V1/V2. These variants differ in 13 out of 118 amino acid residues in the N- terminal immunoglobulin-like domain of SIRPa responsible for CD47 binding. These polymorphic residues are located outside the CD47 binding site and, accordingly, the affinity of CD47 binding to SIRPa variants is similar (Hatherley D, 2008 Immunity 2008 Nov 14;29(5):675-8). Consequently, therapeutic targeting of SIRPa in diverse patient population irrespective of SIRPa genotype necessitates pan-allelic antibodies that cross-react with the two major SIRPa alleles (V1 and V2).

[0006] In addition to considering polymorphic variants when targeting SIRPa, one also should consider SIRPa’s closest relatives, SIRPpI and SIRPy given their high sequence conservation particularly in N-terminal domains. SIRPpI , like SIRPa is also expressed predominantly on cells of the myeloid lineage, but unlike SIRPa, lacks its own signaling cytoplasmic domain. Instead, it harbors a positively charged amino acid residue within the transmembrane region allowing for the stable association with ITAM-containing adapter molecule DAP12 and therefore is presumed to act as an activating receptor. SIRPpI does not bind CD47, and its ligands have not been identified. There are at least two isoforms of SIRPpI (Liu et al 2007 J Mol Biol. 2007 Jan 19;365(3):680-93; Brooke et al. 2004 J Immunol. 2004 Aug 15;173(4):2562-70) that arose through tandem duplication of the gene within the SIRP family gene cluster. SIRPy is exclusively expressed on T-cells and activated NK cells and does bind to CD47 with 10-fold lower affinity than SIRPa:CD47 interaction. Although it does not have intrinsic signaling capacity, there is reported evidence that it plays a role in T-cell transendothelial migration (TEM) and antigen presentation.

[0007] The interaction of SIRPa with CD47 is an important immune checkpoint of the innate response, involved in the regulation of myeloid functions. The interaction between SIRPa and CD47 provides a down-regulatory signal that inhibits host cell phagocytosis. CD47 may be overexpressed on necroptotic hepatocytes and functions as a “don’t eat me” signal thereby avoiding phagocytosis and clearance by liver macrophages that express SIRPa. In an effort to enhance macrophage phagocytosis, anti-human SIRPa antibodies able to disrupt the binding between SIRPa and CD47 have been developed. There is nonetheless a need for improved uses of these antibodies, in particular for tuning their effect in vivo, for example, by enhancing the patient response to the anti-SIRPa antibody or antigen-binding fragment thereof. There is also a need for improved uses of these antibodies in combination with additional therapeutic agents.

SUMMARY

[0008] The disclosure provides a method of treating a SIRPa pathway disease, such as a liver disease or disorder (e.g., MASH), in a subject in need thereof by administering to the subject a dose of an anti-SIRPa antibody or an antigen-binding fragment thereof.

[0014] In an embodiment, the dose of anti-SIRPa antibody or the antigen-binding fragment thereof is about 100 mg.

[0015] In an embodiment, the dose of the anti-SIRPa antibody or the antigen-binding fragment thereof is about 125 mg.

[0016] In an embodiment, the dose of the anti-SIRPa antibody or the antigen-binding fragment thereof is about 150 mg.

[0017] In an embodiment, the dose of the anti-SIRPa antibody or the antigen-binding fragment thereof is about 175 mg.

[0018] In an embodiment, the dose of the anti-SIRPa antibody or the antigen-binding fragment thereof is about 200 mg.

[0019] In an embodiment, the dose of the anti-SIRPa antibody or the antigen-binding fragment thereof is about 225 mg.

[0020] In an embodiment, the dose of the anti-SIRPa antibody or the antigen-binding fragment thereof is about 250 mg.

[0021] In an embodiment, the dose of the anti-SIRPa antibody or the antigen-binding fragment thereof is about 275 mg.

[0022] In an embodiment, the dose of the anti-SIRPa antibody or the antigen-binding fragment thereof is about 300 mg.

[0023] In an embodiment, the dose of the anti-SIRPa antibody or the antigen-binding fragment thereof is administered to the subject in need thereof at a dosing cycle of about twice a week, about once every week (Q1 W), about once every two weeks (Q2W), about once every three weeks (Q3W), or about once every four weeks (Q4W).

[0024] In an embodiment, the dose of the anti-SIRPa antibody or the antigen-binding fragment thereof is administered to the subject in need thereof at a dosing cycle of about once every week (Q1 W).

[0025] In an embodiment, the dose of the anti-SIRPa antibody or the antigen-binding fragment thereof is administered to the subject in need thereof at a dosing cycle of about once every two week (Q2W).

[0026] In an embodiment, the anti-SIRPa antibody or the antigen-binding fragment thereof is administered subcutaneously. [0027] In an embodiment, the SIRPa pathway disorder is a liver disease or disorder In an embodiment, the liver disease or disorder is cirrhosis. In an embodiment, the liver disease or disorder is MASH.

[0028] In an embodiment, the anti-SIRPa antibody or the antigen-binding fragment thereof comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 34 (H-CDR2); and the amino acid sequence of SEQ ID NO: 35 (H-CDR3), and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 or SEQ ID NO: 37 (L-CDR1); the amino acid sequence of SEQ ID NO: 38 (L-CDR2); and the amino acid sequence of SEQ ID NO: 39 (L-CDR3).

[0029] In an embodiment, the anti-SIRPa antibody or the antigen-binding fragment thereof comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 223 (H-CDR1); the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 or SEQ ID NO: 224 (H-CDR2); and the amino acid sequence of SEQ ID NO: 6 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9 or SEQ ID NO: 225 (L-CDR1); the amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 1 1 or SEQ ID NO: 226 (L-CDR2); and the amino acid sequence of SEQ ID NO: 12 or SEQ ID NO: 227 (L-CDR3).

[0030] In an embodiment, the anti-SIRPa antibody or the antigen-binding fragment thereof comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 52 (H-CDR1); the amino acid sequence of SEQ ID NO: 53 (H-CDR2); and the amino acid sequence of SEQ ID NO: 54 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 55 (L-CDR1); the amino acid sequence of SEQ ID NO: 56 (L-CDR2); and the amino acid sequence of SEQ ID NO: 57 (L-CDR3).

[0031] In an embodiment, the anti-SIRPa antibody or the antigen-binding fragment thereof comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 70 (H-CDR2); and the amino acid sequence of SEQ ID NO: 71 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 (L-CDR1); the amino acid sequence of SEQ ID NO: 72 (L-CDR2); and the amino acid sequence of SEQ ID NO: 39 (L-CDR3).

[0034] In an embodiment, the anti-SIRPa antibody or the antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of any one of SEQ ID NOs: 104, 118, 119, 120, 121 , 122, 123, 124 or 221 ; and a light chain variable region comprising the amino acid sequence of any one of SEQ ID NOs: 109, 127, 128, 129, 130, or 222.

[0035] In an embodiment, the anti-SIRPa antibody or the antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of any one of SEQ ID NOs: 100, 101 , 102, 103, or 104; and a light chain variable region comprising the amino acid sequence of any one of SEQ ID NOs: 105, 106, 107, 108, or 109.

SEQ ID NO: 130; or r) a heavy chain variable region comprising the amino acid sequence of

SEQ ID NO: 122; and a light chain variable region comprising the amino acid sequence of

SEQ ID NO: 130; or s) a heavy chain variable region comprising the amino acid sequence of

SEQ ID NO: 124; and a light chain variable region comprising the amino acid sequence of

[0043] In an embodiment, the anti-SIRPa antibody or the antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of any one of SEQ ID NO: 131 , 133, 134, 137 or 135; and a light chain comprising the amino acid sequence of any one of SEQ ID NO: 174, 176, 177, 180, or 178.

BRIEF DESCRIPTION OF THE DRAWINGS

[0045] The foregoing summary, as well as the following detailed description of the disclosure, will be better understood when read in conjunction with the appended figures. For the purpose of illustrating the disclosure, shown in the figures are embodiments which are presently preferred. It should be understood, however, that the disclosure is not limited to the precise arrangements, examples and instrumentalities shown. [0046] Figure 1 shows a dose response curve of cells treated with Antibody A10 (red dots) in efferocytosis of human hepatocytes (CFSE670+, red label) by hMDMs (CRSE450+, blue label), calculated by hMDM signal normalized over IgG isotype control (grey dots). Measurements were taken 1 hour after adding apoptotic primary human hepatocytes to differentiated hMDM following 2-hour pre-treatment with isotype or Antibody A10. The mean ± SEM is shown, where data are from 5 experiments in triplicate. SEM was derived from Prism GraphPad software and statistical significance P versus the respective isotype control was derived by One-way ANOVA with Bonferroni correction, where (***) p<0.001 and (****) p<0.0001.

[0047] Figure 2A-2C shows SIRPa concentration (mg/L) in plasma of human subjects from 0 to 3 weeks post administration of 2000 mg, 2200 mg, 2400 mg, 2600 mg, 2800 mg, 3000 mg, 3200 mg, 3400 mg, or 3600 mg of antibody A10 or 24 mg/kg of antibody X1 (Fig. 2A). Figs. 2B and 2C show the area under the curve (AUC) (mg*h/L) and the median C_min (mg/L) at 3 weeks post administration of 2000 mg, 2200 mg, 2400 mg, 2600 mg, 2800 mg, 3000 mg, 3200 mg, 3400 mg, or 3600 mg of antibody A10 or 24 mg/kg of antibody X1 in human subjects.

DETAILED DESCRIPTION

[0048] This disclosure relates to anti-SIRPa antibodies or antigen-binding fragments thereof for use in the treatment of conditions modulated by CD47-mediated SIRPa signaling. In one aspect, the disclosure provides methods of treating a liver disease or disorder (e.g., MASH) in a patient comprising administering a therapeutically effective amount of an anti- SIRPa antibody or antigen-binding fragment thereof.

[0049] This disclosure also relates to the administration of particular doses and dosing cycles which enhance the health of the patient, with the prescribed doses being unexpectedly higher than the typical doses in the field of antibody immunotherapy. These higher doses are well-tolerated without any significant adverse effects. Additionally, these higher doses are useful in the treatment of patients who have not responded to prior immunotherapeutic treatments or who have exhibited disease progression of a SIRPa (signal regulatory protein alpha) pathway disease, such as a liver disease or disorder (e.g., MASH) despite having received prior treatment.

Definitions

[0050] The generalized structure of antibodies or immunoglobulin is well known to those of skill in the art, these molecules are heterotetrametric glycoproteins, typically of about 150,000 daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each light chain is covalently linked to a heavy chain by one disulfide bond to form a heterodimer, and the heterotrimeric molecule is formed through a covalent disulfide linkage between the two identical heavy chains of the heterodimers. Although the light and heavy chains are linked together by one disulfide bond, the number of disulfide linkages between the two heavy chains varies by immunoglobulin isotype. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has at the amino-terminus a variable domain (VH = variable heavy chain), followed by three orfour constant domains (CH1 , CH2, CH3, and CH4), as well as a hinge region between CH1 and CH2. Each light chain has two domains, an amino-terminal variable domain (VL = variable light chain) and a carboxyterminal constant domain (CL). The VL domain associates non-covalently with the VH domain, whereas the CL domain is commonly covalently linked to the CH1 domain via a disulfide bond. Particular amino acid residues are believed to form an interface between the light and heavy chain variable domains (Chothia et al., 1985, J. Mol. Biol. 186:651 -663, Vargas-Madrazo E, Paz-Garcia E. J Mol Recognit. 2003;16(3):113-120). The variable domains are also referred herein as variable regions, and the constant domains as constant regions.

[0051] Certain domains within the variable domains differ extensively between different antibodies i.e., are “hypervariable.” These hypervariable domains contain residues that are directly involved in the binding and specificity of each particular antibody for its specific antigenic determinant. Hypervariability, both in the light chain and the heavy chain variable domains, is concentrated in three segments known as complementarity determining regions (CDRs) or hypervariable loops (HVLs). CDRs are defined by sequence comparison in Kabat et al., 1991 , In: Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., whereas HVLs are structurally defined according to the three-dimensional structure of the variable domain, as described by Chothia and Lesk, 1987, J. Mol. Biol. 196: 901-917. Where these two methods result in slightly different identifications of a CDR, the structural definition is preferred. As defined by Kabat, CDR-L1 is positioned at about residues 24-34, CDR-L2, at about residues 50-56, and CDR-L3, at about residues 89-97 in the light chain variable domain; CDR-H1 is positioned at about residues 31 - 35, CDR-H2 at about residues 50-65, and CDR-H3 at about residues 95-102 in the heavy chain variable domain. IMGT and NORTH provide alternative definitions of the CDRs (see, Lefranc MP. Unique database numbering system for immunogenetic analysis. Immunol Today (1997) 18:509; and North B, Lehmann A, Dunbrack RLJ. A new clustering of antibody CDR loop conformations. J Mol Biol. (201 1) 406:228-56). Additionally, CDRs may be defined per the Chemical Computing Group (CCG) numbering (Almagro et al., Proteins 2011 ; 79:3050- 3066 and Maier et al, Proteins 2014; 82:1599-1610). The CDR1 , CDR2, CDR3 of the heavy and light chains therefore define the unique and functional properties specific for a given antibody.

[0052] The three CDRs within each of the heavy and light chains are separated by framework regions (FR), which contain sequences that tend to be less variable. From the amino terminus to the carboxy terminus of the heavy and light chain variable domains, the FRs and CDRs are arranged in the order: FR1 , CDR1 , FR2, CDR2, FR3, CDR3, and FR4. The largely D-sheet configuration of the FRs brings the CDRs within each of the chains into close proximity to each other as well as to the CDRs from the other chain. The resulting conformation contributes to the antigen binding site (see Kabat et al., 1991 , NIH Publ. No. 91- 3242, Vol. I, pages 647-669), although not all CDR residues are necessarily directly involved in antigen binding. Those skilled in the art can routinely determine which residues comprise a particular CDR given the variable region amino acid sequence of the antibody. The CDR1 , CDR2, CDR3 of the heavy and light chains therefore define the unique and functional properties specific for a given antibody.

[0053] FR residues and Ig constant domains are generally not directly involved in antigen binding but contribute to antigen binding and/or mediate antibody effector function. Some FR residues are thought to have a significant effect on antigen binding in at least three ways: by noncovalently binding directly to an epitope, by interacting with one or more CDR residues, and by affecting the interface between the heavy and light chains. The constant domains are not directly involved in antigen binding but mediate various Ig effector functions, such as participation of the antibody in antibody-dependent cellular cytotoxicity (ADCC), complementdependent cytotoxicity (CDC) and antibody-dependent cellular phagocytosis (ADCP).

[0054] The light chains of vertebrate immunoglobulins are assigned to one of two clearly distinct classes, kappa (K) and lambda (A), based on the amino acid sequence of the constant domain. By comparison, the heavy chains of mammalian immunoglobulins are assigned to one of five major classes, according to the sequence of the constant domains: IgA, IgD, IgE, IgG, and IgM. IgG and IgA are further divided into subclasses (isotypes), e.g., lgG1 , lgG2, lgG3, lgG4, Ig A1 , and lgA2, respectively. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called a, 6, s, y, and p, respectively. The subunit structures and three-dimensional configurations of the classes of native immunoglobulins are well known.

[0055] The terms, “antibody,” and “anti-SIRPa antibody,” are used herein interchangeably and encompass monoclonal antibodies (including full length monoclonal antibodies), multispecific antibodies (e.g., bispecific antibodies), antibodies with minor modifications such as N- or C-terminal truncations and antibody fragments such as variable domains and other portions of antibodies that exhibit a desired biological activity, e.g., SIRPa binding.

[0056] The term “monoclonal antibody” refers to an antibody obtained from a substantially homogenous population of antibody molecules, i.e., the individual antibodies comprising the population are identical except for possible well-known alterations such as removal of C-terminal lysine from the antibody heavy chain or post-translational modifications such as amino acid isomerization or deamidation, methionine oxidation or asparagine or glutamine deamidation that may be present. Monoclonal antibodies typically bind one antigenic epitope. A bispecific monoclonal antibody binds two distinct antigenic epitopes. A monoclonal antibody may be monospecific or multispecific such as bispecific, monovalent, bivalent or multivalent. It should be understood that monoclonal antibodies can be made by any technique or methodology known in the art; including e.g., the hybridoma method (Kohler et al., 1975, Nature 256:495), or recombinant DNA methods known in the art (see, e.g., U.S. Pat. No. 4,816,567), or methods of isolation of monoclonal recombinantly produced using phage antibody libraries, using techniques described in Clackson et al., 1991 , Nature 352: 624-628, and Marks et al., 1991 , J. Mol. Biol. 222: 581-597.

[0057] Chimeric antibodies consist of the heavy and light chain variable regions of an antibody from one species (e.g., a non-human mammal such as a mouse) and the heavy and light chain constant regions of another species (e.g., human) antibody and can be obtained by linking the DNA sequences encoding the variable regions of the antibody from the first species (e.g., mouse) to the DNA sequences forthe constant regions of the antibody from the second (e.g. human) species and transforming a host with an expression vector containing the linked sequences to allow it to produce a chimeric antibody. Alternatively, the chimeric antibody also could be one in which one or more regions or domains of the heavy and/or light chain is identical with, homologous to, or a variant of the corresponding sequence in a monoclonal antibody from another immunoglobulin class or isotype, or from a consensus or germline sequence. Chimeric antibodies can include fragments of such antibodies, provided that the antibody fragment exhibits the desired biological activity of its parent antibody, for example binding to the same epitope (see, e.g., U.S. Pat. No. 4,816,567; and Morrison et al., 1984, Proc. Natl. Acad. Sci. USA 81 : 6851-6855).

