Antibodies that bind TSLP and methods of use

Abstract

Described herein are novel and improved antibodies that bind to thymic stromal lymphopoietin (TSLP) and methods of use thereof. In certain aspects, described herein are methods of inhibiting TSLP biological activity. In certain aspects, the antibodies and methods described herein are used for treatment of an inflammatory disease or disorder associated with elevated levels of TSLP. In certain aspects, described herein are methods of treating asthma by administering anti-TSLP antibodies.

Description

ANTIBODIES THAT BIND TSLP AND METHODS OF USECROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and benefit of U.S. Provisional Application Number 63 / 662,982, filed June 21, 2024, U.S. Provisional Application Number 63 / 688,717 filed August 29, 2024, U.S. Provisional Application Number 63 / 703,703 filed on October 4, 2024, and 63 / 758,632 filed on February 14, 2025, the contents of each of which are incorporated by reference herein in their entirety.SEQUENCE LISTING

[0002] This application contains a Sequence Listing XML, which has been submitted electronically and is hereby incorporated by reference in its entirety. The XML copy of the Sequence Listing, created on May 30, 2025, is named PRG-059WO_SL.xml and is 462,693 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 antagonists to TSLP for preventing and treating diseases in which human TSLP and human TSLPR are involved in the disease pathology, such as inflammatory and fibrotic disorders.SUMMARY

[0007] The present disclosure provides antibodies, or antigen binding fragments thereof, to TSLP and methods of treating diseases in which human TSLP is involved in disease pathology. The antibodies 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, provided herein are isolated antibodies, or antigen binding fragments thereof, that bind TSLP, comprising: 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: CDR-H1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 1-9; CDR-H2 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 10-12; CDR-H3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 13-18; CDR-L1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 19-24, 271-302; and 387; 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 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 some embodiments, the antibody, or an antigen binding fragment thereof, comprises: CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 1-3; CDR-H2 comprising an amino acid sequence set forth in SEQ ID NO: 10; CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13-15; CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 19-21 and 271-288; CDR-L2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 25-26 and 303-310; and CDR-L3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 27-31 and 311-327.

[0010] In some embodiments, the antibody, or an antigen binding fragment thereof, comprises: CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 4-6; CDR-H2 comprising an amino acid sequence set forth in SEQ ID NO: 11; CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13-15; CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 19-21 and 271-288; CDR-L2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 25-26 and303-310; and CDR-L3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 27-31 and 311-327.

[0011] In some embodiments, the antibody, or an antigen binding fragment thereof, comprises: CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 7-9; CDR-H2 comprising an amino acid sequence set forth in SEQ ID NO: 12; CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 16-18; CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 22-24, 289-302, and 387; CDR-L2 comprising an amino acid sequence of any one of amino acid sequences DDS, DVS, EDS, DDT, DDK, DDL, and DDN; and CDR-L3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 27-31 and 311-327.

[0012] In some embodiments, the antibody, or an antigen binding fragment thereof, 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.

[0013] In some embodiments, the antibody, or an antigen binding fragment thereof, 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.

[0014] In some embodiments, the antibody, or an antigen binding fragment thereof, 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: 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 inSEQ 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.

[0015] In some embodiments, the antibody, or an antigen binding fragment thereof, 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.

[0016] In some embodiments, the antibody, or an antigen binding fragment thereof, 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: 26 or the amino acid sequence DDS; and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 27.

[0017] In some embodiments, the antibody, or an antigen binding fragment thereof, 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 anyone 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.

[0018] In some embodiments, the antibody, or an antigen binding fragment thereof, 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 inSEQ ID NO: 25 or the amino acid sequence DVS; and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 30.

[0019] In some embodiments, the antibody, or an antigen binding fragment thereof, 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.

[0020] In some embodiments, the antibody, or an antigen binding fragment thereof, 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.

[0021] In some embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence selected from the sequences set forth in any one of SEQ ID NOs: 32-36 and 386.

[0022] In some embodiments, the antibody, or an antigen binding fragment thereof, comprises a VL sequence selected from the sequences set forth in any one of SEQ ID NOs: 37-45, 328-364, 371-379 and 381-385.

[0023] In some embodiments, the antibody, or an 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.

[0024] In another aspect, provided herein are isolated antibodies, or antigen binding fragments thereof, that bind TSLP, wherein the antibody, or an 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.

[0025] In some 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.

[0026] In some 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.

[0027] In some 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.

[0028] In some 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.

[0029] In some 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.

[0030] In some 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.

[0031] In some 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.

[0032] In some 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.

[0033] In some 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.

[0034] In some embodiments, the antibody, or an antigen binding fragment thereof, is a humanized, human, or chimeric antibody.

[0035] In some embodiments, the antibody, or an antigen binding fragment thereof, is a humanized antibody.

[0036] In some embodiments, the antibody, or an antigen binding fragment thereof, comprises a heavy chain human constant region of a class selected from IgG, IgA, IgD, IgE, and IgM.

[0037] In some embodiments, the antibody, or an 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.

[0038] In some embodiments, the human Fc region comprises a human IgGl Fc region.

[0039] In some embodiments, the human Fc region comprises a human IgG4 Fc region.

[0040] In some embodiments, the human Fc region comprises a human IgG2 Fc region.

[0041] In some embodiments, the antibody, or an antigen binding fragment thereof, comprises a heavy chain comprising a constant heavy chain sequence selected from the sequences set forth in any one of SEQ ID NOs: 47-270. In some embodiments, the antibody, or an antigen binding fragment thereof, comprises a constant heavy chain sequence set forth in SEQ ID NO: 61 or SEQ ID NO: 173.

[0042] In some embodiments, the antibody, or an antigen binding fragment thereof, comprises a light chain comprising a constant light chain sequence set forth in SEQ ID NO: 46.

[0043] In some embodiments, the antibody, or an 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 forth in any one of SEQ ID NOs: 409-412. In some embodiments, the human lambda light chain constant region comprises a sequence set forth in SEQ ID NO: 409.

[0044] In some 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 to an antibody comprising an Fc region without the one or more amino acid substitutions (e.g., a wild-type Fc region).

[0045] In some 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 a decrease in one or more of, ADCC activity, ADCP activity or CDC activity compared to an antibody comprising an Fc region without the one or more amino acid substitutions e.g., a wild-type Fc region).

[0046] In some embodiments, the one or more amino acid substitutions is selected from the group consisting of S228P (SP), T250Q, M252Y, S254T, T256E, T256D, 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 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 / Q311 V / A378V (QVV), T256D / H285D / T307R / Q311 V / A378V (DDRVV), L309D / Q311H / N434S (DHS), S228P / L235E, 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, 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, the one or more amino acid substitutions is selected from the group consisting of LS, YTE or M257Y / S259T / T261E (YTE using direct numbering), 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.

[0047] In some embodiments, the one or more amino acid substitutions comprises L234A / L235A (LALA) or L239A / L240A (LALA using direct numbering). In some embodiments, the one or more amino acid substitutions comprises LALAGA and N434A.

[0048] In some embodiments, the one or more amino acid substitutions comprises M252Y, S254T, and T256E (YTE) or M257Y / S259T / T261E (YTE using direct numbering) and / or M428L and N434S (LS).

[0049] In some embodiments, the one or more amino acid substitutions comprises L234A / L235A (LALA) and M252Y, S254T, and T256E (YTE) or L239A / L240A (LALA) and M257Y / S259T / T261E (YTE using direct numbering).

[0050] In some embodiments, the Fc region binds to Neonatal Fc receptor (FcRn).

[0051] In some embodiments, the Fc region binds an FcRn with higher affinity at pH 6.0 compared to an antibody comprising a wild-type Fc region.

[0052] In some embodiments, the antibody, or an antigen binding fragment thereof, is a monoclonal antibody.

[0053] In some embodiments, the antibody, or an antigen binding fragment thereof, binds a TSLP sequence set forth in SEQ ID NO: 365 or 366.

[0054] In some embodiments, the antibody, or an antigen binding fragment thereof, is for use in the treatment of an inflammatory disorder or disease.

[0055] In some embodiments, the antibody, or an antigen binding fragment thereof, is for use in the treatment of atopic dermatitis (AD). In some embodiments, the treatment reduces disease severity in a patient and disease severity is assessed by an atopic dermatitis disease severity outcome measure.

[0056] In some embodiments, the antibody, or an antigen binding fragment thereof, is for use in the treatment of asthma.

[0057] In some embodiments, the antibody, or an antigen binding fragment thereof, is for use in the treatment of chronic sinusitis with nasal polyps.

[0058] In some embodiments, the antibody, or an antigen binding fragment thereof, is for use in the treatment of Chronic Rhinosinusitis without Nasal Polyps (CRSsNP).

[0059] In some embodiments, the antibody, or an antigen binding fragment thereof, is for use in the treatment of eosinophilic esophagitis (EoE).

[0060] In some embodiments, the antibody, or an antigen binding fragment thereof, is for use in the treatment of 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).

[0061] In some embodiments, the antibody, or an antigen binding fragment thereof, is for use in the treatment of Churg-Strauss syndrome / Eosinophilic granulomatosis with poly angiitis (EGPA).

[0062] In some embodiments, the antibody, or an antigen binding fragment thereof, is for use in the treatment of Prurigo Nodularis (PN).

[0063] In some embodiments, the antibody, or an antigen binding fragment thereof, is for use in the treatment of Chronic Spontaneous Urticaria (CSU).

[0064] In some embodiments, the antibody, or an antigen binding fragment thereof, is for use in the treatment of Chronic Pruritis of Unknown Origin (CPUO).

[0065] In some embodiments, the antibody, or an antigen binding fragment thereof, is for use in the treatment of Bullous Pemphigoid (BP).

[0066] In some embodiments, the antibody, or an antigen binding fragment thereof, is for use in the treatment of Cold Inducible Urticaria (ColdU).

[0067] In some embodiments, the antibody, or an antigen binding fragment thereof, is for use in the treatment of Allergic Fungal Rhinosinusitis (AFRS).

[0068] In some embodiments, the antibody, or an antigen binding fragment thereof, is for use in the treatment of Allergic Bronchopulmonary Aspergillosis (ABPA).

[0069] In some embodiments, the antibody, or an antigen binding fragment thereof, is for use in the treatment of Chronic Obstructive Pulmonary Disease (COPD).

[0070] In some embodiments, the antibody, or an antigen binding fragment thereof, is for use in the treatment of Crohn’s disease.

[0071] In some embodiments, the antibody, or an antigen binding fragment thereof, is for use in the treatment of lupus.

[0072] In some embodiments, the antibody, or an antigen binding fragment thereof, is for use in the treatment of rheumatoid arthritis (RA).

[0073] In some embodiments, the antibody, or an antigen binding fragment thereof, is for use in the treatment of psoriasis.

[0074] In some embodiments, the antibody, or an antigen binding fragment thereof, is for use in the treatment of ulcerative colitis.

[0075] In some embodiments, the antibody, or an antigen binding fragment thereof, is for use in the treatment of hi dradenitis suppurativa.

[0076] In some embodiments, the antibody, or an antigen binding fragment thereof, is for use in the treatment of celiac disease.

[0077] In some embodiments, the antibody, or an antigen binding fragment thereof, is for use in the treatment of systemic sclerosis.

[0078] In some embodiments, the antibody, or an antigen binding fragment thereof, is for use in the treatment of idiopathic pulmonary fibrosis.

