Antibodies that bind TSLP and methods of use

Abstract

Described herein are methods of using antibodies that bind to thymic stromal lymphopoietin (TSLP). In certain aspects, described herein are methods of inhibiting TSLP biological activity. In certain aspects, the methods described herein are used for treatment of an inflammatory disease or disorder associated with elevated levels of TSLP.

Description

Attorney Docket No.: AOE-008WOAOJ-036PCANTIBODIES THAT BIND TSLP AND METHODS OF USECROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 707.568 (filed October 15, 2024) and U.S. Provisional Application No. 63 / 827,444 (filed June 20, 2025), both of which are incorporated by reference herein in their entirety.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML file format and is hereby incorporated by reference in its entirety. Said XML copy, created on October 14, 2025, is named AOJ-036PC_SL.xml and is 465,491 bytes in size.BACKGROUND

[0003] Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine produced in response to pro-inflammatory stimuli. TSLP has been discovered to promote allergic inflammatory responses primarily through its activity on dendritic and mast cells. Human TSLP expression has been reported to be increased in asthmatic airways correlating to disease severity. In addition, TSLP protein levels are detectable in the concentrated bronchoalveolar lavage (BAL) fluid of asthma patients and other patients suffering from allergic disorders. In addition, TSLP has also been found to promote fibrosis.

[0004] TSLP binds to a heterodimeric receptor consisting of the TSLP receptor (TSLPR) and an IL-7 receptor a chain (IL-7Ra) in dendritic cells, thereby activating the dendritic cells. Upon activation, the dendritic cells express inflammatory chemokines such as thymus and activation-regulated chemokines (TARC (CCL17)), macrophage-derived chemokines (MDC (CCL22)), and the like.

[0005] Activation of dendritic cells by TSLP through the TSLPR is associated with disease pathology, including allergic inflammatory diseases, such as asthma, and autoimmune disease, such as systemic sclerosis.

[0006] Accordingly, there is a need in the art for methods of administering antagonists to TSLP to prevent and treat diseases in which human TSLP and human TSLPR are involved in the disease pathology, such as inflammatory and fibrotic disorders.Attorney Docket No.: AOE-008WOAOJ-036PCSUMMARY

[0007] The present disclosure provides methods for administering antibodies, or antigen binding fragments thereof, to TSLP and methods of treating diseases in which human TSLP is involved in disease pathology. The antibodies, or antigen binding fragments thereof, of the disclosure can include Fc modifications and exhibit longer half-lives than an otherwise identical antibody that does not include the Fc modification, for example, certain anti-TSLP antibodies known in the art.

[0008] In one aspect, the disclosure relates to a method for treating an inflammatory disorder or disease in a subject. The method includes administering to the subject a dose of an anti-thymic stromal lymphopoietin (TSLP) antibody, or antigen binding fragment thereof, wherein the dose is between about 100 mg and about 1,500 mg. The anti-TSLP antibody, or antigen binding fragment thereof, includes a) a variable heavy (VH) chain sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and b) a variable light (VL) chain sequence having three light chain CDR sequences, CDR-L1, CDR-L2, and CDR- L3; wherein the CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 1-9; the CDR-H2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 10-12; the CDR-H3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 13-18; the CDR-L1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 19-24, 271-302, and 387, the CDR-L2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 25-26, 303-310, and amino acid sequences DDS, DVS, EDS, DDT, DDK, DDL, and DDN; and the CDR-L3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 27-31, 311-327, and 367-370.

[0009] In another aspect, the disclosure relates to a method for treating a pathology associated with elevated levels of TSLP in a subject in need thereof. The method includes administering to the subject a dose of an anti-TSLP antibody, or antigen binding fragment thereof, wherein the dose is between about 100 mg and about 1,500 mg. The anti-TSLP antibody, or antigen binding fragment thereof, comprises: a) a variable heavy (VH) chain sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and b) a variable light (VL) chain sequence having three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; wherein the CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 1-9; the CDR-H2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 10-12; the CDR-H3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 13-18; the CDR-L1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 19-24, 271-302, and 387, the CDR-L2 comprises an amino acidAttorney Docket No.: AOE-OQ8WOAOJ-036PC sequence set forth in any one of SEQ ID NOs: 25-26, 303-310, and amino acid sequences DDS, DVS, EDS, DDT, DDK, DDL, and DDN: and the CDR-L3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 27-31, 311-327, and 367-370.

[0010] In another aspect, the disclosure relates to a method of reducing biological activity of TSLP in a subject in need thereof. The method includes administering to the subject a dose of an anti-TSLP antibody, or antigen binding fragment thereof, wherein the dose is between about 100 mg and about 1,500 mg. The anti-TSEP antibody, or antigen binding fragment thereof, comprises a) a variable heavy (VH) chain sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and b) a variable light (VL) chain sequence having three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; wherein the CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 1-9; the CDR-H2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 10-12; the CDR-H3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 13-18; the CDR-L1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 19-24, 271- 302, and 387, the CDR-L2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 25-26, 303-310, and amino acid sequences DDS, DVS, EDS, DDT, DDK, DDL, and DDN; and the CDR-L3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 27-31, 311-327, and 367-370.

[0011] In certain embodiments, the dose is about 125 mg, about 250 mg, about 500 mg, or about 1,000 mg. In certain embodiments, the dose is about 125 mg. In certain embodiments, the dose is about 250 mg. In certain embodiments, the dose is about 500 mg. In certain embodiments, the dose is about 1,000 mg.

[0012] In certain embodiments, the CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 1-3; the -H2 comprises an amino acid sequence set forth in SEQ ID NO: 10; the CDR-H3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 13-15, the CDR-L1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 19-21 and 271-288, the CDR-L2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 25-26 and 303-310; and the CDR-L3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 27-31 and 311-327.

[0013] In certain embodiments, the CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 4-6; the CDR-H2 comprises an amino acid sequence set forth in SEQ ID NO: 11; the CDR-H3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 13-15, the CDR -LI comprises an amino acid sequence set forth in any one of SEQ ID NOs: 19-21 and 271-288, the CDR-L2 comprises an amino acid sequence set forth in anyAttorney Docket No.: AOE-008WOAOJ-036PC one of SEQ ID NOs: 25-26 and 303-310; and the CDR-L3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 27-31 and 311-327.

[0014] In certain embodiments, the CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 7-9; the CDR-H2 comprises an amino acid sequence set forth in SEQ ID NO: 12; the CDR-H3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 16-18; the CDR-L1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 22-24, 289-302, and 387, the CDR-E2 comprises an amino acid sequence of any one of amino acid sequences DDS, DVS, EDS, DDT, DDK, DDL, and DDN; and the CDR-L3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 27-31 and 311-327.

[0015] In certain embodiments, the CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 1, 4, and 7, the CDR-H2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, the CDR-H3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, the CDR-L1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 19 and 22, the CDR-L2 comprises an amino acid sequence set forth in SEQ ID NO: 25 or the amino acid sequence DVS, and the CDR-L3 comprises an amino acid sequence set forth in SEQ ID NO: 27.

[0016] In certain embodiments, the CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 2, 5, and 8, the CDR-H2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, the CDR-H3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, the CDR-L1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 19 and 22, the CDR-L2 comprises an amino acid sequence set forth in SEQ ID NO: 25 or the amino acid sequence DVS, and the CDR-L3 comprises an amino acid sequence set forth in SEQ ID NO: 28.

[0017] In certain embodiments, the CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 2, 5, and 8, the CDR-H2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, the CDR-H3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 14 and 17, the CDR-L1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 20 and 23, the CDR-L2 comprises an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and the CDR-L3 comprises an amino acid sequence set forth in SEQ ID NO: 28.

[0018] In certain embodiments, the CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 2, 5, and 8, the CDR-H2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, the CDR-H3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, the CDR-L1 comprises an aminoAttorney Docket No.: AOE-OQ8WOAOJ-036PC acid sequence set forth in any one of SEQ ID NOs: 21 and 24, the CDR-L2 comprises an amino acid sequence set forth in SEQ ID NO: 25 or the amino acid sequence DVS, and the CDR-L3 comprises an amino acid sequence set forth in SEQ ID NO: 28.

[0019] In certain embodiments, the CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, the CDR-H2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, the CDR-H3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, the CDR-L1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 21 and 24, the CDR-L2 comprises an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and the CDR-L3 comprises an amino acid sequence set forth in SEQ ID NO: 27.

[0020] In certain embodiments, the CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, the CDR-H2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, the CDR-H3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 15 and 18, the CDR-L1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 21 and 24, the CDR-L2 comprises an amino acid sequence set forth in SEQ ID NO: 25 or the amino acid sequence DVS, and the CDR-L3 comprises an amino acid sequence set forth in SEQ ID NO: 29.

[0021] In certain embodiments, the CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, the CDR-H2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, the CDR-H3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, the CDR-L1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 19 and 22, the CDR-L2 comprises an amino acid sequence set forth in SEQ ID NO: 25 or the amino acid sequence DVS, and the CDR-L3 comprises an amino acid sequence set forth in SEQ ID NO: 30.

[0022] In certain embodiments, the CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 1, 4, and 7, the CDR-H2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, the CDR-H3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, the CDR-L1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 19 and 22, the CDR-L2 comprises an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and the CDR-L3 comprises an amino acid sequence set forth in SEQ ID NO: 31.

[0023] In certain embodiments, the CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 2, 5, and 8, the CDR-H2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, the CDR-H3 comprises an amino acidAttorney Docket No.: AOE-008WOAOJ-036PC sequence set forth in any one of SEQ ID NOs: 15 and 18, the CDR-L1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 21 and 24, the CDR-L2 comprises an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and the CDR-L3 comprises an amino acid sequence set forth in SEQ ID NO: 28.

[0024] In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a heavy chain variable domain (VH) sequence selected from a sequence set forth in any one of SEQ ID NOs: 32-36 and 386.

[0025] In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a light chain variable domain (VL) sequence selected from a sequence set forth in any one of SEQ ID NOs: 37-45, 328-364, and 371-385.

[0026] In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence selected from an amino acid sequence set forth in any one of SEQ ID NOs: 32-36 and 386, and a VL sequence selected from an amino acid sequence set forth in any one of SEQ ID NOs: 37-45, 328-364, and 371-385.

[0027] In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence selected from an amino acid sequence set forth in any one of SEQ ID NOs: 32-36 and 386, and a VL sequence selected from an amino acid sequence set forth in any one of SEQ ID NOs: 37-45, 328-364, and 371-385.

[0028] In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 32 and a VL sequence set forth in SEQ ID NO: 37.

[0029] In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 33 and a VL sequence set forth in SEQ ID NO: 38.

[0030] In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 386 and a VL sequence set forth in SEQ ID NO: 39.

[0031] In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 33 and a VL sequence set forth in SEQ ID NO: 40.

[0032] In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 41.Attorney Docket No.: AOE-OQ8WOAOJ-036PC

[0033] In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 35 and a VL sequence set forth in SEQ ID NO: 42.

[0034] In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 43.

[0035] In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 32 and a VL sequence set forth in SEQ ID NO: 44.

[0036] In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 36 and a VL sequence set forth in SEQ ID NO: 45.

[0037] In certain embodiments, the antibody, or antigen binding fragment thereof, is a humanized, human or chimeric antibody.

[0038] In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a heavy chain human constant region of a class selected from IgG, IgA, IgD, IgE, and IgM. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a human Fc region comprising a human heavy chain constant region of the class IgG and a subclass selected from IgGl, IgG2, IgG3, and IgG4. In certain embodiments, the human Fc region comprises a human IgGl Fc region. In certain embodiments, the human Fc region comprises a human IgG4 Fc region. In certain embodiments, the human Fc region comprises a human IgG2 Fc region.

[0039] In certain embodiments, the antibody, an antigen binding fragment thereof, comprises a heavy chain comprising a constant heavy chain sequence selected from the sequences set forth in SEQ ID NOs: 47-270. In some embodiments, the antibody, or antigen binding fragment thereof, comprises a constant heavy chain sequence set forth in SEQ ID NO: 61 or SEQ ID NO: 173.

[0040] In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a light chain comprising a constant light chain sequence set forth in SEQ ID NO: 46.

[0041] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a light chain comprising a human lambda light chain constant region. In some embodiments, the human lambda light chain constant region comprises a sequence set forthAttorney Docket No.: AOE-OQ8WOAOJ-036PC in any one of SEQ ID NOs: 442-445. In some embodiments, the human lambda light chain constant region comprises a sequence set forth in SEQ ID NO: 442.

[0042] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises an Fc region comprising one or more amino acid substitutions, wherein the one or more amino acid substitutions result in an increase in one or more of antibody half-life, ADCC activity, ADCP activity, or CDC activity compared with the Fc region without the one or more amino acid substitutions. In certain embodiments, the Fc region comprises one or more amino acid substitutions, wherein the one or more amino acid substitutions result in a decrease in one or more of ADCC activity, ADCP activity or CDC activity compared to an antibody comprising a wild-type Fc region.

[0043] In certain embodiments, the one or more amino acid substitutions is selected from the group consisting of S228P, M252Y, S254T, T256E, T256D, T250Q, H285D, T307A, T307Q, T307R, T307W, L309D, Q411H, Q311V, A378V, E380A, M428L, N434A, N434S, N297A, D265A, L234A, L235A, and N434W (or e.g., L239A, L240A, M257Y, S259T, and T261E using direct numbering); optionally, wherein 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 (LALA), M428L / N434A (LA), L235A / G237A (LAGA), L234A / L235A / G237A (LALAGA), L234A / L235A / P329G (LALAPG), 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. In some embodiments, theAttorney Docket No.: AOE-OQ8WOAOJ-036PC one or more amino acid substitutions is selected from the group consisting of LS, YTE, T250Q / M428L, T307A / E380A / N434A, DQ, DW, YD, QVV, DHS, LA, 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 / 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, N297A / QVV, D265A / QVV, LALA / QVV, LAGA / QVV, LALAGA / QVV, and LALAPG / QVV. In certain embodiments, the one or more amino acid substitutions comprises L234A / L235A (LALA). In certain embodiments, the one or more amino acid substitutions comprises LALAGA and N434A. In certain embodiments, the one or more amino acid substitutions comprises M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS). In certain embodiments, the one or more amino acid substitutions comprises YTE and LALA. In certain embodiments, the one or more amino acid substitutions comprise YTE at positions 257 / 259 / 261, respectively, (M257Y / S259T / T261E by direct numbering) and LALA mutations at positions 239 / 240, respectively (L239A / L240A by direct numbering).

[0044] In certain embodiments, the Fc region binds to Neonatal Fc receptor (FcRn). In certain embodiments, the Fc region binds an FcRn with higher affinity at pH 6.0 compared to an antibody comprising a wild-type Fc region.

[0045] In certain embodiments, the antibody, or antigen binding fragment thereof, is a monoclonal antibody.

[0046] In certain embodiments, the antibody, or antigen binding fragment thereof, binds a TSLP sequence set forth in SEQ ID NO: 365 or 366.

[0047] In certain embodiments, the inflammatory disorder or disease comprises atopic dermatitis (AD). In certain embodiments, the treatment reduces disease severity in the subject and wherein disease severity is assessed by an atopic dermatitis disease severity outcome measure. In certain embodiments, the inflammatory disorder or disease comprises asthma. In certain embodiments, the inflammatory disorder or disease comprises chronic sinusitis with nasal polyps. In certain embodiments, the inflammatory disorder or disease comprises Chronic Rhinosinusitis without Nasal Polyps (CRSsNP). In certain embodiments, the inflammatory disorder or disease comprises eosinophilic esophagitis (EoE). In certainAttorney Docket No.: AOE-008WOAOJ-036PC embodiments, the inflammatory disorder or disease comprises an Eosinophilic gastrointestinal disorder or disease (EGID) selected from the group consisting of Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), Eosinophilic Colitis (EoC), and Eosinophilic Gastroenteritis (EGE). In certain embodiments, the inflammatory disorder or disease comprises Churg-Strauss syndrome / Eosinophilic granulomatosis with polyangiitis (EGPA). In certain embodiments, the inflammatory disorder or disease comprises Prurigo Nodularis (PN). In certain embodiments, the inflammatory disorder or disease comprises Chronic Spontaneous Urticaria (CSU). In certain embodiments, the inflammatory disorder or disease comprises Chronic Pruritis of Unknown Origin (CPUO). In certain embodiments, the inflammatory disorder or disease comprises Bullous Pemphigoid (BP). In certain embodiments, the inflammatory disorder or disease comprises Cold Inducible Urticaria (ColdU). In certain embodiments, the inflammatory disorder or disease comprises Allergic Fungal Rhinosinusitis (AFRS). In certain embodiments, the inflammatory disorder or disease comprises Allergic Bronchopulmonary Aspergillosis (ABPA). In certain embodiments, the inflammatory disorder or disease comprises Chronic Obstructive Pulmonary Disease (COPD). In certain embodiments, the inflammatory disorder or disease comprises Crohn’s disease. In certain embodiments, the inflammatory disorder or disease comprises lupus. In certain embodiments, the inflammatory disorder or disease comprises rheumatoid arthritis (RA). In certain embodiments, the inflammatory disorder or disease comprises psoriasis. In certain embodiments, the inflammatory disorder or disease comprises ulcerative colitis. In certain embodiments, the inflammatory disorder or disease comprises hidradenitis suppurativa. In certain embodiments, the inflammatory disorder or disease comprises celiac disease. In certain embodiments, the inflammatory disorder or disease comprises systemic sclerosis. In certain embodiments, the inflammatory disorder or disease comprises idiopathic pulmonary fibrosis. In certain embodiments, the inflammatory disorder or disease comprises alopecia areata.

[0048] In certain embodiments, the subject is a human.BRIEF DESCRIPTION OF THE DRAWINGS

[0049] FIG. 1 shows the concentration of Antibody 5 over time following single dose administration of Antibody 5 at 125 mg, 250 mg, 500 mg or 1000 mg.

