Antibodies that bind interleukin 4 receptor alpha in combination with hyaluronidase or a variant thereof

Abstract

Described herein are compositions and combinations comprising an antibody that binds Interleukin 4α Receptor (IL-4Rα) and a hyaluronidase or variant thereof, as well as related methods of treating an inflammatory disorder or disease in a human patient.

Description

ANTIBODIES THAT BIND INTERLEUKIN 4 RECEPTOR ALPHA IN COMBINATION WITH HYALURONIDASE OR A VARIANT THEREOFCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 708,867 (filed October 18, 2024), which is incorporated by reference herein in its entirety.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML file format and is hereby incorporated by reference in its entirety. Said XML copy, created on October 16, 2025, is named AOJ-006PC_SL.xml and is 524,172 bytes in size.FIELD OF THE INVENTION

[0003] Described herein are novel and improved antibodies that bind Interleukin 4a Receptor (IL-4Rα) and methods of use thereof, for example, in the treatment of an inflammatory disease or disorder associated with elevated levels of IL-4 and / or IgE.BACKGROUND

[0004] Interleukin 4 (IL-4) and interleukin 13 (IL- 13) share a common receptor component, the Interleukin-4 Receptor Alpha (IL-4Rα) chain, that pairs with distinct subunits (Nelms. K., et al. (1999) Anna. Rev. Immunol. 17:701-738) and (Jensen, P.L. (2000) Stem Cells 18:61 -62). IL-4Rα pairs with the common Υc chain to form a type I IL-4R complex that is found predominantly in hematopoietic cells and is exclusive for IL-4. IL-4Rα also pairs with the Interleukin- 13 Receptor alpha 1 (IL-13Rα1) subunit to form a type II IL-4R that binds both IL-4 and IL-13. The type II receptor is expressed on both hematopoietic and nonhematopoietic cells. IL-4, (also known as B cell stimulating factor or BSF-1) was originally characterized by its ability to stimulate the proliferation of B cells in response to low concentrations of antibodies directed to surface immunoglobulin. IL-4 has been shown to possess a broad spectrum of biological activities, including growth stimulation 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 IgGl isotypes by stimulated B cells.

[0005] The biological and immunological functions of B -lymphocytes, monocytes, dendritic cells, and fibroblasts are all affected by IL-4 and IL- 13. These cytokines interact with IL-4R to initiate the type 2 inflammatory pathway, which results in Th2 cell differentiation, inflammation, and mucus production. The type-2 inflammatory pathway is first activated in allergic illnesses by aberrant cytokine release resulting from an imbalance of Thl and Th2 differentiation. Th2 cells that have been activated release cytokines, including IL-4, IL-13, and IL-31, which prompt downstream B cells to undergo a change and produce IgE antibodies. Mast cells and basophils are then called upon to degranulate and release inflammatory substances. Simultaneously, the secreted IL-4 and IL- 13 continue to bind to their respective receptors, such as IL-4Rα, that repeatedly promotes TH2 differentiation and subsequent inflammation.

[0006] The important role of IL-4 and IL- 13 in the type-2 inflammation pathway identifies IL-4Rα as a potential target for individuals who exhibit aberrant type-2 inflammatory responses. Unlike medications that target IL-4 and IL- 13 exclusively, targeting IL-4Rα would target both IL-4 and IL- 13. Therefore, novel antibodies that bind IL-4Rα that modify type-2 inflammation to treat immune disorders are needed, alone or in combination with additional therapeutic agents. Accordingly, it is an object of the present invention to provide improved methods for treating patients with inflammatory diseases and conditions. There is also a need for delivering relatively large doses of these antibodies subcutaneously.SUMMARY

[0001] The present invention features compositions and combinations comprising an anti- IL-4Rα antibody and a hyaluronidase or a variant thereof, and methods of treating an inflammatory disorder or disease by administering to a subject in need thereof an anti-IL-4Rα antibody and a hyaluronidase or a variant thereof. Diseases that can be treated according to the methods described herein include atopic dermatitis and asthma, among others.

[0002] Disclosed herein are antibodies, such as recombinant human antibodies, that specifically bind human interleukin-4 receptor alpha (hIL-4Rα). In certain embodiments, the antibodies are characterized by binding to hIL-4Rα with high affinity and by the ability to neutralize hIL-4Rα activity. In specific embodiments, the human antibodies are capable of blocking hIL-13 / hIL-13Rl complex binding to hIL-4Rα, and thus inhibit signaling by hlL- 13. The antibodies can be full-length (for example, an IgGl or IgG4 antibody) or may comprise only an antigen-binding portion (for example, a Fab, F(ab')2 or scFv fragment), andmay be modified to effect functionality, e.g., to abrogate residual effector functions (Reddy el al. (2000) J. Immunol. 164: 1925-1933) and / or extend half-life.

[0003] In a first aspect, the invention provides a composition comprising an isolated antibody, or antigen binding fragment thereof, that binds IL-4Rα and a hyaluronidase or a variant thereof, wherein the antibody, or antigen binding fragment thereof comprises: a) a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and b) a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; wherein: a. CDR-H1 comprises a sequence selected from a sequence set forth in any one of SEQ ID NOs: 1-4, 66-70 and 187- 191; b. CDR-H2 comprises a sequence selected from a sequence set forth in any one of SEQ ID NOs: 5-16, and 71-90; c. CDR-H3 comprises a sequence selected from a sequence set forth in any one of SEQ ID NOs: 17-25 and 92-99, d. CDR-L1 comprises a sequence selected from a sequence set forth in any one of SEQ ID NOs: 26-40 and 100-107, e. CDR-L2 comprises a sequence selected from a sequence set forth in any one of SEQ ID NOs: 41-52 and amino acid sequences LG, KG, EG, SA and LS; and f. CDR-L3 comprises a sequence selected from a sequence set forth in any one of SEQ ID NOs: 53-65.

[0004] In another aspect, the invention provides a combination comprising an isolated antibody, or antigen binding fragment thereof, that binds IL-4Rα and a hyaluronidase or a variant thereof, wherein the antibody, or antigen binding fragment thereof comprises: a) a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and b) a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; wherein: a. CDR-H1 comprises a sequence selected from a sequence set forth in any one of SEQ ID NOs: 1-4, 66-70 and 187- 191 ; b. CDR-H2 comprises a sequence selected from a sequence set forth in any one of SEQ ID NOs: 5-16, and 71-90; c. CDR-H3 comprises a sequence selected from a sequence set forth in any one of SEQ ID NOs: 17-25 and 92-99, d. CDR-L1 comprises a sequence selected from a sequence set forth in any one of SEQ ID NOs: 26-40 and 100-107, e. CDR-L2 comprises a sequence selected from a sequence set forth in any one of SEQ ID NOs: 41-52 and amino acid sequences LG, KG, EG, SA and LS; and f. CDR-L3 comprises a sequence selected from a sequence set forth in any one of SEQ ID NOs: 53-65.

[0005] In another aspect, provided herein is a method of treating an inflammatory disorder or disease in a human patient comprising administering to the patient an isolated antibody, or antigen binding fragment thereof, that binds IL-4Rα and a hyaluronidase or avariant thereof, wherein the antibody, or an antigen binding fragment thereof, comprises: a) a variable heavy (VH) chain sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and b) a variable light (VL) chain sequence having three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; wherein: a. CDR-H1 comprises a sequence selected from a sequence set forth in any one of SEQ ID NOs: 1-4, 66-70 and 187- 191; b. CDR-H2 comprises a sequence selected from a sequence set forth in any one of SEQ ID NOs: 5-16, and 71-90; c. CDR-H3 comprises a sequence selected from a sequence set forth in any one of SEQ ID NOs: 17-25 and 92-99, d. CDR-L1 comprises a sequence selected from a sequence set forth in any one of SEQ ID NOs: 26-40 and 100-107, e. CDR-L2 comprises a sequence selected from a sequence set forth in any one of SEQ ID NOs: 41-52 and amino acid sequences LG, KG, EG, SA and LS; and f. CDR-L3 comprises a sequence selected from a sequence set forth in any one of SEQ ID NOs: 53-65.

[0006] In some embodiments, the antibody, or antigen binding fragment thereof, comprises: a. CDR-H1 comprising a sequence selected from a sequence set forth in any one of SEQ ID NOs: 1-4; b. CDR-H2 comprising a sequence selected from a sequence set forth in any one of SEQ ID NOs: 5-16; c. CDR-H3 comprising a sequence selected from a sequence set forth in any one of SEQ ID NOs: 17-25, d. CDR-L1 comprising a sequence selected from a sequence set forth in any one of SEQ ID NOs: 26-40, e. CDR-L2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 41-52; and f. CDR-L3 comprising a sequence selected from a sequence set forth in any one of SEQ ID NOs: 53-65.

[0007] In some embodiments, the antibody, or antigen binding fragment thereof, comprises: a. CDR-H1 comprising a sequence selected from a sequence set forth in any one of SEQ ID NOs: 66-70; b. CDR-H2 comprising a sequence selected from a sequence set forth in any one of SEQ ID NOs: 71-78; c. CDR-H3 comprising a sequence selected from a sequence set forth in any one of SEQ ID NOs: 17-25, d. CDR-L1 comprising a sequence selected from a sequence set forth in any one of SEQ ID NOs: 26-40, e. CDR-L2 comprising a sequence selected from a sequence set forth in any one of SEQ ID NOs: 41-52; and f. CDR- L3 comprising a sequence selected from a sequence set forth in any one of SEQ ID NOs: 53- 65.

[0008] In some embodiments, the antibody, or antigen binding fragment thereof, comprises: a. CDR-H1 comprising a sequence selected from a sequence set forth in any one of SEQ ID NOs: 187-191; b. CDR-H2 comprising a sequence selected from a sequence set forth in any one of SEQ ID NOs: 79-90; c. CDR-H3 comprising a sequence selected from asequence set forth in any one of SEQ ID NOs: 92-99, d. CDR-L1 comprising a sequence selected from a sequence set forth in any one of SEQ ID NOs: 100-107, e. CDR-L2 comprising a sequence selected from any one of amino acid sequences LG, KG, EG, SA and LS; and f. CDR-L3 comprising a sequence selected from a sequence set forth in any one of SEQ ID NOs: 53-65.

[0009] In some embodiments, the antibody, or antigen binding fragment thereof, does not comprise: a. CDR-H1 set forth in SEQ ID NO: 1; CDR-H2 set forth in SEQ ID NO: 5; CDR-H3 set forth in SEQ ID NO: 17; CDR-L1 set forth in SEQ ID NO: 26; CDR-L2 set forth in SEQ ID NO: 41; and CDR-L3 set forth in SEQ ID NO: 53; or b. CDR-H1 set forth in SEQ ID NO: 66; CDR-H2 set forth in SEQ ID NO: 71: CDR- H3 set forth in SEQ ID NO: 17; CDR-L1 set forth in SEQ ID NO: 26; CDR-L2 set forth in SEQ ID NO: 41; and CDR-L3 set forth in SEQ ID NO: 53; or c. CDR-H1 set forth in SEQ ID NO: 187; CDR-H2 set forth in SEQ ID NO: 79; CDR- H3 set forth in SEQ ID NO: 91; CDR-L1 set forth in SEQ ID NO: 100; CDR-L2 LG; and CDR-L3 set forth in SEQ ID NO: 53.

[0010] In some embodiments, the antibody, or antigen binding fragment thereof, does not comprise any combination of: a. a CDR-H1 set forth in any one of SEQ ID NOs: 1, 66, and 187; b. a CDR-H2 set forth in any one of SEQ ID NOs: 5, 71, and 79; c. a CDR-H3 set forth in any one of SEQ ID NOs: 17 and 91; d. a CDR-L1 set forth in any one of SEQ ID NOs: 26 and 100; e. a CDR-L2 set forth in SEQ ID NO: 41 or the amino acid sequence LG; and f. a CDR-L3 set forth in SEQ ID NO: 53.

[0011] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 18 and 92; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 27 and 101; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 42 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 54.

[0012] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 62, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 18 and 92; aCDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 28 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 42 or the amino acid sequence LG: and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 55.

[0013] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 7, 72, and 81; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 22 and 93; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 29 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 55.

[0014] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 18 and 92; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 28 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 45 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 55.

[0015] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 8, 73, and 82; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 19 and 94; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 30 and 102; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 56.

[0016] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 8, 73, and 82; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 20 and 95; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 31 and 103; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 57.

[0017] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67,and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71. and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 17 and 91; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 32 and 102; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 46 or the amino acid sequence KG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 58.

[0018] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 8, 73, and 82; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 20 and 95; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 32 and 102; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 45 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 59.

[0019] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 68, and 189; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 20 and 95; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 32 and 102; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 45 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 60.

[0020] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 9, 77, and 83; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 18 and 92; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 29 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 60.

[0021] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 9, 77, and 83; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 18 and 92; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 27 and 101; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 57.

[0022] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 18 and 92; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 27 and 101; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0023] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 10, 71, and 84; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 20 and 95; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 27 and 101; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0024] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 18 and 92; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 28 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0025] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 3, 69, and 190; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 8, 73, and 82; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 21 and 96; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 28 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0026] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 7, 72, and 81; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 20 and 95; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 28 and 100; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 42 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 62.

[0027] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 11, 73, and 85; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 18 and 92; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 33 and 102; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0028] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 23, 69, and 190; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 11, 73, and 85; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 19 and 94; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 34 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 60.

[0029] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 11, 73, and 85; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 22 and 93; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 34 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 56.

[0030] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 3, 69, and 190; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 23 and 97; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 28 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 42 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0031] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 7, 72, and81; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 20, 18, and 95; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 27 and 101; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0032] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 7, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 18 and 92; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 27 and 101; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0033] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 24 and 98; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 36 and 102; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 45 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0034] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 8, 73, and 82; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 18 and 92; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 37 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 47 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0035] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 12, 74, and 86; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 24 and 98; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 28 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0036] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 189; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 13, 71, and 87; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 20 and 95; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 28 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0037] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 10, 71, and 84; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 20 and 95; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 34 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 57.

