WO2025137410A1 - Pharmaceutical compositions of anti-il-13 antibodies with and without c-terminal lysine - Google Patents

Abstract

Described herein are pharmaceutical compositions of anti-interleukin (IL)-13 antibodies comprising a mixture of antibodies with and without C-terminal lysine extension. Also provided are pharmaceutical compositions for use in the treatment of an inflammatory disease or disorder.

Description

PHARMACEUTICAL COMPOSITIONS OF ANTI-IL-13 ANTIBODIES WITH AND WITHOUT C-TERMINAL LYSINE

Related Applications

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/612900 (filed on December 20, 2023) the disclosure of which is incorporated by reference herein in its entirety.

Background

[0002] The interleukin (IL)- 13 is a T helper cell subclass 2 (Th2) cytokine, and belongs to the family of type I cytokines. However, IL- 13 is involved in the differentiation of naive T cells into Th2 cells. IL-13 promotes B-cell proliferation and induces class switching to IgG4 and IgE in combination with CD40/CD40L co-stimulation (IL- 13 up-regulates FcsRI and thus helps in IgE priming of mast cells). In monocytes/macrophages, IL-13 up-regulates expression of CD23 and MHC class I and class II antigens; down-regulates the expression of CD14; inhibits antibody-dependent cytotoxicity IL-13; and promotes eosinophil survival, activation, and recruitment. IL- 13 also manifests important functions on nonhematopoietic cells, such as smooth muscle cells, epithelial cells, endothelial cells, and fibroblast cells. IL- 13 enhances proliferation and cholinergic-induced contractions of smooth muscles. In epithelial cells, IL- 13 potently induces chemokine production, alters mucociliary differentiation, decreases ciliary beat frequency of ciliated epithelial cells, and results in goblet cell metaplasia. In endothelial cells, IL- 13 is a potent inducer of vascular cell adhesion molecule 1 (VCAM-1), which is important for recruitment of eosinophils. In human dermal fibroblasts, IL-13 induces type 1 collagen synthesis in human dermal fibroblasts.

[0003] The inhibition of IL- 13 may be used to treat or pre vent inflammatory diseases and conditions, such as those related to elevated levels of IgE, including but not limited to: asthma, allergic rhinitis, urticaria, asthma, allergic rhinitis, urticaria, and allergic or atopic dermatitis. Thus, the development of potent and specific inhibitors of IL-13, for example, inhibitors that remain active for longer terms when administered to subjects, are needed for the prevention and/or treatment of IL- 13 and IgE-mediated diseases or conditions. Furthermore, compositions comprising anti-IL-13 antibodies suitable for administration to patients remains an unmet need. Summary

[0004] Human IgG heavy chain sequences encode a C-terminal lysine residue. Due to the actions of cellular carboxypeptidases, most, but not all, mature antibody molecules recovered from recombinant cell culture production lack a C-terminal lysine on their heavy chains. Without wishing to be bound by theory, it is contemplated that the resulting heterogeneity of C-terminal lysine levels observed in recombinant monoclonal antibodies is due to incomplete processing (Owen et al. (2023) J. Biotechnol. 10;374:38-48). Following human or animal administration, the remaining C-terminal lysine is subject to additional cleavage by carboxypeptidases present in serum (Cai et al. (2011) Biotechnol. Bioeng. 108(2):404-412) so even lower levels are typically observed in vivo.

[0005] The level of C-terminal lysine in antibodies produced in recombinant cell lines can vary based on the cell line used and the cell culture process conditions (Dick et al. (2008) Biotechnol. Bioeng. 100(6) : 1132- 1143 ; Shah et al. (2022) J. Pharm. Sci. 111(9):2445-2450). For example, C-terminal lysine levels in Chinese Hamster Ovary (CHO) cell lines are typically low (<20%) and often <5% of the original level.

[0006] In certain aspects, the present disclosure relates to a composition comprising a mixture of anti-interleukin 13 (IL- 13) antibodies, wherein the mixture comprises a) C- terminal anti IL- 13 antibodies comprising at least one heavy chain having a C-terminal lysine (also referred to herein as “C-terminal lysine antibodies” or “C-terminal antibodies”), and b) non-C-terminal anti IL- 13 antibodies otherwise identical to the C-terminal anti IL- 13 antibodies but lacking the C-terminal lysine (also referred to herein as “non-C-terminal lysine antibodies” or “non-C-terminal antibodies”), wherein each of the non-C-terminal and C- terminal antibodies comprises:

(i) a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and

(ii) a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; wherein:

(a) CDR-H1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 58-99 and 121;

(b) CDR-H2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 100-111;

(c) CDR-H3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 112-120 and 130-140, (d) CDR-L1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 141-144 and 149-152,

(e) CDR-L2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 153-158 and the amino acid sequence LAS; and

(f) CDR-L3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 165-172, and wherein each C-terminal antibody having a C-terminal lysine comprises a heavy chain constant domain comprising a sequence selected from the sequences set forth in SEQ ID NOs: 610-709.

[0007] In certain embodiments, between about 0.01% and about 50% of the antibodies are C-terminal antibodies. In certain embodiments, between about 0.1% and about 20% of the antibodies are C-terminal antibodies. In certain embodiments, between about 0.5% and about 10% of the antibodies are C-terminal antibodies. In certain embodiments, between about 1% and about 5% of the antibodies are C-terminal antibodies. In certain embodiments, between about 5% and about 10% of the antibodies are C-terminal antibodies. In certain embodiments, between about 5% and about 20% of the antibodies are C-terminal antibodies. In certain embodiments, between about 5% and about 30% of the antibodies are C-terminal antibodies.

[0008] In certain embodiments, the anti-IL-13 antibodies comprise a VH sequence selected from the sequences set forth in any one of SEQ ID NOs: 1-32. In certain embodiments, the anti-IL-13 antibodies comprise a VL sequence selected from the sequences set forth in any one of SEQ ID NOs: 33-57. In certain embodiments, the anti-IL-13 antibodies comprise a VH sequence selected from the sequences set forth in any one of SEQ ID NOs: 1-32 and a VL sequence selected from the sequences set forth in any one of SEQ ID NOs: 33-57. In certain embodiments, the anti-IL-13 antibodies comprise a VH comprising an amino acid sequence as set forth in SEQ ID NO: 3 and a VL comprising an amino acid sequence as set forth in SEQ ID NO: 39. In certain embodiments, the anti-IL-13 antibodies comprise a light chain constant region comprising SEQ ID NO: 469.

[0009] In certain embodiments, the composition further comprises one or more pharmaceutically acceptable excipients.

[0010] In another aspect, the disclosure relates to an anti-IL-13 antibody having a light chain comprising a VL comprising SEQ ID NO: 39 and a light chain constant region comprising SEQ ID NO: 469 and a heavy chain comprising a VH comprising SEQ ID NO: 3 and a heavy chain constant region comprising SEQ ID NO: 624. In certain embodiments, the composition further comprises an antibody having a light chain comprising a VL comprising SEQ ID NO: 39 and a light chain constant region comprising SEQ ID NO: 469 and a heavy chain comprising a VH comprising SEQ ID NO: 3 and a heavy chain constant region comprising SEQ ID NO: 439.

[0011] In certain embodiments, the antibodies are produced in a Chinese Hamster Ovary (CHO) cell line.

[0012] In another aspect, the disclosure relates to a vial comprising a composition described herein. In certain embodiments, the volume of the vial is between 1.0 mL and 3.0 mL. In certain embodiments, the volume of the vial is about 2.0 mL. In certain embodiments, the vial is a syringe. In certain embodiments, the syringe is a prefilled syringe. [0013] In another aspect, the disclosure relates to a composition comprising a mixture of anti-interleukin 13 (IL-13) antibodies, wherein the mixture comprises a first IL-13 antibody and a second IL- 13 antibody, wherein each antibody comprises at least one heavy chain, and wherein the first antibody and the second antibody are identical except that the first antibody comprises a lysine at the C-terminus of the at least one heavy chain, and the second antibody lacks the lysine at the C-terminus of the at least one heavy chain, wherein each antibody comprises:

(i) a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and

(ii) a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; wherein:

(a) CDR-H1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 58-99 and 121;

(b) CDR-H2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 100-111;

(c) CDR-H3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 112-120 and 130-140,

(d) CDR-L1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 141-144 and 149-152,

(e) CDR-L2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 153-158 and the amino acid sequence LAS; and (f) CDR-L3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 165-172, and wherein the first antibody comprises a heavy chain constant domain comprising a sequence selected from the sequences set forth in SEQ ID NOs: 610-709.

[0014] In certain embodiments, each anti-IL-13 antibody comprises a VH sequence selected from the sequences set forth in any one of SEQ ID NOs: 1-32. In certain embodiments, each anti-IL-13 antibody comprises a VL sequence selected from the sequences set forth in any one of SEQ ID NOs: 33-57. In certain embodiments, each anti-IL- 13 antibody comprises a VH sequence selected from the sequences set forth in any one of SEQ ID NOs: 1-32 and a VL sequence selected from the sequences set forth in any one of SEQ ID NOs: 33-57. In certain embodiments, each anti-IL-13 antibody comprises a VH comprising an amino acid sequence as set forth in SEQ ID NO: 3 and a VL comprising an amino acid sequence as set forth in SEQ ID NO: 39. In certain embodiments, each antibody comprises a light chain constant region comprising SEQ ID NO: 469.

[0015] In certain embodiments, the antibodies are produced in a Chinese Hamster Ovary (CHO) cell line.

[0016] In another aspect, the disclosure relates to a vial comprising a composition as described herein. In another aspect, the disclosure relates to a bag or a bottle comprising a composition as described herein. In certain embodiments, the extractable volume of the vial is between 1.0 mL and 3.0 mL. In certain embodiments, the extractable volume of the vial is about 2.0 mL.

[0017] In another aspect, the disclosure relates to a composition comprising a mixture of anti-interleukin 13 (IL-13) antibodies, wherein the mixture comprises a) C-terminal anti IL- 13 antibodies comprising a heavy chain having at least one C- terminal lysine, and b) non-C-terminal anti IL- 13 antibodies otherwise identical to the C-terminal anti IL- 13 antibodies but lacking the at least one C-terminal lysine, wherein each of the non-C-terminal and C-terminal antibodies comprises:

(i) a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and

(ii) a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; wherein: (a) CDR-H1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 58-99 and 121;

(b) CDR-H2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 100-111 ;

(c) CDR-H3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 112-120 and 130-140,

(d) CDR-L1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 141-144 and 149-152,

(e) CDR-L2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 153-158 and the amino acid sequence LAS; and

(f) CDR-L3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 165-172, and wherein each C-terminal antibody having at least one C-terminal lysine comprises a heavy chain constant domain having a means for enhancing the half-life of the C-terminal antibody.

Brief Description of the Drawings

[0018] Figure 1 shows the imaged capillary isoelectric focusing (icIEF) profile and relative amounts of basic peaks for Construct 133 encoded without a C-terminal lysine from a 500L production culture. Basic peaks can be seen to the right of the main peak. The x-axis corresponds to pl, and the y-axis to absorbance.

[0019] Figure 2 shows the icIEF profile and relative amounts of basic peaks for Construct 133 encoded with a C-terminal lysine from a 500L production culture. Basic peaks can be seen to the right of the main peak. The x-axis corresponds to pl, and the y-axis to absorbance.

Detailed Description

Definitions

[0020] Unless otherwise defined, all terms of art, notations and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art. The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodologies by those skilled in the art, such as, for example, the widely utilized molecular cloning methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual 4th ed. (2012) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer-defined protocols and conditions unless otherwise noted.

[0021] As used herein, the singular form “a,” “an,” and “the” includes plural references unless indicated otherwise.

[0022] It is understood that aspects and embodiments of the invention described herein include “comprising,” “consisting,” and “consisting essentially of” aspects and embodiments. [0023] For all compositions described herein, and all methods using a composition described herein, the compositions can either comprise the listed components or steps, or can “consist essentially of’ the listed components or steps. When a composition is described as “consisting essentially of’ the listed components, the composition contains the components listed, and may contain other components which do not substantially affect the condition being treated, but do not contain any other components which substantially affect the condition being treated other than those components expressly listed; or, if the composition does contain extra components other than those listed which substantially affect the condition being treated, the composition does not contain a sufficient concentration or amount of the extra components to substantially affect the condition being treated. When a method is described as “consisting essentially of’ the listed steps, the method contains the steps listed, and may contain other steps that do not substantially affect the condition being treated, but the method does not contain any other steps which substantially affect the condition being treated other than those steps expressly listed. As a non-limiting specific example, when a composition is described as ‘consisting essentially of’ a component, the composition may additionally contain any amount of pharmaceutically acceptable carriers, vehicles, or diluents and other such components which do not substantially affect the condition being treated.

[0024] An “effective amount” or “therapeutically effective amount” as used herein refers to an amount of therapeutic compound, such as an anti-IL-13 antibody, administered to an individual, either as a single dose or as part of a series of doses, which is effective to produce or contribute to a desired therapeutic effect, either alone or in combination with another therapeutic modality. Examples of a desired therapeutic effect is enhancing an immune response, slowing or delaying tumor development; stabilization of disease; amelioration of one or more symptoms. An effective amount may be given in one or more dosages.

[0025] The term “treating” (and variations thereof such as “treat” or “treatment”) refers to clinical intervention in an attempt to alter the natural course of a disease or condition in a subject in need thereof. Treatment can be performed during the course of clinical pathology. Desirable effects of treatment include preventing recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.

[0026] The term “sufficient amount” means an amount sufficient to produce a desired effect, e.g., an amount sufficient to modulate an immune response in a subject.

[0027] As used herein, the terms “subject”, “patient”, and “individual” are used interchangeably herein. The term “subject”, “patient”, or “individual” means a mammalian subject. Exemplary subjects include humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, goats, rabbits, and sheep. In certain embodiments, the subject is a human. In certain embodiments the subject has a disease or condition that can be treated with an antibody provided herein.

[0028] The term “pharmaceutical composition” refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective in treating a subject, and which contains no additional components which are unacceptably toxic to the subject in the amounts provided in the pharmaceutical composition. [0029] The terms “modulate” and “modulation” refer to reducing or inhibiting or, alternatively, activating or increasing, a recited variable.

[0030] The terms “increase” and “activate” refer to an increase of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, or greater in a recited variable.

[0031] The terms “reduce” and “inhibit” refer to a decrease of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, or greater in a recited variable.

[0032] The term “about” indicates and encompasses an indicated value and a range above and below that value. In certain embodiments, the term “about” indicates the designated value ± 10%, ± 5%, or ± 1%. In certain embodiments, where applicable, the term “about” indicates the designated value(s) ± one standard deviation of that value(s). [0033] For any of the structural and functional characteristics described herein, methods of determining these characteristics are known in the art.

[0034] The term “optionally” is meant, when used sequentially, to include from one to all of the enumerated combinations and contemplates all sub-combinations.

[0035] The term “amino acid” refers to the twenty common naturally occurring amino acids. Naturally occurring amino acids include alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartic acid (Asp; D), cysteine (Cys; C); glutamic acid (Glu; E), glutamine (Gin; Q), Glycine (Gly; G); histidine (His; H), isoleucine (He; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Vai; V). As used herein, an amino acid described herein may refer to its L-isomer form. For example, methionine may refer to L-methionine, proline may refer to L-proline, and arginine may refer to L- rginine.

[0036] The term “affinity” refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen or epitope). Unless indicated otherwise, as used herein, “affinity” refers to intrinsic binding affinity, which reflects a 1 : 1 interaction between members of a binding pair (e.g., antibody and antigen or epitope).

[0037] The term “kd” (sec-1), as used herein, refers to the dissociation rate constant of a particular antibody - antigen interaction. This value is also referred to as the koff value. [0038] The term “ka” (M-lxsec-1), as used herein, refers to the association rate constant of a particular antibody -antigen interaction. This value is also referred to as the kon value. [0039] The term “KD” (M), as used herein, refers to the dissociation equilibrium constant of a particular antibody -antigen interaction. KD = kd/ka. In certain embodiments, the affinity of an antibody is described in terms of the KD for an interaction between such antibody and its antigen. For clarity, as known in the art, a smaller KD value indicates a higher affinity interaction, while a larger KD value indicates a lower affinity interaction.

[0040] The term “KA” (M-l), as used herein, refers to the association equilibrium constant of a particular antibody- antigen interaction. KA = ka/kd.

[0041] The term “antibody” is used herein in its broadest sense and includes certain types of immunoglobulin molecules comprising one or more antigen-binding domains that specifically bind to an antigen or epitope. An antibody specifically includes intact antibodies (e.g., intact immunoglobulins), antibody fragments, and multi-specific antibodies. [0042] A “anti-IL-13 antibody,” “IL-13 antibody,” or “IL-13 specific antibody” is an antibody, as provided herein, which specifically binds to the antigen IL-13.

[0043] The terms “C-terminal lysine antibody” and “C-terminal antibody” are used interchangeably herein to refer to an antibody which has a lysine at the C-terminus of at least one heavy chain. In certain embodiments, a C-terminal antibody has the following amino acid sequence at the C-terminus of at least one heavy chain: SLSLSPGK (SEQ ID NO: 710). In certain embodiments, a C-terminal antibody has a C-terminal lysine on at least one heavy chain. In certain embodiments, a C-terminal antibody has a C-terminal lysine on at least two heavy chains (e.g., both heavy chains in an antibody having two heavy chains).

[0044] The terms “non-C-terminal lysine antibody” and “non-C-terminal antibody” are used interchangeably herein to refer to an antibody which lacks a lysine at the C-terminus of each of its one or more heavy chains (e.g., both heavy chains in an antibody having two heavy chains). In certain embodiments, a non-C-terminal antibody may have the following amino acid sequence at the C-terminus of one or more heavy chains: SLSLSPG (SEQ ID NO: 711). In certain embodiments, a non-C-terminal antibody may have the following amino acid sequence at the C-terminus of one or more heavy chains: SLSLSP (SEQ ID NO: 712). In certain embodiments, the heavy chain of a non-C-terminal antibody is originally encoded with a C-terminal lysine, but the C-terminal lysine is removed by a carboxypeptidase in a production cell or in serum. In certain embodiments, the heavy chain of a non-C-terminal antibody is originally encoded without a C-terminal lysine and thus does not contain a C- terminal lysine to begin with.

[0045] The term “epitope” means a portion of an antigen that specifically binds to an antibody.

[0046] The term “hypervariable region” or “HVR,” as used herein, refers to each of the regions of an antibody variable domain which are hypervariable in sequence and/or form structurally defined loops (“hypervariable loops”).

[0047] The term “antigen-binding domain” means the portion of an antibody that is capable of specifically binding to an antigen or epitope.

[0048] The term “chimeric antibody” refers to an antibody in which a portion of the heavy and/or light chain is derived from a particular source or species, while the remainder of the heavy and/or light chain is derived from a different source or species.

[0049] The term “human antibody” refers to an antibody which possesses an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or derived from a non-human source that utilizes a human antibody repertoire or human antibody-encoding sequences (e.g., obtained from human sources or designed de novo). Human antibodies specifically exclude humanized antibodies.

