Antibodies that bind to interleukin-4 receptor alpha and methods of use

Abstract

Described herein are novel and improved antibodies that bind to the interleukin-4α receptor (IL-4Rα) and methods of use thereof. In certain aspects, described herein are methods for inhibiting the biological activity of IL-4Rα. In certain aspects, described herein are pharmaceutical compositions comprising anti-IL-4Rα antibodies. In certain aspects, the antibodies and methods described herein are used for the treatment of inflammatory diseases or disorders associated with elevated levels of IL-4 and / or IgE.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to co-pending U.S. Provisional Patent Application No. 63 / 446,763, filed February 17, 2023, U.S. Provisional Patent Application No. 63 / 462,864, filed April 28, 2023, U.S. Provisional Patent Application No. 63 / 596,501, filed November 6, 2023, and U.S. Provisional Patent Application No. 63 / 596,504, filed November 6, 2023, the entire contents of each of which are incorporated herein by reference.

[0002] Described herein are novel and improved antibodies that bind to the interleukin 4α receptor (IL-4Rα) and methods of their use, for example, in the treatment of inflammatory diseases or disorders associated with elevated levels of IL-4 and / or IgE. [Background technology]

[0003] Interleukin-4 (IL-4) and interleukin-13 (IL-13) share a common receptor component, the interleukin-4 receptor alpha (IL-4Rα) chain, which pairs with distinct subunits (Nelms, K., et al. (1999) Annu. Rev. Immunol. 17:701-738) and (Jensen, PL (2000) Stem Cells 18:61-62). IL-4Rα pairs with the common γc chain to form the type I IL-4R complex, which is found primarily on hematopoietic cells and is exclusive to IL-4. IL-4Rα also pairs with the interleukin-13 receptor alpha 1 (IL-13Rα1) subunit to form the type II IL-4R, which binds both IL-4 and IL-13. Type II receptors are expressed on both hematopoietic and non-hematopoietic cells. IL-4 (also known as B cell stimulating factor or BSF-1) was originally characterized by its ability to stimulate B cell proliferation in response to low concentrations of antibody directed against surface immunoglobulin. IL-4 has been shown to have a wide range of biological activities, including stimulating the proliferation of T cells, mast cells, granulocytes, megakaryocytes, and erythrocytes. IL-4 induces the expression of class II major histocompatibility complex molecules in resting B cells and enhances the secretion of IgE and IgG1 isotypes by stimulated B cells.

[0004] The biological and immunological functions of B lymphocytes, monocytes, dendritic cells, and fibroblasts are all influenced by IL-4 and IL-13. These cytokines interact with IL-4R to initiate the type 2 inflammatory pathway, which leads to Th2 cell differentiation, inflammation, and mucus production. The type 2 inflammatory pathway is initially activated in allergic diseases by abnormal cytokine release resulting from an imbalance between Th1 and Th2 differentiation. Activated Th2 cells release cytokines, including IL-4, IL-13, and IL-31, which induce downstream B cells to undergo transformation and produce IgE antibodies. Mast cells and basophils are then required to degranulate and release inflammatory substances. Simultaneously, secreted IL-4 and IL-13 continue to bind to their respective receptors, such as IL-4Rα, repeatedly promoting Th2 differentiation and subsequent inflammation. The important roles of IL-4 and IL-13 in the type 2 inflammatory pathway identify IL-4Rα as a potential target in individuals with aberrant type 2 inflammatory responses. Unlike drugs that exclusively target IL-4 and IL-13, targeting IL-4Rα will target both IL-4 and IL-13. Therefore, new antibodies that bind to IL-4Rα and mitigate type 2 inflammation are needed to treat immune disorders. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Nelms, K., et al. (1999) Annu. Rev. Immunol. 17:701-738 [Non-patent document 2] Jensen, PL (2000) Stem Cells 18:61-62 Summary of the Invention [Means for solving the problem]

[0006] In a first aspect, disclosed herein are antibodies, such as recombinant human antibodies, that specifically bind to human interleukin-4 receptor alpha (hIL-4Rα). In certain embodiments, the antibodies are characterized by binding to hIL-4Rα with high affinity and the ability to neutralize hIL-4Rα activity. In certain embodiments, the human antibodies can block binding of the hIL-13 / hIL-13R1 complex to hIL-4Rα, thereby inhibiting hIL-13-mediated signaling. The antibodies may be full-length (e.g., IgG1 or IgG4 antibodies) or may comprise only an antigen-binding portion (e.g., Fab, F(ab')2, or scFv fragments) and may be modified to confer efficacy, e.g., to abolish residual effector function (Reddy et al. (2000) J. Immunol. 164:1925-1933) and / or to extend half-life.

[0007] In certain aspects, disclosed herein is an isolated antibody that binds to interleukin (IL)-4 receptor alpha (IL-4Rα), the antibody 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 a sequence selected from the sequences represented by SEQ ID NOs: 1-4, 66-70, and 187-191. , b. CDR-H2 comprises a sequence selected from the sequences represented by SEQ ID NOs: 5 to 16 and 71 to 90, c. CDR-H3 comprises a sequence selected from the sequences represented by SEQ ID NOs: 17 to 25 and 92 to 99, d. CDR-L1 comprises a sequence selected from the sequences represented by SEQ ID NOs: 26 to 40 and 100 to 107, e. CDR-L2 comprises a sequence selected from the sequences represented by SEQ ID NOs: 41 to 52 and 108 to 112, and f. CDR-L3 comprises a sequence selected from the sequences represented by SEQ ID NOs: 53 to 65.

[0008] In some embodiments, the antibody comprises a. a CDR-H1 comprising a sequence selected from the sequences represented by SEQ ID NOs: 1 to 4; b. a CDR-H2 comprising a sequence selected from the sequences represented by SEQ ID NOs: 5 to 16; c. a CDR-H3 comprising a sequence selected from the sequences represented by SEQ ID NOs: 17 to 25; d. a CDR-L1 comprising a sequence selected from the sequences represented by SEQ ID NOs: 26 to 40; e. a CDR-L2 comprising a sequence selected from the sequences represented by SEQ ID NOs: 41 to 52; and f. a CDR-L3 comprising a sequence selected from the sequences represented by SEQ ID NOs: 53 to 65.

[0009] In some embodiments, the antibody comprises a. CDR-H1 comprising a sequence selected from the sequences represented by SEQ ID NOs: 66-70, b. CDR-H2 comprising a sequence selected from the sequences represented by SEQ ID NOs: 71-78, c. CDR-H3 comprising a sequence selected from the sequences represented by SEQ ID NOs: 17-25, d. CDR-L1 comprising a sequence selected from the sequences represented by SEQ ID NOs: 26-40, e. CDR-L2 comprising a sequence selected from the sequences represented by SEQ ID NOs: 41-52, and f. CDR-L3 comprising a sequence selected from the sequences represented by SEQ ID NOs: 53-65.

[0010] In some embodiments, the antibody comprises a. a CDR-H1 comprising a sequence selected from the sequences represented by SEQ ID NOs: 187-191; b. a CDR-H2 comprising a sequence selected from the sequences represented by SEQ ID NOs: 79-90; c. a CDR-H3 comprising a sequence selected from the sequences represented by SEQ ID NOs: 92-99; d. a CDR-L1 comprising a sequence selected from the sequences represented by SEQ ID NOs: 100-107; e. a CDR-L2 comprising a sequence selected from the sequences represented by SEQ ID NOs: 108-112; and f. a CDR-L3 comprising a sequence selected from the sequences represented by SEQ ID NOs: 53-65.

[0011] In some embodiments, the antibody does not include: a. CDR-H1 represented by SEQ ID NO: 1, CDR-H2 represented by SEQ ID NO: 5, CDR-H3 represented by SEQ ID NO: 17, CDR-L1 represented by SEQ ID NO: 26, CDR-L2 represented by SEQ ID NO: 41, and CDR-L3 represented by SEQ ID NO: 53, or b. CDR-H1 represented by SEQ ID NO: 67, CDR-H2 represented by SEQ ID NO: 71, CDR-H3 represented by SEQ ID NO: 17, CDR-L1 represented by SEQ ID NO: 26, CDR-L2 represented by SEQ ID NO: 41, and CDR-L3 represented by SEQ ID NO: 53, or c. CDR-H1 represented by SEQ ID NO: 187, CDR-H2 represented by SEQ ID NO: 79, CDR-H3 represented by SEQ ID NO: 91, CDR-L1 represented by SEQ ID NO: 100, CDR-L2 represented by SEQ ID NO: 108, and CDR-L3 represented by SEQ ID NO: 53.

[0012] In some embodiments, the antibody does not comprise any combination of the following: a. CDR-H1 represented by any of SEQ ID NOs: 1, 67, or 187; b. CDR-H2 represented by any of SEQ ID NOs: 5, 71, or 79; c. CDR-H3 represented by any of SEQ ID NOs: 17 or 91; d. CDR-L1 represented by any of SEQ ID NOs: 26 or 100; e. CDR-L2 represented by any of SEQ ID NOs: 41 or 108; and f. CDR-L3 represented by SEQ ID NO: 53.

[0013] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 27 or 101; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 42 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 54.

[0014] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 62, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 42 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 55.

[0015] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 7, 72, or 81; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 22 or 93; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 29 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 55.

[0016] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 45 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 55.

[0017] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 8, 73, or 82; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 19 or 94; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 30 or 102; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 56.

[0018] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 8, 73, or 82; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 31 or 103; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 57.

[0019] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 17 or 91; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 32 or 102; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 46 or 109; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 58.

[0020] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 8, 73, or 82; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 32 or 102; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 45 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 59.

[0021] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 68, or 189; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 32 or 102; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 45 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 60.

[0022] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 9, 77, or 83; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 29 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 60.

[0023] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 9, 77, or 83; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 27 or 101; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 57.

[0024] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 27 or 101; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0025] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 10, 71, or 84; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 27 or 101; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0026] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0027] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 3, 69, or 190; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 8, 73, or 82; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 21 or 96; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0028] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 7, 72, or 81; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 42 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 62.

[0029] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 11, 73, or 85; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 33 or 102; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0030] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 23, 69, or 190; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 11, 73, or 85; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 19 or 94; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 34 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 60.

[0031] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 11, 73, or 85; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 22 or 93; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 34 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 56.

[0032] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 3, 69, or 190; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 23 or 97; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 42 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0033] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 7, 72, or 81; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20, 18, or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 27 or 101; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0034] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 7, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 27 or 101; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0035] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 24 or 98; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 36 or 102; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 45 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0036] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 8, 73, or 82; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 37 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 47 or 110; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0037] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 12, 74, or 86; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 24 or 98; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0038] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 189; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 13, 71, or 87; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0039] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 10, 71, or 84; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 34 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 57.

[0040] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 34 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0041] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 1, 66, or 187; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 5, 71, or 79; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 17 or 91; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 38 or 105; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 48 or 111; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 63.

[0042] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 39 or 106; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 41 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 64.

[0043] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 14, 75, or 88; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 39 or 106; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 49 or 112; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 63.

[0044] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 19 or 94; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 42 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 60.

[0045] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 8, 73, or 82; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 31 or 103; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 58.

[0046] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 3, 69, or 190; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 5, 71, or 79; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 19 or 94; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 33 or 102; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 50 or 110; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0047] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 30 or 101; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 51 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0048] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 3, 67, or 190; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 15, 67, or 89; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 40 or 107; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 52 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0049] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 30 or 102; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 47 or 110; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0050] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 4, 70, or 191; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 11, 73, or 85; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 22, 18, or 93; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 30 or 102; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 60.

[0051] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 14, 75, or 88; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 27 or 101; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 65.

[0052] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 15, 76, or 89; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 19 or 94; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 62.

[0053] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 3, 69, or 190; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 9, 77, or 83; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 19 or 94; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 55.

[0054] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 15, 76, or 89; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 24 or 98; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 34 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 42 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0055] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 32 or 102; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 51 or 110; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0056] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 16, 78, or 90; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 19 or 94; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 45 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 57.

[0057] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 4, 70, or 191; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 16, 78, or 90; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 25 or 99; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 34 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 53.

[0058] In some embodiments, the antibody comprises a heavy chain variable domain (VH) sequence selected from the sequences set forth in SEQ ID NOs: 113-145.

[0059] In some embodiments, the antibody comprises a light chain variable domain (VL) sequence selected from the sequences set forth in SEQ ID NOs: 146-186.

[0060] In some embodiments, the antibody comprises a VH sequence selected from the sequences set forth in SEQ ID NOs: 113-145 and a VL sequence selected from the sequences set forth in SEQ ID NOs: 146-186.

[0061] In a specific aspect, the present specification discloses an isolated antibody that binds to IL-4Rα, the antibody comprising a VH sequence selected from the sequences set forth in SEQ ID NOs: 113 to 145 and a VL sequence selected from the sequences set forth in SEQ ID NOs: 146 to 186.

[0062] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:114 and a VL sequence set forth in SEQ ID NO:147.

[0063] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:114 and a VL sequence set forth in SEQ ID NO:148.

[0064] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:115 and a VL sequence set forth in SEQ ID NO:149.

[0065] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:114 and a VL sequence set forth in SEQ ID NO:150.

[0066] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:116 and a VL sequence set forth in SEQ ID NO:151.

[0067] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:117 and a VL sequence set forth in SEQ ID NO:152.

[0068] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:118 and a VL sequence set forth in SEQ ID NO:153.

[0069] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:117 and a VL sequence set forth in SEQ ID NO:154.

[0070] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:119 and a VL sequence set forth in SEQ ID NO:155.

[0071] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:120 and a VL sequence set forth in SEQ ID NO:156.

[0072] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:120 and a VL sequence set forth in SEQ ID NO:157.

[0073] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:114 and a VL sequence set forth in SEQ ID NO:158.

[0074] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:121 and a VL sequence set forth in SEQ ID NO:158.

[0075] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:114 and a VL sequence set forth in SEQ ID NO:159.

[0076] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:123 and a VL sequence set forth in SEQ ID NO:159.

[0077] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:124 and a VL sequence set forth in SEQ ID NO:160.

[0078] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:125 and a VL sequence set forth in SEQ ID NO:161.

[0079] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:126 and a VL sequence set forth in SEQ ID NO:162.

[0080] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:127 and a VL sequence set forth in SEQ ID NO:163.

[0081] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:128 and a VL sequence set forth in SEQ ID NO:164.

[0082] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:124 and a VL sequence set forth in SEQ ID NO:158.

[0083] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:129 and a VL sequence set forth in SEQ ID NO:165.

[0084] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:130 and a VL sequence set forth in SEQ ID NO:166.

[0085] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:131 and a VL sequence set forth in SEQ ID NO:167.

[0086] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:132 and a VL sequence set forth in SEQ ID NO:159.

[0087] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:133 and a VL sequence set forth in SEQ ID NO:159.

[0088] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:121 and a VL sequence set forth in SEQ ID NO:168.

[0089] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:134 and a VL sequence set forth in SEQ ID NO:169.

[0090] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:113 and a VL sequence set forth in SEQ ID NO:170.

[0091] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:134 and a VL sequence set forth in SEQ ID NO:171.

[0092] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:135 and a VL sequence set forth in SEQ ID NO:172.

[0093] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:136 and a VL sequence set forth in SEQ ID NO:173.

[0094] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:131 and a VL sequence set forth in SEQ ID NO:174.

[0095] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:137 and a VL sequence set forth in SEQ ID NO:175.

[0096] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:114 and a VL sequence set forth in SEQ ID NO:176.

[0097] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:138 and a VL sequence set forth in SEQ ID NO:177.

[0098] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:134 and a VL sequence set forth in SEQ ID NO:178.

[0099] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:139 and a VL sequence set forth in SEQ ID NO:179.

[0100] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:140 and a VL sequence set forth in SEQ ID NO:180.

[0101] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:141 and a VL sequence set forth in SEQ ID NO:181.

[0102] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:142 and a VL sequence set forth in SEQ ID NO:182.

[0103] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:143 and a VL sequence set forth in SEQ ID NO:183.

[0104] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:114 and a VL sequence set forth in SEQ ID NO:184.

[0105] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:144 and a VL sequence set forth in SEQ ID NO:185.

[0106] In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO:145 and a VL sequence set forth in SEQ ID NO:186.

[0107] In some embodiments, the antibody is a humanized antibody, a fully human antibody, or a chimeric antibody.

[0108] In some embodiments, the antibody is a fully human antibody.

[0109] In some embodiments, the antibody comprises a heavy chain human constant region of a class selected from IgG, IgA, IgD, IgE, and IgM.

[0110] In some embodiments, the human Fc region comprises a human heavy chain constant region of the IgG class and subclass selected from IgG1, IgG2, IgG3, and IgG4.

[0111] In some embodiments, the human Fc region comprises a human IgG1 Fc.

[0112] In some embodiments, the human Fc region comprises a human IgG4 Fc.

[0113] In some embodiments, the human Fc region comprises a human IgG2 Fc.

[0114] In some embodiments, the heavy chain comprises a constant heavy chain sequence selected from the sequences represented by SEQ ID NOs: 192-235 and 251-407.

[0115] In certain aspects, described herein is an isolated antibody that binds to interleukin (IL)-4 receptor alpha (IL-4Rα), comprising: a) a variable heavy (VH) chain sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR3-H3; and b) a variable light (VL) chain sequence having three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; the antibody comprising a CDR comprising a sequence set forth in any of SEQ ID NOs: 1, 66, or 187. and a CDR-H1, a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 5, 71, or 79, a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 17 or 91, a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 26 or 100, a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 41 or 108, and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 53, wherein the heavy chain comprises a constant heavy chain sequence selected from the sequences set forth in SEQ ID NOs: 192 to 235 and 251 to 407. In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 113. In some embodiments, the antibody comprises a VL sequence set forth in SEQ ID NO: 146.

[0116] In some embodiments, the light chain comprises a constant light chain sequence comprising the sequence set forth in SEQ ID NO:236.

[0117] In some embodiments, the Fc region comprises one or more amino acid substitutions, which result in an increase in one or more of antibody half-life, ADCC activity, ADCP activity, and / or CDC activity compared to an Fc region that does not comprise the one or more substitutions.

[0118] In some embodiments, the Fc region comprises one or more amino acid substitutions, which result in a decrease in one or more of ADCC activity, ADCP activity, and / or CDC activity compared to an Fc region that does not contain the one or more substitutions.

[0119] In some embodiments, the one or more amino acid substitutions result in an increase in antibody half-life compared to an antibody comprising a wild-type Fc region.

[0120] In some embodiments, the one or more amino acid substitutions are selected from the group consisting of S228P(SP), M252Y, S254T, T256E, T256D, T250Q, H285D, T307A, T307Q, T307R, T307W, L309D, Q411H, Q311V, A378V, E380A, M428L, N434A, N434S, N297A, D265A, L234A, L235A, and N434W. In some embodiments, the one or more amino acid substitutions are a combination of amino acid substitutions selected from the group consisting of: M428L / N434S(LS); M252Y / S254T / T256E(YTE); T250Q / M428L; T307A / E380A / N434A; T256D / T307Q(DQ); T256D / T307W(DW); M252Y / T256D(YD); T307Q / Q311V / A378V(QVV); T256D / H285D / T307R / Q311V / A378V(DDRVV); L309D / Q311H / N434S(DHS); S228P / L235E(SPLE); L234A / L235A, M428L / N434A L234A / G237AL234A / L235A / G237A, L234A / L235A / P329G, 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, LA GA / QVV, LALAGA / QVV, LALAPG / QVV, DDRVV, N297A / DDRVV, D265A / DDRVV, LALA / DDRVV, LAGA / DDRVV, LALAGA / DDRVV, and LALAPG / DDRVV. ;

[0121] In some embodiments, the Fc region binds to the fetal Fc receptor (FcRn).

[0122] In some embodiments, the Fc region binds to FcRn with greater affinity at pH 6.0 compared to an antibody comprising a wild-type Fc region.

[0123] In some embodiments, the Fc region is at 1×10 -7 Binds to FcRn with a KD less than M

[0124] In some embodiments, the antibody is a monoclonal antibody.

[0125] In some embodiments, the antibody binds to the IL-4Rα sequence represented by SEQ ID NOs:237-240.

[0126] In some embodiments, the antibody binds to the IL-4Rα sequence set forth in SEQ ID NOs: 237-240 at a concentration of about 1, 2, 3, 4, 5, 6, 7, 8, 9 x 10 as measured by surface plasmon resonance (SPR).-9 It binds with a KD of less than M.

[0127] In some embodiments, the antibody binds to the IL-4Rα sequence represented by SEQ ID NOs: 237-240 at a concentration of about 1 x 10 as measured by surface plasmon resonance (SPR). -10 It binds with a KD of less than M.

[0128] In some embodiments, the antibody binds to human IL-4Rα at a binding affinity of about 1×10 as measured by surface plasmon resonance (SPR). -9 It binds with a KD of less than M.

[0129] In some embodiments, the antibody exhibits a melting temperature of greater than 68° C. as measured by differential scanning fluorimetry (DSF).