[0038] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 20 and 95; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 34 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0039] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 1, 66, and 187; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 5, 71, and 79; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 17 and 91; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 38 and 105; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 48 or the amino acid sequence SA; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 63.

[0040] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 20 and 95; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 39 and 106; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 41 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 64.

[0041] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 14, 75, and 88; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 20 and 95; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 39 and 106; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 49 or the amino acid sequence LS; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 63.

[0042] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 19 and 94; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 28 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 42 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 60.

[0043] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 8, 73, and 82; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 18 and 92; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 31 and 103; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 58.

[0044] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 3, 69, and 190; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 5, 71, and 79; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 19 and 94; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 33 and 102; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 50 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0045] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71, and80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 18 and 92; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 30 and 101; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 51 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0046] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 3, 67, and 190; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 15, 76, and 89; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 20 and 95; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 40 and 107; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 52 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0047] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 20 and 95; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 30 and 102; a CDR- L2 comprising the sequence set forth in any one of SEQ ID NOs: 47 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0048] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 4, 70, and 191; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 11, 73, or 85; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 22, 18, and 93; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 30 and 102; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 60.

[0049] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 14, 75, and 88; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 18 and 92; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 27 and 101; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 65.

[0050] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 15, 76, and 89; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 19 and 94; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 28 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 62.

[0051] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 3, 69, and 190; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 9, 77, and 83; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 19 and 94; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 28 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 55.

[0052] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 15, 76, and 89; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 24 and 98; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 34 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 42 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0053] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 18 and 92; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 32 and 102; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 51 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0054] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 16, 78, and 90; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 19 and 94; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 28 and 100; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 45 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 57.

[0055] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 4, 70, and 191; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 16, 78, and 90; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 25 and 99; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 34 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 53.

[0056] In some embodiments, wherein the antibody, or antigen binding fragment thereof, comprises a heavy chain variable domain (VH) sequence selected from a sequence set forth in any one of SEQ ID NOs: 113-145.

[0057] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a light chain variable domain (VL) sequence selected from a sequence set forth in any one of SEQ ID NOs: 146-186.

[0058] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence selected from a sequence set forth in any one of SEQ ID NOs: 113- 145, and a VL sequence selected from a sequence set forth in any one of SEQ ID NOs: 146- 186.

[0059] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 114 and a VL sequence set forth in SEQ ID NO: 147.

[0060] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 114 and a VL sequence set forth in SEQ ID NO: 148.

[0061] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 115 and a VL sequence set forth in SEQ ID NO: 149.

[0062] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 114 and a VL sequence set forth in SEQ ID NO: 150.

[0063] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 116 and a VL sequence set forth in SEQ ID NO: 151.

[0064] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 117 and a VL sequence set forth in SEQ ID NO: 152.

[0065] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 118 and a VL sequence set forth in SEQ ID NO: 153.

[0066] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 117 and a VL sequence set forth in SEQ ID NO: 154.

[0067] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 119 and a VL sequence set forth in SEQ ID NO: 155.

[0068] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 120 and a VL sequence set forth in SEQ ID NO: 156.

[0069] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 120 and a VL sequence set forth in SEQ ID NO: 157.

[0070] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 114 and a VL sequence set forth in SEQ ID NO: 158.

[0071] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 121 and a VL sequence set forth in SEQ ID NO: 158.

[0072] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 114 and a VL sequence set forth in SEQ ID NO: 159.

[0073] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 123 and a VL sequence set forth in SEQ ID NO: 159.

[0074] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 124 and a VL sequence set forth in SEQ ID NO: 160.

[0075] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 125 and a VL sequence set forth in SEQ ID NO: 161.

[0076] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 126 and a VL sequence set forth in SEQ ID NO: 162.

[0077] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 127 and a VL sequence set forth in SEQ ID NO: 163.

[0078] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 128 and a VL sequence set forth in SEQ ID NO: 164.

[0079] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 124 and a VL sequence set forth in SEQ ID NO: 158.

[0080] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 129 and a VL sequence set forth in SEQ ID NO: 165.

[0081] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 130 and a VL sequence set forth in SEQ ID NO: 166.

[0082] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 131 and a VL sequence set forth in SEQ ID NO: 167.

[0083] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 132 and a VL sequence set forth in SEQ ID NO: 159.

[0084] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 133 and a VL sequence set forth in SEQ ID NO: 159.

[0085] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 121 and a VL sequence set forth in SEQ ID NO: 168.

[0086] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 134 and a VL sequence set forth in SEQ ID NO: 169.

[0087] In some embodiments, antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 113 and a VL sequence set forth in SEQ ID NO: 170.

[0088] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 134 and a VL sequence set forth in SEQ ID NO: 171.

[0089] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 135 and a VL sequence set forth in SEQ ID NO: 172.

[0090] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 136 and a VL sequence set forth in SEQ ID NO: 173.

[0091] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 131 and a VL sequence set forth in SEQ ID NO: 174.

[0092] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 137 and a VL sequence set forth in SEQ ID NO: 175.

[0093] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 114 and a VL sequence set forth in SEQ ID NO: 176.

[0094] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 138 and a VL sequence set forth in SEQ ID NO: 177.

[0095] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 134 and a VL sequence set forth in SEQ ID NO: 178.

[0096] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 139 and a VL sequence set forth in SEQ ID NO: 179.

[0097] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 140 and a VL sequence set forth in SEQ ID NO: 180.

[0098] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 141 and a VL sequence set forth in SEQ ID NO: 181.

[0099] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 142 and a VL sequence set forth in SEQ ID NO: 182.

[0100] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 143 and a VL sequence set forth in SEQ ID NO: 183.

[0101] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 114 and a VL sequence set forth in SEQ ID NO: 184.

[0102] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 144 and a VL sequence set forth in SEQ ID NO: 185.

[0103] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 145 and a VL sequence set forth in SEQ ID NO: 186.

[0104] In some embodiments, the antibody, or antigen binding fragment thereof, is a humanized, fully human, or chimeric antibody.

[0105] In some embodiments, the antibody, or antigen binding fragment thereof, is a fully human antibody.

[0106] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a heavy chain human constant region of a class selected from IgG, IgA, IgD, IgE, and IgM.

[0107] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a human Fc region comprising a human heavy chain constant region of the class IgG and a subclass selected from IgGl, IgG2, IgG3, and IgG4.

[0108] In some embodiments, the human Fc region comprises a human IgGl Fc region.

[0109] In some embodiments, the human Fc region comprises a human IgG4 Fc region.

[0110] In some embodiments, the human Fc region comprises a human IgG2 Fc region.

[0111] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a heavy chain comprising a constant heavy chain sequence selected from a sequence set forth in any one of SEQ ID NOs: 192-235 and 251-407.

[0112] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 1, 66, and 187; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 5, 71, and 79; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 17 and 91; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 26 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 41 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 53; wherein the antibody, or antigen binding fragment thereof, comprises a heavy chain comprising a constant heavy chain sequence selected from a sequence set forth in any one of SEQ ID NOs: 192-235 and 251- 407. In some embodiments, the antibody, or antigen binding fragment thereof comprises a heavy chain comprising a constant heavy chain sequence selected from a sequence set forth in any one of SEQ ID NOs: 192-234, 251-308, 310-350, and 352-407. In some embodiments, the antibody, or antigen binding fragment thereof does not comprise a constant heavy chain sequence set forth in any of SEQ ID NOs: 235, 309, and 351 (i.e., a human IgG4-SP constant heavy chain region). In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 113. In some embodiments, the antibody, or antigen binding fragment thereof, comprises a VL sequence set forth in SEQ ID NO: 146.

[0113] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a light chain comprising a constant light chain sequence comprising a sequence set forth in SEQ ID NO: 236.

[0114] In some embodiments, the antibody, or antigen binding fragment thereof, comprises an Fc region comprising one or more amino acid substitutions, wherein the one or more amino acid substitutions result in an increase in one or more of antibody half-life,ADCC activity, ADCP activity, and / or CDC activity compared with the Fc region without the one or more amino acid substitutions.

[0115] In some embodiments, the antibody, or antigen binding fragment thereof, comprises an Fc region comprising one or more amino acid substitutions, wherein the one or more amino acid substitutions result in a decrease in one or more of ADCC activity, ADCP activity, and / or CDC activity compared with the Fc region without the one or more amino acid substitutions.

[0116] In some embodiments, the one or more amino acid substitutions results in increased antibody half-life compared to an antibody comprising a wild-type Fc region.

[0117] In some embodiments, the one or more amino acid substitutions is selected from the group consisting of S228P (SP), M252Y, S254T, T256E, T256D, T250Q, H285D, T307A, T307Q, T307R, T307W, L309D, Q411H, Q311V, A378V, E380A, M428L, N434A, N434S, N297A, D265A, L234A, L235A, and N434W. In some embodiments, the one or more amino acid substitutions is 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 (LALA). M428L / N434A (LA), L235A / G237A (LAGA), L234A / L235A / G237A (LALAGA), L234A / L235A / P329G (LALAPG), D265A / YTE, LALA / YTE, LAGA / YTE, LALAGA / YTE, LALAPG / YTE, N297A / LS, D265A / LS, LALA / LS, LALAGA / LS, LALAPG / LS, N297A / DHS, D265A / DHS, LALA / DHS, LAGA / DHS, LALAGA / DHS, LALAPG / DHS, SP / YTE, SPLE / YTE, SP / LS, SPLE / LS, SP / DHS, SPLE / DHS, N297A / LA, D265A / LA, LALA / LA, LAGA / LA, LALAGA / LA, LALAPG / LA, N297A / N434A. D265A / N434A, LALA / N434A, LAGA / N434A, LALAGA / N434A, LALAPG / N434A, N297A / N434W, D265A / N434W, LALA / N434W, LAGA / N434W, LALAGA / N434W, LALAPG / N434W, N297A / DQ, D265A / DQ, LALA / DQ, LAGA / DQ, LALAGA / DQ, LALAPG / DQ, N297A / DW, D265A / DW, LALA / DW, LAGA / DW, LALAGA / DW, LALAPG / DW, N297A / YD, D265A / YD, LALA / YD, LAGA / YD, LALAGA / YD, LALAPG / YD, T307Q / Q311V / A378V (QVV), N297A / QVV, D265A / QVV, LALA / QVV, LAGA / QVV, LALAGA / QVV, LALAPG / QVV, DDRVV, N297A / DDRVV, D265A / DDRVV, LALA / DDRVV, LAGA / DDRVV, LALAGA / DDRVV, and LALAPG / DDRVV. In some embodiments, the one or more amino acid substitutions is selected from the group consistingof LS, YTE, T250Q / M428L, T307A / E380A / N434A, DQ, DW, YD, QVV, DHS, LA, D265A / YTE, LALA / YTE, LAGA / YTE, LALAGA / YTE, LALAPG / YTE, N297A / LS, D265A / LS, LALA / LS, LALAGA / LS, LALAPG / LS, N297A / DHS, D265A / DHS, LALA / DHS, LAGA / DHS, LALAGA / DHS, LALAPG / DHS, SP / YTE, SPLE / YTE, SP / LS, SPLE / LS, SP / DHS, SPLE / DHS, N297A / LA, D265A / LA. LALA / LA, LAGA / LA, LALAGA / LA, LALAPG / LA, N297A / DQ, D265A / DQ, LALA / DQ, LAGA / DQ, LALAGA / DQ, LALAPG / DQ, N297A / DW, D265A / DW, LALA / DW, LAGA / DW, LALAGA / DW, LALAPG / DW, N297A / YD, D265A / YD, LALA / YD, LAGA / YD, LALAGA / YD, LALAPG / YD, N297A / QVV, D265A / QVV, LALA / QVV, LAGA / QVV, LALAGA / QVV, and LALAPG / QVV.

[0118] Although the EU numbering system is typically used to identify the positions of the various Fc mutations described herein, direct numbering can also be used. For example, in certain embodiments, an antibody described herein comprises an Fc region with YTE mutations at positions 260 / 262 / 264. In certain embodiments, an antibody described herein comprises an Fc region with LALA mutations at positions 242 / 243. In certain embodiments, an antibody described herein comprises an Fc region (e.g., an IgGl Fc region) with YTE mutations at positions 260 / 262 / 264 and with LALA mutations at positions 242 / 243. In certain embodiments, the IL-4Rα antibody described herein comprises the VH and VL of mAb 471 (Construct 38) and an Fc region (e.g., an IgGl Fc region) comprising YTE mutations at positions 260 / 262 / 264, respectively and with LALA mutations at positions 242 / 243, respectively.

[0119] In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a heavy chain comprising a heavy chain constant region having a means for extending the half-life of the isolated antibody.

[0120] In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 134, a VL sequence set forth in SEQ ID NO: 178; and a human IgGl Fc region comprising LALA and YTE mutations. In some embodiments, the antibody comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 134, a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 178, a constant heavy chain sequence set forth in SEQ ID NO: 321 and / or a constant heavy chain sequence set forth in SEQ ID NO: 205, and a constant light chain sequence set forth in SEQ ID NO: 236. In some embodiments, the isolated antibody comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 134, a VL domaincomprising the amino acid sequence set forth in SEQ ID NO: 178, a constant heavy chain sequence set forth in SEQ ID NO: 321, and a constant light chain sequence set forth in SEQ ID NO: 236. In some embodiments, the isolated antibody comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 134, a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 178, a constant heavy chain sequence set forth in SEQ ID NO: 205, and a constant light chain sequence set forth in SEQ ID NO: 236. A C-terminal lysine is present in SEQ ID NO: 321, which may be cleaved off during manufacture or after administration, resulting in the sequence of SEQ ID NO: 205. Accordingly, a composition comprising an antibody that binds IL-4Rα comprising the constant heavy chain sequence of SEQ ID NO: 321 that is administered to a subject may comprise antibodies having the constant heavy chain sequence set forth in SEQ ID NO: 321 (e.g., an antibody comprising the heavy chain sequence of SEQ ID NO: 475) or SEQ ID NO: 205 (e.g., an antibody comprising the heavy chain sequence of SEQ ID NO: 476), or a mixture thereof (e.g., a mixture of antibodies containing either a constant heavy chain sequence of SEQ ID NO: 321 or a constant heavy chain sequence of SEQ ID NO: 205 and / or antibodies containing both constant heavy chain sequences (e.g., in an antibody containing two constant heavy chain sequences)).