[0058] The terms “antibody fragment,” “antigen-binding fragment,” “anti-SIRPa antibody fragment,” “anti-SIRPa antibody fragment,” “engineered anti-SIRPa antibody fragment” refer to a portion of a full length anti-SIRPa antibody, in which a variable region or a functional capability is retained, for example, SIRPa binding. Examples of antibody fragments include, but are not limited to, a Fab, Fab', F(ab')2, Fd, Fv, scFv and scFv-Fc fragment, a diabody, a linear antibody, a single-chain antibody, a minibody, a diabody formed from antibody fragments, and multispecific antibodies formed from antibody fragments.

[0059] Antibody fragments can be obtained for example by treating full-length antibodies treated with enzymes such as papain or pepsin to generate useful antibody fragments. Papain digestion is used to produce two identical antigen-binding antibody fragments called “Fab” fragments, each with a single antigen-binding site, and a residual “Fc” fragment. The Fab fragment also contains the constant domain of the light chain and the CH1 domain of the heavy chain. Pepsin treatment yields a F(ab')2 fragment that has two antigen-binding sites and is still capable of cross-linking antigen.

[0060] Another example of antibody fragments according to the disclosure are Fab’ fragments. Fab' fragments differ from Fab fragments by the presence of additional residues including one or more cysteines from the antibody hinge region at the C-terminus of the CH1 domain. F(ab')2 antibody fragments are pairs of Fab' fragments linked by cysteine residues in the hinge region. Other chemical couplings of antibody fragments are also known.

[0061] A “Fv” fragment contains a complete antigen-recognition and binding site consisting of a dimer of one heavy and one light chain variable domain in tight, non-covalent association. In this configuration, the three CDRs of each variable domain interact to define an antigen-biding site on the surface of the VH-VL dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody.

[0062] Antibody fragments may also include “single-chain Fv” or “scFv” fragments. A “single-chain Fv” or “scFv” antibody fragment is a single chain Fv variant comprising the VH and VL domains of an antibody where the domains are present in a single polypeptide chain. The single chain Fv is capable of recognizing and binding antigen. The scFv polypeptide may optionally also contain a polypeptide linker positioned between the VH and VL domains in order to facilitate formation of a desired three-dimensional structure for antigen binding by the scFv (see, e.g., Pluckthun, 1994, in The Pharmacology of Monoclonal Antibodies, Vol. 113, Rosenburg and Moore eds., Springer- Verlag, New York, pp. 269-315).

[0063] Antibody fragments may also form tandem Fd segments, which comprise a pair of tandem Fd segments (VH-CH1-VH-CH1) to form a pair of antigen binding regions. These “linear antibodies” can be bispecific or monospecific as described in, for example, Zapata et al. 1995, Protein Eng. 8(10): 1057-1062.

[0064] The term “human antibody” as used herein includes antibodies or fragments thereof derived from human germline immunoglobulin sequences. The term “human antibody” is not intended to include antibodies in which CDR sequences derived from the germline of another (mammalian) species, such as a mouse, rat or rabbit, have been grafted onto human framework sequences. Thus, as used herein, the term “human antibody” refers to an antibody or fragment thereof in which every part of the protein (e.g., CDR, framework, CL, CH domains (e.g., CH1 , CH2, CH3), hinge, VL, VH) is substantially non-immunogenic in humans, with only minor sequence changes or variations as further described herein below.

[0065] Technologies for creating such a “human antibody” have been described and include, without being limiting, phage display or use of transgenic animals (www. Ablexis.com/technology-alivamab.php; WO 90/05144; D. Marks, H.R. Hoogenboom, T.P. Bonnert, J. McCafferty, A.D. Griffiths and G. Winter (1991) “By-passing immunisation. Human antibodies from V-gene libraries displayed on phage.” J. Mol. Biol., 222, 581 -597; Knappik et al., J. Mol. Biol. 296: 57-86, 2000; S. Carmen and L. Jermutus, “Concepts in antibody phage display.” Briefings in Functional Genomics and Proteomics 2002 1 (2):189-203; Lonberg N, Huszar D. “Human antibodies from transgenic mice.” Int Rev Immunol. 1995;13(1):65-93.; Bruggemann M, Taussig MJ. “Production of human antibody repertoires in transgenic mice.” Curr Opin Biotechnol. 1997 Aug;8(4):455-8.).

[0066] Thus, a human antibody is distinct from e.g., a chimeric or humanized antibody. It is pointed out that a human antibody can be produced by a non-human animal or prokaryotic or eukaryotic cell that is capable of expressing functionally rearranged human immunoglobulin (e.g., heavy chain and/or light chain) genes.

[0067] In one aspect, an anti-SIRPa antibody of the disclosure is a humanized antibody or antibody fragment thereof. A humanized antibody or a humanized antibody fragment is a specific type of chimeric antibody which includes an immunoglobulin amino acid sequence variant, or fragment thereof, which is capable of binding to a predetermined antigen and which, comprises one or more FRs having substantially the amino acid sequence of a human immunoglobulin and one or more CDRs having substantially the amino acid sequence of a non-human immunoglobulin. This non-human amino acid sequence often referred to as an “import” sequence is typically taken from an “import” antibody domain, particularly a variable domain. In general, a humanized antibody includes at least the CDRs or HVLs of a non-human antibody, inserted between the FRs of a human heavy or light chain variable domain. Methods of humanization of antibodies are for example described by Almagro et al., (2008) Frontiers in Bioscience 13, 1619-1633, or in WO 12092374 A2.

[0068] The chimeric, humanized or human antibodies or antigen-binding fragments thereof of the present disclosure may further be engineered. Such engineering includes without limitation the removal or exchange of undesired amino acids, for example to reduce immunogenicity in humans, or to avoid deamidation, undesirable charges or lipophilicity or non-specific binding. Such removal or exchange of undesired amino acids can, for example, be introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo. Moreover, in connection with chimeric or humanized antibodies, it will be understood that certain mouse FR residues may be retained in an antibody or fragment thereof.

[0069] In one aspect, an anti-SIRPa antibody comprises substantially all of at least one, and typically two, variable domains (such as contained, for example, in Fab, Fab', F(ab')2, Fabc, and Fv fragments). In another aspect, an anti-SIRPa antibody also includes at least a portion of an immunoglobulin Fc region, typically that of a human immunoglobulin. Ordinarily, the antibody will contain both the light chain as well as at least the variable domain of a heavy chain. The antibody also may include one or more of the CH1 , hinge, CH2, CH3, and/or CH4 regions of the heavy chain, as appropriate.

[0070] In one aspect, an anti-SIRPa antibody can be selected from any class of immunoglobulins, including IgM, IgG, IgD, IgA and IgE, and any isotype, including lgG1 , lgG2, lgG3, lgG4, Ig A1 and lgA2. An alternative anti-SIRPa antibody can comprise sequences from more than one immunoglobulin class or isotype, and selecting particular modified or unmodified constant domains to optimize desired effector functions is within the ordinary skill in the art.

[0071] For example, the Fc region of an antibody mediates its serum half-life and effector functions, such as complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cell phagocytosis (ADCP). Fc engineering can be employed to optimize antibody properties suited to the pharmacology activity required of them. Where such cytotoxic activity is not desirable, such as targeting an immune cell in the treatment of cancer, the constant domain may be of isotype with reduced effector function, such as lgG4, and/or be modified with known modifications that reduce effector function. Where such cytotoxic activity is desirable, such as for destruction of a targeted tumor cell, the constant domain may be of isotype with increased effector function and/or be modified with known modifications to increase effector function. Several mutations are known to either reduce or increase effector function. See, e.g., “The future of antibodies as cancer drugs” Janice M Reichert, Eugen Dhimolea, Drug Discov Today (2012) Sep;17(17-18):954-63, “Antibody Drug Discovery” (Volume 4 of Molecular medicine and medicinal chemistry) Clive R. Wood, World Scientific, 2012 ISBN 1848166281 , 9781848166288; “FcyR requirements leading to successful immunotherapy” Immunol Rev. (2015) Nov;268(1):104-22.

[0072] In one aspect, the constant domain of an antibody of the present disclosure is lgG4Pro, which has one replacement mutation (Ser228Pro) that prevents Fab-arm exchanging. In another aspect, the constant domain of an antibody of the present disclosure is lgG1 , which has two mutations in the constant region, Leu234Ala and Leu235Ala to reduce effector function.

[0073] The FRs and CDRs, or HVLs, of an engineered anti-SIRPa antibody or antigenbinding fragment thereof need not correspond precisely to the parental sequences. For example, a parental sequence may be altered (e.g., mutagenized) by substitution, insertion or deletion such that the resulting amino acid residue is no longer identical to the original residue in the corresponding position in either parental sequence but the antibody nevertheless retains the function of binding to SIRPa. Such alteration typically will not be extensive and will be conservative alterations. Usually, at least 75% of the engineered antibody residues will correspond to those of the parental sequences, more often at least 90%, and most frequently greater than 95%, or greater than 98% or greater than 99%.

[0074] Immunoglobulin residues that affect the interface between heavy and light chain variable regions (“the VL-VH interface”) are those that affect the proximity or orientation of the two chains with respect to one another. Certain residues that may be involved in interchain interactions include VL residues 34, 36, 38, 44, 46, 87, 89, 91 , 96, and 98 and VH residues 35, 37, 39, 45, 47, 91 , 93, 95, 100, and 103 (utilizing the numbering system set forth in Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md., 1987)). U.S. Pat. No. 6,407,213 also discusses that residues such as VL residues 43 and 85, and VH residues 43 and 60 also may be involved in this interaction. While these residues are indicated for human IgG only, they are applicable across species. Important antibody residues that are reasonably expected to be involved in interchain interactions are selected for substitution into the consensus sequence.

[0075] The terms “consensus sequence” and “consensus antibody” refer to an amino acid sequence which comprises the most frequently occurring amino acid residue at each location in all immunoglobulins of any particular class, isotype, or subunit structure, e.g., a human immunoglobulin variable domain. The consensus sequence may be based on immunoglobulins of a particular species or of many species. A “consensus” sequence, structure, or antibody is understood to encompass a consensus human sequence as described in certain embodiments, and to refer to an amino acid sequence which comprises the most frequently occurring amino acid residues at each location in all human immunoglobulins of any particular class, isotype, or subunit structure. Thus, the consensus sequence contains an amino acid sequence having at each position an amino acid that is present in one or more known immunoglobulins, but which may not exactly duplicate the entire amino acid sequence of any single immunoglobulin. The variable region consensus sequence is not obtained from any naturally produced antibody or immunoglobulin. Kabat et al., 1991 , Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., and variants thereof. The FRs of heavy and light chain consensus sequences, and variants thereof, provide useful sequences for the preparation of human or humanized anti-SIRPa antibodies. See, for example, U.S. Pat. Nos. 6,037,454 and 6,054,297.

[0076] An “isolated” antibody is one that has been identified and separated and/or recovered from a component of its natural environment or from a cell culture from which it was expressed. An isolated antibody or antibody fragment may have one or more co- or post- translational modifications that arise during production, purification, and/or storage of the antibody or antibody fragment. Contaminant components of the antibody's natural environment are those materials that may interfere with diagnostic or therapeutic uses of the antibody, and can be enzymes, hormones, or other proteinaceous or non-proteinaceous solutes. In one aspect, the antibody will be purified to at least greater than 95% isolation by weight of antibody, for example purified to at least greaterthan 95%, 96%, 97%, 98%, or 99%.

[0077] An isolated antibody includes an antibody in situ within recombinant cells in which it is produced, since at least one component of the antibody's natural environment will not be present. Ordinarily however, an isolated antibody will be prepared by at least one purification step in which the recombinant cellular material is removed.

[0078] “Multispecific” refers to a protein, such as an antibody, that specifically binds two or more distinct antigens or two or more distinct epitopes within the same antigen.

[0079] “Bispecific” refers to a protein, such as an antibody, that specifically binds two distinct antigens or two distinct epitopes within the same antigen.

[0080] In some embodiments, the antibody that specifically binds SIRPa or the antigenbinding fragment thereof of the disclosure is a bispecific antibody. In some embodiments, the antibody or the antigen-binding fragment thereof of the disclosure is a multispecific antibody. The monospecific antibodies that specifically bind SIRPa provided herein may be engineered into bispecific antibodies, which are also encompassed within the scope of the disclosure.

[0081] Full-length bispecific antibodies may be generated for example using Fab arm exchange (e.g., half-molecule exchange, exchanging one heavy chain-light chain pair) between two monospecific bivalent antibodies by introducing substitutions at the heavy chain CH3 interface in each half molecule to favor heterodimer formation of two antibody half molecules having distinct specificity either in vitro in cell-free environment or using coexpression. The Fab arm exchange reaction is the result of a disulfide-bond.

[0082] Bispecific antibodies may also be generated using designs such as the Triomab/Quadroma (Trion Pharma/Fresenius Biotech), Knob-in-Hole (Genentech), CrossMAbs (Roche) and the electrostatically-induced CH3 interaction (Chugai, Amgen, NovoNordisk, Oncomed), the LUZ-Y (Genentech), the Strand Exchange Engineered Domain body (SEEDbody) (EMD Serono), the Biclonic (Merus) and as DuoBody® Products (Genmab A/S).

[0083] As used herein, the terms “identical” or “percent identity”, in the context of two or more nucleic acids or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of nucleotides or amino acid residues that are the same, when compared and aligned for maximum correspondence. To determine the percent identity, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first amino acid or nucleic acid sequence for optimal alignment with a second amino or nucleic acid sequence). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity=# of identical positions/total # of positions (e.g., overlapping positions)x100). In some embodiments, the two sequences that are compared are the same length after gaps are introduced within the sequences, as appropriate (e.g., excluding additional sequence extending beyond the sequences being compared). For example, when variable region sequences are compared, the leader and/or constant domain sequences are not considered. For sequence comparisons between two sequences, a “corresponding” CDR refers to a CDR in the same location in both sequences (e.g., CDR-H1 of each sequence).

[0084] The determination of percent identity or percent similarity between two sequences can be accomplished using a mathematical algorithm. A preferred, non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin and Altschul, 1990, Proc. Natl. Acad. Sci. USA 87:2264-2268, modified as in Karlin and Altschul, 1993, Proc. Natl. Acad. Sci. USA 90:5873-5877. Such an algorithm is incorporated into the NBLAST and XBLAST programs of Altschul et al., 1990, J. Mol. Biol. 215:403-410. BLAST nucleotide searches can be performed with the NBLAST program, score=100, wordlength=12, to obtain nucleotide sequences homologous to a nucleic acid encoding a protein of interest. BLAST protein searches can be performed with the XBLAST program, score=50, wordlength=3, to obtain amino acid sequences homologous to protein of interest. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., 1997, Nucleic Acids Res. 25:3389-3402. Alternatively, PSI-Blast can be used to perform an iterated search which detects distant relationships between molecules (Id.). When utilizing BLAST, Gapped BLAST, and PSI-Blast programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. Another preferred, non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, CABIOS (1989). Such an algorithm is incorporated into the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used. Additional algorithms for sequence analysis are known in the art and include ADVANCE and ADAM as described in Torellis and Robotti, 1994, Comput. Appl. Biosci. 10:3- 5; and FASTA described in Pearson and Lipman, 1988, Proc. Natl. Acad. Sci. USA 85:2444- 8. Within FASTA, ktup is a control option that sets the sensitivity and speed of the search. If ktup=2, similar regions in the two sequences being compared are found by looking at pairs of aligned residues; if ktup=1 , single aligned amino acids are examined, ktup can be set to 2 or 1 for protein sequences, or from 1 to 6 for DNA sequences. The default if ktup is not specified is 2 for proteins and 6 for DNA. Alternatively, protein sequence alignment may be carried out using the CLUSTAL W algorithm, as described by Higgins et al., 1996, Methods Enzymol. 266:383-402.

[0085] For diagnostic as well as therapeutic monitoring purposes, the antibodies or antigen-binding fragment thereof of the disclosure also may be conjugated to a label, either a label alone or a label and an additional second agent (prodrug, chemotherapeutic agent and the like). A label, as distinguished from the other second agents, refers to an agent that is a detectable compound or composition and it may be conjugated directly or indirectly to an anti- SIRPa antibody or antigen-binding fragment thereof of the present disclosure. The label may itself be detectable (e.g., radioisotope labels or fluorescent labels) or, in the case of an enzymatic label, may catalyze chemical alteration of a substrate compound or composition that is detectable. Labelled anti-SIRPa antibodies or antigen-binding fragments thereof can be prepared and used in various applications including in vitro and in vivo diagnostics.

[0086] In various aspects of the present disclosure one or more domains of the anti- SIRPa antibodies orantigen-binding fragments thereof will be recombinantly expressed. Such recombinant expression may employ one or more control sequences, i.e., polynucleotide sequences necessary for expression of an operably linked coding sequence in a particular host organism. The control sequences suitable for use in prokaryotic cells include, for example, promoter, operator, and ribosome binding site sequences. Eukaryotic control sequences include, but are not limited to, promoters, polyadenylation signals, and enhancers. These control sequences can be utilized for expression and production of anti-SIPRa antibodies or antigen-binding fragments thereof in prokaryotic and eukaryotic host cells. [0087] A nucleic acid sequence is “operably linked” when it is placed into a functional relationship with another nucleic acid sequence. For example, a nucleic acid presequence or secretory leader is operably linked to a nucleic acid encoding a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation. Generally, “operably linked” means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading frame. However, enhancers are optionally contiguous. Linking can be accomplished by ligation at convenient restriction sites. If such sites do not exist, synthetic oligonucleotide adaptors or linkers can be used.

[0088] As used herein, the expressions “cell,” “cell line,” and “cell culture” are used interchangeably and all such designations include the progeny thereof. Thus, “transformants” and “transformed cells” include the primary subject cell and cultures derived therefrom without regard for the number of transfers, which may for example have been transfected with one or more expression vectors encoding one or more amino acids sequences of an antibody or antigen-binding fragment thereof of the present disclosure.