[0130] In some embodiments, the antibody exhibits a melting temperature of greater than 75° C. as measured by differential scanning fluorimetry (DSF).

[0131] In some embodiments, the antibody exhibits an aggregation temperature of 71.2° C. or greater as measured by differential scanning fluorimetry (DSF).

[0132] In some embodiments, the antibody has a retention time of 15.2 minutes or less as measured by hydrophobic chromatography.

[0133] In some embodiments, the antibody does not have the heavy chain variable region sequence set forth in SEQ ID NO:113.

[0134] In some embodiments, the antibody does not have the heavy chain sequence set forth in SEQ ID NO:146.

[0135] In certain embodiments, the isolated antibody is used to treat an inflammatory disorder or disease. In certain embodiments, the isolated antibody is used to treat atopic dermatitis. In certain embodiments, the isolated antibody is used to treat idiopathic pulmonary fibrosis. In certain embodiments, the isolated antibody is used to treat alopecia areata. In certain embodiments, the isolated antibody is used to treat chronic rhinosinusitis with nasal polyps. In certain embodiments, the isolated antibody is used to treat chronic rhinosinusitis without nasal polyps (CRSsNP). In certain embodiments, the isolated antibody is used to treat eosinophilic esophagitis (EoE). In certain embodiments, the isolated antibody is used to treat an eosinophilic gastrointestinal disorder or disease (ENID) selected from the group consisting of eosinophilic gastritis (EoG), eosinophilic enteritis (EoN), eosinophilic colitis (EoC), and eosinophilic gastroenteritis (EGE). In certain embodiments, the isolated antibody is used to treat Churg-Strauss syndrome / eosinophilic granulomatosis with polyangiitis (EGPA). In certain embodiments, the isolated antibody is used to treat prurigo nodularis (PN). In certain embodiments, the isolated antibody is used to treat chronic suboptimal urticaria (CSU). In certain embodiments, the isolated antibody is used to treat chronic cryptogenic pruritus (CPUO). In certain embodiments, the isolated antibody is used to treat bullous pemphigoid (BP). In certain embodiments, the isolated antibody is used to treat cold-induced urticaria (ColdU). In certain embodiments, the isolated antibody is used to treat allergic fungal rhinosinusitis (AFRS). In certain embodiments, the isolated antibody is used to treat allergic bronchopulmonary aspergillosis (ABPA). In certain embodiments, the isolated antibody is used to treat chronic obstructive pulmonary disease (COPD). In certain embodiments, the isolated antibody is used to treat inflammatory bowel disease, such as Crohn's disease or ulcerative colitis. In certain embodiments, the isolated antibody is used to treat lupus. In certain embodiments, the isolated antibody is used to treat rheumatoid arthritis.

[0136] In certain aspects, disclosed herein is an isolated polynucleotide or set of polynucleotides encoding any of the above-claimed antibodies, their VH, their VL, their light chain, their heavy chain, or antigen-binding portions thereof, optionally wherein the polynucleotide or set of polynucleotides comprises cDNA.

[0137] In certain aspects, disclosed herein is a vector or set of vectors comprising a polynucleotide or set of polynucleotides disclosed herein.

[0138] In certain aspects, disclosed herein are host cells comprising a polynucleotide or set of polynucleotides or a vector or set of vectors disclosed herein.

[0139] In certain aspects, disclosed herein are methods of producing an antibody, the methods comprising expressing the antibody with a host cell disclosed herein and isolating the expressed antibody.

[0140] In certain aspects, disclosed herein is a pharmaceutical composition comprising the antibody of any one of the embodiments disclosed herein and a pharmaceutically acceptable excipient.

[0141] In certain aspects, disclosed herein is a kit comprising an antibody of any one of the embodiments disclosed herein, or a pharmaceutical composition disclosed herein, and instructions for use.

[0142] 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 an antibody 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 of the methods described herein, the inflammatory disorder or disease is alopecia areata. In certain embodiments, the inflammatory disorder or disease is chronic rhinosinusitis 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 (ENID) 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 subitum urticaria (CSU). In certain embodiments, the inflammatory disorder or disease is chronic cryptogenic pruritus (CPUO). In certain embodiments, the inflammatory disorder or disease is bullous pemphigoid (BP). In certain embodiments, the inflammatory disorder or disease is cold-induced 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 lupus. In certain embodiments, the inflammatory disorder or disease is rheumatoid arthritis.

[0143] In certain aspects, disclosed herein are methods for treating a condition associated with elevated levels of IL-4Rα in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of an antibody of any one of the embodiments disclosed herein or a pharmaceutical composition disclosed herein.

[0144] In certain aspects, disclosed herein are methods for reducing the biological activity of IL-4Rα in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of an antibody of any one of the embodiments disclosed herein or a pharmaceutical composition disclosed herein.

[0145] In certain aspects, disclosed herein are methods for suppressing a TH2-type allergic response in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of an antibody of any one of the embodiments disclosed herein or a pharmaceutical composition disclosed herein.

[0146] In certain aspects, disclosed 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 of any one of the embodiments disclosed herein or a pharmaceutical composition disclosed herein. [Brief explanation of the drawings]

[0147] [Figure 1] 1 shows the ability of exemplary antibodies and dupilumab to inhibit the binding of IL-4 and IL-13.

[0148] [Figure 2] 1 shows the ability of exemplary antibodies and dupilumab to inhibit IL-4-induced phosphorylated STAT6 and IL-13-induced phosphorylated STAT6 (pSTAT6).

[0149] [Figure 3] 1 shows the ability of exemplary antibodies and dupilumab to inhibit IL-4-induced TARC secretion and / or IL-13-induced TARC secretion.

[0150] [Figure 4] 1 shows the ability of exemplary antibodies and dupilumab to inhibit IL-4- and IL-13-induced proliferation of TF-1 cells.

[0151] [Figure 5] 1 shows serum concentrations over time of exemplary antibodies (Construct 13 (mAb422), Construct 38 (mAb471), and Dupilumab) following a single intravenous (A) or subcutaneous (B) dose of 25 mg / kg in non-human primates. DETAILED DESCRIPTION OF THE INVENTION

[0152] definition Unless otherwise defined, all technical terms, notations, and other scientific terms used herein shall have the meanings commonly understood by those of ordinary skill in the art. In some cases, terms with commonly understood meanings are defined herein for clarity and / or ready reference, and the inclusion of such definitions herein should not necessarily be construed as representing any difference beyond that commonly understood in the art. The techniques and procedures described or referred to herein are generally well understood and commonly employed by those of ordinary skill in the art using conventional methods, e.g., widely used 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. Where appropriate, procedures involving the use of commercially available kits and reagents are generally performed according to manufacturer-defined protocols and conditions unless otherwise noted.

[0153] As used herein, the singular forms "a," "an," and "the" include plural referents unless otherwise indicated.

[0154] It is understood that aspects and embodiments of the invention described herein include "comprising," "consisting of," and "consisting essentially of" aspects and embodiments.

[0155] For all compositions and methods of using the compositions described herein, the composition may comprise or "consist essentially of" the recited components or steps. When a composition is described as "consisting essentially of" recited components, the composition contains the recited components and may contain other components that do not substantially affect the condition being treated, but does not include any other components other than those explicitly listed that substantially affect the condition being treated. Alternatively, if the composition contains additional components other than the recited components that substantially affect the condition being treated, the composition does not contain the additional components in a concentration or amount sufficient to substantially affect the condition being treated. When a method is described as "consisting essentially of" recited steps, the method includes the recited steps and may include other steps that do not substantially affect the condition being treated, but the method does not include any other steps other than those explicitly listed that substantially affect the condition being treated. As a non-limiting example, when a composition is described as "consisting essentially of" a certain component, the composition may further contain any amount of pharmaceutically acceptable carriers, vehicles, or diluents, and other such components that do not substantially affect the condition being treated.

[0156] As used herein, the term "vector" refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes vectors as self-replicating nucleic acid structures as well as vectors that integrate into the genome of a host cell into which they are 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."

[0157] The terms "host cell," "host cell line," and "host cell culture" are used interchangeably and refer to cells into which 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 include the primary transformed or transfected cell and their derived progeny, respectively. Such progeny may not be completely identical in nucleic acid content to the parent cell and may contain mutations. A "recombinant host cell" or "host cell" refers to a cell containing an exogenous polynucleotide, regardless of the method used for insertion, e.g., direct uptake, transduction, f-mating, or other methods known in the art to generate recombinant host cells.

[0158] As used herein, the term "eukaryote" refers to organisms belonging to the phylogenetic domain Eucarya, such as animals (including but not limited to mammals, insects, reptiles, birds, etc.), ciliates, plants (including but not limited to monocotyledons, dicotyledons, algae, etc.), fungi, yeasts, flagellates, microsporidia, protists, etc.

[0159] As used herein, the term "prokaryote" refers to a prokaryotic organism. For example, non-eukaryotic organisms may 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, extreme halophiles such as Methanococcus jannaschii, Methanobacterium thermoautotrophicum, Haloferax volcanii, and the extreme halophilic species NRC-1, Archaeoglobus fulgidus, Pyrococcus furiosus, Pyrococcus horikoshii, Aeuropyrum pernix, etc.) phylogenetic domain.

[0160] As used herein, an "effective amount" or "therapeutically effective amount" refers to an amount of a therapeutic compound, such as an anti-IL-4R antibody, administered to an individual, either in a single dose or as part of a series, that is effective to produce or contribute to a desired therapeutic effect, either alone or in combination with another therapeutic modality. Examples of desired therapeutic effects are reducing an abnormal immune response, slowing or delaying the onset of disease, stabilizing disease, and ameliorating one or more symptoms. An effective amount can be given in one or more doses.

[0161] 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 may occur during the course of clinical pathology. Desirable effects of treatment include prevention of disease recurrence, alleviation of symptoms, reduction of any direct or indirect pathological consequence of the disease, slowing of disease progression, amelioration or reduction of the disease state, and remission or improved prognosis.

[0162] The term "sufficient amount" means an amount sufficient to produce a desired effect, for example, an amount sufficient to modulate an immune response in a subject.

[0163] As used herein, the term "subject" or "individual" means a mammalian subject. Exemplary subjects include humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, goats, rabbits, and sheep. In certain embodiments, the subject is a human. In some embodiments, the subject has a disease or condition that can be treated with an antibody provided herein. In some aspects, the disease or condition is cancer. In some aspects, the disease or condition is a viral infection.

[0164] The term "in vitro" refers to processes occurring in living cells grown separately from the organism, for example, grown in tissue culture.

[0165] The term "in vivo" refers to a process that occurs in a living organism.

[0166] The term "package insert" is used to refer to instructions typically included in commercial packages (e.g., kits) of therapeutic or diagnostic agents that contain information about the indications, uses, dosages, administration, concomitant therapies, contraindications, and / or warnings regarding the use of such therapeutic or diagnostic agents.

[0167] The term "pharmaceutical composition" refers to a preparation in which the biological activity of the active ingredient contained in the preparation is in a form such that it is effective in treating a subject, and which does not contain any additional ingredients that are unacceptably toxic to a subject in the amounts provided in the pharmaceutical composition.

[0168] The terms "co-administration," "co-administering," and "in combination" include the administration of two or more therapeutic agents simultaneously, simultaneously, or sequentially within an unspecified time limit. In one embodiment, the agents are present in a cell or in a subject's body at the same time or exert simultaneous biological or therapeutic effects. 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 may be administered prior to the administration of a second therapeutic agent.

[0169] The terms "modulate" and "modulation" refer to decreasing or inhibiting, or alternatively activating or increasing, the recited variable.

[0170] The terms "increase" and "activate" refer to a 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 increase in the recited variable.

[0171] The terms "reduce" and "inhibit" refer to a 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 decrease in the recited variable.

[0172] The term "about" denotes and encompasses the indicated value and the range above and below that value. In certain embodiments, the term "about" denotes ±10%, ±5%, or ±1% of the specified value. In certain embodiments, where applicable, the term "about" denotes the specified value(s) ±1 standard deviation of that value(s).

[0173] The term "stimulate" refers to the activation of receptor signaling to induce a biological response associated with receptor activation. An "agonist" is an entity that binds to and stimulates a receptor.

[0174] The term "antagonize" refers to the inhibition of receptor signaling to inhibit the biological response associated with receptor activation. An "antagonist" is an entity that binds to and antagonizes a receptor.

[0175] For all of the structural and functional properties described herein, methods for determining these properties are known in the art.

[0176] The term "optionally," when used consecutively, means inclusive of one to all of the listed combinations, and contemplates all subcombinations.

[0177] The term "amino acid" refers, for example, to the 20 common naturally occurring amino acids, including alanine (Ala, A), arginine (Arg, R), asparagine (Asn, N), aspartic acid (Asp, D), cysteine ​​(Cys, C), glutamic acid (Glu, E), glutamine (Gln, Q), glycine (Gly, G), histidine (His, H), isoleucine (Ile, 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 (Val, V).

[0178] The term "affinity" refers to the strength of the sum of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen or epitope). Unless otherwise indicated, as used herein, "affinity" refers to the intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen or epitope).

[0179] As used herein, the term "kd" (sec-1) refers to the dissociation rate constant of a particular antibody-antigen interaction. This value is also referred to as the koff value.

[0180] As used herein, the term "kd" (M×sec) refers to the association rate constant of a particular antibody-antigen interaction. This value is also referred to as the k value.

[0181] As used herein, the term "KD" (M) 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 the interaction between such antibody and its antigen. For clarity, as is known in the art, a smaller KD value indicates a higher affinity interaction, and a larger KD value indicates a lower affinity interaction.

[0182] As used herein, the term "KA" (M-1) refers to the association equilibrium constant of a particular antibody-antigen interaction. KA=ka / kd.

[0183] The term "antibody" is used herein in its broadest sense and includes a specific type of immunoglobulin molecule that contains one or more antigen-binding domains that specifically bind to an antigen or epitope. Specifically, antibodies include intact antibodies (e.g., intact immunoglobulins), antibody fragments, and multispecific antibodies.

[0184] An "anti-IL-4Rα antibody," "IL-4Rα antibody," or "IL-4Rα-specific antibody" is an antibody provided herein that specifically binds to the antigen IL-4Rα.

[0185] The term "epitope" refers to the part of an antigen that specifically binds to an antibody.

[0186] As used herein, the term "hypervariable region" or "HVR" refers to each of the regions of an antibody variable domain that are hypervariable in sequence and / or form structurally defined loops ("hypervariable loops").

[0187] The term "antigen-binding domain" refers to the part of an antibody capable of specifically binding to an antigen or epitope.

[0188] 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.

[0189] The term "human antibody" or "fully human antibody" refers to an antibody that possesses an amino acid sequence that corresponds to that of an antibody produced by a human or human cell, or an antibody derived from the human antibody repertoire or a non-human source that utilizes human antibody coding sequences (e.g., obtained from a human source or designed de novo). Human antibody strictly excludes humanized antibodies.

[0190] The term "humanized antibody" refers to a protein having a sequence that differs from that of an antibody derived from a non-human species by the substitution, deletion, and / or addition of one or more amino acids such that the humanized antibody is less likely to induce an immune response and / or induces a less severe immune response when administered to a human subject compared to antibodies of the non-human species.

[0191] The term "multispecific antibody" refers to an antibody that comprises two or more different antigen-binding domains that collectively specifically bind to two or more different epitopes.

[0192] A "monospecific antibody" is an antibody that contains one or more binding sites that specifically bind to a single epitope. An example of a monospecific antibody is a naturally occurring IgG molecule that is bivalent (i.e., has two antigen-binding domains) but recognizes the same epitope in each of the two antigen-binding domains. The binding specificity can be present in any suitable valency.

[0193] The term "monoclonal antibody" refers to an antibody from a population of substantially homogeneous antibodies. A substantially homogeneous population of antibodies contains antibodies that are substantially similar and bind to the same epitope(s), except for variants that may normally arise during the production of monoclonal antibodies. Such variants are generally present only in minor amounts. Monoclonal antibodies are typically obtained by a process that includes the selection of a single antibody from a plurality of antibodies. For example, the selection process can be the selection of a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones, yeast clones, bacterial clones, or other recombinant DNA clones. The selected antibody can be further altered, for example, to improve its 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.

[0194] The term "single chain" refers to a molecule comprising amino acid monomers linearly linked by peptide bonds. In certain such embodiments, the C-terminus of the Fab light chain is connected to the N-terminus of the Fab heavy chain in a single-chain Fab molecule. As described in more detail herein, an scFv comprises a polypeptide chain in which the C-terminus of the variable domain of the light chain (VL) is connected to the N-terminus of the variable domain of the heavy chain (VH). Alternatively, an scFv comprises a polypeptide chain in which the C-terminus of the VH is connected to the N-terminus of the VL by a polypeptide chain.

[0195] The "Fab fragment" (also called fragment antigen binding) contains the constant domain of the light chain (CL) and the first constant domain of the heavy chain (CH1), as well as the variable regions VL and VH on the light and heavy chains, respectively. The variable domains contain the complementarity-determining loops (CDRs, also called hypervariable regions (HVRs)) involved in antigen binding. Fab' fragments differ from Fab fragments in that they contain a few additional residues at the carboxy terminus of the heavy chain CH1 domain, including one or more cysteines from the antibody hinge region.

[0196] An "F(ab')2" fragment contains two Fab' fragments linked by a disulfide bond near the hinge region. F(ab')2 fragments can be produced, for example, by recombinant methods or by pepsin digestion of an intact antibody. F(ab')2 fragments can be dissociated, for example, by treatment with β-mercaptoethanol.

[0197] An "Fv" fragment comprises a non-covalently associated dimer of one heavy- and one light-chain variable domain.

[0198] A "single-chain Fv" or "sFv" or "scFv" comprises 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 discussion of scFvs, see Plückthun 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 WO 93 / 16185, U.S. Patent No. 5,571,894, and U.S. Patent No. 5,587,458.

[0199] An "scFv-Fc" fragment comprises an scFv linked to an Fc domain. For example, the Fc domain can be linked to the C-terminus of the scFv. The Fc domain can follow the VH or VL, depending on the orientation of the variable domains of the scFv (i.e., VH-VL or VL-VH). Any suitable Fc domain known in the art or described herein can be used. In some cases, the Fc domain comprises an IgG4 Fc domain.

[0200] The term "single domain antibody" or "sdAb" refers to a molecule in which one variable domain of an antibody specifically binds to an antigen without the presence of the other variable domain. Single domain antibodies and fragments thereof are described in Arabi Ghahroudi et al. (1998) FEBS Letters 414:521-526 and Muyldermans et al. (2001) Trends in Biochem. Sci. 26:230-245, each of which is incorporated by reference in its entirety. Single domain antibodies are also known as sdAbs or nanobodies. SdAbs are fairly stable and easily expressed as fusion partners with the Fc chain of an antibody (Harmsen MM, De Haard HJ (2007) "Properties, production, and applications of camelid single-domain antibody fragments". Appl. Microbiol. Biotechnol. 77(1):13-22).

[0201] The terms "full-length antibody," "intact antibody," and "whole antibody" are used interchangeably herein to refer to an antibody having a structure substantially similar to a naturally occurring antibody structure and having a heavy chain containing an Fc region. For example, when used to refer to an IgG molecule, a "full-length antibody" is an antibody comprising two heavy chains and two light chains.

[0202] The term "antibody fragment" refers to an antibody that contains a portion of an intact antibody, such as the antigen-binding and / or variable region of the intact antibody. Antibody fragments include, for example, Fv fragments, Fab fragments, F(ab')2 fragments, Fab' fragments, scFv (sFv) fragments, and scFv-Fc fragments.

[0203] The term "Fc domain" or "Fc region" is used herein to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. This term includes native sequence Fc regions and variant Fc regions.

[0204] The term "substantially purified" refers to a construct described herein or variant thereof that may be substantially or essentially free from components that normally accompany or interact with the protein as found in its naturally occurring environment, i.e., in a natural cell, or, in certain embodiments, in a host cell in the case of recombinantly produced antibodies that are substantially free of cellular material, and includes preparations of the 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.

[0205] The term "percent identity," in the context of two or more nucleic acid or polypeptide sequences, refers to two or more sequences or subsequences that have a certain percentage of the same nucleotide or amino acid residues when aligned and compared for maximum correspondence, as determined using one of the following sequence comparison algorithms (e.g., publicly available computer software such as BLAST, BLASTP, BLASTN, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, CLUSTAL OMEGA, or MUSCLE software, or algorithms available to those of skill in the art) 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 sequence alignment, including any algorithms necessary to achieve maximal alignment over the entire length of the sequences being compared. Depending on the application, the percent "identity" can apply over a region of the sequences being compared, e.g., a functional domain, or alternatively, over the entire length of the two sequences being compared.

[0206] For sequence comparison, typically, one sequence serves 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 as 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.

[0207] Optimal alignment of sequences for comparison can be performed by the local homology algorithm of Smith & Waterman (1981) Adv. Appl. Math. 2:482, by the homologous alignment algorithm of Needleman & Wunsch (1970) J. Mol. Biol. 48:443, by the search for similar methods 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).