[0050] The term “humanized antibody” refers to a protein having a sequence that differs from the sequence of an antibody derived from a non-human species by one or more amino acid substitutions, deletions, and/or additions, such that the humanized antibody is less likely to induce an immune response, and/or induces a less severe immune response, as compared to the non-human species antibody, when it is administered to a human subject.

[0051] The term “multispecific antibody” refers to an antibody that comprises two or more different antigen-binding domains that collectively specifically bind two or more different epitopes.

[0052] A “monospecific antibody” is an antibody that comprises one or more binding sites that specifically bind to a single epitope. An example of a monospecific antibody is a naturally occurring IgG molecule which, while divalent (z.e., having two antigen-binding domains), recognizes the same epitope at each of the two antigen-binding domains. The binding specificity may be present in any suitable valency.

[0053] The term “monoclonal antibody” refers to an antibody from a population of substantially homogeneous antibodies. A population of substantially homogeneous antibodies comprises antibodies that are substantially similar and that bind the same epitope(s), except for variants that may normally arise during production of the monoclonal antibody. Such variants are generally present in only minor amounts. A monoclonal antibody is typically obtained by a process that includes the selection of a single antibody from a plurality of antibodies. For example, the selection process can be the selection of a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones, yeast clones, bacterial clones, or other recombinant DNA clones. The selected antibody can be further altered, for example, to improve affinity for the target (“affinity maturation”), to humanize the antibody, to improve its production in cell culture, and/or to reduce its immunogenicity in a subject. [0054] The term “single-chain” refers to a molecule comprising amino acid monomers linearly linked by peptide bonds. In a particular such embodiment, the C-terminus of the Fab light chain is connected to the N-terminus of the Fab heavy chain in the single-chain Fab molecule. As described in more detail herein, an scFv has a variable domain of light chain (VL) connected from its C-terminus to the N-terminal end of a variable domain of heavy chain (VH) by a polypeptide chain. Alternately the scFv comprises of polypeptide chain where in the C-terminal end of the VH is connected to the N-terminal end of VL by a polypeptide chain.

[0055] The “Fab fragment” (also referred to as fragment antigen-binding) contains the constant domain (CL) of the light chain and the first constant domain (CHI) of the heavy chain along with the variable domains VL and VH on the light and heavy chains respectively. The variable domains comprise the complementarity determining loops (CDR, also referred to as hypervariable region) that are involved in antigen-binding. Fab' fragments differ from Fab fragments by the addition of a few residues at the carboxy terminus of the heavy chain CHI domain including one or more cysteines from the antibody hinge region.

[0056] “F(ab’)2” fragments contain two Fab’ fragments joined, near the hinge region, by disulfide bonds. F(ab’)2 fragments may be generated, for example, by recombinant methods or by pepsin digestion of an intact antibody. The F(ab’) fragments can be dissociated, for example, by treatment with B-mercaptoethanol.

[0057] “Fv” fragments comprise a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain.

[0058] “Single-chain Fv” or “sFv” or “scFv” includes the VH and VL domains of an antibody, wherein these domains are present in a single polypeptide chain. In one embodiment, the Fv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the scFv to form the desired structure for antigen-binding. For a review of scFv see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994). HER2 antibody scFv fragments are described in WO93/16185; U.S. Pat. No. 5,571,894; and U.S. Pat. No. 5,587,458.

[0059] “scFv-Fc” fragments comprise an scFv attached to an Fc domain. For example, an Fc domain may be attached to the C-terminal of the scFv. The Fc domain may follow the VH or VL, depending on the orientation of the variable domains in the scFv (i.e., VH -VL or VL - VH). Any suitable Fc domain known in the art or described herein may be used. In some cases, the Fc domain comprises an IgG4 Fc domain.

[0060] The term “single domain antibody” or “sdAb” refers to a molecule in which one variable domain of an antibody specifically binds to an antigen without the presence of the other variable domain. Single domain antibodies, and fragments thereof, are described in Arabi Ghahroudi el al., FEBS Letters, 1998, 414:521-526 and Muyldermans el al., Trends in Biochem. Sci., 2001, 26:230-245, each of which is incorporated by reference in its entirety. Single domain antibodies are also known as sdAbs or nanobodies. Sdabs are fairly stable and easy to express as fusion partner with the Fc chain of an antibody (Harmsen MM, De Haard HJ (2007). “Properties, production, and applications of camelid single-domain antibody fragments”. Appl. Microbiol Biotechnol. 77(1): 13-22).

[0061] The terms “full length antibody,” “intact antibody,” and “whole antibody” are used herein interchangeably to refer to an antibody having a structure substantially similar to a naturally occurring antibody structure and having heavy chains that comprise an Fc region. For example, when used to refer to an IgG molecule, a “full length antibody” is an antibody that comprises two heavy chains and two light chains.

[0062] The term “antibody fragment” refers to an antibody that comprises a portion of an intact antibody, such as the antigen-binding or variable region of an intact antibody. Antibody fragments include, for example, Fv fragments, Fab fragments, F(ab’)2 fragments, Fab’ fragments, scFv (sFv) fragments, and scFv-Fc fragments.

[0063] The term “Fc domain” or “Fc region” herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions.

[0064] The term “substantially purified” refers to a construct described herein, or variant thereof that may be substantially or essentially free of components that normally accompany or interact with the protein as found in its naturally occurring environment, i.e. a native cell, or host cell in the case of recombinantly produced antibody that in certain embodiments, is substantially free of cellular material includes preparations of protein having less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1 % (by dry weight or by relative concentration) of contaminating protein.

[0065] The term percent “identity,” in the context of two or more nucleic acid or polypeptide sequences, refer to two or more sequences or subsequences that have a specified percentage of nucleotides or amino acid residues that are the same, when compared and aligned for maximum correspondence, as measured using one of the sequence comparison algorithms described below (e.g., using publicly available computer software such as BLAST, BLASTP, BLASTN, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, CLUSTAL OMEGA, or MUSCLE software or other algorithms available to persons of skill) or by visual inspection. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (ncbi.nlm.nih.gov). Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. Depending on the application, the percent “identity” can exist over a region of the sequence being compared, e.g., over a functional domain, or, alternatively, exist over the full length of the two sequences to be compared.

[0066] For sequence comparison, typically one sequence acts as a reference sequence to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are input into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. The sequence comparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters.

[0067] Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2:482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443 (1970), by the search for similarity method of Pearson & Lipman, Proc. Nat’ I. Acad. Sci. USA 85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by visual inspection (see generally Ausubel et al., infra).

[0068] Ranges recited herein are understood to be shorthand for all of the values within the range, inclusive of the recited endpoints. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 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, and 50.

[0069] It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise.

[0070] In all the embodiments of the invention, “formulation,” “pharmaceutical formulation,” and “pharmaceutical composition” can also be referred to as “stable formulation” without any differentiation.

[0071] As used herein, the term “vial” refers to a container that holds the drug product. In some embodiments, the vial may be a vial, a pen, or a syringe. In some embodiments, the vial may be a vial, e.g., a glass vial or a pre-filled syringe. Anti-IL-13 Antibodies

[0072] In some embodiments, the present disclosure provides compositions comprising (a) a therapeutically effective amount of an isolated antibody that binds interleukin 13 (IL- 13) e.g., at a concentration between 140 mg/mL and 290 mg/mL; (b) a histidine buffer, an acetate buffer, or a succinate buffer; (c) arginine and/or methionine or a salt solution thereof; and (d) a polysorbate or poloxamer, at pH 5.0 to 7.0.

[0073] In some embodiments, the present disclosure further provides formulations comprising: (a) a therapeutically effective amount of an isolated antibody that binds IL- 13 e.g., at a concentration of about 180 mg/mL; (b) a histidine buffer at a concentration of about 10 mM; (c) an arginine salt solution at a concentration of about 120 mM; (d) methionine at a concentration of about 10 mM; and (e) a polysorbate 80 or poloxamer at a concentration of about 0.05% w/v, at pH of about 5.8.

[0074] In some embodiments, the present disclosure further provides formulations comprising: (a) a therapeutically effective amount of an isolated antibody that binds IL- 13 e.g., at a concentration of about 180 mg/mL; (b) a histidine buffer at a concentration of about 10 mM; (c) an arginine salt solution at a concentration of about 80 mM; (d) methionine at a concentration of about 10 mM; and (e) a polysorbate 80 or poloxamer at a concentration of about 0.05% w/v, at pH of about 5.8.

[0075] In some embodiments, the present disclosure further provides formulations comprising: (a) a therapeutically effective amount of an isolated antibody that binds IL- 13 e.g., at a concentration of about 200 mg/mL; (b) a histidine buffer at a concentration of about 10 mM; (c) an arginine salt solution at a concentration of about 120 mM; (d) methionine at a concentration of about 10 mM; and (e) a polysorbate 80 or poloxamer at a concentration of about 0.05% w/v, at pH of about 5.8.

[0076] In certain embodiments, the formulation further comprises sucrose.

[0077] In certain embodiments, the poloxamer is poloxamer 188.

[0078] In certain embodiments, the formulation comprises the formulation comprises:

(a) an interleukin 13 (IL- 13) antibody present at a concentration between 140 mg/mL and 290 mg/mL (e.g., at 180 mg/ml);

(b) a histidine buffer, an acetate buffer, or a succinate buffer (e.g., a histidine buffer at a concentration of 10 mM, wherein the histidine buffer comprises L- histidine and L-histidine HC1 monohydrate); (c) arginine or a salt solution thereof (e.g., L-arginine salt solution at a concentration of 120 mM);

(d) methionine or a salt solution thereof (e.g., L-methionine at a concentration of 10 mM);

(e) a polysorbate (e.g., polysorbate 80 at a concentration of 0.05% w/v) or a poloxamer (e.g., poloxamer 188 at a concentration of 0.5 mg/ml); and

(f) optionally, a metal ion chelator (e.g., EDTA-2Na at a concentration of 0.05 mM); wherein the formulation is at pH 5.0 to 7.0 (e.g., pH 5.8 or pH 6.0).

[0079] In some embodiments, the antibody that binds IL- 13 is a humanized, human, or chimeric antibody. In some embodiments, the antibody that binds IL- 13 is a humanized antibody.

Anti-IL-13 Antibody Structure

[0080] The present application provides antibodies and formulations comprising an antibody which binds IL- 13.

[0081] The recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon, and mu constant region genes, as well as the myriad immunoglobulin variable region genes. Light chains are classified as either kappa or lambda. The “class” of an antibody or immunoglobulin refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called a, 5, e, y, and p, respectively.

[0082] An exemplary immunoglobulin (antibody) structural unit is composed of two pairs of polypeptide chains, each pair having one “light” (about 25 kD) and one “heavy” chain (about 50-70 kD). The N-terminal domain of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms variable light chain (VL) and variable heavy chain (VH) refer to these light and heavy chain domains respectively. The IgGl heavy chain comprises of the VH, CHI, CH2, and CH3 domains respectively from the N- to C-terminus. The light chain comprises of the VL and CL domains from N- to C-terminus. The IgGl heavy chain comprises a hinge between the CHI and CH2 domains. In certain embodiments, the immunoglobulin constructs comprise at least one immunoglobulin domain from IgG, IgM, IgA, IgD, or IgE connected to a therapeutic polypeptide. In some embodiments, the immunoglobulin domain found in an antibody provided herein, is from or derived from an immunoglobulin based construct such as a diabody or a nanobody. In certain embodiments, the immunoglobulin constructs described herein comprise at least one immunoglobulin domain from a heavy chain antibody such as a camelid antibody. In certain embodiments, the immunoglobulin constructs provided herein comprise at least one immunoglobulin domain from a mammalian antibody such as a bovine antibody, a human antibody, a camelid antibody, a mouse antibody, or any chimeric antibody. [0083] In some embodiments, the antibodies provided herein comprise a heavy chain. In one embodiment, the heavy chain is an IgA. In one embodiment, the heavy chain is an IgD. In one embodiment, the heavy chain is an IgE. In one embodiment, the heavy chain is an IgG. In one embodiment, the heavy chain is an IgM. In one embodiment, the heavy chain is an IgGl. In one embodiment, the heavy chain is an IgG2. In one embodiment, the heavy chain is an IgG3. In one embodiment, the heavy chain is an IgG4. In one embodiment, the heavy chain is an IgAl. In one embodiment, the heavy chain is an IgA2.

[0084] In some embodiments, an antibody is an IgGl antibody. In some embodiments, an antibody is an IgG3 antibody. In some embodiments, an antibody is an IgG2 antibody. In some embodiments, an antibody is an IgG4 antibody.

[0085] Generally, native four-chain antibodies comprise six hypervariable regions (HVRs); three in the VH (Hl, H2, and H3), and three in the VL (LI, L2, and L3). HVRs generally comprise amino acid residues from the hypervariable loops and/or from the complementarity determining regions (CDRs), the latter being of highest sequence variability and/or involved in antigen recognition. With the exception of CDR1 in VH, CDRs generally comprise the amino acid residues that form the hypervariable loops. HVRs are also referred to as CDRs, and these terms are used herein interchangeably in reference to portions of the variable region that form the antigen-binding regions. This particular region has been described by Kabat el al., U.S. Dept, of Health and Human Services, Sequences of Proteins of Immunological Interest (1983) and by Chothia et al., J Mol Biol 196:901-917 (1987), where the definitions include overlapping or subsets of amino acid residues when compared against each other. Nevertheless, application of either definition to refer to a CDR of an antibody or variants thereof is intended to be within the scope of the term as defined and used herein. The exact residue numbers which encompass a particular CDR will vary depending on the sequence and size of the CDR. Those skilled in the art can routinely determine which residues comprise a particular CDR given the variable region amino acid sequence of the antibody.

[0086] The amino acid sequence boundaries of a CDR can be determined by one of skill in the art using any of a number of known numbering schemes, including those described by Kabat et al., supra (“Kabat” numbering scheme); Al-Lazikani et al., 1997, J. Mol. Biol., 273:927-948 (“Chothia” numbering scheme); MacCallum et al., 1996, J. Mol. Biol. 262:732- 745 (“Contact” numbering scheme); Lefranc et al. , Dev. Comp. Immunol., 2003, 27:55-77 (“IMGT” numbering scheme); and Honegge and Pliickthun, J. Mol. Biol., 2001, 309:657-70 (“AHo” numbering scheme); each of which is incorporated by reference in its entirety.

[0087] Table 1 provides the positions of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR- H2, and CDR-H3 as identified by the Kabat and Chothia schemes. For CDR-H1, residue numbering is provided using both the Kabat and Chothia numbering schemes.

[0088] CDRs may be assigned, for example, using antibody numbering software, such as Abnum, available at www.bioinf.org.uk/abs/abnum/, and described in Abhinandan and Martin, Immunology, 2008, 45:3832-3839, incorporated by reference in its entirety.

Table 1. Residues in CDRs according to Kabat and Chothia numbering schemes

* The C-terminus of CDR-H1, when numbered using the Kabat numbering convention, varies between H32 and H34, depending on the length of the CDR.

[0089] The “EU numbering scheme” is generally used when referring to a residue in an antibody heavy chain constant region (e.g., as reported in Kabat et al., supra . Unless stated otherwise, the EU numbering scheme is used to refer to residues in antibody heavy chain constant regions described herein.

[0090] One example of an antigen-binding domain is an antigen-binding domain formed by a VH-VL dimer of an antibody. Another example of an antigen-binding domain is an antigen-binding domain formed by diversification of certain loops from the tenth fibronectin type III domain of an Adnectin. An antigen-binding domain can include CDRs 1, 2, and 3 from a heavy chain in that order; and CDRs 1, 2, and 3 from a light chain in that order.

[0091] Epitopes frequently consist of surface-accessible amino acid residues and/or sugar side chains and may have specific three-dimensional structural characteristics, as well as specific charge characteristics. Conformational and non-conformational epitopes are distinguished in that the binding to the former but not the latter may be lost in the presence of denaturing solvents. An epitope may comprise amino acid residues that are directly involved in the binding and other amino acid residues, which are not directly involved in the binding. The epitope to which an antibody binds can be determined using known techniques for epitope determination such as, for example, testing for antibody binding to IL- 13 variants with different point-mutations or to chimeric IL- 13 variants.

[0092] To screen for antibodies which bind to an epitope on a target antigen bound by an antibody of interest (e.g., IL- 13), a routine cross-blocking assay such as that described in Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory, Ed Harlow and David Lane (1988), can be performed. Alternatively, or additionally, epitope mapping can be performed by methods known in the art.

[0093] Chimeric antibodies are antibodies in which a portion of the heavy and/or light chain is derived from a particular source or species, while the remainder of the heavy and/or light chain is derived from a different source or species.

[0094] Human antibodies are antibodies which possess an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or derived from a non-human source that utilizes a human antibody repertoire or human antibody-encoding sequences (e.g., obtained from human sources or designed de novo . Human antibodies specifically exclude humanized antibodies.

[0095] A humanized antibody has a sequence that differs from the sequence of an antibody derived from a non-human species by one or more amino acid substitutions, deletions, and/or additions, such that the humanized antibody is less likely to induce an immune response, and/or induces a less severe immune response, as compared to the non- human species antibody, when it is administered to a human subject. In one embodiment, certain amino acids in the framework and constant domains of the heavy and/or light chains of the non-human species antibody are mutated to produce the humanized antibody. In another embodiment, the constant domain(s) from a human antibody are fused to the variable domain(s) of a non-human species. In another embodiment, one or more amino acid residues in one or more CDR sequences of a non-human antibody are changed to reduce the likely immunogenicity of the non-human antibody when it is administered to a human subject, wherein the changed amino acid residues either are not critical for immunospecific binding of the antibody to its antigen, or the changes to the amino acid sequence that are made are conservative changes, such that the binding of the humanized antibody to the antigen is not significantly worse than the binding of the non-human antibody to the antigen. Examples of how to make humanized antibodies can be found in U.S. Pat. Nos. 6,054,297, 5,886,152 and 5,877,293. For further details, see Jones et al. , Nature, 1986, 321:522-525; Riechmann et al., Nature, 1988, 332:323-329; and Presta, Curr. Op. Struct. Biol., 1992, 2:593-596, each of which is incorporated by reference in its entirety.

[0096] The two or more different epitopes may be epitopes on the same antigen (e.g., a single IL-13) or on different antigens (e.g., different IL-13 molecules, or a IL-13 molecule and a non- IL-13 molecule). In some embodiments, a multi-specific antibody binds two different epitopes (i.e., a “bispecific antibody”). In some embodiments, a multi-specific antibody binds three different epitopes (i.e., a “trispecific antibody”).

[0097] Anti-IL-13 antibodies can include those described herein such as the clones set forth in the drawings and/or tables. In some embodiments, the antibody comprises an alternative scaffold. In some embodiments, the antibody consists of an alternative scaffold. In some embodiments, the antibody consists essentially of an alternative scaffold. In some embodiments, the antibody comprises an antibody fragment. In some embodiments, the antibody consists of an antibody fragment. In some embodiments, the antibody consists essentially of an antibody fragment.