[0089] The term “mammal” for purposes of treatment according to the disclosure refers to any animal classified as a mammal, including humans, domesticated and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, and the like. Preferably, the mammal is a human.

[0090] A “disorder,” as used herein, is any condition that would benefit from treatment with an anti-SIRPa antibody or antigen-binding fragment thereof described herein. This includes chronic and acute disorders or diseases including those pathological conditions that predispose the mammal to the disorder in question. Non-limiting examples or disorders to be treated herein include liver diseases or disorders.

[0091] As used herein, the term “SIRPa pathway disorder” or “SIRPa pathway disease” refers to a condition, which can be alleviated by modulating the interaction between SIRPa and CD47, in particular by inhibiting the SIRPa/CD47 signaling. A “SIRPa pathway disorder” or “SIRPa pathway disease” includes myeloid associated diseases where SIRPa is expressed. A “SIRPa pathway disorder” or “SIRPa pathway disease” also includes conditions characterized by reduced phagocytosis by macrophages and/or dendritic cells that express SIRPa. A SIRPa pathway disease or disorder may be a liver disease or disorder.

[0092] As used herein, the term “liver disease” or “liver disorder” refers to any disease or disorder that affects the liver. Examples of liver diseases or disorders include, but are not limited to, cirrhosis (e.g., decompensated cirrhosis or cirrhosis due to MASH), alcohol-induced liver disease (e.g., alcohol induced cirrhosis), cystic fibrosis-associated liver disease (CFLD), alcohol related liver disease, alpha 1 antitrypsin deficiency, autoimmune hepatitis, benign liver tumors, hemochromatosis, hepatitis A, hepatitis B, hepatitis C, hepatocellular carcinoma, liver cysts, liver cancer, metabolic dysfunction-associated steatotic liver disease (MASLD) such as MASH or MASL, type 1 glycogen storage disease, Wilson’s disease, Alagille syndrome, autoimmune hepatitis, biliary atresia, biliary cirrhosis, congestive hepatopathy, drug induced liver injury, focal nodular hyperplasia, glycogen storage diseases, ischemic hepatitis, lysosomal acid lipase deficiency, polycystic liver disease, progressive familial intrahepatic cholestasis, primary sclerosing cholangitis, and veno-occlusive disease.

[0093] The term cirrhosis refers to scarring (e.g., fibrosis) of the liver.

[0094] The term “metabolic dysfunction-associated steatotic liver disease” (MASLD) refers to a condition which is one cause of a fatty liver, occurring when fat is deposited in the liver not due to excessive alcohol use. MASLD is related to insulin resistance and the metabolic syndrome and may respond to treatments originally developed for other insulinresistant states (e.g., diabetes mellitus type 2) such as weight loss. MASLD can be subclassified as MASH and nonalcoholic fatty liver (MASL). MASH is the more extreme form of MASLD and is regarded as a major cause of cirrhosis of the liver of unknown cause.

[0095] The terms “specifically binds” or “specific binding” in the context of a binding agent, e.g., an antibody or antigen-binding fragment thereof, refers to a binding agent that associates more frequently, more rapidly, with greater duration, with greater affinity, with greater avidity or with some combination of the above, to an antigen or an epitope within the antigen than with an unrelated antigen. In certain embodiments, an antibody or antigenbinding fragment thereof specifically binds to an antigen or epitope within an antigen with a KD of about 0.1 mM or less, preferably less than about 1 pM. Because of the sequence identity between homologous proteins in different species, or variants of a protein within a single species, specific binding can include an antibody or antigen-binding fragment thereof that recognizes a protein in more than one species (e.g., human SIRPa and cyno SIRPa). It is understood that, in certain embodiments, an antibody or antigen-binding fragment thereof that specifically binds a first protein may or may not specifically bind a second protein. As such, "specific binding" does not necessarily require (although it can include) exclusive binding, e.g. binding to a single protein. Thus, an antibody or antigen-binding fragment thereof may, in certain embodiments, specifically bind more than one protein.

[0096] Methods for determining whether two molecules specifically bind a protein are known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. In one embodiment, specific binding is characterized by a KD of about 1 x 10.-7 M (100 nM) or less, about 5 x 10.-8 M (50 nM) or less, about 1 x 10.-8 M (10 nM) or less, or about 5 x 10.-9 M (5 nM) or less according.

[0097] The term “subcutaneous administration” refers to introduction of a drug, for example an anti-SIRPa antibody or antigen-binding fragment thereof of the disclosure, under the skin of a subject such as an animal or human patient, preferable within a pocket between the skin and underlying tissue, by relatively slow, sustained delivery from a drug receptacle. Pinching or drawing the skin up and away from underlying tissue may create the pocket.

[0098] The term “subcutaneous infusion” refers to introduction of a drug, for example an anti-SIRPa antibody or antigen-binding fragment thereof of the disclosure, under the skin of a subject, preferably within a pocket between the skin and underlying tissue, by relatively slow, sustained delivery from a drug receptacle for a period of time including, but not limited to, 30 minutes or less, or 90 minutes or less. Optionally, the infusion may be made by subcutaneous implantation of a drug delivery pump implanted under the skin of the subject, wherein the pump delivers a predetermined amount of drug for a predetermined period of time, such as 30 minutes, 90 minutes, or a time period spanning the length of the treatment regimen.

[0099] The term “subcutaneous bolus” refers to drug administration beneath the skin of a subject, where bolus drug delivery is less than approximately 15 minutes; in another aspect, less than 5 minutes, and in still another aspect, less than 60 seconds. In yet even another aspect, administration is within a pocket between the skin and underlying tissue, where the pocket may be created by pinching or drawing the skin up and away from underlying tissue. For example, “subcutaneous bolus” refers to the administration of an anti-SIRPa antibody or antigen-binding fragment thereof of the disclosure to a subject in less than approximately 15 minutes; in another aspect, less than 5 minutes, and in still another aspect, less than 60 seconds.

[00100] The term “therapeutically effective amount” is used to refer to an amount of an anti-SIRPa antibody or antigen-binding fragment thereof that relieves or ameliorates one or more of the symptoms of the disorder being treated. In doing so, it is that amount that has a beneficial patient outcome. Efficacy can be measured in conventional ways, depending on the condition to be treated.

[00101] The terms “treatment” and “therapy” and the like, as used herein, are meant to include therapeutic as well as prophylactic, orsuppressive measures for a disease ordisorder leading to any clinically desirable or beneficial effect, including but not limited to alleviation or reliefofone ormore symptoms, regression, slowing orcessation of progression ofthe disease ordisorder. Thus, forexample, the term treatment includes the administration of an anti-SIRPa antibody or antigen-binding fragment thereof prior to or following the onset of a symptom of a disease or disorder thereby preventing or removing one or more signs of the disease or disorder. As another example, the term includes the administration of an anti-SIRPa antibody or antigen-binding fragment thereof after clinical manifestation of the disease to combat the symptoms of the disease. Further, administration of an anti-SIRPa antibody or antigen-binding fragment thereof after onset and after clinical symptoms have developed where administration affects clinical parameters of the disease or disorder, such as the degree of tissue injury or the amount or extent of metastasis, whether or not the treatment leads to amelioration of the disease, comprises “treatment” or “therapy” as used herein. Moreover, as long as the compositions of the disclosure either alone or in combination with another therapeutic agent alleviate or ameliorate at least one symptom of a disorder being treated as compared to that symptom in the absence of use of the anti-SIRPa antibody or antigen-binding fragment thereof, the result should be considered an effective treatment of the underlying disorder regardless of whether all the symptoms of the disorder are alleviated or not.

[00102] The term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, which contain information about the indications, usage, administration, contraindications and/or warnings concerning the use of such therapeutic products.

Anti-SIRPa Antibodies

[00104] In an embodiment, the anti-SIRPa antibodies and antigen-binding fragments thereof disclosed herein recognizes a specific linear and/or conformational SIRPa antigen epitope and SIRPa epitope. Suitable SIRPa antigen epitopes and SIRPa epitopes include, but are not limited to, those disclosed in WO 2022/254379, which is hereby incorporated by reference in its entirety.

[00105] CDRs of representative anti-SIRPa antibodies of the present disclosure are provided in Tables 1-25 below. Heavy Chain CDR-1 , CDR-2, CDR3 (HCDR1-3) and Light Chain CDR-1 , CDR-2, CDR3 (L-CDR1 -3) are provided according to the numbering systems according to Kabat, CCG, Chothia, IMGT, and North.

TABLE 1 : KABAT NOMENCLATURE

TABLE 2: IMGT NOMENCLATURE

TABLE 4: CHOTHIA NOMENCLATURE

TABLE 5: NORTH NOMENCLATURE

TABLE 6: KABAT NOMENCLATURE

TABLE 7: IMGT NOMENCLATURE

TABLE 9: CHOTHIA NOMENCLATURE

TABLE 10: NORTH NOMENCLATURE

TABLE 12: IMGT NOMENCLATURE

TABLE 14: CHOTHIA NOMENCLATURE

TABLE 15: NORTH NOMENCLATURE

TABLE 16: KABAT NOMENCLATURE

TABLE 17: IMGT NOMENCLATURE

TABLE 19: CHOTHIA NOMENCLATURE

TABLE 21 : KABAT NOMENCLATURE

TABLE 22: IMGT NOMENCLATURE

TABLE 23: CCG NOMENCLATURE

TABLE 24: CHOTHIA NOMENCLATURE

Anti-SIRPa Antibody Sequences

[00106] Heavy and light chain variable regions of representative anti-SIRPa antibodies of the present disclosure are provided in Tables 26-27 below.

TABLE 26: Heavy Chain Variable Region (VH) Amino Acid Sequences

TABLE 27: Light Chain Variable Region Amino Acid Sequences

[00107] Representative anti-SIRPa antibodies of the present disclosure have the light and/or heavy chain variable regions sequences as set forth in Tables 28 or 29.

TABLE 28: Heavy Chain Variable Region (VH) Amino Acid Sequences

TABLE 29: Light Chain Variable Region (VL) Amino Acid Sequences

[00108] Representative anti-SIRPa antibodies of the present disclosure may comprise a heavy and/or light chain as set forth in Tables 30 or 31 below.

TABLE 30: FULL LENGTH HC SEQUENCES OF ANTI-SIRPa ANTIBODIES.

TABLE 31 : FULL LENGTH LC SEQUENCES OF ANTI-SIRP-a ANTIBODIES.

[00109] Representative anti-SIRPa antibodies of the present disclosure may comprise a heavy and/or light chain constant region as set forth in Tables 32 or 33 below.

Table 32: EXAMPLE HC AND LC SEQUENCES OF THE CONSTANT REGIONS OF ANTI-

SIRPa ANTIBODIES.

Amino Acid Sequence Variants [00110] Variant anti-SIRPa antibodies and antibody fragments thereof can be engineered based on a set of CDRs depicted in Tables 1-25. It is to be understood that in the variant anti- SIRPa antibodies and antibody fragments the amino acid sequence of the CDRs remain unchanged or have minimal changes (e.g., 1-5 changes), but the surrounding regions, e.g., FR regions can be engineered. Amino acid sequence variants of the anti-SIRPa antibody can be prepared by introducing appropriate nucleotide changes into the anti-SIRPa antibody DNA, or by peptide synthesis. Such variants include, for example, deletions from, and/or insertions into and/or substitutions of, residues within the amino acid sequences of the anti-SIRPa antibodies of the examples herein. Any combination of deletions, insertions, and substitutions is made to arrive at the final construct, provided that the final construct possesses the desired characteristics. The amino acid changes also may alter post-translational processes of the human or variant anti-SIRPa antibody, such as changing the number or position of glycosylation sites.

[00111] In some embodiments, the present disclosure includes anti-SIRPa antibodies or antibody fragments thereof having a variable heavy chain and a variable light chain, wherein the variable heavy chain amino acid sequence and the variable light chain amino acid sequence are at least at least 90%, at least 92.5%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequences disclosed in Tables 26-29 provided that the antibody or fragments thereof retain binding to SIRPa-V1 and/or SIRPa-V2.

[00112] In some embodiments, the present disclosure includes anti-SIRPa antibodies or antibody fragments thereof having a variable heavy chain and a variable light chain, wherein the variable heavy chain amino acid sequence and the variable light chain amino acid sequence are at least 80%, at least 85%, at least 90%, at least 92.5%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequences of SEQ ID Nos: 100, 101 , 102, 103, 110, 111 , 112, 113, 114, 115, 116, 117, 104, 118, 119, 120, 121 , 122, 123, 124, or 221 , and SEQ ID Nos: 105, 106, 107, 108,109, 126, 127, 128, 129, 130, or 222, respectively.

[00113] In some embodiments, the present disclosure includes anti-SIRPa antibodies having a heavy chain and a light chain, wherein the heavy chain amino acid sequence and the light chain amino acid sequence are at least 95%, at least 98%, or at least 99% identical to the amino acid sequences disclosed in Tables 30 and 31 provided that the antibody or fragments thereof retain binding to SIRPa-V1 and/or SIRPa-V2.

[00114] In some embodiments, the anti-SIRPa antibodies or antibody fragments thereof comprise a variable heavy chain sequence that comprises an amino acid sequence with at least about 95%, about 96%, about 97%, about 98%, or about 99%, sequence identity to the amino acid sequence set forth in SEQ ID NOs: 100, 101 , 102, 103, 110, 111 , 112, 113, 114, 115, 116, 117, 104, 118, 119, 120, 121 , 122, 123, 124, or 221. In other embodiments, the anti-SIRPa antibodies or antibody fragments thereof retains the binding and/or functional activity of an anti-SIRPa antibody or antibody fragment thereof that comprises the variable heavy chain sequence of SEQ ID NOs: 100, 101 , 102, 103, 110, 111 , 112, 113, 114, 115, 116, 117, 104, 118, 119, 120, 121 , 122, 123, 124, or 221 . In still further embodiments, the anti- SIRPa antibodies or antibody fragments thereof comprise the variable heavy chain sequence of SEQ ID NOs: 100, 101 , 102, 103, 110, 111 , 112, 113, 114, 115, 116, 117, 104, 118, 119, 120, 121 , 122, 123, 124, or 221 and have one or more conservative amino acid substitutions, e.g., 1 , 2, 3, 4, 5, 1-2, 1-3, 1-4 or 1-5 conservative amino acid substitutions in the heavy chain variable sequence. In yet further embodiments, the one or more conservative amino acid substitutions fall within one or more framework regions in SEQ ID NOs: 100, 101 , 102, 103, 110, 111 , 112, 113, 114, 115, 116, 117, 104, 118, 119, 120, 121 , 122, 123, 124, or221 (based on the numbering system of Kabat).

[00115] In some embodiments, the anti-SIRPa antibody or antibody fragment thereof comprises a variable heavy chain sequence with at least about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to the anti-SIRPa heavy chain variable region sequence set forth in 100, 101 , 102, 103, 110, 111 , 112, 113, 114, 115, 116, 117, 104, 118, 119, 120, 121 , 122, 123, 124, or 221 comprises one or more conservative amino acid substitutions in a framework region (based on the numbering system of Kabat), and retains the binding and/or functional activity of an anti-SIRPa antibody or antibody fragment thereof that comprises a variable heavy chain sequence as set forth in SEQ ID NOs: 100, 101 , 102, 103, 110, 111 , 112, 113, 114, 115, 116, 117, 104, 118, 119, 120, 121 , 122, 123, 124, or 221 and a variable light chain sequence as set forth in SEQ ID NOs: 105, 106, 107, 108,109, 126, 127, 128, 129, 130, or 222.

[00116] In some embodiments, the anti-SIRPa antibodies or antibody fragments thereof comprise a variable light chain sequence that comprises an amino acid sequence with at least about 95%, about 96%, about 97%, about 98%, or about 99%, sequence identity to the amino acid sequence set forth in SEQ ID NOs: 105, 106, 107, 108,109, 126, 127, 128, 129, 130, or 222. In other embodiments, the anti-SIRPa antibodies or antibody fragments thereof retains the binding and/or functional activity of an anti-SIRPa antibody or antibody fragment thereof that comprises the variable light chain sequence of SEQ ID NOs: 105, 106, 107, 108,109, 126, 127, 128, 129, 130, or 222. In still further embodiments, the anti-SIRPa antibodies or antibody fragments thereof comprise the variable light chain sequence of SEQ ID NOs: 105, 106, 107, 108,109, 126, 127, 128, 129, 130, or 222 and have one or more conservative amino acid substitutions, e.g., 1 , 2, 3, 4, 5, 1-2, 1-3, 1-4 or 1-5 conservative amino acid substitutions in the light chain variable sequence. In yet further embodiments, the one or more conservative amino acid substitutions fall within one or more framework regions in SEQ ID NOs: 105, 106, 107, 108,109, 127, 128, 129, 130, or 222 (based on the numbering system of Kabat).

[00117] In some embodiments, the anti-SIRPa antibody or antibody fragment thereof comprises a variable light chain sequence with at least about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to the anti-SIRPa light chain variable region sequence set forth in SEQ ID NOs: 105, 106, 107, 108,109, 126, 127, 128, 129, 130, or 222 comprises one or more conservative amino acid substitutions in a framework region (based on the numbering system of Kabat), and retains the binding and/or functional activity of an anti-SIRPa antibody or antibody fragment thereof that comprises a variable heavy chain sequence as set forth in SEQ ID NOs: 100, 101 , 102, 103, 110, 111 , 112, 113, 114, 115, 116, 117, 104, 118, 119, 120, 121 , 122, 123, 124, or 221 and a variable light chain sequence as set forth in SEQ ID NOs: 105, 106, 107, 108,109, 126, 127, 128, 129, 130, or 222.