[0208] 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 / ).

[0209] It is understood that ranges recited herein are shorthand for all values ​​within that range, inclusive of the recited endpoints. For example, the range of 1 to 50 is understood to include any number, combination of numbers, or subrange 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.

[0210] It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0211] Anti-IL-4Rα antibody Antibody structure The present application provides antibodies and compositions comprising the antibodies that bind to IL-4 receptor alpha (IL-4Rα).

[0212] Recognized immunoglobulin genes include kappa, lambda, alpha, gamma, delta, epsilon, and mu constant region genes, as well as numerous other immunoglobulin variable region genes. Light chains are classified as either kappa or lambda. The "class" of an antibody or immunoglobulin refers to the type of constant domain or region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, some of which may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy-chain constant domains corresponding to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0213] An exemplary immunoglobulin (antibody) structural unit consists of two pairs of polypeptide chains, each pair having one "light" chain (approximately 25 kD) and one "heavy" chain (approximately 50-70 kD). The N-terminal domain of each chain defines a variable region of approximately 100-110 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. An IgG1 heavy chain contains, from the N-terminus to the C-terminus, a VH domain, a CH1 domain, a CH2 domain, and a CH3 domain, respectively. The light chain contains, from the N-terminus to the C-terminus, a VL domain and a CL domain. An IgG1 heavy chain contains a hinge between the CH1 and CH2 domains. In certain embodiments, an immunoglobulin construct comprises at least one immunoglobulin domain from IgG, IgM, IgA, IgD, or IgE linked to a therapeutic polypeptide. In some embodiments, the immunoglobulin domains found in the antibodies provided herein are from or derived from immunoglobulin-based constructs such as diabodies or nanobodies. 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 murine antibody, or a chimeric antibody.

[0214] In some embodiments, an antibody provided herein comprises a heavy chain. In one embodiment, the heavy chain is IgA. In one embodiment, the heavy chain is IgD. In one embodiment, the heavy chain is IgE. In one embodiment, the heavy chain is IgG. In one embodiment, the heavy chain is IgM. In one embodiment, the heavy chain is IgG1. In one embodiment, the heavy chain is IgG2. In one embodiment, the heavy chain is IgG3. In one embodiment, the heavy chain is IgG4. In one embodiment, the heavy chain is IgA1. In one embodiment, the heavy chain is IgA2.

[0215] In some embodiments, the antibody is an IgG1 antibody. In some embodiments, the antibody is an IgG3 antibody. In some embodiments, the antibody is an IgG2 antibody. In some embodiments, the antibody is an IgG4 antibody.

[0216] Typically, a natural four-chain antibody contains six HVRs, three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3). HVRs generally contain amino acid residues from the hypervariable loops and / or complementarity-determining regions (CDRs), the latter of which have the highest sequence variability and / or are involved in antigen recognition. With the exception of CDR1 in VH, CDRs generally contain 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 interchangeably herein to refer to the portions of the variable regions that form the antigen-binding region. This particular region is described in Kabat et al., US Department of Health and Human Services, Sequences of Proteins of Immunological Interest (1983), and Chothia et al. (1987) J Mol Biol 196:901-917, where the definitions include overlapping or subsets of amino acid residues relative to each other. Nevertheless, application of either definition to refer to an antibody CDR or variants thereof is intended to be within the scope of the term as defined and used herein. The exact residue numbers that encompass a particular CDR will vary depending on the sequence and size of the CDR. One of ordinary skill in the art can routinely determine which residues comprise a particular CDR, given the amino acid sequence of an antibody variable region.

[0217] The amino acid sequence boundaries of the CDRs can be determined by one of skill in the art using any of several known numbering schemes, including those described by Kabat et al. (supra) (the "Kabat" numbering scheme), Al-Lazikani et al. (1997) J. Mol. Biol. 273:927-948 (the "Chothia" numbering scheme), MacCallum et al. (1996) J. Mol. Biol. 262:732-745 (the "Contact" numbering scheme), Lefranc et al. (2003) Dev. Comp. Immunol. 27:55-77 (the "IMGT" numbering scheme), and Honegge and Pluckthun, (2001) J. Mol. Biol. 309:657-70 (the "AHo" numbering scheme), each of which is incorporated by reference in its entirety.

[0218] Table 1 presents 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.

[0219] CDRs may be assigned using antibody numbering software such as Abnum, available at www.bioinf.org.uk / abs / abnum / and described in Abhinandan and Martin, (2008) Immunology 45:3832-3839, which is incorporated by reference in its entirety. [Table 1]

[0220] The "EU numbering scheme" is generally used when referring to residues in antibody heavy chain constant regions (e.g., as reported in Kabat et al., supra). Unless otherwise specified, the EU numbering scheme is used to refer to residues in antibody heavy chain constant regions described herein.

[0221] One example of an antigen-binding domain is the antigen-binding domain formed by the VH-VL dimer of an antibody. Another example of an antigen-binding domain is the antigen-binding domain formed by diversifying a specific loop from the tenth fibronectin type III domain of an Adnectin. The antigen-binding domain can comprise CDR1, 2, and 3, in that order, from the heavy chain and CDR1, 2, and 3, in that order, from the light chain.

[0222] Epitopes often consist of surface-accessible amino acid residues and / or sugar side chains and may have specific three-dimensional structural and charge characteristics. Conformational and nonconformational epitopes are distinguished in that the binding to the former, but not the latter, is lost in the presence of denaturing solvents. An epitope may include amino acid residues directly involved in binding as well as other amino acid residues not directly involved in binding. The epitope to which an antibody binds can be determined using known techniques for determining epitopes, such as antibody binding tests against IL-4Rα mutants with different point mutations or chimeric IL-4Rα mutants.

[0223] To screen for antibodies that bind to the epitope on the target antigen bound by the antibody of interest (e.g., IL-4Rα), a conventional 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.

[0224] 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.

[0225] A human antibody or fully human antibody is an antibody that possesses an amino acid sequence that corresponds to that of an antibody produced by a human or human cell, or an antibody derived from the human antibody repertoire or a non-human source that utilizes human antibody coding sequences (e.g., obtained from a human source or designed de novo). Human antibody strictly excludes humanized antibodies.

[0226] A humanized antibody has a sequence that differs from that of an antibody derived from a non-human species by substituting, deleting, and / or adding one or more amino acids, such that the humanized antibody is less likely to induce an immune response and / or induces a less severe immune response when administered to a human subject compared to an antibody from the non-human species. In one embodiment, certain amino acids within the framework and constant domains of the heavy and / or light chains of a non-human species antibody are mutated to produce a humanized antibody. In another embodiment, constant domain(s) from a human antibody are fused to variable domain(s) of a non-human species. In another embodiment, one or more amino acid residues in one or more CDR sequences of the non-human antibody are altered to reduce the likelihood of immunogenicity of the non-human antibody when administered to a human subject, provided that none of the altered amino acid residues are critical for immunospecific binding of the antibody to its antigen, or the changes to the amino acid sequence are conservative changes such that binding of the humanized antibody to the antigen is not significantly impaired compared to binding of the non-human antibody to the antigen. Examples of methods for making humanized antibodies can be found in U.S. Patent 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.

[0227] The two or more different epitopes can be epitopes on the same antigen (e.g., a single IL-4Rα) or on different antigens (e.g., different IL-4Rα molecules, or an IL-4Rα molecule and a non-IL-4Rα molecule). In some embodiments, a multispecific antibody binds to two different epitopes (i.e., a "bispecific antibody"). In some embodiments, a multispecific antibody binds to three different epitopes (i.e., a "trispecific antibody").

[0228] Anti-IL-4Rα antibodies can include those described herein, such as the clones set forth in the figures and / or tables. In some embodiments, the antibody comprises an alternative scaffold. In some embodiments, the antibody consists of an alternative scaffold. In some embodiments, the antibody consists essentially of an alternative scaffold. In some embodiments, the antibody comprises an antibody fragment. In some embodiments, the antibody consists of an antibody fragment. In some embodiments, the antibody consists essentially of an antibody fragment.

[0229] In some embodiments, the antibody is a monoclonal antibody.

[0230] In some embodiments, the antibody is a polyclonal antibody.

[0231] In some embodiments, the antibody is produced by a hybridoma, hi other embodiments, the antibody is produced by a recombinant cell that has been engineered to express the desired variable and constant domains.

[0232] In some embodiments, the antibody may be a single chain antibody or other antibody derivative that retains the antigen specificity and lower hinge region or a variant thereof.

[0233] In some embodiments, the antibody may be a polyfunctional antibody, a recombinant antibody, a fully human antibody, a humanized antibody, a fragment or variant thereof, hi certain embodiments, the antibody fragment or derivative thereof is selected from a Fab fragment, a Fab'2 fragment, a CDR, and an scFv. Table 2-1 Table 2-2 Table 2-3 Table 2-4 Table 2-5 Table 2-6 Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 [Table 2-19] [Table 2-20] [Table 2-21] [Table 2-22]

[0234] V H domain In some embodiments, the antibodies provided herein comprise a VH sequence selected from SEQ ID NOs: 113-145.

[0235] In some embodiments, the antibodies provided herein comprise a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the exemplary VH sequences provided in SEQ ID NOs: 113-145. In some embodiments, the antibodies provided herein comprise a VH sequence having 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. H In some embodiments, the antibodies described in this paragraph are referred to herein as "variants." In some embodiments, such variants are derived from the sequences provided herein by, for example, 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 the sequences provided herein, but may be, for example, de novo isolated according to the methods provided herein for obtaining antibodies.

[0236] VL domain In some embodiments, the antibodies provided herein comprise a VL sequence selected from SEQ ID NOs: 146-186.

[0237] In some embodiments, the antibodies provided herein comprise a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the exemplary VL sequences provided in SEQ ID NOs: 146-186. In some embodiments, the antibodies provided herein comprise a VL sequence provided in SEQ ID NOs: 146-186 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 the sequences provided herein by, for example, 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 the sequences provided herein, but may be isolated de novo, for example, according to the methods provided herein for obtaining antibodies.

[0238] VH-VL combination In some embodiments, the antibodies provided herein comprise a VH sequence selected from SEQ ID NOs: 113-145 and a VL sequence selected from SEQ ID NOs: 146-186.

[0239] In certain embodiments, any of SEQ ID NOs: 113-145 can be combined with any of SEQ ID NOs: 146-186.

[0240] In certain aspects, the antibodies provided herein comprise the VH and VL sequences of the constructs presented in Table 2.

[0241] In some embodiments, the antibodies provided herein comprise a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a VH sequence provided in SEQ ID NOs: 113-145, and a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a VL sequence provided in SEQ ID NOs: 146-186. In some embodiments, the antibodies provided herein comprise a VH sequence as provided in SEQ ID NOs: 113-145 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 as provided in SEQ ID NOs: 146-186 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 the sequences provided herein by, for example, 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 the sequences provided herein, but may be isolated de novo, for example, according to the methods provided herein for obtaining antibodies.

[0242] In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 114 and a VL sequence set forth in SEQ ID NO: 147. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 114 and a VL sequence set forth in SEQ ID NO: 148. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 115 and a VL sequence set forth in SEQ ID NO: 149. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 114 and a VL sequence set forth in SEQ ID NO: 150. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 116 and a VL sequence set forth in SEQ ID NO: 151. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 117 and a VL sequence set forth in SEQ ID NO: 152. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 118 and a VL sequence set forth in SEQ ID NO: 153. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 117 and a VL sequence set forth in SEQ ID NO: 154. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 119 and a VL sequence set forth in SEQ ID NO: 155. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 120 and a VL sequence set forth in SEQ ID NO: 156. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 120 and a VL sequence set forth in SEQ ID NO: 157. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 114 and a VL sequence set forth in SEQ ID NO: 158. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 121 and a VL sequence set forth in SEQ ID NO: 158. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 122 and a VL sequence set forth in SEQ ID NO: 158. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 114 and a VL sequence set forth in SEQ ID NO: 159. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 123 and a VL sequence set forth in SEQ ID NO: 159. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 124 and a VL sequence set forth in SEQ ID NO: 160. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 125 and a VL sequence set forth in SEQ ID NO: 161.In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 126 and a VL sequence set forth in SEQ ID NO: 162. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 127 and a VL sequence set forth in SEQ ID NO: 163. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 128 and a VL sequence set forth in SEQ ID NO: 164. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 124 and a VL sequence set forth in SEQ ID NO: 158. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 129 and a VL sequence set forth in SEQ ID NO: 165. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 130 and a VL sequence set forth in SEQ ID NO: 166. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 131 and a VL sequence set forth in SEQ ID NO: 167. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 132 and a VL sequence set forth in SEQ ID NO: 159. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 133 and a VL sequence set forth in SEQ ID NO: 159. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 121 and a VL sequence set forth in SEQ ID NO: 168. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 134 and a VL sequence set forth in SEQ ID NO: 169. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 113 and a VL sequence set forth in SEQ ID NO: 170. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 134 and a VL sequence set forth in SEQ ID NO: 171. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 135 and a VL sequence set forth in SEQ ID NO: 172. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 136 and a VL sequence set forth in SEQ ID NO: 173. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 131 and a VL sequence set forth in SEQ ID NO: 174. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 137 and a VL sequence set forth in SEQ ID NO: 175. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 114 and a VL sequence set forth in SEQ ID NO: 176.In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 138 and a VL sequence set forth in SEQ ID NO: 177. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 134 and a VL sequence set forth in SEQ ID NO: 178. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 139 and a VL sequence set forth in SEQ ID NO: 179. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 140 and a VL sequence set forth in SEQ ID NO: 180. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 141 and a VL sequence set forth in SEQ ID NO: 181. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 142 and a VL sequence set forth in SEQ ID NO: 182. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 143 and a VL sequence set forth in SEQ ID NO: 183. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 114 and a VL sequence set forth in SEQ ID NO: 184. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 144 and a VL sequence set forth in SEQ ID NO: 185. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 145 and a VL sequence set forth in SEQ ID NO: 186.

[0243] In certain embodiments of any of the above-described antibodies, the antibody further comprises a heavy chain comprising a human IgG sequence selected from the sequences set forth in SEQ ID NOs: 192-235 and 251-407.

[0244] In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 113, a VL sequence set forth in SEQ ID NO: 146, and the antibody further comprises a heavy chain comprising a human IgG sequence selected from the sequences set forth in SEQ ID NOs: 192 to 235 and 251 to 407. In certain embodiments of any of the above-described antibodies, the antibody further comprises a constant light chain sequence comprising the sequence set forth in SEQ ID NO: 236.

[0245] In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 134, a VL sequence set forth in SEQ ID NO: 178, a heavy chain constant region comprising a LALA / YTE substitution, and a human kappa light chain constant region. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 134, a VL sequence set forth in SEQ ID NO: 178, a heavy chain constant region comprising the sequence set forth in SEQ ID NO: 205 or SEQ ID NO: 321, and a light chain constant region comprising the sequence set forth in SEQ ID NO: 236. In certain embodiments, the antibody comprises a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the VH sequence provided in SEQ ID NO: 134, and a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the VL sequence provided in SEQ ID NO: 178, a heavy chain constant region comprising a LALA / YTE substitution, and a human kappa light chain constant region. In certain embodiments, the antibody comprises a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the VH sequence provided in SEQ ID NO: 134, and a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the VL sequence provided in SEQ ID NO: 178, SEQ ID NO: 205, or SEQ ID NO: 321. and a heavy chain constant region comprising the sequence set forth in SEQ ID NO:236 or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:205 or SEQ ID NO:321, and a light chain constant region comprising the sequence set forth in SEQ ID NO:236 or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:236.

[0246] In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 130, a VL sequence set forth in SEQ ID NO: 166, a heavy chain constant region comprising a LALA / YTE substitution, and a human kappa light chain constant region. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 130, a VL sequence set forth in SEQ ID NO: 166, a heavy chain constant region comprising the sequence set forth in SEQ ID NO: 205 or SEQ ID NO: 321, and a light chain constant region comprising the sequence set forth in SEQ ID NO: 236. In certain embodiments, the antibody comprises a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the VH sequence provided in SEQ ID NO: 130, and a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the VL sequence provided in SEQ ID NO: 166, a heavy chain constant region comprising a LALA / YTE substitution, and a human kappa light chain constant region. In certain embodiments, the antibody comprises a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the VH sequence provided in SEQ ID NO: 130, and a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the VL sequence provided in SEQ ID NO: 166, SEQ ID NO: 205, or SEQ ID NO: 321. and a heavy chain constant region comprising the sequence set forth in SEQ ID NO:236 or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:205 or SEQ ID NO:321, and a light chain constant region comprising the sequence set forth in SEQ ID NO:236 or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:236.

[0247] In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 121, a VL sequence set forth in SEQ ID NO: 158, a heavy chain constant region comprising a LALA / YTE substitution, and a human kappa light chain constant region. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 121, a VL sequence set forth in SEQ ID NO: 158, a heavy chain constant region comprising the sequence set forth in SEQ ID NO: 205 or SEQ ID NO: 321, and a light chain constant region comprising the sequence set forth in SEQ ID NO: 236. In certain embodiments, the antibody comprises a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the VH sequence provided in SEQ ID NO: 121, and a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the VL sequence provided in SEQ ID NO: 158, a heavy chain constant region comprising a LALA / YTE substitution, and a human kappa light chain constant region. In certain embodiments, the antibody comprises a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the VH sequence provided in SEQ ID NO: 121, and a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the VL sequence provided in SEQ ID NO: 158, SEQ ID NO: 205 or SEQ ID NO: 321. and a heavy chain constant region comprising the sequence set forth in SEQ ID NO:236 or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:205 or SEQ ID NO:321, and a light chain constant region comprising the sequence set forth in SEQ ID NO:236 or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:236.

[0248] CDR In some embodiments, disclosed herein are antibodies that comprise one, two, three, four, five, or six of the CDRs of Table 2. In some embodiments, disclosed herein are six of the Kabat CDRs of Table 2, six of the Chothia CDRs of Table 2, or six of the IMGT CDRs of Table 2.

[0249] In some embodiments, the antibodies provided herein comprise one to three CDRs of a VH domain selected from SEQ ID NOs: 113-145. H In some embodiments, the antibodies provided herein comprise three CDRs of a VH domain selected from SEQ ID NOs: 113-145. 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.

[0250] In some embodiments, the CDRs are CDRs that have at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to CDR-H1, CDR-H2, or CDR-H3 of SEQ ID NOs: 1-112 and 187-191. In some embodiments, the CDR-H1 is CDR-H1 of a VH domain selected from SEQ ID NOs: 113-145 with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the CDR-H2 is CDR-H2 of a VH domain of SEQ ID NOs: 113-145 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: 113-145, 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 the sequences provided herein by, for example, 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 the sequences provided herein, but may be, for example, de novo isolated according to the methods provided herein for obtaining the antibody.

[0251] In some embodiments, the antibodies provided herein comprise one to three CDRs of the VL domain of SEQ ID NOs: 146-186. In some embodiments, the antibodies provided herein comprise two to three CDRs of the VL domain of SEQ ID NOs: 146-186. In some embodiments, the antibodies provided herein comprise three CDRs of the VL domain of SEQ ID NOs: 146-186. 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.

[0252] In some embodiments, the CDRs are CDRs that have at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to CDR-L1, CDR-L2, or CDR-L3 of SEQ ID NOs: 26-65 and 100-112. In some embodiments, the CDR-L1 is CDR-L1 of the VL domain of SEQ ID NOs: 146-186, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the CDR-L2 is CDR-L2 of the VL domain of SEQ ID NOs: 41-52 and 108-112, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the CDR-L3 is the CDR-L3 of the VL domain of SEQ ID NOs: 146-186, 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 the sequences provided herein by, for example, 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 the sequences provided herein, but may be, for example, de novo isolated according to the methods provided herein for obtaining antibodies.

[0253] In some embodiments, the antibodies provided herein comprise one to three CDRs of a VH domain selected from SEQ ID NOs: 113-145 and one to three CDRs of a VL domain selected from SEQ ID NOs: 146-186. In some embodiments, the antibodies provided herein comprise two to three CDRs of a VH domain selected from SEQ ID NOs: 113-145 and two to three CDRs of a VL domain selected from SEQ ID NOs: 146-186. In some embodiments, the antibodies provided herein comprise three CDRs of a VH domain selected from SEQ ID NOs: 113-145 and three CDRs of a VL domain selected from SEQ ID NOs: 146-186. 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.

[0254] In some embodiments, the antibodies provided herein comprise a CDR-H3 selected from SEQ ID NOs: 17-25 and 92-99. 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: 17-25 and 92-99. In some embodiments, the CDR-H3 is a CDR-H3 selected from SEQ ID NOs: 17-25 and 92-99 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 the sequences provided herein by, for example, 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 the sequences provided herein, but may be isolated de novo, for example, according to the methods provided herein for obtaining antibodies.