[0121] In some embodiments, the isolated antibody comprises a heavy chain sequence set forth in SEQ ID NO: 475 and / or SEQ ID NO: 476 and a light chain sequence set forth in SEQ ID NO: 477. In some embodiments, the isolated antibody comprises a heavy chain sequence set forth in SEQ ID NO: 475 and a light chain sequence set forth in SEQ ID NO: 477. The C-terminal lysine in SEQ ID NO: 475 may not be present if cleavage occurs during manufacture or after administration (which would result in the heavy chain sequence of SEQ ID NO: 476).

[0122] In some embodiments, the Fc region binds to Neonatal Fc receptor (FcRn).

[0123] In some embodiments, the Fc region binds an FcRn with higher affinity at pH 6.0 compared to an antibody comprising a wild-type Fc region.

[0124] In some embodiments, the Fc region binds to FcRn with a KD of < 1 x 10'7M at pH 6.0.

[0125] In some embodiments, the antibody, or antigen binding fragment thereof, is a monoclonal antibody.

[0126] In some embodiments, the antibody, or antigen binding fragment thereof, binds an IL-4Rα sequence set forth in any one of SEQ ID NOs: 237-240.

[0127] In some embodiments, the antibody, or antigen binding fragment thereof, binds to an IL-4Rα sequence set forth in any one of SEQ ID NOs: 237-240 with a KD of less than or equal to about 1, 2, 3, 4, 5, 6, 7, 8, 9 x 10’9M, as measured by surface plasmon resonance (SPR).

[0128] In some embodiments, the antibody, or antigen binding fragment thereof, binds to an IL-4Rα sequence set forth in any one of SEQ ID NOs: 237-240 with a KD of less than or equal to about 1 x 1010M, as measured by surface plasmon resonance (SPR).

[0129] In some embodiments, the antibody, or antigen binding fragment thereof, binds to human IL-4Rα with a KD of less than or equal to about 1 x 10’9M, as measured by surface plasmon resonance (SPR).

[0130] In some embodiments, the antibody, or antigen binding fragment thereof, exhibits a melting temperature greater than 68°C as measured by Differential Scanning Fluorometry (DSF).

[0131] In some embodiments, the antibody, or antigen binding fragment thereof, exhibits a melting temperature greater than 75°C as measured by Differential Scanning Fluorometry (DSF).

[0132] In some embodiments, the antibody, or antigen binding fragment thereof, exhibits an aggregation temperature equal to or greater than 71.2°C as measured by Differential Scanning Fluorometry (DSF).

[0133] In some embodiments, the antibody, or antigen binding fragment thereof, has a retention time of 15.2 minutes or less as measured by hydrophobic interaction chromatography.

[0134] In some embodiments, the antibody, or antigen binding fragment thereof, does not have a heavy chain variable region sequence set forth in SEQ ID NO. 113.

[0135] In some embodiments, the antibody, or antigen binding fragment thereof, does not have a heavy chain sequence set forth in SEQ ID NO. 146.

[0136] In some embodiments, the antibody, or antigen binding fragment thereof comprises a heavy chain comprising a constant heavy chain sequence selected from a sequence set forth in any one of SEQ ID NOs: 192-234, 251-308, 310-350, and 352-407. In some embodiments, the antibody, or antigen binding fragment thereof does not comprise a constant heavy chain sequence set forth in any of SEQ ID NOs: 235, 309, and 351 (i.e., a human IgG4-SP constant heavy chain region).

[0137] In certain embodiments, the isolated antibody, or antigen binding fragment thereof, is used in the treatment of an inflammatory disorder or disease. In certain embodiments, the isolated antibody, or antigen binding fragment thereof, is used in the treatment of atopic dermatitis. In certain embodiments, the isolated antibody, or antigen binding fragment thereof, is used in the treatment of idiopathic pulmonary fibrosis. In certain embodiments, the isolated antibody, or antigen binding fragment thereof, is used in the treatment of alopecia areata. In certain embodiments, the isolated antibody, or antigen binding fragment thereof, is used in the treatment of chronic sinusitis with nasal polyps. In certain embodiments, the isolated antibody, or antigen binding fragment thereof, is used in the treatment of Chronic Rhinosinusitis without Nasal Polyps (CRSsNP). In certain embodiments, the isolated antibody, or antigen binding fragment thereof, is used in the treatment of eosinophilic esophagitis (EoE). In certain embodiments, the isolated antibody, or antigen binding fragment thereof, is used in the treatment of Eosinophilic gastrointestinal disorder or disease (EGID) selected from the group consisting of Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), Eosinophilic Colitis (EoC), and Eosinophilic Gastroenteritis (EGE). In certain embodiments, the isolated antibody, or antigen binding fragment thereof, is used in the treatment of Churg-Strauss syndrome / Eosinophilic granulomatosis with polyangiitis (EGPA). In certain embodiments, the isolated antibody, or antigen binding fragment thereof, is used in the treatment of Prurigo Nodularis (PN). In certain embodiments, the isolated antibody, or antigen binding fragment thereof, is used in the treatment of Chronic Spontaneous Urticaria (CSU). In certain embodiments, the isolated antibody, or antigen binding fragment thereof, is used in the treatment of Chronic Pruritis of Unknown Origin (CPUO). In certain embodiments, the isolated antibody, or antigen binding fragment thereof, is used in the treatment of Bullous Pemphigoid (BP). In certain embodiments, the isolated antibody, or antigen binding fragment thereof, is used in the treatment of Cold Inducible Urticaria (ColdU). In certain embodiments, the isolated antibody, or antigen binding fragment thereof, is used in the treatment of Allergic Fungal Rhinosinusitis (AFRS). In certain embodiments, the isolated antibody, or antigen binding fragment thereof, is used in the treatment of Allergic Bronchopulmonary Aspergillosis (ABPA). In certain embodiments, the isolated antibody, or antigen binding fragment thereof, is used in the treatment of Chronic Obstructive Pulmonary Disease (COPD). In certain embodiments, the isolated antibody, or antigen binding fragment thereof, is used in the treatment of an inflammatory bowel disease, such as Crohn’s disease or ulcerative colitis. Incertain embodiments, the isolated antibody, or antigen binding fragment thereof, is used in the treatment of lupus. In certain embodiments, the isolated antibody, or antigen binding fragment thereof, is used in the treatment of rheumatoid arthritis. In certain embodiments, the isolated antibody, or antigen binding fragment thereof, is used in the treatment of psoriasis. In certain embodiments, the isolated antibody, or antigen binding fragment thereof, is used in the treatment of celiac disease. In certain embodiments, the isolated antibody, or antigen binding fragment thereof, is used in the treatment of hidradenitis suppurativa. In certain embodiments, the isolated antibody, or antigen binding fragment thereof, is used in the treatment of systemic sclerosis.

[0138] In certain aspects, disclosed herein is an isolated polynucleotide or set of polynucleotides encoding the antibody of any of the above claims, a VH thereof, a VL thereof, a light chain thereof, a heavy chain thereof, or an antigen-binding portion thereof, and optionally, wherein the polynucleotide or set of polynucleotides comprises cDNA.

[0139] In certain aspects, disclosed herein is a vector or set of vectors comprising the polynucleotide or set of polynucleotides discloses herein.

[0140] In certain aspects, disclosed herein is a host cell comprising the polynucleotide or set of polynucleotides or the vector or set of vectors disclosed herein.

[0141] In certain aspects, disclosed herein is a method of producing an antibody, or antigen binding fragment thereof, the method comprising expressing the antibody, or antigen binding fragment thereof, with the host cell disclosed herein and isolating the expressed antibody.

[0142] In certain aspects, disclosed herein is a pharmaceutical composition comprising the antibody, or antigen binding fragment thereof, of any one of the embodiments disclosed herein and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition further comprises a hyaluronidase or a variant thereof.

[0143] In certain aspects, disclosed herein is a kit comprising the antibody, or antigen binding fragment thereof, of any one of the embodiments disclosed herein or a pharmaceutical composition disclosed herein and instructions for use. In some embodiments, the kit further comprises a hyaluronidase or a variant thereof.

[0144] In certain aspects, described herein is a method for treating an inflammatory disorder or disease in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount an antibody, or antigen binding fragment thereof, described herein or a pharmaceutical compositiondescribed 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 sinusitis with nasal polyps. In certain embodiments, the inflammatory disorder or disease is Chronic Rhinosinusitis without Nasal Polyps (CRSsNP). In certain embodiments, the inflammatory disorder or disease is eosinophilic esophagitis (EoE). In certain embodiments, the inflammatory disorder or disease is an Eosinophilic gastrointestinal disorder or disease (EGID) selected from the group consisting of Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), Eosinophilic Colitis (EoC), and Eosinophilic Gastroenteritis (EGE). In certain embodiments, the inflammatory disorder or disease is Churg-Strauss syndrome / Eosinophilic granulomatosis with polyangiitis (EGPA). In certain embodiments, the inflammatory disorder or disease is Prurigo Nodularis (PN). In certain embodiments, the inflammatory disorder or disease is Chronic Spontaneous Urticaria (CSU). In certain embodiments, the inflammatory disorder or disease is Chronic Pruritis of Unknown Origin (CPUO). In certain embodiments, the inflammatory disorder or disease is Bullous Pemphigoid (BP). In certain embodiments, the inflammatory disorder or disease is Cold Inducible Urticaria (ColdU). In certain embodiments, the inflammatory disorder or disease is Allergic Fungal Rhinosinusitis (AFRS). In certain embodiments, the inflammatory disorder or disease is Allergic Bronchopulmonary Aspergillosis (ABPA). In certain embodiments, the inflammatory disorder or disease is Chronic Obstructive Pulmonary Disease (COPD). In certain embodiments, the inflammatory disorder or disease is an 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. In certain embodiments, the inflammatory disorder or disease is psoriasis. In certain embodiments, the inflammatory disorder or disease is celiac disease. In certain embodiments, the inflammatory disorder or disease is hidradenitis suppurativa. In certain embodiments, the inflammatory disorder or disease is systemic sclerosis.

[0145] In certain aspects, disclosed herein is a method for treating a pathology associated with elevated levels of IL-4, IL- 13, and / or IL-4Rα in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effectiveamount the antibody, or antigen binding fragment thereof, of any one of the embodiments disclosed herein or a pharmaceutical composition disclosed herein.

[0146] In certain aspects, disclosed herein is a method of reducing biological activity of IL-4Rα in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount the antibody, or antigen binding fragment thereof, of any one of the embodiments disclosed herein or a pharmaceutical composition disclosed herein.

[0147] In certain aspects, disclosed herein is a method of inhibiting the TH2 type allergic response in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount the antibody, or antigen binding fragment thereof, of any one of the embodiments disclosed herein or a pharmaceutical composition disclosed herein.

[0148] In certain aspects, disclosed herein is a method of preventing an inflammatory disorder or disease in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount the antibody, or antigen binding fragment thereof, of any one of the embodiments disclosed herein or a pharmaceutical composition disclosed herein.

[0149] In some embodiments of any of the foregoing methods, the method further comprises administering a hyaluronidase or a variant thereof. In some embodiments of any of the foregoing methods, the pharmaceutical composition comprises an antibody, or antigen binding fragment thereof, described herein and a hyaluronidase or a variant thereof.

[0150] In certain aspects, described herein are compositions comprising any of the antibodies, or antigen binding fragments thereof, that bind Interleukin (IL) -4 Receptor alpha (IL-4Rα) described herein and a hyaluronidase or variant thereof.

[0151] In certain aspects, described herein are a combination of any one of the antibodies, or antigen binding fragments thereof, that bind Interleukin (IL)-4 Receptor alpha (IL-4Rα) described herein and a hyaluronidase or variant thereof.

[0152] In certain aspects, described herein are methods of treating an inflammatory disorder or disease in a human patient comprising co-administering to the patient any one of the antibodies, or antigen binding fragments thereof, that bind Interleukin (IL)-4 Receptor alpha (IL-4Rα) described herein and a hyaluronidase or variant thereof.

[0153] In certain embodiments, the antibody, or antigen binding fragment thereof, is a humanized, human, or chimeric antibody. In certain embodiments, the antibody, or antigenbinding fragment thereof, is a humanized antibody. In certain embodiments, the antibody, or antigen binding fragment thereof, is a monoclonal antibody. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a heavy chain human constant region of a class selected from IgG, IgA, IgD, IgE, and IgM. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a human Fc region comprising a human heavy chain constant region of the class IgG and a subclass selected from IgGl, IgG2, IgG3, and IgG4. In certain embodiments, the human Fc region comprises a human IgGl Fc region.

[0154] In certain embodiments the human Fc region comprises a human IgG 1 Fc region with LALA mutations. In certain embodiments the human Fc region comprises a human IgGl Fc region with YTE mutations. In certain embodiments the human Fc region comprises a human IgGl Fc region with LALA and YTE mutations. In certain embodiments, when direct numbering is used these “YTE” and “LALA” mutations can be located at different amino acid position numbers. For example, in one embodiment, the human Fc region comprises a human IgGl Fc region with LALA mutations at L242A / L243A and / or YTE mutations at M260Y / S262T / T264E.

[0155] In certain embodiments, the antibody, or antigen binding fragment thereof, that binds Interleukin (IL)-4 Receptor alpha (IL-4Rα) comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO:2; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 6; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 20; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 30; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 47; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61. In certain embodiments, the antibody, or antigen binding fragment thereof, that binds Interleukin (IL)-4 Receptor alpha (IL-4Rα) comprises a VH sequence set forth in SEQ ID NO: 134 and a VL sequence set forth in SEQ ID NO: 178.

[0156] In certain embodiments, the antibody, or antigen binding fragment thereof, that binds Interleukin (IL)-4 Receptor alpha (IL-4Rα) comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO:1; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 5; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 17; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 26; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 41; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 53. In certain embodiments, the antibody, or antigen binding fragment thereof, that bindsInterleukin (IL)-4 Receptor alpha (IL-4Rα) comprises a VH sequence set forth in SEQ ID NO: 113 and a VL sequence set forth in SEQ ID NO: 146.