[00118] In some embodiments, the present disclosure includes anti-SIRPa antibodies or antigen-binding fragments thereof having an amino acid substitution. These variants have at least one amino acid residue in the anti-SIRPa antibody or antigen-binding fragment thereof removed and a different residue inserted in its place. The sites of greatest interest for substitutional mutagenesis include the hypervariable regions, but FR alterations are also contemplated. Conservative substitutions are shown in Table 33 under the heading of “preferred substitutions.” If such substitutions result in a change in biological activity, then more substantial changes, denominated “exemplary substitutions,” or as further described below in reference to amino acid classes, may be introduced and the products screened.

Table 33: Exemplary amino acid substitutions

[00119] In protein chemistry, it is generally accepted that the biological properties of the antibody can be accomplished by selecting substitutions that differ significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain. Naturally occurring residues are divided into groups based on common side-chain properties:

(1) hydrophobic: norleucine, met, ala, val, leu, ile;

(2) neutral hydrophilic: cys, ser, thr;

(3) acidic: asp, glu;

(4) basic: asn, gin, his, lys, arg;

(5) residues that influence chain orientation: gly, pro; and

(6) aromatic: trp, tyr, phe.

Non-conservative substitutions will entail exchanging a member of one of these classes for another class.

[00120] Any cysteine residue not involved in maintaining the proper conformation of the anti-SIRPa antibody or antigen-binding fragment thereof also may be substituted, generally with serine, to improve the oxidative stability of the molecule, prevent aberrant crosslinking, or provide for established points of conjugation to a cytotoxic or cytostatic compound. Conversely, cysteine bond(s) may be added to the antibody or antigen-binding fragment thereof to improve its stability (particularly where the antibody is an antibody fragment such as an Fv fragment).

[00121] Another type of amino acid variant of the antibody involves altering the original glycosylation pattern of the antibody. The term “altering” in this context means deleting one or more carbohydrate moieties found in the antibody, and/or adding one or more glycosylation sites that were not previously present in the antibody. For example, an antibody may comprise an amino acid substitution at position 297 of the human lgG1 heavy chain to abrogate oligosaccharyltransferase enzyme complex-mediated glycosylation by replacing the asparagine 297 (e.g. N297A, N297G).

[00122] Nucleic acid molecules encoding amino acid sequence variants of an anti-SIRPa antibody or antigen-binding fragment thereof are prepared by a variety of methods known in the art. These methods include, but are not limited to, isolation from a natural source (in the case of naturally occurring amino acid sequence variants) or preparation by oligonucleotide- mediated (or site-directed) mutagenesis, PCR mutagenesis, and cassette mutagenesis of an earlier prepared variant or a non-variant version of the anti-SIRPa antibody or antigen-binding fragment thereof.

[00123] In certain embodiments, the anti-SIRPa antibody is an antibody fragment. There are techniques that have been developed for the production of antibody fragments. Fragments can be derived via proteolytic digestion of intact antibodies (see, e.g., Morimoto et al., 1992, Journal of Biochemical and Biophysical Methods 24:107-117; and Brennan et al., 1985, Science 229:81). Alternatively, the fragments can be produced directly in recombinant host cells. For example, Fab'-SH fragments can be directly recovered from E. coli and chemically coupled to form F(ab')2 fragments (see, e.g., Carteret al., 1992, Bio/Technology 10:163-167). By another approach, F(ab')2 fragments can be isolated directly from recombinant host cell culture. Other techniques for the production of antibody fragments will be apparent to a skilled practitioner.

[00124] In an embodiment, the anti-SIRPa antibodies and antigen-binding fragments thereof can include modifications, such as glycosylation, oxidation, or deamidation.

[00125] In certain embodiments, it may be desirable to use an anti-SIRPa antibody fragment, rather than an intact antibody. It may be desirable to modify the antibody fragment in order to increase its serum half-life. This can be achieved, for example, by incorporation of a salvage receptor binding epitope into the antibody fragment. In one method, the appropriate region of the antibody fragment can be altered (e.g., mutated), or the epitope can be incorporated into a peptide tag that is then fused to the antibody fragment at either end or in the middle, for example, by DNA or peptide synthesis (see, e.g., WO 96/32478). For example, antibody fragments of the disclosure may also be fused to human serum albumin to increase the serum half-life, if the use of a full-length IgG scaffold is undesirable. Such fusion proteins of the antibody fragment with human serum albumin may be advantageous in situations in which two different antibody fragments need to be fused to increase avidity, or to generate a bispecific binding protein with extended serum half-life (see e.g. WO 05/077042 A2).

[00126] Removal of any carbohydrate moieties present on the antibody can be accomplished chemically or enzymatically. Chemical deglycosylation is described by Hakimuddin et al., 1987, Arch. Biochem. Biophys. 259:52 and by Edge et al., 1981 , Anal. Biochem., 118:131. Enzymatic cleavage of carbohydrate moieties on antibodies can be achieved by the use of a variety of endo- and exo-glycosidases as described by Thotakura et al., 1987, Meth. Enzymol 138:350.

[00127] Another type of useful modification comprises linking the antibody to one of a variety of nonproteinaceous polymers, e.g., polyethylene glycol, polypropylene glycol, or polyoxyalkylenes, in the manner set forth in one or more of U.S. Pat. No. 4,640,835, U.S. Pat. No. 4,496,689, U.S. Pat. No. 4,301 ,144, U.S. Pat. No. 4,670,417, U.S. Pat. No. 4,791 ,192 and U.S. Pat. No. 4,179,337.

Dosages

[00128] The anti-SIRPa antibody or antigen-binding fragment thereof may be administered to a subject at a dose of about 100 mg to about 300 mg (e.g., about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg). In some embodiments, the anti-SIRPa antibody or antigenbinding fragment thereof is administered to a subject at a dose of about 100 mg to about 125 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 125 mg to about 150 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 150 mg to about 175 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 175 mg to about 200 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 200 mg to about 225 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 225 mg to about 250 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 250 mg to about 275 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 275 mg to about 300 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered subcutaneously to the subject.

[00129] In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of at least 100 mg to at least 300 mg (e.g., at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, or at least 300 mg). In some embodiments, the anti- SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of at least 100 mg to at least 125 mg. In some embodiments, the anti-SIRPa antibody orantigen- binding fragment thereof is administered to a subject at a dose of at least 125 mg to at least 150 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of at least 150 mg to at least 175 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of at least 175 mg to at least 200 mg. In some embodiments, the anti- SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of at least 200 mg to at least 225 mg. In some embodiments, the anti-SIRPa antibody or antigenbinding fragment thereof is administered to a subject at a dose of at least 225 mg to at least 250 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of at least 250 mg to at least 275 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of at least 275 mg to at least 300 mg. In some embodiments, the anti- SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, or at least 300 mg.

[00130] In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of about 100 mg to about 300 mg (e.g., about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of about 100 mg to about 125 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of about 125 mg to about 150 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of about 150 mg to about 175 mg. In some embodiments, the anti- SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of about 175 mg to about 200 mg. In some embodiments, the anti-SIRPa antibody or antigenbinding fragment thereof is formulated for administration at a dose of about 200 mg to about 225 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of about 225 mg to about 250 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of about 250 mg to about 275 mg. In some embodiments, the anti- SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of about 275 mg to about 300 mg. In some embodiments, the anti-SIRPa antibody or antigenbinding fragment thereof is formulated for administration at a dose of about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg.

[00131] In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of at least 100 mg to at least 300 mg (e.g., at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, or at least 300 mg). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of at least 100 mg to at least 125 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of at least 125 mg to at least 150 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of at least 150 mg to at least 175 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of at least 175 mg to at least 200 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of at least 200 mg to at least 225 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of at least 225 mg to at least 250 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of at least 250 mg to at least 275 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of at least 275 mg to at least 300 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, or at least 300 mg.

[00132] In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered more than one time to the subject. In other words, the anti-SIRPa antibody or antigen-binding fragment thereof is administered in a dosing cycle, wherein the dosing cycle is the time period between one administration of the anti-SIRPa antibody or antigen-binding fragment thereof and the next administration of the anti-SIRPa antibody or antigen-binding fragment thereof, for example, between the first administration of the anti- SIRPa antibody or antigen-binding fragment thereof and the second administration of the anti- SIRPa antibody or antigen-binding fragment thereof. In an embodiment, the anti-SIRPa antibody or antigen-binding fragment thereof is administered several times according to a regular dosing cycle, e.g., the time period between each administration is the same, such as every two weeks (Q2W). In some embodiments, dosing cycles are interrupted by a treatment- free period of time. In other embodiments, dosing cycles are not interrupted by a treatment- free period of time.

[00133] In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dosing cycle (administration interval) of about twice a week to about once every 4 weeks (Q4W) (e.g., about twice a week, about once every week (Q1 W), about once every two weeks (Q2W), about once every three weeks (Q3W), or about once every four weeks (Q4W)). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dosing cycle (administration interval) of about twice a week. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dosing cycle (administration interval) of about once every week (Q1 W). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dosing cycle (administration interval) of about once every two weeks (Q2W). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dosing cycle (administration interval) of about once every three weeks (Q3W). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dosing cycle (administration interval) of about once every four weeks (Q4W).

[00134] In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 100 mg to about 300 mg (e.g., about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg) at a dosing cycle (administration interval) of about twice a week to about once every 4 weeks (Q4W) (e.g., about twice a week, about once every week (Q1 W), about once every two weeks (Q2W), about once every three weeks (Q3W), or about once every four weeks (Q4W)). In some embodiments, the anti-SIRPa antibody or antigenbinding fragment thereof is administered to a subject at a dose of about 100 mg to about 125 mg at a dosing cycle (administration interval) of about twice a week to about once every 4 weeks (Q4W) (e.g., about twice a week, about once every week (Q1 W), about once every two weeks (Q2W), about once every three weeks (Q3W), or about once every four weeks (Q4W)). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 125 mg to about 150 mg at a dosing cycle (administration interval) of about twice a week to about once every 4 weeks (Q4W) (e.g., about twice a week, about once every week (Q1 W), about once every two weeks (Q2W), about once every three weeks (Q3W), or about once every four weeks (Q4W)). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 150 mg to about 175 mg at a dosing cycle (administration interval) of about twice a week to about once every 4 weeks (Q4W) (e.g., about twice a week, about once every week (Q1 W), about once every two weeks (Q2W), about once every three weeks (Q3W), or about once every four weeks (Q4W)). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 175 mg to about 200 mg at a dosing cycle (administration interval) of about twice a week to about once every 4 weeks (Q4W) (e.g., about twice a week, about once every week (Q1 W), about once every two weeks (Q2W), about once every three weeks (Q3W), or about once every four weeks (Q4W)). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 200 mg to about 225 mg at a dosing cycle (administration interval) of about twice a week to about once every 4 weeks (Q4W) (e.g., about twice a week, about once every week (Q1W), about once every two weeks (Q2W), about once every three weeks (Q3W), or about once every four weeks (Q4W)). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 225 mg to about 250 mg at a dosing cycle (administration interval) of about twice a week to about once every 4 weeks (Q4W) (e.g., about twice a week, about once every week (Q1 W), about once every two weeks (Q2W), about once every three weeks (Q3W), or about once every four weeks (Q4W)). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 250 mg to about 275 mg at a dosing cycle (administration interval) of about twice a week to about once every 4 weeks (Q4W) (e.g., about twice a week, about once every week (Q1 W), about once every two weeks (Q2W), about once every three weeks (Q3W), or about once every four weeks (Q4W)). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 275 mg to about 300 mg at a dosing cycle (administration interval) of about twice a week to about once every 4 weeks (Q4W) (e.g., about twice a week, about once every week (Q1W), about once every two weeks (Q2W), about once every three weeks (Q3W), or about once every four weeks (Q4W)). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg at a dosing cycle (administration interval) of about twice a week, about once every week (Q1W), about once every two weeks (Q2W), about once every three weeks (Q3W), or about once every four weeks (Q4W).

[00135] In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 100 mg to about 300 mg (e.g., about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg) at a dosing cycle (administration interval) of about once every week (Q1W). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 100 mg to about 125 mg at a dosing cycle (administration interval) of about once every week (Q1 W). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 125 mg to about 150 mg at a dosing cycle (administration interval) of about once every week (Q1 W). In some embodiments, the anti-SIRPa antibody or antigenbinding fragment thereof is administered to a subject at a dose of about 150 mg to about 175 mg at a dosing cycle (administration interval) of about once every week (Q1 W). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 175 mg to about 200 mg at a dosing cycle (administration interval) of about once every week (Q1 W). In some embodiments, the anti-SIRPa antibody or antigenbinding fragment thereof is administered to a subject at a dose of about 200 mg to about 225 mg at a dosing cycle (administration interval) of about once every week (Q1 W). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 225 mg to about 250 mg at a dosing cycle (administration interval) of about once every week (Q1 W). In some embodiments, the anti-SIRPa antibody or antigenbinding fragment thereof is administered to a subject at a dose of about 250 mg to about 275 mg at a dosing cycle (administration interval) of about once every week (Q1 W). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 275 mg to about 300 mg at a dosing cycle (administration interval) of about once every week (Q1 W). In some embodiments, the anti-SIRPa antibody or antigenbinding fragment thereof is administered to a subject at a dose of about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg at a dosing cycle (administration interval) of about once every week (Q1 W).

[00136] In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 100 mg to about 300 mg (e.g., about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg) at a dosing cycle (administration interval) of about once every 2 weeks (Q2W). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 100 mg to about 125 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 125 mg to about 150 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 150 mg to about 175 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 175 mg to about 200 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W). In some embodiments, the anti- SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 200 mg to about 225 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 225 mg to about 250 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 250 mg to about 275 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W). In some embodiments, the anti-SIRPa antibody or antigenbinding fragment thereof is administered to a subject at a dose of about 275 mg to about 300 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W).

[00137] In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered subcutaneously to a subject at a dose of about 100 mg at a dosing cycle (administration interval) of about once every week (Q1W).

[00138] In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered subcutaneously to a subject at a dose of about 125 mg at a dosing cycle (administration interval) of about once every week (Q1W).

[00139] In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered subcutaneously to a subject at a dose of about 150 mg at a dosing cycle (administration interval) of about once every week (Q1W). [00140] In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered subcutaneously to a subject at a dose of about 175 mg at a dosing cycle (administration interval) of about once every week (Q1W).

[00141] In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered subcutaneously to a subject at a dose of about 200 mg at a dosing cycle (administration interval) of about once every week (Q1W).

[00142] In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered subcutaneously to a subject at a dose of about 225 mg at a dosing cycle (administration interval) of about once every week (Q1W).

[00143] In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered subcutaneously to a subject at a dose of about 250 mg at a dosing cycle (administration interval) of about once every week (Q1W).

[00144] In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered subcutaneously to a subject at a dose of about 275 mg at a dosing cycle (administration interval) of about once every week (Q1W).

[00145] In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered subcutaneously to a subject at a dose of about 300 mg at a dosing cycle (administration interval) of about once every week (Q1W).

[00146] In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered subcutaneously to a subject at a dose of about 100 mg at a dosing cycle (administration interval) of about once every two weeks (Q2W).

[00147] In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered subcutaneously to a subject at a dose of about 125 mg at a dosing cycle (administration interval) of about once every two weeks (Q2W).

[00148] In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered subcutaneously to a subject at a dose of about 150 mg at a dosing cycle (administration interval) of about once every two weeks (Q2W).

[00149] In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered subcutaneously to a subject at a dose of about 175 mg at a dosing cycle (administration interval) of about once every two weeks (Q2W).

[00150] In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered subcutaneously to a subject at a dose of about 200 mg at a dosing cycle (administration interval) of about once every two weeks (Q2W). [00151] In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered subcutaneously to a subject at a dose of about 225 mg at a dosing cycle (administration interval) of about once every two weeks (Q2W).

[00152] In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered subcutaneously to a subject at a dose of about 250 mg at a dosing cycle (administration interval) of about once every two weeks (Q2W).

[00153] In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered subcutaneously to a subject at a dose of about 275 mg at a dosing cycle (administration interval) of about once every two weeks (Q2W).

[00154] In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered subcutaneously to a subject at a dose of about 300 mg at a dosing cycle (administration interval) of about once every two weeks (Q2W).

[00155] The anti-SIRPa antibody or antigen-binding fragment thereof may be administered intravenously to a subject at a dose of about 400 mg to about 2800 mg (e.g., about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, or about 2800 mg).

[00156] In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1400 mg to about 1800 mg (e.g., about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1400 mg to about 1500 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1500 mg to about 1600 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1600 mg to about 1700 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1700 mg to about 1800 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1600 mg. [00157] In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of about 400 mg to about 2800 mg (e.g., about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, or about 2800 mg).

[00158] In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of about 1400 mg to about 1800 mg (e.g., about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of about 1400 mg to about 1500 mg. In some embodiments, the anti- SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of about 1500 mg to about 1600 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of about 1600 mg to about 1700 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of about 1700 mg to about 1800 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg. In some embodiments, the anti-SIRPa antibody or antigenbinding fragment thereof is formulated for administration at a dose of about 1600 mg.

[00159] The anti-SIRPa antibody or antigen-binding fragment thereof may be administered intravenously to a subject at a dose of about 400 mg to about 2800 mg (e.g., about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, or about 2800 mg) at a dosing cycle (administration interval) of about once every 2 weeks (Q2W) to about once every 6 weeks (Q6W) (e.g., about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1400 mg to about 1800 mg (e.g., about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg) at a dosing cycle (administration interval) of about once every 2 weeks (Q2W) to about once every 6 weeks (Q6W) (e.g., about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W)). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg about once every 2 weeks (Q2W) to about once every 6 weeks (Q6W) (e.g., about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W)). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1600 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W).