[0255] In some embodiments, the antibodies provided herein comprise a CDR-H1 selected from SEQ ID NOs: 1-4, 66-70, and 187-191. 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: 1-4, 66-70, and 187-191. In some embodiments, the CDR-H1 is a CDR-H1 selected from SEQ ID NOs: 1-4, 66-70, and 187-191 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 the sequences provided herein, e.g., 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 the sequences provided herein, but may be isolated de novo, e.g., according to the methods provided herein for obtaining antibodies.

[0256] In some embodiments, the antibodies provided herein comprise a CDR-H2 selected from SEQ ID NOs: 5-16 and 71-90. 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: 5-16 and 71-90. In some embodiments, the CDR-H2 is a CDR-H2 selected from SEQ ID NOs: 5-16 and 71-90 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 the sequences provided herein by, for example, 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 the sequences provided herein, but may be isolated de novo, for example, according to the methods provided herein for obtaining antibodies.

[0257] In some embodiments, the antibodies provided herein comprise a CDR-L3 selected from SEQ ID NOs: 53-65. In some aspects, the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the CDR-L3 of SEQ ID NOs: 53-65. In some embodiments, the CDR-L3 is a CDR-L3 selected from SEQ ID NOs: 53-65 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 the sequences provided herein by, for example, 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 the sequences provided herein, but may be isolated de novo, for example, according to the methods provided herein for obtaining antibodies.

[0258] In some embodiments, the antibodies provided herein comprise a CDR-L2 selected from SEQ ID NOs: 41-52 and 108-112. 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: 41-52 and 108-112. In some embodiments, the CDR-L2 is a CDR-L2 selected from SEQ ID NOs: 41-52 and 108-112 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 the sequences provided herein, e.g., 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 the sequences provided herein, but may be isolated de novo, e.g., according to the methods provided herein for obtaining antibodies.

[0259] In some embodiments, the antibodies provided herein comprise a CDR-L1 selected from SEQ ID NOs: 26-40 and 100-107. 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: 26-40 and 100-107. In some embodiments, the CDR-L1 is a CDR-L1 selected from SEQ ID NOs: 26-40 and 100-107 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 the sequences provided herein, e.g., 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 the sequences provided herein, but may be isolated de novo, e.g., according to the methods provided herein for obtaining antibodies.

[0260] In some embodiments, the antibodies provided herein comprise a CDR-H3 selected from SEQ ID NOs: 17-25 and 92-99, a CDR-H2 selected from SEQ ID NOs: 5-16 and 71-90, a CDR-H1 selected from SEQ ID NOs: 1-4, 66-70, and 187-191, a CDR-L3 selected from SEQ ID NOs: 53-65, a CDR-L2 selected from SEQ ID NOs: 41-52 and 108-112, and a CDR-L1 selected from SEQ ID NOs: 26-40 and 100-107. 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: 17-25 and 92-99; 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 SEQ ID NOs: 5-16 and 71-90; and 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: 1-4, 66-70, and 187-191. 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: 53 to 65; 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: 41 to 52 and 108 to 112; 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: 26 to 40 and 100 to 107.In some embodiments, the CDR-H3 is a CDR-H3 selected from SEQ ID NOs: 17-25 and 92-99 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: 5-16 and 71-90 with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; and the CDR-H1 is a CDR-H2 selected from SEQ ID NOs: 1-4, 66-70, and 187-191 with up to 1, 2, 3, 4, or 5 amino acid substitutions. the CDR-L3 is CDR-L3 selected from SEQ ID NOs: 53 to 65 and having up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L2 is CDR-L2 selected from SEQ ID NOs: 41 to 52 and 108 to 112 and having up to 1, 2, 3, 4, 5, or 6 amino acid substitutions; and the CDR-L1 is CDR-L1 selected from SEQ ID NOs: 26 to 40 and 100 to 107 and having up to 1, 2, 3, 4, 5, or 6 amino acid substitutions.

[0261] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 1, 67, or 187; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 5, 71, or 79; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 17 or 91; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 26 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 41 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 53. In some embodiments, CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to CDR-H3 of SEQ ID NO: 17 or 91; CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to CDR-H2 of SEQ ID NO: 5, 71, or 79; and CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to CDR-H1 of SEQ ID NO: 1, 67, or 187. 99% identity, CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to CDR-L3 of SEQ ID NO: 53, CDR-L2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to CDR-L2 of SEQ ID NO: 41 or 108, and CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to CDR-L1 of SEQ ID NO: 26 or 100.In some embodiments, the CDR-H3 is CDR-H3 of SEQ ID NO: 17 or 91 with a maximum of 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H2 is CDR-H2 of SEQ ID NO: 5, 71, or 79 with a maximum of 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H1 is CDR-H1 of SEQ ID NO: 1, 67, or 187 with a maximum of 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L3 is CDR-L3 of SEQ ID NO: 53 with a maximum of 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L2 is CDR-L2 of SEQ ID NO: 41 or 108 with a maximum of 1, 2, 3, or 4 amino acid substitutions; and the CDR-L1 is CDR-L1 of SEQ ID NO: 26 or 100 with a maximum of 1, 2, 3, 4, 5, or 6 amino acid substitutions.

[0262] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 27 or 101; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 42 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 54.

[0263] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 62, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 42 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 55.

[0264] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 7, 72, or 81; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 22 or 93; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 29 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 55.

[0265] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 45 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 55.

[0266] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 8, 73, or 82; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 19 or 94; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 30 or 102; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 56.

[0267] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 8, 73, or 82; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 31 or 103; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 57.

[0268] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 17 or 91; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 32 or 102; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 46 or 109; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 58.

[0269] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 8, 73, or 82; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 32 or 102; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 45 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 59.

[0270] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 68, or 189; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 32 or 102; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 45 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 60.

[0271] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 9, 77, or 83; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 29 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 60.

[0272] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 9, 77, or 83; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 27 or 101; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 57.

[0273] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 27 or 101; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0274] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 10, 71, or 84; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 27 or 101; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0275] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0276] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 3, 69, or 190; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 8, 73, or 82; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 21 or 96; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0277] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 7, 72, or 81; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 42 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 62.

[0278] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 11, 73, or 85; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 33 or 102; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0279] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 23, 69, or 190; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 11, 73, or 85; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 19 or 94; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 34 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 60.

[0280] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 11, 73, or 85; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 22 or 93; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 34 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 56.

[0281] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 3, 69, or 190; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 23 or 97; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 42 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0282] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 7, 72, or 81; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20, 18, or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 27 or 101; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0283] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 7, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 27 or 101; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0284] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 24 or 98; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 36 or 102; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 45 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0285] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 8, 73, or 82; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 37 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 47 or 110; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0286] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 12, 74, or 86; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 24 or 98; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0287] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 189; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 13, 71, or 87; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0288] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 10, 71, or 84; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 34 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 57.

[0289] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 34 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0290] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 1, 66, or 187; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 5, 71, or 79; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 17 or 91; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 38 or 105; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 48 or 111; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 63.

[0291] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 39 or 106; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 41 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 64.

[0292] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 14, 75, or 88; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 39 or 106; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 49 or 112; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 63.

[0293] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 19 or 94; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 42 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 60.

[0294] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 8, 73, or 82; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 31 or 103; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 58.

[0295] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 3, 69, or 190; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 5, 71, or 79; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 19 or 94; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 33 or 102; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 50 or 110; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0296] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 30 or 101; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 51 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0297] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 3, 67, or 190; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 15, 67, or 89; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 40 or 107; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 52 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0298] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 30 or 102; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 47 or 110; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0299] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 4, 70, or 191; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 11, 73, or 85; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 22, 18, or 93; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 30 or 102; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 60.

[0300] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 14, 75, or 88; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 27 or 101; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 65.

[0301] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 15, 76, or 89; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 19 or 94; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 62.

[0302] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 3, 69, or 190; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 9, 77, or 83; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 19 or 94; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 55.

[0303] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 15, 76, or 89; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 24 or 98; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 34 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 42 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0304] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 32 or 102; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 51 or 110; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0305] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 16, 78, or 90; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 19 or 94; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 45 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 57.

[0306] In some embodiments, the antibodies provided herein comprise a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 4, 70, or 191; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 16, 78, or 90; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 25 or 99; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 34 or 100; a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 53.

[0307] In some embodiments, CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to CDR-H3 of Table 2; CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to CDR-H2 of Table 2; and CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to CDR-H1 of Table 2. and CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to CDR-L3 of Table 2; CDR-L2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to CDR-L2 of Table 2; and CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to CDR-L1 of Table 2. In some embodiments, CDR-H3 is CDR-H3 of Table 2 with a maximum of 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; CDR-H2 is CDR-H2 of Table 2 with a maximum of 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; CDR-H1 is CDR-H1 of Table 2 with a maximum of 1, 2, 3, 4, or 5 amino acid substitutions; CDR-L3 is CDR-L3 of Table 2 with a maximum of 1, 2, 3, 4, or 5 amino acid substitutions; CDR-L2 is CDR-L2 of Table 2 with a maximum of 1, 2, 3, or 4 amino acid substitutions; and CDR-L1 is CDR-L1 of Table 2 with a maximum of 1, 2, 3, 4, 5, or 6 amino acid substitutions.

[0308] In certain embodiments of any of the above-described antibodies, the antibody further comprises a heavy chain comprising a human IgG sequence selected from the sequences set forth in SEQ ID NOs: 192-235 and 251-407. In certain embodiments of any of the above-described antibodies, the antibody further comprises a constant light chain sequence comprising the sequence set forth in SEQ ID NO: 236. In certain embodiments of any of the above-described antibodies, the antibody further comprises a heavy chain comprising a human IgG sequence selected from SEQ ID NO: 205 and SEQ ID NO: 321, and a constant light chain sequence comprising the sequence set forth in SEQ ID NO: 236.

[0309] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188, a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 10, 71, or 84, a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95, a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 27 or 101, a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 43 or 108, and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61. In certain embodiments, the antibody further comprises a heavy chain constant region (e.g., an IgG1 constant region) comprising a LALA / YTE substitution. In certain embodiments, the antibody comprises a heavy chain comprising a heavy chain constant region selected from SEQ ID NOs: 205 and 321. In certain embodiments, the antibody comprises a human kappa light chain constant region. In some embodiments, the antibody comprises a constant light chain sequence comprising the sequence set forth in SEQ ID NO: 236.

[0310] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188, a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80, a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 24 or 98, a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 36 or 102, a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 45 or 108, and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61. In certain embodiments, the antibody further comprises a heavy chain constant region (e.g., an IgG1 constant region) comprising a LALA / YTE substitution. In certain embodiments, the antibody comprises a heavy chain comprising a heavy chain constant region selected from SEQ ID NOs: 205 and 321. In certain embodiments, the antibody comprises a human kappa light chain constant region. In some embodiments, the antibody comprises a constant light chain sequence comprising the sequence set forth in SEQ ID NO: 236.

[0311] In some embodiments, the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188, a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80, a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95, a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 30 or 102, a CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 47 or 110, and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61. In certain embodiments, the antibody further comprises a heavy chain constant region (e.g., an IgG1 constant region) comprising a LALA / YTE substitution. In certain embodiments, the antibody comprises a heavy chain comprising a heavy chain constant region selected from SEQ ID NOs: 205 and 321. In certain embodiments, the antibody comprises a human kappa light chain constant region. In some embodiments, the antibody comprises a constant light chain sequence comprising the sequence set forth in SEQ ID NO: 236.

[0312] 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 the sequences provided herein by, for example, affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants or clones are not derived from the sequences provided herein, but may be, for example, de novo isolated according to the methods provided herein for obtaining antibodies.

[0313] Fc area The structures of various immunoglobulin Fc regions, and the glycosylation sites contained therein, are known in the art. See Schroeder and Cavacini, J. (2010) Allergy Clin. Immunol. 125:S41-52, which is incorporated by reference in its entirety. The Fc region can be a naturally occurring Fc region or an Fc region that has been modified as described in the art or elsewhere in this disclosure.

[0314] Unless otherwise specified herein, the numbering of amino acid residues in the Fc region or constant region follows the EU numbering system, also known as 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. As used herein, the "Fc polypeptide" of a dimeric Fc refers to one of the two polypeptides forming the dimeric Fc domain, i.e., a polypeptide comprising the C-terminal constant region of an immunoglobulin heavy chain capable of stable self-association. For example, the Fc polypeptide of a dimeric IgG Fc comprises the constant domain sequences of IgG CH2 and IgG CH3. The Fc may be of the classes IgA, IgD, IgE, IgG, and IgM, some of which may be further classified into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.

[0315] The terms "Fc receptor" and "FcR" are used to describe receptors that bind to the Fc region of an antibody. For example, an FcR may be a native-sequence human FcR. Generally, FcRs are those that bind IgG antibodies (gamma receptors) and include receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternatively spliced ​​forms of these receptors. FcγRII receptors include FcγRIIA (an "activating receptor") and FcγRIIB (an "inhibiting receptor"), which have similar amino acid sequences that differ primarily in their cytoplasmic domains. Immunoglobulins of other isotypes can also be bound by a particular FcR (see, e.g., Janeway et al., ImmunoBiology: the immune system in health and disease, (Elsevier Science Ltd., NY) (4th ed., 1999)). Activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. The inhibitory receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic domain (reviewed in Daeron, (1997) Annu. Rev. Immunol. 15:203-234). FcRs are reviewed in Ravetch and Kinet, (1991) Annu. Rev. Immunol 9:457-92, Capel et al. (1994) Immunomethods 4:25-34, and de Haas et al. (1995) J. Lab. Clin. Med. 126:330-41. Other FcRs, including those identified in the future, are encompassed by the term "FcR" herein. The term also includes the fetal receptor, FcRn, which is involved in the transfer of maternal IgGs to the fetus (Guyer et al. (1976) J. Immunol. 117:587, and Kim et al. (1994) J. Immunol. 24:249).

[0316] Modifications in the CH2 domain can affect the binding of FcR to Fc. Some amino acid modifications in the Fc region are known in the art to selectively change the affinity of Fc to different Fc gamma receptors. In some embodiments, Fc comprises one or more modifications to promote selective binding to Fc-gamma receptors.

[0317] Exemplary mutations that alter binding of FcR to Fc are listed below: ·S298A / E333A / K334A, S298A / E333A / K334A / K326A (Lu et al. (2011) J Immunol Methods 365(1-2):132-41), ·F243L / R292P / Y300L / V305I / P396L, F243L / R292P / Y300L / L235V / P396L (Stavenhagen et al. (2007) Cancer Res. 67(18):8882-90, Nordstrom et al. (2011) Breast Cancer Res.13(6):R123), ·F243L (Stewart et al. (2011) Protein Eng Des Sel.24(9):671-8.), S298A / E333A / K334A (Shields et al. (2001) J Biol Chem.276(9):6591-604), ·S239D / I332E / A330L, S239D / I332E (Lazar et al. (2006) Proc Natl Acad Sci USA.103(11):4005-10), ·S239D / S267E, S267E / L328F (Chu et al. (2008) Mol Immunol.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 / D270L / I332E, S239E / S267E / H268D, L234F / S267E / N325L, G237F / V266L / S267D and other mutations listed in WO2011 / 120134 and WO2011 / 120135, which are incorporated herein 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 the mutations on page 283.

[0318] In some embodiments, the antibodies described herein contain modifications to improve their ability to mediate effector function. Such modifications are known in the art and include defucosylation or engineering the affinity of the Fc for activating receptors, primarily FCGR3a for ADCC and C1q for CDC. Table 3 below summarizes various designs reported in the literature for effector function engineering.

[0319] Methods for producing antibodies with little or no fucose at the Fc glycosylation site (EU numbering of Asn297) without altering the amino acid sequence are known in the art. GlymaX® technology (ProBioGen AG) is based on the introduction of a gene for an enzyme that deflects the cellular pathway of fucose biosynthesis into the cells used for antibody production. This prevents the antibody-producing cells from adding the sugar "fucose" to the carbohydrate moiety of N-linked antibodies. (von Horsten et al. (2010) Glycobiology. 2010 Dec;20(12):1607-18. Another approach to obtaining antibodies with reduced levels of fucosylation can be found in U.S. Pat. No. 8,409,572, which teaches that cell lines for antibody production can be selected for their ability to reduce the level of fucosylation in the antibody, so that they can be fully defucosylated (meaning they contain no detectable fucose) or partially defucosylated, i.e., the isolated antibody contains less than 95%, 85%, 75%, 65%, 55%, 45%, 35%, 25%, 15%, or 5% of the amount of fucose typically found in a similar antibody produced by a mammalian expression system.

[0320] Thus, in one embodiment, the antibodies described herein can comprise a dimeric Fc that contains one or more amino acid modifications that confer improved effector function as described in Table 3. In another embodiment, the antibodies can be defucosylated to improve effector function. [Table 3]

[0321] Fc modifications that 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 reducing effector function via glycosylation modifications, using IgG2 / IgG4 scaffolds, or introducing 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) J. Mol. Biol. 420:204-219) describe certain modifications to reduce complement binding to FcgR or Fc.

[0322] Specific non-limiting examples of known amino acid modifications to reduce complement binding to FcgR or Fc include those identified in Table 4 below. [Table 4]

[0323] Methods for producing antibodies with little or no fucose at the Fc glycosylation site (EU numbering of Asn297) without altering the amino acid sequence are well known in the art. GlymaxX® technology (ProBioGen AG) is based on the introduction of a gene encoding an enzyme that deflects the cellular pathway of fucose biosynthesis into cells used for antibody production. This prevents the antibody-producing cells from adding the sugar "fucose" to the carbohydrate moiety of N-linked antibodies. (von Horsten et al. (2010) Glycobiology 20(12):1607-18). Examples of cell lines capable of producing defucosylated antibodies include CHO-DG44, which stably overexpress the bacterial oxidoreductase GDP-6-deoxy-D-lyxo-4-hexylose reductase (RMD) (see von Horsten et al. (2010) supra), or Lec13 CHO cells, which are deficient in protein fucosylation (see Ripka et al. (1986) Arch. Biochem. Biophys. 249:533-545; U.S. Patent Publication No. 2003 / 0157108; WO2004 / 056312, each of which is incorporated by reference in its entirety), and knockout cell lines such as alpha-1,6-fucosyltransferase gene or FUT8 knockout CHO cells (Yamane-Ohnuki et al. (2004) Biotech. Bioeng. 87:614-622; Kanda et al. (2005) Biotech. Bioeng. 87:614-622). (See, e.g., WO 2003 / 085107, and WO 2006) Biotechnol. Bioeng. 94:680-688, each of which is incorporated by reference in its entirety. Another approach to obtaining antibodies with reduced levels of fucosylation can be found in U.S. Patent No. 8,409,572, which teaches selecting cell lines for antibody production for their ability to elicit low fucosylation levels in the antibody.

[0324] Examples of cell lines capable of producing defucosylated antibodies include CHO-DG44, which stably overexpress the bacterial oxidoreductase GDP-6-deoxy-D-lyxo-4-hexylose reductase (RMD) (see von Horsten et al. (2010) supra), or Lec13 CHO cells, which are deficient in protein fucosylation (see Ripka et al. (1986) (supra); U.S. Patent Publication No. 2003 / 0157108; WO2004 / 056312, each of which is incorporated by reference in its entirety), and knockout cell lines, such as alpha-1,6-fucosyltransferase gene or FUT8 knockout CHO cells (Yamane-Ohnuki et al. (2004) (supra); Kanda et al. (2005) (supra). al. (2006), (supra), and WO2003 / 085107, each of which is incorporated by reference in its entirety.

[0325] The antibody can be completely defucosylated (meaning it contains no detectable fucose) or partially defucosylated, i.e., 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 typically found for a similar antibody produced in a mammalian expression system.

[0326] In some embodiments, the antibodies provided herein comprise an IgG1 domain that has a reduced fucose content at Asn297 compared to naturally occurring IgG1 domains. Such Fc domains are known to have improved ADCC. See Shields et al. (2002) J. Biol. Chem. 277:26733-26740, incorporated by reference in its entirety. In some embodiments, such antibodies do not comprise any fucose at Asn297. The amount of fucose can be determined using any suitable method, such as, for example, that described in WO2008 / 077546, incorporated by reference in its entirety.

[0327] In certain embodiments, the antibodies provided herein comprise an Fc region with one or more amino acid substitutions that improve ADCC, such as substitutions at one or more of the Fc region positions 298, 333, and / or 334. In some embodiments, the antibodies provided herein comprise an Fc region with one or more amino acid substitutions at positions 239, 332, and 330, as described in Lazar et al. (2006), supra, which is incorporated by reference in its entirety.

[0328] Other exemplary glycosylation variants that can be incorporated into the antibodies provided herein are described in, e.g., U.S. Patent Publication Nos. 2003 / 0157108, 2004 / 0093621, 2003 / 0157108, 2003 / 0115614, 2002 / 0164328, 2004 / 0093621, 2004 / 0132140, 2004 / 011 0704, 2004 / 0110282, 2004 / 0109865, International Patent Publication Nos. 2000 / 61739, 2001 / 29246, 2003 / 085119, 2003 / 084570, 2005 / 035586, 2005 / 035778, 2005 / 053742, 2002 / 031140, Okazaki et al. (2004) J. Mol. Biol., 2004, 336:1239-1249, and Yamane-Ohnuki et al. (2004), supra (each of which is incorporated by reference in its entirety).