[0050] FIG. 2 shows blood eosinophil counts as percent change from baseline over time following single dose administration of Antibody 5 at 125 mg, 250 mg, 500 mg or 1000 mg as compared to placebo.Attorney Docket No.: AOE-008WOAOJ-036PC

[0051] FIG. 3 shows serum IL-5 levels as percent change from baseline over time following single dose administration of Antibody 5 at 125 mg, 250 mg, 500 mg or 1000 mg as compared to placebo.

[0052] FIG. 4 shows serum IL- 13 levels as percent change from baseline over time following single dose administration of Antibody 5 at 125 mg, 250 mg, 500 mg or 1000 mg as compared to placebo.

[0053] FIG. 5 shows serum IgE levels as percent change from baseline over time following single dose administration of Antibody 5 at 125 mg, 250 mg, 500 mg or 1000 mg as compared to placebo.DETAILED DESCRIPTIONDefinitions

[0054] 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.

[0055] As used herein, the singular forms “a,” “an,” and “the” include plural references unless indicated otherwise.

[0056] It is understood that aspects and embodiments of the invention described herein include “comprising,” “consisting,” and “consisting essentially of’ aspects and embodiments.

[0057] 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 theAttorney Docket No.: AOE-OQ8WOAOJ-036PC 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.

[0058] The term “vector,” as used herein, refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes the vector as a selfreplicating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as “expression vectors.”

[0059] The terms “host cell,” “host cell line,” and “host cell culture” are used interchangeably herein and refer to cells into which an exogenous nucleic acid has been introduced, and the progeny of such cells. Host cells include “transformants” (or “transformed cells”) and “transfectants” (or “transfected cells”), which each include the primary transformed or transfected cell and progeny derived therefrom. Such progeny may not be completely identical in nucleic acid content to a parent cell, and may contain mutations. A “recombinant host cell” or “host cell” refers to a cell that includes an exogenous polynucleotide, regardless of the method used for insertion, for example, direct uptake, transduction, f-mating, or other methods known in the art to create recombinant host cells.

[0060] As used herein, the term “eukaryote” refers to organisms belonging to the phylogenetic domain Eukarya, such as animals (including but not limited to, mammals, insects, reptiles, birds, etc.), ciliates, plants (including but not limited to, monocots, dicots, algae, etc.), fungi, yeasts, flagellates, microsporidia, protists, etc.

[0061] As used herein, the term “prokaryote” refers to prokaryotic organisms. For example, a non-eukaryotic organism can belong to the Eubacteria (including but not limited to, Escherichia coli, Thermits thermophilus, Bacillus stearothermophilus, Pseudomonas fluorescens. Pseudomonas aeruginosa, Pseudomonas putida, etc.) phylogenetic domain, orAttorney Docket No.: AOE-OQ8WOAOJ-036PC the Archaea (including but not limited to, Methanococcus jannaschii, Methanobacterium thermoautotrophicum, Halobacterium such as Haloferax volcanii and Halobacterium species NRC-1, Archaeoglobus fulgidus, Pyrococcus furiosus, Pyrococcus horikoshii, Aeuropyrum pernix, etc.) phylogenetic domain.

[0062] An “effective amount” or “therapeutically effective amount” as used herein refers to an amount of therapeutic compound, such as an anti-TSLP antibody, or antigen binding fragment thereof, 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 reducing an aberrant immune response, slowing or delaying disease development; stabilization of disease; and amelioration of one or more symptoms. An effective amount may be given in one or more dosages.

[0063] 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, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.

[0064] 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.

[0065] As used herein, the terms “subject,” “patient,” and “individual” are used interchangeably and each temi 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 some embodiments the subject has a disease or condition that can be treated with an antibody, or antigen binding fragment thereof, provided herein. In some aspects, the disease or condition is atopic dermatitis. In some aspects, the disease or condition is asthma.

[0066] The term “zn vitro” refers to processes that occur in a living cell growing separate from a living organism, e.g., growing in tissue culture.

[0067] The term “in vivo” refers to processes that occur in a living organism.

[0068] The term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic or diagnostic products e.g., kits) that contain information about the indications, usage, dosage, administration, combination therapy,Attorney Docket No.: AOE-OQ8WOAOJ-036PC contraindications, and / or warnings concerning the use of such therapeutic or diagnostic products.

[0069] 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.

[0070] As used herein, the term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms, which are suitable for contact with the tissues of a subject, such as a mammal (e.g., a human) without excessive toxicity, irritation, allergic response, and other problem complications commensurate with a reasonable benefit / risk ratio. Preferably, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals and more particularly in humans.

[0071] The terms “co-administration,” “co-administer,” and “in combination with” include the administration of two or more therapeutic agents either simultaneously, concurrently or sequentially within no specific time limits. In one embodiment, the agents are present in the cell or in the subject's body at the same time or exert their biological or therapeutic effect at the same time. In one embodiment, the therapeutic agents are in the same composition or unit dosage form. In other embodiments, the therapeutic agents are in separate compositions or unit dosage forms. In certain embodiments, a first agent can be administered prior to the administration of a second therapeutic agent.

[0072] The terms “modulate” and “modulation” refer to reducing or inhibiting or, alternatively, activating or increasing, a recited variable.

[0073] 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.

[0074] 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.

[0075] 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).Attorney Docket No.: AOE-OQ8WOAOJ-036PC

[0076] The term “agonize” refers to the activation of receptor signaling to induce a biological response associated with activation of the receptor. An “agonist” is an entity that binds to and agonizes a receptor.

[0077] The term “antagonize” refers to the inhibition of receptor signaling to inhibit a biological response associated with activation of the receptor. An “antagonist” is an entity that binds to and antagonizes a receptor.

[0078] For any of the structural and functional characteristics described herein, methods of determining these characteristics are known in the art.

[0079] The term “optionally” is meant, when used sequentially, to include from one to all of the enumerated combinations and contemplates all sub-combinations.

[0080] The term “amino acid” refers to, for example, 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).

[0081] 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).

[0082] 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.

[0083] The term “ka” (M-lxsec-1), as used herein, refers to the association rate constant of a particular antibody- anti gen interaction. This value is also referred to as the kon value.

[0084] The term “KD” (M), as used herein, refers to the dissociation equilibrium constant of a particular antibody-antigen interaction. KD = kd / ka. In some 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.

[0085] The term “KA” (M-l), as used herein, refers to the association equilibrium constant of a particular antibody-antigen interaction. KA = ka / kd.

[0086] As used herein, “administration” refers to providing or giving a subject a therapeutic agent (e.g., an anti-TSLP antibody, or an antigen binding fragment thereof,Attorney Docket No.: AOE-OQ8WOAOJ-036PC described herein) by any effective route. Exemplary routes of administration are described herein below.

[0087] As used herein, the term “polypeptide” describes a single polymer in which the monomers are amino acid residues which are covalently conjugated together through amide bonds. A polypeptide is intended to encompass any amino acid sequence, either naturally occurring, recombinant, or synthetically produced.

[0088] As used herein, the terms “nucleic acid” and “polynucleotide,” used interchangeably herein, refer to a polymeric form of nucleosides in any length. Typically, a polynucleotide is composed of nucleosides that are naturally found in DNA or RNA (e.g., adenosine, thymidine, guanosine, cytidine, uridine, deoxyadenosine, deoxythymidine, deoxyguanosine, and deoxycytidine) joined by phosphodiester bonds. The term encompasses molecules comprising nucleosides or nucleoside analogs containing chemically- or biologically-modified bases, modified backbones, etc., whether or not found in naturally occurring nucleic acids, and such molecules may be preferred for certain applications. Where this application refers to a polynucleotide it is understood that both DNA, RNA, and in each case both single- and double-stranded forms (and complements of each single-stranded molecule) are provided.

[0089] As used herein, the terms “conservative mutation,” “conservative substitution,” and “conservative amino acid substitution” refer to a substitution of one or more amino acids for one or more different amino acids that exhibit similar physicochemical properties, such as polarity, electrostatic charge, and steric volume. These properties are summarized for each of the twenty naturally occurring amino acids in TABLE 1 below.TABLE 1. Representative physicochemical properties of naturally occurring amino acidsAttorney Docket No.: AOE-008WOAOJ-036PCFrom TABLE 1 it is appreciated that the conservative amino acid families include (i) G, A,V, L, and I; (ii) D and E; (iii) C, S, and T; (iv) H, K, and R; (v) N and Q; and (vi) F, Y, andW. A conservative mutation or substitution is therefore one that substitutes one amino acid for a member of the same amino acid family (e.g., a substitution of Ser for Thr or Lys for Arg).

[0090] The term “antibody” is used herein in its broadest sense and includes certain types of immunoglobulin molecules comprising one or more antigen-binding domains thatAttorney Docket No.: AOE-OQ8WOAOJ-036PC specifically bind to an antigen or epitope. An antibody specifically includes intact antibodies (e.g., intact immunoglobulins), antibody fragments, and multi-specific antibodies.

[0091] An “anti-TSLP antibody,” “TSLP antibody,” or “TSLP specific antibody” is an antibody, as provided herein, which specifically binds to the antigen TSLP.

[0092] The term “epitope” means a portion of an antigen that specifically binds to an antibody.

[0093] 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”).

[0094] The term “antigen-binding domain” means the portion of an antibody that is capable of specifically binding to an antigen or epitope.

[0095] 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.

[0096] The term “human antibody” or “fully 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.

[0097] 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.

[0098] 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.

[0099] 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 (i.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.

[0100] The term “monoclonal antibody” refers to an antibody from a population of substantially homogeneous antibodies. A population of substantially homogeneous antibodiesAttorney Docket No.: AOE-OQ8WOAOJ-036PC 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.

[0101] 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 a polypeptide chain wherein the C-terminal end of the VH is connected to the N-terminal end of VL by a polypeptide chain.

[0102] 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 (HVR)) 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.

[0103] “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.

[0104] “Fv” fragments comprise a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain.

[0105] “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 andAttorney Docket No.: AOE-OQ8WOAOJ-036PCVL 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).

[0106] “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 (z'.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.

[0107] 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 et al., (1998) FEBS Letters 414:521-526 and Muyldermans et al. (2001) Trends in Biochem. Sci. 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).

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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 aboutAttorney Docket No.: AOE-008WOAOJ-036PC30%, 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) of contaminating protein.

[0112] 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.

[0113] 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.

[0114] Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith & Waterman, (1981) Adv. Appl. Math. 2:482, by the homology alignment algorithm of Needleman & Wunsch, (1970) J. Mol. Biol. 48:443, by the search for similarity method of Pearson & Lipman, (1988) Proc. Nat’l. Acad. Sci. USA 85:2444, 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., supra).

[0115] One example of an algorithm that is suitable for determining percent sequence identity and sequence similarity is the BLAST algorithm, which is described in Altschul et al. (1990) J. Mol. Biol. 215:403-410. Software for performing BLAST analyses is publiclyAttorney Docket No.: AOE-OQ8WOAOJ-036PC available through the National Center for Biotechnology Information (www.ncbi.nlm.nih.gov / ).

[0116] 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.

[0117] 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.

[0118] The term “atopic dermatitis disease severity outcome measure” refers to a determination of certain signs, symptoms, features or parameters that have been associated with atopic dermatitis and that can be quantitatively or qualitatively assessed. Exemplary atopic dermatitis disease severity outcome measures include “Eczema Area and Severity Index” (EASI), “Severity Scoring of Atopic Dermatitis” (SCORAD), “Validated Investigator Global Assessment- Atopic Dermatitis” (vIGA-AD), “Investigator Global Assessment of Signs” (IGSA), Rajka / Langeland Atopic Dermatitis Severity Score, “Body Surface Area” (BSA), and patient-reported outcomes including Pruritus Visual Analog Scale (an aspect of disease severity assessed as part of SCORAD), Sleep Loss Visual Analog Scale (an aspect of disease severity assessed as part of SCORAD), Atopic Dermatitis Symptom Diary (ADSD), Atopic Dermatitis Impact Questionnaire (ADIQ), Dermatology Life Quality Index (DLQI) (Finlay and Khan, Clin Exper Dermatol 1994;19:210), 5-D Itch Scale (Elman et al., Br J Dermatol 2010; 162(3): 587-593), Itch Numeric Rating Scale (I-NRS) (see Naegeli et al., International Journal of Dermatology. 2015;54(6):715-722; and Newton L, et al., J. Patient Rep. Outcomes. 2019;3(1):42), and the Patient-Oriented Eczema Measure (POEM) (www.nottingham.ac.uk / research / groups / cebd / resources / poem.aspx).TSLP Binding ProteinsAntibody Structure

[0119] Provided herein are TSLP binding proteins that bind to TSLP. In certain embodiments, the TSLP binding protein is an antibody, or an antigen binding fragment thereof. In certain embodiments, the TSLP binding protein is an antibody, or an antigen binding fragment thereof, comprising a modified Fc region.Attorney Docket No.: AOE-OQ8WOAOJ-036PC

[0120] 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. There are four subtypes of human lambda light chain constant region (Xi, X2, , X7), which are encoded by the genes IGLC1, IGCL2, IGLC3, and IGLC7. 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, 6, 8, y, and p, respectively.

[0121] 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 terns variable light chain (VL) and variable heavy chain (VH) refer to these light and heavy chain domains, respectively. The IgGl heavy chain comprises the VH, CHI, CH2, and CH3 domains, respectively from the N- to C-terminus. The light chain comprises 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 is 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.

[0122] 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.Attorney Docket No.: AOE-008WOAOJ-036PC

[0123] 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.

[0124] Generally, native four-chain antibodies comprise six HVRs; three in the VH (Hl, H2, H3), and three in the VL (LI, L2, 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. Hypervariable regions (HVRs) are also referred to as “complementarity determining regions” (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 et al., U.S. Dept, of Health and Human Services, Sequences of Proteins of Immunological Interest (1983) and by Chothia et al. (1987) J Mol Biol 196:901-917, 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.

[0125] 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. (2003) Dev. Comp. Immunol. 27:55-77 (“IMGT” numbering scheme); and Honegge and Pliickthun (2001) J. Mol. Biol. 309:657-70 (“AHo” numbering scheme); each of which is incorporated by reference in its entirety.

[0126] TABLE 2 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.

[0127] 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.Attorney Docket No.: AOE-008WO AOJ-036PCTABLE 2. 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.

[0128] 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.

[0129] 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.

[0130] 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-confonnational 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 TSLP variants with different point-mutations, or to chimeric TSLP variants.

[0131] To screen for antibodies which bind to an epitope on a target antigen bound by an antibody of interest (e.g., TSLP), 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.Attorney Docket No.: AOE-OQ8WOAOJ-036PC

[0132] 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.

[0133] Human, or fully human, antibodies are antibodies 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.

[0134] 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. (1986) Nature 321 :522-525; Riechmann et al. (1988) Nature 332:323-329; and Presta (1992) Curr. Op. Struct. Biol. 2:593-596, each of which is incorporated by reference in its entirety.

[0135] Anti- TSLP 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.Attorney Docket No.: AOE-OQ8WOAOJ-036PC

[0136] In some embodiments, the antibodies are monoclonal antibodies.

[0137] In some embodiments, the antibodies are polyclonal antibodies.

[0138] 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.

[0139] 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.

[0140] In some embodiments, the antibodies may be polyfunctional antibodies, recombinant antibodies, fully human antibodies, humanized antibodies, or fragments or variants thereof. In particular embodiments, the antibody fragment or a derivative thereof is selected from a Fab fragment, a F(ab')2 fragment, a CDR, and scFv.Attorney Docket No.: AOE-008WOAOJ-036PCTABLE 3. Sequences of anti-TSLP antibody constructs - CDRsAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCTABLE 4. Sequences of anti-TSLP antibody constructs - VH and VLAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCTABLE 5. Sequences of additional anti-TSLP antibody constructs - CDRsAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCTABLE 6. Sequences of anti-TSLP antibody constructs - VH and VLAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCVH Domains

[0141] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a VH sequence selected from any one of SEQ ID NOs: 32-36 and 386.

[0142] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to an illustrative VH sequence provided in any one of SEQ ID NOs: 32-36 and 386. In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a VH sequence provided in any one of SEQ ID NOs: 32-36 and 386, 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 aspects, 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

[0143] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a VL sequence selected from any one of SEQ ID NOs: 37-45, 328-364, 371-379, and 381-385.

[0144] In some embodiments, an antibody, or an antigen binding fragment thereof, 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 any one of SEQ ID NOs: 37-45, 328-364, 371-379, and 381-385. In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a VL sequence provided in any one of SEQ ID NOs: 37-45, 328-364, 371-379, and 381-385, 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 aspects, 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, byAttorney Docket No.: AOE-OQ8WOAOJ-036PC 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

[0145] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a VH sequence selected from any one of SEQ ID NOs: 32-36 and 386; and a VL sequence selected from any one of SEQ ID NOs: 37-45, 328-364, 371-379, and 381- 385.

[0146] In certain aspects, any one of SEQ ID NOs: 32-36 and 386 can be combined with any one of SEQ ID NOs: 37-45, 328-364, 371-379, and 381-385.

[0147] In certain aspects, an antibody, or antigen binding fragment thereof, provided herein comprises a VH sequence and a VL sequence of a construct provided in TABLE 4 (e.g., a VH sequence and a VL sequence from the same row of TABLE 4).

[0148] In certain aspects, an antibody provided herein, or antigen binding fragment thereof, comprises a VH sequence and a VL sequence of a construct provided in TABLE 6 (e.g., a VH sequence and a VL sequence from the same row of TABLE 6).

[0149] In certain aspects, an antibody, or an antigen binding fragment thereof, provided herein comprises a VH sequence and a VL sequence of a construct provided in PCT Application No. PCT / US2025 / 034623, incorporated by reference herein in its entirety. In certain aspects, an antibody, or antigen binding fragment thereof, provided herein comprises a VH sequence and a VL sequence from Table 4 or Table 11 in PCT Application No.PCT / US2025 / 034623 (e.g., a VH sequence and a VL sequence from the same row of Table 4 or Table 11).