[0157] In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a human Fc region comprising a human IgG sequence selected from a sequence set forth in any one of SEQ ID NOs: 192-235 and 251-407. In certain embodiments, the antibody, or antigen binding fragment thereof comprises a heavy chain comprising a constant heavy chain sequence selected from a sequence set forth in any one of SEQ ID NOs: 192- 234, 251-308, 310-350, and 352-407. In certain embodiments, the antibody, or antigen binding fragment thereof does not comprise a constant heavy chain sequence set forth in any of SEQ ID NOs: 235, 309, and 351 (i.e., a human IgG4-SP constant heavy chain region). In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a heavy chain comprising a constant heavy chain sequence set forth in SEQ ID NO: 321. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a light chain comprising a constant light chain sequence set forth in SEQ ID NO: 236.

[0158] In some embodiments, the antibody, or antigen binding fragment thereof, comprises an Fc region comprising one or more amino acid substitutions, wherein the one or more amino acid substitutions result in an increase in one or more of antibody half-life, ADCC activity, ADCP activity, or CDC activity compared with the Fc region without the one or more amino acid substitutions.

[0159] In some embodiments, the antibody, or antigen binding fragment thereof, comprises an Fc region comprising one or more amino acid substitutions, wherein the one or more amino acid substitutions result in a decrease in one or more of, ADCC activity, ADCP activity or CDC activity compared to an antibody comprising a wild-type Fc region.

[0160] In certain embodiments, the one or more amino acid substitutions is selected from the group consisting of S228P, M252Y, S254T, T256E, T256D, T250Q, H285D, T307A, T307Q, T307R, T307W, L309D, Q411H, Q311V, A378V, E380A, M428L, N434A, N434S, N297A, D265A, L234A, L235A, and N434W; optionally, wherein the one or more amino acid substitutions comprises a plurality of amino acid substitutions selected from the group consisting of M428L / N434S (LS), M252Y / S254T / T256E (YTE), T250Q / M428L, T307A / E380A / N434A, T256D / T307Q (DQ), T256D / T307W (DW), M252Y / T256D (YD), T307Q / Q311V / A378V (QVV), T256D / H285D / T307R / Q311V / A378V (DDRVV), L309D / Q311H / N434S (DHS), S228P / L235E (SPLE), L234A / L235A (LALA), M428L / N434A (LA), L235A / G237A (LAGA), L234A / L235A / G237A (LALAGA),L234A / L235A / P329G (LALAPG), D265A / YTE, LALA / YTE, LAGA / YTE, LALAGA / YTE, LALAPG / YTE, N297A / LS, D265A / LS, LALA / LS, LALAGA / LS, LALAPG / LS, N297A / DHS, D265A / DHS, LALA / DHS, LAGA / DHS, LALAGA / DHS, LALAPG / DHS, SP / YTE, SPLE / YTE, SP / LS, SPLE / LS, SP / DHS, SPLE / DHS, N297A / LA, D265A / LA, LALA / LA, LAGA / LA, LALAGA / LA, LALAPG / LA, N297A / N434A, D265A / N434A, LALA / N434A, LAGA / N434A, LALAGA / N434A, LALAPG / N434A, N297A / N434W, D265A / N434W, LALA / N434W, LAGA / N434W, LALAGA / N434W, LALAPG / N434W, N297A / DQ, D265A / DQ, LALA / DQ, LAGA / DQ, LALAGA / DQ, LALAPG / DQ, N297A / DW, D265A / DW, LALA / DW, LAGA / DW, LALAGA / DW, LALAPG / DW, N297A / YD, D265A / YD, LALA / YD, LAGA / YD, LALAGA / YD, LALAPG / YD, T307Q / Q311 V / A378V (QVV), N297A / QVV, D265A / QVV, LALA / QVV, LAGA / QVV, LALAGA / QVV, LALAPG / QVV, DDRVV, N297A / DDRVV, D265A / DDRVV, LALA / DDRVV, LAGA / DDRVV, LALAGA / DDRVV, and LALAPG / DDRVV. In certain embodiments, the one or more amino acid substitutions is selected from the group consisting of LS, YTE, T250Q / M428L, T307A / E380A / N434A, DQ, DW, YD, QVV, DHS, LA, D265A / YTE, LALA / YTE, LAGA / YTE, LALAGA / YTE, LALAPG / YTE, N297A / LS, D265A / LS, LALA / LS, LALAGA / LS, LALAPG / LS, N297A / DHS, D265A / DHS, LALA / DHS, LAGA / DHS, LALAGA / DHS, LALAPG / DHS, SP / YTE, SPLE / YTE, SP / LS. SPLE / LS, SP / DHS, SPLE / DHS, N297A / LA, D265A / LA, LALA / LA, LAGA / LA, LALAGA / LA, LALAPG / LA, N297A / DQ, D265A / DQ, LALA / DQ, LAGA / DQ, LALAGA / DQ, LALAPG / DQ, N297A / DW, D265A / DW, LALA / DW, LAGA / DW, LALAGA / DW, LALAPG / DW, N297A / YD, D265A / YD, LALA / YD, LAGA / YD, LALAGA / YD, LALAPG / YD, N297A / QVV, D265A / QVV, LALA / QVV, LAGA / QVV, LALAGA / QVV, and LALAPG / QVV.

[0161] In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a human IgGl Fc region with LALA and YTE mutations.

[0162] In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 134, a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 178, and a human IgGl Fc region comprising LALA and YTE substitutions. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 134, a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 178, a constant heavy chain sequence set forth in SEQ IDNO: 321 and / or a constant heavy chain sequence set forth in SEQ ID NO: 205, and a constant light chain sequence set forth in SEQ ID NO: 236. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 134, a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 178, a constant heavy chain sequence set forth in SEQ ID NO: 321, and a constant light chain sequence set forth in SEQ ID NO: 236. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a heavy chain sequence set forth in SEQ ID NO: 475 and a light chain sequence set forth in SEQ ID NO: 477. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 134, a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 178, a constant heavy chain sequence set forth in SEQ ID NO: 205, and a constant light chain sequence set forth in SEQ ID NO: 236. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a heavy chain sequence set forth in SEQ ID NO: 476 and a light chain sequence set forth in SEQ ID NO: 477.

[0163] In certain embodiments, the Fc region of the antibody binds to Neonatal Fc receptor (FcRn). In certain embodiments, the Fc region binds an FcRn with higher affinity at pH 6.0 compared to an antibody comprising a wild-type Fc region. In certain embodiments, the Fc region binds to FcRn with a KD of < 1 x 107M at pH 6.0.

[0164] In certain embodiments, the antibody, or antigen binding fragment thereof, binds an IL-4Rα sequence set forth in any one of SEQ ID NOs: 237-240. In certain embodiments, the antibody, or antigen binding fragment thereof, binds to an IL-4Rα sequence set forth in any one of SEQ ID NOs: 237-240 with a KD of less than or equal to about 1, 2, 3, 4, 5, 6, 7, 8, 9 x 10’9M, as measured by surface plasmon resonance (SPR). In certain embodiments, the antibody, or antigen binding fragment thereof, binds to an IL-4Rα sequence set forth in any one of SEQ ID NOs: 237-240 with a KD of less than or equal to about 1 x 1010M, as measured by surface plasmon resonance (SPR). In certain embodiments, the antibody, or antigen binding fragment thereof, binds to human IL-4Rα with a KD of less than or equal to about 1 x 10‘9M, as measured by surface plasmon resonance (SPR).

[0165] In certain embodiments, the antibody, or antigen binding fragment thereof, exhibits a melting temperature greater than 68°C as measured by Differential Scanning Fluorometry (DSF). In certain embodiments, the antibody, or antigen binding fragment thereof, exhibits a melting temperature greater than 75°C as measured by DifferentialScanning Fluorometry (DSF). In certain embodiments, the antibody, or antigen binding fragment thereof, exhibits an aggregation temperature equal to or greater than 71.2°C as measured by Differential Scanning Fluorometry (DSF). In certain embodiments, the antibody, or antigen binding fragment thereof, has a retention time of 15.2 minutes or less as measured by hydrophobic interaction chromatography.

[0166] Any suitable hyaluronidase or variant thereof can be used in the compositions, combinations, and methods described herein. In certain embodiments, the hyaluronidase is a soluble hyaluronidase. In certain embodiments, the hyaluronidase is a recombinant human hyaluronidase. In certain embodiments, the recombinant human hyaluronidase comprises the amino acid sequence set forth in any one of SEQ ID NOs: 408-417 and 419-474, or a mixture thereof. In certain embodiments, the recombinant human hyaluronidase is rHuPH20 (i.e., a composition comprising one or more of SEQ ID NOs: 410-415). In certain embodiments, the rHuPH20 formulation is ENHANZE®.

[0167] In one embodiment, the recombinant human hyaluronidase includes a sequence of amino acids in any one of SEQ ID NOs: 408-417 and 419-474, or has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to a sequence of amino acids included in any one of SEQ ID NOs: 408-417 and 419-474 and retains hyaluronidase activity. In one embodiment, the recombinant human hyaluronidase comprises a sequence having at least 95%, 96%, 97%, 98%, or 99% to the amino acid sequence of SEQ ID NO: 408. In one embodiment, the recombinant human hyaluronidase comprises a sequence having at least 95%, 96%, 97%, 98%, or 99% to the amino acid sequence of SEQ ID NO: 410. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:408. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:408. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:409. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:409. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NQ:410. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:410. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:411. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ IDN0:411. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:412. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:412. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:413. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:413. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:414. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:414. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:415. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:415. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:416. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:416. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:417. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:417. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:419. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:419. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:420. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:420. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:421 . In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:421. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:422. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:422. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:423. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:423. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:424. Inanother embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:424. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:425. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:425. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:426. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:426. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:427. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:427. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:428. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:428. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:429. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:429. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:430. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:430. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:431. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:431. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:432. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:432. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:433. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:433. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:434. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:434. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:435. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:435. In anotherembodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:436. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:436. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:437. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:437. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:438. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:438. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:439. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:439. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:440. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:440. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:441. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:441. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:442. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO: 442. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:443. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:443. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:444. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:444. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:445. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:445. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:446. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:446. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:447. In another embodiment, therecombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:447. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:448. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:448. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:449. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO: 449. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:450. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:450. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:451. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:451. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:452. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:452. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:453. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:453. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:454. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:454. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:455. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:455. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:456. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:456. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:457. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:457. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:458. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:458. In another embodiment, the recombinanthuman hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:459. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:459. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:460. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:460. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:461. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:461. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:462. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:462. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:463. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:463. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:464. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:464. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:465. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:465. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:466. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:466. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:467. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:467. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:468. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:468. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:469. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:469. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NQ:470. In another embodiment, the recombinant humanhyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:470. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:471. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:471. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:472. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:472. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:473. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:473. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:474. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:474.

[0168] In certain embodiments, the hyaluronidase or variant thereof and the anti-IL-4Rα antibody, or antigen binding fragment thereof, are administered in separate formulations. In certain embodiments, the hyaluronidase or variant thereof and the anti-IL-4Rα antibody, or antigen binding fragment thereof, are administered simultaneously in separate formulations. In certain embodiments, the hyaluronidase or variant thereof is administered to the patient prior to administration of the anti-IL-4Rα antibody, or antigen binding fragment thereof. In certain embodiments, the hyaluronidase or variant thereof is administered to the patient after administration of the anti-IL-4Rα antibody, or antigen binding fragment thereof. In certain embodiments, the hyaluronidase or variant thereof and the anti-IL-4Rα antibody, or antigen binding fragment thereof, are mixed and administered in a single formulation. In certain embodiments, the hyaluronidase or variant thereof and the anti-IL-4Rα antibody, or antigen binding fragment thereof, are administered by subcutaneous injection. In certain embodiments, the hyaluronidase or variant thereof and the anti-IL-4Rα antibody, or antigen binding fragment thereof, are administered by intravenous injection.

[0169] In certain embodiments, the hyaluronidase is rHuPH20 administered at a concentration of 5,000, 6,000, 7,000, 8,000, 9,000, 10,000, 11,000, 12,000, 13,000, 14,000, 15,000, 16,000, 17,000, 18,000, 19,000, 20,000, 21,000, 22,000, 23,000, 24,000, 25,000, 26,000, 27,000, 28,000, 29,000, 30,000, 31,000, 32,000, 33,000, 34,000, 35,000, 36,000, 37,000, 38.000, 39,000, or 40,000 units.

[0170] In certain embodiments, methods of treating an inflammatory disorder or disease in a human patient are provided, wherein the method comprises co-administering to the patient any one of the antibodies, or antigen binding fragments thereof, that bind Interleukin (IL)-4 Receptor alpha (IL-4Rα) described herein and a hyaluronidase or variant thereof. In certain embodiments, the inflammatory disorder or disease is atopic dermatitis. In certain embodiments, the treatment reduces disease severity in the patient and wherein disease severity is assessed by an atopic dermatitis disease severity outcome measure. In certain embodiments, the inflammatory disorder or disease is asthma, idiopathic pulmonary fibrosis, alopecia areata, chronic sinusitis with nasal polyps, Chronic Rhinosinusitis without Nasal Polyps (CRSsNP), eosinophilic esophagitis (EoE), Churg-Strauss syndrome / Eosinophilic granulomatosis with polyangiitis (EGPA), Prurigo Nodularis (PN), Chronic Spontaneous Urticaria (CSU), Chronic Pruritis of Unknown Origin (CPUO), Bullous Pemphigoid (BP), Cold Inducible Urticaria (ColdU), Allergic Fungal Rhinosinusitis (AFRS), Allergic Bronchopulmonary Aspergillosis (ABPA), Chronic Obstructive Pulmonary Disease (COPD), an inflammatory bowel disease, such as Crohn’s disease or ulcerative colitis, lupus, rheumatoid arthritis (RA), psoriasis, celiac disease, hidradenitis suppurativa, or systemic sclerosis. In certain embodiments, the inflammatory disorder or disease is an Eosinophilic gastrointestinal disorder or disease (EGID) selected from the group consisting of Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), Eosinophilic Colitis (EoC), and Eosinophilic Gastroenteritis (EGE).