[0079] In some embodiments, the antibody, or an antigen binding fragment thereof, is for use in the treatment of alopecia areata.

[0080] In another aspect, provided herein is an isolated polynucleotide or set of polynucleotides encoding an antibody or an antigen binding fragment thereof disclosed herein, a VH thereof, a VL thereof, a light chain thereof, or a heavy chain thereof, and optionally, wherein the polynucleotide or set of polynucleotides comprises cDNA.

[0081] In another aspect, provided herein is a vector or set of vectors comprising the polynucleotide or set of polynucleotides disclosed herein.

[0082] In another aspect, provided herein is a host cell comprising the polynucleotide or set of polynucleotides disclosed herein or the vector or set of vectors disclosed herein.

[0083] In another aspect, provided herein is a method of producing an antibody, or an antigen binding fragment thereof, the method comprising expressing the antibody with a host cell disclosed herein and isolating the expressed antibody.

[0084] In another aspect, provided herein is a pharmaceutical composition comprising an antibody, or an antigen binding fragment thereof, disclosed herein and a pharmaceutically acceptable excipient. In another aspect, provided herein is a kit comprising an antibody, or an antigen binding fragment thereof, disclosed herein or a pharmaceutical composition disclosed herein and instructions for use.

[0085] In another aspect, provided herein is a method for treating an inflammatory disorder or disease in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of an antibody, or an antigen binding fragment thereof, disclosed herein or a pharmaceutical composition disclosed herein.

[0086] In some embodiments, the mammalian subject is a human.

[0087] In some embodiments, the inflammatory disorder or disease is atopic dermatitis.

[0088] In some embodiments, the inflammatory disorder or disease is asthma.

[0089] In some embodiments, the inflammatory disorder or disease is ChronicObstructive Pulmonary Disease (COPD).

[0090] In some embodiments, the inflammatory disorder or disease is chronic sinusitis with nasal polyps. In some embodiments, the inflammatory disorder or disease is Chronic Rhinosinusitis without Nasal Polyps (CRSsNP). In some embodiments, the inflammatory disorder or disease is eosinophilic esophagitis (EoE). In some embodiments, the inflammatory disorder or disease is an Eosinophilic gastrointestinal disorder or disease (EGID), such as Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), Eosinophilic Colitis (EoC), or Eosinophilic Gastroenteritis (EGE). In some embodiments, the inflammatory disorder or disease is Churg-Strauss syndrome / Eosinophilic granulomatosis with polyangiitis (EGPA). In some embodiments, the inflammatory disorder or disease is Prurigo Nodularis (PN).

[0091] In some embodiments, the inflammatory disorder or disease is Chronic Spontaneous Urticaria (CSU). In some embodiments, the inflammatory disorder or disease is Chronic Pruritis of Unknown Origin (CPUO). In some embodiments, the inflammatory disorder or disease is Bullous Pemphigoid (BP). In some embodiments, the inflammatory disorder or disease is Cold Inducible Urticaria (ColdU). In some embodiments, the inflammatory disorder or disease is Allergic Fungal Rhinosinusitis (AFRS). In some embodiments, the inflammatory disorder or disease is Allergic Bronchopulmonary Aspergillosis (ABPA). In some embodiments, the inflammatory disorder or disease is celiac disease. In some embodiments, the inflammatory disorder or disease is an inflammatory bowel disease, such as Crohn’s disease or ulcerative colitis. In some embodiments, the inflammatory disorder or disease is lupus. In some embodiments, the inflammatory disorder or disease is rheumatoid arthritis (RA). In some embodiments, the inflammatory disorder or disease is psoriasis. In some embodiments, the inflammatory disorder or disease is hidradenitis suppurativa. In some embodiments, the inflammatory disorder or disease is systemic sclerosis. In some embodiments, the inflammatory disorder or disease is idiopathic pulmonary fibrosis. In some embodiments, the inflammatory disorder or disease is alopecia areata.

[0092] In another aspect, provided herein is a method for treating a pathology associated with elevated levels of TSLP in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of an antibody, or an antigen binding fragment thereof, disclosed herein or a pharmaceutical composition disclosed herein.

[0093] In another aspect, provided herein is a method of reducing biological activity of TSLP in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of an antibody, or an antigen binding fragment thereof, disclosed herein or a pharmaceutical composition disclosed herein.

[0094] In another aspect, provided herein is a method of preventing an inflammatory disorder or disease in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of an antibody, or an antigen binding fragments thereof, disclosed herein or a pharmaceutical composition disclosed herein.

[0095] In another aspect, provided herein is a method of reducing levels of Thymus and Activation Regulated Chemokine (TARC) / CCL17 in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of an antibody, or an antigen binding fragment thereof, disclosed herein or a pharmaceutical composition disclosed herein.

[0096] In another aspect, provided herein is a method of reducing levels of macrophage- derived chemokine (MDC (CCL22)) in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of an antibody, or an antigen binding fragment thereof, disclosed herein or a pharmaceutical composition disclosed herein.

[0097] In some embodiments, the mammalian subject is a human.

[0098] In another aspect, 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) as measured by cross-linking mass spectrometry.

[0099] In another aspect, 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; SEQID NO: 401) but not amino acids 120-128 of SEQ ID NO: 365 (WRRFNRPLL; SEQ ID NO: 404).BRIEF DESCRIPTION OF FIGURES

[0100] FIG. 1A - FIG. ID show the ability of exemplary antibodies and a positive control antibody (antibody based on published sequences of tezepelumab) to inhibit TSLP binding. FIG. ID also includes an isotype control.

[0101] FIG. 2A - FIG. 2C show the ability of exemplary antibodies and a positive control antibody (antibody based on published sequences of tezepelumab) to inhibit the STAT5-induced expression of luciferase. FIG. 2C also includes an isotype control.

[0102] FIG. 3A - FIG. 3C show the ability of exemplary antibodies and a positive control antibody (antibody based on published sequences of tezepelumab) to inhibit the proliferation of Baf3 cells. FIG. 3C also includes an isotype control.

[0103] FIG. 4A - FIG. 4D show the ability of exemplary antibodies and a positive control antibody (antibody based on published sequences of tezepelumab) to inhibit TSLP- induced TARC secretion.

[0104] FIG. 5 is a graph showing the serum concentration of Antibody 5 and a positive control antibody (antibody based on published sequences of tezepelumab) over time when injected intravenously (IV) or subcutaneously (SC) in vivo in non-human primates.

[0105] FIG. 6 is a schematic of TSLP with a positive control antibody (antibody based on published sequences of tezepelumab) and Antibody 5 epitope mapping regions shown in medium gray and black speckles, respectively, as measured by Hydrogen-Deuterium Exchange (HDX) mass spectrometry.

[0106] FIG. 7 is a schematic of TSLP with a positive control antibody (antibody based on published sequences of tezepelumab) and Antibody 5 epitope mapping regions shown in medium gray and black speckles, respectively, as measured by cross-linking mass spectrometry (XL-MS).DETAILED DESCRIPTIONDefinitions

[0107] Unless otherwise defined, all terms of art, notations, and other scientific terminology used herein are intended to have the meanings commonly understood by those ofskill 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.

[0108] As used herein, the singular forms “a,” “an,” and “the” include plural references unless indicated otherwise.

[0109] It is understood that aspects and embodiments of the invention described herein include “comprising,” “consisting,” and “consisting essentially of’ aspects and embodiments.

[0110] For all compositions described herein, and all methods using a composition described herein, the compositions can either comprise the listed components or steps, or can “consist essentially of’ the listed components or steps. When a composition is described as “consisting essentially of’ the listed components, the composition contains the components listed and may contain other components which do not substantially affect the condition being treated, but do not contain any other components which substantially affect the condition being treated other than those components expressly listed; or, if the composition does contain extra components other than those listed which substantially affect the condition being treated, the composition does not contain a sufficient concentration or amount of the extra components to substantially affect the condition being treated. When a method is described as “consisting essentially of’ the listed steps, the method contains the steps listed, and may contain other steps that do not substantially affect the condition being treated, but the method does not contain any other steps which substantially affect the condition being treated other than those steps expressly listed. As a non-limiting specific example, when a composition is described as “consisting essentially of’ a component, the composition may additionally contain any amount of pharmaceutically acceptable carriers, vehicles, or diluents and other such components which do not substantially affect the condition being treated.

[0111] 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 self-replicating 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.”

[0112] 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.

[0113] 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.

[0114] 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, Thermus thermophilus, Bacillus stearothermophilus, Pseudomonas fluorescens, Pseudomonas aeruginosa, Pseudomonas putida, etc.) phylogenetic domain, or 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.

[0115] An “effective amount” or “therapeutically effective amount” as used herein refers to an amount of therapeutic compound, such as an anti-TSLP antibody, or an 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 are 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.

[0116] 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.

[0117] 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.

[0118] As used herein, the terms “subject,” “patient,” and “individual” mean 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 an 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.

[0119] The term “z z vitro" refers to processes that occur in a living cell growing separate from a living organism, e.g., growing in tissue culture.

[0120] The term “z z vzvo” refers to processes that occur in a living organism.

[0121] 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, contraindications, and / or warnings concerning the use of such therapeutic or diagnostic products.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] The terms “modulate” and “modulation” refer to reducing or inhibiting or, alternatively, activating or increasing, a recited variable.

[0126] 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.

[0127] 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.

[0128] 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).

[0129] 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.

[0130] 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.

[0131] For any of the structural and functional characteristics described herein, methods of determining these characteristics are known in the art.

[0132] The term “optionally” is meant, when used sequentially, to include from one to all of the enumerated combinations and contemplates all sub-combinations.

[0133] 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).

[0134] 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).

[0135] 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.

[0136] The term “ka” (M-l*sec-l), as used herein, refers to the association rate constant of a particular antibody-antigen interaction. This value is also referred to as the kon value.

[0137] 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.

[0138] The term “KA” (M-l), as used herein, refers to the association equilibrium constant of a particular antibody-antigen interaction. KA = ka / kd.

[0139] 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, described herein) by any effective route. Exemplary routes of administration are described herein below.

[0140] 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.

[0141] 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, deoxy guanosine, and deoxy cytidine) 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.

[0142] 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 acidsTom 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).

[0143] The term “antibody” is used herein in its broadest sense and includes certain types of immunoglobulin molecules comprising one or more antigen-binding domains that specifically bind to an antigen or epitope. An antibody specifically includes intact antibodies (e.g., intact immunoglobulins), antibody fragments, and multi-specific antibodies.

[0144] An “anti-TSLP antibody,” “TSLP antibody,” or “TSLP specific antibody” is an antibody, as provided herein, which specifically binds to the antigen TSLP.

[0145] The term “epitope” means a portion of an antigen that specifically binds to an antibody.

[0146] The terms “hypervariable region” or “HVR,” as used herein, refer to each of the regions of an antibody variable domain which are hypervariable in sequence and / or form structurally-defined loops (“hypervariable loops”).

[0147] The term “antigen-binding domain” means the portion of an antibody that is capable of specifically binding to an antigen or epitope.

[0148] 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.

[0149] The terms “human antibody” or “fully human antibody” refer 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.

[0150] 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.

[0151] 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.

[0152] 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.