[0150] In some embodiments, an antibody, or an antigen binding fragment thereof, 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 any one of SEQ ID NOs: 32-36 and 386; 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 any one of SEQ ID NOs: 37-45, 328-364, 371 -379, and 381 -385. In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a VH sequence provided in any one of SEQ ID NOs: 32-36 and 386, 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 any one ofAttorney Docket No.: AOE-OQ8WOAOJ-036PCSEQ ID NOs: 37-45, 328-364, 371-379, and 381-385, 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 aspects, 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.

[0151] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 32 and a VL sequence set forth in SEQ ID NO: 37.

[0152] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 33 and a VL sequence set forth in SEQ ID NO: 38.

[0153] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 386 and a VL sequence set forth in SEQ ID NO: 39.

[0154] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 33 and a VL sequence set forth in SEQ ID NO: 40.

[0155] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 41.

[0156] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 35 and a VL sequence set forth in SEQ ID NO: 42.

[0157] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 43.

[0158] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 32 and a VL sequence set forth in SEQ ID NO: 44.Attorney Docket No.: AOE-OQ8WOAOJ-036PC

[0159] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 36 and a VL sequence set forth in SEQ ID NO: 45.

[0160] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 328.

[0161] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 329.

[0162] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 330.

[0163] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 331.

[0164] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 332.

[0165] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 333.

[0166] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 334.

[0167] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 335.

[0168] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 336.

[0169] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 337.Attorney Docket No.: AOE-OQ8WOAOJ-036PC

[0170] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 338.

[0171] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 339.

[0172] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 340.

[0173] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 341.

[0174] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 342.

[0175] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 343.

[0176] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 344.

[0177] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 345.

[0178] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 346.

[0179] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 347.

[0180] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 348.Attorney Docket No.: AOE-OQ8WOAOJ-036PC

[0181] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 349.

[0182] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 350.

[0183] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 351.

[0184] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 352.

[0185] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 353.

[0186] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 354.

[0187] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 355.

[0188] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 356.

[0189] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 357.

[0190] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 358.

[0191] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 359.Attorney Docket No.: AOE-OQ8WOAOJ-036PC

[0192] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 360.

[0193] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 361.

[0194] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 362.

[0195] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 363.

[0196] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 364.

[0197] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 371.

[0198] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 372.

[0199] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 373.

[0200] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 374.

[0201] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 375.

[0202] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 376.Attorney Docket No.: AOE-008WOAOJ-036PC

[0203] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 377.

[0204] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 378.

[0205] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 379.

[0206] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 381.

[0207] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 382.

[0208] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 383.

[0209] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 384.

[0210] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 35 and a VL sequence set forth in SEQ ID NO: 385.

[0211] In certain embodiments of any of the antibodies or antigen binding fragments thereof described above, the antibody further comprises a heavy chain comprising a human IgG sequence selected from a sequence set forth in any one of SEQ ID NOs: 47-270. In certain embodiments, the heavy chain comprises a human IgG sequence selected from SEQ ID NO: 61 and SEQ ID NO: 173.

[0212] Although a C-terminal lysine may be present in the corresponding coding sequence of the constant heavy chain region (e.g., in a sequence encoding any one of SEQ ID NOs: 159-270), it may be cleaved off during manufacture or after administration (resulting in, e.g., a constant heavy chain sequence of any one of SEQ ID NOs: 47-158). Accordingly,Attorney Docket No.: AOE-008WOAOJ-036PC any of the antibodies or antigen binding fragments thereof described above may comprise a human IgG sequence containing a C-terminal lysine (e.g., any one of SEQ ID NOs: 159-270), a human IgG sequence lacking a C-terminal lysine (e.g., any one of SEQ ID NOs: 47-158), or a mixture thereof e.g., a mixture of the same heavy chain constant sequence with and without a C-terminal lysine, such as a mixture of SEQ ID NO: 173 and SEQ ID NO: 61).

[0213] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34; a VL sequence set forth in SEQ ID NO: 441; and the antibody further comprises a heavy chain comprising a human IgG sequence selected from a sequence set forth in any one of SEQ ID NOs: 47-270 (e.g., SEQ ID NOs: 47-50, 52-162, and 164-270, such as SEQ ID NO: 173 or SEQ ID NO: 61).

[0214] In certain embodiments of any of the antibodies, or an antigen binding fragments thereof, described above, the antibody further comprises a constant light chain sequence comprising a sequence set forth in any one of SEQ ID NOs: 442-445 (e.g., SEQ ID NO: 442).

[0215] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34, a VL sequence set forth in SEQ ID NO: 41, a heavy chain constant region (e.g., an IgGl Fc region) comprising LALA / YTE substitutions, and a human lambda light chain constant region (e.g., a lambda light chain constant region of subtype 1, 2, 3, or 7, such as a lambda light chain constant region set forth in any one of SEQ ID NOs: 442-445). In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34, a VL sequence set forth in SEQ ID NO: 41, a heavy chain constant region comprising a sequence set forth in SEQ ID NO: 61 or SEQ ID NO: 173, and a light chain constant region comprising a sequence set forth in SEQ ID NO: 442. In certain embodiments, the antibody, or an antigen binding fragment thereof, 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 NO: 34; 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 NO: 41, a heavy chain constant region (e.g., an IgGl Fc region) comprising LALA / YTE substitutions, and a human lambda light chain constant region (e.g., a lambda light chain constant region of subtype 1, 2, 3, or 7, such as a lambda light chain constant region set forth in any one of SEQ ID NOs: 442-445). In certain embodiments, the antibody, or an antigen binding fragment thereof, 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 NO: 34; and aAttorney Docket No.: AOE-008WOAOJ-036PCVL 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 NO: 41, a heavy chain constant region comprising a sequence set forth in SEQ ID NO: 61 or SEQ ID NO: 173 or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 61 or SEQ ID NO: 173, and a light chain constant region comprising a sequence set forth in SEQ ID NO: 442, or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 442.

[0216] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34, a VL sequence set forth in SEQ ID NO: 41, a heavy chain constant region comprising a sequence set forth in SEQ ID NO: 61 or SEQ ID NO: 173, and a light chain constant region comprising a sequence set forth in SEQ ID NO: 442. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 34, a VL sequence set forth in SEQ ID NO: 41, a heavy chain constant region comprising a sequence set forth in SEQ ID NO: 173, and a light chain constant region comprising a sequence set forth in SEQ ID NO: 4442. In some embodiments, the antibody comprises a heavy chain sequence set forth in SEQ ID NO: 446 and / or 448 and a light chain sequence set forth in SEQ ID NO: 447. In some embodiments, the antibody comprises a heavy chain sequence set forth in SEQ ID NO: 446 and a light chain sequence set forth in SEQ ID NO: 447. The heavy chain sequence of SEQ ID NO: 446 contains a C-terminal lysine, which may be cleaved off during manufacture or after administration, resulting in an antibody containing the heavy chain sequence of SEQ ID NO: 448.

[0217] In n certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34, a VL sequence set forth in SEQ ID NO: 43, a heavy chain constant region (e.g., an IgGl Fc region) comprising LALA / YTE substitutions, and a human lambda light chain constant region (e.g., a lambda light chain constant region of subtype 1, 2, 3, or 7, such as a lambda light chain constant region set forth in any one of SEQ ID NOs: 442-445). In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34, a VL sequence set forth in SEQ ID NO: 43, a heavy chain constant region comprising a sequence set forth in SEQ ID NO: 61 or SEQ ID NO: 173, and a light chain constant region comprising a sequence set forth in SEQ ID NO: 442. In certain embodiments, the antibody, or an antigen binding fragment thereof, 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 SEQAttorney Docket No.: AOE-OQ8WOAOJ-036PCID NO: 34; 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 NO: 43, a heavy chain constant region (e.g., an IgGl Fc region) comprising LALA / YTE substitutions, and a human lambda light chain constant region (e.g., a lambda light chain constant region of subtype 1, 2, 3, or 7, such as a lambda light chain constant region set forth in any one of SEQ ID NOs: 442-445). In certain embodiments, the antibody, or an antigen binding fragment thereof, 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 NO: 34; 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 NO: 43, a heavy chain constant region comprising a sequence set forth in SEQ ID NO: 61 or SEQ ID NO: 173 or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 61 or SEQ ID NO: 173, and a light chain constant region comprising a sequence set forth in SEQ ID NO: 442 or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 442.

[0218] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34, a VL sequence set forth in SEQ ID NO: 43, a heavy chain constant region comprising a sequence set forth in SEQ ID NO: 61 or SEQ ID NO: 173, and a light chain constant region comprising a sequence set forth in SEQ ID NO: 442. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 34, a VL sequence set forth in SEQ ID NO: 43, a heavy chain constant region comprising a sequence set forth in SEQ ID NO: 173, and a light chain constant region comprising a sequence set forth in SEQ ID NO: 442. In some embodiments, the antibody comprises a heavy chain sequence set forth in SEQ ID NO: 449 and a light chain sequence set forth in SEQ ID NO: 450. The heavy chain sequence of SEQ ID NO: 449 contains a C- terminal lysine, which may be cleaved off during manufacture or after administration.CDRs

[0219] In some embodiments, disclosed herein is an antibody, or an antigen binding fragment thereof, comprising 1, 2, 3, 4, 5, or 6 of the CDRs of TABLE 3. In some embodiments, disclosed herein is an antibody, or an antigen binding fragment thereof, comprising 6 of the Kabat CDRs of TABLE 3, 6 of the Chothia CDRs of TABLE 3, or 6 of the IMGT CDRs of TABLE 3. In some embodiments, the antibody, or an antigen bindingAttorney Docket No.: AOE-OQ8WOAOJ-036PC fragment thereof, comprises 6 of the Kabat CDRs, 6 of the Chothia CDRs, or 6 of the IMGT CDRs from a single row of TABLE 3 (e.g., 6 CDRs from the same antibody).

[0220] In some embodiments, disclosed herein is an antibody, or an antigen binding fragment thereof, comprising 1, 2, 3, 4, 5, or 6 of the CDRs of TABLE 5. In some embodiments, disclosed herein is an antibody, or an antigen binding fragment thereof, comprising 6 of the Kabat CDRs of TABLE 5, 6 of the Chothia CDRs of TABLE 5, or 6 of the IMGT CDRs of TABLE 5. In some embodiments, the antibody, or an antigen binding fragment thereof, comprises 6 of the Kabat CDRs, 6 of the Chothia CDRs, or 6 of the IMGT CDRs from a single row of TABLE 5 (e.g., 6 CDRs from the same antibody).

[0221] In some embodiments, disclosed herein is an antibody, or an antigen binding fragment thereof, comprising 1, 2, 3, 4, 5, or 6 of the CDRs of an antibody provided in PCT Application No. PCT / US2025 / 034623, incorporated by reference herein in its entirety, such as 1, 2, 3, 4, 5, or 6 of the CDRs in Table 3 or Table 10 in PCT Application No.PCT / US2025 / 034623. In some embodiments, disclosed herein is an antibody, or an antigen binding fragment thereof, comprising 1, 2, 3, 4, 5, or 6 of the Kabat CDRs of an antibody, or an antigen binding fragment thereof, provided in PCT Application No. PCT / US 2025 / 034623. In some embodiments, disclosed herein is an antibody, or an antigen binding fragment thereof, comprising 1, 2, 3, 4, 5, or 6 of the Chothia CDRs of an antibody, or an antigen binding fragment thereof, provided in PCT Application No. PCT / US2025 / 034623. In some embodiments, disclosed herein is an antibody, or an antigen binding fragment thereof, comprising 1, 2, 3, 4, 5, or 6 of the IMGT CDRs of an antibody provided in PCT Application No. PCT / US2025 / 034623. In some embodiments, the antibody, or an antigen binding fragment thereof, comprises 6 of the Kabat CDRs, 6 of the Chothia CDRs, or 6 of the IMGT CDRs from a single row of Table 3 or Table 10 in in PCT Application No.PCT / US2025 / 034623 (e.g., 6 CDRs from the same antibody).

[0222] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises one to three CDRs of a VH domain selected from SEQ ID NOs: 32-36 and 386. In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises two to three CDRs of a VH domain selected from SEQ ID NOs: 32-36 and 386. In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises three CDRs of a VH domain selected from SEQ ID NOs: 32-36 and 386. In some aspects, the CDRs are Exemplary CDRs. In some aspects, the CDRs are Kabat CDRs. In some aspects, the CDRs are Chothia CDRs. In some aspects, the CDRs areAttorney Docket No.: AOE-008WOAOJ-036PCIMGT CDRs. In some aspects, the CDRs are AbM CDRs. In some aspects, the CDRs are Contact CDRs.

[0223] 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 to a CDR-H1, CDR-H2, or CDR-H3 selected from SEQ ID NOs: 1-18. In some embodiments, the CDR-H1 is a CDR-H1 of a VH domain selected from any one of SEQ ID NOs: 32-36 and 386, 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 selected from any one of SEQ ID NO: 32-36 and 386, 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 any one of SEQ ID NOs: 32-36 and 386, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some aspects, 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.

[0224] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises one to three CDRs of a VL domain selected from SEQ ID NOs: 37-45, 328-364, 371-379, and 381-385. In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises two to three CDRs of a VL domain selected from SEQ ID NO: 37-45, 328-364, 371-379, and 381-385. In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises three CDRs of a VL domain selected from SEQ ID NO: 37-45, 328-364, 371-379 and 381-385. In some aspects, the CDRs are Exemplary CDRs. In some aspects, the CDRs are Kabat CDRs. In some aspects, the CDRs are Chothia CDRs. In some aspects, the CDRs are IMGT CDRs. In some aspects, the CDRs are AbM CDRs. In some aspects, the CDRs are Contact CDRs.

[0225] 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 to a CDR-L1, CDR-L2, or CDR-L3 selected from SEQ ID NOs: 19-31, 271-327, 367-370, 387, and amino acid sequences DVS, EDS, DDT, DDK, DDL, DDN, and DDS. In some embodiments, the CDR- L1 is a CDR-L1 of a VL domain selected from any one of SEQ ID NOs: 37-45, 328-364,Attorney Docket No.: AOE-008WOAOJ-036PC371-379, and 381-385, 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 selected from any one of SEQ ID NOs: 37-45, 328-364, 371-379, and 381-385, 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 selected from any one of SEQ ID NOs: 37-45, 328-364, 371-379, and 381-385, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some aspects, 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.

[0226] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises one to three CDRs of a VH domain selected from SEQ ID NOs: 32-36 and 386 and one to three CDRs of a VL domain selected from SEQ ID NOs: 37-45, 328-364, 371-379, and 381-385. In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises two to three CDRs of a VH domain selected from SEQ ID NOs: 32-36 and 386 and two to three CDRs of a VL domain selected from SEQ ID NOs: 37-45, 328-364, 371-379, and 381-385. In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises three CDRs of a VH domain selected from SEQ ID NOs: 32-36 and 386 and three CDRs of a VL domain selected from SEQ ID NOs: 37-45, 328-364, 371-379, and 381-385. In some aspects, the CDRs are Exemplary CDRs. In some aspects, the CDRs are Kabat CDRs. In some aspects, the CDRs are Chothia CDRs. In some aspects, the CDRs are IMGT CDRs. In some aspects, the CDRs are AbM CDRs. In some aspects, the CDRs are Contact CDRs.

[0227] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H3 selected from any one of SEQ ID NOs: 13-18. In some aspects, the CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a CDR-H3 selected from any one of SEQ ID NOs: 13-18. In some embodiments, the CDR-H3 is a CDR-H3 selected from any one of SEQ ID NOs: 13-18, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodiesAttorney Docket No.: AOE-OQ8WOAOJ-036PC 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.

[0228] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 selected from any one of SEQ ID NOs: 1-9. In some aspects, the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a CDR-H1 selected from any one of SEQ ID NOs: 1-9. In some embodiments, the CDR-H1 is a CDR-H1 selected from any one of SEQ ID NOs: 1-9, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some aspects, 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.

[0229] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H2 selected from any one of SEQ ID NOs: 10-12. In some aspects, the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a CDR-H2 selected from any one of SEQ ID NOs: 10-12. In some embodiments, the CDR-H2 is a CDR-H2 selected from any one of SEQ ID NOs: 10-12, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some aspects, 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.Attorney Docket No.: AOE-008WOAOJ-036PC

[0230] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-L3 selected from any one of SEQ ID NOs: 27-31, 311- 327, and 367-370. In some aspects, the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a CDR-L3 selected from any one of SEQ ID NOs: 27-31, 311-327, and 367-370. In some embodiments, the CDR-L3 is a CDR- L3 selected from any one of SEQ ID NOs: 27-31, 311-327, and 367-370, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some aspects, 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.

[0231] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-L2 selected from any one of SEQ ID NOs: 25-26, 303- 310, and amino acid sequences DDS, DVS, EDS, DDT, DDK, DDL, and DDN. In some aspects, the CDR-L2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a CDR-L2 selected from any one of SEQ ID NOs: 25-26, 303-310, and amino acid sequences DDS, DVS, EDS, DDT, DDK, DDL, and DDN. In some embodiments, the CDR-L2 is a CDR-L2 selected from any one of SEQ ID NOs: 25-26, 303- 310, and amino acid sequences DDS, DVS, EDS, DDT, DDK, DDL, and DDN, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some aspects, 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.

[0232] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-L1 selected from any one of SEQ ID NOs: 19-24, 271 - 302, and 387. In some aspects, the CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%,Attorney Docket No.: AOE-008WOAOJ-036PC94%, 95%, 96%, 97%, 98%, or 99% identity to a CDR-L1 selected from any one of SEQ ID NOs: 19-24, 271-302, and 387. In some embodiments, the CDR-L1 is a CDR-L1 selected from any one of SEQ ID NOs: 19-24, 271-302, and 387, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some aspects, 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.