[0329] In some embodiments, the antibodies provided herein comprise an Fc region with at least one galactose residue in the oligosaccharide attached to the Fc region. Such antibody variants may have improved CDC function. Examples of such antibody variants are described, for example, in WO1997 / 30087, WO1998 / 58964, and WO1999 / 22764, each of which is incorporated by reference in its entirety.

[0330] In some embodiments, the antibodies provided herein contain one or more alterations that improve or decrease C1q binding and / or CDC. See U.S. Patent No. 6,194,551, WO 99 / 51642, and Idusogie et al. (2000) J. Immunol., 164:4178-4184, each of which is incorporated by reference in its entirety.

[0331] In certain embodiments, the heavy chain comprises a constant heavy chain sequence selected from the sequences represented by SEQ ID NOs: 192-235 and 251-407. In certain embodiments, the constant heavy chain sequence (e.g., a constant heavy chain sequence selected from SEQ ID NOs: 192-235 and 251-306) further comprises a C-terminal lysine (SEQ ID NOs: 307-407). C-terminal lysines may be present in the corresponding coding sequences of the constant heavy chain region, but are prone to cleavage during manufacturing or after administration. Thus, heavy chain constant region sequences with or without a C-terminal lysine are provided herein.

[0332] In certain embodiments, the antibodies provided herein comprise the VH and VL sequences set forth in Table 2, together with a heavy chain constant region selected from the sequences set forth in SEQ ID NOs: 192-235 and 251-407. In certain embodiments, the antibodies provided herein comprise the VH and VL sequences set forth in Table 2, together with a heavy chain constant region and a light chain constant region set forth in SEQ ID NO: 146. H Sequence and V L Contains arrays.

[0333] In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 113 and a VH sequence set forth in SEQ ID NO: 146. L The constant heavy chain comprises a human IgG sequence selected from the sequences represented by SEQ ID NOs: 192 to 235 and 251 to 407.

[0334] In certain embodiments, the Fc region comprises one or more amino acid substitutions, which result in an increase in one or more of antibody half-life, ADCC activity, ADCP activity, or CDC activity, compared to an Fc region that does not contain the one or more substitutions. In certain embodiments, the one or more amino acid substitutions result in an increase in antibody half-life at pH 6.0, compared to an antibody comprising a wild-type Fc region. In certain embodiments, the antibody has an increased half-life that is about 10,000-fold, 1,000-fold, 500-fold, 100-fold, 50-fold, 20-fold, 10-fold, 9-fold, 8-fold, 7-fold, 6-fold, 5-fold, 4.5-fold, 4-fold, 3.5-fold, 3-fold, 2.5-fold, 2-fold, 1.95-fold, 1.9-fold, 1.85-fold, 1.8-fold, 1.75-fold, 1.7-fold, 1.65-fold, 1.6-fold, 1.55-fold, 1.50-fold, 1.45-fold, 1.4-fold, 1.35-fold, 1.3-fold, 1.25-fold, 1.2-fold, 1.15-fold, 1.1-fold, or 1.05-fold longer compared to an antibody comprising a wild-type Fc region. In certain embodiments, the antibody has an increased half-life that is about 10,000-fold, 1,000-fold, 500-fold, 100-fold, 50-fold, 20-fold, 10-fold, 9-fold, 8-fold, 7-fold, 6-fold, 5-fold, 4.5-fold, 4-fold, 3.5-fold, 3-fold, 2.5-fold, 2-fold, 1.95-fold, 1.9-fold, 1.85-fold, 1.8-fold, 1.75-fold, 1.7-fold, 1.65-fold, 1.6-fold, 1.55-fold, 1.50-fold, 1.45-fold, 1.4-fold, 1.35-fold, 1.3-fold, 1.25-fold, 1.2-fold, 1.15-fold, 1.1-fold, or 1.05-fold longer than 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 than dupilumab.

[0335] In certain embodiments, the Fc region comprises one or more amino acid substitutions, which result in a decrease in one or more of ADCC activity, ADCP activity, or CDC activity compared to an Fc region that does not contain the one or more substitutions.

[0336] In certain embodiments, the one or more amino acid substitutions are selected from the group consisting of S228P(SP), M252Y, S254T, T256E, T256D, T250Q, H285D, T307A, T307Q, T307R, T307W, L309D, Q411H, Q311V, A378V, E380A, M428L, N434A, N434S, N297A, D265A, L234A, L235A, and N434W. In certain embodiments, the one or more amino acid substitutions comprise a specific combination of amino acid substitutions selected from the group consisting of: M428L / N434S(LS); M252Y / S254T / T256E(YTE); T250Q / M428L; T307A / E380A / N434A; T256D / T307Q(DQ); T256D / T307W(DW); M252 Y / T256D(YD);T307Q / Q311V / A378V(QVV);T256D / H285D / T307R / Q311V / A378V(DDRVV);L309D / Q3 11H / N434S(DHS);S228P / L235E(SPLE);L234A / L235A(LA), M428L / N434A, L234A / G237A(LAGA), L2 34A / L235A / G237A(LALAGA), L234A / L235A / P329G, D265A / YTE, LALA / YTE, LAGA / YTE, LALAGA / YTE , LALAPG / YTE, N297A / LS;D265A / LS;LALA / LS;LALAGA / LS;LALAPG / LS;N297A / DHS;D265A / DHS;LAL A / DHS;LAGA / DHS;LALAGA / DHS;LALAPG / DHS;SP / YTE;SPLE / YTE;SP / LS;SPLE / LS, SP / DHS;SPLE / D HS;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, LA GA / QVV, LALAGA / QVV, LALAPG / QVV, DDRVV, N297A / DDRVV, D265A / DDRVV, LALA / DDRVV, LAGA / DDRVV, LALAGA / DDRVV, and LALAPG / DDRVV. ;

[0337] In certain embodiments, the Fc region binds to an Fcγ receptor selected from the group consisting of FcγRI, FcγRIIa, FcγRIIb, FcγRIIc, FcγRIIIa, and FcγRIIIb, hi certain embodiments, the Fc region binds to an Fcγ receptor with greater affinity at pH 6.0 compared to an antibody comprising a wild-type Fc region.

[0338] join The affinity of a molecule X for its partner Y is determined by the dissociation equilibrium constant (K D ) The kinetic factors 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®).

[0339] With respect to antibody binding to a target molecule, the terms "binds to," "specific binding to," "specifically binds to," "specific for," "selectively binds to," and "selective for" a particular antigen (e.g., a polypeptide target) or epitope on a particular antigen refer to binding that is measurably different from a nonspecific or nonselective interaction (e.g., with a non-target molecule). Specific binding can be measured, for example, by measuring binding to the target molecule (i.e., IL-4Rα) and comparing it to binding to the non-target molecule. Specific binding can also be determined by competition with a control molecule that mimics the epitope recognized on the target molecule. Specific binding is then indicated if binding of the antibody to the target molecule is competitively inhibited by the control molecule. In some embodiments, the affinity of the anti-IL-4Rα antibody for the non-target molecule is less than about 50% of its affinity for IL-4Rα. In some embodiments, the affinity of the anti-IL-4Rα antibody for the non-target molecule is less than about 40% of its affinity for IL-4Rα. In some embodiments, the affinity of the anti-IL-4Rα antibody for the non-target molecule is less than about 30% of its affinity for IL-4Rα. In some embodiments, the affinity of the anti-IL-4Rα antibody for the non-target molecule is less than about 20% of its affinity for IL-4Rα. In some embodiments, the affinity of the anti-IL-4Rα antibody for the non-target molecule is less than about 10% of its affinity for IL-4Rα. In some embodiments, the affinity of the anti-IL-4Rα antibody for the non-target molecule is less than about 1% of its affinity for IL-4Rα. In some embodiments, the affinity of the anti-IL-4Rα antibody for the non-target molecule is less than about 0.1% of its affinity for IL-4Rα.

[0340] As used herein in the context of two or more antibodies, the terms "compete with" or "cross-compete with" indicate that the two or more antibodies compete for binding to an antigen (e.g., IL-4Rα). In one exemplary assay, IL-4Rα is coated on a surface and contacted with a first anti-IL-4Rα antibody, followed by the addition of a second anti-IL-4Rα antibody. In another exemplary assay, the first anti-IL-4Rα antibody is coated on a surface and contacted with IL-4Rα, followed by the addition of a second anti-IL-4Rα antibody. In either assay, antibodies compete with each other if the presence of the first anti-IL-4Rα antibody reduces the binding of the second anti-IL-4Rα antibody. The term "compete with" also includes antibody combinations in which one antibody reduces the binding of another antibody, but no competition is observed when the antibodies are added in the reverse order. However, in some embodiments, the first and second antibodies inhibit each other's binding 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. One of skill in the art can select the concentration of antibody to use in a competition assay based on the affinity of the antibody for IL-4 and the valency of the antibody. The assays described in this definition are exemplary, and one of skill in the art can utilize any suitable assay to determine whether 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. (2001) Cytometry 44:30-37, and Finco et al. (2011) J. Pharm. Biomed. Anal. 54:351-358, each of which is incorporated by reference in its entirety.

[0341] A test antibody competes with a reference antibody if an excess of the test antibody (e.g., at least 2-fold, 5-fold, 10-fold, 20-fold, or 100-fold) inhibits or blocks binding of the reference antibody by, for example, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%, as measured in a competitive binding assay. Antibodies identified by a competitive assay (competing antibodies) include antibodies that bind to the same epitope as the reference antibody and antibodies that bind to an adjacent epitope sufficiently close that steric hindrance exists for binding of the reference antibody to the epitope. For example, a second competing antibody can be identified that competes with a first antibody described herein for binding to IL-4Rα. In certain cases, the second antibody can block or inhibit binding of the first antibody by, for example, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%, as measured in a competitive binding assay. In certain cases, the second antibody can replace the first antibody by more than 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%.

[0342] In certain embodiments, the antibody binds to the IL-4Rα sequence represented by SEQ ID NOs: 237-240.

[0343] In certain embodiments, the antibody binds to the IL-4Rα sequences set forth in SEQ ID NOs: 237-240 at a concentration of about 1, 2, 3, 4, 5, 6, 7, 8, 9 x 10 as measured by surface plasmon resonance (SPR). -9 K below M D In certain embodiments, the antibody binds to the IL-4Rα sequences represented by SEQ ID NOs: 237-240 at a binding affinity of about 1 x 10 as measured by surface plasmon resonance (SPR). -10 K below M D In certain embodiments, the antibody binds to human IL-4Rα at about 1×10 as measured by surface plasmon resonance (SPR). -9 K below M D Combine with.

[0344] In some embodiments, the antibodies provided herein bind to IL-4Rα with a concentration of 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 10×10, as measured by ELISA or any other suitable method known in the art. -8 K below M D In some embodiments, the antibodies provided herein bind to IL-4Rα at 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 10×10, as measured by ELISA or any other suitable method known in the art. -9 K below M D Combine with.

[0345] In some embodiments, the K of the antibodies provided herein for binding IL-4Rα D is 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 when measured by ELISA or any other suitable method known in the art. -8 In some embodiments, the antibodies provided herein bind to IL-4Rα at a concentration of about 1 x 10 M as measured by ELISA or any other suitable method known in the art.-8 M or less, or 1 x 10 -9 K below M D Combine with.

[0346] In some embodiments, the antibodies provided herein bind to IL-4Rα with a binding activity of 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, 1.0, 1.2, 1.4, 1.6, 1.8, 1.8, 1.9 ... 0.55, 1.50, 1.45, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.85, 0.8, 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, 0.05, 0.01, 0.005, 0.001, 0.0005, or 0.0001 x 10 -8 K below or equal to M D In some embodiments, the antibodies provided herein bind to IL-4Rα at 5 to 3, 4 to 2, 3 to 1, 1.9 to 1.8, 1.8 to 1.7, 1.7 to 1.6, 1.6 to 1.5, 1.9 to 1.5, 1.5 to 1, 1 to 0.8, 1 to 0.5, 0.9 to 0.6, 0.7 to 0.4, 0.6 to 0.2, 0.5 to 0.3, 0.3 to 0.2, 0.2 to 0.1, 0.1 to 0.01, 0.01 to 0.001, or 0.001 to 0.0001 x 10 -8 K of M D Combine with.

[0347] In some embodiments, the antibodies provided herein bind to FcRn with an affinity at pH 7.4 to 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 ratio (pH 7.4 / pH 6.0) as measured by ELISA or any other suitable method known in the art. In some embodiments, the antibodies provided herein bind to FcRn at a concentration 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, as measured by ELISA or any other suitable method known in the art. -8 The ratio of M (pH 6.0 / pH 7.4) binds with affinity at pH 6.0 relative to pH 7.4.

[0348] function "Effector function" refers to a biological activity mediated by the Fc region of an antibody, which activity may vary depending on the antibody isotype. Examples of antibody effector functions include blocking, activating, or antagonizing receptor ligands, C1q 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 effector function of the anti-IL-4Rα antibodies described herein is antagonism, blocking the binding of IL-4Rα to IL-4 and / or IL-13.

[0349] Pharmaceutical Composition The present application provides compositions comprising antibodies, including pharmaceutical compositions comprising any one or more of the antibodies described herein together with one or more pharmaceutically acceptable excipients. In some embodiments, the compositions are sterile. Pharmaceutical compositions generally comprise an effective amount of an antibody.

[0350] These compositions may contain, in addition to one or more of the antibodies disclosed herein, pharmaceutically acceptable excipients, carriers, buffers, stabilizers, or other materials known to those skilled in the art. Such materials should be non-toxic and should not interfere with the effectiveness of the active ingredient. The precise characteristics of the carrier or other materials may depend on the route of administration, e.g., oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, or intraperitoneal.

[0351] Pharmaceutical compositions for oral administration can be in the form of tablets, capsules, powders, or liquids. Tablets can contain solid carriers such as gelatin or adjuvants. Liquid pharmaceutical compositions generally contain liquid carriers such as water, petroleum, animal or vegetable oils, mineral oil, or synthetic oil. Physiological saline, dextrose, or other sugar solutions, or glycols such as ethylene glycol, propylene glycol, or polyethylene glycol can be included.

[0352] For intravenous, cutaneous or subcutaneous injection, or injection at the site of pain, the active ingredient is in the form of a parenterally acceptable aqueous solution that is pyrogen-free and has appropriate pH, isotonicity, and stability. Those skilled in the art are well able to prepare appropriate solutions using isotonic vehicles such as sodium chloride injection, Ringer's injection, lactated Ringer's injection, etc. Preservatives, stabilizers, buffers, antioxidants, and / or other additives may be included as necessary.

[0353] The anti-IL-4Rα antibody administered to an individual is preferably a "therapeutically effective amount" or a "prophylactically effective amount" sufficient to show benefit in the individual (although in some cases, prophylaxis may be considered treatment). The actual amount administered, as well as the rate and duration of administration, will depend on the nature and severity of the protein aggregation disorder being treated. Prescribing treatment, e.g., determining dosage, is within the responsibility of general practitioners and other physicians, and will usually take into account the disorder being treated, the condition of the individual patient, the site of delivery, the method of administration, and other factors known to practitioners. Examples of techniques and protocols for the above procedures can be found in Remington's Pharmaceutical Sciences, 16th edition, Osol, A. (ed), 1980.

[0354] The compositions may be administered alone or in combination with other treatments, either simultaneously or sequentially depending on the condition being treated.

[0355] method Preparation method The antibodies described herein may be produced using recombinant methods and compositions described, for example, in U.S. Patent No. 4,816,567. In one embodiment, an isolated nucleic acid encoding an antibody described herein is provided. Such a nucleic acid may encode an amino acid sequence comprising the VL and / or VH of the antibody (e.g., the light and / or heavy chain 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 multicistronic vector. In a further embodiment, a host cell comprising such a nucleic acid is provided. In one such embodiment, the host cell comprises (e.g., has been transformed with) (1) a vector comprising a nucleic acid encoding an amino acid sequence comprising the VL of the antibody and an amino acid sequence comprising the VH of an antigen-binding polypeptide construct, or (2) a first vector comprising a nucleic acid encoding an amino acid sequence comprising the VL of the antigen-binding polypeptide construct and a second vector comprising a nucleic acid encoding an amino acid sequence comprising the VH of the antigen-binding polypeptide construct. In one embodiment, the host cell is a eukaryotic cell, such as a Chinese hamster ovary (CHO) cell, or a human embryonic kidney (HEK) cell, or a lymphoid cell (e.g., a Y0, NS0, Sp20 cell). In one embodiment, a method of producing an antibody is provided, the method comprising culturing a host cell comprising nucleic acid encoding an antibody provided above under conditions suitable for expression of the antibody, and optionally recovering the antibody from the host cell (or host cell culture medium).

[0356] For recombinant production of an antibody, nucleic acid encoding the antibody, e.g., as described above, is isolated and inserted into one or more vectors for further cloning and / or expression in host cells. Such nucleic acid can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes capable of binding specifically to genes encoding the antibody heavy and light chains).

[0357] When an antibody or variant thereof is recombinantly produced by a host cell, in certain embodiments, the protein 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 an antibody or variant thereof is recombinantly produced by a host cell, in certain embodiments, the protein 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, a "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%, particularly at least about 75%, 80%, 85%, more particularly at least about 90%, at least about 95%, at least about 99% or greater, as determined by suitable methods such as SDS / PAGE analysis, RP-HPLC, SEC, and capillary electrophoresis.

[0358] Suitable host cells for cloning or expressing the antibody-encoding vectors include prokaryotic or eukaryotic cells described herein.

[0359] A recombinant host cell or host cell is a cell that contains an exogenous polynucleotide, regardless of the method used for insertion, such as direct uptake, transduction, f-mating, or other methods known in the art for generating recombinant host cells. The exogenous polynucleotide may be maintained as a non-integrated vector, such as a plasmid, or alternatively, may be integrated into the host genome. Host cells may include CHO, CHO derivatives, NS0, Sp20, CV-1, VERO-76, HeLa, HepG2, Per.C6, or BHK.

[0360] For example, antibodies may be produced in bacteria, particularly where glycosylation and Fc effector functions are not required. For expression of antibody fragments and polypeptides in bacteria, see, e.g., U.S. Patent Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Vol. 248 (BKC Lo, ed., Humana Press, Totowa, NJ, 2003), pp. 245-254, which describes the expression of antibody fragments in E. coli.) After expression, the antibody can be isolated from the bacterial cell paste in a soluble fraction and further purified.

[0361] In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for antibody-encoding vectors, including fungal and yeast strains whose glycosylation pathways have been "humanized," resulting in the production of antibodies with partial or fully human glycosylation patterns. See Gerngross (2004) Nat. Biotech. 22:1409-1414, and Li et al. (2006) Nat. Biotech. 24:210-215.

[0362] Suitable host cells for the expression of glycosylated antibodies are also derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant cells and insect cells. Numerous baculovirus strains have been identified that can be used with insect cells, particularly for transfection of Spodoptera frugiperda cells.

[0363] Plant cell cultures can also be used as hosts. See, e.g., U.S. Patent Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (which describe PLANTIBODIES™ technology for producing antibodies in transgenic plants).

[0364] Vertebrate cells can also be used as hosts. For example, mammalian cell lines adapted to grow in suspension can be useful. Other examples of useful mammalian host cell lines include SV40 (COS-7) transformed monkey kidney CV1 line, human embryonic kidney line (e.g., 293 or 293 cells described in Graham et al. (1977) J. Gen Virol. 36:59), baby hamster kidney cells (BHK), mouse Sertoli cells (e.g., TM4 cells described 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 hepatocytes (BRL 3A), human lung cells (W138), human hepatocytes (Hep G2), mouse mammary tumor (MMT060562), TRI cells (e.g., Mather et al. Annals NY Acad. Sci. 383:44-68 (1982)), MRC5 cells, and FS4 cells. Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR-CHO cells (Urlaub et al. (1980) Proc. Natl. Acad. Sci. USA 77:4216), 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 (BKC Lo, ed., Humana Press, Totowa, NJ), pp. 255-268 (2003).

[0365] 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 nucleic acids encoding the antibody in a predetermined ratio and expressing the nucleic acids in the at least one mammalian cell. In some embodiments, the predetermined ratio of nucleic acids is determined in transient transfection experiments to determine the relative ratio of input nucleic acids that results in the highest percentage of antibody in the expression product.

[0366] In some embodiments, the methods of producing antibodies in stable mammalian cells described herein, wherein the expression product of at least one stable mammalian cell comprises a high percentage of the desired glycosylated antibody, or other antibody, relative to the monomeric heavy or light chain polypeptides.

[0367] In some embodiments, methods for producing glycosylated antibodies in stable mammalian cells as described herein include identifying and purifying a desired glycosylated antibody, in some embodiments, by one or both of liquid chromatography and mass spectrometry.