[0153] The term “monoclonal antibody” refers to an antibody from a population of substantially homogeneous antibodies. A population of substantially homogeneous antibodies comprises antibodies that are substantially similar and that bind the same epitope(s), except for variants that may normally arise during production of the monoclonal antibody. Such variants are generally present in only minor amounts. A monoclonal antibody is typically obtained by a process that includes the selection of a single antibody from a plurality of antibodies. For example, the selection process can be the selection of a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones, yeast clones, bacterial clones, or other recombinant DNA clones. The selected antibody can be further altered, forexample, 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.

[0154] 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.

[0155] 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.

[0156] “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.

[0157] “Fv” fragments comprise a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain.

[0158] “Single-chain Fv” or “sFv” or “scFv” includes the VH and VL domains of an antibody, wherein these domains are present in a single polypeptide chain. In one embodiment, the Fv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the scFv to form the desired structure for antigen-binding. For a review of scFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994). HER2 antibody scFv fragments are described in WO93 / 16185; U.S. Pat. No. 5,571,894; and U.S. Pat. No. 5,587,458.

[0159] “ scFv-Fc” fragments comprise an scFv attached to an Fc domain. For example, anFc domain may be attached to the C-terminal of the scFv. The Fc domain may follow the VH or VL, depending on the orientation of the variable domains in the scFv (i.e., VH-VL or VL- VH). Any suitable Fc domain known in the art or described herein may be used. In some cases, the Fc domain comprises an IgG4 Fc domain.

[0160] The terms “single domain antibody” or “sdAb” refer 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 etal., (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). AppL Microbiol Biotechnol. 77(1): 13-22).

[0161] The terms “full length antibody,” “intact antibody,” and “whole antibody” are used herein interchangeably herein 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.

[0162] 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.

[0163] The terms “Fc domain” or “Fc region” herein are used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The terms include native sequence Fc regions and variant Fc regions.

[0164] The term “substantially purified” refers to a construct described herein, or variant thereof that may be substantially or essentially free of components that normally accompany or interact with the protein as found in its naturally occurring environment, i.e. a native cell, or host cell in the case of recombinantly produced antibody that in certain embodiments, is substantially free of cellular material includes preparations of protein having less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% (by dry weight) of contaminating protein.

[0165] The term percent “identity,” in the context of two or more nucleic acids or polypeptide sequences, refer to two or more sequences or sub-sequences 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.

[0166] 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.

[0167] 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).

[0168] 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 publicly available through the National Center for Biotechnology Information (www.ncbi.nlm.nih.gov / ).

[0169] 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.

[0170] 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.

[0171] 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 (LNRS) (see Naegeli et al., International Journal of Dermatology . 2015;54(6):715-722; and Newton L, et al., J. Patient Rep. Outcomes. 2019;3(l):42), and the Patient-Oriented Eczema Measure (POEM) (www.nottingham.ac.uk / research / groups / cebd / resources / poem.aspx).TSLP Binding ProteinsAntibody Structure

[0172] 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.

[0173] The recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon, and mu constant region genes, as well as the myriad immunoglobulin variableregion genes. Light chains are classified as either kappa or lambda. There are four subtypes of human lambda light chain constant region ( i, 2, 3, 7), 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, 5, a, y, and p, respectively.

[0174] An exemplary immunoglobulin (antibody) structural unit is composed of two pairs of polypeptide chains, each pair having one “light” (about 25 kD) and one “heavy” chain (about 50-70 kD). The N-terminal domain of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms variable light chain (VL) and variable heavy chain (VH) refer to these light and heavy chain domains, respectively. The IgGl heavy chain comprises 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.

[0175] 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.

[0176] 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.

[0177] Generally, native four-chain antibodies comprise six HVRs; three in the VH (Hl, H2, and H3), and three in the VL (LI, L2, and L3). HVRs generally comprise amino acid residues from the hypervariable loops and / or from the complementarity determining regions (CDRs), the latter being of highest sequence variability and / or involved in antigen recognition. With the exception of CDR1 in VH, CDRs generally comprise the amino acid residues that form the hypervariable loops. 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 etal., 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.

[0178] 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. 2621132- 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.

[0179] 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.

[0180] CDRs may be assigned, for example, using antibody numbering software, such as Abnum, available at www.bioinf.org.uk / abs / abnum / , and described in Abhinandan and Martin, Immunology, 2008, 45:3832-3839, incorporated by reference in its entirety.TABLE 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.

[0181] 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 cd.. supra). Unless stated otherwise, the EU numbering scheme is used to refer to residues in antibody heavy chain constant regions described herein.

[0182] 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.

[0183] Epitopes frequently consist of surface-accessible amino acid residues and / or sugar side chains and may have specific three-dimensional structural characteristics, as well as specific charge characteristics. Conformational and non-conformational epitopes are distinguished in that the binding to the former but not the latter may be lost in the presence of denaturing solvents. An epitope may comprise amino acid residues that are directly involved in the binding, and other amino acid residues, which are not directly involved in the binding. The epitope to which an antibody binds can be determined using known techniques for epitope determination such as, for example, testing for antibody binding to TSLP or TSLP variants with different point-mutations, or to chimeric TSLP variants.

[0184] To screen for antibodies which bind to an epitope on a target antigen bound by an antibody of interest (e.g., TSLP and / or TSLP receptor), 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.

[0185] 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.

[0186] 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.

[0187] 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.

[0188] 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, theantibody consists of an antibody fragment. In some embodiments, the antibody consists essentially of an antibody fragment.

[0189] In some embodiments, the antibodies are monoclonal antibodies.

[0190] In some embodiments, the antibodies are polyclonal antibodies.

[0191] 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.

[0192] 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.

[0193] 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.IBLE 3. Sequences of anti-TSLP antibody constructs - CDRsTABLE 4. Sequences of anti-TSLP antibody constructs - VH and VLVH Domains

[0194] 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.

[0195] 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 thisparagraph 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

[0196] 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.

[0197] 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, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.VH-VL Combinations

[0198] 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; and a VL sequence selected from any one of SEQ ID NOs: 37-45, 328-364, 371-379 and 381-385.

[0199] 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.

[0200] 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 TABLE 4 (e.g., a VH sequence and a VL sequence from the same row of TABLE 4). 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 TABLE 11 (e.g., a VH sequence and a VL sequence from the same row of TABLE 11).

[0201] 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 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, 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.

[0202] 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.

[0203] 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.

[0204] 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.

[0205] 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.

[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: 41.

[0207] 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.

[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: 43.

[0209] 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.

[0210] 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.

[0211] 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.

[0212] 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.

[0213] 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.

[0214] 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.

[0215] 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.

[0216] 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.

[0217] 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.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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.

[0222] 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.

[0223] 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.

[0224] 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.

[0225] 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.

[0226] 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.

[0227] 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.

[0228] 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.

[0229] 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.

[0230] 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.

[0231] 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.

[0232] 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.

[0233] 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.

[0234] 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.

[0235] 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.

[0236] 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.

[0237] 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.

[0238] 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.

[0239] 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.

[0240] 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.

[0241] 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.

[0242] 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.

[0243] 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.

[0244] 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.

[0245] 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.

[0246] 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.

[0247] 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.

[0248] 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.

[0249] 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.

[0250] 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.

[0251] 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.

[0252] 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.

[0253] 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.

[0254] 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.

[0255] 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.

[0256] 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.

[0257] 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.

[0258] 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.

[0259] 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.

[0260] 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.

[0261] 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.

[0262] 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.

[0263] 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, 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).

[0264] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 417; and a VL sequence set forth in SEQ ID NO: 418; 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: 47-50, 52-162, and 164-270. 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 any one of SEQ ID NOs: 409-412.

[0265] 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 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: 409-412). 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: 409. 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 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: 409-412). 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 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: 409, or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 409.

[0266] 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: 409. 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 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: 409-412). 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 orSEQ ID NO: 173, and a light chain constant region comprising a sequence set forth in SEQ ID NO: 409. 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 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: 409-412). 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: 409 or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 409.

[0267] 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: 409.CDRs

[0268] 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 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 (e.g., 6 CDRs from the same antibody).

[0269] 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 10. In some embodiments, disclosed herein is an antibody, or an antigen binding fragment thereof, comprising 6 of the Kabat CDRs of TABLE 10, 6 of the Chothia CDRs of TABLE 10, or 6 of the IMGT CDRs of TABLE 10. 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 10 (e.g., 6 CDRs from the same antibody).

[0270] 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 are IMGT CDRs. In some aspects, the CDRs are AbM CDRs. In some aspects, the CDRs are Contact CDRs.

[0271] 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 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 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 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.

[0272] 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.

[0273] 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, DVS, EDS, DDT, DDK, DDL, DDN, and DDS. In some embodiments, the CDR-L1 is a CDR-L1 of a VL domain selected from SEQ ID NOs: 37-45, 328-364, 371-379 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 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 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.

[0274] 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 SEQID 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.

[0275] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H3 selected from 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 SEQ ID NOs: 13-18. In some embodiments, the CDR-H3 is a CDR-H3 selected from 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 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.

[0276] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 selected from 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 SEQ ID NOs: 1-9. In some embodiments, the CDR-H1 is a CDR-H1 selected from 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.

[0277] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H2 selected from 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 SEQ ID NOs: 10-12. In some embodiments, the CDR-H2 is a CDR-H2 selected from 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.

[0278] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-L3 selected from 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 SEQ ID NOs: 27-31, 311-327, and 367-370. In some embodiments, the CDR-L3 is a CDR-L3 selected from 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.

[0279] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-L2 selected from 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 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 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.

[0280] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-L1 selected from SEQ ID NOs: 19-24, 271-302, and 387. In some aspects, 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: 19-24, 271-302, and 387. In some embodiments, the CDR-L1 is a CDR-L1 selected from 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.

[0281] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H3 selected from SEQ ID NOs: 13-18; a CDR-H2 selected from SEQ ID NOs: 10-12; a CDR-H1 selected from SEQ ID NOs: 1-9; a CDR-L3 selected from SEQ ID NOs: 27-31, 311-327, and 367-370; a CDR-L2 selected from 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 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 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 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 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 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 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 SEQ ID NOs: 19-24, 271-302, and 387. In some embodiments, the CDR-H3 is a CDR-H3 selected from 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 of SEQ ID NOs: 10-12, 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: 1-9, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L3 is a CDR-L3 selected from 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 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 SEQ ID NOs: 19-24, 271-302, and 387, with up to 1, 2, 3, 4, 5, or 6 amino acid substitutions.

[0282] 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%, or99% 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- L1 selected from SEQ ID NOs: 21 and 24, with up to 1, 2, 3, 4, 5, or 6 amino acid substitutions.

[0283] 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.

[0284] 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, andthe 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 to 1, 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.

[0285] 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.

[0286] 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.

[0287] 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.

[0288] 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: 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.

[0289] 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.

[0290] 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.

[0291] 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: 26 or the amino acid sequence DDS; and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 31.

[0292] 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.

[0293] 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.

[0294] 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.

[0295] 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.

[0296] 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.

[0297] 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.

[0298] 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.

[0299] 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.

[0300] 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.

[0301] 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.

[0302] 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.

[0303] 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.

[0304] 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.

[0305] 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.

[0306] 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.

[0307] 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.

[0308] 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.

[0309] 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.

[0310] 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.

[0311] 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.

[0312] 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 and 298; 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.

[0313] 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.

[0314] 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.

[0315] 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.

[0316] 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.

[0317] 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.

[0318] 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.

[0319] 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.

[0320] 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.

[0321] 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.

[0322] 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.