[0233] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H3 selected from any one of SEQ ID NOs: 13-18, a CDR- H2 selected from any one of SEQ ID NOs: 10-12, a CDR-H1 selected from any one of SEQ ID NOs: 1-9, a CDR-L3 selected from any one of SEQ ID NOs: 27-31, 311-327, and 367- 370, a CDR-L2 selected from any one of SEQ ID NOs: 25-26, 303-310, and amino acid sequences DDS, DVS, EDS, DDT, DDK, DDL, and DDN, and a CDR-L1 selected from any one of SEQ ID NOs: 19-24, 271-302, and 387. In some embodiments, the CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a CDR-H3 selected from any one of SEQ ID NOs: 13-18, the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a CDR-H2 selected from any one of SEQ ID NOs: 10-12, the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a CDR-H1 selected from any one of SEQ ID NOs: 1-9, the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a CDR-L3 selected from any one of SEQ ID NOs: 27-31, 311-327, and 367-370, the CDR-L2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a CDR-L2 selected from any one of SEQ ID NOs: 25-26, 303-310, and amino acid sequences DDS, DVS, EDS, DDT, DDK, DDL, DDN, DVS, and DDS, and the CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a CDR-L1 selected from any one of SEQ ID NOs: 19-24, 271- 302, and 387. In some embodiments, the CDR-H3 is a CDR-H3 selected from any one of SEQ ID NOs: 13-18, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H2 is a CDR-H2 selected from any one of SEQ ID NOs: 10-12, with up to 1, 2, 3, 4, 5, 6, 7, or 8Attorney Docket No.: AOE-OQ8WOAOJ-036PC amino acid substitutions: the CDR-H1 is a CDR-H1 selected from any one of SEQ ID NOs: 1-9, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L3 is a CDR-L3 selected from any one of SEQ ID NOs: 27-31, 311-327, and 367-370, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L2 is a CDR-L2 selected from any one of SEQ ID NOs: 25-26, 303-310, and amino acid sequences DDS, DVS, EDS, DDT, DDK, DDL, DDN, DVS, and DDS, with up to 1, 2, 3, or 4 amino acid substitutions; and the CDR-L1 is a CDR-L1 selected from any one of SEQ ID NOs: 19-24, 271-302, and 387, with up to 1, 2, 3, 4, 5, or 6 amino acid substitutions.

[0234] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 3, 6, and 9; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 10, 11, and 12; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 13 and 16; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 21 and 24; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 27. In some embodiments, the CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a CDR-H3 selected from SEQ ID NOs: 13 and 16, the CDR- H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a CDR-H2 selected from SEQ ID NOs: 10, 11, and 12, the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a CDR-H1 selected from SEQ ID NOs: 3, 6, and 9, the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a CDR-L3 of SEQ ID NO: 27, the CDR-L2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a CDR-L2 selected from SEQ ID NO: 26 and the amino acid sequence DDS, and the CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a CDR-L1 selected from SEQ ID NOs: 21 and 24. In some embodiments, the CDR-H3 is a CDR-H3 selected from SEQ ID NOs: 13 and 16, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions: the CDR-H2 is a CDR-H2 selected from SEQ ID NOs: 10, 11, and 12, 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: 3, 6, and 9, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L3 is a CDR-L3 of SEQ ID NO: 27 with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L2 is a CDR-L2 selected from SEQ ID NO: 26 and the amino acid sequence DDS, with up to 1, 2, 3, or 4 amino acid substitutions; and the CDR-L1 is a CDR-Attorney Docket No.: AOE-008WOAOJ-036PCLI selected from SEQ ID NOs: 21 and 24, with up to 1, 2, 3, 4, 5, or 6 amino acid substitutions.

[0235] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 3, 6, and 9; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 10, 11, and 12; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 13 and 16; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 21 and 24; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 27.

[0236] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 3, 6, and 9; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 10, 11, and 12; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 13 and 16; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 19 and 22; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 25 or the amino acid sequence DVS; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 30. In some embodiments, the CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a CDR-H3 selected from SEQ ID NOs: 13 and 16, the CDR- H2 has at least about 80%, 90%, 91%, 92%, 93%. 94%. 95%. 96%, 97%, 98%, or 99% identity to a CDR-H2 selected from SEQ ID NOs: 10, 11, and 12, the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a CDR-H1 selected from SEQ ID NOs: 3, 6, and 9, the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a CDR-L3 of SEQ ID NO: 30, the CDR-L2 has at least about 80%. 90%. 91%. 92%. 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a CDR-L2 selected from SEQ ID NO: 25 and the amino acid sequence DVS, and the CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a CDR-L1 selected from SEQ ID NOs: 19 and 22. In some embodiments, the CDR-H3 is a CDR-H3 selected from SEQ ID NOs: 13 and 16, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H2 is a CDR-H2 selected from SEQ ID NOs: 10, 11, and 12, 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: 3, 6, and 9, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L3 is a CDR-L3 of SEQ ID NO: 30 with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR- L2 is a CDR-L2 selected from SEQ ID NO: 25 and the amino acid sequence DVS, with up toAttorney Docket No.: AOE-008WOAOJ-036PC1, 2, 3, or 4 amino acid substitutions; and the CDR-L1 is a CDR-L1 selected from SEQ ID NOs: 19 and 22, with up to 1, 2, 3, 4, 5, or 6 amino acid substitutions.

[0237] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 3, 6, and 9; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 10, 11, and 12; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 13 and 16; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 19 and 22; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 25 or the amino acid sequence DVS; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 30.

[0238] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 1, 4, and 7, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 19 and 22, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 25 or the amino acid sequence DVS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 27.

[0239] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 2, 5, and 8, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 19 and 22, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 25 or the amino acid sequence DVS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 28.

[0240] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 2, 5, and 8, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 1 1, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 14 and 17, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 20 and 23, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 28.Attorney Docket No.: AOE-008WOAOJ-036PC

[0241] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 2, 5, and 8, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 21 and 24, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 25 or the amino acid sequence DVS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 28.

[0242] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 15 and 18, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 21 and 24, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 25 or the amino acid sequence DVS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 29.

[0243] In some embodiments, an antibody, or an antigen binding fragment thereof, provided comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 1, 4, and 7, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 19 and 22, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 31.

[0244] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 2, 5, and 8, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 15 and 18, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 21 and 24, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 28.Attorney Docket No.: AOE-OQ8WOAOJ-036PC

[0245] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 271 and 289, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 303 or the amino acid sequence DVS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 311.

[0246] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 272 and 290, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 304 or the amino acid sequence EDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 312.

[0247] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 273 and 291, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 313.

[0248] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 273 and 291, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 313.Attorney Docket No.: AOE-OQ8WOAOJ-036PC

[0249] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 273 and 291, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 313.

[0250] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 274 and 292, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 314.

[0251] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 274 and 292, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 314.

[0252] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 273 and 291, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 315.Attorney Docket No.: AOE-OQ8WOAOJ-036PC

[0253] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 275 and 293, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 305 or the amino acid sequence DDT, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 316.

[0254] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 276 and 290, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 317.

[0255] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 273 and 291, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 313.

[0256] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 273 and 291, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 306 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 313.Attorney Docket No.: AOE-OQ8WOAOJ-036PC

[0257] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 274 and 292, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 314.

[0258] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 277 and 291, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 318.

[0259] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 278 and 294, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 318.

[0260] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 273 and 291, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 319.Attorney Docket No.: AOE-OQ8WOAOJ-036PC

[0261] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 279 and 295, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 313.

[0262] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 280 and 296, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 320.

[0263] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 281 and 297, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 321.

[0264] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 282, 298, and 387, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 322.Attorney Docket No.: AOE-OQ8WOAOJ-036PC

[0265] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 274 and 292, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 314.

[0266] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 277 and 291, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 318.

[0267] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 281 and 297, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 323.

[0268] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 276 and 290, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 29.Attorney Docket No.: AOE-OQ8WOAOJ-036PC

[0269] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 283, 298, and 387, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 307 or the amino acid sequence DDK, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 324.

[0270] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 284 and 291, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 313.

[0271] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 285 and 299, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 313.

[0272] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 286 and 300, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 308 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 325.Attorney Docket No.: AOE-OQ8WOAOJ-036PC

[0273] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 274 and 292, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 314.

[0274] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 273 and 291, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 313.

[0275] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 274 and 292, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 314.

[0276] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 273 and 291, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 313.Attorney Docket No.: AOE-OQ8WOAOJ-036PC

[0277] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 281 and 297, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 29.

[0278] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 274 and 292, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 314.

[0279] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 274 and 292, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 326.

[0280] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 287 and 301, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 309 or the amino acid sequence DDL, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 327.Attorney Docket No.: AOE-008WOAOJ-036PC

[0281] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 288 and 302, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 310 or the amino acid sequence DDN, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 29.

[0282] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 19 and 22, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 25 or the amino acid sequence DVS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 368.

[0283] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, a CDR-H2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, a CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, a CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 21 and 24, a CDR-L2 comprising an amino acid sequence set forth in SEQ ID NO: 25 or the amino acid sequence DVS, and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 369.

[0284] In some embodiments, the CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a CDR-H3 of TABLE 3; the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a CDR-H2 of TABLE 3, the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a CDR-H1 of TABLE 3, the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a CDR-L3 of TABLE 3, the CDR-L2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a CDR-L2 of TABLE 3, and the CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a CDR-L1 ofAttorney Docket No.: AOE-OQ8WOAOJ-036PCTABLE 3. In some embodiments, the CDR-H3 is a CDR-H3 of TABLE 3, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H2 is a CDR-H2 of TABLE 3, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H1 is a CDR-H1 of TABLE 3, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L3 is a CDR-L3 of TABLE 3 with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L2 is a CDR-L2 of TABLE 3, with up to 1, 2, 3, or 4 amino acid substitutions; and the CDR-L1 is a CDR-L1 of TABLE 3, with up to 1, 2, 3, 4, 5, or 6 amino acid substitutions.

[0285] In some embodiments, the CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a CDR-H3 of TABLE 5, the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a CDR-H2 of TABLE 5, the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a CDR-H1 of TABLE 5, the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a CDR-L3 of TABLE 5, the CDR-L2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a CDR-L2 of TABLE 5, and the CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a CDR-L1 of TABLE 5. In some embodiments, the CDR-H3 is a CDR-H3 of TABLE 5, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H2 is a CDR-H2 of TABLE 5, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H1 is a CDR-H1 of TABLE 5, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L3 is a CDR-L3 of TABLE 5, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L2 is a CDR-L2 of TABLE 5, with up to 1, 2, 3, or 4 amino acid substitutions; and the CDR-L1 is a CDR-L1 of TABLE 5, with up to 1, 2, 3, 4, 5, or 6 amino acid substitutions.

[0286] In certain embodiments of any of the antibodies or antigen binding fragments thereof described above, the antibody further comprises a heavy chain comprising a human IgG sequence selected from a sequence set forth in any one of SEQ ID NOs: 47-270. In certain embodiments of any of the antibodies or antigen binding fragments thereof described above, the antibody further comprises a constant light chain sequence comprising a sequence set forth in SEQ ID NO: 442. In certain embodiments of any of the antibodies or antigen binding fragments thereof described above, the antibody further comprises a heavy chain comprising a human IgG sequence selected from SEQ ID NO: 61 or SEQ ID NO: 173 and a constant light chain sequence comprising a sequence set forth in SEQ ID NO: 442.Attorney Docket No.: AOE-OQ8WOAOJ-036PC

[0287] In some embodiments, the antibody, or an antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 3, 6, and 9; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 10, 11, and 12; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 13 and 16; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 21 and 24; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS: and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 27. In certain embodiments, the antibody further comprises a heavy chain constant region (e.g., an IgGl constant region) comprising LALA / YTE substitutions. In certain embodiments, the antibody comprises a heavy chain comprising a heavy chain constant region selected from SEQ ID NO: 61 or SEQ ID NO: 173. In certain embodiments, the antibody comprises a human lambda light chain constant region (e.g., a lambda light chain constant region of subtype 1, 2, 3, or 7, such as a lambda light chain constant region set forth in any one of SEQ ID NOs: 442-445). In some embodiments, the antibody comprises a constant light chain sequence comprising a sequence set forth in SEQ ID NO: 442.

[0288] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 3, 6, and 9; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 10, 11, and 12; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 13 and 16; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 19 and 22; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 25 or the amino acid sequence DVS; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 30. In certain embodiments, the antibody further comprises a heavy chain constant region (e.g., an IgGl constant region) comprising LALA / YTE substitutions. In certain embodiments, the antibody comprises a heavy chain comprising a heavy chain constant region selected from SEQ ID NO: 61 or SEQ ID NO: 173. In certain embodiments, the antibody comprises a human lambda light chain constant region (e.g., a lambda light chain constant region of subtype 1, 2, 3, or 7, such as a lambda light chain constant region set forth in any one of SEQ ID NOs: 442-445). In some embodiments, the antibody comprises a constant light chain sequence comprising a sequence set forth in SEQ ID NO: 442.

[0289] In some aspects, 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 derivedAttorney Docket No.: AOE-008WOAOJ-036PC 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.Fc Region

[0290] 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. (2010) Allergy Clin. Immunol. 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.

[0291] 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, IgG2, IgGs, IgG4, IgAi, and IgA2.

[0292] In certain embodiments, provided human IgGl Fc regions include an SRDEL (SEQ ID NO: 469) allotype or an SREEM (SEQ ID NO: 470) allotype.

[0293] 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)).Attorney Docket No.: AOE-008WOAOJ-036PCActivating receptor Fey R II A contains an immunoreceptor tyrosine-based activation motif (IT AM) 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, Amu. 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)).

[0294] 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 that can selectively alter the affinity of the Fc for different Fc-gamma receptors. In some aspects, the Fc comprises one or more modifications designed to promote selective binding of Fc-gamma receptors.

[0295] Exemplary mutations that may alter the binding of FcRs to the Fc are listed below (in EU numbering format):• S298A / E333A / K334A, S298A / E333A / K334A / K326A (Lu Y, Vernes JM, Chiang N, et al., J Immunol Methods. 2011 Feb 28;365(l-2): 132-41);• 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, et al., Breast Cancer Res. 2011 Nov 30;13(6):R123);• F243L (Stewart R, Thom G, Levens M, et al., Protein Eng Des Sei. 2011Sep;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);• S239D / I332E / A330L, S239D / I332E (Lazar GA, Dang W, Karki S, et al., Proc NatlAcad Sci U SA. 2006 Mar 14;103(l l):4005-10);• S239D / S267E, S267E / L328F (Chu SY, Vostiar I, Karki S, et al., Mol Immunol. 2008Sep;45(15):3926-33);• S239D / D265S / S298A / I332E, S239E / S298A / K326A / A327H, G237F / S298A / A330L / I332E, S239D / I332E / S298A, S239D / K326E / A330L / I332E / S298A, G236A / S239D / D270 L / 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.Attorney Docket No.: AOE-OQ8WOAOJ-036PCStrohl, Woodhead Publishing series in Biomedicine No 11, ISBN 1 907568 37 9, Oct 2012) lists mutations on page 283.

[0296] In some embodiments, an antibody, or an antigen binding fragment thereof, described herein includes modifications intended to improve its ability to mediate effector function. Such modifications that can have this effect 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 7 summarizes various designs reported in the literature for effector function engineering.

[0297] 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). Examples of cell lines capable of producing defucosylated antibody include CHO-DG44 with stable overexpression of the bacterial oxi doreduct ase GDP-6-deoxy-D-lyxo-4-hexylose reductase (RMD) {see Henning von Horsten etal., 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; and 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). 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.

[0298] 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.Attorney Docket No.: AOE-OQ8WOAOJ-036PC

[0299] In some aspects, an antibody, or an antigen binding fragment thereof, provided herein comprises an Fc domain (e.g., 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.

[0300] In certain embodiments, an antibody, or an antigen binding fragment thereof, 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 some embodiments, an antibody, or an antigen binding fragment thereof, 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.

[0301] 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, and 2004 / 0109865; International Pat. Pub. Nos. 2000 / 61739, 2001 / 29246, 2003 / 085119, 2003 / 084570, 2005 / 035586, 2005 / 035778; 2005 / 053742, and 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 incoiporated by reference in its entirety.

[0302] In some embodiments, an antibody, or an antigen binding fragment thereof, 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 variants are described, for example, in WO 1997 / 30087; WO 1998 / 58964; and WO 1999 / 22764; each of which is incorporated by reference in its entirety.

[0303] 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 7 that may confer improved effector function. In another embodiment, the antibody can be afucosylated to improve effector function.Attorney Docket No.: AOE-OQ8WOAOJ-036PCTABLE 7. CH2 domains and effector function engineering

[0304] Fc modifications intended 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), each of which is incorporated by reference in its entirety, describe specific modifications intended to reduce FcgR or complement binding to the Fc.

[0305] Specific, non-limiting examples of amino acid modifications intended to reduce FcgR or complement binding to the Fc include those identified in the following TABLE 8:Attorney Docket No.: AOE-008WOAOJ-036PCTABLE 8. Modifications designed to reduce FcgR or complement binding to the Fc

[0306] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises one or more alterations that are designed to improve or diminish 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 incoiporated by reference in its entirety.

[0307] In certain embodiments, the heavy chain comprises a constant heavy chain sequence selected from the sequences set forth in SEQ ID NOs: 47-270. In certain embodiments, the constant heavy chain sequence, (e..g., a constant heavy chain sequence selected from SEQ ID NOs: 47-158) further comprises a C-terminal lysine (SEQ ID NOs: 159-270). Although a C-terminal lysine may be present in the corresponding coding sequence of the constant heavy chain region, it may be cleaved off during manufacture or afterAttorney Docket No.: AOE-008WOAOJ-036PC administration. Accordingly, sequences of heavy chain constant regions with and without the C-terminal lysine are provided herein. Consequently, a composition resulting from the manufacture of an antibody comprising a C-terminal lysine in the corresponding coding sequence of the constant heavy chain region (e.g., an antibody with a coding sequence that encodes any one of SEQ ID NOs: 159-270) may comprise antibodies having a constant heavy chain sequence containing a C-terminal lysine (e.g., selected from any one of SEQ ID NOs: 159-270), antibodies having a constant heavy chain sequence lacking a C-terminal lysine (e.g., the corresponding sequence of any one of SEQ ID NOs: 47-158), or a mixture thereof. For example, a composition comprising an antibody comprising the constant heavy chain sequence of SEQ ID NO: 173 that is administered to a subject may comprise antibodies having the constant heavy chain sequence set forth in SEQ ID NO: 173 or SEQ ID NO: 61, or a mixture thereof (e.g., a mixture of antibodies having either a constant heavy chain sequence of SEQ ID NO: 173 or a constant heavy chain sequence of SEQ ID NO: 61 and / or antibodies containing both constant heavy chain sequences (e.g., in a single antibody containing two constant heavy chain sequences)).