[0098] In some embodiments the antibodies are monoclonal antibodies.

[0099] In some embodiments the antibodies are polyclonal antibodies.

[00100] In some embodiments the antibodies are produced by hybridomas. In other embodiments, the antibodies are produced by recombinant cells engineered to express the desired variable and constant domains.

[00101] In some embodiments the antibodies may be single chain antibodies or other antibody derivatives retaining the antigen specificity and the lower hinge region or a variant thereof.

[00102] In some embodiments the antibodies may be poly functional antibodies, recombinant antibodies, human antibodies, humanized antibodies, fragments or variants thereof. In particular embodiments, the antibody fragment or a derivative thereof is selected from a Fab fragment, a Fab'2 fragment, a CDR, and ScFv.

[00103] In some embodiments, the antibodies are capable of forming an immune complex. For example, an immune complex can be a tumor cell covered by antibodies.

[00104]

Sequences of IL- 13 Antibodies VH Domains

[00105] In some embodiments, the present disclosure further provides an isolated antibody that binds IL-13, comprising: (i) a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and (ii) a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR- L3; wherein: (a) CDR-H1 comprises a sequence selected from the sequences set forth in any one of SEQ ID NOs: 58-99 and 121; (b) CDR-H2 comprises a sequence selected from the sequences set forth in any one of SEQ ID NOs: 100-111; (c) CDR-H3 comprises a sequence selected from the sequences set forth in any one of SEQ ID NOs: 112-120 and 130-140, (d) CDR-L1 comprises a sequence selected from the sequences set forth in any one of SEQ ID NOs: 141-144 and 149-152, (e) CDR-L2 comprises a sequence selected from the sequences set forth in any one of SEQ ID NOs: 153-158 and the amino acid sequence LAS; and (f) CDR-L3 comprises a sequence selected from the sequences set forth in any one of SEQ ID NOs: 165-172.

[00106] In some embodiments, the present disclosure further provides an isolated antibody that binds IL-13, comprising: (i) a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and (ii) a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR- L3; wherein: (a) CDR-H1 comprises a sequence selected from the sequences set forth in any one of SEQ ID NO: 58, SEQ ID NO: 68, and SEQ ID NO: 85; (b) CDR-H2 comprises a sequence selected from the sequences set forth in any one of SEQ ID NO: 100, SEQ ID NO: 104, and SEQ ID NO: 108; (c) CDR-H3 comprises a sequence selected from the sequences set forth in any one of SEQ ID NO: 112 and SEQ ID NO: 130, (d) CDR-L1 comprises a sequence selected from the sequences set forth in any one of SEQ ID NO: 141 and SEQ ID NO: 149, (e) CDR-L2 comprises a sequence selected from the sequences set forth in any one of SEQ ID NO: 153 and SEQ ID NO: 164; and (f) CDR-L3 comprises the sequence set forth in SEQ ID NO: 165. [00107] In some embodiments, an antibody provided herein comprises a VH sequence selected from SEQ ID NOs: 1-32. In some embodiments, an antibody provided herein comprises a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a VH sequence provided in SEQ ID NOs: 1-32. In some embodiments, an antibody provided herein comprises a VH sequence provided in SEQ ID NOs: 1-32, with up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as “variants.” In some embodiments, such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.

VL Domains

[00108] In some embodiments, an antibody provided herein comprises a VL sequence selected from SEQ ID NOs: 33-57. In some embodiments, an antibody provided herein comprises a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a VL sequence provided in SEQ ID NOs: 33-57. In some embodiments, an antibody provided herein comprises a VL sequence provided in SEQ ID NOs: 33-57 with up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as “variants.” In some embodiments, such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.

VH-VL Combinations

[00109] In some embodiments, an antibody provided herein comprises a VH sequence selected from SEQ ID NOs: 1-32; and a VL sequence selected from SEQ ID NOs: 33-57, such as any of the VH-VL combinations set forth for Constructs 3-127 and 132-144 in Table 2, below.

[00110] In certain aspects, any of SEQ ID NOs: 1-32 can be combined with any of SEQ ID NOs: 33-57.

[00111] In certain embodiments, the antibody comprises a VH sequence selected from the sequences set forth in SEQ ID NOs: 1-32 and a VL sequence set forth in SEQ ID NO: 39. [00112] In certain embodiments, the antibody comprises the VH sequence set forth in SEQ ID NO: 3 and the VL sequence set forth in SEQ ID NO: 39.

[00113] In some embodiments, an antibody provided herein comprises a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a VH sequence provided in SEQ ID NOs: 1-32; and a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a VL sequence provided in SEQ ID NOs: 33-57 . In some embodiments, an antibody provided herein comprises a VH sequence provided in SEQ ID NOs: 1-32, with up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions; and a VL sequence provided in SEQ ID NOs: 33-57, with up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as “variants.” In some embodiments, such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.

[00114] In some embodiments, an antibody provided herein comprises a VH sequence and a VL sequence selected from combinations set forth for Constructs 3-127 and 132-144 in Table 2, below. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 1 and a VL sequence set forth in SEQ ID NO: 33. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 2 and a VL sequence set forth in SEQ ID NO: 33. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 3 and a VL sequence set forth in SEQ ID NO: 35. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 4 and a VL sequence set forth in SEQ ID NO: 35. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 5 and a VL sequence set forth in SEQ ID NO: 35. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 6 and a VL sequence set forth in SEQ ID NO: 35. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 35. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 3 and a VL sequence set forth in SEQ ID NO: 36. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 4 and a VL sequence set forth in SEQ ID NO: 36. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 5 and a VL sequence set forth in SEQ ID NO: 36. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 6 and a VL sequence set forth in SEQ ID NO: 36. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 36. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 3 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 4 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 5 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 6 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 3 and a VL sequence set forth in SEQ ID NO: 40. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 4 and a VL sequence set forth in SEQ ID NO: 40. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 5 and a VL sequence set forth in SEQ ID NO: 40. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 6 and a VL sequence set forth in SEQ ID NO: 40. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 40. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 8 and a VL sequence set forth in SEQ ID NO: 42. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 9 and a VL sequence set forth in SEQ ID NO: 43. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 44. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 45. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 46. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 47. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 48. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 49. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 50. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 51. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 52. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 53. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 54. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 55. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 56. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 57. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 10 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 11 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 12 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 13 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 14 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 15 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 16 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 17 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 18 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 19 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 20 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 21 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 22 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 23 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 24 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 25 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 26 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 27 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 28 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 28 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 29 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 30 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 31 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 32 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 8 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 8 and a VL sequence set forth in SEQ ID NO: 51. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 3 and a VL sequence set forth in SEQ ID NO: 51.

[00115] In certain embodiments, the isolated antibody comprises a heavy chain variable domain comprising a framework region sequence selected from a sequence set forth in SEQ ID NOs: 198-229, 255-256, 258-259, 261-285, 311-315, 317-342, 368-369, 371-399, and 540-580. In certain embodiments, the isolated antibody comprises a heavy chain variable domain comprising 1, 2, 3, or 4 framework region sequences selected from a sequence set forth in SEQ ID NOs: 198-229, 255-256, 258-259, 261-285, 311-315, 317-342, 368-369, 371-399, and 540-580.

[00116] In certain embodiments, the isolated antibody comprises a light chain variable domain comprising a framework region sequence selected from a sequence set forth in SEQ ID NOs: 230-231, 233-235, 239, 241-254, 286, 288, 290-291, 293, 296-310, 343-345, 347, 400-424, and 581-609. In certain embodiments, the isolated antibody comprises a light chain variable domain comprising 1, 2, 3, or 4 framework region sequences selected from a sequence set forth in SEQ ID NOs: 230-231, 233-235, 239, 241-254, 286, 288, 290-291, 293, 296-310, 343-345, 347, 400-424, and 581-609.

[00117] In certain embodiments, the isolated antibody comprises a heavy chain variable domain comprising 1, 2, 3, or 4 framework region sequences selected from a sequence set forth in SEQ ID NOs: 198-229, 255-256, 258-259, 261-285, 311-315, 317-342, 368-369, 371-399, and 540-580, and comprises a light chain variable domain comprising 1, 2, 3, or 4 framework region sequences selected from a sequence set forth in SEQ ID NOs: 230-231, 233-235, 239, 241-254, 286, 288, 290-291, 293, 296-310, 343-345, 347, 400-424, and 581- 609.

Table 2. Anti-interleukin (IL)-13 antibody VH-VL sequences

*Names correspond with name in informal sequence listing

[00118] In some embodiments, a VH domain listed for any one of Constructs 3-127 and 132-144 in Table 2 can be combined with a heavy chain constant (HC) domain provided herein. In certain embodiments, an anti-IL-13 antibody comprises a VH domain selected from any one the VH domains of Constructs 3-127 and 132-144 in Table 2 or a VH domain having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and a heavy chain constant (HC) domain comprising a sequence selected from any one of SEQ ID NOs: 435-468, 484-539, and 610-709 or an HC domain having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto. Each and every combination of (1) VH/VL listed for Constructs 3-127 and 132-144 in Table 2 and (2) HC domain is contemplated herein. In certain embodiments, the HC domain is an IgGl HC domain.

[00119] In certain embodiments, the HC domain includes IgG4-SP, hlgGl-LALA-YTE, hlgGl-LAGA YTE, hlgGl-LALA-LS, IgG4-YTE HC, and IgG4-LS.

[00120] In some embodiments, such an IgG4-SP HC constant domain has the sequence: ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPRE EQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS RLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 427).

[00121] In some embodiments, such a hlgGl-LALA-YTE HC constant domain has the sequence:

ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP EAAGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE PQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 439). [00122] In some embodiments, such a hlgGl-LAGA YTE HC constant domain has the sequence:

ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP ELAGAPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 440). [00123] In some embodiments, such a hlgGl-LALA-LS HC constant domain has the sequence:

[00124] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV

EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVLHEALHSHYTQKSLSLSPG (SEQ ID NO: 446).

[00125] In some embodiments, such an IgG4-YTE HC constant domain has the sequence: ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ

SSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLG GPSVFLFPPKPKDTLYITREPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPRE EQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS RLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 457).

[00126] In some embodiments, such an IgG4-LS HC constant domain has the sequence: ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ

SSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPRE EQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS RLTVDKSRWQEGNVFSCSVLHEALHSYTQKSLSLSLGK (SEQ ID NO: 460).

[00127] In some embodiments, such a hlgGl-LALA-YTE HC C-terminal lysine variant constant domain has the sequence:

ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP EAAGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE

PQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 624). [00128] In some embodiments, such a hlgGl-LAGA YTE HC C-terminal lysine variant constant domain has the sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP ELAGAPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSRDELTKNQVSLTCLVKGFYPSD1AVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 625).

[00129] In some embodiments, such a hlgGl-LALA-LS HC C-terminal lysine variant constant domain has the sequence:

[00130] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO: 631).

[00131] In some embodiments, a VL domain listed for Constructs 3-127 and 132-144 in Table 2 can be combined with a light chain constant (LC) domain provided herein. In some embodiments, the LC domain is a human kappa LC constant domain. In some embodiments, such a human kappa LC constant domain has the sequence: RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 469).

CDRs

[00132] In some embodiments, an antibody provided herein comprises one to three CDRs of a VH domain selected from SEQ ID NOs: 1-32, such as any of the CDRs listed in Table 3, Table 4, or Table 5, below. In some embodiments, an antibody provided herein comprises two to three CDRs of a VH domain selected from SEQ ID NOs: 1-32. In some embodiments, an antibody provided herein comprises three CDRs of a VH domain selected from SEQ ID NOs: 1-32. In some embodiments, the CDRs are Exemplary CDRs. In some embodiments, the CDRs are Kabat CDRs. In some embodiments, the CDRs are Chothia CDRs. In some embodiments, the CDRs are IMGT CDRs. In some embodiments, the CDRs are AbM CDRs. In some embodiments, the CDRs are Contact CDRs.

[00133] In some embodiments, the CDRs are CDRs having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with a CDR-H1, CDR-H2, or CDR-H3 of SEQ ID NOs: 58-140. In some embodiments, the CDR-H1 is a CDR-H1 of a VH domain selected from SEQ ID NOs: 1-32, with up to 1, 2, 3, 4, or 5 amino acid substitutions. In some embodiments, the CDR-H2 is a CDR-H2 of a VH domain of SEQ ID NO: 1-32, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the CDR-H3 is a CDR-H3 of a VH domain selected from SEQ ID NOs: 1-32, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as “variants.” In some embodiments, such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.

[00134] In some embodiments, an antibody provided herein comprises one to three CDRs of a VL domain of SEQ ID NOs: 33-57, such as any of the CDRs listed in Table 6, Table 7, or Table 8, below. In some embodiments, an antibody provided herein comprises two to three CDRs of a VL domain of SEQ ID NOs: 33-57. In some embodiments, an antibody provided herein comprises three CDRs of a VL domain of SEQ ID NOs: 33-57. In some embodiments, the CDRs are Exemplary CDRs. In some embodiments, the CDRs are Kabat CDRs. In some embodiments, the CDRs are Chothia CDRs. In some embodiments, the CDRs are IMGT CDRs. In some embodiments, the CDRs are AbM CDRs. In some embodiments, the CDRs are Contact CDRs.

[00135] In some embodiments, the CDRs are CDRs having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with a CDR-L1, CDR-L2, or CDR-L3 of SEQ ID NOs: 141-188. In some embodiments, the CDR-L1 is a CDR-L1 of a VL domain of SEQ ID NOs: 33-57, with up to 1, 2, 3, 4, or 5 amino acid substitutions. In some embodiments, the CDR-L2 is a CDR-L2 of a VL domain of SEQ ID NOs: 33-57 , with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the CDR-L3 is a CDR- L3 of a VL domain of SEQ ID NOs: 33-57, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as “variants.” In some embodiments, such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.

[00136] In some embodiments, an antibody provided herein comprises one to three CDRs of a VH domain selected from SEQ ID NOs: 1-32 and one to three CDRs of a VL domain of SEQ ID NOs: 33-57 . In some embodiments, an antibody provided herein comprises two to three CDRs of a VH domain selected from SEQ ID NOs: 1-32 and two to three CDRs of a VL domain of SEQ ID NOs: 33-57. In some embodiments, an antibody provided herein comprises three CDRs of a VH domain selected from SEQ ID NOs: 1-32 and three CDRs of a VL domain of SEQ ID NOs: 33-57. In some embodiments, the CDRs are Exemplary CDRs. In some embodiments, the CDRs are Kabat CDRs. In some embodiments, the CDRs are Chothia CDRs. In some embodiments, the CDRs are IMGT CDRs. In some embodiments, the CDRs are AbM CDRs. In some embodiments, the CDRs are Contact CDRs.

[00137] In some embodiments, an antibody provided herein comprises a CDR-H3 selected of SEQ ID NOs: 112-120 and 130-40. In some embodiments, the CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H3 of SEQ ID NOs: 112-120 or 130-40. In some embodiments, the CDR-H3 is a CDR-H3 selected of SEQ ID NOs: 112-120 and 130-40, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as “variants.” In some embodiments, such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.

[00138] In some embodiments, an antibody provided herein comprises a CDR-H1 of SEQ ID NOs: 58-99 and 121. In some embodiments, the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H1 of SEQ ID NOs: 58-99 or 121. In some embodiments, the CDR-H1 is a CDR-H1 of SEQ ID NOs: 58-99 or 121, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as “variants.” In some embodiments, such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.

[00139] In some embodiments, an antibody provided herein comprises a CDR-H2 of any one of SEQ ID NOs: 100-111. In some embodiments, the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H2 of any one of SEQ ID NOs: 100-111. In some embodiments, the CDR-H2 is a CDR-H2 of any one of SEQ ID NOs: 100-111, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as “variants.” In some embodiments, such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.

[00140] In some embodiments, an antibody provided herein comprises a CDR-L3 selected from SEQ ID NOs: 165-172. In some embodiments, the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L3 of SEQ ID NOs: 165-172. In some embodiments, the CDR-L3 is a CDR-L3 of SEQ ID NOs: 165- 172, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as “variants.” In some embodiments, such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.

[00141] In some embodiments, an antibody provided herein comprises a CDR-L2 selected from SEQ ID NOs: 153-158 and the amino acid sequence LAS. In some embodiments, the CDR-L2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L2 selected from SEQ ID NOs: 153-158 and the amino acid sequence LAS. In some embodiments, the CDR-L2 is a CDR-L2 selected from SEQ ID NOs: 153-158 and the amino acid sequence LAS, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as “variants.” In some embodiments, such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.

[00142] In some embodiments, an antibody provided herein comprises a CDR-L1 selected from SEQ ID NOs: 141-144 and 149-152. In some embodiments, the CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR- L1 selected from SEQ ID NOs: 141-144 and 149-152. In some embodiments, the CDR-L1 is a CDR-L1 selected from SEQ ID NOs: 141-144 and 149-152, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as “variants.” In some embodiments, such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.

[00143] In some embodiments, an antibody provided herein comprises a CDR-H3 selected from SEQ ID NOs: 112-120 and 130-140, a CDR-H2 of SEQ ID NOs: 100-111, a CDR-H1 selected from SEQ ID NOs: 58-99 and 121, a CDR-L3 selected from SEQ ID NOs: 165-172, a CDR-L2 selected from SEQ ID NOs: 153-158 and the amino acid sequence LAS, and a CDR-L1 selected from SEQ ID NOs: 141-144 and 149-152. In some embodiments, the CDR- H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H3 selected from SEQ ID NOs: 112-120 and 130-140, the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H2 of SEQ ID NOs: 100-111, the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H1 selected from SEQ ID NOs: 58-99 and 121, the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L3 selected from SEQ ID NOs: 165-172, the CDR-L2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L2 selected from SEQ ID NOs: 153-158 and the amino acid sequence LAS, and the CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L1 selected from SEQ ID NOs: 141-144 and 149-152. In some embodiments, the CDR-H3 is a CDR-H3 selected from SEQ ID NOs: 112-120 and 130-140, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H2 is a CDR- H2 of SEQ ID NOs: 100-111, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H1 is a CDR-H1 selected from SEQ ID NOs: 58-99 and 121, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L3 is a CDR-L3 selected from SEQ ID NOs: 165-172, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L2 is a CDR-L2 selected from SEQ ID NOs: 153-158 and the amino acid sequence LAS, with up to 1, 2, 3, or 4 amino acid substitutions; and the CDR-L1 is a CDR-L1 selected from SEQ ID NOs: 141-144 and 149- 152, with up to 1, 2, 3, 4, 5, or 6 amino acid substitutions.