[0323] 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.

[0324] 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.

[0325] 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.

[0326] 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.

[0327] 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.

[0328] 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.

[0329] 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.

[0330] 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.

[0331] 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.

[0332] 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 of TABLE 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.

[0333] 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 10; 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 10, 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 10, 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 10, 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 10, 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 10. In some embodiments, the CDR-H3 is a CDR-H3 of TABLE 10, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H2 is a CDR-H2 of TABLE 10, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H1 is a CDR-H1 of TABLE 10, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L3 is a CDR-L3 of TABLE 10 with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L2 is a CDR-L2 of TABLE 10, with up to 1, 2, 3, or 4 amino acid substitutions; and the CDR-L1 is a CDR-L1 of TABLE 10, with up to 1, 2, 3, 4, 5, or 6 amino acid substitutions.

[0334] 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: 409. 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: 409.

[0335] 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: 409-412). In some embodiments, the antibody comprises a constant light chain sequence comprising a sequence set forth in SEQ ID NO: 409.

[0336] 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, theantibody 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: 409-412). In some embodiments, the antibody comprises a constant light chain sequence comprising a sequence set forth in SEQ ID NO: 409.

[0337] 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 derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants or cones are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.Fc Region

[0338] 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.

[0339] 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.

[0340] In certain embodiments, provided human IgGl Fc regions include an SRDEL (SEQ ID NO: 440) allotype or an SREEM (SEQ ID NO: 441) allotype.

[0341] 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., laneway et al., Immuno Biology: the immune system in health and disease, (Elsevier Science Ltd., NY) (4th ed., 1999)).Activating receptor FcyRIIA contains an immunoreceptor tyrosine-based activation motif (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, Annu. Rev. Immunol 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs, including those to be identified in the future, are encompassed by the term “FcR” herein. The term also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol. 117:587 (1976); and Kim et al., J. Immunol. 24:249 (1994)).

[0342] 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.

[0343] 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 et al., J Immunol Methods.2011 Feb 28;365(l-2): 132-41);• F243L / R292P / Y300L / V305I / P396L, F243L / R292P / Y300L / L235V / P396L(Stavenhagen et al., Cancer Res. 2007 Sep 15;67(18):8882-90; Nordstrom et al., Breast Cancer Res . 2011 Nov 30;13(6):R123);• F243L (Stewart et al., Protein Eng Des Sei. 2011 Sep;24(9):671-8.), S298A / E333A / K334A (Shields et al., JBiolChem. 2001 Mar 2;276(9):6591- 604);• S239D / I332E / A330L, S239D / I332E (Lazar et al., Proc Natl Acad Sci U S A. 2006 Mar14;103(l l):4005-10);• S239D / S267E, S267E / L328F (Chu et al., Mol Immunol. 2008 Sep;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. Strohl, Woodhead Publishing series in Biomedicine No 11, ISBN 1 907568 37 9, Oct 2012) lists mutations on page 283.

[0344] 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 5 summarizes various designs reported in the literature for effector function engineering.

[0345] 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 oxidoreductase GDP-6- deoxy-D-lyxo-4-hexylose reductase (RMD) (see Henning von Horsten et al. , Glycobiol 2010, 20: 1607-1618) or Lecl3 CHO cells, which are deficient in protein fucosylation (see Ripka et al., Arch. Biochem. Biophys., 1986, 249:533-545; U.S. Pat. Pub. No. 2003 / 0157108; and WO 2004 / 056312; each of which is incorporated by reference in its entirety), and knockout cell lines, such as alpha- 1,6-fucosyltransf erase 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 canbe 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.

[0346] 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.

[0347] 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.

[0348] 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.

[0349] 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 incorporated by reference in its entirety.

[0350] 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 CDCfunction. Examples of such antibody variants are described, for example, in WO 1997 / 30087; WO 1998 / 58964; and WO 1999 / 22764; each of which his incorporated by reference in its entirety.

[0351] 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 5 that may confer improved effector function. In another embodiment, the antibody can be afucosylated to improve effector function.TABLE 5. CH2 domains and effector function engineering

[0352] 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. WO2006 / 105338 (Xencor), U.S. Patent Publication No. 2012 / 0225058 (Xencor), U.S. Patent Publication No. 2012 / 0251531 (Genentech), and Strop et al. ((2012) 7. Mol. Biol. 420: 204- 219), each of which is incorporated by reference in its entirety, describe specific modifications designed to reduce FcgR or complement binding to the Fc.

[0353] 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 6:TABLE 6. Modifications designed to reduce FcgR or complement binding to the Fc

[0354] 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 incorporated by reference in its entirety.

[0355] 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 after 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)).

[0356] 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 409-412.

[0357] In certain embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a VH sequence and a VL sequence provided in TABLE 11 (e.g., a VH sequence and a VL sequence from the same row of TABLE 11), together with a heavy chain constant region selected from a sequence set forth in SEQ ID NOs: 47-270. In certainembodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a VH sequence and a VL sequence provided in TABLE 11, 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 409-412.

[0358] 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; 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: 409-412).

[0359] In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 413 and / or SEQ ID NO: 419. In certain embodiments, the antibody comprises a light chain comprising an amino acid sequence set forth in SEQ ID NO: 414. In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 413 and a light chain comprising an amino acid sequence set forth in SEQ ID NO: 414. In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 419 and a light chain comprising an amino acid sequence set forth in SEQ ID NO: 414.

[0360] In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 420. In certain embodiments, the antibody comprises a light chain comprising an amino acid sequence set forth in SEQ ID NO: 421. In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 420 and a light chain comprising an amino acid sequence set forth in SEQ ID NO: 421.

[0361] In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 422. In certain embodiments, the antibody comprises a light chain comprising an amino acid sequence set forth in SEQ ID NO: 423. In certain embodiments, the antibody comprises a heavy chain comprising an amino acidsequence set forth in SEQ ID NO: 422 and a light chain comprising an amino acid sequence set forth in SEQ ID NO: 423.

[0362] In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 424. In certain embodiments, the antibody comprises a light chain comprising an amino acid sequence set forth in SEQ ID NO: 425. In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 424 and a light chain comprising an amino acid sequence set forth in SEQ ID NO: 425.

[0363] In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 426. In certain embodiments, the antibody comprises a light chain comprising an amino acid sequence set forth in SEQ ID NO: 427. In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 426 and a light chain comprising an amino acid sequence set forth in SEQ ID NO: 427.

[0364] In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 428. In certain embodiments, the antibody comprises a light chain comprising an amino acid sequence set forth in SEQ ID NO: 429. In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 428 and a light chain comprising an amino acid sequence set forth in SEQ ID NO: 429.

[0365] In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 430. In certain embodiments, the antibody comprises a light chain comprising an amino acid sequence set forth in SEQ ID NO: 431. In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 430 and a light chain comprising an amino acid sequence set forth in SEQ ID NO: 431.

[0366] In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 432. In certain embodiments, the antibody comprises a light chain comprising an amino acid sequence set forth in SEQ ID NO: 433. In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 432 and a light chain comprising an amino acid sequence set forth in SEQ ID NO: 433.

[0367] In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 434. In certain embodiments, the antibody comprises a light chain comprising an amino acid sequence set forth in SEQ ID NO: 435. In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 434 and a light chain comprising an amino acid sequence set forth in SEQ ID NO: 435.

[0368] In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 436. In certain embodiments, the antibody comprises a light chain comprising an amino acid sequence set forth in SEQ ID NO: 437. In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 436 and a light chain comprising an amino acid sequence set forth in SEQ ID NO: 437.

[0369] In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 438. In certain embodiments, the antibody comprises a light chain comprising an amino acid sequence set forth in SEQ ID NO: 439. In certain embodiments, the antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 438 and a light chain comprising an amino acid sequence set forth in SEQ ID NO: 439.

[0370] In certain embodiments, 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 to an antibody comprising an Fc region without the one or more amino acid substitutions (e.g., a wild-type Fc region). 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 an Fc region without the one or more amino acid substitutions (e.g., 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 dupilumab. 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, 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.

[0371] In certain embodiments, an antibody described herein comprises a heavy chain constant domain having a means for increasing the half-life of the antibody.

[0372] 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.

[0373] 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.

[0374] 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 Fc without the one or more amino acid substitutions.

[0375] In certain embodiments, the one or more amino acid substitutions is selected from the group consisting of S228P (SP), T250Q, M252Y, S254T, T256E, T256D, 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) or M257Y / S259T / T261E (YTE using direct numbering), T250Q / M428L, T307A / E380A / N434A, T256D / T307Q (DQ), T256D / T307W (DW), M252Y / T256D (YD), T307Q / Q311 V / A378V (QVV), T256D / H285D / T307R / Q311 V / A378V (DDRVV), L309D / Q311H / N434S (DHS), S228P / L235E (SPLE), L234A / L235A (LALA) 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, 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.

[0376] 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 LALA mutations at positions 239 and 240, respectively. In certain embodiments, an antibody described herein comprises an 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.

[0377] In certain embodiments the human Fc region comprises a human IgGl Fc with LALA mutations. In certain embodiments, the human Fc region comprises a human IgGl Fc with YTE mutations. In certain embodiments, the human Fc region comprises a human IgGl Fc 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 with LALA mutations at L239A / L240A and / or YTE mutations at M257Y / S259T / T261E.

[0378] In certain embodiments, the Fc region binds an Fey Receptor selected from the group consisting of: FcyRI, FcyRIIa, FcyRIIb, FcyRIIc, FcyRIIIa, and FcyRIIIb. In certainembodiments, the Fc region binds an Fey Receptor with higher affinity at pH 6.0 compared to an antibody comprising a wild-type Fc region.Binding

[0379] 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®).

[0380] 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.

[0381] 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 and 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.

[0382] 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 competitivebinding 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%.

[0383] In certain embodiments, the antibody, or an antigen binding fragment thereof, binds a TSLP sequence set forth in SEQ ID NO: 365 or 366.

[0384] 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.

[0385] 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).

[0386] 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, 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.

[0387] 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 lO x IO’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.

[0388] 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, provided 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 10'9M as measured by ELISA or any other suitable method known in the art.

[0389] 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.

[0390] 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 10’8M as measured by ELISA or any other suitable method known in the art.Function

[0391] “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 modificationsare 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).

[0392] 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.

[0393] Pharmaceutical Compositions 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.

[0394] 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.

[0395] 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.

[0396] 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 of 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.

[0397] 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.

[0398] 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

[0399] 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, isolated nucleic acid encoding an antibody, or an antigen binding fragment thereof, described herein is provided. Such nucleic acids 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 nucleic acids are provided. In one embodiment, the nucleic acid is provided in a multi ci str onic 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 first 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).

[0400] 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).

[0401] 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%, or at least about 85%, and more specifically, a purity level of at least about 90%, a purity level of at least about 95%, or 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.

[0402] Suitable host cells for cloning or expression of antibody-encoding vectors include prokaryotic or eukaryotic cells described herein.

[0403] Recombinant host cells or host cells are cells that include 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. 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, NS0, Sp2O, CV-1, VERO-76, HeLa, HepG2, Per.C6, or BHK.

[0404] 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 / v coli.) After expression, the antibody may be isolated from the bacterial cell paste in a soluble fraction and can be further purified.

[0405] 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).

[0406] 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 baculoviral strains have been identified which may be used in conjunction with insect cells, particularly for transfection of Spodoptera frugiperda cells.