[0171] In certain aspects, described herein are compositions comprising an antibody, or antigen binding fragment thereof, that binds Interleukin (IL)-4 Receptor alpha (IL-4Rα) and a hyaluronidase or variant thereof, wherein the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 2; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 6; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 20; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 30; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 47; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61. In certain embodiments, the antibody, or antigen binding fragment thereof, that binds Interleukin (IL)-4 Receptor alpha (IL-4Rα) 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, or antigen binding fragment thereof, comprises a heavy chain comprising a constant heavy chain sequence set forth in any one of SEQ ID NOs: 192- 235 and 251-407. In certain embodiments, the antibody, or antigen binding fragment thereof,comprises a heavy chain comprising a constant heavy chain sequence set forth in SEQ ID NO: 321. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a light chain comprising a constant light chain sequence set forth in SEQ ID NO: 236. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 134, a VL sequence set forth in SEQ ID NO: 178, a constant heavy chain sequence set forth in SEQ ID NO: 321, and a constant light chain sequence set forth in SEQ ID NO: 236. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a heavy chain sequence set forth in SEQ ID NO: 475 and a light chain sequence set forth in SEQ ID NO: 477.

[0172] In certain aspects, described herein are compositions comprising an antibody, or antigen binding fragment thereof, that binds Interleukin (lL)-4 Receptor alpha (lL-4Rα) and a hyaluronidase or variant thereof, wherein the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO:1; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 5; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 17: a CDR-L1 comprising the sequence set forth in SEQ ID NO: 26; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 41; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 53. In certain embodiments, the antibody, or antigen binding fragment thereof, that binds Interleukin (IL)-4 Receptor alpha (IL-4Rα) comprises a VH sequence set forth in SEQ ID NO: 113 and a VL sequence set forth in SEQ ID NO: 146. In certain embodiments, the antibody, or antigen binding fragment thereof comprises a heavy chain comprising a constant heavy chain sequence selected from a sequence set forth in any one of SEQ ID NOs: 192-234, 251-308, 310-350, and 352-407. In certain embodiments, the antibody, or antigen binding fragment thereof does not comprise a constant heavy chain sequence set forth in any of SEQ ID NOs: 235, 309, and 351 (z.e., a human IgG4-SP constant heavy chain region).

[0173] In certain aspects, described herein are a combination of an antibody, or antigen binding fragment thereof, that binds IL-4Rα, and a hyaluronidase or variant thereof, wherein the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO:2; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 6; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 20; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 30; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 47; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61. In other aspects, described herein are a combination of an antibody, or antigen bindingfragment thereof, that binds Interleukin (IL)-4 Receptor alpha (IL-4Rα), wherein the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 134 and a VL sequence set forth in SEQ ID NO: 178, and a hyaluronidase or variant thereof. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a heavy chain comprising a constant heavy chain sequence set forth in any one of SEQ ID NOs: 192-235 and 251-407. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a heavy chain comprising a constant heavy chain sequence set forth in SEQ ID NO: 321. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a light chain comprising a constant light chain sequence set forth in SEQ ID NO: 236. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 134, a VL sequence set forth in SEQ ID NO: 178, a constant heavy chain sequence set forth in SEQ ID NO: 321, and a constant light chain sequence set forth in SEQ ID NO: 236. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a heavy chain sequence set forth in SEQ ID NO: 475 and a light chain sequence set forth in SEQ ID NO: 477. In certain aspects, described herein are a combination of an antibody, or antigen binding fragment thereof, that binds IL-4Rα, and a hyaluronidase or variant thereof, wherein the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO:1; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 5; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 17; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 26; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 41 ; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 53. In certain embodiments, the antibody that binds Interleukin (IL)-4 Receptor alpha (IL-4Rα) comprises a VH sequence set forth in SEQ ID NO: 113 and a VL sequence set forth in SEQ ID NO: 146. In certain embodiments, the antibody, or antigen binding fragment thereof comprises a heavy chain comprising a constant heavy chain sequence selected from a sequence set forth in any one of SEQ ID NOs: 192-234, 251-308, 310-350, and 352-407. In certain embodiments, the antibody, or antigen binding fragment thereof does not comprise a constant heavy chain sequence set forth in any of SEQ ID NOs: 235, 309, and 351 (z.e., a human IgG4-SP constant heavy chain region).

[0174] In certain aspects, described herein are methods of treating an inflammatory disorder or disease in a human patient comprising co-administering to the patient an antibody, or antigen binding fragment thereof, that binds Interleukin (IL)-4 Receptor alpha (IL-4Rα),and a hyaluronidase or variant thereof, wherein the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO:2; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 6; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 20; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 30; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 47; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61. In other aspects, described herein are methods of treating an inflammatory disorder or disease in a human patient comprising co-administering to the patient an antibody, or antigen binding fragment thereof, that binds Interleukin (IL)-4 Receptor alpha (IL-4Rα), and a hyaluronidase or variant thereof, wherein the antibody, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, comprises a heavy chain comprising a constant heavy chain sequence set forth in any one of SEQ ID NOs: 192-235 and 251-407. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a heavy chain comprising a constant heavy chain sequence set forth in SEQ ID NO: 321. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a light chain comprising a constant light chain sequence set forth in SEQ ID NO: 236. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 134, a VL sequence set forth in SEQ ID NO: 178, a constant heavy chain sequence set forth in SEQ ID NO: 321, and a constant light chain sequence set forth in SEQ ID NO: 236. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a heavy chain sequence set forth in SEQ ID NO: 475 and a light chain sequence set forth in SEQ ID NO: 477.

[0175] In certain aspects, described herein are methods of treating an inflammatory disorder or disease in a human patient comprising co-administering to the patient an antibody, or antigen binding fragment thereof, that binds Interleukin (IL)-4 Receptor alpha (IL-4Rα), and a hyaluronidase or variant thereof, wherein the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 1; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 5; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 17; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 26; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 41; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 53. In other aspects, described herein are methods of treating an inflammatory disorder or disease in a human patient comprising co-administeringto the patient an antibody, or antigen binding fragment thereof, that binds Interleukin (IL)-4 Receptor alpha (IL-4Rα), and a hyaluronidase or variant thereof, wherein the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 113 and a VL sequence set forth in SEQ ID NO: 146. In certain embodiments, the antibody, or antigen binding fragment thereof comprises a heavy chain comprising a constant heavy chain sequence selected from a sequence set forth in any one of SEQ ID NOs: 192-234, 251-308, 310-350, and 352-407. In certain embodiments, the antibody, or antigen binding fragment thereof does not comprise a constant heavy chain sequence set forth in any of SEQ ID NOs: 235, 309, and 351 (z.e., a human IgG4-SP constant heavy chain region).

[0176] In certain aspects, described herein are kits for treating an inflammatory disorder or disease in a human patient, the kit comprising: (a) a dose of any one of the antibodies, or antigen binding fragments thereof, that binds IL-4Rα described herein; (b) a dose of a hyaluronidase or variant thereof; and (c) instructions. In certain embodiments, the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO:2; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 6; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 20; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 30; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 47; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61. In certain embodiments, the antibody, or antigen binding fragment thereof, that binds IL- 4Rα 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, or antigen binding fragment thereof, that binds IL-4Rα comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO:1; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 5; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 17; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 26; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 41; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 53. In certain embodiments, the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VH sequence set forth in SEQ ID NO: 113 and a VL sequence set forth in SEQ ID NO: 146. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a heavy chain comprising a constant heavy chain sequence set forth in any one of SEQ ID NOs: 192-235 and 251-407. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 134, a VL sequence set forth in SEQ ID NO: 178, a constant heavy chain sequence set forth in SEQ ID NO: 321, and a constant light chainsequence set forth in SEQ ID NO: 236. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a heavy chain sequence set forth in SEQ ID NO: 475 and a light chain sequence set forth in SEQ ID NO: 477.

[0177] In certain embodiments, the hyaluronidase is a soluble hyaluronidase. In certain embodiments, the hyaluronidase is a recombinant human hyaluronidase or variant thereof. In certain embodiments, the hyaluronidase is a recombinant human hyaluronidase. In certain embodiments, the recombinant human hyaluronidase comprises the amino acid sequence set forth in any one of SEQ ID NOs: 408-417 and 419-474, or a mixture thereof. In certain embodiments, the recombinant human hyaluronidase is rHuPH20 (i.e., a composition comprising one or more of SEQ ID NOs: 410-415). In certain embodiments, the rHuPH20 formulation is ENHANZE®.

[0178] In certain embodiments, the kit is for use in treating an inflammatory disorder or disease. In certain embodiments, the inflammatory disorder or disease is atopic dermatitis. In certain embodiments, the inflammatory disorder or disease is selected from the group consisting of asthma, idiopathic pulmonary fibrosis, alopecia areata, chronic sinusitis with nasal polyps, Chronic Rhinosinusitis without Nasal Polyps (CRSsNP), eosinophilic esophagitis (EoE), Churg-Strauss syndrome / Eosinophilic granulomatosis with polyangiitis (EGPA), Prurigo Nodularis (PN), Chronic Spontaneous Urticaria (CSU), Chronic Pruritis of Unknown Origin (CPUO), Bullous Pemphigoid (BP), Cold Inducible Urticaria (ColdU), Allergic Fungal Rhinosinusitis (AFRS), Allergic Bronchopulmonary Aspergillosis (ABPA), Chronic Obstructive Pulmonary Disease (COPD), an inflammatory bowel disease, such as Crohn’s disease or ulcerative colitis, lupus, rheumatoid arthritis (RA), psoriasis, celiac disease, hidradenitis suppurativa, and systemic sclerosis. In certain embodiments, the inflammatory disorder or disease is an Eosinophilic gastrointestinal disorder or disease (EGID) selected from the group consisting of Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), Eosinophilic Colitis (EoC), and Eosinophilic Gastroenteritis (EGE).DETAILED DESCRIPTION

[0179] Described herein are compositions and combinations containing anti-IL-4Rα antibodies, or antigen binding fragments thereof, and methods of use thereof. The compositions and combinations containing an anti-IL-4Rα antibody, or antigen binding fragment thereof, described herein further comprise a hyaluronidase or a variant thereof. Also described herein are methods of treating a subject having an inflammatory disorder ordisease, such as atopic dermatitis, by administering an anti-IL-4Rα antibody, or antigen binding fragment thereof, described herein and a hyaluronidase or a variant thereof. The anti- IL-4Rα antibody, or antigen binding fragment thereof, and the hyaluronidase or a variant thereof may be administered separately or may be co-formulated and administered in a single composition.Definitions

[0180] Unless otherwise defined, all terms of art, notations and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art. The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodologies by those skilled in the art, such as, for example, the widely utilized molecular cloning methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual 4th ed. (2012) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer-defined protocols and conditions unless otherwise noted.

[0181] As used herein, the singular forms “a,” “an,” and “the” include plural references unless indicated otherwise.

[0182] It is understood that aspects and embodiments of the invention described herein include “comprising,” “consisting,” and “consisting essentially of’ aspects and embodiments.

[0183] For all compositions described herein, and all methods using a composition described herein, the compositions can either comprise the listed components or steps, or can “consist essentially of’ the listed components or steps. When a composition is described as “consisting essentially of’ the listed components, the composition contains the components listed and may contain other components which do not substantially affect the condition being treated, but do not contain any other components which substantially affect the condition being treated other than those components expressly listed; or, if the composition does contain extra components other than those listed which substantially affect the condition being treated, the composition does not contain a sufficient concentration or amount of the extra components to substantially affect the condition being treated. When a method isdescribed as “consisting essentially of’ the listed steps, the method contains the steps listed, and may contain other steps that do not substantially affect the condition being treated, but the method does not contain any other steps which substantially affect the condition being treated other than those steps expressly listed. As a non-limiting specific example, when a composition is described as “consisting essentially of’ a component, the composition may additionally contain any amount of pharmaceutically acceptable carriers, vehicles, or diluents and other such components which do not substantially affect the condition being treated.

[0184] The term “vector,” as used herein, refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes the vector as a selfreplicating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as “expression vectors.”

[0185] The terms “host cell,” “host cell line,” and “host cell culture” are used interchangeably herein and refer to cells into which an exogenous nucleic acid has been introduced, and the progeny of such cells. Host cells include “transformants” (or “transformed cells”) and “transfectants” (or “transfected cells”), which each include the primary transformed or transfected cell and progeny derived therefrom. Such progeny may not be completely identical in nucleic acid content to a parent cell, and may contain mutations. A “recombinant host cell” or “host cell” refers to a cell that includes an exogenous polynucleotide, regardless of the method used for insertion, for example, direct uptake, transduction, f-mating, or other methods known in the art to create recombinant host cells.

[0186] As used herein, the term “eukaryote” refers to organisms belonging to the phylogenetic domain Eukarya such as animals (including but not limited to, mammals, insects, reptiles, birds, etc.), ciliates, plants (including but not limited to, monocots, dicots, algae, etc.), fungi, yeasts, flagellates, microsporidia, protists, etc.

[0187] As used herein, the term “prokaryote” refers to prokaryotic organisms. For example, a non-eukaryotic organism can belong to the Eubacteria (including but not limited to, Escherichia coli, Thermits thermophilus, Bacillus stearothermophilus, Pseudomonas fluorescens, Pseudomonas aeruginosa, Pseudomonas putida, etc.) phylogenetic domain, or the Archaea (including but not limited to, Methanococcus jannaschii, Methanobacterium thermoautotrophicum, Halobacterium such as Haloferax volcanii and Halobacterium speciesNRC-1, Archaeoglobus fulgidus, Pyrococcus furiosus, Pyrococcus horikoshii, Aeuropyrum pernix, etc.) phylogenetic domain.