[00144] In some embodiments, an antibody provided herein comprises a CDR-H3 of SEQ ID NOs: 112, 121, and 130, a CDR-H2 of SEQ ID NOs: 100, 104, and 108, a CDR-Hl of SEQ ID NOs: 58, 68, and 85, a CDR-L3 of SEQ ID NOs: 168, 173, and 181, a CDR-L2 of SEQ ID NOs: 153 and the amino acid sequence LAS, and a CDR-L1 of SEQ ID NOs: 141 and 149. In some embodiments, the CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H3 of SEQ ID NOs: 112 or 130, the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H2 of SEQ ID NOs: 100, 104 or 108, the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H1 of SEQ ID NOs: 58, 68 or 85, the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L3 of SEQ ID NO: 168, the CDR-L2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L2 of SEQ ID NOs: 153 or the amino acid sequence LAS, and the CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR- L1 of SEQ ID NOs: 141 or 149. In some embodiments, the CDR-H3 is a CDR-H3 of SEQ ID NOs: 112 or 130, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H2 is a CDR-H2 of SEQ ID NOs: 100, 104 or 108, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H1 is a CDR-H1 of SEQ ID NOs: 58, 68 or 85, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L3 is a CDR-L3 of SEQ ID NO: 168 with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L2 is a CDR-L2 of SEQ ID NOs: 153 or the amino acid sequence LAS, with up to 1, 2, 3, or 4 amino acid substitutions; and the CDR-L1 is a CDR-L1 of SEQ ID NOs: 141 or 149, with up to 1, 2, 3, 4, 5, or 6 amino acid substitutions.

[00145] In some embodiments, an antibody provided herein comprises a CDR-H3 of SEQ ID NOs: 112, 121 or 130, a CDR-H2 of SEQ ID NOs: 100, 104 or 108, a CDR-H1 of SEQ ID NOs: 58, 68, or 85, a CDR-L3 of SEQ ID NO: 165, a CDR-L2 of SEQ ID NOs: 153 or the amino acid sequence LAS, and a CDR-L1 of SEQ ID NOs: 141 or 149. In some embodiments, the CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H3 of SEQ ID NOs: 112 or 130, the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H2 of SEQ ID NOs: 100, 104 or 108, the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H1 of SEQ ID NOs: 58, 68 or 85, the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L3 of SEQ ID NO: 165, the CDR-L2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L2 of SEQ ID NOs: 153 or the amino acid sequence LAS, and the CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L1 of SEQ ID NOs: 141 or 149. In some embodiments, the CDR-H3 is a CDR-H3 of SEQ ID NOs: 112 or 130, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H2 is a CDR-H2 of SEQ ID NOs: 100, 104 or 108, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H1 is a CDR-H1 of SEQ ID NOs: 58, 68 or 85, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L3 is a CDR-L3 of SEQ ID NO: 165, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L2 is a CDR-L2 of SEQ ID NO: 153 or the amino acid sequence LAS, with up to 1, 2, 3, or 4 amino acid substitutions; and the CDR-L1 is a CDR-L1 of SEQ ID NOs: 141 or 149, with up to 1, 2, 3, 4, 5, or 6 amino acid substitutions. [00146] In some embodiments, an antibody provided herein comprises a CDR-H3 of SEQ ID NOs: 112 or 130, a CDR-H2 of SEQ ID NOs: 100, 104, or 108, a CDR-H1 of SEQ ID NOs: 58, 68, or 85, a CDR-L3 of SEQ ID NO: 165, a CDR-L2 of SEQ ID NO: 158 or the amino acid sequence LAS, and a CDR-L1 of SEQ ID NOs: 141 or 149. In some embodiments, the CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H3 of SEQ ID NOs: 112 or 130, the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H2 of SEQ ID NOs: 100, 104, orl08, the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H1 of SEQ ID NOs: 58, 68 or 85, the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L3 of SEQ ID NO: 165, the CDR-L2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L2 of SEQ ID NO: 158 or the amino acid sequence LAS, and the CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L1 of SEQ ID NOs: 141 or 149. In some embodiments, the CDR-H3 is a CDR-H3 of SEQ ID NOs: 112 or 130, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H2 is a CDR-H2 of SEQ ID NOs: 100, 104, or 108, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H1 is a CDR-H1 of SEQ ID NOs: 58, 68, or 85, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L3 is a CDR-L3 of SEQ ID NO: 165, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L2 is a CDR-L2 of SEQ ID NO: 158 or the amino acid sequence LAS, with up to 1, 2, 3, or 4 amino acid substitutions; and the CDR-L1 is a CDR- L1 of SEQ ID NOs: 141 or 149, with up to 1, 2, 3, 4, 5, or 6 amino acid substitutions.

[00147] In some embodiments, an antibody provided herein comprises a CDR-H3 of SEQ ID NOs: 112, 121 or 130, a CDR-H2 of SEQ ID NOs: 100, 104 or 108, a CDR-H1 of SEQ ID NOs: 58, 67, or 84, a CDR-L3 of SEQ ID NO: 165, a CDR-L2 of SEQ ID NOs: 153 or the amino acid sequence LAS, and a CDR-L1 of SEQ ID NOs: 141 or 149. In some embodiments, the CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H3 of SEQ ID NOs: 112 or 130, the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H2 of SEQ ID NOs: 100, 104 or 108, the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H1 of SEQ ID NOs: 58, 67 or 84, the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L3 of SEQ ID NO: 165, the CDR-L2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L2 of SEQ ID NOs: 153 or the amino acid sequence LAS, and the CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L1 of SEQ ID NOs: 141 or 149. In some embodiments, the CDR-H3 is a CDR-H3 of SEQ ID NOs: 112 or 130, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H2 is a CDR-H2 of SEQ ID NOs: 100, 104 or 108, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H1 is a CDR-H1 of SEQ ID NOs: 58, 67 or 84, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L3 is a CDR-L3 of SEQ ID NO: 165, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L2 is a CDR-L2 of SEQ ID NO: 153 or the amino acid sequence LAS, with up to 1, 2, 3, or 4 amino acid substitutions; and the CDR-L1 is a CDR-L1 of SEQ ID NOs: 141 or 149, with up to 1, 2, 3, 4, 5, or 6 amino acid substitutions.

[00148] In some embodiments, an antibody provided herein comprises a CDR-H3 of SEQ ID NOs: 112 or 130, a CDR-H2 of SEQ ID NOs: 100, 104, or 108, a CDR-H1 of SEQ ID NOs: 58, 67, or 84, a CDR-L3 of SEQ ID NO: 165, a CDR-L2 of SEQ ID NO: 158 or the amino acid sequence LAS, and a CDR-L1 of SEQ ID NOs: 141 or 149. In some embodiments, the CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H3 of SEQ ID NOs: 112 or 130, the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H2 of SEQ ID NOs: 100, 104, orl08, the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H1 of SEQ ID NOs: 58, 67 or 84, the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L3 of SEQ ID NO: 165, the CDR-L2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L2 of SEQ ID NO: 158 or the amino acid sequence LAS, and the CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L1 of SEQ ID NOs: 141 or 149. In some embodiments, the CDR-H3 is a CDR-H3 of SEQ ID NOs: 112 or 130, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H2 is a CDR-H2 of SEQ ID NOs: 100, 104, or 108, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H1 is a CDR-H1 of SEQ ID NOs: 58, 67, or 84, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L3 is a CDR-L3 of SEQ ID NO: 165, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L2 is a CDR-L2 of SEQ ID NO: 158 or the amino acid sequence LAS, with up to 1, 2, 3, or 4 amino acid substitutions; and the CDR-L1 is a CDR- L1 of SEQ ID NOs: 141 or 149, with up to 1, 2, 3, 4, 5, or 6 amino acid substitutions. [00149] In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this disclosure are referred to herein as “variants” or “clones”. In some embodiments, such variants or clones are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants or cones are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.

[00150] In certain aspects, the antibodies disclosed herein do not include antibodies disclosed in US Patent number 9,067,994.

Table 3. Anti-interleukin (IL)-13 antibody Heavy Chain Kabat CDRs

*Names correspond with name in informal sequence listing.

Table 4. Anti-interleukin (IL)-13 antibody Heavy Chain Chothia CDRs

*Names correspond with name in informal sequence listing.

Table 5. Anti-interleukin (IL)-13 antibody Heavy Chain IMGT CDRs

*Names correspond with name in informal sequence listing.

Table 6. Anti-interleukin (IL)-13 antibody Light Chain Kabat CDRs

*Names correspond with name in informal sequence listing.

Table 7. Anti-interleukin (IL)- 13 antibody Light Chain Chothia CDRs

*Names correspond with name in informal sequence listing.

Table 8. Anti-interleukin (IL)-13 antibody Light Chain IMGT CDRs

*Names correspond with name in informal sequence listing.

[00151] In some embodiments, antibody that binds IL- 13 does not comprise: (a) CDR-H1 set forth in SEQ ID NO: 58; CDR-H2 set forth in SEQ ID NO: 100; CDR-H3 set forth in SEQ ID NO: 112; CDR-L1 set forth in SEQ ID NO: 141; CDR-L2 set forth in SEQ ID NO: 153; and CDR-L3 set forth in SEQ ID NO: 165; or (b) CDR-H1 set forth in SEQ ID NO: 67; CDR-H2 set forth in SEQ ID NO: 104; CDR-H3 set forth in SEQ ID NO: 112; CDR-L1 set forth in SEQ ID NO: 141; CDR-L2 set forth in SEQ ID NO: 153; and CDR-L3 set forth in SEQ ID NO: 165; or

(c) CDR-HI set forth in SEQ ID NO: 84; CDR-H2 set forth in SEQ ID NO: 108; CDR-H3 set forth in SEQ ID NO: 130; CDR-L1 set forth in SEQ ID NO: 149; CDR-L2 set forth in the amino acid sequence LAS; and CDR-L3 set forth in SEQ ID NO: 165.

[00152] In some embodiments, antibody that binds IL- 13 does not comprise any combination of: (a) a CDR-HI set forth in any of SEQ ID NOs: 58, 67, or 84; (b) a CDR-H2 set forth in any of SEQ ID NOs: 100, 104, or 108; (c) a CDR-H3 set forth in any of SEQ ID NOs: 112 or 130;

(d) a CDR-L1 set forth in any of SEQ ID NOs: 141 or 149; (e) a CDR-L2 set forth in any of SEQ ID NOs: 153 or 154; and (f) a CDR-L3 set forth in SEQ ID NO: 165.

Fc Region

[00153] The structures of the Fc regions of various immunoglobulins, and the glycosylation sites contained therein, are known in the art. See Schroeder and Cavacini, J. Allergy Clin. Immunol., 2010, 125:S41-52, incorporated by reference in its entirety. The Fc region may be a naturally occurring Fc region, or an Fc region modified as described in the art or elsewhere in this disclosure.

[00154] Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991. An “Fc polypeptide” of a dimeric Fc as used herein refers to one of the two polypeptides forming the dimeric Fc domain, i. e. a polypeptide comprising C-terminal constant regions of an immunoglobulin heavy chain, capable of stable self-association. For example, an Fc polypeptide of a dimeric IgG Fc comprises an IgG CH2 and an IgG CH3 constant domain sequence. An Fc can be of the class IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGi, IgGi. IgG , IgG₄, IgAi, and IgAo. [00155] The terms “Fc receptor” and “FcR” are used to describe a receptor that binds to the Fc region of an antibody. For example, an FcR can be a native sequence human FcR. Generally, an FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the FcyRI, FcyRII, and FcyRIII subclasses, including allelic variants and alternatively spliced forms of these receptors. FcyRII receptors include FcyRIIA (an “activating receptor”) and FcyRIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof. Immunoglobulins of other isotypes can also be bound by certain FcRs (see, e.g., Janeway et al., Immuno Biology: the immune system in health and disease, (Elsevier Science Ltd., NY) (4th ed., 1999)). Activating receptor FcyRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. Inhibiting receptor FcyRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain (reviewed in Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs, including those to be identified in the future, are encompassed by the term “FcR” herein. The term also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol. 117:587 (1976); and Kim et al., J. Immunol. 24:249 (1994)).

[00156] Modifications in the CH2 domain can affect the binding of FcRs to the Fc. A number of amino acid modifications in the Fc region are known in the art for selectively altering the affinity of the Fc for different Fcgamma receptors. In some aspects, the Fc comprises one or more modifications to promote selective binding of Fc-gamma receptors.

[00157] Exemplary mutations that alter the binding of FcRs to the Fc are listed below: [00158] S298A/E333A/K334A, S298A/E333A/K334A/K326A (Lu Y, Vernes JM, Chiang N, et al. J Immunol Methods . 2011 Feb 28;365(1-2):132-41);

[00159] F243L/R292P/Y300L/V305I/P396L, F243L/R292P/Y300L/L235V/P396L

(Stavenhagen JB, Gorlatov S, Tuaillon N, et al. Cancer Res. 2007 Sep 15;67( 18):8882- 90; Nordstrom JL, Gorlatov S, Zhang W, el al. Breast Cancer Res. 2011 Nov 30;13(6):R123); [00160] F243L (Stewart R, Thom G, Levens M, et al. Protein Eng Des Sei. 2011

Sep;24(9):671-8.), S298A/E333A/K334A (Shields RL, Namenuk AK, Hong K, et al. J Biol Chem. 2001 Mar 2;276(9):6591-604); [00161] S239D/I332E/A330L, S239D/I332E (Lazar GA, Dang W, Karki S, et al. Proc Natl

Acad Sci U SA. 2006 Mar 14;103(ll):4005-10);

[00162] S239D/S267E, S267E/L328F (Chu SY, Vostiar I, Karki S, et al. Mol Immunol. 2008

Sep;45(15):3926-33);

[00163] S239D/D265S/S298A/I332E, S239E/S298A/K326A/A327H, G237F/S298A/A330L/I

332E, S239D/I332E/S298A, S239D/K326E/A330L/I332E/S298A, G236A/S239D/D270L/I332E , S239E/S267E/H268D, L234F/S267E/N325L, G237F/V266L/S267D and other mutations listed in WO2011/120134 and WO2011/120135, herein incorporated by reference. Therapeutic Antibody Engineering (by William R. Strohl and Lila M. Strohl, Woodhead Publishing series in Biomedicine No 11, ISBN 1 907568 37 9, Oct 2012) lists mutations on page 283.

[00164] In certain embodiments an antibody described herein includes modifications designed to improve its ability to mediate effector function. Such modifications are known in the art and include afucosylation, or engineering of the affinity of the Fc towards an activating receptor, mainly FCGR3a for ADCC, and towards Clq for CDC. The following Table 9 summarizes various designs reported in the literature for effector function engineering.

[00165] Methods of producing antibodies with little or no fucose on the Fc glycosylation site (Asn 297 EU numbering) without altering the amino acid sequence are well known in the art. The GlymaX® technology (ProBioGen AG) is based on the introduction of a gene for an enzyme which deflects the cellular pathway of fucose biosynthesis into cells used for antibody production. This prevents the addition of the sugar “fucose” to the N-linked antibody carbohydrate part by antibody-producing cells, (von Horsten et al. (2010) Glycobiology . 2010 Dec; 20 (12): 1607- 18. Another approach to obtaining antibodies with lowered levels of fucosylation can be found in U.S. Patent No. 8,409,572, which teaches selecting cell lines for antibody production for their ability to yield lower levels of fucosylation on antibodies can be fully afucosylated (meaning they contain no detectable fucose) or they can be partially afucosylated, meaning that the isolated antibody contains less than 95%, less than 85%, less than 75%, less than 65%, less than 55%, less than 45%, less than 35%, less than 25%, less than 15% or less than 5% of the amount of fucose normally detected for a similar antibody produced by a mammalian expression system.

[00166] Thus, in one embodiment, an antibody described herein can include a dimeric Fc that comprises one or more amino acid modifications as noted in Table 9 that confer improved effector function. In another embodiment, the antibody can be afucosylated to improve effector function.

Table 9: CH2 domains and effector function engineering

[00167] Fc modifications designed to reduce FcgR and/or complement binding and/or effector function are known in the art. Recent publications describe strategies that have been used to engineer antibodies with reduced or silenced effector activity (see Strohl, WR (2009), Curr Opin Biotech 20:685-691, and Strohl, WR and Strohl LM, “Antibody Fc engineering for optimal antibody performance” In Therapeutic Antibody Engineering, Cambridge: Woodhead Publishing (2012), pp 225-249). These strategies include reduction of effector function through modification of glycosylation, use of IgG2/IgG4 scaffolds, or the introduction of mutations in the hinge or CH2 regions of the Fc. For example, U.S. Patent Publication No. 2011/0212087 (Strohl), International Patent Publication No. WO 2006/105338 (Xencor), U.S. Patent Publication No. 2012/0225058 (Xencor), U.S. Patent Publication No. 2012/0251531 (Genentech), and Strop et al ((2012) J. Mol. Biol. 420: 204-219) describe specific modifications to reduce FcgR or complement binding to the Fc.

[00168] Specific, non-limiting examples of known amino acid modifications designed to reduce FcgR or complement binding to the Fc include those identified in the following Table 10: Table 10: Modifications to reduce FcgR or complement binding to the Fc

[00169] Methods of producing antibodies with little or no fucose on the Fc glycosylation site (Asn 297 EU numbering) without altering the amino acid sequence are well known in the ait. The GlymaxX® technology (ProBioGen AG) is based on the introduction of a gene for an enzyme which deflects the cellular pathway of fucose biosynthesis into cells used for antibody production. This prevents the addition of the sugar “fucose” to the N-linked antibody carbohydrate part by antibody-producing cells, (von Horsten et al. (2010) Glycobiology . 2010 Dec; 20 (12): 1607- 18.) Examples of cell lines capable of producing defucosylated antibody include CHO-DG44 with stable overexpression of the bacterial oxidoreductase GDP-6-deoxy-D- lyxo-4-hexylose reductase (RMD) (see Henning von Horsten et al., Glycobiol 2010, 20:1607- 1618) or Lecl3 CHO cells, which are deficient in protein fucosylation see Ripka et al., Arch. Biochem. Biophys., 1986, 249:533-545; U.S. Pat. Pub. No. 2003/0157108; WO 2004/056312; each of which is incorporated by reference in its entirety), and knockout cell lines, such as alpha- 1,6-fucosyltransferase gene or FUT8 knockout CHO cells (see Yamane-Ohnuki et al., Biotech. Bioeng., 2004, 87: 614-622; Kanda et al., Biolechnol. Bioeng., 2006, 94:680-688; and WO 2003/085107; each of which is incorporated by reference in its entirety). Another approach to obtaining antibodies with lowered levels of fucosylation can be found in U.S. Patent No. 8,409,572, which teaches selecting cell lines for antibody production for their ability to yield lower levels of fucosylation on antibodies.

[00170] Examples of cell lines capable of producing defucosylated antibody include CHO- DG44 with stable overexpression of the bacterial oxidoreductase GDP-6-deoxy-D-lyxo-4- hexylose reductase (RMD) (see Henning von Horsten et al., Glycobiol 2010, 20:1607-1618) or Lecl3 CHO cells, which are deficient in protein fucosylation (see Ripka et al., Arch. Biochem. Biophys., 1986, 249:533-545; U.S. Pat. Pub. No. 2003/0157108; WO 2004/056312; each of which is incorporated by reference in its entirety), and knockout cell lines, such as alpha- 1,6- fucosyltransferase gene or FUT8 knockout CHO cells (see Yamane-Ohnuki et al., Biotech. Bioeng., 2004, 87: 614-622; Kanda et al., Biotechnol. Bioeng., 2006, 94:680-688; and WO 2003/085107; each of which is incorporated by reference in its entirety).