[0407] 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).

[0408] 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 3 A); human lung cells (W138); human liver cells (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, NS0 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).

[0409] 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.

[0410] 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.

[0411] 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.

[0412] 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 withprotein 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 can 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.

[0413] 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.

[0414] 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.

[0415] 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

[0416] 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.

[0417] 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.

[0418] 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.

[0419] 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 antigenbinding 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 the 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 (ABPA). 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 usedin 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.

[0420] In certain aspects, described herein is a method for treating an inflammatory disorder or disease in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of 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 ordisease 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.

[0421] In certain aspects, described herein are methods for treating an inflammatory disorder or disease in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of the 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.

[0422] In certain aspects, described herein are methods for treating a pathology associated with elevated levels of TSLP and / or TSLPR in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of an antibody, or an antigen binding fragment thereof, or a pharmaceutical composition described herein.

[0423] In certain aspects, described herein are methods of reducing biological activity of TSLP and / or TSLPR in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of an antibody, or an antigen binding fragment thereof, or a pharmaceutical composition described herein.

[0424] In certain aspects, described herein are methods of preventing an inflammatory disorder or disease in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of an antibody, or an antigen binding fragment thereof, or a pharmaceutical composition described herein.

[0425] In certain aspects, described herein are methods for reducing levels of 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 chemokine is a type 2 chemokine. In certain embodiments, the type 2 chemokine is TARC or MDC.

[0426] In certain aspects, described herein are methods for reducing levels of a type 2 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. Incertain embodiments, the method reduces the level of the type 2 chemokine by at least about 50%, 60%, 70%, 80%, 85%, 90%, or 95%.

[0427] In certain aspects, described herein are methods of reducing levels of Thymus and Activation Regulated Chemokine (TARC) / CCL17 in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of an antibody, or an antigen binding fragment thereof, or a pharmaceutical composition described herein. In certain embodiments, the method reduces the level of TARC / CCL17 by at least about 50%, 60%, 70%, 80%, 85%, 90%, or 95%.

[0428] In certain aspects, described herein are methods of reducing levels of macrophage- derived chemokine (MDC (CCL22)) in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of an antibody, or an antigen binding fragment thereof, or a pharmaceutical composition described herein. In certain embodiments, the method reduces the level of MDC by at least about 50%, 60%, 70%, 80%, 85%, 90%, or 95%.

[0429] In certain aspects, described herein are methods for treating asthma in a patient, wherein the method comprises administering an anti-TSLP antibody, or an antigen binding fragment thereof.Methods of Administration

[0430] 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) or M257Y / S259T / T261E (YTE using direct numbering) and / or M428L and N434S (LS) or M433L / N439S (LS using directnumbering). The Fc domain may further comprise amino acid modifications L234A / L235A (LALA) or L239A / L240A (LALA) using direct numbering)(e.g., LALA / YTE or LALA / LS).

[0431] 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 course 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.

[0432] 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.Kits and Articles of Manufacture

[0433] 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, pharmaceutically acceptable excipient, package insert, and 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 antibodycompositions or kits described herein. Examples of an article of manufacture include vials (including sealed vials).EXAMPLES

[0434] 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.

[0435] 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 and Company, 1993); A.L. Lehninger, Biochemistry (Worth Publishers, Inc., current addition); Sambrook, el al.. Molecular Cloning: A Laboratory Manual (2nd Edition, 1989); Methods In Enzymology (S. Colowick and N. Kaplan eds., Academic Press, Inc.); Remington'sPharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990); Carey and Sundberg Advanced Organic Chemistry 3rdEd. (Plenum Press) Vols A and B (1992).MethodsGene synthesis and plasmid construction

[0436] The coding sequences for the heavy chain (HC) and light chain (LC) of the antibody were generated by DNA synthesis and PCR and subsequently subcloned into mammalian expression-based plasmids for protein expression in a mammalian cell system. The gene sequences in the expression vectors were confirmed by DNA sequencing.Expression of antibody constructs

[0437] Transient expression of antibodies was performed by co-transfection of paired HC and LC constructs into CHO cells using the polyethylenimine (PEI) method. Briefly, CHO cells at approximately 5.5 x 106 / mL in a shake flask were used as the host. Transfection was initiated by adding a mixture of 1 mg / L DNA and 7 mg / L PEI in OptiMEM™ medium (Invitrogen) to the cells followed by gentle mixing. Cells were then cultured in an incubator shaker at 120 rpm, 37 °C, and 8% CO2 for 9 days. Feeding with peptone and glucose was carried out 24 h later and every 2-3 days thereafter depending on the cell density andviability. The cell culture was terminated on day 9 when cell viability reduced to < 80%. The conditioned medium was harvested for protein purification.Purification of antibody construct

[0438] Protein purification by affinity chromatography and ion exchange chromatography was performed using an AKTA pure instrument (GE Lifesciences). Conditional medium expressing target antibody was harvested by centrifugation at 4,000 rpm, 50 min, and filtered with a 0.22 pm filter. The harvested supernatants were loaded to a column of Mabselect™ SuRe™ (GE Healthcare). After washing the column with Buffer A (PBS, PH 7.4), the protein was eluted with Buffer B (1 M Glycine, pH 2.7), and immediately neutralized with 1 / 10 volume of Buffer D (1 M sodium citrate, pH 6.0). The affinity purified antibody was then buffer exchanged into 20 mM sodium acetate pH 5.5.SEC-HPLC Analysis of Antibody Construct

[0439] Analytical SEC-HPLC was performed using a Shimadzu LC-10 HPLC instrument (Shimadzu Corp.). 20 pl sample on 1 mg / mL was loaded to a Superdex® 200 Increase 5 / 150GL column (GE Lifesciences). The mobile phase was 2xPBS with a flow rate of 0.3 mL / min, 15 min.Measuring Antibody-TSLP Binding Kinetics Using Surface Plasmon Resonance

[0440] A Biacore 8K SPR system (GE Healthcare) equipped with Series S Sensor Chip Protein G (Cytiva, Cat. 29179315) was used to determine the binding kinetic rate and affinity constants at 25 °C and in a running buffer of HBS-EP+ (10 mM HEPES pH 7.4, 150 mM NaCl, 3 mM EDTA, 0.05% Surfactant P20). Following a stabilization period in running buffer, the anti-TSLP monoclonal antibody (mAb) constructs (diluted to 1 pg / mL) were captured onto flow cell 2 (active) for 60 sec at a flow rate of 10 pL / min. Recombinant human TSLP protein , His Tag were prepared at concentrations of 0, 0.39, 0.78, 1.56, 3.13, 6.25, 12.5, and 0 nM and injected over flow cell 1 (reference) and flow cell 2 (active) for 180 sec at a flow rate of 30 pL / min. Recombinant cynomolgus TSLP protein, His Tag was prepared at concentrations of 0, 0.39, 0.78, 1.56, 3.13, 6.25, 12.5, 25, and 0 nM and injected over flow cell 1 (reference) and flow cell 2 (active) for 180 sec at a flow rate of 30 pL / min. Samples were injected in a multi-cycle manner over freshly captured mAb by regenerating the capture surfaces with injection of glycine pH 1.5 for 30 sec at a flow rate of 30 pL / min. The data was processed and analyzed with Biacore Insight Evaluation Software Version 2.0.15.12933 (GE Healthcare) as follows. Responses from flow cell 1 (reference) were subtracted from the responses from flow cell 2 (active). The responses from the two buffer blank injections werethen subtracted from the reference subtracted data (2-1) to yield double-referenced data, which were fit to an 1 : 1 binding model to determine the apparent association (ka) and dissociation rate constants (kd). Their ratio provided the apparent equilibrium dissociation constant or affinity constant (KD = kd / ka).Assessing blockade by ELISA

[0441] Human or cynomolgus non-human primate (NHP) TSLPR (2 pg / mL) coated on a MaxiSorp plate for 16 hours at 4 °C. The coated plate was blocked for 2 hours at 37 °C. Antibodies (Antibody 5 or an antibody based on published sequences of tezepelumab (positive control)) of increasing concentrations up to 2 nM were incubated with 3.3 ng / mL biotinylated recombinant cynomolgus NHP TSLP or 5 ng / mL biotinylated recombinant human TSLP at 4 °C for 30 minutes. Then, test antibody (TA)-TSLP mixture was added to blocked plates and incubated for 1 h at 37 °C. After washing, plates were incubated with Streptavidin-HRP for 1 h at 37 °C. After washing, 3,3',5,5'-tetramethylbenzidine (TMB) was added to each well for 5 minutes and incubated at room temperature until color developed, then quenched with stop solution and absorbance was read. Reactions were stopped by addition of IN HC1 and optical density (OD) was read at 450 nm. Inhibition% was calculated as 1- (OD450 of sample / OD450 of ‘Ligand only’). ICso and IC90 of TAs was calculated through non-linear regression.Example 1: Assessing the Affinity of Engineered TSLP Antibodies to TSLP, FcRn, Fc-receptors, and Clq

[0442] Using the methods described above, the affinity of anti-TSLP antibodies and the binding kinetics thereof were assessed using surface plasmon resonance (SPR) as compared to control antibodies.

[0443] As measured by SPR, the antibodies exhibited strong affinity to TSLP. The antibodies were shown to bind to human (Hu) TSLP with sub-nanomolar affinity and were cross-reactive to non-human primate (NHP) cynomolgus monkey (cyno) TSLP with sub- nanomolar affinities as summarized in TABLE 7 and TABLE 8.

[0444] Additionally, the binding affinity of Antibody 5 (which contains 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 sequence set forth in SEQ ID NO: 173 (hlgGl-LALA / YTE), and a human lambda light chain constant region sequence set forth in SEQ ID NO: 409) to human Fc- receptors and Clq was also measured by SPR at neutral pH, except for FcRn, which was assessed at both pH 6.0 and 7.4. A non-modified IgGl format (rituximab) was used as apositive control in this experiment, with rituximab produced based on publicly available sequences. Antibody 5 demonstrated a YTE-dependent increase in FcRn binding at pH 6.0 and a LALA-dependent attenuation of Fc-dependent binding compared to an IgGl control, as summarized in TABLE 9.IBLE 7. Summary of tested antibodies 1-9 (binding and functional assays))ata from two donors (donor 1 and donor 2) D=Not determined due to low signalIBLE 8. Summary of additional tested antibodies (binding, functional assay, biophysical properties)TABLE 9. Binding affinity of Antibody 5 to FcRn, Fc-receptors, and ClqExample 2: Inhibition of TSLP Binding to TSLPR

[0445] TSLP binding to TSLPR was used to evaluate the functional blockade of antibodies against this binding interaction in an ELISA. Briefly, as described in the Methods section, assay plates were coated with TSLPR then blocked with bovine serum albumin (BSA). Biotinylated TSLP and serially diluted test antibodies were pre-incubated then added to the plates. After washing the plates, horseradish peroxidase (HRP)-conjugated streptavidin (SA-HRP) was added followed by TMB for color development. The reaction was quenched with 1 N HC1 and absorbance at 450 nM was measured using a plate reader. Subsequent data were analyzed using GraphPad Prism. ICso and IC90 values were determined as the concentration of antibody required to inhibit 50% or 90%, respectively, of the maximum absorbance when no test antibody was added. The relative IC50 (Rel. IC50) values were determined against an antibody based on published sequences of tezepelumab (positive control) as the reference antibody.