[0308] In certain embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a VH sequence and a VL sequence provided in TABLE 4 (e.g., a VH sequence and a VL sequence from the same row of TABLE 4), together with a heavy chain constant region selected from a sequence set forth in SEQ ID NOs: 47-270. In certain embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a VH sequence and a VL sequence provided in TABLE 4, together with a heavy chain constant region and a light chain constant region selected from the sequences set forth in SEQ ID NOs: 46 and 442-445.

[0309] In certain embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a VH sequence and a VL sequence provided in TABLE 6 (e.g., a VH sequence and a VL sequence from the same row of TABLE 6), together with a heavy chain constant region selected from a sequence set forth in SEQ ID NOs: 47-270. In certain embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a VH sequence and a VL sequence provided in TABLE 6, together with a heavy chain constant region and a light chain constant region selected from the sequences set forth in SEQ ID NOs: 46 and 442-445.

[0310] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ IDAttorney Docket No.: AOE-OQ8WOAOJ-036PCNO: 41; and the constant heavy chain comprises a human IgG sequence selected from a sequence set forth in SEQ ID NOs: 47-270 (e.g., SEQ ID NO: 61 or SEQ ID NO: 173). In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 43; and the constant heavy chain comprises a human IgG sequence selected from a sequence set forth in SEQ ID NOs: 47-270 (e.g., SEQ ID NO: 61 or SEQ ID NO: 173). In certain embodiments, the antibody comprises a human lambda light chain constant region sequence (e.g., any one of SEQ ID NOs: 442-445).

[0311] In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 446 and / or SEQ ID NO: 448. In certain embodiments, the antibody comprises a light chain comprising an amino acid sequence set forth in SEQ ID NO: 447. In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 446 and a light chain comprising an amino acid sequence set forth in SEQ ID NO: 447. The heavy chain sequence of SEQ ID NO: 446 contains a C-terminal lysine, which may be cleaved off during manufacture or after administration, resulting in an antibody containing the heavy chain sequence of SEQ ID NO: 448. In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 448 and a light chain comprising an amino acid sequence set forth in SEQ ID NO: 447.

[0312] In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 449. In certain embodiments, the antibody comprises a light chain comprising an amino acid sequence set forth in SEQ ID NO: 450. In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 449 and a light chain comprising an amino acid sequence set forth in SEQ ID NO: 450.

[0313] In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 451. In certain embodiments, the antibody comprises a light chain comprising an amino acid sequence set forth in SEQ ID NO: 452. In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 451 and a light chain comprising an amino acid sequence set forth in SEQ ID NO: 452.

[0314] In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 453. In certain embodiments, the antibodyAttorney Docket No.: AOE-OQ8WOAOJ-036PC comprises a light chain comprising an amino acid sequence set forth in SEQ ID NO: 454. In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 453 and a light chain comprising an amino acid sequence set forth in SEQ ID NO: 454.

[0315] In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 455. In certain embodiments, the antibody comprises a light chain comprising an amino acid sequence set forth in SEQ ID NO: 456. In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 455 and a light chain comprising an amino acid sequence set forth in SEQ ID NO: 456.

[0316] In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 457. In certain embodiments, the antibody comprises a light chain comprising an amino acid sequence set forth in SEQ ID NO: 458. In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 457 and a light chain comprising an amino acid sequence set forth in SEQ ID NO: 458.

[0317] In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 469. In certain embodiments, the antibody comprises a light chain comprising an amino acid sequence set forth in SEQ ID NO: 460. In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 459 and a light chain comprising an amino acid sequence set forth in SEQ ID NO: 460.

[0318] In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 461. In certain embodiments, the antibody comprises a light chain comprising an amino acid sequence set forth in SEQ ID NO: 462. In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 461 and a light chain comprising an amino acid sequence set forth in SEQ ID NO: 462.

[0319] In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 463. In certain embodiments, the antibody comprises a light chain comprising an amino acid sequence set forth in SEQ ID NO: 464. In certain embodiments, the antibody comprises a heavy chain comprising an amino acidAttorney Docket No.: AOE-008WOAOJ-036PC sequence set forth in SEQ ID NO: 463 and a light chain comprising an amino acid sequence set forth in SEQ ID NO: 464.

[0320] In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 465. In certain embodiments, the antibody comprises a light chain comprising an amino acid sequence set forth in SEQ ID NO: 466. In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 465 and a light chain comprising an amino acid sequence set forth in SEQ ID NO: 466.

[0321] In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 467. In certain embodiments, the antibody comprises a light chain comprising an amino acid sequence set forth in SEQ ID NO: 468. In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 467 and a light chain comprising an amino acid sequence set forth in SEQ ID NO: 468.

[0322] In certain embodiments, the Fc region comprises one or more amino acid substitutions, wherein the one or more amino acid substitutions result in an increase in one or more of antibody half-life, ADCC activity, ADCP activity, or 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. In certain embodiments, the antibody has an increased half-life that is about 10,000-fold, 1,000-fold, 500-fold, 100-fold, 50-fold, 20-fold, 10-fold, 9- fold, 8-fold, 7-fold, 6-fold, 5-fold, 4.5-fold, 4-fold, 3.5-fold, 3-fold, 2.5-fold, 2-fold, 1.95- fold, 1.9-fold, 1.85-fold, 1.8-fold, 1.75-fold, 1.7-fold, 1.65-fold, 1.6-fold, 1.55-fold, 1.50-fold, 1.45-fold, 1.4-fold, 1.35-fold, 1.3-fold, 1.25-fold, 1.2-fold, 1.15-fold, 1.1 -fold, or 1.05-fold longer compared to an antibody comprising a wild-type Fc region. In certain embodiments, the antibody has an increased half-life that is about 10,000-fold, 1,000-fold, 500-fold, 100- fold, 50-fold, 20-fold, 10-fold, 9-fold, 8-fold, 7-fold, 6-fold, 5-fold, 4.5-fold, 4-fold, 3.5-fold, 3-fold, 2.5-fold, 2-fold, 1.95-fold, 1.9-fold, 1.85-fold, 1.8-fold, 1.75-fold, 1.7-fold, 1.65-fold, 1.6-fold, 1.55-fold, 1.50-fold, 1.45-fold, 1.4-fold, 1.35-fold, 1.3-fold, 1.25-fold, 1.2-fold, 1.15-fold, 1.1 -fold, or 1.05-fold longer compared to tezepelumab. In certain embodiments, the antibody has an increased half-life that is about 2.5-fold, 2.4-fold, 2.3-fold, 2.2-fold, 2.1- fold, 2.0-fold, 1.9-fold, or 1.8-fold longer compared to tezepelumab. In certain embodiments,Attorney Docket No.: AOE-OQ8WOAOJ-036PC the one or more amino acid substitutions results in increased antibody half-life in a subject (e.g., in a human subject) compared to an antibody comprising a wild-type Fc region.

[0323] In certain embodiments, an antibody described herein comprises a heavy chain constant domain having a means for increasing the half-life of the antibody.

[0324] In some embodiments, in a non-human primate, the half-life of an anti-TSLP antibody described herein is at least 14, 15, 16, 17, 18, or 19 days when the anti-TSLP antibody is administered intravenously.

[0325] In some embodiments, in a non-human primate, the half-life of an anti-TSLP antibody described herein is at least 17, 18, 19, 20, 21, 22, or 23 days when the anti-TSLP antibody is administered subcutaneously.

[0326] In certain embodiments, the Fc region comprises one or more amino acid substitutions, wherein the one or more substitutions result in a decrease in one or more of ADCC activity, ADCP activity, or CDC activity compared with the Fc without the one or more substitutions.

[0327] 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 (or, e.g., L239A, L240A, M257Y, S259T, and T261E using direct numbering). In certain embodiments, the one or more amino acid substitutions comprises a specific combination of amino acid substitutions selected from the group consisting of M428L / N434S (LS), M252Y / S254T / T256E (YTE) using EU numbering or M257Y / S259T / T261E (YTE) using direct numbering, 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 (LALA) using EU numbering or L239A / L240A (LALA) using direct numbering, M428L / N434A (LA), L235A / G237A (LAGA), L234A / L235A / G237A (LALAGA), L234A / L235A / P329G (LALAPG), 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,Attorney Docket No.: AOE-008WOAOJ-036PCLALA / 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.

[0328] Although the EU numbering system is typically used to identify the positions of the various Fc mutations described herein, direct numbering can also be used. For example, in certain embodiments, an antibody described herein comprises an Fc region with YTE mutations at positions 257, 259, and 261, respectively. In certain embodiments, an antibody described herein comprises an Fc region with EALA mutations at positions 239 and 240, respectively. In certain embodiments, an antibody described herein comprises an Fc region (e.g., an IgGl Fc region) with YTE mutations at positions 257, 259, and 261, respectively, and with LALA mutations at positions 239 and 240, respectively. In certain embodiments, an antibody described herein comprises the VH and VL of Antibody 5 and an Fc region comprising YTE mutations at positions 257, 259, and 261 (M257Y / S259T / T261E), respectively and with LALA mutations at positions 239 and 240 (L239A / L240A), respectively.

[0329] In certain embodiments the human Fc region comprises a human IgGl Fc region with LALA mutations. In certain embodiments, the human Fc region comprises a human IgGl Fc region with YTE mutations. In certain embodiments, the human Fc region comprises a human IgGl Fc region with LALA and YTE mutations. In certain embodiments, when direct numbering is used, “YTE” and “LALA” mutations can be located at different amino acid position numbers. For example, a human Fc region can comprise a human IgGl Fc region with LALA mutations at L239A / L240A and / or YTE mutations at M257Y / S259T / T261E.

[0330] 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.Attorney Docket No.: AOE-008WOAOJ-036PCBinding

[0331] 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®).

[0332] 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 non -target molecule). Specific binding can be measured, for example, by measuring binding to a target molecule (i.e., an TSLP) 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 some embodiments, the affinity of an anti-TSLP antibody, or an antigen binding fragment thereof, for a non-target molecule is less than about 50% of the affinity for TSLP. In some embodiments, the affinity of an anti-TSLP antibody, or an antigen binding fragment thereof, for a non-target molecule is less than about 40% of the affinity for TSLP. In some embodiments, the affinity of an anti-TSLP antibody, or an antigen binding fragment thereof, for a non-target molecule is less than about 30% of the affinity for TSLP. In some embodiments, the affinity of an anti-TSLP antibody, or an antigen binding fragment thereof, for a non-target molecule is less than about 20% of the affinity for TSLP. In some embodiments, the affinity of an anti-TSLP antibody, or an antigen binding fragment thereof, for a non-target molecule is less than about 10% of the affinity for TSLP. In some embodiments, the affinity of an anti-TSLP antibody, or an antigen binding fragment thereof, for a non-target molecule is less than about 1% of the affinity for TSLP. In some embodiments, the affinity of an anti-TSLP antibody, or an antigen binding fragment thereof, for a non-target molecule is less than about 0.1% of the affinity for TSLP.

[0333] 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., TSLP). In one exemplary assay, TSLP is coated on a surface andAttorney Docket No.: AOE-008WOAOJ-036PC contacted with a first anti-TSLP antibody, after which a second anti-TSLP antibody is added. In another exemplary assay, a first anti-TSLP antibody is coated on a surface and contacted with TSLP, and then a second anti-TSLP antibody is added. If the presence of the first anti- TSLP antibody reduces binding of the second anti-TSLP 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 some embodiments, the first and second antibodies inhibit binding of each other, regardless of the order in which they are added. In some 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 TSLP 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.

[0334] 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 TSLP 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%.Attorney Docket No.: AOE-008WOAOJ-036PC

[0335] In certain embodiments, the antibody, or an antigen binding fragment thereof, binds a TSLP sequence set forth in SEQ ID NO: 365 or 366. Provided herein is an antibody or an antigen-binding fragment thereof that binds an epitope of TSLP within amino acids 15- 31 of SEQ ID NO: 365 (YLSTISKDLITYMSGTK; SEQ ID NO: 402). In certain embodiments, the epitope e.g., an epitope of TSLP within amino acids 15-31 of SEQ ID NO: 365 is measured by cross-linking mass spectrometry.

[0336] Also provided herein is an antibody or an antigen-binding fragment thereof that binds an epitope of TSLP within amino acids 20-26 of SEQ ID NO: 365 (SKDLITY; SEQ ID NO: 408) and amino acids 66-70 of SEQ ID NO: 365 (AKEMF; SEQ ID NO: 401) but not amino acids 120-128 of SEQ ID NO: 365 (WRRFNRPLL; SEQ ID NO: 404).

[0337] In certain embodiments, the antibody, or an antigen binding fragment thereof, binds to a TSLP sequence set forth in SEQ ID NO: 365 or 366 with a KD of less than or equal to about I, 2, 3, 4, 5, 6, 7, 8, or 9 x 10’9M, as measured by surface plasmon resonance (SPR). In certain embodiments, the antibody, or an antigen binding fragment thereof, binds to a TSLP sequence set forth in SEQ ID NO: 365 or 366 with a KD of less than or equal to about 1 x 10’10M, as measured by SPR. In certain embodiments, the antibody, or an antigen binding fragment thereof, binds to human TSLP with a KD of less than or equal to about 1 x 10’9M, as measured by SPR.

[0338] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein binds TSLP 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 10’8M, as measured by ELISA or any other suitable method known in the art. In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein binds TSLP 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 10’9M, as measured by ELISA or any other suitable method known in the art.

[0339] In some embodiments, the KD of the antibody, or an antigen binding fragment thereof, provided herein for the binding of TSLP 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 10'8M, as measured by ELISA or any other suitable method known in the art. In some embodiments, an antibody, or an antigen binding fragment thereof, providedAttorney Docket No.: AOE-OQ8WOAOJ-036PC herein binds TSLP with a KD of less than or equal to about 1 x 10’8M, or less than or equal to about 1 x 109M as measured by ELISA or any other suitable method known in the art.

[0340] In some embodiments, the antibody, or an antigen binding fragment thereof, provided herein binds TSLP 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 10'8M, or less, as measured by ELISA or any other suitable method known in the art. In some embodiments, the antibody, or an antigen binding fragment thereof, provided herein binds TSLP 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‘8M as measured by ELISA or any other suitable method known in the art.

[0341] In some embodiments, the antibody, or an antigen binding fragment thereof, provided herein binds FcRn with an affinity at pH 7.4 compared to pH 6.0 at a ratio (pH 7.4 / pH 6.0) of about 10,000, 1,000, 500, 100, 50, 20, 10, 9, 8, 7, 6, 5, 4.5, 4, 3.5, 3, 2.5, 2, 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, or 1.05, as measured by ELISA or any other suitable method known in the art. In some embodiments, the antibody, or an antigen binding fragment thereof, provided herein binds FcRn with an affinity at pH 6.0 compared to pH 7.4 at a ratio (pH 6.0 / pH 7.4) of about 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 10sM as measured by ELISA or any other suitable method known in the art.Function

[0342] “Effector functions’’ refer to those biological activities mediated by the Fc region of an antibody, which activities may vary depending on the antibody isotype. Examples of antibody effector functions include receptor ligand blocking, agonism, or antagonism, Clq binding to activate complement dependent cytotoxicity (CDC), Fc receptor binding to activate antibody-dependent cellular cytotoxicity (ADCC), and antibody dependent cellular phagocytosis (ADCP). In some embodiments, the anti-TSLP antibody described herein includes modifications 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 antibody -dependent cellular cytotoxicity (ADCC), and towards Clq for complement-dependent cytotoxicity (CDC).Attorney Docket No.: AOE-008WOAOJ-036PC

[0343] In some aspects, the anti-TSLP antibody provided herein comprises a Fc domain (e.g., IgGl) with reduced fucose content at position Asn 297 (EU numbering) compared to a naturally occurring Fc domain. Such Fc domains are known to have improved ADCC. In some aspects, such antibodies do not comprise any fucose at position Asn 297.In some embodiments, the anti-TSLP antibody described 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 some embodiments, the anti-TSLP antibody provided herein comprises an Fc region with one or more amino acid substitutions at positions 239, 332, and 330.Pharmaceutical Compositions

[0344] The present application provides compositions comprising the antibodies or antigen binding fragments thereof described herein, including pharmaceutical compositions comprising any one or more of the antibodies or antigen binding fragments thereof described herein with one or more pharmaceutically acceptable excipients. In some embodiments the composition is sterile. The pharmaceutical compositions generally comprise an effective amount of an antibody, or an antigen binding fragment thereof.

[0345] These compositions can comprise, in addition to one or more of the antibodies or antigen binding fragments thereof disclosed herein, a pharmaceutically acceptable excipient, carrier, buffer, stabilizer, or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material can depend on the route of administration, e.g. oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, and intraperitoneal routes.

[0346] Pharmaceutical compositions for oral administration can be in tablet, capsule, powder, or liquid form. A tablet can include a solid carrier such as gelatin or an adjuvant. Liquid pharmaceutical compositions generally include a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil, or synthetic oil. Physiological saline solution, dextrose, or other saccharide solution or glycols such as ethylene glycol, propylene glycol, or polyethylene glycol can be included.

[0347] For intravenous, cutaneous or subcutaneous injection, or injection at the site of affliction, the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity, and stability. Those ofAttorney Docket No.: AOE-OQ8WOAOJ-036PC relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer’s Injection, and Lactated Ringer’s Injection. Preservatives, stabilizers, buffers, antioxidants, and / or other additives can be included, as required.