[00171] Antibodies can be fully afucosylated (meaning they contain no detectable fucose) or they can be partially afucosylated, meaning that the isolated antibody contains less than 95%, less than 85%, less than 75%, less than 65%, less than 55%, less than 45%, less than 35%, less than 25%, less than 15% or less than 5% of the amount of fucose normally detected for a similar antibody produced by a mammalian expression system.

[00172] In some aspects, an antibody provided herein comprises an IgGl domain with reduced fucose content at position Asn 297 compared to a naturally occurring IgGl domain. Such Fc domains are known to have improved ADCC. See Shields et al., J. Biol. Chem., 2002, 277:26733-26740, incorporated by reference in its entirety. In some aspects, such antibodies do not comprise any fucose at position Asn 297. The amount of fucose may be determined using any suitable method, for example as described in WO 2008/077546, incorporated by reference in its entirety.

[00173] In certain embodiments, an antibody provided herein comprises an Fc region with one or more amino acid substitutions which improve ADCC, such as a substitution at one or more of positions 298, 333, and 334 of the Fc region. In certain embodiments, an antibody provided herein comprises an Fc region with one or more amino acid substitutions at positions 239, 332, and 330, as described in Lazar et al., Proc. Natl. Acad. Sci. USA, 2006,103:4005-4010, incorporated by reference in its entirety.

[00174] Other illustrative glycosylation variants which may be incorporated into the antibodies provided herein are described, for example, in U.S. Pat. Pub. Nos. 2003/0157108, 2004/0093621, 2003/0157108, 2003/0115614, 2002/0164328, 2004/0093621, 2004/0132140, 2004/0110704, 2004/0110282, 2004/0109865; International Pat. Pub. Nos. 2000/61739, 2001/29246, 2003/085119, 2003/084570, 2005/035586, 2005/035778; 2005/053742, 2002/031140; Okazaki et al., J. Mol. Biol., 2004, 336:1239-1249; and Yamane-Ohnuki et al., Biotech. Bioeng., 2004, 87: 614-622; each of which is incorporated by reference in its entirety. [00175] In certain embodiments, an antibody provided herein comprises an Fc region with at least one galactose residue in the oligosaccharide attached to the Fc region. Such antibody variants may have improved CDC function. Examples of such antibody valiants are described, for example, in WO 1997/30087; WO 1998/58964; and WO 1999/22764; each of which his incorporated by reference in its entirety.

[00176] In certain embodiments, an antibody provided herein comprises one or more alterations that improves or diminishes Clq binding and/or CDC. See U.S. Pat. No. 6,194,551; WO 99/51642; and Idusogie et al., J. Immunol., 2000, 164:4178-4184; each of which is incorporated by reference in its entirety.

[00177] In certain embodiments, the heavy chain comprises a constant heavy chain sequence set forth in SEQ ID NO: 439 or SEQ ID NO: 624.

[00178] In certain embodiments, the isolated antibody described herein comprises a constant light chain sequence set forth in SEQ ID NO: 469.

[00179] In certain embodiments, the isolated antibody comprises a constant heavy chain sequence selected from SEQ ID NO: 439 and 624 and a constant light chain sequence comprising SEQ ID NO: 469, wherein the antibody further comprises a VH comprising an amino acid sequence having at least 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3 and a VL comprising an amino acid sequence at least 95% 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 39.

[00180] In certain embodiments, the isolated antibody comprises a constant heavy chain sequence selected from SEQ ID NO: 439 and 624 and a constant light chain sequence comprising SEQ ID NO: 469, wherein the antibody further comprises a VH comprising an amino acid sequence having at least 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3 and a VL comprising an amino acid sequence at least 95% 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 39, wherein the VH comprises a HCDR1 comprising SEQ ID NO: 58, SEQ ID NO: 68, or SEQ ID NO: 85; a HCDR2 comprising SEQ ID NO: 100, SEQ ID NO: 104, or SEQ ID NO: 108; and a HCDR3 comprising SEQ ID NO: 112 or SEQ ID NO: 130; and the VL comprises a LCDR1 comprising SEQ ID NO: 141 or SEQ ID NO: 149; a LCDR2 comprising SEQ ID NO: 153 or SEQ ID NO: 164, and a LCDR3 comprising SEQ ID NO: 165. [00181] In certain embodiments, the anti-IL-13 antibody comprises a light chain comprising a VL comprising SEQ ID NO: 39 and a light chain constant region comprising SEQ ID NO: 469 and a heavy chain comprising a VH comprising SEQ ID NO: 3 and a heavy chain constant region comprising SEQ ID NO: 624. In certain embodiments, the composition further comprises an antibody having a light chain comprising a VL comprising SEQ ID NO: 39 and a light chain constant region comprising SEQ ID NO: 469 and a heavy chain comprising a VH comprising SEQ ID NO: 3 and a heavy chain constant region comprising SEQ ID NO: 439.

[00182] In certain embodiments, the Fc region comprises one or more amino acid substitutions, wherein the one or more substitutions result in increased antibody half-life, increased ADCC activity, increased ADCP activity, or increased CDC activity compared with the Fc without the one or more substitutions. In certain embodiments, the one or more amino acid substitutions results in increased antibody half-life at pH 6.0 compared to an antibody comprising a wild-type Fc region.

[00183] In certain embodiments, the one or more amino acid substitutions is selected from the group consisting of S228P (SP); M252Y, S254T, T256E, T256D, T250Q, H285D, T307A, T307Q, T307R, T307W, L309D, Q411H, Q311V, A378V, E380A, M428L, N434A, N434S, N297A, D265A, L234A, L235A, and N434W. In certain embodiments, the one or more amino acid substitutions comprises a plurality of amino acid substitutions selected from the group consisting of M428L/N434S (LS); M252Y/S254T/T256E (YTE); T250Q/M428L;

T307A/E380A/N434A; T256D/T307Q (DQ); T256D/T307W (DW); M252Y/T256D (YD);

T307Q/Q311V/A378V (QVV); T256D/H285D/T307R/Q311V/A378V (DDRVV); L309D/Q311H/N434S (DHS); S228P/L235E (SPLE); L234A/L235A (LA), M428L/N434A L234A/G237A (LALA), L234A/L235A/G237A, L234A/L235A/P329G, N297A, D265A/YTE, LALA/YTE, LAGA/YTE, LALAGA/YTE, LALAPG/YTE, N297A/LS; D265A/LS; LALA/LS; LALAGA/LS; LALAPG/LS; N297A/DHS; D265A/DHS; LALA/DHS; LAGA/DHS;

LALAGA/DHS; LALAPG/DHS; SP/YTE; SPLE/YTE; SP/LS; SPLE/LS, SP/DHS; SPLE/DHS; N297A/LA; D265A/LA, LALA/LA, LAGA/LA, LALAGA/LA, LALAPG/LA, N297A/N434A; D265A/N434A; LALA/N434A, LAGA/N434A, LALAGA/N434A, LALAPG/N434A, N297A/N434W, D265A/N434W, LALA/N434W, LAGA/N434W, LALAGA/N434W, LALAPG/N434W, N297A/DQ, D265A/DQ, LALA/DQ, LAGA/DQ, LALAGA/DQ, LALAPG/DQ, N297A/DW, D265A/DW, LALA/DW, LAGA/DW, LALAGA/DW, LALAPG/DW N297A/YD, D265A/YD, LALA/YD, LAGA/YD, LALAGA/YD, LALAPG/YD, T307Q/Q311V/A378V (QVV), N297A/QVV, D265A/QVV, LALA/QVV, LAGA/QVV, LALAGA/QVV, LALAPG/QVV, DDRVV, N297A/DDRVV, D265A/DDRVV, LALA/DDRVV, LAGA/DDRVV, LALAGA/DDRVV, and LALAPG/DDRVV.

[00184] In certain embodiments, the antibodies described herein comprise an Fc region with YTE mutations at positions 253, 255, and 257. In certain embodiments, the antibodies described herein comprise an Fc region with LALA mutations at positions 235 and 236, respectively. In certain embodiments, the antibodies described herein comprise an Fc region with YTE mutations at positions 253, 255 and 257 and with LALA mutations at positions 235 and 236. In certain embodiments, the antibodies described herein comprise the heavy and light chain variable regions of Construct 133 and an Fc region comprising YTE mutations at positions 253, 255 and 257, respectively and with LALA mutations at positions 235 and 236, respectively.

[00185] In certain embodiments, the antibodies described herein comprise a human IgGl Fc with LALA mutations. In certain embodiments, the antibodies described herein comprise a human IgGl Fc with YTE mutations. In certain embodiments, the antibodies described herein comprise a human IgGl Fc with LALA and YTE mutations. In certain embodiments, when direct numbering is used these “YTE” and “LALA” mutations can be located at different amino acid position numbers. For example, in one embodiment, the human Fc region comprises a human IgGl Fc with LALA mutations at L235A/L236A and/or YTE mutations at M253Y/S255T/T257E.

[00186] In certain embodiments, the Fc region binds an Fey Receptor selected from the group consisting of: FcyRI, FcyRIIa, FcyRIIb, FcyRIIc, FcyRIIIa, and FcyRIIIb. In certain embodiments, the Fc region binds an Fey Receptor with higher affinity at pH 6.0 compared to an antibody comprising a wild-type Fc region.

Modifications

YTE Substitutions

[00187] In certain embodiments, the fragment crystallizable region (Fc region) of the anti-IL- 13 antibody described herein carries a triple substitution M252Y/S254T/T256E (YTE) designed to increase the half-life of the IgG. In certain embodiments, the Fc region of the anti-IL-13 antibody described herein carries a triple substitution M253Y/S255T/T257E (YTE) designed to increase the half-life of the IgG. YTE substitutions (also referred to herein as YTE mutations) can increase the binding of the modified IgG to the human neonatal Fc receptor (FcRn). FcRn- bound IgG is recycled via lysosomal salvage, resulting in the IgG returning to the circulation. Thus, the YTE mutations confer greater FcRn-IgG binding, prolonging the IgG serum half-life compared to an unmodified IgG.

LALA Substitutions

[00188] In certain embodiments, the anti-IL-13 antibodies described herein additionally carry Fc region amino acid substitutions L234A/L235A or L235A/L236A in the IgGl heavy chain, commonly called LALA substitutions or LALA mutations. These changes can impair Fc receptor binding to IgG and prevent undesired effector cell activation.

Binding

[00189] In certain embodiments, an anti-IL-13 antibody described herein is a high-affinity IgGl humanized monoclonal antibody (mAb) that binds IL-13. In certain embodiments, the anti- IL-13 antibody described herein comprises a IgGl constant region comprising YTE substitutions and LALA substitutions. [00190] Without wishing to be bound by theory, the binding of the anti-IL-13 antibodies described herein to IL- 13 is believed to prevent the formation of the IL-13Ral/IL-4Ra active receptor heterodimer and subsequent IL- 13 -mediated signaling. The direct consequences of IL- 13 signaling in atopic dermatitis (AD) pathology include dermal thickening, increased CD4⁺ T cell infiltration, and dermal barrier disruption. Consequently, preventing receptor heterodimer formation is believed to decrease the clinical severity of AD.

[00191] The affinity of a molecule X for its partner Y can be represented by the dissociation equilibrium constant (KD). The kinetic components that contribute to the dissociation equilibrium constant are described in more detail below. Affinity can be measured by common methods known in the art, including those described herein, such as surface plasmon resonance (SPR) technology (e.g., BIACORE®) or biolayer interferometry (e.g., FORTEBIO®).

[00192] With regard to the binding of an antibody to a target molecule, the terms “bind,” “specific binding,” “specifically binds to,” “specific for,” “selectively binds,” and “selective for” a particular antigen (e.g., a polypeptide target) or an epitope on a particular antigen mean binding that is measurably different from a non-specific or non-selective interaction (e.g., with a nontarget molecule). Specific binding can be measured, for example, by measuring binding to a target molecule (i.e., IL- 13) and comparing it to binding to a non-target molecule. Specific binding can also be determined by competition with a control molecule that mimics the epitope recognized on the target molecule. In that case, specific binding is indicated if the binding of the antibody to the target molecule is competitively inhibited by the control molecule. In certain embodiments, the affinity of an anti-IL-13 antibody for a non-target molecule is less than about 50% of the affinity for IL- 13. In certain embodiments, the affinity of an anti-IL-13 antibody for a non-target molecule is less than about 40% of the affinity for IL- 13. In certain embodiments, the affinity of an anti-IL-13 antibody for a non-target molecule is less than about 30% of the affinity for IL- 13. In certain embodiments, the affinity of an anti-IL-13 antibody for a non-target molecule is less than about 20% of the affinity for IL- 13. In certain embodiments, the affinity of an anti-IL-13 antibody for a non-target molecule is less than about 10% of the affinity for IL- 13. In certain embodiments, the affinity of an anti- IL- 13 antibody for a non-target molecule is less than about 1% of the affinity for IL-13. In certain embodiments, the affinity of an anti-IL-13 antibody for a non-target molecule is less than about 0.1% of the affinity for IL-13. [00193] When used herein in the context of two or more antibodies, the term “competes with” or “cross-competes with” indicates that the two or more antibodies compete for binding to an antigen e.g., IL-13). In one exemplary assay, IL-13 is coated on a surface and contacted with a first anti-IL-13 antibody, after which a second anti-IL-13 antibody is added. In another exemplary assay, a first anti-IL-13 antibody is coated on a surface and contacted with IL-13, and then a second anti-IL-13 antibody is added. If the presence of the first anti-IL-13 antibody reduces binding of the second anti-IL-13 antibody, in either assay, then the antibodies compete with each other. The term “competes with” also includes combinations of antibodies where one antibody reduces binding of another antibody, but where no competition is observed when the antibodies are added in the reverse order. However, in certain embodiments, the first and second antibodies inhibit binding of each other, regardless of the order in which they are added. In certain embodiments, one antibody reduces binding of another antibody to its antigen by at least 25%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% as measured in a competitive binding assay. A skilled artisan can select the concentrations of the antibodies used in the competition assays based on the affinities of the antibodies for IL- 13 and the valency of the antibodies. The assays described in this definition are illustrative, and a skilled artisan can utilize any suitable assay to determine if antibodies compete with each other. Suitable assays are described, for example, in Cox et al., “Immunoassay Methods,” in Assay Guidance Manual [Internet], Updated December 24, 2014 (ncbi.nlm.nih.gov/books/NBK92434/; accessed September 29, 2015); Silman et al., Cytometry, 2001, 44:30-37; and Finco et al., J. Pharm. Biomed. Anal., 2011, 54:351-358; each of which is incorporated by reference in its entirety.

[00194] A test antibody competes with a reference antibody if an excess of a test antibody (e.g., at least 2x, 5x, lOx, 20x, or lOOx) inhibits or blocks binding of the reference antibody by, e.g., at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as measured in a competitive binding assay. Antibodies identified by competition assay (competing antibody) include antibodies binding to the same epitope as the reference antibody and antibodies binding to an adjacent epitope sufficiently proximal to the epitope bound by the reference antibody for steric hindrance to occur. For example, a second, competing antibody can be identified that competes for binding to IL- 13 with a first antibody described herein. In certain instances, the second antibody can block or inhibit binding of the first antibody by, e.g., at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as measured in a competitive binding assay. In certain instances, the second antibody can displace the first antibody by greater than 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%.

[00195] In certain embodiments, the antibody binds an IL- 13 sequence set forth in SEQ ID NOs: 472-475.

[00196] In certain embodiments, the antibody binds to an IL- 13 sequence set forth in SEQ ID NOs: 472-475 with a KD of less than or equal to about 1, 2, 3, 4, 5, 6, 7, 8, 9 x 10'⁹ M, as measured by surface plasmon resonance (SPR). In certain embodiments, the antibody binds to an IL-13 sequence set forth in SEQ ID NOs: 472-475 with a KD of less than or equal to about 1 x 10‘¹⁰M, as measured by surface plasmon resonance (SPR). In certain embodiments, the antibody binds to human IL- 13 with a KD of less than or equal to about 1 x 10‘⁹ M, as measured by surface plasmon resonance (SPR).

[00197] In certain embodiments, an antibody provided herein binds IL-13 with a KD of less than or equal to about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.95, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 x 10’⁸ M, as measured by ELISA or any other suitable method known in the art. In certain embodiments, an antibody provided herein binds IL- 13 with a KD of less than or equal to about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.95, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 x 10’⁹ M, as measured by ELISA or any other suitable method known in the art.

[00198] In certain embodiments, the KD of an antibody provided herein for the binding of IL- 13 is between about 0.001-0.01, 0.01-0.1, 0.01-0.05, 0.05-0.1, 0.1-0.5, 0.5-1, 0.25-0.75, 0.25-0.5, 0.5-0.75, 0.75-1, 0.75-2, 1.1-1.2, 1.2-1.3, 1.3-1.4, 1.4-1.5, 1.5-1.6, 1.6-1.7, 1.7-1.8, 1.8-1.9, 1.9-2, 1-2, 1-5, 2-7, 3-8, 3-5, 4-6, 5-7, 6-8, 7-9, 7-10, or 5-10 x 10‘⁸ M, as measured by ELISA or any other suitable method known in the art. In certain embodiments, an antibody provided herein binds IL- 13 with a KD of less than or equal to about 1 x 10'⁸ M, or less than or equal to above 1 x 10‘⁹ M as measured by ELISA or any other suitable method known in the art.

[00199] In certain embodiments, an antibody provided herein binds IL- 13 with a KD of less than or equal to about 10, 9, 8, 7, 6, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.98, 1.95, 1.9, 1.85, 1.8, 1.75, 1.7, 1.65, 1.6, 1.55, 1.50, 1.45, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.85, 0.8, 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, 0.05, 0.01, 0.005, 0.001, 0.0005, or 0.0001 x 10’⁸ M, or less, as measured by ELISA or any other suitable method known in the art . In certain embodiments, an antibody provided herein binds IL- 13 with a KD between 5-3, 4-2, 3-1, 1.9-1.8, 1.8-1.7, 1.7-1.6, 1.6-1.5, 1.9-1.5, 1.5-1, 1-0.8, 1-0.5, 0.9-0.6, 0.7-0.4, 0.6-0.2, 0.5-0.3, 0.3-0.2, 0.2-0.1, 0.1-0.01, 0.01-0.001, or 0.001-0.0001 x 10’⁸ M as measured by ELISA or any other suitable method known in the art.