[0446] Rel. IC50 results are summarized in the Rel. IC50, competition / blocking ELISA column of TABLE 7, TABLE 8, and FIG. 1A-FIG. ID. The IC90 results were as follows:the binding of human TSLP to the human TSLPR was inhibited by Antibody 5 at an IC90 of 0.22 nM, compared to 0.17 nM for the positive control.Example 3: Inhibition of TSLP Signaling Through TSLPR and / or IL-7Ra

[0447] The TSLP -responsive luciferase reporter Ba / F3 cell line is a murine Ba / F3 cell line engineered to express both TSLPR (also known as CRLF2, cytokine receptor like factor 2) and IL-7Ra separated by a self-cleaving P2A peptide. The construct was delivered by lentiviral transduction of STAT5 luciferase reporter Ba / F3 cells, which express a firefly luciferase reporter driven by STAT5 response elements located upstream of the promoter. After activation by TSLP, the endogenous transcription factor STAT5 binds to the response elements, inducing transcription of the luciferase reporter gene.

[0448] Inhibition of luciferase expression in BaF3 cells was used to evaluate the functional activity of antibodies to block TSLP-induced signaling. Briefly, BaF3 cells were collected and seeded at 50,000 cells per well in 100 pL. Antibodies were serially diluted and incubated with recombinant human TSLP at a final concentration of 5 ng / mL for 30 minutes at 4 °C. The antibody:TSLP mixture was then added to an engineered Ba / F3 cell line (murine interleukin-3 dependent pro-B cell) overexpressing human TSLPR and IL-7Ra with a luciferase reporter (Ba / F3-TSLPR-IL7Ra-luc-9El l) and incubated at 37 °C for 6 hours. Following this, the cells were incubated with ONE-Glo Luciferase for 2 minutes at room temperature before measuring luminescence. The mean fluorescence intensity (MFI) of cells in each well was recorded by fluorescence-activated cell sorting (FACS) using a BD FACSCanto II and subsequent data were analyzed using GraphPad Prism. IC50 and IC90 values were determined as the concentration of antibody required to inhibit 50% or 90%, respectively, of the maximum MFI of luciferase detected with incubation of TSLP alone. Relative IC50 values were also determined against an antibody based on published sequences of tezepelumab (positive control) as the reference antibody.

[0449] Results are summarized in TABLE 7, TABLE 8, and FIG. 2A-FIG. 2C. As shown in TABLE 7 and TABLE 8, clones were identified that demonstrated more effective inhibition of luciferase expression as compared to the positive control by up to about 7-fold (such as, for example, Antibody 5 and Antibody 7). The IC90 results were as follows: TSLP- driven STAT5 cell signaling was inhibited by Antibody 5, with an IC90 of 77.62 nM, compared to 26.93 nM for the positive control.

[0450] Taken together, these results demonstrated that Antibody 5 blocked TSLP from binding to TSLPR, preventing the formation of the TSLPR / IL-7Ra heterocomplex and inhibiting downstream signaling pathways, including STAT5 activation.Example 4: Inhibition of Cell Proliferation in Ba / F3 Cells Overexpressing Human TSLPR and IL-7Ra

[0451] Ba / F3 cells overexpressing human TSLPR and IL-7Ra with a luciferase reporter (Ba / F3-TSLPR-IL7Ra-luc-9El 1) were collected, plated, and washed twice with PBS. 5,000 cells / well were seeded in 96-well culture plates in 50 pL of assay medium (1640 containing 10% FBS). Serial dilutions of the antibody were prepared (500 nM, 1 :5 dilution) with a final concentration of 5 ng / mL of human TSLP protein (EC50) in assay medium. The mixture of antibody and TSLP protein in 50 pL of assay medium was added to the cells in the wells for 30 minutes at 4 °C. Meanwhile, 50 pL of assay medium was added to the unstimulated control wells. The cells were incubated at 37 °C with 5% CO2 for 72 hours. 100 pL of CellTiter-Glo reagent per well was added and rocked at room temperature for ~2 minutes to allow for cell lysis. The relative light unit (RLU) of the plate was read using a luminescence plate reader and subsequent data were analyzed using GraphPad Prism. IC50 values were determined as the concentration of antibody required to inhibit 50% of the maximum RLU of luciferase detected with incubation of TSLP alone. Results are summarized in FIG. 3A-3C and TABLES 7 and 8

[0452] These results demonstrated that Antibody 5 significantly inhibited cell proliferation (a functional outcome of cell activation) with an IC90 of 212.98 nM, compared with 135.67 nM for positive control.Example 5: Inhibition of TSLP-Induced Release of Chemokines in PBMC Cells

[0453] Inhibition of chemokines (TARC and MDC) secretion by peripheral blood mononuclear (PBMC) cells was used to evaluate the functional activity of antibodies to block TSLP -induced biological activity. Briefly, human PBMC cells from three healthy donors were seeded at 20,000 cells in 100 pL of DMEM + 10% FBS and cultured overnight at 37 °C. The next day, the cell culture media was discarded and cells were gently washed with fresh media. A 150 pL mixture of TSLP, purified antibody, and hTNF-a (1 : 1 : 1 by volume) were added to the wells, resulting in a final concentration of 1 ng / mL recombinant human TSLP, 0-100 nM purified antibody, and 200 ng / mL hTNF-a; or 1.5 ng / mL hIL-4, 0-100 nM purified antibody, and 50 ng / mL TNF-a. Some repeat experiments did not include TNF-a inculture. Cells were incubated in this mixture at 37 °C for 48 hours. Following incubation, culture supernatant was collected and MDC and TARC concentrations were measured using an MSD multiplex assay, and analyzed according to manufacturer’s instructions. The determined concentrations of TARC and MDC in each well were analyzed using GraphPad Prism. ICso and IC90 values were determined as the concentration of antibody required to inhibit 50% and 90%, respectively, of the maximum TARC concentration detected with incubation of only 1 ng / mL of TSLP and 200 ng / mL hTNF-a. Relative IC50 values were also determined against an antibody based on published sequences of the positive control as the reference antibody.

[0454] Results are summarized in TABLE 7 and FIG. 4A-FIG. 4D. As shown in TABLE 7, clones were identified that demonstrated more effective inhibition of TSLP induced TARC as compared to the positive control by up to about 7-fold (such as, for example, Antibody 5 and Antibody 7). The IC90 results were as follows: in TSLP-stimulated PBMCs, Antibody 5 inhibited secretion of TARC with an IC90 of 228.72 nM compared to 80.71 nM for the positive control and MDC secretion was 582.29 nM for Antibody 5 and 188.74 nM for positive control. The IC50 results were as follows: Antibody 5 inhibited secretion of TARC with an IC50 was 8.72 nM compared to 3.68 nM for positive control, and MDC secretion was 18.90 nM for Antibody 5 and 7.20 nM for positive control.

[0455] Taken together, these results demonstrated that Antibody 5 reduced the TSLP- induced production of Type 2 chemokines like TARC and MDC from immune cells, potentially reducing the recruitment of T cells and subsequently reducing Type 2 inflammation.Example 6: Assessing Affinity-Capture Self-Interaction Nanoparticle Spectroscopy (AC-SIN S) and Other Biophysical Properties

[0456] Polyclonal goat anti-human IgG Fc antibodies and goat non-specific antibodies were buffer exchanged into 20 mM NaAc (pH 4.3). Concentrations were normalized to 0.4 mg / mL. A 4: 1 volume ratio mix of capture :non-capture IgG solution was prepared for an 80% capture capacity coating solution. A gold nanoparticle solution was mixed with a coating solution at a 9: 1 volume ratio and incubated at 37 °C for 1 hr. Empty sites on the gold nanoparticles were blocked with thiolated polyethylene glycol (final concentration 0.1 pM) and incubated at 37 °C for 1 hr. The particle solution was passed through a 0.22 pm PVDF membrane. Particles were eluted into a collection tube using phosphate buffered saline (PBS)at 1 / 10 of the starting volume. 10 pL of the 10X concentrated coated particles were incubated with 100 pL of test antibody solution (50 pg / mL or above in PBS) at 37 °C for 2 hr in a polypropylene plate. lOOpL of the resulting solution was transferred into a polystyrene UV transparent plate and centrifuged to bring the solution menisci to the same level. Absorbance data from 510 to 570 nm was collected at an increment of 2 nm.

[0457] A Baculovirus Particle assay (BVP) was used to assess non-specific binding. 96- well plates were coated with 50 pL of a 0.15% baculovirus suspension, followed by overnight incubation at 4 °C. Plates were washed three times with 300 pL of 1 x PBST and blocked with 250 pL per well of 1% BSA in 1 * PBST at 37 °C for 2 hours. After another round of washing, 50 pL of serially diluted samples were added in duplicate and incubated at 37 °C for 1 hour. Plates were washed again, then incubated with 50 pL per well of secondary antibody at 37 °C for 30 minutes. Following six additional washes, 100 pL of TMB substrate was added to each well and developed for 15 minutes. The reaction was stopped with 50 pL of 1 N HC1, and absorbance was read at 450 nm using a SpectraMax Plus 384 plate reader.

[0458] Melting Temperature 2 (TM2) and protein thermal shifts were assessed by Intrinsic fluorescence method using Uncle (Unchained Labs, ChemPartners). 9 pl of sample were loaded into the UNi device and run with a thermal ramp from 20-95 °C, with a ramp rate of 0.5 °C / minute. Initial and final Dynamic light scattering (DLS) measurements were taken with 4 acquisitions of 5 seconds each. Uncle software calculated the Tmof each sample using the first derivative of the barycentric mean (BCM) of fluorescence intensity. The Tagg(unfolding and aggregation) for each sample was calculated using the intensity of scattered light at 266 or 473 nm, and the sizes and poly dispersity of each sample were calculated from the DLS correlation function.

[0459] Results of the tested antibodies are summarized in TABLE 8 and TABLE 12. All antibodies exhibited a Akmax < 5 nm in the AC-SINS assay, demonstrating minimal selfassociation comparable to the positive control. Antibody 5 was essentially unchanged from positive control and possessed favorable biophysical properties.Example 7: Assessing the Affinity of Engineered TSLP Antibodies to TSLP

[0460] Using the methods described above, additional anti-TSLP antibodies were generated. The sequences of these additional antibodies are summarized in TABLE 10 and TABLE 11. The affinity of these additional anti-TSLP antibodies to TSLP and the bindingkinetics thereof were assessed using surface plasmon resonance (SPR) as compared to control antibodies.

[0461] As measured by SPR, the antibodies exhibited strong affinity to TSLP. The antibodies were shown to bind to human (Hu) TSLP with sub-nanomolar affinity and were cross-reactive to non-human primate (NHP) cynomolgus monkey (cyno) TSLP with sub- nanomolar affinities as summarized in TABLE 12.

[0462] The assays as described herein were used to evaluate the antibodies’ abilities to inhibit TSLP binding to TSLPR and / or IL-7Ra, inhibit cell proliferation in Ba / F3 cells, and inhibit TSLP-induced release of TARC in PBMC cells. The results are summarized inTABLE 12IBLE 10. Sequences of anti-TSLP antibody constructs - CDRsIBLE 11. Sequences of anti-TSLP antibody constructs - VH / VLIBLE 12. Summary of tested antibodies for Antibodies 47-61 (binding, functional assay, and biophysical properties)Example 8: Further Preclinical Characterization of an Exemplary anti-TSLP Antibody

[0463] A broader data set generated from the assays described in the previous Examples for an exemplary anti-TSLP antibody and comparator molecules were analyzed, with the competition / blocking ELISA and BAF3 data analyzed via a four-parameter non-linear regression curve fitting model.