[00160] In some embodiments, the dosing regimen comprises administration of a loading dose and one or more maintenance doses. In some embodiments, the loading dose is administered intravenously to a subject. In some embodiments, the one or more maintenance doses are administered subcutaneously to a subject.

[00161] In some embodiments, the dosing regimen comprises administration of a loading dose of about 400 mg to about 2800 mg (e.g., about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, or about 2800 mg). In some embodiments, the dosing regimen comprises administration of a loading dose of about 400 mg to about 500 mg. In some embodiments, the dosing regimen comprises administration of a loading dose of about 500 mg to about 600 mg. In some embodiments, the dosing regimen comprises administration of a loading dose of about 600 mg to about 700 mg. In some embodiments, the dosing regimen comprises administration of a loading dose of about 700 mg to about 800 mg. In some embodiments, the dosing regimen comprises administration of a loading dose of about 800 mg to about 900 mg. In some embodiments, the dosing regimen comprises administration of a loading dose of about 900 mg to about 1000 mg. In some embodiments, the dosing regimen comprises administration of a loading dose of about 1000 mg to about 1100 mg. In some embodiments, the dosing regimen comprises administration of a loading dose of about 1100 mg to about 1200 mg. In some embodiments, the dosing regimen comprises administration of a loading dose of about 1200 mg to about 1300 mg. In some embodiments, the dosing regimen comprises administration of a loading dose of about 1300 mg to about 1400 mg. In some embodiments, the dosing regimen comprises administration of a loading dose of about 1400 mg to about 1500 mg. In some embodiments, the dosing regimen comprises administration of a loading dose of about 1500 mg to about 1600 mg. In some embodiments, the dosing regimen comprises administration of a loading dose of about 1600 mg to about 1700 mg. In some embodiments, the dosing regimen comprises administration of a loading dose of about 1700 mg to about 1800 mg. In some embodiments, the dosing regimen comprises administration of a loading dose of about 1800 mg to about 1900 mg. In some embodiments, the dosing regimen comprises administration of a loading dose of about 1900 mg to about 2000 mg. In some embodiments, the dosing regimen comprises administration of a loading dose of about 2000 mg to about 2100 mg. In some embodiments, the dosing regimen comprises administration of a loading dose of about 2100 mg to about 2200 mg. In some embodiments, the dosing regimen comprises administration of a loading dose of about 2200 mg to about 2300 mg. In some embodiments, the dosing regimen comprises administration of a loading dose of about 2300 mg to about 2400 mg. In some embodiments, the dosing regimen comprises administration of a loading dose of about 2400 mg to about 2500 mg. In some embodiments, the dosing regimen comprises administration of a loading dose of about 2500 mg to about 2600 mg. In some embodiments, the dosing regimen comprises administration of a loading dose of about 2600 mg to about 2700 mg. In some embodiments, the dosing regimen comprises administration of a loading dose of about 2700 mg to about 2800 mg. In some embodiments, the dosing regimen comprises administration of a loading dose of about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1 100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, or about 2800 mg.

[00162] In some embodiments, the dosing regimen comprises administration of one or more maintenance doses of about 100 mg to about 300 mg (e.g., about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg). In some embodiments, the dosing regimen comprises administration of one or more maintenance doses of about 100 mg to about 125 mg. In some embodiments, the dosing regimen comprises administration of one or more maintenance doses of about 125 mg to about 150 mg. In some embodiments, the dosing regimen comprises administration of one or more maintenance doses of about 150 mg to about 175 mg. In some embodiments, the dosing regimen comprises administration of one or more maintenance doses of about 175 mg to about 200 mg. In some embodiments, the dosing regimen comprises administration of one or more maintenance doses of about 200 mg to about 225 mg. In some embodiments, the dosing regimen comprises administration of one or more maintenance doses of about 225 mg to about 250 mg. In some embodiments, the dosing regimen comprises administration of one or more maintenance doses of about 250 mg to about 275 mg. In some embodiments, the dosing regimen comprises administration of one or more maintenance doses of about 275 mg to about 300 mg. In some embodiments, the dosing regimen comprises administration of one or more maintenance doses of about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg.

[00163] In some embodiments, the one or more maintenance doses are administered at a regular interval for a period of time. In some embodiments the one or more maintenance doses are administered at a dosing cycle (administration interval) of about twice a week, to about once every 4 weeks (Q4W) (e.g., about twice a week, about once every week (Q1 W), about once every two weeks (Q2W), about once every three weeks (Q3W), or about once every four weeks (Q4W)).

[00164] In some embodiments, the dosing regimen comprises administration of a loading dose of about 400 mg to about 2800 mg (e.g., about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1 100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, or about 2800 mg) and one or more maintenance doses of about 100 mg to about 300 mg (e.g., about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg), wherein the one or more maintenance doses are administered at a dosing cycle (administration interval) of about twice a week to about once every 4 weeks (Q4W) (e.g., about twice a week, about once every week (Q1W), about once every two weeks (Q2W), about once every three weeks (Q3W), or about once every four weeks (Q4W)). In some embodiments, the dosing regimen comprises administration of a loading dose of about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, or about 2800 mg and one or more maintenance doses of about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg, wherein the one or more maintenance doses are administered at a dosing cycle (administration interval) of about twice a week, about once every week (Q1 W), about once every two weeks (Q2W), about once every three weeks (Q3W), or about once every four weeks (Q4W).

Therapeutic Uses

[00165] In an embodiment, the anti-SIRPa antibodies or antigen-binding fragments thereof of the disclosure are useful fortreating and/or preventing a SIRPa pathway disease ordisorder including, for example a liver disease or disorder (e.g., MASH). In another embodiment, the anti-SIRPa antibodies or antigen-binding fragments thereof of the disclosure are useful as a medicament.

[00166] Accordingly, in an embodiment, the disclosure provides a method of modulating the interaction between SIRPa and CD47 in a patient comprising administering to the patient an anti-SIRPa antibody or antigen-binding fragment thereof in an amount sufficient to block CD47-mediated SIRPa signaling in the patient. In an embodiment, the disclosure provides an anti-SIRPa antibody or antigen-binding fragment thereof for use in modulating the interaction between SIRPa and CD47 in a subject. In an embodiment, the disclosure provides the use of an anti-SIRPa antibody or antigen-binding fragment thereof in the manufacture of a medicament for modulating the interaction between SIRPa and CD47 in a subject.

[00167] In an embodiment, the disclosure provides a method of treating a SIRPa pathway disease ordisorder in a patient comprising administering to the patient an anti-SIRPa antibody or antigen-binding fragment thereof according to the present disclosure. In an embodiment, the disclosure provides an anti-SIRPa antibody or antigen-binding fragment thereof for use in treating or preventing a liverdisease ordisorder, (e.g., fibrosis caused in part by a liverdisease or disorder) in a patient. In an embodiment, the disclosure provides the use of an anti-SIRPa antibody or antigen-binding fragment thereof in the manufacture of a medicament fortreating or preventing a liver disease or disorder.

[00168] Accordingly, in an embodiment, the disclosure provides a method of treating or preventing one of the above diseases or disorders in a patient comprising administering to the patient an anti-SIRPa antibody or antigen-binding fragment thereof according to the disclosure. In an embodiment, the disclosure provides an anti-SIRPa antibody or antigenbinding fragment thereof for use in treating or preventing one of the above diseases or disorders in a patient. In an embodiment, the disclosure provides the use of an anti-SIRPa antibody or antigen-binding fragment thereof in the manufacture of a medicament fortreating and/or preventing one of the above diseases or disorders in a patient.

[00169] In an embodiment, the liver disease or disorder is selected from the group consisting of: cirrhosis (e.g., decompensated cirrhosis or cirrhosis due to MASH), alcohol- induced liver disease (e.g., alcohol induced cirrhosis), cystic fibrosis-associated liver disease (CFLD), alcohol related liver disease, alpha 1 antitrypsin deficiency, autoimmune hepatitis, benign liver tumors, hemochromatosis, hepatitis A, hepatitis B, hepatitis C, hepatocellular carcinoma, liver cysts, liver cancer, metabolic dysfunction-associated steatotic liver disease (MASLD) such as MASH or MASL, type 1 glycogen storage disease, Wilson’s disease, Alagille syndrome, autoimmune hepatitis, biliary atresia, biliary cirrhosis, congestive hepatopathy, drug induced liver injury, focal nodular hyperplasia, glycogen storage diseases, ischemic hepatitis, lysosomal acid lipase deficiency, polycystic liver disease, progressive familial intrahepatic cholestasis, primary sclerosing cholangitis, and veno-occlusive disease. In a further embodiment, the liver disease or disorder is metabolic dysfunction-associated steatotic liver disease (MASLD). In a further embodiment, the liver disease or disorder is MASH. In a further embodiment, the liver disease or disorder is MASL. In a further embodiment, the liver disease or disorder is Wilson’s disease. In a further embodiment, the liver disease or disorder is hemochromatosis. In a further embodiment, the liver disease or disorder is autoimmune hepatitis. In a further embodiment, the liver disease or disorder is alcoholic liver disease. In a further embodiment, the liver disease or disorder is decompensated cirrhosis. In a further embodiment, the liver disease or disorder is cirrhosis due to MASH.

[00170] In an embodiment, the patient has at least one SIRPa V1 allele (i.e. is either homozygous and has two SIRPa V1 alleles or is heterozygous for SIRPa and has one SIRPa V1 allele). In an embodiment, the patient is homozygous for SIRPa and is SIRPa V1/SIRPa V1 . In an embodiment, the patient is heterozygous for SIRPa and is SIRPa V1 /SIRPa V2.

[00171] The anti-SIRPa antibodies or antigen-binding fragments thereof of the disclosure are useful fortreating and/or preventing liver diseases or disorders (e.g., MASH; autoimmune hepatitis; viral infections such as Hepatitis A, B, C, D, or E or Ebstein-Barr Virus or Cytomegalovirus, among others; Wilson’s disease; hemochromatosis; alpha-one-antitrypsin deficiency; congestive hepatopathy (e.g., right-sided heart failure); Alagille syndrome; biliary atresia; biliary cirrhosis; congestive hepatopathy; drug induced liver injury; focal nodular hyperplasia; glycogen storage diseases; ischemic hepatitis; lysosomal acid lipase deficiency; polycystic liver disease; progressive familial intrahepatic cholestasis; primary sclerosing cholangitis; veno-occlusive disease and/or ischemic hepatitis, etc.), with or without cirrhosis). For example, treating MASH may refer to ameliorating, alleviating, or modulating at least one of the symptoms or pathological features associated with MASH; e.g., hepatosteatosis, hepatocellular ballooning, hepatic inflammation and fibrosis; e.g. may refer to slowing progression, reducing or stopping at least one of the symptoms or pathological features associated with MASH, e.g. hepatosteatosis, hepatocellular ballooning, hepatic inflammation and fibrosis. It may also refer to preventing, delaying, or reversing liver cirrhosis or a need for liver transplantation. Additionally, the anti-SIRPa antibodies or antigen-binding fragments thereof of the disclosure are useful in the preparation of a medicament for the treatment and/or prevention of hepatocellulardiseases with orwithout cirrhosis. In an embodiment, the methods and uses described herein include increasing clearance of dead hepatocytes (e.g., hepatocytes in the liver) in a subject in need thereof (e.g., a subject suspected of having or diagnosed as having hepatocellular liver disease, with or without cirrhosis) comprising administering to the subject a therapeutically effective amount of an anti-SIRPa antibody or an antigen-binding fragment thereof as disclosed herein. In an embodiment, the methods and uses described herein include promoting tissue repair (e.g., tissue repair in the liver) in a subject in need thereof (e.g., a subject suspected of having or diagnosed as having hepatocellular liver disease, with or without cirrhosis) comprising administering to the subject a therapeutically effective amount of an anti-SIRPa antibody or an antigen-binding fragment thereof as disclosed herein. In an embodiment, the methods and uses described herein include decreasing inflammation (e.g., inflammation in the liver) in a subject in need thereof (e.g., a subject suspected of having or diagnosed as having hepatocellular liver disease, with or without cirrhosis) comprising administering to the subject a therapeutically effective amount of an anti-SIRPa antibody or an antigen-binding fragment thereof as disclosed herein. In an embodiment, the methods and uses described herein include treating and/or preventing either compensated or decompensated cirrhosis due to hepatocellular diseases in a subject in need thereof (e.g., a subject suspected of having or diagnosed as having cirrohosis due to hepatocellular diseases) comprising administering to the subject a therapeutically effective amount of an anti-SIRPa antibody or an antigen-binding fragment thereof as disclosed herein.

[00172] As used herein, “non-alcoholic steatohepatitis”, “NASH”, “metabolic dysfunction- associated steatohepatitis” and “MASH” are used interchangeably and refer to non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD) in which there is inflammation and/or fibrosis in the liver (i.e., hepatic fibrosis). Exemplary methods of determining the stage of NASH are described, for example, in Kleiner et al, 2005, Hepatology, 41 (6): 1313-1321 , and Brunt et al, 2007, Modern Pathol, 20: S40- S48.

Administration Route

[00173] Various delivery systems are known and can be used to administerthe anti-SIRPa antibody or an antigen-binding fragment thereof. Methods of introduction include but are not limited to intravitreal, eye drops, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The anti-SIRPa antibody or an antigenbinding fragment thereof can be administered, for example by infusion, bolus or injection, and can be administered together with other biologically active agents. Administration can be systemic or local. Formulations for such injections may be prepared in, for example, prefilled syringes that include an anti-SIRPa antibody or an antigen-binding fragment thereof.

[00174] To be used in therapy, the anti-SIRPa antibody of the disclosure is formulated into pharmaceutical compositions appropriate to facilitate administration to animals or humans. Typical formulations of the binding molecule or antibody molecule described herein can be prepared by mixing the binding molecule or antibody molecule with physiologically acceptable carriers, excipients or stabilizers, in the form of lyophilized or otherwise dried formulations or aqueous solutions or aqueous or non-aqueous suspensions. Carriers, excipients, modifiers or stabilizers are nontoxic at the dosages and concentrations employed.

[00175] In an embodiment, the pharmaceutical composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous or subcutaneous administration to a subject. Typically, compositions for administration by injection are solutions in sterile isotonic aqueous buffer. Where necessary, the pharmaceutical composition can also include a solubilizing agent and a local anaesthetic such as lignocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachet indicating the quantity of active agent. Where the pharmaceutical is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the pharmaceutical is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.

[00176] Further, the pharmaceutical composition can be provided as a pharmaceutical kit comprising (a) a container containing an anti-SIRPa antibody or an antigen-binding fragment thereof in lyophilized form and (b) a second container containing a pharmaceutically acceptable diluent (e.g., sterile water) for injection. The pharmaceutically acceptable diluent can be used for reconstitution or dilution of the lyophilized anti-SIRPa antibody or antigenbinding fragment thereof. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

[00177] The present disclosure is now described with reference to the following Example. This Example is provided for the purpose of illustration only and the disclosure should in no way be construed as being limited to this Examples, but rather should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.

[00178] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative example, make and utilize the compounds of the present disclosure and practice the claimed methods. The following working example therefore, specifically points out the preferred embodiments of the present disclosure, and is not to be construed as limiting in any way the remainder of the disclosure.

EXAMPLES

Example 1 : Reduction of Liver Fibrosis and Inflammation with an Anti-SIRPa Antibody in a CDAA Diet Induced MASH Model.

[00179] MY1 (Garcia, et al. J Immunol. 2011 ;187:2268) was tested in a choline-deficient L-amino acid defined (CDAA) diet induced mouse MASH model that produces steatosis, inflammation, and fibrosis. MY1 is a mouse SIRPa blocking antibody and was used in place of the corresponding human molecule (Antibody A10) since the human molecule does not cross-react with murine SIRPa.

[00180] Briefly, a CDAA diet was fed to three groups of male C57/BL6 mice (7-8 weeks of age, n = 30) for 12 weeks to induce a MASH phenotype, and a choline-sufficient amino acid- defined (CSAA) diet was fed to a different group of mice for 12 weeks as a control. At week 4, MY1 or an IgG isotype control was administrated to the mice fed the CDAA diet for an additional 8 weeks. The treatment and control groups are summarized in the table below.

[00181] Mice fed the CDAA diet exhibited an increase of circulating cell death marker, CCK18M30, from 123.2 ± 5.56 mIU/ml to 274.4 ± 14.68 mIU/ml and an increase in inflammatory cytokine, IL-8, from 89.18 ± 12.92 pg/ml to 217.7 ± 17.42 pg/ml (as compared to mice fed a CSAA diet). - 83 -dditionally, the CDAA diet induced a significant increase of liver cCASP3 from 1 .44 ± 0.77 % to 7.72 ± 1.1 % (****p<0.01 ), indicating increased liver cell death. Mice fed the CDAA diet also exhibited an increase in total collagen from 0.16 ± 0. 02 % to 1 .07 ± 0.09 % (****p<0.01).

[00182] The two groups of mice that were fed the CDAA diet were subsequently administered 10 mg/kg MY1 once a week (qw) or 10 mg/kg twice per week (Q2W). The third group of mice was administered 10 mg/kg of an IgG isotype control intraperitoneally twice per week (Q2W).