[0188] An “effective amount” or “therapeutically effective amount” as used herein refers to an amount of therapeutic compound, such as an anti-IL-4Rα antibody, or antigen binding fragment thereof, administered to an individual, either as a single dose or as part of a series of doses, which is effective to produce or contribute to a desired therapeutic effect, either alone or in combination with another therapeutic modality. Examples of a desired therapeutic effect are reducing an aberrant immune response, slowing or delaying disease development, stabilization of disease, and amelioration of one or more symptoms. An effective amount may be given in one or more dosages.

[0189] The term “treating” (and variations thereof such as “treat” or “treatment”) refers to clinical intervention in an attempt to alter the natural course of a disease or condition in a subject in need thereof. Treatment can be performed during the course of clinical pathology. Desirable effects of treatment include preventing recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.

[0190] The term “sufficient amount” means an amount sufficient to produce a desired effect, e.g., an amount sufficient to modulate an immune response in a subject.

[0191] As used herein, the terms “subject,” “patient,” and “individual” are used interchangeably herein and each term 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 atopic dermatitis. In some aspects, the disease or condition is asthma.

[0192] The term “in vitro” refers to processes that occur in a living cell growing separate from a living organism, e.g., growing in tissue culture.

[0193] The term “in vivo” refers to processes that occur in a living organism.

[0194] The term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic or diagnostic products (e.g., kits) that contain information about the indications, usage, dosage, administration, combination therapy,contraindications and / or warnings concerning the use of such therapeutic or diagnostic products.

[0195] The term “pharmaceutical composition” refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective in treating a subject, and which contains no additional components which are unacceptably toxic to the subject in the amounts provided in the pharmaceutical composition.

[0196] As used herein, the term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms, which are suitable for contact with the tissues of a subject, such as a mammal (e.g., a human) without excessive toxicity, irritation, allergic response, and other problem complications commensurate with a reasonable benefit / risk ratio. Preferably, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals and more particularly in humans.

[0197] The terms “co-administration,” “co-administer,” and “in combination with” include the administration of two or more therapeutic agents either simultaneously, concurrently or sequentially within no specific time limits. In one embodiment, the agents are present in the cell or in the subject's body at the same time or exert their biological or therapeutic effect at the same time. In one embodiment, the therapeutic agents are in the same composition or unit dosage form. In other embodiments, the therapeutic agents are in separate compositions or unit dosage forms. In certain embodiments, a first agent can be administered prior to the administration of a second therapeutic agent.

[0198] The terms “modulate” and “modulation” refer to reducing or inhibiting or, alternatively, activating or increasing, a recited variable.

[0199] The terms “increase” and “activate” refer to an increase of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, or greater in a recited variable.

[0200] The terms “reduce” and “inhibit” refer to a decrease of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, or greater in a recited variable.

[0201] The term “about” indicates and encompasses an indicated value and a range above and below that value. In certain embodiments, the term “about” indicates the designatedvalue ± 10%, ± 5%, or ± 1%. In certain embodiments, where applicable, the term “about” indicates the designated value(s) ± one standard deviation of that value(s).

[0202] The term “agonize” refers to the activation of receptor signaling to induce a biological response associated with activation of the receptor. An “agonist” is an entity that binds to and agonizes a receptor.

[0203] The term “antagonize” refers to the inhibition of receptor signaling to inhibit a biological response associated with activation of the receptor. An “antagonist” is an entity that binds to and antagonizes a receptor.

[0204] For any of the structural and functional characteristics described herein, methods of determining these characteristics are known in the art.

[0205] The term “optionally” is meant, when used sequentially, to include from one to all of the enumerated combinations and contemplates all sub-combinations.

[0206] The term “amino acid” refers to, for example, the twenty common naturally occurring amino acids. Naturally occurring amino acids include alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartic acid (Asp; D), cysteine (Cys; C), glutamic acid (Glu; E), glutamine (Gin; Q), Glycine (Gly; G), histidine (His; H), isoleucine (He; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Vai; V).

[0207] The term “affinity” refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen or epitope). Unless indicated otherwise, as used herein, “affinity” refers to intrinsic binding affinity, which reflects a 1 : 1 interaction between members of a binding pair (e.g., antibody and antigen or epitope).

[0208] The term “kd” (sec-1), as used herein, refers to the dissociation rate constant of a particular antibody-antigen interaction. This value is also referred to as the koff value.

[0209] The term “ka” (M-lxsec-1), as used herein, refers to the association rate constant of a particular antibody-antigen interaction. This value is also referred to as the kon value.

[0210] The term “KD” (M), as used herein, refers to the dissociation equilibrium constant of a particular antibody- anti gen interaction. KD = kd / ka. In some embodiments, the affinity of an antibody is described in terms of the KD for an interaction between such antibody and its antigen. For clarity, as known in the art, a smaller KD value indicates a higher affinity interaction, while a larger KD value indicates a lower affinity interaction.

[0211] The term “KA” (M-l), as used herein, refers to the association equilibrium constant of a particular antibody-antigen interaction. KA = ka / kd.

[0212] As used herein, “administration” refers to providing or giving a subject a therapeutic agent (e.g., an anti-IL-4Rα antibody, or an antigen binding fragment thereof, described herein) by any effective route. Exemplary routes of administration are described herein below.

[0213] As used herein, the term “polypeptide” describes a single polymer in which the monomers are amino acid residues which are covalently conjugated together through amide bonds. A polypeptide is intended to encompass any amino acid sequence, either naturally occurring, recombinant, or synthetically produced.

[0214] As used herein, the terms “nucleic acid” and “polynucleotide,” used interchangeably herein, refer to a polymeric form of nucleosides in any length. Typically, a polynucleotide is composed of nucleosides that are naturally found in DNA or RNA (e.g., adenosine, thymidine, guanosine, cytidine, uridine, deoxyadenosine, deoxythymidine, deoxyguanosine, and deoxycytidine) joined by phosphodiester bonds. The term encompasses molecules comprising nucleosides or nucleoside analogs containing chemically- or biologically-modified bases, modified backbones, etc., whether or not found in naturally occurring nucleic acids, and such molecules may be preferred for certain applications. Where this application refers to a polynucleotide it is understood that both DNA, RNA, and in each case both single- and double-stranded forms (and complements of each single-stranded molecule) are provided.

[0215] As used herein, the terms “conservative mutation,” “conservative substitution,” and “conservative amino acid substitution” refer to a substitution of one or more amino acids for one or more different amino acids that exhibit similar physicochemical properties, such as polarity, electrostatic charge, and steric volume. These properties are summarized for each of the twenty naturally occurring amino acids in TABLE 1 below.TABLE 1. Representative physicochemical properties of naturally occurring amino acidsFrom TABLE 1 it is appreciated that the conservative amino acid families include (i) G, A,V, L. and I; (ii) D and E; (iii) C, S, and T; (iv) H, K, and R; (v) N and Q; and (vi) F, Y, andW. A conservative mutation or substitution is therefore one that substitutes one amino acid for a member of the same amino acid family (e.g., a substitution of Ser for Thr or Lys for Arg).

[0216] The term “antibody” is used herein in its broadest sense and includes certain types of immunoglobulin molecules comprising one or more antigen-binding domains that specifically bind to an antigen or epitope. An antibody specifically includes intact antibodies (e.g., intact immunoglobulins), antibody fragments, and multi-specific antibodies.

[0217] A “anti-IL-4Rα antibody,” “IL-4Rα antibody,” or “IL-4Rα specific antibody” is an antibody, as provided herein, which specifically binds to the antigen lL-4Rα.

[0218] The term “epitope” means a portion of an antigen that specifically binds to an antibody.

[0219] The term “hypervariable region” or “HVR,” as used herein, refers to each of the regions of an antibody variable domain which are hypervariable in sequence and / or form structurally defined loops (“hypervariable loops”).

[0220] The term “antigen-binding domain” means the portion of an antibody that is capable of specifically binding to an antigen or epitope.

[0221] 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.

[0222] The term “human antibody” or “fully human antibody” refers to an antibody which possesses an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or derived from a non-human source that utilizes a human antibody repertoire or human antibody -encoding sequences e.g., obtained from human sources or designed de novo). Human antibodies specifically exclude humanized antibodies.

[0223] The term “humanized antibody” refers to a protein having a sequence that differs from the sequence of an antibody derived from a non-human species by one or more amino acid substitutions, deletions, and / or additions, such that the humanized antibody is less likely to induce an immune response, and / or induces a less severe immune response, as compared to the non-human species antibody, when it is administered to a human subject.

[0224] The term “multispecific antibody’’ refers to an antibody that comprises two or more different antigen-binding domains that collectively specifically bind two or more different epitopes.

[0225] A “monospecific antibody” is an antibody that comprises one or more binding sites that specifically bind to a single epitope. An example of a monospecific antibody is a naturally occurring IgG molecule which, while divalent (i.e., having two antigen-binding domains), recognizes the same epitope at each of the two antigen-binding domains. The binding specificity may be present in any suitable valency.

[0226] The term “monoclonal antibody” refers to an antibody from a population of substantially homogeneous antibodies. A population of substantially homogeneous antibodies comprises antibodies that are substantially similar and that bind the same epitope(s), except for variants that may normally arise during production of the monoclonal antibody. Such variants are generally present in only minor amounts. A monoclonal antibody is typically obtained by a process that includes the selection of a single antibody from a plurality of antibodies. For example, the selection process can be the selection of a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones, yeast clones, bacterial clones, or other recombinant DNA clones. The selected antibody can be further altered, for example, to improve affinity for the target (“affinity maturation”), to humanize the antibody, to improve its production in cell culture, and / or to reduce its immunogenicity in a subject.

[0227] The term “single-chain” refers to a molecule comprising amino acid monomers linearly linked by peptide bonds. In a particular such embodiment, the C-terminus of the Fab light chain is connected to the N-terminus of the Fab heavy chain in the single-chain Fab molecule. As described in more detail herein, an scFv has a variable domain of light chain (VL) connected from its C-terminus to the N-terminal end of a variable domain of heavy chain (VH) by a polypeptide chain. Alternately, the scFv comprises a polypeptide chain wherein the C-terminal end of the VH is connected to the N-terminal end of VL by a polypeptide chain.

[0228] The “Fab fragment” (also referred to as fragment antigen-binding) contains the constant domain (CL) of the light chain and the first constant domain (CHI) of the heavy chain along with the variable domains VL and VH on the light and heavy chains respectively. The variable domains comprise the complementarity determining loops (CDR, also referred to as hypervariable region (HVR)) that are involved in antigen-binding. Fab' fragments differfrom Fab fragments by the addition of a few residues at the carboxy terminus of the heavy chain CHI domain including one or more cysteines from the antibody hinge region.

[0229] “F(ab’)2” fragments contain two Fab’ fragments joined, near the hinge region, by disulfide bonds. F(ab’)2 fragments may be generated, for example, by recombinant methods or by pepsin digestion of an intact antibody. The F(ab’) fragments can be dissociated, for example, by treatment with B-mercaptoethanoL

[0230] “Fv” fragments comprise a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain.

[0231] “Single-chain Fv” or “sFv” or “scFv’’ includes the VH and VL domains of an antibody, wherein these domains are present in a single polypeptide chain. In one embodiment, the Fv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the scFv to form the desired structure for antigen-binding. For a review of scFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994).

[0232] “scFv-Fc” fragments comprise an scFv attached to an Fc domain. For example, an Fc domain may be attached to the C-terminal of the scFv. The Fc domain may follow the VH or VL, depending on the orientation of the variable domains in the scFv (z.e., VH -VL or VL- VH). Any suitable Fc domain known in the art or described herein may be used. In some cases, the Fc domain comprises an IgG4 Fc domain.

[0233] The term “single domain antibody” or “sdAb” refers to a molecule in which one variable domain of an antibody specifically binds to an antigen without the presence of the other variable domain. Single domain antibodies, and fragments thereof, are described in Arabi Ghahroudi et al. (1998) FEBS Letters 414:521-526 and Muyldermans et al. (2001) Trends in Biochem. Sci. 26:230-245, each of which is incorporated by reference in its entirety. Single domain antibodies are also known as sdAbs or nanobodies. SdAbs are fairly stable and easy to express as fusion partner with the Fc chain of an antibody (Harmsen MM, De Haard HJ (2007) “Properties, production, and applications of camelid single-domain antibody fragments,” Appl. Microbiol Biotechnol. 77(1): 13-22).

[0234] The terms “full length antibody,” “intact antibody,” and “whole antibody” are used herein interchangeably to refer to an antibody having a structure substantially similar to a naturally occurring antibody structure and having heavy chains that comprise an Fc region. For example, when used to refer to an IgG molecule, a “full length antibody” is an antibody that comprises two heavy chains and two light chains.

[0235] The term “antibody fragment” refers to an antibody that comprises a portion of an intact antibody, such as the antigen-binding or variable region of an intact antibody. Antibody fragments include, for example, Fv fragments, Fab fragments, F(ab’)2 fragments, Fab’ fragments, scFv (sFv) fragments, and scFv-Fc fragments.

[0236] The term “Fc domain” or “Fc region” herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions.

[0237] The term “substantially purified” refers to a construct described herein, or variant thereof that may be substantially or essentially free of components that normally accompany or interact with the protein as found in its naturally occurring environment, i.e. a native cell, or host cell in the case of recombinantly produced antibody that in certain embodiments, is substantially free of cellular material includes preparations of protein having less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1 % (by dry weight) of contaminating protein.

[0238] The term percent “identity,” in the context of two or more nucleic acid or polypeptide sequences, refer to two or more sequences or subsequences that have a specified percentage of nucleotides or amino acid residues that are the same, when compared and aligned for maximum correspondence, as measured using one of the sequence comparison algorithms described below (e.g., using publicly available computer software such as BLAST, BLASTP, BLASTN, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, CLUSTAL OMEGA, or MUSCLE software or other algorithms available to persons of skill) or by visual inspection. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (ncbi.nlm.nih.gov). Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. Depending on the application, the percent “identity” can exist over a region of the sequence being compared, e.g., over a functional domain, or, alternatively, exist over the full length of the two sequences to be compared.

[0239] For sequence comparison, typically one sequence acts as a reference sequence to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are input into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. The sequencecomparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters.