[0368] If necessary, antibodies can be purified or isolated after expression. Proteins can be isolated or purified by a variety of methods known to those skilled in the art. Standard purification methods include chromatographic techniques, including ion exchange, hydrophobic interaction, affinity, size exclusion, or gel filtration, as well as reversed-phase chromatography performed at atmospheric or elevated pressure using systems such as FPLC and HPLC. Purification methods also include electrophoretic, immunological, precipitation, dialysis, and chromatofocusing techniques. Ultrafiltration and diafiltration techniques combined with protein concentration are also useful. As is well known in the art, various natural proteins bind to Fc and antibodies, and these proteins may find use in the present invention in purifying antibodies. For example, bacterial proteins A and G bind to the Fc region. Similarly, bacterial protein L binds to the Fab region of some antibodies. Purification can often be enabled by specific fusion partners. For example, antibodies can be purified using glutathione resins when GST fusions are used, or Ni when His tags are used. +2 It can be purified using affinity chromatography, or if a flag tag is used, using immobilized anti-flag antibodies. For general guidance on suitable purification techniques, see, for example, Protein Purification: Principles and Practice, 3rd Ed., Scopes, Springer-Verlag, NY, 1994 (incorporated by reference in its entirety). The degree of purification required varies depending on the use of the antibody. In some cases, no purification is necessary.

[0369] In certain embodiments, 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.

[0370] In certain 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 derivatives.

[0371] Furthermore, the antibodies described herein can be chemically synthesized using techniques known in the art (see, e.g., Creighton, 1983, Proteins: Structures and Molecular Principles, W.H. Freeman & Co., NY, and Hunkapiller et al. (1984) Nature, 310:105-111). For example, a polypeptide corresponding to a fragment of a polypeptide can be synthesized using a peptide synthesizer. Furthermore, if desired, non-classical amino acids or chemical amino acid analogs can be introduced as a substitution or addition into the polypeptide sequence. Non-classical amino acids generally include, but are not limited to, D-isomers of common amino acids, such as 2,4-diaminobutyric acid, alpha-aminoisobutyric acid, 4-aminobutyric acid, Abu, 2-aminobutyric acid, g-Abu, e-Ahx, 6-aminohexanoic acid, Aib, 2-aminoisobutyric acid, 3-aminopropionic acid, ornithine, norleucine, norvaline, hydroxyproline, sarcosine, citrulline, homocitrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, alanine, fluoroamino acids, engineered amino acids such as methylamino acids, C-methyl amino acids, N-methyl amino acids, and amino acid analogs. Additionally, amino acids can be D (dextrorotatory) or L (levorotatory).

[0372] How to use In one aspect, the present application provides a method of contacting IL-4Rα with an anti-IL-4Rα antibody, such as a human or humanized antibody, which results in inhibition of binding of IL-4 to IL-4 receptor alpha expressed on a cell.

[0373] In certain aspects, the present application provides methods of using an isolated anti-IL-4Rα antibody described herein for treating a disorder or disease in a subject. In certain aspects, the present application describes methods of treating a subject in need of treatment with an anti-IL-4Rα antibody, the method comprising administering to the mammalian subject a therapeutically effective amount of an anti-IL-4Rα antibody described herein or a pharmaceutical composition comprising an anti-IL-4Rα antibody. In certain embodiments, the present application provides methods of treating a disorder or disease associated with elevated levels of IL-4 and / or IgE in a subject.

[0374] In certain aspects, described herein are methods for treating a condition associated with IL-4, IL-13 and / or IL-4Rα activity, the methods comprising administering to a mammalian subject a therapeutically effective amount of an isolated anti-IL-4Rα antibody or a pharmaceutical composition comprising an isolated anti-IL-4Rα antibody described herein.

[0375] In certain aspects, the antibodies and antibody fragments disclosed herein are useful for treating diseases and disorders that are ameliorated, inhibited, or alleviated by reducing the activity of IL-4, IL-13, and / or IL-4Rα. These disorders include those characterized by aberrant or overexpression of IL-4 and / or IL-13, or an abnormal host response to IL-4 and / or IL-13 production. IL-4- and IL-13-related disorders that can be treated by the antibodies or antibody fragments of the present disclosure include inflammatory disorders or diseases. Non-limiting examples of disorders that may be treated by the antibodies or antibody fragments of the disclosure include atopic dermatitis (AD), asthma (mild, moderate, or severe), chronic rhinosinusitis with nasal polyps, chronic rhinosinusitis without nasal polyps (CRSsNP), eosinophilic gastrointestinal disorder or disease (ENID) selected from the group consisting of eosinophilic esophagitis (EoE), eosinophilic gastritis (EoG), eosinophilic enteritis (EoN), eosinophilic colitis (EoC), and eosinophilic gastroenteritis (EGE), Chugoku kappa (CHK) syndrome. These include Strauss syndrome / eosinophilic granulomatosis with polyangiitis (EGPA), prurigo nodularis (PN), chronic subitum urticaria (CSU), chronic cryptogenic pruritus (CPUO), bullous pemphigoid (BP), cold-induced urticaria (ColdU), allergic fungal rhinosinusitis (AFRS), allergic bronchopulmonary aspergillosis (ABPA), chronic obstructive pulmonary disease (COPD), inflammatory bowel diseases such as Crohn's disease or ulcerative colitis, lupus, and rheumatoid arthritis.

[0376] In certain aspects, described herein are methods of 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 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.

[0377] In certain aspects, described herein are methods for treating a condition associated with elevated levels of IL-4 and / or IL-13 in a mammalian subject in need thereof, the methods comprising administering to the mammalian subject a therapeutically effective amount of an antibody or pharmaceutical composition described herein.

[0378] In certain aspects, described herein are methods for reducing the biological activity of IL-4, IL13 and / or IL-4Rα in a mammalian subject in need thereof, the methods comprising administering to the mammalian subject a therapeutically effective amount of an antibody or pharmaceutical composition described herein.

[0379] In certain aspects, described herein are methods for 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 pharmaceutical composition described herein.

[0380] Administration method In some embodiments, the methods provided herein are useful for treating a disease or disorder in an individual. In one embodiment, the individual is a human and the antibody is an anti-IL-4Rα antibody described herein.

[0381] In some embodiments, the antibody is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intracerebroventricularly, or intranasally. An effective amount of an anti-IL-4Rα antibody can be administered to treat a disease or disorder. The appropriate dosage of an anti-IL-4Rα antibody can be determined based on the type of disease or disorder being treated, the type of anti-IL-4Rα antibody, the severity and course of the disease or disorder, the individual's clinical condition, the individual's clinical history and response to treatment, and the discretion of the attending physician.

[0382] In certain embodiments, the anti-IL-4Rα antibody is administered every six weeks or every two months.

[0383] In some embodiments, the antibodies provided herein are administered with at least one additional therapeutic agent. Any suitable additional therapeutic or immunotherapeutic agent may be administered with the antibodies provided herein. Additional therapeutic agents include, but are not limited to, agents used to treat or prevent diseases or disorders, such as inflammatory diseases or disorders associated with elevated levels of IL-4, IL-13, and / or IgE.

[0384] The additional therapeutic agent can be administered by any suitable means. In some embodiments, an antibody provided herein and the additional therapeutic agent are comprised in the same pharmaceutical composition. In some embodiments, an antibody provided herein and the additional therapeutic agent are comprised in different pharmaceutical compositions.

[0385] In embodiments in which an antibody provided herein and an additional therapeutic agent are included in different pharmaceutical compositions, administration of the antibody can occur prior to, simultaneously with, and / or after administration of the additional therapeutic agent. In some embodiments, administration of an antibody provided herein and an additional therapeutic agent occurs within about one month of each other. In some embodiments, administration of an antibody provided herein and an additional therapeutic agent occurs within about one week of each other. In some embodiments, administration of an antibody provided herein and an additional therapeutic agent occurs within about one day of each other. In some embodiments, administration of an antibody provided herein and an additional therapeutic agent occurs within about 12 hours of each other. In some embodiments, administration of an antibody provided herein and an additional therapeutic agent occurs within about one hour of each other.

[0386] Kits and Products The present application provides kits comprising any one or more of the antibody compositions described herein and instructions for use. In some embodiments, the kit further comprises a component selected from a secondary antibody, an immunohistochemistry reagent, a pharmaceutically acceptable excipient, a package insert, and instructions, and any combination thereof. In a specific embodiment, the kit comprises a pharmaceutical composition comprising any one or more of the antibody compositions described herein together with one or more pharmaceutically acceptable excipients.

[0387] The present application provides an article of manufacture comprising any one of the antibody compositions described herein, or a kit. An example of an article of manufacture is a vial (including a sealed vial). [Example]

[0388] Below are examples of specific embodiments for carrying out the present invention. The examples are presented 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.

[0389] The practice of the present invention will employ, unless otherwise indicated, conventional methods of protein chemistry, biochemistry, recombinant DNA technology, and pharmacology, which are within the skill of one of ordinary skill in the art. Such techniques are explained fully in the literature, 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, et al., Molecular Cloning: A Laboratory Manual (2nd Edition, 1989); Methods In Enzymology (S. Colowick and N. Kaplan eds., Academic Press, Inc.); Remington's Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990); Carey and Sundberg Advanced Organic Chemistry 3 rd Ed. (Plenum Press) Vols A and B (1992).

[0390] method Gene synthesis and plasmid construction The coding sequences for the antibody HC and LC were generated by DNA synthesis and PCR, and then subcloned into pTT5-based plasmids for protein expression in mammalian cell lines. The gene sequences of the expression vectors were confirmed by DNA sequencing.

[0391] Purification of antibody constructs Protein purification by affinity chromatography and ion exchange chromatography was performed using an AKTA Pure instrument (GE Lifesciences). Conditioned medium expressing the target antibody was collected by centrifugation at 4000 rpm for 50 minutes and filtered through a 0.22 μm filter. The collected supernatant was loaded onto a Mabselect™ SuRe™ (GE Healthcare) column. 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.

[0392] Measurement of antibody-IL-4 binding kinetics using surface plasmon resonance Binding kinetics and affinity constants were determined in a running buffer of HBS-EP+ (10 mM HEPES pH 7.4, 150 mM NaCl, 3 mM EDTA, 0.05% surfactant P20) at 25° C. using a BIACORE® 8K SPR system (GE HealthCare) equipped with a Series S sensor chip Protein G (Cytiva, catalog 29179315). Following a stabilization period in the running buffer, anti-IL13 mAb constructs (diluted to 1 μg / mL) were captured on flow cell 2 (active) for 60 seconds at a flow rate of 10 μL / min. Recombinant human IL-4 protein, His tag (Acro catalog IL3-H52H4) was prepared at concentrations of 0, 0.39, 0.78, 1.56, 3.13, 6.25, 12.5, and 0 nM and injected for 180 seconds at a flow rate of 30 μL / min over flow cell 1 (reference) and flow cell 2 (active). Recombinant cynomolgus monkey IL-4 protein, His tag (SINO BIOLOGICAL, catalog 11057-C07H) was prepared at concentrations of 0, 0.39, 0.78, 1.56, 3.13, 6.25, 12.5, 25, and 0 nM and injected for 180 seconds at a flow rate of 30 μL / min over flow cell 1 (reference) and flow cell 2 (active). Samples were injected over the newly captured mAb in multiple cycles by injecting glycine, pH 1.5, for 30 seconds at a flow rate of 30 μL / min to regenerate the capture surface. Data were processed and analyzed using BIACORE® Insight Evaluation Software version 2.0.15.12933 (GE Healthcare) as follows: The response from flow cell 1 (reference) was subtracted from the response from flow cell 2 (active). The responses from two buffer blank injections were then subtracted from the reference-subtracted data (2-1) to obtain double-referenced data, which were fitted to a 1:1 binding model to determine the apparent association rate constant (ka) and dissociation rate constant (kd). Their ratio gave the apparent equilibrium dissociation constant or affinity constant (KD = kd / ka).

[0393] Example 1: Affinity maturation of anti-IL-4Rα antibodies Dupilumab was used as a parent antibody for further CDR diversification to identify clones with improved potency, manufacturability, and pharmacokinetics.

[0394] To diversify the CDRs while maintaining at least dupilumab's potency, we introduced various mutations into all CDRs of both the heavy and light chains. Using site-directed PCR mutagenesis, we generated separate libraries for each CDR in both the heavy and light chains, resulting in six unique libraries with an average of two to three amino acid substitutions per chain. Individual mutants were displayed as Fabs using a phage display system, and within each library, mutants were panned through two rounds of selection. The first round of selection consisted of biotinylated 1 nM hIL-4Rα, and the output of that round was then divided into four different secondary rounds of parallel selection consisting of A) biotinylated 1 nM hIL-4Rα in buffer containing 100 nM unlabeled hIL-4Rα for 4 hours at room temperature with washing, B) biotinylated 0.1 nM hIL-4Rα in buffer containing 10 nM unlabeled hIL-4Rα for 4 hours at room temperature with washing, C) biotinylated 50 nM cyIL-4Rα without washing, and D) biotinylated 5 nM cyIL-4Rα without washing.

[0395] Mutant clones from the output of each arm of the secondary selection were analyzed using surface plasmon resonance (SPR) assays using periplasmic extracts of each mutant clone and compared to dupilumab to evaluate k as a surrogate measure of binding affinity. off The CDRs were analyzed and bioinformatics analysis of the sequences identified patterns of enrichment. Mutants that showed no loss or improved binding relative to dupilumab and showed population enrichment throughout selection were combined into a single library containing all variants of both the heavy and light chains. Fabs containing random combinatorial mixes of these individual CDR variants were rescreened in a phage display system using multiple combinations of the selection strategies outlined in Table 5. [Table 5]

[0396] Example 2: Determination of antibody affinity to IL-4Rα The binding affinities (KD) of antibodies to human and cynomolgus IL-4Rα were determined by surface plasmon resonance (SPR) using a Carterra LSA. Briefly, an HC30M sensor chip pre-functionalized with a polyclonal mixture of goat anti-human Fc antibodies was used to capture purified antibodies at levels of 100-1000 RLU. Antigen concentrations ranging from 200 nM to 0.13 nM were then injected over the surface at a rate of 2 mL / min. The chip was regenerated between different concentrations of antigen using 200 mM phosphoric acid, and the antibodies were recaptured as described above. The KD was then measured. D The association and dissociation rate constants were determined by fitting to a 1:1 Langmuir binding model using Kinetics Software from Carterra, from which values ​​were derived. The results are summarized in Table 6.

[0397] The majority of antibodies bind to human IL-4Rα with low picomolar affinity comparable to dupilumab. Additionally, several antibodies showed improved cross-reactivity to cynomolgus IL-4Rα, some with low nanomolar affinity. [Table 6-1] [Table 6-2] [Table 6-3]

[0398] Example 3: Improvement of antibody affinity for FcRn at pH 6.0 Binding affinity (K ) of antibodies to human and cynomolgus monkey FcRn at pH 6.0 D ) is a reliable correlate of in vivo half-life. K DThe affinity of the antibody is determined by surface plasmon resonance (SPR) using a BIACORE® 8K. Briefly, purified antibody normalized to 0.5 mg / mL is captured for 60 seconds at a flow rate of 10 μL / min using a protein G-functionalized SPR chip. A paired channel containing buffer alone is used as a reference. Human or cynomolgus FcRn at concentrations ranging from 25 nM to 0.39 nM is then injected over the surface with the captured purified antibody and into the reference channel. The chip is regenerated between different concentrations of IL-13 using 10 mM glycine HCl, pH 1.5, and the antibody is recaptured as described above. The affinity measurements described are performed at both pH 7.4 and pH 6.0. The K is then measured. D Association and dissociation rate constants were determined by fitting to a 1:1 Langmuir binding model using BIACORE® Insight Evaluation Software, from which values ​​were derived. This predicted that all improved antibodies would exhibit improved binding to FcRn at pH 6.0 compared to dupilumab, a strong indication that such antibodies would have extended half-lives in vivo. This was further confirmed in pharmacokinetic studies in cynomolgus monkeys.

[0399] Example 4: Inhibition of IL-13 and IL-4 binding to hIL-13Rα / hIL-4Rα Binding of IL-13 and IL-4 to cells overexpressing hIL-13Ra / hIL-4Rα was used to assess the functional blocking of this binding interaction by antibodies. Briefly, HEK293 cells previously transduced to stably express both hIL-13Rα and hIL-4Rα were cultured and harvested. Cells were seeded at 200,000 cells per well in 100 μL. The cells were washed and the supernatant discarded. Cells were resuspended in 100 μL of a 1:1 mixture of biotinylated hIL-13 or biotinylated hIL-4 and purified antibody, which had been previously incubated for 1 hour, to yield final concentrations of 0.05 μg / mL hIL-13 or 0.04 μg / mL hIL-4 and 0–100 nM purified antibody. Cells were stained in this mixture for 1 hour at 4°C. The cells were then washed and stained with 100 μL of Alexa Fluor 488-conjugated streptavidin at a 1:1000 dilution to detect binding of biotinylated hIL-13 or biotinylated hIL-4 on the cell surface. The cells were incubated at 4°C for 1 hour, protected from light. The cells were then washed, and the MFI of cells in each well was recorded by FACS using a BD FACSCanto II. The data was then analyzed using GraphPad Prism. IC50 values ​​were determined as the concentration of antibody required to inhibit 50% of the maximal MFI of biotinylated hIL-13 or biotinylated hIL-4 surface detected by incubation with 0.05 μg / mL hIL-13 alone or 0.04 μg / mL hIL-4 alone. The results are summarized in Table 7, Table 8, Figure 1A, and Figure 1B. [Table 7-1] [Table 7-2] [Table 7-3] All values ​​are relative to dupilumab; <1.000 is more potent.

[0400] Certain constructs shown in Table 8 were modified to replace the IgG4 YTE heavy chain constant region with the IgG1 YTE LALA heavy chain constant region (SEQ ID NO: 321). These antibodies were tested for their ability to inhibit IL-13 and IL-4 binding to hIL-13Rα / hIL-4Rα in comparison to dupilumab. The results are summarized in Table 8. Values ​​are absolute IC 50 Reflects the measured values. [Table 8]

[0401] Example 5: Inhibition of IL-13- and IL-4-induced phosphorylation of STAT6 in HT-29 cells Inhibition of STAT6 phosphorylation in HT-29 cells was used to assess the functional activity of antibodies blocking IL-13- and IL-4-induced biological activity. Briefly, HT-29 cells were starved overnight in RMPI1640 + 0.1% FBS. Cells were harvested and seeded at 50,000 cells per well in 100 μL. Simultaneously, 100 μL of a mixture of hIL-13 or hIL-4 with purified antibody (1:1 volume ratio) was added to the same well, resulting in final concentrations of 10 ng / mL hIL-13 or 5 ng / mL hIL-4 and 0–50 nM purified antibody. Cells were incubated at 37°C for 1 hour, followed by fixation, permeabilization, and staining with PE-conjugated anti-pSTAT6 antibody. The MFI of cells in each well was recorded by FACS using a BD FACSCanto II, and the data were subsequently analyzed using GraphPad Prism. IC50 values ​​were determined as the concentration of antibody required to inhibit 50% of the maximal MFI of pSTAT6 detected by incubation with 10 ng / mL hIL-13 alone or 5 ng / mL hIL-4 alone. The results are summarized in Table 9, Table 10, Figures 2A and 2B.

[0402] As shown in Table 9, clones were identified that showed up to approximately two-fold more effective inhibition of IL-13 and / or IL-4-induced phosphorylation of STAT6 compared to dupilumab (e.g., Construct 15, Construct 18, Construct 21, Construct 23, Construct 24, Construct 27, and Construct 28). [Table 9-1] [Table 9-2] [Table 9-3]

[0403] The constructs shown in Table 10 were modified to replace the IgG4 YTE heavy chain constant region with the IgG1 YTE LALA constant region (SEQ ID NO: 321). These constructs were tested for their ability to inhibit IL-13 and / or IL-4 induced phosphorylation of STAT6 in comparison to dupilumab. The results are summarized in Table 10. Values ​​are absolute IC 50 Reflects the measured values. [Table 10]

[0404] Example 6: Inhibition of IL-13- and IL-4-induced TARC release from A549 cells Inhibition of TARC secretion by A549 cells was used to assess the functional activity of antibodies blocking IL-13- and IL-4-induced biological activity. Briefly, A549 cells were seeded at 20,000 cells / well in 100 μL of DMEM + 10% FBS and cultured overnight at 37°C. The next day, the cell culture medium was discarded, and the cells were gently washed with fresh medium. A 150 μL mixture of hIL-13, purified antibody, and hTNFα (volume ratio 1:1:1) was added to each well to obtain final concentrations of 20 ng / mL hIL-13, 0–100 nM purified antibody, and 200 ng / mL hTNFα or 1.5 ng / mL hIL-4, 0–100 nM purified antibody, and 50 ng / mL TNFα. Cells were incubated in this mixture for 20–24 hours at 37°C. After incubation, culture supernatants were collected and the amount of TARC present was analyzed using a commercially available TARC ELISA kit (R&D Systems). The analysis was performed according to the manufacturer's instructions. The determined TARC concentration in each well was analyzed using GraphPad Prism. IC50 values ​​were determined as the concentration of antibody required to inhibit 50% of the maximal TARC concentration detected in the incubation of 20 ng / mL hIL-13 and 200 ng / mL hTNFα alone, or 1.5 ng / mL hIL4 and 50 ng / mL hTNFα alone. The results are summarized in Table 11, Table 12, Figures 3A and 3B.