[00183] Two circulating biomarkers for liver damage and inflammation were then measured (cytokeratin 18 neoepitope M30 (cCK18 M30) and lnterleukin-8 (IL-8)). Briefly, plasma was collected with EDTA tubes during takedown of the mice. Next, the plasma samples were centrifuged at 10,000 xg for 10 minutes at 4 °C and stored at -20 °C. Circulating cCK18 M30 was measured from a 30 pL plasma sample diluted with sample diluent at a 1 :4 ratio and then measured by ELISA. IL-8 was measured in the blood plasma (35 pL) after 4 weeks with a 2-fold dilution using a MSD V-PLEX Proinflammatory Panel (Meso Scale Diagnostics, LLC). Statistical analysis was then performed using GraphPad Prism. Data are presented as mean ± SE, with statistical significance set at p < 0.05. Mice treated with 10 mg/kg of MY1 twice per week (q2w) demonstrated a reduction in cCK18 M30 to 246.4 ± 13.45 mIU/ml (10.2%) and a reduction in IL-8 to 149.8 ± 24.74 pg/ml (31 .2%, *p<0.05). There was no observed reduction of cCK18 M30 or IL-8 in mice treated with 10 mg/kg MY1 every week (qw).

[00184] Tissue samples were also taken from the MY1 treated mice to assess liver dead cell clearance and accelerated tissue repair. Briefly, tissue samples were fixed in 4% paraformaldehyde for at least 24 hours at 4 °C and paraffin embedded. Samples were then deparaffinized and re-hydrated. Next, Masson’s trichrome staining was performed according to standard protocols. Sections were incubated with an anti-human cleaved caspase-3 (cCASP3) antibody by immunohistochemistry (IHC) to measure dead cell clearance in the liver. An Al based classifier was used for detection of collogen area in the stained tissue to detect fibrosis. Mice treated with 10 mg/kg of MY1 twice per week (q2w) exhibited a reduction of cCASP3 to 5.47 ± 0.08% (29.1 %, *p<0.05) and a reduction of total collagen to 0.75 ± 0.12% (29.5%, *p<0.05) in comparison to the IgG-treated CDAA diet group.

Example 2: Promotion of Dead Cell Clearance, and Supression of Liver Inflammation and Fibrosis with an Anti-S I RPa Antibody in CCL Induced Liver Damage Model

[00185] MY1 was tested in a mouse model of carbon tetrachloride (CCI₄) induced liver damage to assess its effect on dead cell clearance, inflammation, and liver fibrosis. Male C57/BL6 mice (8 weeks old, n=28) were administered CCI₄ once every three days (first dose at 0.875 ml/kg; second and third dose at 2.25 ml/kg) to the mice by mouth for 8-9 days to induce liver damage. At day 6 or 7 of the study, MY1 or an IgG isotype control was administrated intraperitoneally in three CCI₄ treated groups at 3 mg/kg, 10 mg/kg, or20 mg/kg. The treatment and control groups are summarized in the table below.

[00186] The levels of several circulating biomarkers for liver damage were measured including, cleaved cytokeratin 18 (cCK18), aspartate transaminase (AST), alanine transaminase (ALT), and tissue inhibitor of metalloproteinase 1 (TIMP-1). Briefly, plasma was collected with EDTA tubes during takedown of the mice. Next, the plasma samples were centrifuged at 10,000 x g for 10 minutes at 4 °C and stored at -20 °C. Total cCK18 was then measured in 30 pL of the plasma sample, diluted with sample diluent at a 1 :4 ratio and then measured by ELISA. AST and ALT were measured with the Cobas Integra 400 plus (Roche Diagnostics) following the manufacturers’ protocol. TIMP-1 was also measured using a plasma sample diluted with assay dilutant at a 1 :3 ratio and then measured by ELISA.

[00187] Mice treated with 3 mg/kg, 10 mg/kg, or 20 mg/kg of MY1 demonstrated a reduction in total cCK18 from 15.06 ± 0.96 ng/ml (IgG isotype control) to 8.04 ± 1.51 ng/ml (3 mg/kg, ***p<0.01), 8.29 ± 1 .44 ng/ml (10 mg/kg, ***p<0.01) and 5.49 ± 0.9 ng/ml (20 mg/kg, ****p<0.01). In addition, mice treated with MY1 demonstrated a reduction in AST from 1 ,135 ± 173.5 u/L (IgG isotype control) to 926.7 ± 185.4 u/L (3 mg/kg), 673.5 ± 84.6 u/L (10 mg/kg), and 495.3 ± 86.83 u/L (20 mg/kg, **p<0.01). Mice treated with MY1 also demonstrated a reduction in ALT from 2,038 ± 261.2 u/L (IgG isotype control) to 1 ,494 ± 365.7 u/L (3 mg/kg), 1 ,062 ± 198.6 u/L (10 mg/kg, *p<0.05), and 637.6 ± 1 19 u/L (20 mg/kg, ***p<0.01). In addition, mice treated with MY1 showed a reduction in fibrotic marker represented by circulating TIMP- 1. Compared to the IgG isotype control group (4,188 ± 500.6 pg/ml), MY1 treated groups exhibited a reduction in TIMP-1 to 3,538 ± 484.2 pg/ml (3 mg/kg), 2,740 ± 305.8 pg/ml (10 mg/kg, *p<0.05) and 2,650 ± 221 .3 pg/ml (20 mg/kg, *p<0.05).

[00188] Tissue samples were also taken from MY1 treated mice to assess dead liver cell clearance or accelerated tissue repair. Briefly, tissue samples were fixed in 4% paraformaldehyde for at least 24 hours at 4 °C and paraffin embedded. Samples were then deparaffinized and re-hydrated. Next, Masson’s trichrome staining was performed according to standard protocols. Sections were incubated with an anti-human cleaved caspase-3 (cCASP3) antibody by immunohistochemistry (IHC) to measure dead cell clearance in the liver. An Al based classifier was used for detection of lesion area in the stained tissue to detect tissue repair. Another set of sections were incubated with an anti-receptor-interacting kinase 3 (RIP3) antibody to measure dead cell clearance in the liver.

[00189] Mice treated with MY1 exhibited a decreased positive signal reflected by percentage of total liver area from 0.020 ±0.003 % (IgG isotype control group) to 0.015 ± 0.004% (10mg/kg) and to 0.01 ±0.001 % (20 mg/kg). Mice treated with MY1 also exhibited a reduction in lesion area from 10.89 ± 2.185 % (IgG isotype control group) to 6.802 ± 0.682 % (10mg/kg) and to 5.707 ± 1.041 % (20 mg/kg, *p<0.05). Mice treated with MY1 also demonstrated a decrease in RIP3 signal reflected by percentage of total liver area from 29.48 ± 5.12% (IgG isotype control group), to 14.82 ± 3.17% (10 mg/kg, *p<0.05) and to 17.78 ±1 .77% (20 mg/kg). There was no observed reduction in mice treated with 3 mg/kg of MY1 in comparison to the IgG isotype control.

Example 3: Reduction of Liver Dead Cell Accumulation, Inflammatory Cytokine Secretion, and Fibrosis with an anti-SIRPa Antibody in a choline-deficient L-amino acid defined (CDAA) Diet Induced MASH Model.

[00190] MY1 was tested in CDAA diet induced mouse MASH model that produces steatosis, inflammation, and fibrosis to assess its effect on circulating biomarkers and liver tissue.

[00191] A CDAA diet was provided to two groups of male C57/BL6 mice (7-8 weeks of age, n = 22) during the entire study to induce a MASH phenotype, and a CSAA diet was fed to another group of mice as a control. During week 1 of the study, two doses of IgG isotype control or MY1 were administered intraperitoneally to the mice to accelerate peak plasma exposure level, but in weeks 2-4, the mice were given one dose per week. The treatment and control groups are summarized in the table below.

[00192] The levels of several circulating biomarkers for liver damage and inflammation were measured including cCK18, interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor alpha (TNFa), and TIMP-1. Briefly, plasma was collected with EDTA tubes during takedown of the mice. Next, the plasma samples were centrifuged at 10,000 x g for 10 minutes at 4 °C and stored at -20 °C. Total cCK18 was then measured in the plasma (30 pL), diluted with sample diluent at a 1 :4 ratio, and measured by ELISA. IL-6, IL-8, and TNFa were measured in the blood plasma (35 pL) after 4 weeks with a 2-fold dilution using a MSD V-PLEX Proinflammatory Panel (Meso Scale Diagnostics, LLC). TIMP-1 was measured from plasma samples, diluted with assay diluent at a 1 :3 ratio, and then measured by ELISA.

[00193] Mice fed the CDAA diet for four weeks exhibited an induced MASH phenotype compared to those mice fed the CSAA diet. Indeed, the CDAA diet induced an increase of circulating cell death marker, cCK18, from 0.21 ± 0.13 ng/ml (CSAA) to 4.19 ± 0.38 pg/ml (CDAA). Additionally, the mice fed a CDAA diet showed increases of inflammatory cytokines, IL-6, IL-8, and TNFa, from 9.19 ± 3.77, 83.63 ± 12.69, and 6.44 ± 0.87 pg/ml (CSAA) to 31.3 ± 4.69, 266.3 ± 25.54, and 52.07 ± 6.11 pg/ml (CDAA), respectively. Mice fed the CDAA diet also exhibited an increase in soluble fibrosis biomarker, TIMP-1 , from 399.7 ± 65.28 pg/ml to 2,354 ± 145.7 pg/ml.

[00194] Two groups of mice that were fed the CDAA diet were then administered 10 mg/kg of MY1 or IgG isotype control antibody. Mice treated with MY1 exhibited a reduction of circulating cell death marker, cCK18, by 27.7% (*p<0.05) compared to the IgG isotype control group. Additionally, mice treated with MY1 showed a reduction in circulating inflammatory cytokines relative to the IgG isotype control. For example, IL-6 was reduced to 12.38 ± 1.47 pg/ml (60.4%, **p<0.01), IL-8 was reduced to 222.9 ± 18.38 pg/ml (19.5%), and TNFa was reduced to 30.24 ± 2.53 (41.9%, **p<0.01). In addition, treatment of MY1 also reduced circulating TIMP-1 to 1 ,669 ± 110 pg/ml (29.1% vs IgG isotype control group, **p<0.01).

[00195] Tissue samples were also taken from the MY1 treated mice to further assess dead cell clearance and fibrosis suppression. Briefly, tissue samples were taken from the mice and were fixed in 4% paraformaldehyde for at least 24 hours at 4 °C and paraffin embedded. Samples were then de paraffinized and re-hydrated. Next, Masson’s trichrome staining was performed according to standard protocols.

[00196] Samples were manually stained for terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) and sequential IHC CK18 to monitor dead cell signal. An Al based classifier was used for detection of collogen and aSMA area in the stained tissue to detect fibrosis. Statistical analysis was performed using GraphPad Prism. Comparison between groups were performed using unpaired t-test with Welch’s correction. Data are presented as mean ± SE, with statistical significance set at p < 0.05.

[00197] Mice fed the CDAA diet showed a statistically significant increase of liver aSMA from 0.97 ± 0.29% to 2.04 ± 0.26% (****p<0.01) compared to the CSAA diet. Mice fed the CDAA diet also exhibited an increase of total collagen from 1.3 ± 0. 16% to 2.4 ± 0.27% (****p<0.01) and an increase of TUNEL and CK18 colocalization from 0.02 ± 0.01% to 0.45 ± 0.05% (****p<0.01) relative to the CSAA diet.

[00198] Two groups of mice that were fed the CDAA diet were then administered 10 mg/kg of MY1 or IgG isotype control antibody. Treatment with MY1 reduced aSMA signal to 1 .31 ± 0.08% (35.8%, *p<0.05), total collagen to 1.27 ± 0.14% (47.3%, **p<0.01), and TUNEL and CK18 colocalization to 0.25 ± 0.09% (45.52%, *p<0.05) when compared to the IgG isotype control.

Example 4: Anti-SIRPa Antibodies Increase Efferocytosis. [00199] SIRPa-CD47 interaction forms an anti-efferocytotic signal thereby preventing phagocytosis of cells by macrophages. An efferocytosis assay was employed using primary human monocyte-derived macrophages (hMDMs) and H2O2-treated primary human hepatocytes (to induce apoptosis) to determine whether an anti-SIRPa antibody increases phagocytosis of damaged/apoptotic hepatocytes. Briefly, hMDMs were labelled with CFSEblue and hepatocytes were labelled with CFSEred. If hMDM cells engulfed damaged hepatocytes, the hMDM cells emit both a red and a blue signal, detected by FACs.

[00200] The hMDMs showed an increased uptake of apoptotic hepatocytes following treatment with an anti-SIRPa antibody (Antibody A10) in a dose dependent manner up to 30% (EC90: 2.793 nM) (FIG. 1). The results suggest interfering with SIRPa-CD47 interaction by treatment with Antibody A10 leads to modulation of efferocytosis capacity of hMDMs in engulfing H2O2-treated human hepatocytes.

Example 5: Pharmacometric Analyses of Anti-SIRPa Antibodies

[00201] A single dose of 600 mg, 1200 mg, 1600 mg, 2400 mg, or 3600 mg of antibody A10 was administered by intravenous (i.v.) injection to each of three adult human subjects. Similarly, 6 mg/kg, 12 mg/kg, 18 mg/kg, 24 mg/kg, or 36 mg/kg was administered by i.v. injection to each of 6 to 12 adult human subjects. Blood was collected from each of the subjects from 0 to 504 hours following administration. The concentration of each antibody in the serum was measured by ELISA to assess pharmacokinetics. Briefly, blood was allowed to clot at room temperature for at least 30 minutes. Samples were centrifuged at about 1500- 2000xg at 2-8°C. within one hour of collection. Blood was collected as stored at -60° C to -80° C until analysis.

[00202] Serum concentration-time profiles (e.g., see FIG. 2A-2C) were used to estimate the following PK parameters using a two-compartment analysis: antibody clearance (CL), volume (V), peripheral volume, Q, Vmax, and K_m. Each subject was analyzed separately, and results for each dose group were summarized as mean ± standard deviation (SD). The modeling approach included a population PK-PD (serum concentration and peripheral target engagement (TE)) component and a minimal physiologically-based pharmacokinetic (mPBPK) (PET data-tumor lesion activity) component. Proof of clinical principle was reached by 24 mg/kg antibody X1 treatment. Subsequently, the mPBPK model was used to predict antibody A10 tumor exposure and target engagement at dose regimens that match antibody X1 target engagement.

[00203] Population PK model estimates confirmed the PK findings demonstrating greater than 50% higher elimination for antibody A10 (linear and non-linear components) as compared to antibody X1 (Table 34). Moreover, no significant differences in binding affinity (Kd) to the peripheral target could be identified between antibody A10 and antibody X1. The data suggests that the antibody A10 antibody surprisingly has a shorter half-life than that of the antibody X1 and may require an increased dose or dosing frequency to match the exposure of antibody X1 more closely at lower doses.

Table 34. PopPK-PD Model Estimates

Parameter Unit Estimate Cl 95%

Clearance L/h 0.0151 0.0123-0.0187 Volume L 3.3 3.15-3.47 Peripheral Volume L 2.26 1.86-2.75

Antibody 10

L/h 0.0243 0.0142 -0.0416

Vmax mg/h 0.284 0.229-0.352 KM mg/L 0.171 0.116-0.25

Clearance L/h 0.0093 0.00825-

0.0105

Volume L 3.3 3.15-3.47

Peripheral Volume L 2.4 1.99-2.89

Antibody X1 Q L/h 0.0347 0.0169 -0.0712

Vmax mg/h 0.187 0.148-0.236 KM mg/L 0.859 0.542- 1.36

Kd nM 0.321 0.247-0.418

EmaxV1V1 1501.1 0.996 0.993-0.998

EmaxV1V1 1443.1 0.938 0.924-0.95 EmaxV1V2 0.633 0.633-0.633

Example 6: A Phase Ila Study of Antibody A10 in Patients With Compensated Cirrhosis Due to MASH.

[00204] This Example describes a Phase Ila randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of antibody A10 in patients with compensated cirrhosis due to MASH. Patients will undergo a screening period, a treatment period of approximately 12 weeks, and a follow-up period of approximately 90 days after last dose administration of antibody A10. In total, the study will last approximately 154 days.