[0240] Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith & Waterman (1981) Adv. Appl. Math. 2:482, by the homology alignment algorithm of Needleman & Wunsch (1970) J. Mol. Biol. 48:443, by the search for similarity method of Pearson & Lipman (1988) Proc. Nat’l. Acad. Set. 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).

[0241] 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 / ).

[0242] Ranges recited herein are understood to be shorthand for all of the values within the range, inclusive of the recited endpoints. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22. 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44. 45, 46, 47, 48, 49, and 50.

[0243] It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise.

[0244] The term “atopic dermatitis disease severity outcome measure” refers to a determination of certain signs, symptoms, features or parameters that have been associated with atopic dermatitis and that can be quantitatively or qualitatively assessed. Exemplary atopic dermatitis disease severity outcome measures include “Eczema Area and Severity Index” (EASI), “Severity Scoring of Atopic Dermatitis” (SCORAD), “Validated Investigator Global Assessment- Atopic Dermatitis” (vIGA-AD), “Investigator Global Assessment of Signs” (IGSA), Rajka / Langeland Atopic Dermatitis Severity Score, “Body Surface Area” (BSA), and patient-reported outcomes including Pruritus Visual Analog Scale (an aspect of disease severity assessed as part of SCORAD), Sleep Loss Visual Analog Scale (an aspect of disease severity assessed as part of SCORAD), Atopic Dermatitis Symptom Diary (ADSD), Atopic Dermatitis Impact Questionnaire (ADIQ), Dermatology Life Quality Index (DLQI)(Finlay and Khan, Clin Exp er Dermatol 1994; 19:210), 5-D Itch Scale (Elman el al., Br J Dermatol 2010;162(3):587-593), Itch Numeric Rating Scale (I-NRS) (see Naegeli et al.. International Journal of Dermatology. 2015;54(6):715-722; and Newton L, et al., I. Patient Rep. Outcomes. 2019;3(l):42), and the Patient-Oriented Eczema Measure (POEM) (www.nottingham.ac.uk / research / groups / cebd / resources / poem.aspx).Hyaluronidases

[0245] As used herein, “hyaluronidase” refers to an enzyme that degrades hyaluronic acid, which constitutes an essential part of the extracellular matrix. Included in this definition are naturally occurring hyaluronidases, recombinant hyaluronidases, both human and from other sources, as well as variants thereof. Such hyaluronidases include, but are not limited to, nonhuman hyaluronidases, including bacterial hyaluronidases, bovine hyaluronidases, ovine hyaluronidases, and variants thereof. Reference to hyaluronidase refers to all forms, including variants.

[0246] Hyaluronidases were initially discovered in bacteria, and are now known to be widely distributed in nature and have been found in many different species, including insects, snakes, and mammals. Human hyaluronidase is present both in organs (e.g., testis, spleen, skin, eyes, liver, kidneys, uterus, and placenta) and in body fluids (e.g., tears, blood, and semen). In the human, six different hyaluronidases, HYAL1-4, HYAL-P1 and PH-20, have been identified. PH-20 exerts the strongest biologic activity, is found in high concentrations in the testicles, and can be localized on the head and the acrosome of human spermatozoa (see, e.g., Weber GC, et al., Adv. Exp. Med. Biol. 2019;1148:255-277).

[0247] Hyaluronidases are classified into three categories according to their mechanism of action (see, e.g., Jung H., Arch. Plast. Surg. 2020 Jul;47(4):297-300). First, mammalian hyaluronidases are endo-P-N-acetylhexosaminidases that break down P-1,4 glycosidic linkages to form tetrasaccharides. Second, leech / hookworm hyaluronidases are endo-P-D- glucuronidases that break down P-1,3 glycosidic bonds to form pentasaccharides and hexasaccharides. Finally, microbial hyaluronidases are classified as hyaluronate lyases.Unlike other hyaluronidases, they do not catalyze hydrolysis reactions. Instead, they produce unsaturated disaccharides through a P-elimination reaction at P-1,4 glycosidic linkage.

[0248] Hyaluronidases can also be classified into two types according to the pH at which they are most active (see, e.g., Jung H., Arch. Plast. Surg. 2020 Jul;47(4):297-300). Acidactive hyaluronidases are activated at a pH of 3 to 4. Neutral-active hyaluronidases, whichinclude the hyaluronidase enzymes found in snake and bee venom, are activated at a pH of 5 to 8 (see, e.g., Cavallini M, et al., Aesthet. Surg. J. 2013;33: 1167-74).

[0249] Hyaluronidase use has become more diverse and widespread in clinical practice. Today, animal-derived bovine or ovine testicular hyaluronidases, as well as synthetic hyaluronidases, are clinically applied as adjuncts to increase the bioavailability of drugs, for the therapy of extravasations, or for the management of complications associated with the aesthetic injection of hyaluronic acid-based fillers.

[0250] Exemplary of hyaluronan degrading enzymes are hyaluronidases, and particular chondroitinases and lyases that have the ability to depolymerize hyaluronan. Exemplary chondroitinases that are hyaluronan degrading enzymes include, but are not limited to, chondroitin ABC lyase (also known as chondroitinase ABC), chondroitin AC lyase (also known as chondroitin sulfate lyase or chondroitin sulfate eliminase) and chondroitin C lyase. Chondroitin ABC lyase comprises two enzymes, chondroitin-sulfate-ABC endolyase (EC 4.2.2.20) and chondroitin-sulfate-ABC exolyase (EC 4.2.2.21). Exemplary chondroitin- sulfate-ABC endolyases and chondroitin-sulfate-ABC exolyases include, but are not limited to, those from Proteus vulgaris and Flavobacterium heparinum (the Proteus vulgaris chondroitin-sulfate-ABC endolyase (e.g., see Sato et al. (1994) Appl. Microbiol. Biotechnol. 41 ( 1 ) : 39-46)) . Exemplary chondroitinase AC enzymes from the bacteria include, but are not limited to, those from Flavobacterium heparinum, Victivallis vadensis, and Arthrobacter aurescens (see, e.g., Tkalec et al. (2000) Applied and Environmental Microbiology 66( 1):29- 35; Ernst et al. (1995) Critical Reviews in Biochemistry and Molecular Biology 30(5):387- 444). Exemplary chondroitinase C enzymes from the bacteria include, but are not limited to, those from Streptococcus and Flavobacterium (Hibi et al. (1989) FEMS-Microbiol-Lett. 48(2):121-4; Michelacci et al. (1976) J. Biol. Chem. 251 :1154-8; Tsuda et al. (1999) Eur. J. Biochem. 262: 127-133).

[0251] Hyaluronidases include bacterial hyaluronidases (EC 4.2.2.1 or EC 4.2.99.1), hyaluronidases from leeches, other parasites, and crustaceans (EC 3.2.1.36), and mammaliantype hyaluronidases (EC 3.2.1.35). Hyaluronidases include any of non-human origin including, but not limited to, murine, canine, feline, leporine, avian, bovine, ovine, porcine, equine, piscine, ranine, bacterial, and any from leeches, other parasites, and crustaceans. Exemplary non-human hyaluronidases include hyaluronidases from cows (SEQ ID NOs:10, 11, 64 of US Patent No.: 8,568,713) and BH55 (U.S. Pat. Nos. 5,747,027 and 5,827,721), yellow jacket wasp (SEQ ID NOs: 12 and 13 of US Patent No.: 8,568,713), honey bee (SEQID NO: 14 of US Patent No.: 8,568,713), white-face hornet (SEQ ID NO: 15 of US Patent No.:8,568,713), paper wasp (SEQ ID NO:16 of US Patent No.: 8,568,713), mouse (SEQ ID NOs: 17-19, and 32 of US Patent No.: 8,568,713), pig (SEQ ID NOs:20-21of US Patent No.:8,568,713), rat (SEQ ID NOs:22-24, and 31 of US Patent No.: 8,568,713), rabbit (SEQ ID NO:25 of US Patent No.: 8,568,713), sheep (SEQ ID NOs:26, 27, 63 and 65 of US Patent No.: 8,568,713), orangutan (SEQ ID NO:28 of US Patent No.: 8,568,713), cynomolgus monkey (SEQ ID NO:29 of US Patent No.: 8,568,713), guinea pig (SEQ ID NQ:30 of US Patent No.: 8,568,713), Arthrobacter sp. (strain FB24) (SEQ ID NO:67 of US Patent No.:8.568.713), Bdellovibrio bacteriovoms (SEQ ID NO:68 of US Patent No.: 8,568,713), Propionibacterium acnes (SEQ ID NO:69 of US Patent No.: 8,568,713), Streptococcus agalactiae ((SEQ ID NO:70 of US Patent No.: 8,568,713); 18RS21 (SEQ ID NO:71 of US Patent No.: 8,568,713 ); serotype la (SEQ ID NO:72 of US Patent No.: 8,568,713); serotype III (SEQ ID NO:73 of US Patent No.: 8,568,713), Staphylococcus aureus (strain COL) (SEQ ID NO:74 of US Patent No.: 8,568,713 ); strain MRSA252 (SEQ ID NOs:75 and 76 of US Patent No.: 8,568,713 of US Patent No.: 8,568,713); strain MSSA476 (SEQ ID NO:77 of US Patent No.: 8,568,713); strain NCTC 8325 (SEQ ID NO:78 of US Patent No.: 8,568,713 ); strain bovine RF122 (SEQ ID NOs:79 and 80 of US Patent No.: 8,568,713); strain USA300 (SEQ ID NO:81 of US Patent No.: 8,568,713), Streptococcus pneumoniae (SEQ ID NO:82 of US Patent No.: 8,568,713); strain ATCC BAA-255 / R6 (SEQ ID NO:83 of US Patent No.:8.568.713); serotype 2, strain D39 / NCTC 7466 (SEQ ID NO:84 of US Patent No.:8.568.713), Streptococcus pyogenes (serotype (SEQ ID NO:85 of US Patent No.: 8,568,713); serotype M2, strain MGAS10270 (SEQ ID NO:86 of US Patent No.: 8,568,713); serotype M4, strain MGAS 10750 (SEQ ID NO:87 of US Patent No.: 8,568,713); serotype M6 (SEQ ID NO:88 of US Patent No.: 8,568,713); serotype M12, strain MGAS2096 (SEQ ID NOs:89 and 90 of US Patent No.: 8,568,713); serotype M12, strain MGAS9429 (SEQ ID NO:91 of US Patent No.: 8,568,713); serotype M28 (SEQ ID NO:92 of US Patent No.: 8,568,713); Streptococcus suis (SEQ ID NOs:93-95 of US Patent No.: 8,568,713 ); Vibrio fischeri (strain ATCC 700601 / ES 114 (SEQ ID NO:96 of US Patent No.: 8,568,713), and the Streptomyces hyaluronolyticus hyaluronidase enzyme, which is specific for hyaluronic acid and does not cleave chondroitin or chondroitin sulfate (Ohya, T. and Kaneko, Y. (1970) Biochim. Biophys. Acta 198:607). Hyaluronidases also include those of human origin. Exemplary human hyaluronidases include PH20 (SEQ ID NO: 1 of US Patent No. 8,568,713), HYAL1 (SEQ ID NO:36 of US Patent Patent No.: 8,568,713),HYAL3 (SEQ ID NO:38 of US Patent No.: 8,568,713), and HYAL4 (SEQ ID NO:36 of US Patent No.: 8,568,713). The sequences and contents of US Patent No. 8,568,713 are expressly incorporated herein by reference. Also included amongst hyaluronidases are soluble hyaluronidases, including, ovine and bovine PH20, soluble human PH20 and soluble rHuPH20. Examples of commercially available bovine or ovine soluble hyaluronidases include Vitrase® (ovine hyaluronidase) and Amphadase ® (bovine hyaluronidase).

[0252] Hyaluronidases as described herein include precursor hyaluronan degrading enzyme polypeptides and mature hyaluronan degrading enzyme polypeptides (such as those in which a signal sequence has been removed), truncated forms thereof that have activity, and includes allelic variants and species variants, variants encoded by splice variants, and other variants, including polypeptides that have at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity to the polypeptides set forth in SEQ ID NOs:408-417 and 419-474. Hyaluronidases also include those that contain chemical or posttranslational modifications and those that do not contain chemical or posttranslational modifications. Such modifications include, but are not limited to, pegylation, albumination, glycosylation, farnesylation, carboxylation, hydroxylation, phosphorylation, and other polypeptide modifications known in the art.

[0253] As used herein, a soluble hyaluronidase refers to a polypeptide characterized by its solubility under physiologic conditions. Soluble hyaluronidases can be distinguished, for example, by its partitioning into the aqueous phase of a Triton X-l 14 solution warmed to 37 °C (Bordier et al., (1981) J. Biol. Chem., 256:1604-7). Membrane-anchored, such as lipid anchored hyaluronidases, will partition into the detergent rich phase, but will partition into the detergent-poor or aqueous phase following treatment with Phospholipase-C. Included among soluble hyaluronidases are membrane anchored hyaluronidases in which one or more regions associated with anchoring of the hyaluronidase to the membrane has been removed or modified, where the soluble form retains hyaluronidase activity. Soluble hyaluronidases include recombinant soluble hyaluronidases and those contained in or purified from natural sources.

[0254] As used herein, activity refers to a functional activity or activities of a polypeptide or portion thereof associated with a full-length (complete) protein. Functional activities include, but are not limited to, biological activity, catalytic or enzymatic activity, antigenicity (ability to bind or compete with a polypeptide for binding to an anti-polypeptide antibody),immunogenicity, ability to form multimers, and the ability to specifically bind to a receptor or ligand for the polypeptide.