[0464] The binding of Antibody 5 to recombinant human and non-human primate (NHP) TSLP was assessed by SPR. Antibody 5-mediated blockade of TSLP binding to its receptor (TSLPR) was measured with ELISA. The effects of Antibody 5 on TSLP-induced signaling were assessed in reporter assays and primary human cells. An antibody based on the published sequence of tezepelumab was included as a positive control across in vitro and in vivo experiments characterizing Antibody 5.

[0465] Antibody 5 bound human and NHP TSLP with high affinity (19.8 and 118.6 pM, respectively). Antibody 5 blocked TSLP binding to the TSLPR with an ICso of 0.116 nM (human) and 0.332 nM (NHP). Antibody 5 inhibited STAT5 phosphorylation, TSLP- stimulated cell proliferation, and PBMC TARC release, all at nanomolar concentrations and with a potency similar to the positive control. The results of these analyses are shown in TABLE 13 and TABLE 14

[0466] In vitro pharmacology assays described herein support that Antibody 5 inhibited downstream signaling pathways of TSLPR / IL-7Ra heterocomplex by blocking TSLP from binding to TSLPR. Antibody 5 also reduced the TSLP-induced production of Type 2 chemokines, such as TARC and MDC, from immune cells, which could reduce the recruitment of T cells and subsequently reduce Type 2 inflammation. These data support the use of Antibody 5 for the treatment of inflammatory diseases.TABLE 13. Binding and functional data for Tezepelumab compared to Antibody 5* the 95% confidence intervals for the Antibody 5 and positive control potency (TARC release IC50 and IC90) overlap and are not significantly different.TABLE 14. Binding to human and NHP TSLP of Tezepelumab compared to Antibody 5Example 9: Pharmacokinetic Characterization of an Exemplary anti-TSLP Antibody In Vivo in NHPs

[0467] The pharmacokinetics of Antibody 5 were assessed in NHPs (5 animals / group) following a single bolus (50 mg / kg) intravenous or subcutaneous administration on Day 0, as compared to the positive control. Blood samples were collected at pre-dose, 0.0069, 0.0417, 0.1667, 0.3333, 1, 2, 4, 7, 14, 21, 28, 35, 42, 49, 56, 63, 77, and 91 days and processed for serum. Serum samples were evaluated for human IgG concentration by ELISA.

[0468] Minor cage side observations were recorded following doses of the positive control, but it still appeared to be well-tolerated.

[0469] Antibody 5 doses were well-tolerated with no abnormal cage side observations. Two animals in the SC dosing group demonstrated sudden and / or dramatic acceleration in antibody clearance over the course of the study and were deemed to represent apparent antidrug antibodies (AD As) and were removed from the analysis (TABLE 15).The PK profile of Antibody 5 in NHPs showed increased half-life and reduced clearance similar to that seen with other half-life-extended mAbs. In addition, Antibody 5 had a superior half-life and exposure (AUC) compared to the positive control (FIG. 5 and TABLE 15). The half-life of Antibody 5 was 19.96 days (IV) and 23.60 days (SC), whereas the halflife for the positive control was 11.43 days (IV) and 10.60 days (SC), with a bioavailability of 88%. Antibody 5 did not exhibit any notable bioavailability or stability liabilities.TABLE 15. Pharmacokinetic parameters of Antibody 5 compared to positive control inNHPsAUCO-inf = area under the serum concentration versus time curve from time 0 extrapolated to infinity;CL = clearance;Cmax = maximum observed serum concentration;%F = absolute subcutaneous bioavailability;IV = intravenous;N / A = not applicable;SC = subcutaneous;Vz = volume of distributionExample 10: Antibody 5 Epitope Mapping using Hydrogen-Deuterium Exchange and Cross-Linking Mass Spectrometry

[0470] Using Hydrogen-Deuterium Exchange Mass Spectrometry (HDX) and Crosslinking Mass Spectrometry (XL-MS), the binding epitopes of Antibody 5 to TSLP were mapped.

[0471] In brief, using HDX, TSLP was incubated in D2O-buffer for increasing amounts of time, such that labile hydrogens on protein exchanged with deuterium ions in solution. The reaction was quenched at pH = 2 to stop the proton exchange. Then, the sample was digested with pepsin, and the fragmented protein was analyzed using mass spectroscopy (MS) to detect peptides with increased mass compared to baseline digestion (no buffer exchange, immediate pH quenching, and pepsin digestion). 97.7% of the human TSLP sequence was covered by the 37 pepsin peptides identified (data not shown). The same steps were repeated with antibody:TSLP incubated together, and epitope binding was indicated by changes in TSLP peptide mass, which occurs when peptide regions are obstructed by antibody binding, thereby preventing deuterium exchange. As shown in FIG. 6, Antibody 5 was found to bind to TSLP at residues 20-26 (SKDLITY; SEQ ID NO: 408) and 66-70 (AKEMF; SEQ ID NO: 401) but not 120-128 (WRRFNRPLL; SEQ ID NO: 404); meanwhile the positive control was found to bind to TSLP at residues 19-26 (ISKDLITY; SEQ ID NO: 405), 66-70 (AKEMF; SEQ ID NO: 401), and 120-128 (WRRFNRPLL; SEQ ID NO: 404).

[0472] Meanwhile, in the XL-MS experiments, in brief, the antibody and antigen were incubated together in the presence of amine-amine crosslinker (BS3). The cross-linked complex was then digested individually with four different enzymes (trypsin, chymotrypsin, elastase, and thermolysin). Digestions were run through MS, and fragments with cross-linked antibody: TSLP peptides were mapped. 100% of the human TSLP sequence was covered by the trypsin, chymotrypsin, elastase, and thermolysin peptides identified (data not shown). Sequence information from both antibody variable regions and TSLP were used to identify binding sites. As shown in FIG. 7, the positive control HCDR3 and LCDR2 were found to bind to TSLP at residues 67-73 (KEMFAMK; SEQ ID NO: 406) and the positive control HCDR1 and LCDR3 were found to bind to TSLP at residues 121-129 (RRFNRPLLK; SEQ ID NO: 407). Meanwhile, Antibody 5 HCDR1 and LCDR2 were found to bind to TSLP at residues 15-31 (YLSTISKDLITYMSGTK; SEQ ID NO: 402) and Antibody 5 HCDR1, HCDR3, LCDR1, and LCDR3 were found to bind to TSLP at residues 64-73 (SLAKEMFAMK; SEQ ID NO: 403). Three amino acids in the CDR sequences of AntibodyAttorney Docket No.: PRG-059WO5 that were different from those in the positive control were Gly28Val, Asp95Thr, and His96Phe. It can be noted that Gly28Val increased hydrophobicity; Asp95Thr removed negative charge, thereby increasing potential for hydrogen binding; and His96Phe removed positive charge, thereby increasing hydrophobicity.

[0473] Taken together, these studies demonstrated by both HDX-MS and XL-MS that Antibody 5 shows overlapping yet distinct binding epitopes on TSLP as compared to the positive control.INCORPORATION BY REFERENCE

[0474] The entire disclosure of each of the patent and scientific documents referred to herein is incorporated by reference for all purposes.EQUIVALENTS

[0475] The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting on the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.132IPTS / 200013902.2INFORMAL SEQUENCE LISTING*SEQ ID NOs: 47 and 159 are hlgGl sequences having a SRDEL (SEQ ID NO: 440) allotype. The disclosure also encompasses SREEM (SEQ ID NO: 441) allotype variants of any of the SRDEL (SEQ ID NO: 440) allotype sequences set forth in the table above, and either a SRDEL (SEQ ID NO: 440) allotype heavy chain constant region sequence or a SREEM (SEQ ID NO: 441) allotype heavy chain constant region sequence may be included in an anti-TSLP antibody described herein.

Claims

1. CLAIMS1. An isolated antibody, or an antigen binding fragment thereof, that binds thymic stromal lymphopoietin (TSLP), comprising: 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; and f. CDR-L3 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 27-31, 311-327, and 367-370.

2. The isolated antibody, or the antigen binding fragment thereof, of claim 1, wherein the antibody comprises: a. CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 1-3; b. CDR-H2 comprising an amino acid sequence set forth in SEQ ID NO: 10; c. CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13-15; d. CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 19-21 and 271-288; e. CDR-L2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 25-26 and 303-310; andf. CDR-L3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 27-31 and 311-327.

3. The isolated antibody, or the antigen binding fragment thereof, of claim 1, wherein the antibody comprises: a. CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 4-6; b. CDR-H2 comprising an amino acid sequence set forth in SEQ ID NO: 11; c. CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13-15; d. CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 19-21 and 271-288; e. CDR-L2 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 25-26 and 303-310; and f. CDR-L3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 27-31 and 311-327.

4. The isolated antibody, or the antigen binding fragment thereof, of claim 1, wherein the antibody comprises: a. CDR-H1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 7-9; b. CDR-H2 comprising an amino acid sequence set forth in SEQ ID NO: 12; c. CDR-H3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 16-18; d. CDR-L1 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 22-24, 289-302, and 387; e. CDR-L2 comprising an amino acid sequence of any one of amino acid sequences DDS, DVS, EDS, DDT, DDK, DDL, and DDN; and f. CDR-L3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 27-31 and 311-327.

5. The isolated antibody, or the antigen binding fragment thereof, of any one of claims 1-4, wherein the antibody 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.

6. The isolated antibody, or the antigen binding fragment thereof, of any one of claims 1-4, wherein the antibody 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.

7. The isolated antibody, or the antigen binding fragment thereof, of any one of claims 1-4, wherein the antibody 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: 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.

8. The isolated antibody, or the antigen binding fragment thereof, of any one of claims 1-4, wherein the antibody 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.

9. The isolated antibody, or the antigen binding fragment thereof, of any one of claims 1-4, wherein the antibody 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: 26 or the amino acid sequence DDS; and a CDR-L3 comprising an amino acid sequence set forth in SEQ ID NO: 27.

10. The isolated antibody, or the antigen binding fragment thereof, of any one of claims 1-4, wherein the antibody 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.

11. The isolated antibody, or the antigen binding fragment thereof, of any one of claims 1-4, wherein the antibody 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: 30.

12. The isolated antibody, or the antigen binding fragment thereof, of any one of claims 1-4, wherein the antibody 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.

13. The isolated antibody, or the antigen binding fragment thereof, of any one of claims 1-4, wherein the antibody 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.

14. The isolated antibody, or the antigen binding fragment thereof, of any one of claims 1-13, wherein the antibody comprises a heavy chain variable domain (VH) sequence selected from the sequences set forth in SEQ ID NOs: 32-36 and 386.

15. The isolated antibody, or the antigen binding fragment thereof, of any one of claims 1-14, wherein the antibody comprises a light chain variable domain (VL) sequence selected from the sequences set forth in SEQ ID NOs: 37-45, 328-364, 371-379 and 381-385.

16. The isolated antibody, or the antigen binding fragment thereof, of any one of claims 1-15, wherein the antibody 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.

17. An isolated antibody, or the antigen binding fragment thereof, that binds TSLP, wherein the antibody 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.