[00205] The study will enrol patients with definitive or probable MASH cirrhosis, as per the Liver Forum definition (e.g., historical biopsy). Inclusion criteria may include, for example, one or more of the following: patients who are about 18 to about 75 years old, patients who meet the criteria for Child-Pugh category A, and/or patients who have adequate organ function defined as all of the following: 1) total bilirubin about <1 .5 times the upper limit of normal (ULN) and a direct bilirubin about <50% of total bilirubin, 2) for patients with Gilbert’s syndrome: total bilirubin about <3 x ULN or direct bilirubin about <1 .5 x ULN; 3) aspartate transaminase (AST) and alanine transaminase (ALT) about <5 x ULN; 4) alkaline phosphatase about <1 .5 x ULN; INR <1.4; 5) Model for End-Stage Liver Disease (MELD) score about <12 at screening visit; and 6) platelet count about >1 10,000/mL. Exclusion criteria may include, for example, one or more of the following:

1 . major surgery (major according to the investigator’s assessment) performed within about 24-weeks prior to randomization or planned within about 6 months after screening, (e.g., hip replacement);

2. any documented active or suspected malignancy or history of malignancy within 5-years priorto screening, especially suspected, confirmed, or history of hepatocellular carcinoma, excluding appropriately treated basal cell carcinoma of the skin or in situ carcinoma of uterine cervix;

3. suspected or confirmed portal vein thrombosis within about 6 months of enrollment;

4. a history of liver transplantation;

5. current listing for liver transplantation;

6. present or past evidence of decompensating events of liver cirrhosis in the opinion of the investigator, including but not limited to variceal hemorrhage, ascites, and/or hepatic encephalopathy;

7. clinically significant portal hypertension defined by any one of the following: FibroScan® about >25 kPA if the platelets are about >150,000/pL; Fibroscan® about >20 kPA if platelets are about <150,000/pL; a history of esophageal or gastric varices (about >grade 1) on endoscopy; ELF about >11 .3; or hepatic venous pressure gradient (HVPG) about >10 mm Hg;

8. not expected to comply with the protocol requirements or not expected to complete the study as scheduled (e.g., chronic alcohol or drug abuse or any other condition that, in the investigator’s opinion, makes the patient an unreliable study participant);

9. previous enrollment in this study;

10. current enrollment in another investigational device or drug study, or less than about 30 days since ending another investigational device or drug study(s) or receiving other investigational treatment(s); 1 1 . any condition not covered by any of the other exclusion criteria which, in the investigator’s opinion, might jeopardize the patient’s safety or compliance with the protocol;

12. patients who meet the criteria of a vulnerable person, defined as pregnant or breastfeeding woman; persons deprived of their liberty; minors; persons that may have insufficient power, intelligence, education, resources, strength, or other needed attributes to protect their own interests; or unable to explicitly give consent, as per local regulation;

13. current or past significant alcohol consumption (defined as intake of about >210 g/ week in males and about >140 g/ week in females on average over a consecutive period of more than 3 months) or inability to reliably quantify alcohol consumption based on investigator judgement within about the last 5 years (The Alcohol Use Disorders Identification Test (AUDIT) shall be used a standardized screening tool for alcohol use disorder);

14. patients who meet any of the following cardiac criteria: mean resting corrected QT interval (QTcF) about >470 ms; and/or any other relevant ECG finding at screening;

15. intake of any of the following restricted medications: medications historically associated with liver injury, hepatic steatosis, or steatohepatitis (e.g., oral or intravenous corticosteroids, methotrexate, valproic acid, tamoxifen, tetracycline, or amiodarone) for more than about 14 consecutive days within about 12 weeks prior to screening visit and while enrolled in the study, GLP-1 receptor agonists, as monotherapy or in combination with other agents (such as GLP-1 ZGIP), during trial treatment and about 90 days prior to first treatment and while enrolled in this trial;

16. patients who must or wish to continue the intake of restricted medications or any drug considered likely to interfere with the safe conduct of the study;

17. the presence of other forms of acute or chronic liver disease (e.g., viral hepatitis, autoimmune liver disease, primary biliary sclerosis, primary sclerosing cholangitis, Wilson’s disease, hemochromatosis, or alpha-1 antitrypsin deficiency) that meet any of the following parameters: active hepatitis B (HBV) or C (HBC) with positive hepatitis B surface antigen (HbsAg); positive total anti-hepatitis B core antigen (anti-HBc), a hepatitis C virus (HCV) viral load above the limit of quantification (HCV RNA positive) (patients treated for hepatitis C must have a negative RNA test at screening and also be HCV RNA negative for at least about 3 years prior to screening in order to be eligible for the study); or clinical suspicion for autoimmune liverdisease based on both of the following: a) increased total IgG orgamma- globulin levels and serologic markers (e.g., antinuclear antibodies (ANA), anti-smooth muscle antibodies (ASMA) at a titer of at least about 1 :40, anti-liver/kidney microsomal-1 (anti-LKM- 1) antibodies, anti-liver cytosol antibody-1 (ALC-1), or anti-soluble liver/liver pancreas (anti- SLA/LP) antibodies) and b) a biopsy suggestive of autoimmune hepatitis in the view of the clinical investigator (e.g., interface hepatitis or lymphocytic infiltration); 18. known hypersensitivity to any of the ingredients used in the study drug formulation, or any of the medications used and/or known history of allergy to any study drug or similar class drug;

19. a history of severe hypersensitivity reactions to monoclonal antibodies;

20. patients who are pregnant, nursing, or who plan to become pregnant while in the study;

21. an active, known, or suspected autoimmune disease (patients with hypothyroidism only requiring hormone replacement, skin disorder (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment within about 5 years prior to randomization are permitted to enroll); or

22. a known immunocompromised status, including patients having undergone organ transplantation, using chronic immunosuppressants, who are positive for HIV, or have recurrent or chronic systemic bacterial, fungal, viral, or protozoal infections that, in the opinion of the investigator, place the patient at an increased risk.

[00206] Patients who are enrolled will receive either an intravenous infusion of 1600 mg of antibody A10 ora placebo comprising approximately 100 mL of 0.9% sodium chloride every 3 weeks (Q3W). Planned enrolment for this study is 36 participants for approximately 24 evaluable participants. Patients will be randomized (without stratification) in a 1 :1 ratio to antibody A10 or placebo. Initially, a pilot cohort (Cohort A) of 6 patients (3 receiving placebo and 3 receiving antibody A10) will be treated. A Safety Review Committee (SRC), established to review individual and aggregated safety data, will allow randomization of patients in Cohort B if safety is confirmed after each patient within Cohort A surpasses 21 days of treatment. Patients who do not receive all scheduled doses (at visits 2, 6, 8, and 10) and miss the end of treatment (EoT) visit will be replaced, at the sponsor’s discretion. The actual number of participants entered may therefore exceed N=24 if additional participants are needed to account for dropouts, but the total sample size will not exceed N=36.

[00207] The main objective of the study is to investigate the safety, tolerability, PK, and/or PD of antibody A10 in adult patients with compensated hepatic cirrhosis due to MASH. The main primary endpoints include, for example, the occurrence of treatment-emergent, drug- related adverse events (AEs) in the antibody A10 and placebo arm. The efficacy of antibody A10 will be determined by the change in pro-C3 from baseline to the end of treatment as measured by biomarker and PD assays.

[00208] Secondary end points may include, for example, the occurrence of AEs (including clinically relevant findings, from medical examination safety laboratory test, 12-lead ECG, and vital signs) and the change from baseline in fibrosis-related soluble biomarker pro-C3 after 12 weeks of treatment. The study will also evaluate additional safety endpoints including, for example, changes from baseline in cardiac function related biomarkers (e.g., B-type natriuretic peptide (BNP), N-terminal pro b-type natriuretic peptide (NT-proBNP), high sensitivity (hs- TNT), high-density lipoprotein (HDL), low-density lipoprotein (LDL), or total cholesterol), kidney function related biomarkers (e.g., creatinine, estimated glomerular rate (eGFR), orspot urine albumin-creatinine ratio (UACR)), and diabetes related biomarkers (e.g., hemoglobin A1 C (HbA1 c), insulin, C-peptide, or homeostasis model assessment of insulin resistance (HOMA-IR)) after 12 weeks of treatment.

[00209] The study will also examine exploratory biomarkers and the pharmacodynamics of antibody A10 as measured by a receptor occupancy assay on whole blood monocytes to confirm direct target engagement as well as changes from baseline in fibrosis-related biomarkers (e.g., PRO-C6, or ELF score (tissue inhibitor of metalloproteinases 1 (TIMP1 ), hyaluronic acid (HA), procollagen type III amino terminal propeptide (PIIINP)), inflammation- related biomarkers (e.g., high-sensitivity C-reactive protein (hs-CRP), cytokines (e.g., IFN-y, IL-1 p, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, or TNF-a), gene expression profiles from blood cells, glycoprotein nmb (GPNMB), or Galectin-3), CK18 (M30 and M65), other disease activity related biomarkers (e.g., bile acid profile or miRNA signature), liver stiffness (kPa), spleen stiffness (kPa), and liver fat content (dB/m) after 12 weeks of treatment. Composite scores indicative of disease activity will also be determined based measurements including a Fibrosis-4 (Fib-4) index indicative of the level of liver fibrosis (age, AST, ALT, platelets), FibroScan®-AST (FAST) score, Agile3+ 1 Agile4, MELD utilizing total bilirubin, INR, creatinine, and MELD-Na (total bilirubin, INR, creatinine, sodium). Biomarkers will be evaluated for monitoring of treatment response (e.g., change from baseline assessment) and potential to predict treatment response/ non-response (e.g., correlation of baseline data with treatment outcome for relevant endpoints). The liver and spleen will be evaluated using, for example, the FibroScan® Expert 630 device, a non-invasive advanced technique using vibration controlled transient elastography (VCTE) technology. Evaluations will be performed in fasted condition and in accordance with the FibroScan® imaging manual. The liver (and spleen) stiffness will be evaluated via utilizing vibration controlled transient elastography measurements (VCTE, in kPa), and liver fat will be assessed by using the Controlled Attenuation Parameter (CAP, in dB/m). Exploratory, pre-specified pharmacogenomic analyses of RNA isolated from whole patient blood samples will also be performed to evaluate the response of individuals with different genetic variations (e.g., rs58542926 polymorphism in transmembrane 6 superfamily member 2 (TM6SF2) to antibody A10.

[00210] Along with the above-mentioned exploratory biomarkers, several additional safety laboratory measurements relevant for the assessment of the pharmacodynamic effect of antibody A10 will be analysed. Such safety measurements include changes from baseline in cardiac function related biomarkers (e.g., B-type natriuretic peptide (BNP), N-terminal pro b- type natriuretic peptide (NT-proBNP), troponin T, high sensitivity (hs-TNT), high-density lipoprotein (HDL), low-density lipoprotein (LDL), or total cholesterol), kidney function related biomarkers (e.g., creatinine, estimated glomerular rate (eGFR), or spot urine albumincreatinine ratio (UACR)), and diabetes related biomarkers (e.g., hemoglobin A1 C (HbA1c), insulin, C-peptide, or homeostasis model assessment of insulin resistance (HOMA-IR)) after 12 weeks of treatment.

[00211] An individual patient may be discontinued from the study if they experience an adverse event or their liver tests indicate certain abnormalities. An individual patient with abnormal baseline levels of aminotransferases (e.g., > 1.5 x ULN of ALT, AST), ALP, or total bilirubin will discontinue the study if their liver tests indicate all of the following: AST, ALT, or ALP > 2 x baseline or 5 x ULN (whichever comes first), = TBL > 2 x ULN or INR >1.5 or increased by 0.2 if starting with baseline INR >1.5; AST or ALT >3 x baseline or >8 x ULN, whichever comes first; and an increase in ALP >2 x baseline and DB by >1 mg/dL from baseline value without an alternative etiology. An individual patient with normal baseline levels of aminotransferases (e.g., < 1 .5 x ULN of ALT, AST), ALP, total bilirubin, direct bilirubin (DB), and INR will discontinue the study if their liver tests indicate all of the following: AST, ALT, or ALP > 2 x baseline or 3 x ULN (whichever comes first), along with TBL >2 x ULN or INR >1 .5 or increased by 0.2 if starting with baseline INR >1.5; ALT or AST >5 x ULN; and increase in ALP >3 x ULN and DB by >1 mg/dL from baseline value without an alternative etiology. An individual patient will also discontinue the study if they experience an AE of common terminology criteria for adverse events (CTCAE) grade 3 or higher that is possibly related to the study drug, experience an AE of CTCAE grade 4, a CRS (any CTCAE grade of confirmed CRS) or IRR (CTCAE grade 3 or higher), or any other adverse event including clinically relevant change or abnormality in laboratory, vital signs, or ECG that the investigator judges to warrant discontinuation of study treatment. Further, if the patient’s clinical, laboratory, or radiologic results indicate the development of decompensated cirrhosis (e.g., variceal haemorrhage, hepatic encephalopathy, or ascites) or a Fridericia’s (cube root) correction (QTcF) prolongation >500 ms or QTcF change from baseline >60 ms confirmed by repeated testing, they will discontinue the study. A patient will also discontinue the study if they can no longer receive the study drug for medical reasons such as surgery, serious or severe drug induced liver injury attributable to the study drug, severe hypersensitivity reaction, other Aes, other diseases, or pregnancy.

[00212] Specific embodiments provided herein can be further limited in the claims using “consisting of” or “consisting essentially of’ language. When used in the claims, whether as filed or added per amendment, the transition term “consisting of’ excludes any element, step, or ingredient not specified in the claims. The transition term “consisting essentially of’ limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristics). Embodiments so claimed are inherently or expressly described and enabled herein.

[00213] In cases where numerical values are indicated herein, the skilled person will understand that the technical effect of the feature in question is ensured within an interval of accuracy, which typically encompasses a deviation of the numerical value given of ± 10% or of ± 5%. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed considering the number of reported significant digits and by applying ordinary rounding techniques.

[00214] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight and median size, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained.

[00215] The terms “a,” “an,” “the” and similar referents used in the context of the description herein (especially in the context of the following claims) are to be construed to cover both the singularand the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the specification and does not pose a limitation on the scope of the claims. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the description.

[00216] Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive and covers both “or” and “and.”

[00217] Groupings of alternative elements or embodiments provided herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified, thus fulfilling the written description of all Markush groups used in the appended claims.

[00218] Certain embodiments are described herein, including the best mode known for carrying out methods provided herein. Of course, variations on these described embodiments will become apparent upon reading the foregoing description. One can be expected to employ such variations as appropriate and can be practiced other than as specifically described herein. Accordingly, this description includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the description unless otherwise indicated herein or otherwise clearly contradicted by context.

[00219] It is to be understood that the embodiments provided herein are illustrative of the principles of the description herein. Other modifications that can be employed are within the scope of the description. Thus, by way of example, but not of limitation, alternative configurations can be utilized in accordance with the teachings herein. Accordingly, the presented information is not limited to that precisely as shown and described.

[00220] While the present description has been described and illustrated herein by references to various specific materials, procedures, and examples, it is understood that the description is not restricted to the particular combinations of materials and procedures selected for that purpose. Numerous variations of such details can be implied as will be appreciated. It is intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the specification being indicated by the following claims. All references, patents, and patent applications referred to in this application are herein incorporated by reference in their entirety.

[00221] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood. Although other probes, compositions, methods, and kits similar, or equivalent, to those described herein can be used in the practice described herein, the materials and methods are described herein. It is to be understood that the terminology used herein is for the purpose of describing embodiments only and is not intended to be limiting.

[00222] Unless specifically stated or obvious from context, as used herein, the term “about” is understood as within a range of normal tolerance, for example within 2 standard deviations of the mean. About is understood to be within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1 %, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values provided herein are modified by the term “about.”

[00223] A stated range is understood to be any value between and at the limits of the stated range. As examples, a range between 1 and 5 includes 1 , 2, 3, 4, and 5; a range between 1 and 10 includes 1 , 2, 3, 4, 5, 6, 7, 8, 9, and 10; and a range between 1 and 100 includes 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 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, 96, 97, 98, 99, and 100.

[00224] Any aspect or embodiment described herein can be combined with any other aspect or embodiment as described herein.

Claims

WHAT IS CLAIMED IS:

1 . A method of treating a SIRPa pathway disease in a subject in need thereof, the method comprising administering to the subject in need thereof a dose of about 100 mg to about 300 mg of an anti-SIRPa antibody or an antigen-binding fragment thereof; wherein the anti-SIRPa antibody or the antigen-binding fragment thereof comprises: a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 34 (H-CDR2); and the amino acid sequence of SEQ ID NO: 35 (H-CDR3), and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 or SEQ ID NO: 37 (L-CDR1); the amino acid sequence of SEQ ID NO: 38 (L-CDR2); and the amino acid sequence of SEQ ID NO: 39 (L-CDR3), or b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 223 (H-CDR1); the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 or SEQ ID NO: 224 (H-CDR2); and the amino acid sequence of SEQ ID NO: 6 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9 or SEQ ID NO: 225 (L-CDR1); the amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 11 or SEQ ID NO: 226 (L-CDR2); and the amino acid sequence of SEQ ID NO: 12 or SEQ ID NO: 227 (L-CDR3), or c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 52 (H-CDR1); the amino acid sequence of SEQ ID NO: 53 (H-CDR2); and the amino acid sequence of SEQ ID NO: 54 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 55 (L-CDR1); the amino acid sequence of SEQ ID NO: 56 (L-CDR2); and the amino acid sequence of SEQ ID NO: 57 (L-CDR3), or d) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 70 (H-CDR2); and the amino acid sequence of SEQ ID NO: 71 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 (L-CDR1); the amino acid sequence of SEQ ID NO: 72 (L-CDR2); and the amino acid sequence of SEQ ID NO: 39 (L-CDR3), or e) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 243 (H-CDR1); the amino acid sequence of SEQ ID NO: 87 (H-CDR2); and the amino acid sequence of SEQ ID NO: 88 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 (L-CDR1); the amino acid sequence of SEQ ID NO: 72 (L-CDR2); and the amino acid sequence of SEQ ID NO: 89 (L-CDR3).

2. A method of treating a SIRPa pathway disease in a subject in need thereof, the method comprising administering to the patient a dose of about 100 mg to about 300 mg of an anti-SIRPa antibody or an antigen-binding fragment thereof, wherein the anti-SIRPa antibody or the antigen-binding fragment thereof comprises: a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 34 (H-CDR2); the amino acid sequence of SEQ ID NO: 35 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 233, wherein amino acids X1 = D or G and X2 = L or A (L-CDR1); the amino acid sequence of SEQ ID NO: 38, (L-CDR2); the amino acid sequence of SEQ ID NO: 39 (L-CDR3), or b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 228 (H-CDR1), wherein amino acids X1 = N or D; the amino acid sequence of SEQ ID NO: 229, wherein X1=Y or D, X2=N or T, X3=N or Q, and X4=S or P (H-CDR2); the amino acid sequence of SEQ ID NO: 6 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 230, wherein X1 =K or R, X2= N or T, X3=G or A and X4=N, A or T (L-CDR1); the amino acid sequence of SEQ ID NO: 231 , wherein X1=L, Q or G and X2=N or S (L-CDR2); the amino acid sequence of SEQ ID NO: 232, wherein X1=M or G (L-CDR3).

3. The method according to claim 1 or 2, wherein the dose of the anti-SIRPa antibody or the antigen-binding fragment thereof is about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg.

4. The method according to claim 1 or 2, wherein the dose of anti-SIRPa antibody or the antigen-binding fragment thereof is about 100 mg.

5. The method according to claim 1 or 2, wherein the dose of the anti-SIRPa antibody or the antigen-binding fragment thereof is about 125 mg.