Antibody Compositions

[00200] Human IgG typically is produced with a C-terminal lysine, given that IgG heavy chain genes encode a C-terminal lysine. However, the C-terminal lysine is often cleaved off by intracellular carboxypeptidases during antibody bioproduction in cell culture. C-terminal lysine clipping is also observed in serum (Cai et al., Biotechnol. Bioeng. 2011; 108:404- 12). While the absence of the C-terminal lysine reportedly does not induce conformational changes to antibody structure and was thought to have no impact on activity (e.g., CDC), recent studies suggest that antibodies lacking the C-terminal lysine had higher CDC activity compared to the corresponding antibody with the C-terminal lysine (van den Bremer ET. MAbs 2Qi5', .fil 2, Tang et al., MAbs 2013;5: 114; Biotechnol. J. 2018;13:1700476). Binding of antibodies to FcgRIIIa-Vall76 and human FcRn does not appeal’ to be altered by C-terminal lysine clipping (Faid et al., Ear. J. Pharm. Sci. 2021; 159: 105730). In certain contexts, the expression of antibodies in recombinant cells lines with a heavy chain that does not encode a C-terminal lysine have been shown to have lower specific productivities compared to cell lines that express a heavy chain that encode a C- terminal lysine, potentially due to slower heavy chain synthesis and faster antibody degradation (Hu et al., Biotechnol. Prog. 2017;33:786-94) or altered interactions between C-terminal amino acid sequences and ribosomes (Owen et al., J. Biotechnol. 2023;374:38-48).

[00201] The level of C-terminal lysine in antibodies produced in recombinant cell lines can vary based on the cell line used and the cell culture process conditions (Dick et al. (2008) Biotechnol. Bioeng. 100(6): 1132- 1143; Shah et al. (2022) J. Pharm. Sci. l l l(9):2445-2450). For example, C-terminal lysine levels in Chinese Hamster Ovary (CHO) cell lines are typically low (<20%) and often <5% of the original level.

[00202] Theoretically, an antibody heavy chain can have no C-terminal lysine (e.g., both heavy chains lacking a C-terminal lysine in an antibody having two heavy chains), one C- terminal lysine on either heavy chain, or a C-terminal lysine on both heavy chains (i.e., two C- terminal lysines). When a bateh of antibody has <5% C-terminal lysine, antibodies with two C- terminal lysines are rare; the predominant species of lysine-containing antibody in such batches is an antibody with one C-terminal lysine. When C-terminal lysine is being quantified, depending on the method used, the result may not differentiate between one lysine and two lysines, but rather whether the antibody has a C-terminal lysine or not. Methods to differentiate between different C-terminal lysine containing species of antibody include, e.g., charged based analytical methods such as ion exchange chromatography (e.g., IEF, cIEF, CEX) (see, e.g., WO2013/158273, the contents of which are herein incorporated by reference in its entirety). Methods such as mass spectrometry and peptide mapping including those described in the Examples, e.g., LC-MS/MS, are also suitable for analyzing whether C-terminal lysines are present on heavy chains.

[00203] In certain aspects, the present disclosure relates to compositions comprising a mixture of anti-interleukin 13 (IL- 13) antibodies, wherein a portion of the anti-IL-13 antibodies comprise a C-terminal lysine (“C-terminal lysine antibodies” or “C-terminal antibodies”) and a portion lack a C-terminal lysine (“non-C-terminal lysine antibodies” or “non-C-terminal antibodies”). The percentage of C-terminal lysine antibodies and non-C-terminal lysine antibodies can vary depending upon the cell line used and the cell culture process conditions. For example, in certain embodiments, between about between about 0.01% and about 50% of the antibodies are C- terminal antibodies, 0.01% and about 20% of the antibodies are C-terminal antibodies, between about 0.01% and about 10% of the antibodies are C-terminal antibodies, between about 0.01% and about 1% of the antibodies are C-terminal antibodies, between about 0.1% and about 50% of the antibodies are C-terminal antibodies, between about 0.1% and about 30% of the antibodies are C-terminal antibodies, between about 0.1% and about 20% of the antibodies are C-terminal antibodies, between about 0.1% and about 10% of the antibodies are C-terminal antibodies, between about 0.1% and about 1% of the antibodies are C-terminal antibodies, between about 0.5% and about 50% of the antibodies are C-terminal antibodies, between about 0.5% and about 30% of the antibodies are C-terminal antibodies, between about 0.5% and about 20% of the antibodies are C-terminal antibodies, between about 0.5% and about 10% of the antibodies are C-terminal antibodies, between about 0.5% and about 5% of the antibodies are C-terminal antibodies, between about 0.5% and about 1% of the antibodies are C-terminal antibodies, between about 1% and about 50% of the antibodies are C-terminal antibodies, between about 1% and about 30% of the antibodies are C-terminal antibodies, between about 1% and about 20% of the antibodies are C-terminal antibodies between about 1% and about 10% of the antibodies are C-terminal antibodies, or between about 1% and about 5% of the antibodies are C-terminal antibodies, between about 5% and about 50% of the antibodies are C-terminal antibodies, between about 5% and about 30% of the antibodies are C-terminal antibodies, between about 5% and about 20% of the antibodies are C-terminal antibodies between about 5% and about 10% of the antibodies are C-terminal antibodies, between about 10% and about 50% of the antibodies are C-terminal antibodies, between about 10% and about 30% of the antibodies are C-terminal antibodies, or between about 10% and about 20% of the antibodies are C-terminal antibodies. [00204] Some antibodies have high retention of C-terminal lysine, e.g., depending on the conditions of preparation or cell culture conditions used. For example, PCT Publication WO2013/158273, the contents of which are herein incorporated by reference in its entirety, describes a percentage range of C-terminal lysine containing adalimumab of about 7.2% up to about 26.6% (19.5% Lysl and 7.1% Lys2 from Figure 17 of WO2013/158273) based on different cell lines and cell culture conditions (e.g., different concentrations of arginine). Accordingly, in certain embodiments, a batch of antibody is made with a C-terminal lysine on the input sequence and the resulting output is a mixture of antibody containing greater than 5%, greater than 6%, greater than 7%, greater than 8%, greater than 9%, greater than 10%, greater than 11%, greater than 12%, greater than 13%, greater than 14%, greater than 15%, greater than 16%, greater than 17%, greater than 18%, greater than 19%, greater than 20%, greater than 21%, greater than 22%, greater than 23%, greater than 24%, greater than 25%, greater than 26%, greater than 27%, greater than 28%, greater than 29%, or greater than 30% of antibody having a C-terminal lysine. In another embodiment, the output mixture contains 5-30%, 5-25%, 5-20%, 5-15%, 5-10%, 10-30%, 10-25%, 10-20%, 10-15%, 15-30%, 15-25%, 15-20%, 20-30%, 20- 25%, or 25-30% of antibody having a C-terminal lysine. In another embodiment, the output mixture contains about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30% of antibody having a C-terminal lysine. In another embodiment, the output mixture contains 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%, or 30% of antibody having a C-terminal lysine.

[00205] In certain embodiments, each of the non-C-terminal and C-terminal antibodies comprises:

(i) a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and

(ii) a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; wherein:

(a) CDR-H1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 58-99 and 121;

(b) CDR-H2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 100-111;

(c) CDR-H3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 112-120 and 130-140,

(d) CDR-L1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 141-144 and 149-152,

(e) CDR-L2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 153-158 and the amino acid sequence LAS; and

(f) CDR-L3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 165-172.

[00206] In certain embodiments, each C-terminal antibody comprises a heavy chain constant domain comprising a sequence selected from the sequences set forth in SEQ ID NOs: 610-709. In certain embodiments, each C-terminal antibody comprises a heavy chain constant domain comprising a sequence selected from the sequences set forth in SEQ ID NOs: 610, 614-641, and 651-709.

[00207] In certain embodiments, the anti-IL-13 antibodies comprise a VH sequence selected from the sequences set forth in any one of SEQ ID NOs: 1-32. In certain embodiments, the anti- IL-13 antibodies comprise a VL sequence selected from the sequences set forth in any one of SEQ ID NOs: 33-57. In certain embodiments, the anti-IL-13 antibodies comprise a VH sequence selected from the sequences set forth in any one of SEQ ID NOs: 1-32 and a VL sequence selected from the sequences set forth in any one of SEQ ID NOs: 33-57. In certain embodiments, the anti-IL-13 antibodies comprise a VH comprising an amino acid sequence as set forth in SEQ ID NO: 3 and a VL comprising an amino acid sequence as set forth in SEQ ID NO: 39. In certain embodiments, the anti-IL-13 antibodies comprise a light chain constant region comprising SEQ ID NO: 469. In certain embodiments, the heavy chain constant region of the C-terminal antibody is SEQ ID NO: 624, and the heavy chain constant region of the non-C- terminal antibody is SEQ ID NO: 439.

[00208] In certain embodiments, the composition comprises an anti-IL-13 antibody having a light chain comprising a VL comprising SEQ ID NO: 39 and a light chain constant region comprising SEQ ID NO: 469 and a heavy chain comprising a VH comprising SEQ ID NO: 3 and a heavy chain constant region comprising SEQ ID NO: 624. In certain embodiments, the composition further comprises an antibody having a light chain comprising a VL comprising SEQ ID NO: 39 and a light chain constant region comprising SEQ ID NO: 469 and a heavy chain comprising a VH comprising SEQ ID NO: 3 and a heavy chain constant region comprising SEQ ID NO: 439.

[00209] In another aspect, the disclosure relates to a composition comprising a mixture of anti-interleukin 13 (IL- 13) antibodies, wherein the mixture comprises a first IL- 13 antibody and a second IL-13 antibody. In certain embodiments, each antibody comprises at least one heavy chain, and the first antibody and the second antibody are identical except that the first antibody comprises a lysine at the C-terminus of the at least one heavy chain, and the second antibody lacks the lysine at the C-terminus of the at least one heavy chain. In certain embodiments, each antibody comprises:

(i) a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and

(ii) a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; wherein:

(a) CDR-H1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 58-99 and 121;

(b) CDR-H2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 100-111;

(c) CDR-H3 comprises a sequence selected from the sequences set forth in SEQ

ID NOs: 112-120 and 130-140, (d) CDR-L1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 141-144 and 149-152,

(e) CDR-L2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 153-158 and the amino acid sequence LAS; and

(f) CDR-L3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 165-172.

[00210] In certain embodiments, the first antibody comprises a heavy chain constant domain comprising a sequence selected from the sequences set forth in SEQ ID NOs: 610-709. In certain embodiments, each C-terminal antibody comprises a heavy chain constant domain comprising a sequence selected from the sequences set forth in SEQ ID NOs: 610, 614-641, and 651-709. In certain embodiments, each C-terminal antibody having at least one C-terminal lysine comprises a heavy chain constant domain having a means for enhancing the half-life of the C-terminal antibody.

[00211] In certain embodiments, each anti-IL-13 antibody comprises a VH sequence selected from the sequences set forth in any one of SEQ ID NOs: 1-32. In certain embodiments, each anti-IL-13 antibody comprises a VL sequence selected from the sequences set forth in any one of SEQ ID NOs: 33-57. In certain embodiments, each anti-IL-13 antibody comprises a VH sequence selected from the sequences set forth in any one of SEQ ID NOs: 1-32 and a VL sequence selected from the sequences set forth in any one of SEQ ID NOs: 33-57. In certain embodiments, each anti-IL-13 antibody comprises a VH comprising an amino acid sequence as set forth in SEQ ID NO: 3 and a VL comprising an amino acid sequence as set forth in SEQ ID NO: 39. In certain embodiments, each antibody comprises a light chain constant region comprising SEQ ID NO: 469.

Pharmaceutical Formulations

[00212] In some embodiments, the present disclosure provides pharmaceutical formulations that comprise a therapeutically effective amount of an IL- 13 antibody disclosed herein. The pharmaceutical formulation comprises one or more excipients and is maintained at a certain pH. Non-limiting examples of an “excipient,” as used herein, include any non-therapeutic agent added to the formulation to provide a desired physical or chemical property, for example, pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption, or penetration.

Excipients and pH

[00213] Excipients may be selected for their suitability for intravenous or subcutaneous administration, providing the necessary stabilizing, buffering capacity, and tonicity. The formulation can improve the stability of the anti-IL-13 and can provide a sterile solution suitable for subcutaneous or intravenous administration. In some embodiments the excipients contained in the formulation are pharmacopoeial grade excipients. In some embodiments, the excipients in the formulation comprise a histidine buffer, an acetate buffer, or a succinate buffer; arginine and/or methionine or a salt solution thereof; and a polysorbate. In some embodiments, the formulation further comprises a sugar or sugar alcohol.

[00214] The one or more excipients in the pharmaceutical formulation of the present invention can comprise a buffering agent. The term “buffering agent,” as used herein, refers to one or more components that when added to an aqueous solution is able to protect the solution against variations in pH when adding acid or alkali, or upon dilution with a solvent. In addition to histidine buffers, acetate buffers, and succinate buffers, in certain embodiments, phosphate buffers, glycinate buffers, carbonate buffers, citrate buffers and the like can be used. In some embodiments, sodium, potassium or ammonium ions can serve as counterion.

[00215] In certain embodiments, the buffer or buffer system, such as a histidine buffer, acetate buffer, or succinate buffer, comprises at least one buffer that has a buffering range that overlaps fully or in part with the range of between 5.5 and 6.5 (e.g., between 5.6 and 6.4, 5.7 and 6.3, 5.6 and 5.9, and 5.7 and 5.8). In some embodiments, the pH is between 5.6 and 5.9. In some embodiments, the pH is between 5.7 and 5.8.

[00216] In some embodiments, the buffer has a pH of about 5.5. In some embodiments, the buffer has a pH of about 5.6. In some embodiments, the buffer has a pH of about 5.7. In some embodiments, the buffer has a pH of about 5.8. In some embodiments, the buffer has a pH of about 5.9. In some embodiments, the buffer has a pH of about 6.0. Under the rules of scientific rounding, a pH greater than or equal to 5.45 and smaller than or equal to 5.55 is rounded as 5.5. [00217] In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration between 5 mM and 15 mM (e.g., between 6 mM and 14 mM, 7 mM and 13 mM, 8 mM and 12 mM, 9 mM and 11 mM, and about 10 mM). In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration between 6 mM and 14 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration between 7 mM and 13 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration between 8 mM and 12 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration between 9 mM and 11 mM.

[00218] In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 1 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 2 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 3 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 4 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 5 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 6 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 7 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 8 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 9 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 10 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 11 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 12 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 13 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 14 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 15 mM.

[00219] In some embodiments the formulation comprises a histidine buffer, acetate buffer, or succinate buffer. In some embodiments the formulation comprises a histidine buffer. In some embodiments the formulation comprises an acetate buffer. In some embodiments, the formulation comprises a succinate buffer. [00220] In some embodiments, a histidine buffer (e.g., L-histidine, L-histidine HO monohydrate) acts as a buffering agent. In some embodiments, the histidine buffer comprises a histidine and a histidine salt. In some embodiments, the histidine is L-histidine. In some embodiments, the histidine salt is histidine HO monohydrate.

[00221] In some embodiments, the formulation comprises methionine.

[00222] In some embodiments, the methionine is at a concentration between 5 mM and 50 mM (e.g., between 5 mM and 40 mM, between 5 mM and 30 mM, between 5 mM and 20 mM, between 5 mM and 10 mM, between 10 mM and 50 mM, between 10 mM and 40 mM, between 10 mM and 30 mM, between 10 mM and 20 mM, between 20 mM and 50 mM, between 20 mM and 40 mM, between 20 mM and 30 mM, between 30 mM and 50 mM, between 30 mM and 40 mM, between 40 mM and 50 mM, between 6 mM and 14 mM, 7 mM and 13 mM, 8 mM and 12 mM, 9 mM and 11 mM, and about 10 mM). In some embodiments, the methionine is at a concentration between 6 mM and 14 mM. In some embodiments, the methionine is at a concentration between 7 mM and 13 mM. In some embodiments, the methionine is at a concentration between 8 mM and 12 mM. In some embodiments, the methionine is at a concentration between 9 mM and 11 mM.

[00223] In some embodiments, the methionine is at a concentration of about 1 mM. In some embodiments, the methionine is at a concentration of about 2 mM. In some embodiments, the methionine is at a concentration of about 3 mM. In some embodiments, the methionine is at a concentration of about 4 mM. In some embodiments, the methionine is at a concentration of about 5 mM. In some embodiments, the methionine is at a concentration of about 6 mM. In some embodiments, the methionine is at a concentration of about 7 mM. In some embodiments, the methionine is at a concentration of about 8 mM. In some embodiments, the methionine is at a concentration of about 9 mM. In some embodiments, the methionine is at a concentration of about 10 mM. In some embodiments, the methionine is at a concentration of about 11 mM. In some embodiments, the methionine is at a concentration of about 12 mM. In some embodiments, the methionine is at a concentration of about 13 mM. In some embodiments, the methionine is at a concentration of about 14 mM. In some embodiments, the methionine is at a concentration of about 15 mM.

[00224] In some embodiments, the formulation comprises arginine. In some embodiments, the formulation comprises an arginine salt solution. In some embodiments, the arginine or arginine salt solution acts as a viscosity modulator. In some embodiments, the arginine salt solution salt solution comprises HC1 monohydrate.

[00225] In some embodiments, the arginine salt solution is at a concentration between 40 mM and 250 mM (e.g., between 50 mM and 200 mM, 60 mM and 150 mM, 70 mM and 125 mM, 80 mM and 100 mM, and about 90 mM). In some embodiments, the arginine salt solution is at a concentration of about 80 mM. In some embodiments, the arginine salt solution is at a concentration of about 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, 120 mM, 125 mM, 150 mM, 200 mM, or 250 mM.

[00226] The one or more excipients in the pharmaceutical formulation disclosed herein further comprises a surfactant. The term “surfactant,” as used herein, refers to a surface active molecule containing both a hydrophobic portion (e.g., alkyl chain) and a hydrophilic portion e.g., carboxyl and carboxylate groups). Surfactants are useful in pharmaceutical formulations for reducing aggregation of a therapeutic protein. Surfactants suitable for use in the pharmaceutical formulations arc generally non-ionic surfactants and include, but arc not limited to, polysorbates (e.g., polysorbates 20 or 80); poloxamers (e.g., poloxamer 188); sorbitan esters and derivatives; Triton; sodium laurel sulfate; sodium octyl glycoside; lauryl-, myristyl-, linoleyl-, or stearyl- sulfobetadine; lauryl-, myristyl-, linoleyl- or stearyl-sarcosine; linoleyl-, myristyl-, or cetylbetaine; lauramidopropyl-cocamidopropyl-, linoleamidopropyl-, myristamidopropyl-, palmidopropyl-, or isostearamidopropylbetaine (e.g., lauroamidopropyl); myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-dimethylamine; sodium methyl cocoyl-, or disodium methyl oleyl-taurate; and the MONAQUATTM series (Mona Industries, Inc., Paterson, N.J.), polyethylene glycol, polypropyl glycol, and copolymers of ethylene and propylene glycol (e.g., Pluronics, PF68, etc.). In certain embodiments, the surfactant is a polysorbate. In certain embodiments, the surfactant is polysorbate 80.