[0405] As shown in Table 11, clones were identified that showed up to approximately 3-fold (e.g., construct 2 and construct 15) more effective inhibition of IL-13 and / or IL-4-induced TARC compared to dupilumab. [Table 11-1] [Table 11-2]

[0406] The constructs shown in Table 12 were modified to replace the IgG4 YTE heavy chain constant region with the IgG1 YTE LALA heavy chain constant region (SEQ ID NO: 321). These constructs were tested for their ability to inhibit IL-13 and / or IL-4 induced TARC in comparison to dupilumab. The results are summarized in Table 12. Values ​​are absolute IC 50 Reflects the measured values. [Table 12]

[0407] Example 7: Inhibition of IL-13- and IL-4-induced proliferation of TF-1 cells TF-1 cell proliferation or its inhibition was used to assess the functional activity of antibodies blocking IL-13- and IL-4-induced biological activity. Briefly, TF-1 cells were harvested and starved for 4 hours in RPMI 1640 + 10% FBS without additional cytokines. During this time, a mixture of hIL-13 or hIL-4 and purified antibody (1:1 volume ratio) was prepared and added to each well at 50 μL. After starvation, TF-1 cells were harvested again and seeded at 15,000 cells per well in 50 μL, resulting in a final concentration of 4 ng / mL hIL-13 or 0.5 ng / mL hIL-4 and 0–5 nM purified antibody. Cells were then incubated at 37°C for 72 hours, and cell proliferation was quantified using CellTiter-Glo (Promega) according to the manufacturer's instructions. Luminescence was recorded using a SpectraMax M5 multimode plate reader, and data were analyzed using GraphPad Prism. IC50 values ​​were determined as the concentration of antibody required to obtain 50% of the maximum luminescence detected when TF-1 cells were incubated with 4 ng / mL hIL-13 alone or 0.5 ng / mL hIL-4 alone. The results are summarized in Table 13, Table 14, Figures 4A and 4B. [Table 13-1] [Table 13-2]

[0408] The constructs shown in Table 14 were modified to replace the IgG4 YTE heavy chain constant region with the IgG1 YTE LALA heavy chain constant region (SEQ ID NO: 321). These constructs were tested for their ability to inhibit IL-13-induced TF-1 proliferation in comparison to dupilumab. The results are summarized in Table 14. Values ​​are absolute IC 50 Reflects the measured values. [Table 14]

[0409] Example 8: Improving the developability of anti-IL-4Rα antibodies The manufacturing and clinical performance of antibodies are often improved by improving the biophysical properties of the antibody itself. To assess some of these characteristics, purified antibodies were analyzed for their hydrophobicity and nonspecificity. Briefly, for hydrophobicity, 10 μg of purified antibody was injected onto a hydrophobic interaction chromatography (HIC) butyl 1.7 μm column in a mobile phase of sodium phosphate to capture the antibody on the column, followed by elution of the antibody with ammonium sulfate. The retention time of the antibody was used as a measure directly proportional to hydrophobicity. That is, a shorter retention time indicates a less hydrophobic antibody.

[0410] Nonspecificity was assessed using ELISA. Briefly, ELISA plates were coated with a 0.15% baculovirus particle (BVP) suspension and incubated overnight at 4°C. Plates were blocked with 1% BSA for 2 hours at 37°C. 200 nM purified antibody was added and incubated for 1 hour at 37°C. Binding of purified antibodies was detected using an HRP-conjugated goat anti-human IgG Fc antibody and incubated for 0.5 hours at 37°C. Between all steps, plates were washed multiple times with PBS-T. Plates were developed over a 15-minute course using the substrate TMB, and the reaction was stopped by the addition of 1N HCl. Absorbance at 450 nm was recorded using a SpectraMax Plus 384 multiplate reader, and data were analyzed using GraphPad Prism. The absorbance at 450 nm for each antibody was used as a measure directly proportional to nonspecificity; i.e., lower absorbance indicates an antibody expected to have lower nonspecific binding. The results are summarized in Table 15.

[0411] As shown in Table 15 below, nearly all of the antibodies exhibit lower HIC and BVP scores than dupilumab. [Table 15-1] [Table 15-2]

[0412] Example 9: Improvement of solubility and viscosity of anti-IL-4Rα antibody Purified antibodies are analyzed for their maximum solubility and corresponding viscosity. Briefly, for maximum solubility, purified antibodies are formulated and concentrated in 20 mM histidine, 4% sucrose, 0.04% PS80, and buffers of pH X, Y, and Z. The antibody concentration at this point is assessed and determined to be the maximum solubility of the antibody at that pH. The viscosity of the antibody at that concentration and pH is then determined. Some antibodies show improved solubility of over 150 mg / mL and higher viscosity compared to dupilumab, which allows these antibodies to deliver a larger dose per administration, thereby reducing the frequency of injections to patients.

[0413] Example 10. Determination of antibody affinity for IL-4Rα The binding affinity (KD) of exemplary antibodies for human IL-4Rα was determined using the Kinetic Exclusion Assay (KD). Briefly, the antibody and recombinant human IL-4Rα were equilibrated in solution. Sample equilibration was performed using a titration of recombinant human IL-4Rα, yielding a total set of 11-13 concentrations of antibody at fixed concentrations ranging from 2.27 pM to 100 pM for each antibody, and 2-fold dilutions from starting concentrations ranging from 9.78 pM to 1.00 nM. Samples were incubated for periods ranging from 3.5 h to 340 h until complete equilibrium was reached. Once the samples reached equilibrium, any free antibody was captured from the equilibrated solution using azlactone beads previously coated with recombinant human IL-4Rα. The captured antibody was then detected with Alexa Fluor 647-labeled goat anti-human IgG. A KinExA 4000 instrument was used to capture the fluorescent signal and convert it into a voltage signal that was directly proportional to the amount of free antibody in all equilibrated samples, allowing the apparent affinity of the antibody to be determined. The results are summarized in Table 16. [Table 16]

[0414] Most of the exemplary antibodies bind to human IL-4Rα with femtomolar affinity, compared to dupilumab, which binds with low picomolar affinity.

[0415] Example 11. Pharmacokinetic analysis of anti-IL-4Rα antibody An in vivo pharmacokinetic (PK) study was conducted to evaluate the antibody half-life extension for dupilumab. Cynomolgus monkeys (Macaca fascicularis) were used in the study. The matched SQ / IV cohorts were all male and ranged in weight from 2.52 to 3.86 kg. Animals were administered dupilumab, exemplary antibody construct 13 (mAb422), or exemplary antibody construct 38 (mAb471) by intravenous (IV) bolus or subcutaneous (SQ) injection at doses of 1, 5, or 25 mg / kg on day 0, as shown in Table 17. The IgG4 YTE constant heavy chain region of construct 13 and construct 38 was replaced with the IgG1 YTE LALA constant region (SEQ ID NO: 321). Serum samples were collected periodically throughout the study. [Table 17] PK parameters were determined from cynomolgus monkey serum samples through Day 91. PK analysis demonstrated that the half-lives of Construct 13 and Construct 38 were 17.62 and 25.60 days, respectively, compared to 10.88 days for dupilumab (25 mg / kg IV). The results are summarized in Table 17. PK analysis demonstrated that the exemplary antibodies, Construct 13 (mAb422) and Construct 38 (mAb471), had improved half-lives compared to that of dupilumab across different routes of administration (Table 17, Figures 5A and 5B). The half-life of Construct 38 when dosed at 5 and 1 mg / kg IV remained superior to dupilumab when dosed at 25 mg / kg IV. The extended half-life of the exemplary antibodies may allow for less frequent dosing compared to currently available treatment protocols, reducing injection burden and improving compliance for patients living with COPD and other diseases.

[0416] When bioavailability (F) is determined, the antibodies disclosed herein are shown to have bioavailability comparable to dupilumab. Results for exemplary antibodies and dupilumab are summarized in Table 18. Construct 38 (mAb471) demonstrated bioavailability comparable to dupilumab. [Table 18]

[0417] Example 12. Binning experiment using (dupilumab) anti-IL-4Rα antibody Epitope binning is a technique used to cluster different mAbs based on the specific region of the antigen recognized by the antibody (in this case, IL-4Rα). In binning studies with immobilized dupilumab, no response was observed for constructs mAb410, mAb411, mAb412, mAb413, mAb414, mAb415, mAb416, mAb417, mAb418, mAb419, mAb420, mAb421, mAb422, mAb422B, mAb423, mAb424, mAb425, mAb426, mAb427, mAb428, mAb429, mAb431, mAb432, mAb433, mAb434, mAb435, mAb436, mAb437, mAb439, mAb443, mAb450, mAb470, mAb471, and mAb476. This indicates that the listed mAbs and dupilumab are binned together, providing evidence that the mAbs likely bind to similar or the same epitopes on IL-4Rα and therefore likely have the same biological effect.

[0418] Example 13. Estimation of half-life The half-life of an antibody is a product of degradation or excretion by three pathways: pinocytosis, target-mediated drug disposition (TMDD), and receptor-mediated endocytosis.

[0419] Pinocytosis: Pinocytosis is a nonspecific process by which extracellular fluids and materials are taken up into cells, resulting in internalized vesicles that then fuse with lysosomes. All antibodies are subject to this excretory pathway.

[0420] TMDD: This is a receptor-mediated endocytosis process, meaning that the interaction of an antibody with its receptor leads to the internalization of the antibody-receptor complex and its subsequent degradation via lysosomes, specialized organelles, or areas within the cell that degrade molecules and other biocompatible materials. TMDD is commonly observed with mAbs that have receptor targets, such as dupilumab, which targets IL-4Rα.

[0421] Receptor-mediated endocytosis: Binding of antibodies to Fc-gamma receptors present on many immune cells can also trigger a clearance process similar to that seen in TMDD. However, independent preclinical studies have demonstrated that this degradation pathway, if it plays a role at all, is not the primary pathway for antibody elimination.

[0422] To estimate the half-life of the disclosed antibodies binned with dupilumab, the VL and VH domains of dupilumab were combined with the IgG1-YTE constant region ("IL-4Rα tool compound") and the half-life in non-human primates (NHPs) was determined. The IL-4Rα tool compound incorporating the YTE amino acid substitutions exhibited a half-life of 18.5 days compared to 10.5 days for dupilumab, a 76% increase. Therefore, the improved half-life of the IL-4Rα tool compound suggests that the antibodies disclosed herein offer significantly improved dosing compared to prior art antibodies (e.g., dupilumab).

[0423] As noted above, antibody recycling due to increased affinity for FcRn affects degradation via pinocytosis but not excretion via target-mediated pharmacokinetics (TMDD). Therefore, the increased half-life provided by the YTE mutation in antibodies with membrane-bound targets was used in the following analysis.

[0424] As an example, CDX-0159 is an antibody targeting the KIT (c-KIT / CD117) receptor tyrosine kinase with a YTE amino acid substitution for half-life extension currently in clinical development. In NHPs, CDX-0159 demonstrated a half-life of 22 days compared with 4.8 days for CDX-0158, a non-half-life-extended antibody directed against the same target. Clinically, CDX-0159 demonstrated a half-life of 32 days, suggesting an approximately 1.5-fold increase over the NHP data. Furthermore, CDX-0159 demonstrated a human half-life approximately five times longer than that of CDX-0158, a non-half-life-extended antibody directed against the same target (32 days for CDX-0159 compared with 6 days for CDX-0158).

[0425] As another example, VRDN-002 is an IGF-1 receptor-targeting antibody currently in clinical development with a recirculating Fc modification (i.e., YTE or LS or similar amino acid substitution) to extend its half-life. In NHPs, VRDN-002 demonstrated a half-life of 14 days compared to 6.4 days for teprotumumab, a non-half-life-extended antibody directed against the same target. Clinically, VRDN-002 demonstrated a half-life of approximately 30–40 days in interim analyses, suggesting a roughly 2–3-fold increase over the NHP data. Furthermore, VRDN-002 demonstrated a human half-life approximately 3–4 times longer than that of teprotumumab, a non-half-life-extended antibody directed against the same target (approximately 30–40 days for VRDN-002 compared to approximately 10–11 days for teprotumumab).

[0426] Based on these studies (and depending on the approach taken), it is expected that the human half-life of the antibodies disclosed herein may be approximately 30-60 days, based on a 1.5-3 fold increase in the transition from NHP to human, i.e., approximately 45 to 70 days, and a 3-5 fold increase in the transition from a non-half-life extended antibody to a half-life extended antibody directed against the same receptor target.

[0427] To further estimate the half-lives of the antibodies disclosed herein, a two-compartment model with first-order absorption and parallel linear and Michaelis-Menten elimination (the latter corresponding to the TMDD effect associated with targeting membrane-bound IL4Ra) was constructed to predict the concentration (drug level) over time for both dupilumab and the antibodies disclosed herein. Parameters included 0.0447 day for elimination rate (ke), 2.74 L for core volume (Vc), 0.306 day for absorption rate (ka), and 64.2% for bioavailability.

[0428] Efficacy in inflammatory conditions such as COPD is トラフ , or the minimum concentration of the mAb. Therefore, based on the above model, the C トラフ The C of dupilumab when maintained at 300 mg SC every 2 weeks was approximately 75 mg / L. トラフ Given the overlapping epitopes between dupilumab and the antibodies disclosed herein that are binned with dupilumab, and the similarity in their respective potencies across multiple in vitro assays, it is possible to predict the exposure required for potential clinical activity of the antibodies disclosed herein. The K was targeted to be equal to 100 mg / L to maintain antibody concentrations above approximately 75 mg / L. 消失 and half-life modeling, a maintenance dose of the antibodies disclosed herein every six weeks would require a half-life of at least 42 days, and a maintenance dose of the antibodies disclosed herein every two months would require a half-life of at least 59 days.

[0429] Thus, it is contemplated that the antibodies disclosed herein can be administered every six weeks if they exhibit a half-life of at least 42 days, or every two months if they exhibit a half-life of at least 59 days.

[0430] Incorporation by Reference The entire disclosure of each of the patents and scientific articles referenced herein is incorporated by reference for all purposes.

[0431] equivalent The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. Accordingly, the foregoing embodiments are to be considered in all respects as illustrative and not limiting of the invention described herein. The scope of the invention is, therefore, 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. [Table 19-1] [Table 19-2] [Table 19-3] [Table 19-4] [Table 19-5] [Table 19-6] [Table 19-7] [Table 19-8] [Table 19-9] [Table 19-10] [Table 19-11] [Table 19-12] Table 19-13 Table 19-14 Table 19-15 Table 19-16 Table 19-17 Table 19-18 Table 19-19 Table 19-20 Table 19-21 Table 19-22 Table 19-23 Table 19-24 Table 19-25 Table 19-26 Table 19-27 Table 19-28 Table 19-29 Table 19-30 Table 19-31 Table 19-32 Table 19-33 Table 19-34 Table 19-35 Table 19-36 Table 19-37 Table 19-38 Table 19-39 Table 19-40 Table 19-41 Table 19-42 Table 19-43 Table 19-44 Table 19-45 Table 19-46 Table 19-47 Table 19-48 Table 19-49 Table 19-50 Table 19-51 Table 19-52 Table 19-53 Table 19-54 Table 19-55 Table 19-56 Table 19-57 Table 19-58 Table 19-59 Table 19-60 Table 19-61 Table 19-62 Table 19-63 Table 19-64 Table 19-65 Table 19-66 Table 19-67 Table 19-68 Table 19-69 Table 19-70 Table 19-71 Table 19-72 Table 19-73 Table 19-74 Table 19-75

Claims

1. 1. An isolated antibody that binds to interleukin (IL)-4 receptor alpha (IL-4Rα), said antibody 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; a. the CDR-H1 comprises a sequence selected from the sequences represented by SEQ ID NOs: 1-4, 66-70, and 187-191; b. the CDR-H2 comprises a sequence selected from the sequences represented by SEQ ID NOs: 5 to 16 and 71 to 90; c. the CDR-H3 comprises a sequence selected from the sequences represented by SEQ ID NOs: 17-25 and 92-99; d. the CDR-L1 comprises a sequence selected from the sequences represented by SEQ ID NOs: 26-40 and 100-107; e. the CDR-L2 comprises a sequence selected from the sequences represented by SEQ ID NOs: 41-52 and 108-112; and (f) The isolated antibody as described above, wherein the CDR-L3 comprises a sequence selected from the sequences represented by SEQ ID NOs: 53 to 65.

2. The antibody a. A CDR-H1 comprising a sequence selected from the sequences represented by SEQ ID NOs: 1 to 4; b. The CDR-H2 comprises a sequence selected from the sequences represented by SEQ ID NOs: 5 to 16; c. The CDR-H3 comprises a sequence selected from the sequences represented by SEQ ID NOs: 17 to 25; d. The CDR-L1 comprises a sequence selected from the sequences represented by SEQ ID NOs: 26 to 40; e. The CDR-L2 comprises a sequence selected from the sequences represented by SEQ ID NOs: 41 to 52; and (f) The isolated antibody of claim 1, wherein the CDR-L3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 53-65.

3. The antibody a. A CDR-H1 comprising a sequence selected from the sequences represented by SEQ ID NOs: 66 to 70; b. the CDR-H2 comprises a sequence selected from the sequences represented by SEQ ID NOs: 71 to 78; c. The CDR-H3 comprises a sequence selected from the sequences represented by SEQ ID NOs: 17 to 25; d. The CDR-L1 comprises a sequence selected from the sequences represented by SEQ ID NOs: 26 to 40; e. The CDR-L2 comprises a sequence selected from the sequences represented by SEQ ID NOs: 41 to 52; and (f) The isolated antibody of claim 1, wherein the CDR-L3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 53-65.

4. The antibody a. A CDR-H1 comprising a sequence selected from the sequences represented by SEQ ID NOs: 187-191; b. the CDR-H2 comprises a sequence selected from the sequences represented by SEQ ID NOs: 79 to 90; c. The CDR-H3 comprises a sequence selected from the sequences represented by SEQ ID NOs: 92 to 99; d. The CDR-L1 comprises a sequence selected from the sequences represented by SEQ ID NOs: 100 to 107; e. The CDR-L2 comprises a sequence selected from the sequences represented by SEQ ID NOs: 108 to 112; and (f) The isolated antibody of claim 1, wherein the CDR-L3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 53-65.

5. The antibody a. CDR-H1 represented by SEQ ID NO: 1, CDR-H2 represented by SEQ ID NO: 5, CDR-H3 represented by SEQ ID NO: 17, CDR-L1 represented by SEQ ID NO: 26, CDR-L2 represented by SEQ ID NO: 41, and CDR-L3 represented by SEQ ID NO: 53, or b. CDR-H1 represented by SEQ ID NO: 67, CDR-H2 represented by SEQ ID NO: 71, CDR-H3 represented by SEQ ID NO: 17, CDR-L1 represented by SEQ ID NO: 26, CDR-L2 represented by SEQ ID NO: 41, and CDR-L3 represented by SEQ ID NO: 53; or c. CDR-H1 represented by SEQ ID NO: 187, CDR-H2 represented by SEQ ID NO: 79, CDR-H3 represented by SEQ ID NO: 91, CDR-L1 represented by SEQ ID NO: 100, CDR-L2 represented by SEQ ID NO: 108, and CDR-L3 represented by SEQ ID NO: 53; 10. The isolated antibody of claim 1, wherein the antibody is free of:

6. The antibody a. CDR-H1 represented by any of SEQ ID NOs: 1, 67, or 187; b. CDR-H2 represented by any of SEQ ID NOs: 5, 71, or 79; c. CDR-H3 represented by either SEQ ID NO: 17 or 91; d. CDR-L1 represented by either SEQ ID NO: 26 or 100; e. CDR-L2 represented by either SEQ ID NO: 41 or 108, and f. CDR-L3 represented by SEQ ID NO: 53; The isolated antibody of claim 5, which does not contain any combination of:

7. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 6, 71, or 80, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 18 or 92, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 27 or 101, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 42 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

54.

8. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 62, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 6, 71, or 80, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 18 or 92, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 28 or 100, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 42 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

55.

9. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 7, 72, or 81, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 22 or 93, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 29 or 100, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 43 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

55.

10. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 6, 71, or 80, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 18 or 92, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 28 or 100, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 45 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

55.

11. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 8, 73, or 82, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 19 or 94, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 30 or 102, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 43 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

56.

12. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 8, 73, or 82, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 20 or 95, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 31 or 103, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 43 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

57.

13. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 6, 71, or 80, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 17 or 91, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 32 or 102, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 46 or 109, and CDR-L3 comprising the sequence represented by SEQ ID NO:

58.

14. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 8, 73, or 82, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 20 or 95, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 32 or 102, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 45 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

59.

15. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises: CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 68, or 189; CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 6, 71, or 80; CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 20 or 95; CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 32 or 102; CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 45 or 108; and CDR-L3 comprising the sequence represented by SEQ ID NO:

60.

16. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 9, 77, or 83, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 18 or 92, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 29 or 100, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 43 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

60.

17. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 9, 77, or 83, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 18 or 92, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 27 or 101, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 43 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

57.

18. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 6, 71, or 80, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 18 or 92, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 27 or 101, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 43 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

61.

19. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 10, 71, or 84, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 20 or 95, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 27 or 101, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 43 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

61.

20. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 6, 71, or 80, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 18 or 92, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 28 or 100, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 43 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

61.

21. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 3, 69, or 190, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 8, 73, or 82, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 21 or 96, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 28 or 100, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 43 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

61.

22. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 7, 72, or 81, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 20 or 95, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 28 or 100, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 42 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

62.

23. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 11, 73, or 85, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 18 or 92, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 33 or 102, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 43 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

61.

24. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 23, 69, or 190, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 11, 73, or 85, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 19 or 94, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 34 or 100, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 43 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

60.

25. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 11, 73, or 85, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 22 or 93, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 34 or 100, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 43 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

56.

26. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 3, 69, or 190, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 6, 71, or 80, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 23 or 97, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 28 or 100, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 42 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

61.

27. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 7, 72, or 81, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 20, 18, or 95, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 27 or 101, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 43 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

61.

28. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 7, 71, or 80, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 18 or 92, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 27 or 101, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 43 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

61.

29. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 6, 71, or 80, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 24 or 98, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 36 or 102, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 45 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

61.

30. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 8, 73, or 82, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 18 or 92, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 37 or 100, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 47 or 110, and CDR-L3 comprising the sequence represented by SEQ ID NO:

61.

31. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 12, 74, or 86, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 24 or 98, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 28 or 100, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 43 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

61.

32. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 189, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 13, 71, or 87, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 20 or 95, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 28 or 100, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 43 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

61.

33. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 10, 71, or 84, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 20 or 95, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 34 or 100, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 43 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

57.

34. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 6, 71, or 80, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 20 or 95, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 34 or 100, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 43 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

61.

35. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 1, 66, or 187, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 5, 71, or 79, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 17 or 91, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 38 or 105, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 48 or 111, and CDR-L3 comprising the sequence represented by SEQ ID NO:

63.

36. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 6, 71, or 80, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 20 or 95, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 39 or 106, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 41 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

64.

37. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 14, 75, or 88, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 20 or 95, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 39 or 106, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 49 or 112, and CDR-L3 comprising the sequence represented by SEQ ID NO:

63.

38. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 6, 71, or 80, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 19 or 94, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 28 or 100, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 42 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

60.

39. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 8, 73, or 82, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 18 or 92, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 31 or 103, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 43 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

58.

40. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 3, 69, or 190, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 5, 71, or 79, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 19 or 94, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 33 or 102, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 50 or 110, and CDR-L3 comprising the sequence represented by SEQ ID NO:

61.

41. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 6, 71, or 80, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 18 or 92, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 30 or 101, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 51 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

61.

42. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 3, 67, or 190, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 15, 67, or 89, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 20 or 95, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 40 or 107, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 52 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

61.

43. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 6, 71, or 80, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 20 or 95, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 30 or 102, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 47 or 110, and CDR-L3 comprising the sequence represented by SEQ ID NO:

61.

44. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 4, 70, or 191, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 11, 73, or 85, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 22, 18, or 93, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 30 or 102, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 43 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

60.

45. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 14, 75, or 88, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 18 or 92, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 27 or 101, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 43 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

65.

46. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 15, 76, or 89, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 19 or 94, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 28 or 100, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 43 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

62.

47. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 3, 69, or 190, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 9, 77, or 83, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 19 or 94, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 28 or 100, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 43 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

55.

48. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 15, 76, or 89, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 24 or 98, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 34 or 100, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 42 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

61.

49. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 6, 71, or 80, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 18 or 92, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 32 or 102, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 51 or 110, and CDR-L3 comprising the sequence represented by SEQ ID NO:

61.

50. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 2, 67, or 188, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 16, 78, or 90, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 19 or 94, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 28 or 100, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 45 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

57.

51. 7. The isolated antibody of any one of claims 1 to 6, wherein the antibody comprises CDR-H1 comprising the sequence represented by any one of SEQ ID NOs: 4, 70, or 191, CDR-H2 comprising the sequence represented by any one of SEQ ID NOs: 16, 78, or 90, CDR-H3 comprising the sequence represented by any one of SEQ ID NOs: 25 or 99, CDR-L1 comprising the sequence represented by any one of SEQ ID NOs: 34 or 100, CDR-L2 comprising the sequence represented by any one of SEQ ID NOs: 43 or 108, and CDR-L3 comprising the sequence represented by SEQ ID NO:

53.

52. 10. The isolated antibody of any one of the preceding claims, wherein the antibody comprises a heavy chain variable domain (VH) sequence selected from the sequences represented by SEQ ID NOs: 113-145.

53. 2. The isolated antibody of any one of the preceding claims, wherein the antibody comprises a light chain variable domain (VL) sequence selected from the sequences represented by SEQ ID NOs: 146-186.

54. 10. The isolated antibody of any one of the preceding claims, wherein the antibody comprises a VH sequence selected from the sequences represented by SEQ ID NOs: 113-145 and a VL sequence selected from the sequences represented by SEQ ID NOs: 146-186.

55. An isolated antibody that binds to IL-4Rα, the antibody comprising a VH sequence selected from the sequences represented by SEQ ID NOs: 113-145 and a VL sequence selected from the sequences represented by SEQ ID NOs: 146-186.

56. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 114 and a VL sequence represented by SEQ ID NO:

147.

57. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 114 and a VL sequence represented by SEQ ID NO:

148.

58. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 115 and a VL sequence represented by SEQ ID NO:

149.

59. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 114 and a VL sequence represented by SEQ ID NO:

150.

60. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 116 and a VL sequence represented by SEQ ID NO:

151.

61. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 117 and a VL sequence represented by SEQ ID NO:

152.

62. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 118 and a VL sequence represented by SEQ ID NO:

153.

63. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 117 and a VL sequence represented by SEQ ID NO:

154.

64. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 119 and a VL sequence represented by SEQ ID NO:

155.

65. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 120 and a VL sequence represented by SEQ ID NO:

156.

66. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 120 and a VL sequence represented by SEQ ID NO:

157.

67. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 114 and a VL sequence represented by SEQ ID NO:

158.

68. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 121 and a VL sequence represented by SEQ ID NO:

158.

69. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 122 and a VL sequence represented by SEQ ID NO:

158.

70. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 114 and a VL sequence represented by SEQ ID NO:

159.

71. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 123 and a VL sequence represented by SEQ ID NO:

159.

72. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 124 and a VL sequence represented by SEQ ID NO:

160.

73. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 125 and a VL sequence represented by SEQ ID NO:

161.

74. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 126 and a VL sequence represented by SEQ ID NO:

162.

75. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 127 and a VL sequence represented by SEQ ID NO:

163.

76. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 128 and a VL sequence represented by SEQ ID NO:

164.

77. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 124 and a VL sequence represented by SEQ ID NO:

158.

78. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 129 and a VL sequence represented by SEQ ID NO:

165.

79. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 130 and a VL sequence represented by SEQ ID NO:

166.

80. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 131 and a VL sequence represented by SEQ ID NO:

167.

81. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 132 and a VL sequence represented by SEQ ID NO:

159.

82. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 133 and a VL sequence represented by SEQ ID NO:

159.

83. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 121 and a VL sequence represented by SEQ ID NO:

168.

84. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 134 and a VL sequence represented by SEQ ID NO:

169.

85. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 113 and a VL sequence represented by SEQ ID NO:

170.

86. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 134 and a VL sequence represented by SEQ ID NO:

171.

87. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 135 and a VL sequence represented by SEQ ID NO:

172.

88. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 136 and a VL sequence represented by SEQ ID NO:

173.

89. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 131 and a VL sequence represented by SEQ ID NO:

174.

90. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 137 and a VL sequence represented by SEQ ID NO:

175.

91. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 114 and a VL sequence represented by SEQ ID NO:

176.

92. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 138 and a VL sequence represented by SEQ ID NO:

177.

93. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 134 and a VL sequence represented by SEQ ID NO:

178.

94. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 139 and a VL sequence represented by SEQ ID NO:

179.

95. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 140 and a VL sequence represented by SEQ ID NO:

180.

96. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 141 and a VL sequence represented by SEQ ID NO:

181.

97. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 142 and a VL sequence represented by SEQ ID NO:

182.

98. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 143 and a VL sequence represented by SEQ ID NO:

183.

99. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 114 and a VL sequence represented by SEQ ID NO:

184.

100. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 144 and a VL sequence represented by SEQ ID NO:

185.

101. 56. The isolated antibody of claim 54 or 55, wherein the antibody comprises a VH sequence represented by SEQ ID NO: 145 and a VL sequence represented by SEQ ID NO:

186.

102. 10. The isolated antibody of any one of the above claims, wherein the antibody is a humanized antibody, a fully human antibody, or a chimeric antibody.

103. 10. The isolated antibody of any one of the above claims, wherein the antibody is a fully human antibody.

104. 10. The isolated antibody of any one of the preceding claims, wherein the antibody comprises a heavy chain human constant region of a class selected from IgG, IgA, IgD, IgE, and IgM.

105. 10. The isolated antibody of claim 1, wherein the human Fc region comprises a human heavy chain constant region of the IgG class and subclass selected from IgG1, IgG2, IgG3, and IgG4.

106. 106. The isolated antibody of claim 105, wherein the human Fc region comprises a human IgG1 Fc.

107. The isolated antibody of claim 105, wherein the human Fc region comprises a human IgG4 Fc.

108. The isolated antibody of claim 105, wherein the human Fc region comprises a human IgG2 Fc.

109. 2. The isolated antibody of any one of the preceding claims, wherein the heavy chain comprises a constant heavy chain sequence selected from the sequences represented by SEQ ID NOs: 192-235 and 251-407.

110. 1. An isolated antibody that binds to interleukin (IL)-4 receptor alpha (IL-4Rα), comprising: a) a variable heavy (VH) chain sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR3-H3; and b) a variable light (VL) chain sequence having three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein the antibody comprises CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 1, 66, or 187; CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 5, 71, or 79; CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 17 or 91; CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 26 or 100; CDR-L2 comprising the sequence set forth in any of SEQ ID NOs: 41 or 108; and CDR-L3 comprising the sequence set forth in SEQ ID NO: 53; and the heavy chain comprises a constant heavy chain sequence selected from the sequences set forth in SEQ ID NOs: 192-235 and 251-407.

111. 111. The isolated antibody of claim 110, wherein the antibody comprises a VH sequence represented by SEQ ID NO:

113.

112. 112. The isolated antibody of claim 110 or 111, wherein the antibody comprises a VL sequence represented by SEQ ID NO:

146.

113. 2. The isolated antibody of claim 1, wherein the light chain comprises a constant light chain sequence comprising the sequence set forth in SEQ ID NO:

236.

114. 10. The isolated antibody of claim 1, wherein the Fc region comprises one or more amino acid substitutions that result in an increase in one or more of antibody half-life, ADCC activity, ADCP activity, or CDC activity compared to the Fc region not comprising the one or more substitutions.

115. 114. The isolated antibody of any one of claims 1-113, wherein the Fc region comprises one or more amino acid substitutions that result in a decrease in one or more of ADCC activity, ADCP activity, or CDC activity compared to an antibody comprising a wild-type Fc region.

116. wherein the one or more amino acid substitutions are selected from the group consisting of S228P, M252Y, S254T, T256E, T256D, T250Q, H285D, T307A, T307Q, T307R, T307W, L309D, Q411H, Q311V, A378V, E380A, M428L, N434A, N434S, and optionally the one or more amino acid substitutions are selected from the group consisting of i) M428L / N434S, ii) M252Y / S254T / T256E, iii) T250Q / 115. The isolated antibody of claim 114, comprising multiple amino acid substitutions selected from the group consisting of: M428L, iv) T307A / E380A / N434A, v) T256D / T307Q, vi) T256D / T307W, vii) M252Y / T256D, viii) T307Q / Q311V / A378V, ix) T256D / H285D / T307R / Q311V / A378V, x) L309D / Q311H / N434S, and xi) S228P / L235E.

117. The isolated antibody of any one of the above claims, wherein the Fc region binds to a fetal Fc receptor (FcRn).

118. 118. The isolated antibody of claim 117, wherein the Fc region binds to FcRn with higher affinity at pH 6.0 compared to an antibody comprising a wild-type Fc region.

119. The Fc region is 1×10 －７ K less than M Ｄ 119. The isolated antibody of claim 117 or 118, which binds to FcRn at

120. 10. The isolated antibody of claim 1, wherein the antibody is a monoclonal antibody.

121. The antibody of any one of the above claims, wherein the antibody binds to the IL-4Rα sequences represented by SEQ ID NOs: 237-240, 245-247, and 258.

122. The antibody binds to the IL-4Rα sequences represented by SEQ ID NOs: 237-240, 245-247, and 258 with a binding affinity of about 1, 2, 3, 4, 5, 6, 7, 8, 9 x 10 as measured by surface plasmon resonance (SPR). －９ K below M Ｄ 10. The isolated antibody of claim 1, wherein the antibody binds to the nucleotide sequence of ...

123. The antibody binds to the IL-4Rα sequences represented by SEQ ID NOs: 237-240, 245-247, and 258 with a binding affinity of about 1 x 10 as measured by surface plasmon resonance (SPR). －１０ K below M Ｄ 123. The isolated antibody of claim 122, which binds to

124. The antibody binds to human IL-4Rα with an affinity of about 1×10 as measured by surface plasmon resonance (SPR). －９ K below M Ｄ 122. The isolated antibody of claim 121, which binds to

125. 10. The isolated antibody of any one of the preceding claims, wherein the antibody exhibits a melting temperature of greater than 68°C as measured by differential scanning fluorimetry (DSF).

126. 126. The isolated antibody of claim 125, wherein the antibody exhibits a melting temperature of greater than 75°C as measured by differential scanning fluorimetry (DSF).

127. 10. The isolated antibody of any one of the preceding claims, wherein the antibody exhibits an aggregation temperature of 71.2°C or greater as measured by differential scanning fluorimetry (DSF).

128. 10. The isolated antibody of any one of the preceding claims, wherein the antibody has a retention time of 15.2 minutes or less as measured by hydrophobic chromatography.

129. 129. The isolated antibody of any one of claims 1 to 110 and 112 to 128, wherein the antibody does not have the heavy chain sequence set forth in SEQ ID NO:

113.

130. 130. The isolated antibody of any one of claims 1 to 111 and 113 to 129, wherein the antibody does not have the heavy chain sequence set forth in SEQ ID NO:

146.

131. 10. The isolated antibody of any one of the preceding claims for use in the treatment of an inflammatory disorder or disease.

132. 132. The isolated antibody of claim 131 for use in treating atopic dermatitis (AD).

133. 133. The isolated antibody of claim 132, wherein the treatment reduces disease severity in the patient, wherein disease severity is assessed by an atopic dermatitis disease severity outcome measure.

134. 132. The isolated antibody of claim 131 for use in the treatment of asthma.

135. 133. The isolated antibody of claim 132 for use in treating chronic rhinosinusitis with nasal polyps.

136. 132. The isolated antibody of claim 131 for use in the treatment of chronic rhinosinusitis without nasal polyps (CRSsNP).

137. 132. The isolated antibody of claim 131 for use in the treatment of eosinophilic esophagitis (EoE).

138. 132. The isolated antibody of claim 131 for use in treating an eosinophilic gastrointestinal disorder or disease (ENID) selected from the group consisting of eosinophilic gastritis (EoG), eosinophilic enteritis (EoN), eosinophilic colitis (EoC), and eosinophilic gastroenteritis (EGE).

139. 132. The isolated antibody of claim 131 for use in treating Churg-Strauss syndrome / eosinophilic granulomatosis with polyangiitis (EGPA).

140. 132. The isolated antibody of claim 131 for use in the treatment of prurigo nodularis (PN).

141. 132. The isolated antibody of claim 131 for use in the treatment of chronic spontaneous urticaria (CSU).

142. 132. The isolated antibody of claim 131 for use in treating chronic pruritus of unknown cause (CPUO).

143. 132. The isolated antibody of claim 131 for use in the treatment of bullous pemphigoid (BP).

144. 132. The isolated antibody of claim 131 for use in treating cold-induced urticaria (ColdU).

145. 132. The isolated antibody of claim 131 for use in the treatment of allergic fungal rhinosinusitis (AFRS).

146. 132. The isolated antibody of claim 131 for use in the treatment of allergic bronchopulmonary aspergillosis.

147. 132. The isolated antibody of claim 131 for use in treating chronic obstructive pulmonary disease (COPD).

148. An isolated polynucleotide or set of polynucleotides encoding an antibody, its VH, its VL, its light chain, its heavy chain, or an antigen-binding portion thereof according to any one of the preceding claims, optionally wherein the polynucleotide or set of polynucleotides comprises cDNA.

149. 149. A vector or set of vectors comprising the polynucleotide or set of polynucleotides of claim 148.

150. 150. A host cell comprising a polynucleotide or set of polynucleotides according to claim 148, or a vector or set of vectors according to claim 149.

151. 151. A method of producing an antibody, comprising expressing the antibody with the host cell of claim 150 and isolating the expressed antibody.

152. A pharmaceutical composition comprising the antibody of any one of claims 1 to 147 and a pharmaceutically acceptable excipient.

153. A kit comprising an antibody according to any one of claims 1 to 147 or a pharmaceutical composition according to claim 152, and instructions for use.

154. 152. A method of treating an inflammatory disorder or disease in a mammalian subject in need thereof, comprising administering to said mammalian subject a therapeutically effective amount of an antibody of any one of claims 1 to 147 or a pharmaceutical composition of claim 152.

155. 155. The method of claim 154, wherein the inflammatory disorder or disease is atopic dermatitis.

156. 155. The method of claim 154, wherein the inflammatory disorder or disease is asthma.

157. 155. The method of claim 154, wherein the inflammatory disorder or disease is chronic sinusitis with nasal polyps.

158. 155. The method of claim 154, wherein the inflammatory disorder or disease is chronic rhinosinusitis without nasal polyps (CRSsNP).

159. 155. The method of claim 154, wherein the inflammatory disorder or disease is eosinophilic esophagitis (EoE).

160. 155. The method of claim 154, wherein the inflammatory disorder or disease is an eosinophilic gastrointestinal disorder or disease (ENID) selected from the group consisting of eosinophilic gastritis (EoG), eosinophilic enteritis (EoN), eosinophilic colitis (EoC), and eosinophilic gastroenteritis (EGE).

161. 155. The method of claim 154, wherein the inflammatory disorder or disease is Churg-Strauss syndrome / eosinophilic granulomatosis with polyangiitis (EGPA).

162. 155. The method of claim 154, wherein the inflammatory disorder or disease is prurigo nodularis (PN).

163. 155. The method of claim 154, wherein the inflammatory disorder or disease is chronic subidial urticaria (CSU).

164. 155. The method of claim 154, wherein the inflammatory disorder or disease is chronic pruritus of unknown origin (CPUO).

165. 155. The method of claim 154, wherein the inflammatory disorder or disease is bullous pemphigoid (BP).

166. 155. The method of claim 154, wherein the inflammatory disorder or disease is cold-induced urticaria (ColdU).

167. 155. The method of claim 154, wherein the inflammatory disorder or disease is allergic fungal rhinosinusitis (AFRS).

168. 155. The method of claim 154, wherein the inflammatory disorder or disease is allergic bronchopulmonary aspergillosis (ABPA).

169. 155. The method of claim 154, wherein the inflammatory disorder or disease is chronic obstructive pulmonary disease (COPD).

170. 152. A method of treating a condition associated with elevated levels of IL-4 and / or IL-13 in a mammalian subject in need thereof, said method comprising administering to said mammalian subject a therapeutically effective amount of an antibody of any one of claims 1 to 147 or a pharmaceutical composition of claim 152.

171. 152. A method for reducing the biological activity of IL-4, IL-13 and / or IL-4Rα in a mammalian subject in need thereof, said method comprising administering to said mammalian subject a therapeutically effective amount of an antibody of any one of claims 1 to 147 or a pharmaceutical composition of claim 152.

172. A method for inhibiting a TH2-type allergic response in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of an antibody according to any one of claims 1 to 147 or a pharmaceutical composition according to claim 152.

173. 152. A method of preventing an inflammatory disorder or disease in a mammalian subject in need thereof, comprising administering to said mammalian subject a therapeutically effective amount of an antibody of any one of claims 1 to 147 or a pharmaceutical composition of claim 152.

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