18. The isolated antibody, or the antigen binding fragment thereof, of claim 16 or 17, wherein the antibody comprises a VH sequence set forth in SEQ ID NO: 32 and a VL sequence set forth in SEQ ID NO: 37.

19. The isolated antibody, or the antigen binding fragment thereof, of claim 16 or 17, wherein the antibody comprises a VH sequence set forth in SEQ ID NO: 33 and a VL sequence set forth in SEQ ID NO: 38.

20. The isolated antibody, or the antigen binding fragment thereof, of claim 16 or 17, wherein the antibody comprises a VH sequence set forth in SEQ ID NO: 386 and a VL sequence set forth in SEQ ID NO: 39.

21. The isolated antibody, or the antigen binding fragment thereof, of claim 16 or 17, wherein the antibody comprises a VH sequence set forth in SEQ ID NO: 33 and a VL sequence set forth in SEQ ID NO: 40.

22. The isolated antibody, or the antigen binding fragment thereof, of claim 16 or 17, wherein the antibody comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 41.

23. The isolated antibody, or the antigen binding fragment thereof, of claim 16 or 17, wherein the antibody comprises a VH sequence set forth in SEQ ID NO: 35 and a VL sequence set forth in SEQ ID NO: 42.

24. The isolated antibody, or the antigen binding fragment thereof, of claim 16 or 17, wherein the antibody comprises a VH sequence set forth in SEQ ID NO: 34 and a VL sequence set forth in SEQ ID NO: 43.

25. The isolated antibody, or the antigen binding fragment thereof, of claim 16 or 17, wherein the antibody comprises a VH sequence set forth in SEQ ID NO: 32 and a VL sequence set forth in SEQ ID NO: 44.

26. The isolated antibody, or the antigen binding fragment thereof, of claim 16 or 17, wherein the antibody comprises a VH sequence set forth in SEQ ID NO: 36 and a VL sequence set forth in SEQ ID NO: 45.

27. The isolated antibody, or the antigen binding fragment thereof, of any one of claims 1-26, wherein the antibody is a humanized, human, or chimeric antibody.

28. The isolated antibody, or the antigen binding fragment thereof, of any one of claims 1-27, wherein the antibody is a humanized antibody.

29. The isolated antibody, or the antigen binding fragment thereof, of any one of claims 1-28, wherein the antibody comprises a heavy chain human constant region of a class selected from IgG, IgA, IgD, IgE, and IgM.

30. The isolated antibody, or the antigen binding fragment thereof, of any one of claims 1-29, 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.

31. The isolated antibody, or the antigen binding fragment thereof, of claim 30, wherein the human Fc region comprises a human IgGl Fc region.

32. The isolated antibody, or the antigen binding fragment thereof, of claim 30, wherein the human Fc region comprises a human IgG4 Fc region.

33. The isolated antibody, or the antigen binding fragment thereof, of claim 30, wherein the human Fc region comprises a human IgG2 Fc region.

34. The isolated antibody, or the antigen binding fragment thereof, of any one of claims 1-33, wherein the antibody comprises a heavy chain comprising a constant heavy chain sequence selected from the sequences set forth in any one of SEQ ID NOs: 47-270.

35. The isolated antibody, or the antigen binding fragment thereof, of any one of claims 1-34, wherein the antibody comprises a light chain comprising a human lambda light chain constant region.

36. The isolated antibody, or the antigen binding fragment thereof, of claim 35, wherein the human lambda light chain constant region comprises a sequence set forth in any one of SEQ ID NOs: 409-412.

37. The isolated antibody, or the antigen binding fragment thereof, of any one of claims 1-36, wherein the antibody comprises a 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 to an antibody comprising an Fc region without the one or more amino acid substitutions (e.g., a wild-type Fc region).

38. The isolated antibody, or the antigen binding fragment thereof, of any one of claims 1-36, wherein the antibody comprises a Fc region comprising 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 an Fc region without the one or more amino acid substitutions (e.g., a wild-type Fc region).

39. The isolated antibody, or the antigen binding fragment thereof, of claim 37 or 38, wherein the one or more amino acid substitutions is selected from the group consisting of S228P (SP), T250Q, M252Y, S254T, T256E, T256D, 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 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 / Q311 V / A378V (DDRVV), L309D / Q311H / N434S (DHS), S228P / L235E, 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, 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.

40. The isolated antibody, or the antigen binding fragment thereof, of any one of claims 37-39, wherein the one or more amino acid substitutions is selected from the group consisting of LS, M252Y / S254T / T256E (YTE) or M257Y / S259T / T261E (YTE using direct numbering), 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.

41. The isolated antibody, or the antigen binding fragment thereof, of claim 39 or 40, wherein the one or more amino acid substitutions comprises L234A / L235A (LALA using EU numbering) or L239A / L240A (LALA using direct numbering).

42. The isolated antibody, or the antigen binding fragment thereof, of claim 39, wherein the one or more amino acid substitutions comprises LALAGA and N434A.

43. The isolated antibody, or the antigen binding fragment thereof, of claim 39 or 40, wherein the one or more amino acid substitutions comprises M252Y, S254T, and T256E (YTE) or M257Y / S259T / T261E (YTE using direct numbering) and / or M428L and N434S (LS).

44. The isolated antibody, or the antigen binding fragment thereof, of claim 39 or 40, wherein the one or more amino acid substitutions comprises L234A / L235A (LALA using EU numbering) and M252Y / S254T / T256E (YTE using EU numbering) or L239A / L240A (LALA using direct numbering) and M257Y / S259T / T261E (YTE using direct numbering).

45. The isolated antibody, or the antigen binding fragment thereof, of any one of claims 1-44, wherein the Fc region binds to Neonatal Fc receptor (FcRn).

46. The isolated antibody, or the antigen binding fragment thereof, of claim 45, wherein the Fc region binds an FcRn with higher affinity at pH 6.0 compared to an antibody comprising a wild-type Fc region.

47. The isolated antibody, or the antigen binding fragment thereof, of any one of claims 1-46, wherein the antibody is a monoclonal antibody.

48. The isolated antibody, or the antigen binding fragment thereof, of any one of claims 1-47, wherein the antibody binds a TSLP sequence set forth in SEQ ID NO: 365 or 366.

49. The isolated antibody, or the antigen binding fragment thereof, of any one of claims 1-48 for use in the treatment of an inflammatory disorder or disease.

50. The isolated antibody, or the antigen binding fragment thereof, for use of claim 49 wherein the inflammatory disorder or disease is atopic dermatitis (AD).

51. The isolated antibody, or the antigen binding fragment thereof, for use of claim 50, wherein the treatment reduces disease severity in a patient and wherein disease severity is assessed by an atopic dermatitis disease severity outcome measure.

52. The isolated antibody, or the antigen binding fragment thereof, for use of claim 49 wherein the inflammatory disorder or disease is asthma.

53. The isolated antibody, or the antigen binding fragment thereof, for use of claim 49 wherein the inflammatory disorder or disease is Chronic Obstructive Pulmonary Disease (COPD).

54. The isolated antibody, or the antigen binding fragment thereof, for use of claim 49 wherein the inflammatory disorder or disease is chronic sinusitis with nasal polyps, Chronic Rhinosinusitis without Nasal Polyps (CRSsNP), eosinophilic esophagitis (EoE), an Eosinophilic gastrointestinal disorder or disease (EGID), Churg-Strauss syndrome / Eosinophilic granulomatosis with polyangiitis (EGPA), Prurigo Nodularis (PN), Chronic Spontaneous Urticaria (CSU), Chronic Pruritis of Unknown Origin (CPUO), Bullous Pemphigoid (BP), Cold Inducible Urticaria (ColdU), Allergic Fungal Rhinosinusitis (AFRS), Allergic Bronchopulmonary Aspergillosis (ABPA), inflammatory bowel disease, lupus, rheumatoid arthritis (RA), psoriasis, hidradenitis suppurativa, celiac disease, systemic sclerosis, idiopathic pulmonary fibrosis, or alopecia areata.

55. The isolated antibody, or the antigen binding fragment thereof, for use of claim 54, wherein the inflammatory bowel disease is Crohn’s disease or ulcerative colitis.

56. The isolated antibody, or the antigen binding fragment thereof, for use of claim 54, wherein the EGID is Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), Eosinophilic Colitis (EoC), or Eosinophilic Gastroenteritis (EGE).

57. An isolated polynucleotide or set of polynucleotides encoding the antibody or the antigen binding fragment of any one of claims 1-56, a VH thereof, a VL thereof, a light chain thereof, or a heavy chain thereof, and optionally, wherein the polynucleotide or set of polynucleotides comprises cDNA.

58. A vector or set of vectors comprising the polynucleotide or set of polynucleotides of claim 57.

59. A host cell comprising the polynucleotide or set of polynucleotides of claim 57 or the vector or set of vectors of claim 58.

60. A method of producing an antibody, the method comprising expressing the antibody of any one of claims 1-48 with the host cell of claim 59 and isolating the expressed antibody.

61. A pharmaceutical composition comprising the antibody of any one of claims 1-48 and a pharmaceutically acceptable excipient.

62. A kit comprising the antibody of any one of claims 1-48 or the pharmaceutical composition of claim 61 and instructions for use.

63. A method for treating an inflammatory disorder or disease in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of the antibody of any one of claims 1-48 or the pharmaceutical composition of claim 61.

64. The method of claim 63, wherein the mammalian subject is a human.

65. The method of claim 63 or 64, wherein the inflammatory disorder or disease is atopic dermatitis.

66. The method of claim 63 or 64, wherein the inflammatory disorder or disease is asthma.

67. The method of claim 63 or 64, wherein the inflammatory disorder or disease is Chronic Obstructive Pulmonary Disease (COPD).

68. The method of claim 63 or 64, wherein the inflammatory disorder or disease is chronic sinusitis with nasal polyps, Chronic Rhinosinusitis without Nasal Polyps (CRSsNP), eosinophilic esophagitis (EoE), an Eosinophilic gastrointestinal disorder or disease (EGID), Churg-Strauss syndrome / Eosinophilic granulomatosis with polyangiitis (EGPA), Prurigo Nodularis (PN), Chronic Spontaneous Urticaria (CSU), Chronic Pruritis of Unknown Origin (CPUO), Bullous Pemphigoid (BP), Cold Inducible Urticaria (ColdU), Allergic Fungal Rhinosinusitis (AFRS), Allergic Bronchopulmonary Aspergillosis (ABPA), celiac disease, inflammatory bowel disease, lupus, rheumatoid arthritis (RA), psoriasis, hidradenitis suppurativa, systemic sclerosis, idiopathic pulmonary fibrosis, or alopecia areata.

69. The method of claim 68, wherein the inflammatory bowel disease is Crohn’s disease or ulcerative colitis.

70. The method of claim 68, wherein the EGID is Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), Eosinophilic Colitis (EoC), or Eosinophilic Gastroenteritis (EGE).

71. A method for treating a pathology associated with elevated levels of TSLP in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of the antibody of any one of claims 1-48 or the pharmaceutical composition of claim 61.

72. A method of reducing biological activity of TSLP in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of the antibody of any one of claims 1-48 or the pharmaceutical composition of claim 61.

73. A method of preventing an inflammatory disorder or disease in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of the antibody of any one of claims 1-48 or the pharmaceutical composition of claim 61.

74. The method of any one of claims 63-73, wherein the mammalian subject is a human.

75. 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) as measured by cross-linking mass spectrometry.

76. 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).

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