[0348] For the anti-TSLP antibody, or an antigen binding fragment thereof, that is to be given to an individual, administration is preferably in a “therapeutically effective amount” or “prophylactically effective amount” (as the case can be, although prophylaxis can be considered therapy), this being sufficient to show benefit to the individual. The actual amount administered, and rate and time-course of administration, will depend on a number of factors, e.g., the nature and severity of the disease being treated. Prescription of treatment, e.g. decisions on dosage etc., is within the responsibility of general practitioners and other medical doctors, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration, and other factors known to practitioners. Examples of the techniques and protocols mentioned above can be found in Remington’s Pharmaceutical Sciences, 16th edition, Osol, A. (ed), 1980.

[0349] A composition can be administered alone or in combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated.MethodsMethods of Preparation

[0350] Antibodies or antigen binding fragments thereof described herein can be produced using recombinant methods and compositions, e.g., as described in U.S. Pat. No. 4,816,567. In one embodiment, an isolated nucleic acid encoding an antibody, or an antigen binding fragment thereof, described herein is provided. Such a nucleic acid may encode an amino acid sequence comprising the VL and / or an amino acid sequence comprising the VH of the antibody (e.g., the light and / or heavy chains of the antibody) or an amino acid sequence comprising the VHH of a single domain antibody. In a further embodiment, one or more vectors (e.g., expression vectors) comprising such a nucleic acid are provided. In one embodiment, the nucleic acid is provided in a multicistronic vector. In a further embodiment, a host cell comprising such a nucleic acid is provided. In one such embodiment, a host cell comprises (e.g., has been transformed with): (1) a vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL of the antibody and an amino acid sequence comprising the VH of the antigen-binding polypeptide construct, or (2) a firstAttorney Docket No.: AOE-OQ8WOAOJ-036PC vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL of the antigen-binding polypeptide construct and a second vector comprising a nucleic acid that encodes an amino acid sequence comprising the VH of the antigen-binding polypeptide construct. In one embodiment, the host cell is eukaryotic, e.g. a Chinese Hamster Ovary (CHO) cell, human embryonic kidney (HEK) cell, or lymphoid cell (e.g., YO, NSO, Sp20 cell). In one embodiment, a method of making an antibody is provided, wherein the method comprises culturing a host cell comprising nucleic acid encoding the antibody, as provided above, under conditions suitable for expression of the antibody, and optionally recovering the antibody from the host cell (or host cell culture medium).

[0351] For recombinant production of the antibody, a nucleic acid encoding an antibody, e.g., as described above, is isolated and inserted into one or more vectors for further cloning and / or expression in a host cell. Such a nucleic acid may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the antibody).

[0352] When an antibody or variant thereof is recombinantly produced by the host cells, the protein in certain embodiments is present at about 30%, about 25%, about 20%, about 15%, about 10%, about 5%, about 4%, about 3%, about 2%, or about 1% or less of the dry weight of the cells. When the antibody or variant thereof is recombinantly produced by the host cells, the protein, in certain embodiments, is present in the culture medium at about 5 g / L, about 4 g / L, about 3 g / L, about 2 g / L, about 1 g / L, about 750 mg / L, about 500 mg / L, about 250 mg / L, about 100 mg / L, about 50 mg / L, about 10 mg / L, or about 1 mg / L or less of the dry weight of the cells. In certain embodiments, “substantially purified” antibody produced by the methods described herein, has a purity level of at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, specifically, a purity level of at least about 75%, at least about 80%, at least about 85%, and more specifically, a purity level of at least about 90%, a purity level of at least about 95%, a purity level of at least about 99% or greater as determined by appropriate methods such as SDS / PAGE analysis, RP-HPLC, SEC, and capillary electrophoresis.

[0353] Suitable host cells for cloning or expression of antibody-encoding vectors include prokaryotic or eukaryotic cells described herein.

[0354] Recombinant host cells or host cells are cells that include an exogenous polynucleotide, regardless of the method used for insertion, for example, direct uptake,Attorney Docket No.: AOE-008WOAOJ-036PC transduction, f-mating, or other methods known in the art to create recombinant host cells. The exogenous polynucleotide may be maintained as a nonintegrated vector, for example, a plasmid, or alternatively, may be integrated into the host genome. Host cells can include CHO, derivatives of CHO, NSO, Sp2O, CV-1, VERO-76, HeLa, HepG2, Per.C6, or BHK.

[0355] For example, an antibody may be produced in bacteria, in particular when glycosylation and Fc effector function are not needed. For expression of antibody fragments and polypeptides in bacteria, see, e.g., U.S. Pat. Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology , Vol. 248 (B.K.C. Lo, ed., Humana Press, Totowa, N.J., 2003), pp. 245-254, describing expression of antibody fragments in E. coli.) After expression, the antibody may be isolated from the bacterial cell paste in a soluble fraction and can be further purified.

[0356] In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for antibody -encoding vectors, including fungi and yeast strains whose glycosylation pathways have been “humanized,” resulting in the production of an antibody with a partially or fully human glycosylation pattern. See Gerngross, Nat. Biotech. 22: 1409-1414 (2004), and Li et al., Nat. Biotech. 24:210-215 (2006).

[0357] Suitable host cells for the expression of glycosylated antibodies are also derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. Numerous baculo viral strains have been identified which may be used in conjunction with insect cells, particularly for transfection of Spodoptera frugiperda cells.

[0358] Plant cell cultures can also be utilized as hosts. See, e.g., U.S. Pat. Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (describing PLANTIBODIES™ technology for producing antibodies in transgenic plants).

[0359] Vertebrate cells may also be used as hosts. For example, mammalian cell lines that are adapted to grow in suspension may be useful. Other examples of useful mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-7): human embryonic kidney line (293 or 293 cells as described, e.g., in Graham et al., J. Gen Virol. 36:59 (1977)); baby hamster kidney cells (BHK); mouse sertoli cells (TM4 cells as described, e.g., in Mather, Biol. Reprod. 23:243-251 (1980)); monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HELA); canine kidney cells (MDCK; buffalo rat liver cells (BRL 3A); human lung cells (W138); human liver cellsAttorney Docket No.: AOE-008WOAOJ-036PC(Hep G2); mouse mammary tumor (MMT 060562); TRI cells, as described, e.g., in Mather et al., Annals N.Y. Acad. Sci. 383:44-68 (1982); MRC 5 cells; and FS4 cells. Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR- CHO cells (Urlaub et al.. Proc. Natl. Acad. Sci. USA 77:4216 (1980)); and myeloma cell lines such as Y0, NSO and Sp2 / 0. For a review of certain mammalian host cell lines suitable for antibody production, see, e.g., Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (B.K.C. Lo, ed., Humana Press, Totowa, N.J.), pp. 255-268 (2003).

[0360] In one embodiment, the antibodies described herein are produced in stable mammalian cells, by a method comprising: transfecting at least one stable mammalian cell with a nucleic acid encoding the antibody, in a predetermined ratio: and expressing the nucleic acid in the at least one mammalian cell. In some embodiments, the predetermined ratio of the nucleic acid is determined in transient transfection experiments to determine the relative ratio of input nucleic acids that results in the highest percentage of the antibody in the expressed product.

[0361] In some embodiments, the method of producing an antibody in stable mammalian cells as described herein results in the expression product of the at least one stable mammalian cell comprising a larger percentage of the desired glycosylated antibody as compared to the monomeric heavy or light chain polypeptides, or other antibodies.

[0362] In some embodiments, the method of producing a glycosylated antibody in stable mammalian cells described herein comprises identifying and purifying the desired glycosylated antibody. In some embodiments, the said identification is by one or both of liquid chromatography and mass spectrometry.

[0363] If required, the antibodies can be purified or isolated after expression. Proteins may be isolated or purified in a variety of ways known to those skilled in the art. Standard purification methods include chromatographic techniques, including ion exchange, hydrophobic interaction, affinity, sizing or gel filtration, and reversed-phase, carried out at atmospheric pressure or at high pressure using systems such as FPLC and HPLC. Purification methods also include electrophoretic, immunological, precipitation, dialysis, and chromatofocusing techniques. Ultrafiltration and diafiltration techniques, in conjunction with protein concentration, are also useful. As is well known in the art, a variety of natural proteins bind Fc and antibodies, and these proteins can find use in the present invention for purification of antibodies. For example, the bacterial proteins A and G bind to the Fc region. Likewise, the bacterial protein L binds to the Fab region of some antibodies. Purification canAttorney Docket No.: AOE-OQ8WOAOJ-036PC often be enabled by a particular fusion partner. For example, antibodies may be purified using glutathione resin if a GST fusion is employed, Ni+2affinity chromatography if a His-tag is employed or immobilized anti-flag antibody if a flag-tag is used. For general guidance in suitable purification techniques, see, e.g. incorporated entirely by reference Protein Purification: Principles and Practice, 3rd Ed., Scopes, Springer-Verlag, NY, 1994, incorporated entirely by reference. The degree of purification necessary will vary depending on the use of the antibodies. In some instances, no purification is necessary.

[0364] In certain embodiments, the antibodies are purified using Anion Exchange Chromatography including, but not limited to, chromatography on Q-sepharose, DEAE sepharose, poros HQ, poros DEAF, Toyopearl Q, Toyopearl QAE, Toyopearl DEAE, Resource / Source Q and DEAE, Fractogel Q, and DEAE columns.

[0365] In specific embodiments, the proteins described herein are purified using Cation Exchange Chromatography including, but not limited to, SP-sepharose, CM sepharose, poros HS, poros CM, Toyopearl SP, Toyopearl CM, Resource / Source S and CM, Fractogel S, and CM columns and their equivalents and comparables.

[0366] In addition, antibodies described herein can be chemically synthesized using techniques known in the art (e.g., see Creighton, 1983, Proteins: Structures and Molecular Principles, W. H. Freeman & Co., N.Y; and Hunkapiller et al., Nature, 310:105-111 (1984)). For example, a polypeptide corresponding to a fragment of a polypeptide can be synthesized by use of a peptide synthesizer. Furthermore, if desired, nonclassical amino acids or chemical amino acid analogs can be introduced as a substitution or addition into the polypeptide sequence. Non-classical amino acids include, but are not limited to, to the D-isomers of the common amino acids, 2,4diaminobutyric acid, alpha-amino isobutyric acid, 4aminobutyric acid, Abu, 2-amino butyric acid, g-Abu, e-Ahx, 6amino hexanoic acid, Aib, 2-amino isobutyric acid, 3-amino propionic acid, ornithine, norleucine, norvaline, hydroxyproline, sarcosine, citrulline, homocitrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, alanine, fluoro-amino acids, designer amino acids such as methyl amino acids, C-methyl amino acids, N-methyl amino acids, and amino acid analogs in general. Furthermore, the amino acid can be D (dextrorotary) or L (levorotary).Methods of Use

[0367] In an aspect, the present application provides methods of contacting TSLP with an anti-TSLP antibody, or an antigen binding fragment thereof, such as a human or humanized antibody. This can result in inhibition of TSLP binding to TSLPR.Attorney Docket No.: AOE-OQ8WOAOJ-036PC

[0368] In an aspect, the present application provides methods of using the isolated anti- TSLP antibodies or antigen binding fragments thereof described herein for treatment of a disorder or disease in a subject. In certain aspects, described herein is a method for treating a subject in need thereof with an anti-TSLP antibody, or an antigen binding fragment thereof, the method comprising administering to the subject (e.g., a mammalian subject) a therapeutically effective amount of an anti-TSLP antibody, or an antigen binding fragment thereof, or pharmaceutical composition comprising an anti-TSLP antibody, or an antigen binding fragment thereof, described herein. In certain embodiments, the present application provides methods of treating a disorder or disease associated with elevated levels of TSLP in a subject.

[0369] In certain aspects, described herein are methods for treating a pathology associated with TSLP activity, the method comprising administering to a mammalian subject a therapeutically effective amount of an isolated anti-TSLP antibody, or an antigen binding fragment thereof, or a pharmaceutical composition comprising an isolated anti-TSLP antibody, or an antigen binding fragment thereof, described herein.

[0370] In certain aspects, the antibodies and antibody fragments disclosed herein are useful for treating diseases and disorders which are improved, inhibited, or ameliorated by reducing TSLP activity. These disorders include those characterized by abnormal or excess expression of TSLP or by an abnormal host response to TSLP production. TSLP related disorders which are treated by the antibodies or antibody fragments of the disclosure include an inflammatory disorder or disease. In certain embodiments, the anti-TSLP antibody, or an antigen binding fragment thereof, is used in the treatment of atopic dermatitis. In certain embodiments, the treatment reduces disease severity in a subject and wherein disease severity is assessed by an atopic dermatitis disease severity outcome measure. In certain embodiments, the anti-TSLP antibody, or an antigen binding fragment thereof, is used in the treatment of asthma. In certain embodiments, the anti-TSLP antibody, or an antigen binding fragment thereof, is used in the treatment of idiopathic pulmonary fibrosis. In certain embodiments, the anti-TSLP antibody, or an antigen binding fragment thereof, is used in the treatment of alopecia areata. In certain embodiments, the anti-TSLP antibody, or an antigen binding fragment thereof, is used in the treatment of chronic sinusitis with nasal polyps. In certain embodiments, the anti-TSLP antibody, or an antigen binding fragment thereof, is used in the treatment of Chronic Rhinosinusitis without Nasal Polyps (CRSsNP). In certain embodiments, the anti-TSLP antibody, or an antigen binding fragment thereof, is used in theAttorney Docket No.: AOE-008WOAOJ-036PC treatment of eosinophilic esophagitis (EoE). In certain embodiments, the anti-TSLP antibody, or an antigen binding fragment thereof, is used in the treatment of an Eosinophilic gastrointestinal disorder or disease (EGID), such as Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), Eosinophilic Colitis (EoC), or Eosinophilic Gastroenteritis (EGE). In certain embodiments, the anti-TSLP antibody, or an antigen binding fragment thereof, is used in the treatment of Churg-Strauss syndrome / Eosinophilic granulomatosis with polyangiitis (EGPA). In certain embodiments, the anti-TSLP antibody, or an antigen binding fragment thereof, is used in the treatment of Prurigo Nodularis (PN). In certain embodiments, the anti-TSLP antibody, or an antigen binding fragment thereof, is used in the treatment of Chronic Spontaneous Urticaria (CSU). In certain embodiments, the anti-TSLP antibody, or an antigen binding fragment thereof, is used in the treatment of Chronic Pruritis of Unknown Origin (CPUO). In certain embodiments, the anti-TSLP antibody, or an antigen binding fragment thereof, is used in the treatment of Bullous Pemphigoid (BP). In certain embodiments, the anti-TSLP antibody, or an antigen binding fragment thereof, is used in the treatment of Cold Inducible Urticaria (ColdU). In certain embodiments, the anti-TSLP antibody, or an antigen binding fragment thereof, is used in the treatment of Allergic Fungal Rhinosinusitis (AFRS). In certain embodiments, the anti-TSLP antibody, or an antigen binding fragment thereof, is used in the treatment of Allergic Bronchopulmonary Aspergillosis (AB PA). In certain embodiments, the anti-TSLP antibody, or an antigen binding fragment thereof, is used in the treatment of Chronic Obstructive Pulmonary Disease (COPD). In certain embodiments, the anti-TSLP antibody, or an antigen binding fragment thereof, is used in the treatment of an inflammatory bowel disease, such as Crohn’s disease or ulcerative colitis. In certain embodiments, the anti-TSLP antibody, or an antigen binding fragment thereof, is used in the treatment of psoriasis. In certain embodiments, the anti-TSLP antibody, or an antigen binding fragment thereof, is used in the treatment of lupus. In certain embodiments, the anti-TSLP antibody, or an antigen binding fragment thereof, is used in the treatment of rheumatoid arthritis. In certain embodiments, the anti-TSLP antibody, or an antigen binding fragment thereof, is used in the treatment of hi dradenitis suppurativa. In certain embodiments, the anti-TSLP antibody, or an antigen binding fragment thereof, is used in the treatment of celiac disease. In certain embodiments, the anti-TSLP antibody, or an antigen binding fragment thereof, is used in the treatment of systemic sclerosis.

[0371] In certain aspects, described herein is a method for treating an inflammatory disorder or disease in a mammalian subject in need thereof, the method comprisingAttorney Docket No.: AOE-OQ8WOAOJ-036PC administering to the mammalian subject a therapeutically effective amount of an anti-TSLP antibody, or an antigen binding fragment thereof, described herein or a pharmaceutical composition described herein. In certain embodiments of the methods described herein, the inflammatory disorder or disease is atopic dermatitis. In certain embodiments, the inflammatory disorder or disease is asthma. In certain embodiments, the inflammatory disorder or disease is idiopathic pulmonary fibrosis. In certain embodiments, the inflammatory disorder or disease is alopecia areata. In certain embodiments, the inflammatory disorder or disease is chronic sinusitis with nasal polyps. In certain embodiments, the inflammatory disorder or disease is Chronic Rhinosinusitis without Nasal Polyps (CRSsNP). In certain embodiments, the inflammatory disorder or disease is eosinophilic esophagitis (EoE). In certain embodiments, the inflammatory disorder or disease is an Eosinophilic gastrointestinal disorder or disease (EGID) selected from the group consisting of Eosinophilic Gastritis (EoG), Eosinophilic enteritis (EoN), Eosinophilic colitis (EoC), and Eosinophilic Gastroenteritis (EGE). In certain embodiments, the inflammatory disorder or disease is Churg-Strauss syndrome / Eosinophilic granulomatosis with polyangiitis (EGPA). In certain embodiments, the inflammatory disorder or disease is Prurigo Nodularis (PN). In certain embodiments, the inflammatory disorder or disease is Chronic Spontaneous Urticaria (CSU). In certain embodiments, the inflammatory disorder or disease is Chronic Pruritis of Unknown Origin (CPUO). In certain embodiments, the inflammatory disorder or disease is Bullous Pemphigoid (BP). In certain embodiments, the inflammatory disorder or disease is Cold Inducible Urticaria (ColdU). In certain embodiments, the inflammatory disorder or disease is Allergic Fungal Rhinosinusitis (AFRS). In certain embodiments, the inflammatory disorder or disease is Allergic Bronchopulmonary Aspergillosis (ABPA). In certain embodiments, the inflammatory disorder or disease is Chronic Obstructive Pulmonary Disease (COPD). In certain embodiments, the inflammatory disorder or disease is inflammatory bowel disease, such as Crohn’s disease or ulcerative colitis. In certain embodiments, the inflammatory disorder or disease is psoriasis. In certain embodiments, the inflammatory disorder or disease is lupus. In certain embodiments, the inflammatory disorder or disease is rheumatoid arthritis. In certain embodiments, the inflammatory disorder or disease is celiac disease. In certain embodiments, the inflammatory disorder or disease is hidradenitis suppurativa. In certain embodiments, the inflammatory disorder or disease is systemic sclerosis.Attorney Docket No.: AOE-008WOAOJ-036PC

[0372] In certain aspects, described herein are methods for treating an inflammatory disorder or disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the antibody, or an antigen binding fragment thereof, or a pharmaceutical composition described herein. In certain embodiments, the inflammatory disorder or disease is atopic dermatitis. In certain embodiments, the inflammatory disorder or disease is asthma. In certain embodiments, the inflammatory disorder or disease is nasal polyps.