[00227] In some embodiments, the pharmaceutical formulation comprises a poloxamer. In some embodiments, the poloxamer is poloxamer 188. In some embodiments, the concentration of poloxamer 188 in the pharmaceutical formulation is between 0.4 mg/mL to 1.5 mg/mL, between 0.4 mg/mL to 1.0 mg/mL, between 0.4 mg/mL to 0.6 mg/mL, between 0.5 mg/mL to 1.5 mg/mL, between 0.5 mg/mL to 1.0 mg/mL, between 0.5 mg/mL to 0.6 mg/mL, between 0.8 mg/mL to 1.5 mg/mL, between 0.8 mg/mL to 1.2 mg/mL, between 1.0 mg/mL to 1.5 mg/mL, or between 1.0 mg/mL to 1.2 mg/mL. In some embodiments, the concentration of poloxamer 188 in the pharmaceutical formulation is about 0.5 mg/mL. In some embodiments, the concentration of poloxamer 188 in the pharmaceutical formulation is about 1.0 mg/mL. In some embodiments, the concentration of poloxamer 188 in the pharmaceutical formulation is 0.5 mg/mL. In some embodiments, the concentration of poloxamer 188 in the pharmaceutical formulation is 1.0 mg/mL.

[00228] In some embodiments, a polysorbate acts as a stabilizer. In some embodiments, the polysorbate is at a concentration between 0.01% w/v and 0.15% w/v (e.g., between 0.02% and 0.14%, 0.03% and 0.13%, 0.04% and 0.12%, 0.05% and 0.11%, or about 0.1%). In some embodiments, the polysorbate is at a concentration between 0.02% and 0.14%. In some embodiments, the polysorbate is at a concentration between 0.03% and 0.13%. In some embodiments, the polysorbate is at a concentration between 0.04% and 0.12%. In some embodiments, the polysorbate is at a concentration between 0.05% and 0.11%.

[00229] In some embodiments, the polysorbate is at a concentration of about 0.01% w/v, about 0.02% w/v, about 0.03% w/v, about 0.04% w/v, about 0.05% w/v, about 0.06% w/v, about 0.07% w/v, about 0.08% w/v, about 0.09% w/v, about 0.1% w/v, about 0.11% w/v, about 0.12%, about 0.13% w/v, about 0.14% w/v, or about 0.15% w/v.

[00230] In some embodiments, the polysorbate is polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80. In some embodiments, the polysorbate is polysorbate 20. In some embodiments, the polysorbate is polysorbate 40. In some embodiments, the polysorbate is polysorbate 60. In some embodiments, the polysorbate is polysorbate 80.

[00231] The one or more excipients in the pharmaceutical formulation of the present invention further comprises a sugar or sugar alcohol. Sugars and sugar alcohols are useful in pharmaceutical formulations as a thermal stabilizer. In certain embodiments, the pharmaceutical formulation comprises a sugar, for example, a monosaccharide (glucose, xylose, or erythritol), a disaccharide (e.g., sucrose, trehalose, maltose, or galactose), or an oligosaccharide e.g., stachyose). In specific embodiments, the pharmaceutical formulation comprises sucrose. In certain embodiments, the pharmaceutical composition comprises a sugar alcohol, for example, a sugar alcohol derived from a monosaccharide (e.g., mannitol, sorbitol, or xylitol), a sugar alcohol derived from a disaccharide (e.g., lactitol or maltitol), or a sugar alcohol derived from an oligosaccharide. In specific embodiments, the pharmaceutical formulation comprises sucrose. [00232] In some embodiments, a sugar or sugar alcohol (e.g., sucrose) acts as a stabilizer. In some embodiments, the sugar or sugar alcohol is at a concentration between 1% w/v and 10% w/v (e.g., between 3% w/v and 10% w/v, between 5% w/v and 10% w/v, between 8% w/v and 10% w/v, between 3% and 8% w/v, or between 5% w/v and 8% w/v). In some embodiments, the sugar or sugar alcohol is at a concentration between 1% w/v and 5% w/v (e.g., between 2% w/v and 4% w/v, or about 3% w/v). In some embodiments, the sugar or sugar alcohol is at a concentration between 2% w/v and 4% w/v. In some embodiments, the sugar or sugar alcohol is at a concentration of about 1%, about 2%, about 3%, about 4%, about 5% w/v, about 6% w/v, about 7% w/v, about 8% w/v, about 9% w/v, or about 10% w/v. In some embodiments, the sugar or sugar alcohol is a disaccharide. In some embodiments, the disaccharide is sucrose.

[00233] In some embodiments, the formulation is adjusted to final volume in water for injection (WFI).

[00234] In certain embodiments, the drug product is diluted in an aqueous carrier suitable for the route of administration, e.g., intravenous administration. Exemplary carriers include sterile water for injection (SWFI), bacteriostatic water for injection (BWFI), a pH buffered solution (e.g., phosphate-buffered saline), sterile saline solution, Ringer's solution, or dextrose solution. In one embodiment, when the pharmaceutical formulation is prepared for intravenous administration, the pharmaceutical formulation can be diluted in a 5% dextrose solution (D5W).

Dosage Forms

[00235] Prior to pharmaceutical use, the pharmaceutical formulation can be diluted in an aqueous carrier if suitable for the route of administration. For intravenous administration, suitable carriers include sterile water for injection (SWFI), bacteriostatic water for injection (BWFI), a pH buffered solution (e.g., phosphate-buffered saline), sterile saline solution, Ringer’s solution, or dextrose solution. For example, when the pharmaceutical formulation is prepared for intravenous administration, the pharmaceutical formulation may comprises a dextrose solution, such as a 5% dextrose solution (D5W). In certain embodiments, the diluted pharmaceutical formulation is isotonic and suitable for administration by intravenous infusion, e.g., D5W. In certain embodiments, the formulation is diluted in about 50 mL D5W, 100 mL D5W, 150 mL D5W, 200 mL D5W, 250 mL D5W, 300 mL D5W, 350 mL D5W, 400 mL D5W, 450 mL D5W, 500 mL D5W, or 1 L D5W. [00236] The pharmaceutical formulation comprises the anti-IL-13 antibody or mixture of anti- IL-13 antibodies at a concentration suitable for storage. In certain embodiments, the pharmaceutical formulation comprises the anti-IL-13 antibody or mixture of anti-IL-13 antibodies at a concentration between 160 mg/mL and 220 mg/mL (e.g., between 170 mg/mL and 210 mg/mL, 180 mg/mL and 200 mg/mL, or about 190 mg/mL). In some embodiments, the anti-IL-13 antibody is at a concentration between 170 mg/mL and 210 mg/mL. In some embodiments, the anti-IL-13 antibody or mixture of anti-IL-13 antibodies is at a concentration between 180 mg/mL and 200 mg/mL.

[00237] In some embodiments, the anti-IL-13 antibody or mixture of anti-IL-13 antibodies is at a concentration of about 160 mg/mL, about 170 mg/mL, about 180 mg/mL, about 190 mg/mL, about 200 mg/mL, about 210 mg/mL, about 220 mg/mL, about 230 mg/mL, about 240 mg/mL, or about 250 mg/mL.

[00238] Formulations described herein may be included in e.g., a vial. In some embodiments, the vial is a syringe. In some embodiments, the syringe is a prcfillcd syringe.

[00239] In some embodiments, the extractable volume of the vial is between 1.0 mL and 3.0 mL. In some embodiments, the volume of the vial is about 2.0 mL. As used herein, the “extractable volume” of the vial is the amount that can be withdrawn from the receptacle. The fill volume is greater than the extractable volume to ensure that the extractable volume can be obtained.

[00240] In certain embodiments, the pharmaceutical formulation is delivered using a bag, an autoinjector, or an on-body delivery device. In certain embodiments, the pharmaceutical formulation is packaged in a vial e.g., a vial, bottle, bag, pen, or syringe). In certain embodiments, the vial comprises an overfill to allow for complete removal of the intended dose. In certain embodiments, the vial comprises an overfill of 5 to 35%, 10 to 30%, 15 to 25%, or 10 to 20%. In a particular embodiment, the vial comprises an overfill of about 20%.

[00241] In certain embodiments, the formulation may be a liquid formulation. In certain embodiments, the amount of anti-IL-13 antibody in the container is suitable for administration as a single dose. In certain embodiments, the amount of anti-IL-13 antibody in the container is suitable for administration in multiple doses. In certain embodiments, the pharmaceutical formulation comprises the anti-IL-13 antibody in an amount of 0.1 to 200 mg. In certain embodiments, the pharmaceutical formulation comprises the anti-IL-13 antibody in an amount of 1 to 200 mg, 10 to 200 mg, 20 to 200 mg, 50 to 200 mg, 100 to 200 mg, 200 to 500 mg, 500 to 2000 mg, 1000 to 2000 mg, 0.1 to 1000 mg, 1 to 1000 mg, 10 to 1000 mg, 20 to 1000 mg, 50 to 1000 mg, 100 to 1000 mg, 200 to 1000 mg, 500 to 1000 mg, 0.1 to 500 mg, 1 to 500 mg, 10 to 500 mg, 20 to 500 mg, 50 to 500 mg, 100 to 500 mg, 200 to 500 mg, 0.1 to 200 mg, 1 to 200 mg, 10 to 200 mg, 20 to 200 mg, 50 to 200 mg, 100 to 200 mg, 0.1 to 100 mg, 1 to 100 mg, 10 to 100 mg, 20 to 100 mg, 50 to 100 mg, 0.1 to 50 mg, 1 to 50 mg, 10 to 50 mg, 20 to 50 mg, 0.1 to 20 mg, 1 to 20 mg, 10 to 20 mg, 0.1 to 10 mg, 1 to 10 mg, or 0.1 to 1 mg. In certain embodiments, the pharmaceutical formulation comprises the anti-IL-13 antibody in an amount of about 0.1 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1500 mg, or about 2000 mg.

Methods of Use

[00242] In some embodiments, the present application also provides compositions comprising a formulation, vial (e.g. pre-filled syringe) described herein for use in methods of treating an inflammatory disorder or disease, such as atopic dermatitis, in a patient in need thereof. In certain embodiments, the patient has been diagnosed with moderate-to-severe atopic dermatitis. In certain embodiments, the patient has had moderate-to-severe atopic dermatitis for at least one year. In certain embodiments, the patient is a pediatric patient.

[00243] In certain embodiments, the patient has one or more of: (a) an Eczema Area and Severity Index Score (EASI) of >10 (e.g., an EASI of >16 or an EASI >10 and < 16), (b) an Investigator Global Assessment (IGA) score of >3 and (c) a body surface area (BSA) of >10%. In certain embodiments, the patient has an Eczema Area and Severity Index Score (EASI) of >10. In certain embodiments, the patient has an Eczema Area and Severity Index Score (EASI) of >16. In certain embodiments, the patient has an Eczema Area and Severity Index Score (EASI) of >10 and less than 16. In certain embodiments, the patient has an Investigator Global Assessment (IGA) score of >3. In certain embodiments, the patient has a body surface area (BSA) of >10%. [00244] The “Investigator Global Assessment” or “IGA” is an assessment measure used globally to rate the severity of the patient’s AD (Simpson E, et al. J Am Acad Dermatol. 2020;83(3):839-846). It is based on a 5-point scale ranging from 0 (clear) to 4 (severe) and a score is selected using descriptors that best describe the overall appearance of the lesions at a given time point. It is not necessary that all characteristics under Morphological Description be present. The IGA can be conducted prior to conducting the EASI and BSA assessments.

[00245] The “Eczema Area and Severity Index” or “EASE is a measure used in clinical settings to assess the severity and extent of AD (Hanifin et al., Exp Dermatol. 2001; 10: 11-18). EASI is a composite index with scores ranging from 0 to 72, with the higher values indicating more severe and or extensive disease. The severity of erythema, induration/papulation, excoriation, and lichenification can be assessed by a clinician or other medical professional on a scale of 0 (absent) to 3 (severe) for each of the 4 body areas: head and neck, trunk, upper limbs, and lower limbs, with half points allowed. In addition, the extent of AD involvement in each of the 4 body areas can be assessed as a percentage by body surface area of head, trunk, upper limbs, and lower limbs, and converted to a score of 0 to 6. A total score (0 - 72) is assigned based on the sum of total scores for each of the four body region scores.

[00246] The “Scoring of Atopic Dermatitis” or “SCORAD” is a validated clinical tool for assessing the extent and intensity of AD developed by the European Task Force on Atopic Dermatitis (Consensus report of the European Task Force on Atopic Dermatitis. Dermatology. 1993; 186(l):23-31). There are 3 components to the assessment: (i) the extent of AD is assessed as a percentage of each defined body area and reported as the sum of all areas, with a score ranging from 0 to 100 (assigned as “A” in the overall SCORAD calculation); (ii) the severity of 6 symptoms of AD: redness, swelling, oozing/crusting, excoriation, skin thickening/lichenification, dryness. Each item is graded as follows: none (0), mild (1), moderate (2), or severe (3) (for a maximum of 18 total points, assigned as “B” in the overall SCORAD calculation); (iii) subjective assessment of itch and of sleeplessness is recorded for each symptom using a visual analogue scale (VAS), where 0 is no itch (or sleeplessness) and 10 is the worst imaginable itch (or sleeplessness), with a maximum possible score of 20 (assigned as “C” in the overall SCORAD calculation). The SCORAD Index formula is: A/5 + 7B/2 + C. The maximal score of the SCORAD Index is 103. [00247] Pruritus Numerical Rating Scale (NRS) is an 11 -point scale used by patients (and if applicable, with help of parents/caregiver if required) to rate their worst itch severity over the past 24 hours with 0 indicating “No itch” and 10 indicating “Worst itch imaginable” (Phan NQ, et al. Acta Derm Venereal 2012; 92: 502-507). Assessments are recorded by the patient daily using an electronic diary. The baseline pruritus NRS is determined based on the average of daily Pruritus NRS during the 7 days immediately preceding baseline. A minimum of 4 daily scores out of the 7 days immediately preceding baseline is required for this calculation.

[00248] Sleep loss scale rates patient’s sleep loss due to pruritus on a 5-point Likert scale (with scores ranging from 0 [not at all], 1 [a little], 2 [moderately], 3 [quite a bit], to 4 [unable to sleep at all]). Assessments will be recorded daily by the patient using an electronic diary.

[00249] The Patient-Oriented Eczema Measure (POEM) is a 7-item, validated, questionnaire completed by the patient (and if applicable, with help of parents/ caregiver if required) to assess disease symptoms over the last week (Centre of Evidence Based Dermatology. POEM - Patient Oriented Eczema Measure. Available at www.nottingham.ac.uk/research/groups/cebd/resources/poem.aspx). Patients are asked to respond to 7 questions on skin dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping. All 7 answers cany equal weight with a total possible score from 0 to 28 (answers scored as: No days=0; 1- 2 days = 1; 3-4 days = 2; 5-6 days = 3; everyday = 4). A high score is Indicative of a poor quality of life. POEM responses are captured weekly using an electronic diary.

[00250] The Dermatology Life Quality Index (DLQI) is a 10-item, validated questionnaire completed by the patient or caregiver, used to assess the impact of skin disease on the quality of life of the patient (Finlay, A. Y. and Khan, G. K. 1994. Clinical and Experimental Dermatology 1993 Sep 23; 19:210-216). The 10 questions cover the following topics: symptoms, embarrassment, shopping and home care, clothes, social and leisure, sport, work or study, close relationships, sex, and treatment, over the previous week. Each question is scored from 0 to 3 (“not at all,” “a little,” “a lot,” and “very much”), giving a total score ranging from 0 to 30. A high score is indicative of a poor quality of life.

[00251] In certain embodiments, methods described herein comprise determining one or more of the following characteristics of the patient at baseline and during and after the induction period: Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), Body Surface Area (BSA), Pruritus Numerical Rating Scale (NRS), Sleep loss scale, SCORing Atopic Dermatitis (SCORAD), Patient Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI). In certain embodiments, methods described herein comprise determining the following characteristic of the patient at baseline and during and after the induction period: Eczema Area and Severity Index (EASI). In certain embodiments, methods described herein comprise determining the following characteristic of the patient at baseline and during and after the induction period: Investigator Global Assessment (IGA). In certain embodiments, methods described herein comprise determining the following characteristic of the patient at baseline and during and after the induction period: Body Surface Area (BSA). In certain embodiments, methods described herein comprise determining the following characteristic of the patient at baseline and during and after the induction period: Pruritus Numerical Rating Scale (NRS). In certain embodiments, methods described herein comprise determining the following characteristic of the patient at baseline and during and after the induction period: Sleep loss scale, SCORing Atopic Dermatitis (SCORAD). In certain embodiments, methods described herein comprise determining the following characteristic of the patient at baseline and during and after the induction period: Patient Oriented Eczema Measure (POEM). In certain embodiments, methods described herein comprise determining the following characteristic of the patient at baseline and during and after the induction period: Dermatology Life Quality Index (DLQI). [00252] In certain embodiments, a patient described herein is determined to have one or more of the following characteristics of the patient at baseline and during and after the induction period: Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), Body Surface Area (BSA), Pruritus Numerical Rating Scale (NRS), Sleep loss scale, SCORing Atopic Dermatitis (SCORAD), Patient Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI). In certain embodiments, a patient herein is determined to have a characteristic Eczema Area and Severity Index (EASI) at baseline and during and after the induction period. In certain embodiments, a patient herein is determined to have a characteristic Investigator Global Assessment (IGA) at baseline and during and after the induction period. In certain embodiments, a patient herein is determined to have a characteristic Body Surface Area (BSA) at baseline and during and after the induction period. In certain embodiments, a patient herein is determined to have a characteristic Pruritus Numerical Rating Scale (NRS) at baseline and during and after the induction period. In certain embodiments, a patient herein is determined to have a characteristic Sleep loss scale, SCORing Atopic Dermatitis (SCORAD) at baseline and during and after the induction period. In certain embodiments, a patient herein is determined to have a characteristic Patient Oriented Eczema Measure (POEM) at baseline and during and after the induction period. In certain embodiments, a patient herein is determined to have a characteristic Dermatology Life Quality Index (DLQI) at baseline and during and after the induction period.

[00253] In an aspect, the present application provides methods of contacting IL- 13 with an anti-IL-13 antibody, such as a human, humanized, or chimeric antibody, which results in inhibition of IL-13 binding to an IL-13 receptor expressed on a cell.

[00254] In an aspect, the present application provides compositions comprising a formulation, vial, or bag described herein for use in the treatment of asthma, idiopathic pulmonary fibrosis, alopecia areata, chronic sinusitis with nasal polyps, Chronic Rhinosinusitis without Nasal Polyps (CRSsNP), eosinophilic esophagitis (EoE), an Eosinophilic gastrointestinal disorder or disease (ENID) selected from the group consisting of Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), Eosinophilic Colitis (EoC), and Eosinophilic Gastroenteritis (EGE), Churg- Strauss syndrome/Eosinophilic granulomatosis with polyangiitis (EGPA), Prurigo Nodularis (PN), of Chronic Spontaneous Urticaria (CSU), Chronic Pruritis of Unknown Origin (CPUO), Bullous Pemphigoid (BP), Cold Inducible Urticaria (ColdU), Allergic Fungal Rhinosinusitis (AFRS), Allergic Bronchopulmonary Aspergillosis (ABPA), or Chronic Obstructive Pulmonary Disease (COPD).