6. The method according to claim 1 or 2, wherein the dose of the anti-SIRPa antibody or the antigen-binding fragment thereof is about 150 mg.

7. The method according to claim 1 or 2, wherein the dose of the anti-SIRPa antibody or the antigen-binding fragment thereof is about 175 mg.

8. The method according to claim 1 or 2, wherein the dose of the anti-SIRPa antibody or the antigen-binding fragment thereof is about 200 mg.

9. The method according to claim 1 or 2, wherein the dose of the anti-SIRPa antibody or the antigen-binding fragment thereof is about 225 mg.

10. The method according to claim 1 or 2, wherein the dose of the anti-SIRPa antibody or the antigen-binding fragment thereof is about 250 mg.

11. The method according to claim 1 or 2, wherein the dose of the anti-SIRPa antibody or the antigen-binding fragment thereof is about 275 mg.

12. The method according to claim 1 or 2, wherein the dose of the anti-SIRPa antibody or the antigen-binding fragment thereof is about 300 mg.

13. The method according to claim 1 or 2, wherein the dose of the anti-SIRPa antibody or the antigen-binding fragment thereof is administered to the subject in need thereof at a dosing cycle of about twice a week, about once every week (Q1 W), about once every two weeks (Q2W), about once every three weeks (Q3W), or about once every four weeks (Q4W).

14. The method according to any one of claims 1 to 12, wherein the dose of the anti-SIRPa antibody or the antigen-binding fragment thereof is administered to the subject in need thereof at a dosing cycle of about once every week (Q1 W).

15. The method according to any one of claims 1 to 12, wherein the dose of the anti-SIRPa antibody or the antigen-binding fragment thereof is administered to the subject in need thereof at a dosing cycle of about once every two weeks (Q2W).

16. The method according to any one of the proceeding claims, wherein the anti- SIRPa antibody or the antigen-binding fragment thereof is administered subcutaneously.

17. The method according to any one of the proceeding claims, wherein the SIRPa pathway disorder is a liver disease or disorder.

18. The method according to claim 17, wherein the liver disease or disorder is cirrhosis.

19. The method according to claim 17, wherein the liver disease or disorder is MASH.

20. The method according to claim 1 , wherein the anti-SIRPa antibody or the antigen-binding fragment thereof comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 34 (H-CDR2); and the amino acid sequence of SEQ ID NO: 35 (H-CDR3), and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 or SEQ ID NO: 37 (L-CDR1); the amino acid sequence of SEQ ID NO: 38 (L-CDR2); and the amino acid sequence of SEQ ID NO: 39 (L-CDR3).

21 . The method according to claim 1 , wherein the anti-SIRPa antibody or the antigen-binding fragment thereof comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 223 (H-CDR1); the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 or SEQ ID NO: 224 (H-CDR2); and the amino acid sequence of SEQ ID NO: 6 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9 or SEQ ID NO: 225 (L-CDR1); the amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 11 or SEQ ID NO: 226 (L-CDR2); and the amino acid sequence of SEQ ID NO: 12 or SEQ ID NO: 227 (L-CDR3).

22. The method according to claim 1 , wherein the anti-SIRPa antibody or the antigen-binding fragment thereof comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 52 (H-CDR1); the amino acid sequence of SEQ ID NO: 53 (H-CDR2); and the amino acid sequence of SEQ ID NO: 54 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 55 (L-CDR1); the amino acid sequence of SEQ ID NO: 56 (L-CDR2); and the amino acid sequence of SEQ ID NO: 57 (L-CDR3).

23. The method according to claim 1 , wherein the anti-SIRPa antibody or the antigen-binding fragment thereof comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 70 (H-CDR2); and the amino acid sequence of SEQ ID NO: 71 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 (L-CDR1); the amino acid sequence of SEQ ID NO: 72 (L-CDR2); and the amino acid sequence of SEQ ID NO: 39 (L-CDR3).

24. The method according to claim 1 , wherein the anti-SIRPa antibody or the antigen-binding fragment thereof comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 243 (H-CDR1); the amino acid sequence of SEQ ID NO: 87 (H-CDR2); and the amino acid sequence of SEQ ID NO: 88 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 (L-CDR1); the amino acid sequence of SEQ ID NO: 72 (L-CDR2); and the amino acid sequence of SEQ ID NO: 89 (L-CDR3).

25. The method according to claim 1 , wherein the anti-SIRPa antibody or the antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of any one of SEQ ID NOs: 100, 110, 11 1 , 1 12, 113, 1 14, 1 15, 116, or 1 17; and a light chain variable region comprising the amino acid sequence of any one of SEQ ID NOs: 105, 125, or 126.

26. The method according to claim 1 , wherein the anti-SIRPa antibody or the antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of any one of SEQ ID NOs: 104, 1 18, 119, 120, 121 , 122, 123, 124 or 221 ; and a light chain variable region comprising the amino acid sequence of any one of SEQ ID NOs: 109, 127, 128, 129, 130, or 222.

27. The method according to claim 1 , wherein the anti-SIRPa antibody or the antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of any one of SEQ ID NOs: 100, 101 , 102, 103, or 104; and a light chain variable region comprising the amino acid sequence of any one of SEQ ID NOs: 105, 106, 107, 108, or 109.

28. The method according to claim 25, wherein the anti-SIRPa antibody or the antigen-binding fragment thereof comprises: a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 100; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 105; or b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 110; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 125; or c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 111 ; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 125; or d) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 112; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 125; or e) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 113; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 125; or f) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 114; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 125; or g) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 115; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 125; or h) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 116; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 125; or i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 117; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 125; or j) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 110; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 126; or k) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 111 ; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 126; or l) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 112; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 126; or m) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 113; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 126; or n) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 114; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 126; or o) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 115; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 126; or p) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 117; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 126.

29. The method according to claim 26, wherein the anti-SIRPa antibody or the antigen-binding fragment thereof comprises: a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 104; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 109; or b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 118; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 127; or c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 118; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 128; or d) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 119; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 127; or e) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 119; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 129; or f) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 120; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 127; or g) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 120; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 129; or h) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 121 ; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 127; or i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 122; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 127; or j) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 118; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 130; or k) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 121 ; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 129; or l) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 122; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 129; or m) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 119; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 130; or n) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 123; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 127; or o) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 120; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 130; or p) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 123; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 129; or q) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 121 ; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 130; or r) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 122; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 130; or s) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 124; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 129; or t) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 124; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 127; or u) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 123; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 130; or v) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 124; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 130; or w) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 221 ; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 222.

30. The method according to claim 27, wherein the anti-SIRPa antibody or the antigen-binding fragment thereof comprises: a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 100; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 105; or b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 101 ; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 106; or c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 102; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 107; or d) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 103; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 108; or e) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 104; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 109.

31 . The method according to claim 25, wherein the anti-SIRPa antibody or the antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of any one of SEQ ID NO: 131 , 138, 139, 140, 141 , 142, 143, 144, 145, 146, 147, 148, 149, 150, 151 , 152, or 217; and a light chain comprising the amino acid sequence of any one of SEQ ID NO: 174, 181 , 182, 183, 184, 185, 186, 187, 188, 189, 190, 191 , 192, 193, 194, 195, or 218.

32. The method according to claim 31 , wherein the anti-SIRPa antibody or the antigen-binding fragment thereof comprises: a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 131 ; and a light chain comprising the amino acid sequence of SEQ ID NO: 174; or b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 138; and a light chain comprising the amino acid sequence of SEQ ID NO: 181 ; or c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 139; and a light chain comprising the amino acid sequence of SEQ ID NO: 182; or d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 140; and a light chain comprising the amino acid sequence of SEQ ID NO: 183; or e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 141 ; and a light chain comprising the amino acid sequence of SEQ ID NO: 184; or f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 142; and a light chain comprising the amino acid sequence of SEQ ID NO: 185; or g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 143; and a light chain comprising the amino acid sequence of SEQ ID NO: 186; or h) a heavy chain comprising the amino acid sequence of SEQ ID NO: 144; and a light chain comprising the amino acid sequence of SEQ ID NO: 187; or i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 145; and a light chain comprising the amino acid sequence of SEQ ID NO: 188; or j) a heavy chain comprising the amino acid sequence of SEQ ID NO: 146; and a light chain comprising the amino acid sequence of SEQ ID NO: 189; or k) a heavy chain comprising the amino acid sequence of SEQ ID NO: 147; and a light chain comprising the amino acid sequence of SEQ ID NO: 190; or l) a heavy chain comprising the amino acid sequence of SEQ ID NO: 148; and a light chain comprising the amino acid sequence of SEQ ID NO: 191 ; or m) a heavy chain comprising the amino acid sequence of SEQ ID NO: 149; and a light chain comprising the amino acid sequence of SEQ ID NO: 192; or n) a heavy chain comprising the amino acid sequence of SEQ ID NO: 150; and a light chain comprising the amino acid sequence of SEQ ID NO: 193; or o) a heavy chain comprising the amino acid sequence of SEQ ID NO: 151 ; and a light chain comprising the amino acid sequence of SEQ ID NO: 194; or p) a heavy chain comprising the amino acid sequence of SEQ ID NO: 152; and a light chain comprising the amino acid sequence of SEQ ID NO: 195; or q) a heavy chain comprising the amino acid sequence of SEQ ID NO: 217; and a light chain comprising the amino acid sequence of SEQ ID NO: 218.

33. The method according to claim 26, wherein the anti-SIRPa antibody or the antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of any one of SEQ ID NO: 135, 153, 154, 155, 156, 157, 158, 159, 160, 161 , 162, 163, 164, 165, 166, 167, 168, 169, 170, 171 , 172, 173, or 219; and a light chain comprising the amino acid sequence of any one of SEQ ID NO: 178, 196, 197, 198, 199, 200, 201 , 202, 203, 204, 205, 206, 207, 208, 209, 210, 211 , 212, 213, 214, 215, 216, or 220.

34. The method according to claim 33, wherein the anti-SIRPa antibody or the antigen-binding fragment thereof comprises: a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 135; and a light chain comprising the amino acid sequence of SEQ ID NO: 178; or b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 153; and a light chain comprising the amino acid sequence of SEQ ID NO: 196; or c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 154; and a light chain comprising the amino acid sequence of SEQ ID NO: 197; or d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 155; and a light chain comprising the amino acid sequence of SEQ ID NO: 198; or e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 156; and a light chain comprising the amino acid sequence of SEQ ID NO: 199; or f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 157 ; and a light chain comprising the amino acid sequence of SEQ ID NO: 200; or g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 158; and a light chain comprising the amino acid sequence of SEQ ID NO: 201 ; or h) a heavy chain comprising the amino acid sequence of SEQ ID NO: 159; and a light chain comprising the amino acid sequence of SEQ ID NO: 202; or i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 160; and a light chain comprising the amino acid sequence of SEQ ID NO: 203; or j) a heavy chain comprising the amino acid sequence of SEQ ID NO: 161 ; and a light chain comprising the amino acid sequence of SEQ ID NO: 204; or k) a heavy chain comprising the amino acid sequence of SEQ ID NO: 162; and a light chain comprising the amino acid sequence of SEQ ID NO: 205; or l) a heavy chain comprising the amino acid sequence of SEQ ID NO: 163; and a light chain comprising the amino acid sequence of SEQ ID NO: 206; or m) a heavy chain comprising the amino acid sequence of SEQ ID NO: 164; and a light chain comprising the amino acid sequence of SEQ ID NO: 207; or n) a heavy chain comprising the amino acid sequence of SEQ ID NO: 165; and a light chain comprising the amino acid sequence of SEQ ID NO: 208; or o) a heavy chain comprising the amino acid sequence of SEQ ID NO: 166; and a light chain comprising the amino acid sequence of SEQ ID NO: 209; or p) heavy chain comprising the amino acid sequence of SEQ ID NO: 167; and a light chain comprising the amino acid sequence of SEQ ID NO: 210; or q) a heavy chain comprising the amino acid sequence of SEQ ID NO: 168; and a light chain comprising the amino acid sequence of SEQ ID NO: 211 ; or r) a heavy chain comprising the amino acid sequence of SEQ ID NO: 169; and a light chain comprising the amino acid sequence of SEQ ID NO: 212; or s) a heavy chain comprising the amino acid sequence of SEQ ID NO: 170; and a light chain comprising the amino acid sequence of SEQ ID NO: 213; or t) a heavy chain comprising the amino acid sequence of SEQ ID NO: 171 ; and a light chain comprising the amino acid sequence of SEQ ID NO: 214; or u) a heavy chain comprising the amino acid sequence of SEQ ID NO: 172; and a light chain comprising the amino acid sequence of SEQ ID NO: 215; or v) a heavy chain comprising the amino acid sequence of SEQ ID NO: 173; and a light chain comprising the amino acid sequence of SEQ ID NO: 216; or w) a heavy chain comprising the amino acid sequence of SEQ ID NO: 219; and a light chain comprising the amino acid sequence of SEQ ID NO: 220.

35. The method according to claim 27, wherein the anti-SIRPa antibody or the antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of any one of SEQ ID NO: 131 , 133, 134, 137, or 135; and a light chain comprising the amino acid sequence of any one of SEQ ID NO: 174, 176, 177, 180, or 178.

36. The method according to claim 35, wherein the anti-SIRPa antibody or the antigen-binding fragment thereof comprises: a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 131 ; and a light chain comprising the amino acid sequence of SEQ ID NO: 174; or b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 133; and a light chain comprising the amino acid sequence of SEQ ID NO: 176; or c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 134; and a light chain comprising the amino acid sequence of SEQ ID NO: 177; or d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 137; and a light chain comprising the amino acid sequence of SEQ ID NO: 180; or e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 135; and a light chain comprising the amino acid sequence of SEQ ID NO: 178; or f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 132; and a light chain comprising the amino acid sequence of SEQ ID NO: 175; or g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 136; and a light chain comprising the amino acid sequence of SEQ ID NO: 179.

37. Use of an anti-SIRPa antibody or an antigen-binding fragment thereof for the manufacture of a medicament for the treatment of a SIRPa pathway disease, wherein the anti- SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of about 100 mg to about 300 mg of the anti-SIRPa antibody or antigen-binding fragment thereof; wherein the anti-SIRPa antibody or the antigen-binding fragment thereof comprises: a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 34 (H-CDR2); and the amino acid sequence of SEQ ID NO: 35 (H-CDR3), and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 or SEQ ID NO: 37 (L-CDR1); the amino acid sequence of SEQ ID NO: 38 (L-CDR2); and the amino acid sequence of SEQ ID NO: 39 (L-CDR3), or b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 223 (H-CDR1); the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 or SEQ ID NO: 224 (H-CDR2); and the amino acid sequence of SEQ ID NO: 6 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9 or SEQ ID NO: 225 (L-CDR1); the amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 11 or SEQ ID NO: 226 (L-CDR2); and the amino acid sequence of SEQ ID NO: 12 or SEQ ID NO: 227 (L-CDR3), or c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 52 (H-CDR1); the amino acid sequence of SEQ ID NO: 53 (H-CDR2); and the amino acid sequence of SEQ ID NO: 54 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 55 (L-CDR1); the amino acid sequence of SEQ ID NO: 56 (L-CDR2); and the amino acid sequence of SEQ ID NO: 57 (L-CDR3), or d) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 70 (H-CDR2); and the amino acid sequence of SEQ ID NO: 71 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 (L-CDR1); the amino acid sequence of SEQ ID NO: 72 (L-CDR2); and the amino acid sequence of SEQ ID NO: 39 (L-CDR3), or e) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 243 (H-CDR1); the amino acid sequence of SEQ ID NO: 87 (H-CDR2); and the amino acid sequence of SEQ ID NO: 88 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 (L-CDR1); the amino acid sequence of SEQ ID NO: 72 (L-CDR2); and the amino acid sequence of SEQ ID NO: 89 (L-CDR3).

38. An anti-SIRPa antibody or an antigen-binding fragment thereof for use in the treatment of a SIRPa pathway disease, wherein a dose of about 100 mg to about 300 mg of the anti-SIRPa antibody or antigen-binding fragment thereof is administered to the subject in need thereof; wherein the anti-SIRPa antibody or the antigen-binding fragment thereof comprises: a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 34 (H-CDR2); and the amino acid sequence of SEQ ID NO: 35 (H-CDR3), and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 or SEQ ID NO: 37 (L-CDR1); the amino acid sequence of SEQ ID NO: 38 (L-CDR2); and the amino acid sequence of SEQ ID NO: 39 (L-CDR3), or b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 223 (H-CDR1); the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 or SEQ ID NO: 224 (H-CDR2); and the amino acid sequence of SEQ ID NO: 6 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9 or SEQ ID NO: 225 (L-CDR1); the amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 11 or SEQ ID NO: 226 (L-CDR2); and the amino acid sequence of SEQ ID NO: 12 or SEQ ID NO: 227 (L-CDR3), or c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 52 (H-CDR1); the amino acid sequence of SEQ ID NO: 53 (H-CDR2); and the amino acid sequence of SEQ ID NO: 54 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 55 (L-CDR1); the amino acid sequence of SEQ ID NO: 56 (L-CDR2); and the amino acid sequence of SEQ ID NO: 57 (L-CDR3), or d) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 70 (H-CDR2); and the amino acid sequence of SEQ ID NO: 71 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 (L-CDR1); the amino acid sequence of SEQ ID NO: 72 (L-CDR2); and the amino acid sequence of SEQ ID NO: 39 (L-CDR3), or e) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 243 (H-CDR1); the amino acid sequence of SEQ ID NO: 87 (H-CDR2); and the amino acid sequence of SEQ ID NO: 88 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 (L-CDR1); the amino acid sequence of SEQ ID NO: 72 (L-CDR2); and the amino acid sequence of SEQ ID NO: 89 (L-CDR3).