[0373] In certain aspects, described herein are methods for treating a pathology associated with elevated levels of TSLP and / or TSLPR in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an antibody, or an antigen binding fragment thereof, or a pharmaceutical composition described herein.

[0374] In certain aspects, described herein are methods of reducing biological activity of TSLP and / or TSLPR in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an antibody, or an antigen binding fragment thereof, or a pharmaceutical composition described herein.

[0375] In certain aspects, described herein are methods of preventing an inflammatory disorder or disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an antibody, or an antigen binding fragment thereof, or a pharmaceutical composition described herein.

[0376] In certain aspects, described herein are methods for reducing a level of a cytokine and / or a chemokine in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of an anti-TSLP antibody, or an antigen binding fragment thereof, or a pharmaceutical composition described herein. In certain embodiments, the cytokine or chemokine is a type 2 cytokine or chemokine. In certain embodiments, the cytokine is IL-5.

[0377] In certain aspects, described herein are methods for reducing a level of a type 2 cytokine or chemokine in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of an anti-TSLP antibody, or an antigen binding fragment thereof, or a pharmaceutical composition described herein. In certain embodiments, the method reduces the level of the type 2 cytokine or chemokine by at least about 50%, 60%, 70%, 80%, 85%, 90%, or 95%.Attorney Docket No.: AOE-008WOAOJ-036PC

[0378] In certain aspects, described herein are methods for treating asthma in a subject, wherein the method comprises administering an anti-TSLP antibody, or an antigen binding fragment thereof.Methods of Administration

[0379] In some embodiments, the methods provided herein are useful for the treatment of a disease or disorder in an individual. In an embodiment, the individual is a human and the antibody is an anti-TSLP antibody, or an antigen binding fragment thereof, described herein. Described herein, in certain embodiments, are methods of treating an inflammatory disorder or disease in a patient in need thereof, the method comprising subcutaneously or intravenously administering to the patient an effective amount of an anti-TSLP antibody, or an antigen binding fragment thereof, comprising a modified Fc region. Further described herein, in certain embodiments, are methods of treating an inflammatory disorder or disease in a patient in need thereof, the method comprising subcutaneously or intravenously administering to the patient an effective amount of an anti-TSLP antibody, or an antigen binding fragment thereof, wherein the anti-TSLP antibody or the antigen binding fragment thereof specifically binds to an epitope of TSLP and comprises a Fc domain comprising amino acid modifications M252Y, S254T, and T256E (YTE) using EU numbering or M257Y / S259T / T261E (YTE) using direct numbering and / or M428L and N434S (LS) using EU numbering or M433L / N439S (LS) using direct numbering. The Fc domain may further comprise amino acid modifications L234A / L235A (LALA) using EU numbering or L239A / L240A (LALA) using direct numbering (e.g., LALA / YTE or LALA / LS).

[0380] In some embodiments, an antibody, or an antigen binding fragment thereof, is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. An effective amount of an anti-TSLP antibody, or an antigen binding fragment thereof, may be administered for the treatment of a disease or disorder. In some embodiments, administration of the anti-TSLP antibody, or an antigen binding fragment thereof, is intravenous or subcutaneous. In some embodiments, administration of the anti-TSLP antibody, or an antigen binding fragment thereof, is intravenous. In some embodiments, administration of the anti-TSLP antibody, or an antigen binding fragment thereof, is subcutaneous. The appropriate dosage of the anti-TSLP antibody, or an antigen binding fragment thereof, may be determined based on the type of disease or disorder to be treated, the type of the anti-TSLP antibody, the severity and courseAttorney Docket No.: AOE-OQ8WOAOJ-036PC of the disease or disorder, the clinical condition of the individual, the individual’s clinical history and response to the treatment, and the discretion of the attending physician.

[0381] In certain embodiments, the anti-TSLP antibody, or an antigen binding fragment thereof, is administered in an amount of about 50 mg to about 1500 mg, for example, in an amount of about 150 mg, about 300 mg, about 600 mg, or about 1200 mg. In certain embodiments, the anti-TSLP antibody, or an antigen binding fragment thereof, is administered weekly, every two weeks, every three weeks, every four weeks, every six weeks, or every two months.

[0382] In certain embodiments, the anti-TSLP antibody, or an antigen binding fragment thereof, is administered in an amount of about 125 mg, about 250 mg, about 500 mg, or about 1,000 mg.Kits and Articles of Manufacture

[0383] The present application provides kits comprising any one or more of the antibody compositions described herein and instructions for use. In some embodiments, the kits further contain a component selected from any of secondary antibodies, reagents for immunohistochemistry analysis, a pharmaceutically acceptable excipient, a package insert, and an instruction manual and any combination thereof. In one specific embodiment, the kit comprises a pharmaceutical composition comprising any one or more of the antibody compositions described herein, with one or more pharmaceutically acceptable excipients. The present application also provides articles of manufacture comprising any one of the antibody compositions or kits described herein. Examples of an article of manufacture include vials (including sealed vials).EXAMPLES

[0384] Below are examples of specific embodiments for carrying out the present invention. The examples are offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should, of course, be allowed for.

[0385] The practice of the present invention will employ, unless otherwise indicated, conventional methods of protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the skill of the art. Such techniques are explained fully in the literature. See, e.g., T.E. Creighton, Proteins: Structures and Molecular Properties (W.H. Freeman andAttorney Docket No.: AOE-008WOAOJ-036PCCompany, 1993); A.L. Lehninger, Biochemistry (Worth Publishers, Inc., current addition); Sambrook, et al.. Molecular Cloning: A Laboratory Manual (2nd Edition, 1989); Methods In Enzymology (S. Colowick and N. Kaplan eds., Academic Press, Inc.); Remington's Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990); Carey and Sundberg Advanced Organic Chemistry 3rdEd. (Plenum Press) Vols A and B(1992).Example 1: A Phase 1, Randomized, Blinded, Placebo-Controlled, First-In-Human Study of the Safety, Tolerability, and Pharmacokinetics of Single Ascending Doses of Antibody 5 in Healthy Participants

[0386] This Example describes a study evaluating the safety and tolerability of single doses of Antibody 5 in healthy participants. Antibody 5 comprises the sequences of SEQ ID NOs: 34 (VH), 41 (VL), 173 (heavy chain constant region), and 442 (light chain constant region), which form the heavy chain sequence of SEQ ID NO: 446 and the light chain sequence of SEQ ID NO: 447.Methods

[0387] This study evaluates single ascending doses (SAD) of Antibody 5 administered subcutaneously (SC) in healthy participants. In each of 4 treatment cohorts (maximum), 8 participants are randomized 6:2 to Antibody 5 or placebo of 0.9% sodium chloride solution (up to 32 participants total):Cohort 1 - Antibody 5 Dose 125 milligram (mg) or placebo;Cohort 2 - Antibody 5 Dose 250 mg or placebo;Cohort 3 - Antibody 5 Dose 500 mg or placebo; and Cohort 4 - Antibody 5 Dose 1,000 mg or placebo.

[0388] The duration of the study is up to approximately 267 days, including screening and safety follow-up.OutcomesPrimary outcome

[0389] Incidence of treatment-emergent adverse events (TEAEs) coded using the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.Assessment methodAttorney Docket No.: AOE-008WOAOJ-036PC

[0390] TEAEs (including those leading to discontinuation of study drag): via interviews, physical examinations, and review of clinical safety laboratory test results and ECG reports. The Investigator or designee reviews each event (including injection site reactions) and assesses its severity based on CTCAE version 5.0:Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated;- Grade 2: Moderate; minimal, local, or non-invasive intervention indicated; limiting age-appropriate instrumental activities of daily living;Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting selfcare activities of daily living;Grade 4: Life-threatening consequences; urgent intervention indicated;Grade 5: Death related to AE. Clinical safety laboratory findings- serum chemistry (including liver function tests, electrolytes, and kidney function tests), full blood count and coagulation tests; and urinalysis are assessed. Vital signs are measured on the arm opposite any IV canulae. Clinically significant laboratory findings and ECG findings are reported as adverse events. Vital signs assessed include heart rate through stethoscope, blood pressure through digital sphygmomanometer, body temperature, and respiratory rate. Clinical research unit (CRU) standards are used for determining normal ranges.Timepoint

[0391] Day 1: 0-hours (pre-dose), 4-, 8-, 24-, 48-, and 72- hours post-dose and on Days 8, 15, 22, 29, 57, 85, 113, 141, 169, 197, and 225 post-dose.Secondary outcome

[0392] Assessment of pharmacokinetics (PK) parameters: Cmax, tmax, AUCo-iast, AUCo-inf, Lambda-Z, ti / 2, CL / F, Vz / F.Assessment method

[0393] Serum samples are used to assess concentrations of Antibody 5. Concentrationtime data is analyzed by non-compartmental methods to assess PK outcomes including maximum observed serum concentration (Cmax), time to C max (tmax), area under the plasma concentration-time curve (AUC) from time 0 to the last quantifiable time point (AUCo-iast), AUC from time 0 extrapolated to infinity (AUCo-inf), terminal elimination rate constantAttorney Docket No.: AOE-OQ8WOAOJ-036PC(Lambda-Z), terminal elimination half-life (ti / 2), apparent clearance (CL / F), and apparent volume of distribution (Vz / F).Timepoint

[0394] Day 1 : 0 -hours (pre-dose), 4-, 8-, 24-, 48-, and 72- hours post-dose and on Days 8, 15, 22, 29, 57, 85, 113, 141, 169, 197, and 225 post-dose.Secondary outcome

[0395] Number of participants with anti-drug antibodies (ADA).Assessment method

[0396] Serum samples are used to assess anti-drug antibodies (ADA) outcomes. Analysis of samples for ADA are performed using a validated ADA assay in a 3-tier format (screen, confirm, titer) and neutralizing antibody (NAb) assay in samples that have positive titers for ADA. Immunogenicity data summaries include incidence of samples screened positive for ADA, incidence of samples confirmed positive for ADA, and summaries of ADA titers and NAb, as applicable.Timepoint

[0397] Day 1 : 0-hours (pre-dose) and on Days 15, 22, 29, 57, 85, 1 13, 141, 169, 197, and 225 post-dose.Secondary outcome

[0398] PK parameters in participants with and without ADA.Assessment method

[0399] PK parameters are summarized by ADA status (presence or absence of ADA) to evaluate potential impact of ADA on PK.Timepoint

[0400] Day 1 : 0 -hours (pre-dose), 4-, 8-, 24-, 48-, and 72- hours post-dose and on Days 8, 15, 22, 29, 57, 85, 113, 141, 169, 197, and 225 post-dose.Exploratory outcome

[0401] Exploration of potential changes in biomarkers after single doses of Antibody 5 in healthy participants.

[0402] Changes over time in pSTAT5, TARC, IL-13, IgE, whole blood-based transcriptome assessment and other markers are assessed.Attorney Docket No.: AOE-008WOAOJ-036PCEligibilityKey inclusion criteria- Healthy men and women, in the opinion of the Investigator and as determined by physical examination, laboratory screening tests, and medical history;18 to 65 years of age with a body mass index of 18.0 to 32.0 kilogram per square meter (kg / m2) (inclusive), weight less than (<) 120 kilogram (kg);- Willing to use a highly effective method of contraception through 30 days after end of study (EOS) or 5 half-lives after the last administration of study drug, whichever is longer; and- Willing to abstain from alcohol, tobacco, and illicit drug use for 48 hours prior to admission to the CRU (Day -1) and during the inpatient period.Key exclusion criteriaEvidence of clinically significant abnormalities or disease, including but not limited to: o Glycosylated hemoglobin (hemoglobin Ale) > 6.5% and / or diagnosis of diabetes mellitus (history of gestational diabetes mellitus, fully resolved, is permitted) o Positive test for human immunodeficiency virus (HIV) antibody o Acute or chronic hepatitis B or C as evidenced by hepatitis B surface antigen (HBsAg) and / or hepatitis C antibody (HCV Ab); evidence of resolved infection or status post-vaccination with the presence of antibodies or documented absence of viral deoxyribonucleic acid on polymerase chain reaction is allowed o Positive tuberculosis blood test o Diagnosis or suspected diagnosis of immunodeficiency or autoimmune diseases, or undergoing immunosuppressive therapy such as anticancer chemotherapy or radiotherapy before the study, or has received systemic corticosteroid treatment (topical corticosteroids are acceptable) within the past 120 days before dosing o Significant history or clinical manifestation of any metabolic, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, orAttorney Docket No.: AOE-OQ8WOAOJ-036PC psychiatric disorder, acute or chronic infectious diseases and malignancies, as determined by the Investigator o History or presence of conditions which, in the judgment of the Investigator, are known to interfere with the absorption, distribution, metabolism, or excretion of drugs o Liver function tests (z. e. , alanine aminotransferase, aspartate aminotransferase) > 1.5 times the upper limit of normal; elevated bilirubin is not allowed unless due to Gilbert's syndrome o Impaired renal function defined as an estimated glomerular filtration rate < 60 mL / min / 1.73 m2 at Screening and Day -1 o Any other laboratory, vital sign (e.g., hypertension that could be unsafe for study drug administration per Investigator assessment), ECG abnormality (e.g., QTc corrected using Fridericia’s formula [QTcF] prolongation), clinically significant medical condition (e.g., cardiac failure), or finding that, in the Investigator's opinion (in consultation with the medical monitor), is likely to unfavorably alter the risk of study participation, confound study results, or interfere with the study conduct or compliance; participants may be rescreened and tests may be repeated at the Investigator's discretion. Note: participants with history of non-clinically significant disease (e.g., childhood asthma, migraines, non-hospitalized depression, Gilbert’s syndrome, cholecystectomy) that, in the Investigator's opinion, is not likely to unfavorably alter the risk of study participation, confound study results, or interfere with the study conduct or compliance may be eligible for the studyHistory of any of the following: o Clinically significant opportunistic infection (e.g., invasive candidiasis or pneumocystis pneumonia) within 5 years prior to screening; and o Serious local infection (e.g., cellulitis) or system infection (e.g., septicemia) within 3 months prior to screening.Positive Corona Vims Disease of 2019 (COVID-19) test at admission to the CRUAttorney Docket No.: AOE-008WOAOJ-036PCKnown history of illicit drug abuse, harmful alcohol use (defined as an average of > 10 standard drinks per week or at the Investigator’s discretion) or alcoholism, and / or excessive tobacco use (defined as > 5 cigarettes or e- cigarette equivalent (0.5 mL e-cigarette fluid equivalent to 5 cigarettes) per day) within 2 years prior to screening; positive screen for drugs of abuse (except tetrahydrocannabinol (THC)), or positive alcohol breath test at screening or admission to the CRU (or at the Investigator’s discretion), and participants must abstain from cigarette smoking and vaping for the duration of their stay in the CRU. Participants are rescreened for drugs of abuse or alcohol breath test at the Investigator’s discretion;- History of severe allergic reactions or hypersensitivity (i.e., anaphylaxis);Known or suspected intolerance or hypersensitivity to any biologic medication or known allergies or clinically significant reactions to murine, chimeric, or human proteins, monoclonal antibodies (mAbs) or antibody fragments, or to any components of the formulation of Antibody 5 and its excipients used in this study;If female, nursing, lactating, pregnant, or plans to become pregnant within 30 days of EOS or 5 half-lives (whichever is longer) of study drug administration; Use of any prescription or nonprescription medication 7 days prior to dosing through CRU discharge Day 4 (exception: contraceptives, hormone replacement therapy, vitamins, over-the-counter (OTC) antihistamines, OTC topical steroids, or acetaminophen / paracetamol up to 2 gram per day prior to dosing is permitted);- Vaccination within 30 days prior to administration of Antibody 5; and Use of any investigational drug therapy within 30 days or 5 half-lives (whichever is longer) prior to study drug dosing through 5 half-lives after the last dose of study drug.Attorney Docket No.: AOE-008WO AOJ-036PCExample 2: A Phase 1, Randomized, Blinded, Placebo-Controlled, First-In-Human Study of the Safety, Tolerability, and Pharmacokinetics of Single Ascending Doses of Antibody 5 in Healthy Participants: Interim Results

[0403] The study described in Example 1 was conducted and interim results therefrom are reported herein.

[0404] The baseline characteristics of participants in the study described in Example 1 are shown in TABLE 9.TABLE 9. Baseline Characteristics of Participants

[0405] Treatment-emergent adverse events (TEAEs) from the study described in Example 1 are shown in TABLE 10.TABLE 10. Overall Treatment-Emergent Adverse EventsAttorney Docket No.: AOE-008WOAOJ-036PC* Grade 3 TEAE was gastritis and unrelated to study drug. The patient presented with abdominal and left flank pain, was treated with analgesics and was discharged on oral antireflux medication.** Drug-related TEAEs were headache (1 subject), neutropenia (1 subject), injection site erythema, nausea and vomiting (1 subject); and nausea (1 subject). All resolved by the time the last data was collected.