[00255] In an aspect, the present application provides methods for treating an inflammatory disorder or disease in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of the formulation, vial, or bag described herein.

[00256] In some embodiments, the inflammatory disorder or disease is atopic dermatitis.

[00257] In some embodiments, the inflammatory disorder or disease is asthma, idiopathic pulmonary fibrosis, alopecia areata, chronic sinusitis with nasal polyps, Chronic Rhinosinusitis without Nasal Polyps (CRSsNP), eosinophilic esophagitis (EoE), an Eosinophilic gastrointestinal disorder or disease (ENID) selected from the group consisting of Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), Eosinophilic Colitis (EoC), and Eosinophilic Gastroenteritis (EGE), Churg-Strauss syndrome/Eosinophilic granulomatosis with polyangiitis (EGPA), Prurigo Nodularis (PN), of Chronic Spontaneous Urticaria (CSU), Chronic Pruritis of Unknown Origin (CPUO), Bullous Pemphigoid (BP), Cold Inducible Urticaria (ColdU), Allergic Fungal Rhinosinusitis (AFRS), Allergic Bronchopulmonary Aspergillosis (ABPA), or Chronic Obstructive Pulmonary Disease (COPD).

[00258] In some embodiments, the inflammatory disorder or disease is asthma. In some embodiments, the inflammatory disorder or disease is idiopathic pulmonary fibrosis. In some embodiments, the inflammatory disorder or disease is alopecia areata. In some embodiments, the inflammatory disorder or disease is chronic sinusitis with nasal polyps. In some embodiments, the inflammatory disorder or disease is Chronic Rhinosinusitis without Nasal Polyps (CRSsNP). In some embodiments, the inflammatory disorder or disease is eosinophilic esophagitis (EoE). In some embodiments, the inflammatory disorder or disease is an Eosinophilic gastrointestinal disorder or disease (ENID) selected from the group consisting of Eosinophilic Gastritis (EoG). In some embodiments, the inflammatory disorder or disease is Eosinophilic Enteritis (EoN). In some embodiments, the inflammatory disorder or disease is Eosinophilic Colitis (EoC). In some embodiments, the inflammatory disorder or disease is and Eosinophilic Gastroenteritis (EGE). In some embodiments, the inflammatory disorder or disease is Churg-Strauss syndrome/Eosinophilic granulomatosis with polyangiitis (EGPA). In some embodiments, the inflammatory disorder or disease is Prurigo Nodularis (PN). In some embodiments, the inflammatory disorder or disease is of Chronic Spontaneous Urticaria (CSU). In some embodiments, the inflammatory disorder or disease is Chronic Pruritis of Unknown Origin (CPUO). In some embodiments, the inflammatory disorder or disease is Bullous Pemphigoid (BP). In some embodiments, the inflammatory disorder or disease is Cold Inducible Urticaria (ColdU). In some embodiments, the inflammatory disorder or disease is Allergic Fungal Rhinosinusitis (AFRS). In some embodiments, the inflammatory disorder or disease is Allergic Bronchopulmonary Aspergillosis (ABPA). In some embodiments, the inflammatory disorder or disease is Chronic Obstructive Pulmonary Disease (COPD).

[00259] In an aspect, the present application provides methods for treating a pathology associated with elevated levels of IL- 13 in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of the formulation or vial described herein.

[00260] In an aspect, the present application provides methods of reducing biological activity of IL- 13 in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of the formulation or vial described herein.

[00261] In an aspect, the present application provides methods of inhibiting the TH2 type allergic response in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of the formulation or vial described herein.

[00262] In an aspect, the present application provides methods of reducing levels of Thymus and Activation Regulated Chemokine (TARC)/CCL17 in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of the formulation or vial described herein.

[00263] In an aspect, the present application provides methods of preventing an inflammatory disorder or disease in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of the formulation or vial described herein.

[00264] In some embodiments, the formulation or vial is administered subcutaneously or intravenously.

Examples

Example 1: Peptide Mapping by LC-MS/MS to Determine Presence and Approximate Amounts of Antibody Retaining a C-Terminal Lysine (500 L production culture)

[00265] Peptide mapping was used to identify and approximate the amounts of C-terminal lysine retained in a batch of anti-IL-13 antibodies.

[00266] The anti-IL-13 antibodies used in this experiment were generated from stable CHO cell lines transfected with expression vectors encoding the sequences for Construct 133 (which has the VH and VL sequences of SEQ ID NOs: 3 and 39, respectively, the light chain constant region sequence of SEQ ID NO: 469, and the heavy chain constant region sequence of SEQ ID NO: 439 (lacks C-terminal lysine) or SEQ ID NO: 624) and express the antibody. The cell lines were serially expanded in vessels of increasing size and volume to reach a cell number sufficient to seed the 500L production bioreactor. The production bioreactor step involved a fed-batch process of approximately 14 days followed by a harvest step where the cell culture was clarified. The clarified harvest was purified using three chromatography steps: protein A capture, anion exchange, and cation exchange chromatography. Purified products were then concentrated, diafiltered, and formulated.

[00267] The purified antibodies were then denatured with guanidine hydrochloride (Gdn-HCl) and reduced by dithiothreitol (DTT), followed by cysteine-alkylation with iodoacetamide (IAM). Proteolytic digestion was performed with endoproteinase Lys-C/Trypsin and thermolysin. The peptides were separated by reversed phase liquid chromatography with detection at 214 nm, and by a mass spectrometer operating with full MS scan followed by tandem mass spectrometry (MS/MS) scans. Peptide sequences were assigned by comparing masses to theoretical sequences of Construct 133, and the presence of C-terminal lysine was determined; all masses agreed with theoretical within 10.0 ppm. Quantitation of antibodies with C-terminal lysine was determined by its relative area in extracted ion chromatograms (EICs).

[00268] Table 11 shows that, for Construct 133 encoded with the C-terminal lysine on the input sequence, about 3% to 4% of the output sequences included a C-terminal lysine. The remaining antibody species (96.3%) lacked the C-terminal lysine.

Table 11. Output sequences having a C-terminal lysine, no C-terminal lysine, or some other species at the C-terminus when the input sequence is with or without the C-terminal lysine.

Example 2: Quantitative Analysis of Antibody Retaining the C-Terminal Lysine via iCIEF (500 L production culture)

[00269] Imaged capillary isoelectric focusing (iCIEF) is a charge heterogeneity analysis method used to monitor the percentage of charge variant species. The isoelectric point (pl) is an intrinsic property of a specific protein molecule and is the pH at which the protein molecule does not carry net electrical charge. Under an external electric field, the charge variants move along a continuous pH gradient formed by ampholytes and stop where the pH equals its pl, since the protein carries no net electrical charge and would not be attracted by either electrode. Different antibody species with different pl values are focused and separated in different positions, thereby resolving charge-based isoforms, pl values and relative abundance of the resolved peaks are quantified using chromatographic software, and the relative abundance of the main peak as well as acidic and basic peak groups are reported. In this Example, iCIEF was used to monitor and quantify the presence/absence of C-terminal lysine on Construct 133 from a 500L production culture.

[00270] Briefly, Construct 133 encoded without a C-terminal lysine or with a C-terminal lysine, generated using the 500 L production culture described in Example 1, were mixed with a master mixture to generate a loading mixture, which contained Pharmalyte 8-10.5, Pharmalyte 3- 10, 1% MC, pl marker 7.05, pl marker 9.22, urea, and ultrapure water at a final product concentration of 0.2 mg/mL. The loading mixture was loaded into a Maurice CIEF cartridge and analyzed with a Maurice Capillary Isoelectric Focusing Analyzer with a whole-column detection camera.

[00271] Figure 1 shows the icIEF profile for Construct 133 encoded without a C-terminal lysine. Figure 2 shows the icIEF profile for Construct 133 encoded with a C-terminal lysine. Results showed that the basic peak at about pl 8.3 was larger in Figure 2 than in Figure 1. This larger peak in Figure 2 is due to the presence of C-terminal lysine, which is a basic amino acid. [00272] Next, the percentage of Construct 133 with a C-terminal lysine was quantified. Since basic peaks reflect the antibody with retained C-terminal lysine in addition to other modifications which can lead to basic peaks, the percentage of antibody with C-terminal lysine can be estimated by subtracting basic peaks of the sample treated with carboxypeptidase B (CPB), which removes the residual C-terminal lysine, from the basic peaks of the sample not treated with CPB.

[00273] The basic peaks of Construct 133 encoded without a C-terminal lysine (shown in Figure 1 and referred to as reference standard (“RS”) in Table 12) were quantified. As shown in Table 12, this sample had about 4.2% basic peaks, corresponding to basic peaks resulting from modifications other than C-terminal lysine since the encoded antibody does not include a C- terminal lysine. [00274] Next, a portion of Construct 133 encoded with a C-terminal lysine was treated with CPB to remove any residual C-terminal lysine. As shown in Table 13, this resulted in about 8.0% basic peaks. When Construct 133 encoding a C-terminal lysine was treated with CPB, this yielded about 5.0% basic peaks. Accordingly, the amount of remaining C-terminal lysine in Construct 133 was about 3.0% (i.e., 8.0% minus 5.0%).

Table 12. Percentage of Basic Peaks in Construct 133 encoded without a C-Terminal Lysine

Table 13: Percentage of Basic Peaks in Construct 133 encoded with a C-Terminal Lysine treated with or without carboxypeptidase B

Example 3: Quantitative Analysis of Antibody Retaining the C-Terminal Lysine via iCIEF (2000 L production culture)

[002751 In this Example, iCIEF was used to monitor and quantify the presence/absence of C- terminal lysine on Construct 133 from a 2000 L production culture.

[00276] Samples were prepared and processed essentially as described in Examples 1 and 2, but upscaled to a 2000 L production culture.

[00277] The basic peaks of Construct 133 encoded without a C-terminal lysine or with a C- terminal lysine treated either with or without CPB were quantified. Tables 14 and 15 summarize the results for no treatment or treatment with CPB, respectively, of Construct 133 encoded without a C-terminal lysine. Table 16 summarizes the results for no treatment or treatment with CPB of Construct 133 encoded with a C-terminal lysine.

[00278] Without CPB treatment, % basic peaks of Construct 133 encoded without a C- terminal lysine was 3.5-4.1% (Table 14), whereas with CPB treatment, % basic peaks was about 3.9%-4.9% (Table 15). This difference in % basic peaks between with and without CPB treatment was likely due to analytical variability; % basic peaks did not decrease after CPB treatment because there is no C-terminal lysine to remove from the antibody.

[00279] With respect to Construct 133 encoded with a C-terminal lysine, without CPB treatment, % basic peaks was 7.5%, whereas with CPB treatment, % basic peaks was 3.8% (Table 16). This suggests that the sample had about 3.7% Construct 133 with a C-terminal lysine (i.e., 7.5% minus 3.8%). Given this relatively low level, the C-terminal lysine would likely be predominantly on one heavy chain, with very low amounts of the antibody having the C-terminal lysine on both heavy chains. This value (i.e., 3.7%) using the 2000 L production lot is similar to that obtained using the 500L production lot (~3%) based on the same analytical approach.

Table 14. Percentage of Basic Peaks in Construct 133 encoded without a C-Terminal Lysine without carboxypeptidase B treatment

*The data for RS-X is from a separate experiment than those of RS-1 to RS-3. Table 15. Percentage of Basic Peaks in Construct 133 encoded without a C-Terminal Lysine with carboxypeptidase B treatment

*The data for RS-X is from a separate experiment than those of RS-1 to RS-3. Table 16. Percentage of Basic Peaks in Construct 133 encoded with a C-Terminal Lysine with or without carboxypeptidase B treatment

Informal sequence listing

Claims

WHAT IS CLAIMED IS:

1. A composition comprising a mixture of anti-interleukin 13 (IL- 13) antibodies, wherein the mixture comprises a) C-terminal anti IL- 13 antibodies comprising a heavy chain having at least one C- terminal lysine, and b) non-C-terminal anti IL- 13 antibodies otherwise identical to the C-terminal anti IL- 13 antibodies but lacking the at least one C-terminal lysine, wherein each of the non-C-terminal and C-terminal antibodies comprises:

(i) a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and

(ii) a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; wherein:

(a) CDR-H1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 58-99 and 121;

(b) CDR-H2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 100-111;

(c) CDR-H3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 112-120 and 130-140,

(d) CDR-L1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 141-144 and 149-152,

(e) CDR-L2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 153-158 and the amino acid sequence LAS; and

(f) CDR-L3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 165-172, and wherein each C-terminal antibody having at least one C-terminal lysine comprises a heavy chain constant domain comprising a sequence selected from the sequences set forth in SEQ ID NOs: 624, 610-623, and 625-709.

2. The composition of claim 1, wherein between about 0.01% and about 50% of the antibodies are C-terminal antibodies.

3. The composition of claim 1, wherein between about 0.1% and about 20% of the antibodies are C-terminal antibodies.

4. The composition of claim 1, wherein between about 0.5% and about 10% of the antibodies are C-terminal antibodies.

5. The composition of claim 1, wherein between about 1% and about 5% of the antibodies are C-terminal antibodies.

6. The composition of claim 1, wherein between about 5% and about 30% of the antibodies are C-terminal antibodies.

7. The composition of any one of claims 1-6, wherein the anti-IL-13 antibodies comprise a VH sequence selected from the sequences set forth in any one of SEQ ID NOs: 3, 1, 2, and 4-32.

8. The composition of any one of claims 1-7, wherein the anti-IL-13 antibodies comprise a VL sequence selected from the sequences set forth in any one of SEQ ID NOs: 39, 33-38, and 40-57.

9. The composition of any one of claims 1-6, wherein the anti-IL-13 antibodies comprise a VH sequence selected from the sequences set forth in any one of SEQ ID NOs: 3, 1, 2, and 4-32 and a VL sequence selected from the sequences set forth in any one of SEQ ID NOs: 39, 33-38, and 40-57.

10. The composition of claim 9, wherein the anti-IL-13 antibodies comprise a VH comprising an amino acid sequence as set forth in SEQ ID NO: 3 and a VL comprising an amino acid sequence as set forth in SEQ ID NO: 39.

11. The composition of any one of claims 1-10, wherein the anti-IL-13 antibodies comprise a light chain constant region comprising SEQ ID NO: 469.

12. The composition of any one of claims 1-11, further comprising one or more pharmaceutically acceptable excipients.

13. An anti-IL-13 antibody having a light chain comprising a VL comprising SEQ ID NO: 39 and a light chain constant region comprising SEQ ID NO: 469 and a heavy chain comprising a VH comprising SEQ ID NO: 3 and a heavy chain constant region comprising SEQ ID NO: 624.

14. A composition comprising the antibody of claim 12 and an antibody having a light chain comprising a VL comprising SEQ ID NO: 39 and a light chain constant region comprising SEQ ID NO: 469 and a heavy chain comprising a VH comprising SEQ ID NO: 3 and a heavy chain constant region comprising SEQ ID NO: 439.

15. The composition of any one of claims 1-12 and 14, wherein the antibodies were produced in a Chinese Hamster Ovary (CHO) cell line.

16. A vial comprising the composition of any one of claims 1-12, 14, and 15.

17. The vial of claim 16, wherein the extractable volume of the vial is between 1.0 mL and 3.0 mL.

18. The vial of claim 17, wherein the extractable volume of the vial is about 2.0 mL.

19. The vial of any one of claims 16-18, wherein the vial is a syringe.

20. The vial of claim 19, wherein the syringe is a prcfillcd syringe.

21. A composition comprising a mixture of anti-interleukin 13 (IL-13) antibodies, wherein the mixture comprises a first IL- 13 antibody and a second IL- 13 antibody, wherein each antibody comprises at least one heavy chain, and wherein the first antibody and the second antibody are identical except that the first antibody comprises a lysine at the C-terminus of the at least one heavy chain, and the second antibody lacks the lysine at the C-terminus of the at least one heavy chain, wherein each antibody comprises:

(i) a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences,

CDR-H1, CDR-H2, and CDR-H3; and (ii) a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; wherein:

(a) CDR-H1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 58-99 and 121;

(b) CDR-H2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 100-111;

(c) CDR-H3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 112-120 and 130-140,

(d) CDR-L1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 141-144 and 149-152,

(e) CDR-L2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 153-158 and the amino acid sequence LAS; and

(f) CDR-L3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 165-172, and wherein the first antibody comprises a heavy chain constant domain comprising a sequence selected from the sequences set forth in SEQ ID NOs: 624, 610-623, and 625-709.

22. The composition of claim 21, wherein each anti-IL-13 antibody comprises a VH sequence selected from the sequences set forth in any one of SEQ ID NOs: 3, 1, 2, and 4-32.

23. The composition of claim 21 or claim 22, wherein each anti-IL-13 antibody comprises a VL sequence selected from the sequences set forth in any one of SEQ ID NOs: 39, 33-38, and 40-57.

24. The composition of claim 21, wherein each anti-IL-13 antibody comprises a VH sequence selected from the sequences set forth in any one of SEQ ID NOs: 3, 1, 2, and 4-32 and a VL sequence selected from the sequences set forth in any one of SEQ ID NOs: 39, 33-38, and 40-57.

25. The composition of any one of claims 21-24, wherein each anti-IL-13 antibody comprises a VH comprising an amino acid sequence as set forth in SEQ ID NO: 3 and a VL comprising an amino acid sequence as set forth in SEQ ID NO: 39.

26. The composition of any one of claims 21-25, wherein each antibody comprises a light chain constant region comprising SEQ ID NO: 469.

27. The composition of any one of claims 24-26, wherein the antibodies were produced in a Chinese Hamster Ovary (CHO) cell line.

28. A vial comprising the composition of any one of claims 21-27.

29. The vial of claim 28, wherein the extractable volume of the vial is between 1.0 mL and 3.0 mL.

30. The vial of claim 29, wherein the volume of the vial is about 2.0 mL.

31. The vial of any one of claims 28-30, wherein the vial is a syringe.

32. The vial of claim 31, wherein the syringe is a prefilled syringe.

33. A composition comprising a mixture of anti-interleukin 13 (IL- 13) antibodies, wherein the mixture comprises a) C-terminal anti IL- 13 antibodies comprising a heavy chain having at least one C- terminal lysine, and b) non-C -terminal anti IL- 13 antibodies otherwise identical to the C-terminal anti IL- 13 antibodies but lacking the at least one C-terminal lysine, wherein each of the non-C-terminal and C-terminal antibodies comprises:

(i) a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and

(ii) a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; wherein:

(a) CDR-H1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 58-99 and 121;

(b) CDR-H2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 100-111;

(c) CDR-H3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 112-120 and 130-140,

(d) CDR-L1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 141-144 and 149-152, (e) CDR-L2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 153-158 and the amino acid sequence LAS; and

(f) CDR-L3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 165-172, and wherein each C-terminal antibody having at least one C-terminal lysine comprises a heavy chain constant domain having a means for enhancing the half-life of the C-terminal antibody.