[0406] The summary concentration-time profiles following administration of Antibody 5 are shown in FIG. 1. Pharmacokinetic parameters are summarized in TABLE 11. Based on target exposures of other anti-TSLP antibodies, the half-life of Antibody 5 suggests that administration of Antibody 5 once every three months or once every six months could provide therapeutic efficacy.Attorney Docket No.: AOE-OQ8WOAOJ-036PCTABLE 11. Pharmacokinetic Parameter Summary

[0407] Blood eosinophil counts as the percent change from baseline are shown in FIG. 2. All Antibody 5-treated groups showed a greater percent change (decrease) in blood eosinophil count from baseline as compared to the placebo group.

[0408] Serum IL-5 levels as the percent change from baseline are shown in FIG. 3. All Antibody 5-treated groups showed a greater percent change (decrease) from baseline in serum IL-5 level as compared to the placebo group.

[0409] Serum IL-13 levels as the percent change from baseline are shown in FIG. 4.

[0410] Serum IgE levels as the percent change from baseline are shown in FIG. 5.Attorney Docket No.: AOE-008WOAOJ-036PCINFORMAL SEQUENCE LISTINGAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PCAttorney Docket No.: AOE-008WOAOJ-036PC*SEQ ID NOs: 47 and 159 are hlgGl sequences having a SRDEL (SEQ ID NO: 469) allotype. The disclosure also encompasses SREEM (SEQ ID NO: 470) allotype variants of any of the SRDEL (SEQ ID NO: 469) allotype sequences set forth in the table above, and either a SRDEL (SEQ ID NO: 469) allotype heavy chain constant region sequence or a SREEM (SEQ ID NO: 470) allotype heavy chain constant region sequence may be included in an anti-TSLP antibody described herein.

Claims

Attorney Docket No.: AOE-008WOAOJ-036PCCLAIMS1. A method for treating an inflammatory disorder or disease in a subject, wherein the method comprises administering to the subject a dose of an anti-thymic stromal lymphopoietin (TSLP) antibody, or an antigen binding fragment thereof, wherein the dose is between about 100 mg and about 1,500 mg, wherein the anti-TSLP antibody comprises: a) a variable heavy (VH) chain sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and b) a variable light (VL) chain sequence having three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; wherein: a. the CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 1-9; b. the CDR-H2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 10-12; c. the CDR-H3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 13-18; d. the CDR-L1 comprises an amino acid sequence an amino acid sequence set forth in any one of SEQ ID NOs: 19-24, 271-302, and 387, e. the CDR-L2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 25-26, 303-310, and amino acid sequences DDS, DVS, EDS, DDT, DDK, DDL, and DDN; and f. the CDR-L3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 27-31, 31 1-327, and 367-370.

2. A method for treating a pathology associated with elevated levels of TSLP in a subject in need thereof, the method comprising administering to the subject a dose of an anti- TSLP antibody, or an antigen binding fragment thereof, wherein the dose is between about 100 mg and about 1,500 mg, wherein the anti-TSLP antibody comprises: a) a variable heavy (VH) chain sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and b) a variable light (VL) chain sequence having three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; wherein: a. the CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 1-9;Attorney Docket No.: AOE-OQ8WOAOJ-036PC b. the CDR-H2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 10-12: c. the CDR-H3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 13-18: d. the CDR-L1 comprises an amino acid sequence an amino acid sequence set forth in any one of SEQ ID NOs: 19-24, 271-302, and 387, e. the CDR-L2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 25-26, 303-310, and amino acid sequences DDS, DVS, EDS, DDT, DDK, DDL, and DDN; and f. the CDR-L3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 27-31, 311-327, and 367-370.

3. A method of reducing biological activity of TSLP in a subject in need thereof, the method comprising administering to the subject a dose of an anti-TSLP antibody, or an antigen binding fragment thereof, wherein the dose is between about 100 mg and about 1,500 mg, wherein the anti-TSLP antibody comprises: a) a variable heavy (VH) chain sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and b) a variable light (VL) chain sequence having three light chain CDR sequences, CDR-L1, CDR- L2, and CDR-L3; wherein: a. CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 1-9: b. CDR-H2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 10-12; c. CDR-H3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 13-18; d. CDR-L1 comprises an amino acid sequence an amino acid sequence set forth in any one of SEQ ID NOs: 19-24, 271 -302, and 387, e. CDR-L2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 25-26, 303-310, and amino acid sequences DDS, DVS, EDS, DDT, DDK, DDL, and DDN; andAttorney Docket No.: AOE-OQ8WOAOJ-036PC f. CDR-L3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 27-31, 311-327, and 367-370.

4. The method of any one of claims 1-3, wherein the dose is about 125 mg, about 250 mg, about 500 mg, or about 1,000 mg.

5. The method of claim 4, wherein the dose is about 125 mg.

6. The method of claim 4, wherein the dose is about 250 mg.

7. The method of claim 4, wherein the dose is about 500 mg.

8. The method of claim 4, wherein the dose is about 1,000 mg.

9. The method of any one of claims 1-8, wherein: a. CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 1-3; b. CDR-H2 comprises an amino acid sequence set forth in SEQ ID NO: 10; c. CDR-H3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 13-15; d. CDR-L1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 19-21 and 271-288, e. CDR-L2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 25-26 and 303-310; and f. CDR-L3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 27-31 and 311-327.

10. The method of any one of claims 1-8, wherein: a. CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 4-6; b. CDR-H2 comprises an amino acid sequence set forth in SEQ ID NO: 11 ; c. CDR-H3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 13-15; d. CDR-L1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 19-21 and 271-288,Attorney Docket No.: AOE-OQ8WOAOJ-036PC e. CDR-L2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 25-26 and 303-310; and f. CDR-L3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 27-31 and 311-327.

11. The method of any one of claims 1-8, wherein: a. CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 7-9: b. CDR-H2 comprises an amino acid sequence set forth in SEQ ID NO: 12; c. CDR-H3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 16-18; d. CDR-L1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 22-24, 289-302, and 387, e. CDR-L2 comprises an amino acid sequence of any one of amino acid sequences DDS, DVS, EDS, DDT, DDK, DDL, and DDN; and f. CDR-L3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 27-31 and 31 1-327.

12. The method of any one of claims 1-8, wherein the CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 1, 4, and 7, the CDR-H2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, the CDR-H3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, the CDR-L1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 19 and 22, the CDR-L2 comprises an amino acid sequence set forth in SEQ ID NO: 25 or the amino acid sequence DVS, and the CDR-L3 comprises an amino acid sequence set forth in SEQ ID NO: 27.

13. The method of any one of claims 1-8, wherein the CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 2, 5, and 8, the CDR-H2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, the CDR-H3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, the CDR-L1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 19 and 22, the CDR-L2 comprises an amino acid sequence set forth in SEQ ID NO: 25 or the amino acid sequence DVS, and the CDR-L3 comprises an amino acid sequence set forth in SEQ ID NO: 28.Attorney Docket No.: AOE-008WOAOJ-036PC14. The method of any one of claims 1-8, wherein the CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 2, 5, and 8, the CDR-H2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, the CDR-H3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 14 and 17, the CDR-L1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 20 and 23, the CDR-L2 comprises an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and the CDR-E3 comprises an amino acid sequence set forth in SEQ ID NO: 28.

15. The method of any one of claims 1-8 any one of claims 1-6, wherein the CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 2, 5, and 8, the CDR- H2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, the CDR-H3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 13 and16. the CDR-L1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 21 and 24, the CDR-L2 comprises an amino acid sequence set forth in SEQ ID NO: 25 or the amino acid sequence DVS, and the CDR-L3 comprises an amino acid sequence set forth in SEQ ID NO: 28.

16. The method of any one of claims 1-8, wherein the CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, the CDR-H2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, the CDR-H3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, the CDR-L1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 21 and 24, the CDR-L2 comprises an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and the CDR-L3 comprises an amino acid sequence set forth in SEQ ID NO: 27.

17. The method of any one of claims 1-8, wherein the CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, the CDR-H2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, the CDR-H3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 15 and 18, the CDR-L1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 21 and 24, the CDR-L2 comprises an amino acid sequence set forth in SEQ ID NO: 25 or the amino acid sequence DVS, and the CDR-L3 comprises an amino acid sequence set forth in SEQ ID NO: 29.

18. The method of any one of claims 1-8, wherein the CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, and 9, the CDR-H2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, the CDR-H3 comprises anAttorney Docket No.: AOE-OQ8WOAOJ-036PC amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, the CDR-L1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 19 and 22, the CDR-L2 comprises an amino acid sequence set forth in SEQ ID NO: 25 or the amino acid sequence DVS, and the CDR-L3 comprises an amino acid sequence set forth in SEQ ID NO: 30.

19. The method of any one of claims 1-8, wherein the CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 1, 4, and 7, the CDR-H2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, the CDR-H3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 16, the CDR-L1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 19 and 22, the CDR-L2 comprises an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and the CDR-L3 comprises an amino acid sequence set forth in SEQ ID NO: 31.

20. The method of any one of claims 1-8, wherein the CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 2, 5, and 8, the CDR-H2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 10, 11, and 12, the CDR-H3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 15 and 18, the CDR-L1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 21 and 24, the CDR-L2 comprises an amino acid sequence set forth in SEQ ID NO: 26 or the amino acid sequence DDS, and the CDR-L3 comprises an amino acid sequence set forth in SEQ ID NO: 28.

21. The method of any one of claims 1-8, wherein the antibody, or antigen binding fragment thereof, comprises a heavy chain variable domain (VH) sequence selected from a sequence set forth in any one of SEQ ID NOs: 32-36 and 386.

22. The method of any one of claims 1-8, wherein the antibody, or antigen binding fragment thereof, comprises a light chain variable domain (VL) sequence selected from a sequence set forth in any one of SEQ ID NOs: 37-45, 328-364, 371-379, and 381-385.

23. The method of any one of claims 1-8, wherein the antibody, or antigen binding fragment thereof, comprises a VH sequence selected from an amino acid sequence set forth in any one of SEQ ID NOs: 32-36 and 386, and a VL sequence selected from an amino acid sequence set forth in any one of SEQ ID NOs: 37-45, 328-364, 371-379, and 381-385.

24. The method of any one of claims 1-8, wherein the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 32 and a VL sequence set forth in SEQ ID NO: 37.Attorney Docket No.: AOE-OQ8WOAOJ-036PC25. The method of any one of claims 1-8, wherein the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 33 and a VL sequence set forth in SEQ ID NO: 38.

26. The method of any one of claims 1-8, wherein the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 386 and a VL sequence set forth in SEQ ID NO: 39.

27. The method of any one of claims 1-8, wherein the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 33 and a VL sequence set forth in SEQ ID NO: 40.

28. The method of any one of claims 1-8, wherein the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 41.

29. The method of any one of claims 1-8, wherein the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 35 and a VL sequence set forth in SEQ ID NO: 42.

30. The method of any one of claims 1-8, wherein the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 43.

31. The method of any one of claims 1-8, wherein the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 32 and a VL sequence set forth in SEQ ID NO: 44.

32. The method of any one of claims 1-8, wherein the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 36 and a VL sequence set forth in SEQ ID NO: 45.

33. The method of any one of the preceding claims, wherein the antibody is a humanized, human, or chimeric antibody.

34. The method of claim 33, wherein the antibody is a humanized antibody.

35. The method of any one of the preceding claims, wherein the antibody comprises a heavy chain human constant region of a class selected from IgG, IgA, IgD, IgE, and IgM.Attorney Docket No.: AOE-OQ8WOAOJ-036PC36. The method of any one of the preceding claims, wherein the antibody comprises a human Fc region comprising a human heavy chain constant region of the class IgG and a subclass selected from IgGl, IgG2, IgG3, and IgG4.

37. The method of claim 36, wherein the human Fc region comprises a human IgGl Fc region.

38. The method of claim 36, wherein the human Fc region comprises a human IgG4 Fc region.

39. The method of claim 36, wherein the human Fc region comprises a human IgG2 Fc region.

40. The method of any one of the preceding claims, wherein the antibody comprises a heavy chain comprising a constant heavy chain sequence selected from a sequence set forth in any one of SEQ ID NOs: 47-270.

41. The method of any one of the preceding claims, wherein the antibody comprises a light chain comprising a constant light chain sequence set forth in SEQ ID NO: 442.

42. The method of any one of the preceding claims, wherein the antibody comprises an Fc region comprising one or more amino acid substitutions, wherein the one or more amino acid substitutions result in an increase in one or more of antibody half-life, ADCC activity, ADCP activity, or CDC activity compared with the Fc region without the one or more amino acid substitutions.

43. The method of any one of claims 1-41, wherein the Fc region comprises one or more amino acid substitutions, wherein the one or more amino acid substitutions result in a decrease in one or more of, ADCC activity, ADCP activity or CDC activity compared to an antibody comprising a wild-type Fc region.

44. The method of claim 42 or 43, wherein 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; optionally, wherein 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),Attorney Docket No.: AOE-OQ8WOAOJ-036PCL309D / Q311H / N434S (DHS), S228P / L235E (SPLE), L234A / L235A (LALA). M428L / N434A (LA), L235A / G237A (LAGA), L234A / L235A / G237A (LALAGA), L234A / L235A / P329G (LALAPG), 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.

45. The method of claim 44, wherein the one or more amino acid substitutions is selected from the group consisting of LS, YTE, T250Q / M428L, T307A / E380A / N434A, DQ, DW, YD, QVV, DHS, LA, 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 / 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, N297A / QVV, D265A / QVV, LALA / QVV, LAGA / QVV, LALAGA / QVV, and LALAPG / QVV46. The method of claim 44, wherein the one or more amino acid substitutions comprises L234A / L235A (LALA).

47. The method of claim 44, wherein the one or more amino acid substitutions comprises LALAGA and N434A.

48. The method of claim 44 or 45, wherein the one or more amino acid substitutions comprisesAttorney Docket No.: AOE-OQ8WOAOJ-036PC49. The method of claim 44 or 45, wherein the one or more amino acid substitutions comprises YTE and LALA.

50. The method of claim 44 or 45, wherein the one or more amino acid substitutions comprise YTE at positions 257 / 259 / 261, respectively, (M257Y / S259T / T261E) and LALA mutations at positions 239 / 240, respectively (L239A / L240A), wherein the numbering is according to direct numbering.

51. The method of any one of the preceding claims, wherein the Fc region binds to Neonatal Fc receptor (FcRn).

52. The method of claim 51, wherein the Fc region binds an FcRn with higher affinity at pH 6.0 compared to an antibody comprising a wild-type Fc region.

53. The method of any one of the preceding claims, wherein the antibody is a monoclonal antibody.

54. The method of any one of the preceding claims, wherein the antibody binds a TSLP sequence set forth in SEQ ID NO: 365 or 366.

55. The method of any one of claims 1 and 4-54, wherein the inflammatory disorder or disease comprises atopic dermatitis (AD).

56. The method of claim 55, wherein the treatment reduces disease severity in the subject and wherein disease severity is assessed by an atopic dermatitis disease severity outcome measure.

57. The method of any one of claims 1 and 4-54, wherein the inflammatory disorder or disease comprises asthma.

58. The method of any one of claims 1 and 4-54, wherein the inflammatory disorder or disease comprises chronic sinusitis with nasal polyps.

59. The method of any one of claims 1 and 4-54, wherein the inflammatory disorder or disease comprises Chronic Rhinosinusitis without Nasal Polyps (CRSsNP).

60. The method of any one of claims 1 and 4-54, wherein the inflammatory disorder or disease comprises eosinophilic esophagitis (EoE).

61. The method of any one of claims 1 and 4-54, wherein the inflammatory disorder or disease comprises an Eosinophilic gastrointestinal disorder or disease (EGID) selected fromAttorney Docket No.: AOE-OQ8WOAOJ-036PC the group consisting of Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), Eosinophilic Colitis (EoC), and Eosinophilic Gastroenteritis (EGE).

62. The method of any one of claims 1 and 4-54, wherein the inflammatory disorder or disease comprises Churg-Strauss syndrome / Eosinophilic granulomatosis with polyangiitis (EGPA).

63. The method of any one of claims 1 and 4-54, wherein the inflammatory disorder or disease comprises Prurigo Nodularis (PN).

64. The method of any one of claims 1 and 4-54, wherein the inflammatory disorder or disease comprises Chronic Spontaneous Urticaria (CSU).

65. The method of any one of claims 1 and 4-54, wherein the inflammatory disorder or disease comprises Chronic Pruritis of Unknown Origin (CPUO).

66. The method of any one of claims 1 and 4-54, wherein the inflammatory disorder or disease comprises Bullous Pemphigoid (BP).

67. The method of any one of claims 1 and 4-54, wherein the inflammatory disorder or disease comprises Cold Inducible Urticaria (ColdU).

68. The method of any one of claims 1 and 4-54, wherein the inflammatory disorder or disease comprises Allergic Fungal Rhinosinusitis (AFRS).

69. The method of any one of claims 1 and 4-54, wherein the inflammatory disorder or disease comprises Allergic Bronchopulmonary Aspergillosis (ABPA).

70. The method of any one of claims 1 and 4-54, wherein the inflammatory disorder or disease comprises Chronic Obstructive Pulmonary Disease (COPD).

71. The method of any one of claims 1 and 4-54, wherein the inflammatory disorder or disease comprises Crohn’s disease.

72. The method of any one of claims 1 and 4-54, wherein the inflammatory disorder or disease comprises lupus.

73. The method of any one of claims 1 and 4-54, wherein the inflammatory disorder or disease comprises rheumatoid arthritis (RA).

74. The method of any one of claims 1 and 4-54, wherein the inflammatory disorder or disease comprises psoriasis.Attorney Docket No.: AOE-OQ8WOAOJ-036PC75. The method of any one of claims 1 and 4-54, wherein the inflammatory disorder or disease comprises ulcerative colitis.

76. The method of any one of claims 1 and 4-54, wherein the inflammatory disorder or disease comprises hidradenitis suppurativa.

77. The method of any one of claims 1 and 4-54, wherein the inflammatory disorder or disease comprises celiac disease.

78. The method of any one of claims 1 and 4-54, wherein the inflammatory disorder or disease comprises systemic sclerosis.

79. The method of any preceding claim, wherein the subject is a human.

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