[0255] As used herein, hyaluronidase activity refers to the ability to enzymatically catalyze the cleavage of hyaluronic acid. The United States Pharmacopeia (USP) XXII assay for hyaluronidase determines hyaluronidase activity indirectly by measuring the amount of higher molecular weight hyaluronic acid, or hyaluronan, (HA) substrate remaining after the enzyme is allowed to react with the HA for 30 min at 37 °C (USP XXII-NF XVII (1990) 644- 645 United States Pharmacopeia Convention, Inc, Rockville, Md.). A Reference Standard solution can be used in an assay to ascertain the relative activity, in units, of any hyaluronidase. In vitro assays to determine the hyaluronidase activity of hyaluronidases, such as soluble rHuPH20, are known in the art. Exemplary assays include the microturbidity assay described below (see, e.g., Example 3 of US Patent No. :8, 568, 713) that measures cleavage of hyaluronic acid by hyaluronidase indirectly by detecting the insoluble precipitate formed when the uncleaved hyaluronic acid binds with serum albumin. Reference Standards can be used, for example, to generate a standard curve to determine the activity in Units of the hyaluronidase being tested.

[0256] As used herein, "functionally equivalent amount" or grammatical variations thereof, with reference to a hyaluronan degrading enzyme, refers to the amount of hyaluronan degrading enzyme that achieves the same effect as an amount (such as a known number of Units of hyaluronidase activity) of a reference enzyme, such as a hyaluronidase. For example, the activity of any hyaluronan degrading enzyme can be compared to the activity of rHuPH20 to determine the functionally equivalent amount of a hyaluronan degrading enzyme that would achieve the same effect as a known amount of rHuPH20. For example, the ability of a hyaluronan degrading enzyme to act as a spreading or diffusing agent can be assessed by injecting it into the lateral skin of mice with trypan blue (see, e.g., U.S. Pat. Publication No. 20050260186), and the amount of hyaluronan degrading enzyme required to achieve the same amount of diffusion as, for example, 100 units of a Hyaluronidase Reference Standard, can be determined. The amount of hyaluronan degrading enzyme required is, therefore, functionally equivalent to 100 units.

[0257] Exemplary hyaluronan degrading enzymes are hyaluronidases, particularly soluble hyaluronidases, such as a PH20, or a truncated or variant form thereof. The PH20 can be, for example, an ovine, bovine or truncated human PH20. The human PH20 mRNA transcript is normally translated to generate a 509 amino acid precursor polypeptide (SEQ ID NO:408;and replicated below) containing a 35 amino acid signal sequence at the N-terminus (amino acid residue positions 1-35) and a 19 amino acid glycosylphosphatidylinositol (GPI) anchor attachment signal sequence at the C-terminus (amino acid residue positions 491-509). The mature PH20 is, therefore, a 474 amino acid polypeptide set forth in SEQ ID NO:409. Following transport of the precursor polypeptide to the ER and removal of the signal peptide, the C-terminal GPI-attachment signal peptide is cleaved to facilitate covalent attachment of a GPI anchor to the newly-formed C-terminal amino acid at the amino acid position corresponding to position 490 of the precursor polypeptide set forth in SEQ ID NO:408. Thus, a 474 amino acid GPI-anchored mature polypeptide with an amino acid sequence set forth in SEQ ID NO:409 is produced.

[0258] The amino acid sequence of the human PH20 precursor polypeptide (SEQ ID NO: 408; 509 amino acids) is as follows:MGVEKFKHIFFRSFVKSSGVSQIVFTFEEIPCCETENFRAPPVIPNVPFEWAWNAPSEF CEGKFDEPEDMSEFSFIGSPRINATGQGVTIFYVDREGYYPYIDSITGVTVNGGIPQKIS EQDHEDKAKKDITFYMPVDNEGMAVIDWEEWRPTWARNWKPKDVYKNRSIEEVQ QQNVQESETEATEKAKQEFEKAGKDFEVETIKEGKELRPNHEWGYYLFPDCYNHHY KKPGYNGSCFNVEIKRNDDESWEWNESTAEYPSIYENTQQSPVAATEYVRNRVREAI RVSKIPDAKSPEPVFAYTRIVFTDQVEKFESQDEEVYTFGETVAEGASGIVIWGTESIM RSMKSCEEEDNYMETIENPYIINVTEAAKMCSQVECQEQGVCIRKNWNSSDYEHENP DNFAIQEEKGGKFTVRGKPTEEDEEQFSEKFYCSCYSTLSCKEKADVKDTDAVDVCI ADGVCIDAFEKPPMETEEPQIFYNASPSTESATMFIVSIEFEIISSVASE.

[0259] The amino acid sequence of the mature PH20 polypeptide (SEQ ID NO: 409; 474 amino acids) is as follows:ENFRAPPVIPNVPFEWAWNAPSEFCEGKFDEPEDMSEFSFIGSPRINATGQGVTIFYVD REGYYPYIDSITGVTVNGGIPQKISEQDHEDKAKKDITFYMPVDNEGMAVIDWEEWR PTWARNWKPKDVYKNRSIEEVQQQNVQESETEATEKAKQEFEKAGKDFEVETIKEG KEERPNHEWGYYEFPDCYNHHYKKPGYNGSCFNVEIKRNDDESWEWNESTAEYPSI YENTQQSPVAATEYVRNRVREAIRVSKIPDAKSPEPVFAYTRIVFTDQVEKFESQDEE VYTFGETVAEGASGIVIWGTESIMRSMKSCEEEDNYMETIENPYIINVTEAAKMCSQV ECQEQGVCIRKNWNSSDYEHENPDNFAIQEEKGGKFTVRGKPTEEDEEQFSEKFYCS CYSTESCKEKADVKDTDAVDVCIADGVCIDAFEKPPMETEEPQIFYNASPSTESATMF IVSIEFEIISSVASE.

[0260] Human PH20 exhibits hyaluronidase activity at both neutral and acid pH. In one aspect, human PH20 is the prototypical neutral-active hyaluronidase that is generally locked to the plasma membrane via a GPI anchor. In another aspect, PH20 is expressed on the inner acrosomal membrane where it has hyaluronidase activity at both neutral and acid pH. It appears that PH20 contains two catalytic sites at distinct regions of the polypeptide: the Peptide 1 and Peptide 3 regions (Cherr et al., (2001) Matrix Biology 20:515-525). Evidence suggests that the Peptide 1 region of PH20, which corresponds to amino acid positions 107- 137 of the mature polypeptide set forth in SEQ ID NO:409 and positions 142-172 of the precursor polypeptide set forth in SEQ ID NO:408, is required for enzyme activity at neutral pH. Amino acids at positions 111 and 113 (corresponding to the mature PH20 polypeptide set forth in SEQ ID NO:409) within this region appear to be important for activity, as mutagenesis by amino acid replacement results in PH20 polypeptides with 3% hyaluronidase activity or undetectable hyaluronidase activity, respectively, compared to the wild-type PH20 (Arming et al., (1997) Eur. J. Biochem. 247:810-814).

[0261] The Peptide 3 region, which corresponds to amino acid positions 242-262 of the mature polypeptide set forth in SEQ ID NO:409, and positions 277-297 of the precursor polypeptide set forth in SEQ ID NO:408, appears to be important for enzyme activity at acidic pH. Within this region, amino acids at positions 249 and 252 of the mature PH20 polypeptide appear to be essential for activity, and mutagenesis of either one results in a polypeptide essentially devoid of activity (Arming et al., (1997) Eur. J. Biochem. 247:810- 814).

[0262] In addition to the catalytic sites, PH20 also contains a hyaluronan-binding site. Experimental evidence suggest that this site is located in the Peptide 2 region, which corresponds to amino acid positions 205-235 of the precursor polypeptide set forth in SEQ ID NO: 408 and positions 170-200 of the mature polypeptide set forth in SEQ ID NO:409. This region is highly conserved among hyaluronidases and is similar to the heparin binding motif. Mutation of the arginine residue at position 176 (corresponding to the mature PH20 polypeptide set forth in SEQ ID NO:409) to a glycine results in a polypeptide with only about 1 % of the hyaluronidase activity of the wild type polypeptide (Arming et al., (1997) Eur. J. Biochem. 247:810-814).

[0263] There are seven potential N-linked glycosylation sites in human PH20 at N82, N166, N235, N254, N368, N393, N490 of the polypeptide exemplified in SEQ ID NO:408. Because amino acids 36 to 464 of SEQ ID NQ:408 appear to contain the minimally activehuman PH20 hyaluronidase domain, the N-linked glycosylation site N-490 is not required for proper hyaluronidase activity. There are six disulfide bonds in human PH20. Two disulfide bonds between the cysteine residues C60 and C351 and between C224 and C238 of the polypeptide exemplified in SEQ ID NO:408 (corresponding to residues C25 and C316, and C189 and C203 of the mature polypeptide set forth in SEQ ID NO:409, respectively). A further four disulfide bonds are formed between the cysteine residues C376 and C387; between C381 and C435; between C437 and C443; and between C458 and C464 of the polypeptide exemplified in SEQ ID NO: 408 (corresponding to residues C341 and C352; between C346 and C400; between C402 and C408; and between C423 and C429 of the mature polypeptide set forth in SEQ ID NO:409, respectively).

[0264] As used herein, soluble recombinant human PH20 (rHuPH20) refers to a soluble form of human PH20 that is recombinantly expressed in Chinese Hamster Ovary (CHO) cells. Soluble human PH20 or sHuPH20 includes mature polypeptides lacking all or a portion of the glycosylphospatidylinositol (GPI) attachment site at the C-terminus such that upon expression, the polypeptides are soluble.

[0265] Soluble rHuPH20 is encoded by a nucleic acid that includes the signal sequence and is set forth in SEQ ID NO:418. Also included are DNA molecules that are allelic variants thereof and other soluble variants. The nucleic acid encoding soluble rHuPH20 is expressed in CHO cells which secrete the mature polypeptide.

[0266] SEQ ID NO:418 encodes amino acids 1-482 of the human PH20 precursor polypeptide (amino acids 1-482 of SEQ ID NO: 408). Post translational processing removes the 35 amino acid signal sequence, leaving a 447 amino acid soluble recombinant human PH20 (SEQ ID NO: 410). As produced in the culture medium, there is heterogeneity at the C- temiinus such that the product, designated rHuPH20, includes a mixture of species that can include any one or more of SEQ ID NOs: 410-415 in various abundance. Typically, rHuPH20 is produced in cells that facilitate correct N-glycosylation to retain activity, such as CHO cells (e.g., DG44 CHO cells). rHuPH20 may be produced by expressing a polynucleotide encoding amino acids 36-482 of SEQ ID NO: 408 in a cell, such as a CHO cell, and the polynucleotide encoding amino acids 36-482 of SEQ ID NO: 408 may be linked to the native signal sequence (amino acids 1-35 of SEQ ID NO: 408, as in SEQ ID NO: 418) or a heterologous signal sequence. The production of rHuPH20 is described in U.S. Patent No. 8,568,713 and U.S. Patent No. 8,343,487, each of which is incorporated herein by reference.

[0267] Exemplary sHuPH20 polypeptides include mature polypeptides having an amino acid sequence set forth in any one of SEQ ID NOs:410-417 and 419-474. Other variants can have 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to any one of SEQ ID NOs:410-417 and 419-474, as long they retain a hyaluronidase activity and are soluble. Corresponding allelic variants and other variants also are included, including those corresponding to the precursor human PH20 polypeptide set forth in SEQ ID NO:408 and the mature human PH20 polypeptide set forth in SEQ ID NO: 409.

[0268] rHuPH20 was approved by the US Food and Drug Administration in 2005 as an adjuvant to increase the dispersion and absorption of other injected drugs. Recombinant human hyaluronidase PH20 is a transiently and locally-acting permeation enhancer that increases the dispersion and absorption of other injected agents. Recombinant human hyaluronidase PH20 depolymerizes hyaluronic acid (HA) at the injection site causing rapid decrease in the viscosity of the extracellular matrix, allowing bulk fluid flow and facilitating dispersion and absorption of coadministered agents (rHuPH20 Investigator’s Brochure, 2018).

[0269] rHuPH20 is a glycosylated single chain protein with up to 447 amino acids, synthesized in CHO cells. As described above, rHuPH20 may be produced from a polynucleotide encoding amino acids 1-482 of SEQ ID NO: 408 (set forth in SEQ ID NO: 418), and post translational processing removes the 35 amino acid signal sequence, resulting in a polypeptide containing amino acids 36-482 of SEQ ID NO: 408 (set forth in SEQ ID NO: 410). As produced in the culture medium there is heterogeneity at the C-terminus such that the resulting rHuPH20 includes a mixture of species that can include any one or more of SEQ ID NOs: 410-415 in various abundance. Recombinant human hyaluronidase PH20 degrades HA under physiologic conditions and acts as a spreading factor in vivo. Therefore, when combined (co-mixed) or co-formulated with certain injectable drugs, rHUPH20 facilitates the absorption and dispersion of these drugs by temporarily reducing resistance to bulk fluid flow in the subcutaneous space. The permeability barrier in these tissues is restored to pre-injection levels within 24 to 48 hours after injection of rHuPH20.

[0270] Any suitable hyaluronidase (e.g., a recombinant human hyaluronidase) can be used in the methods, compositions, and combinations described herein, including, but not limited to, those described in US Patent No.: 7,767,429 (e.g., SEQ ID NO: 1), US Patent No.: 7,846,431 (e.g-, SEQ ID NO: 1), US Patent No.: 7,871,607 (e.g., SEQ ID NO:1), US PatentNo.: 8,105,586 (e.g., SEQ ID NO:1), US Patent No.: 8,202,517 (e.g., SEQ ID NO: 1), US Patent No.: 8,257,699 (e.g., SEQ ID NO:1), US Patent No.: 8,450,470 (e.g., SEQ ID NO:1), US Patent No.: 8,431,124 (e.g., SEQ ID NO:1),US Patent No.: 8,431,380 (e.g., SEQ ID NO:1), US Patent No.: 8,580,252 (e.g., SEQ ID NO:1), US Patent No.: US 8,765,685 (e.g., SEQ ID NO:1), US Patent No.: US 8,772,246 (e.g., SEQ ID NO: 1),US Patent No.: US 9,211,315 (e.g., SEQ ID NO:1), US Patent No.: US 9,562,223 (e.g., SEQ ID NO: 1), US Patent No.: US 9,677,061 (e.g., SEQ ID NO:1), US Patent No.: US 9,677,062 (e.g., SEQ ID NO:1), US Patent No.: US 5,721,348 (e.g., SEQ ID NO:6), US 20210155913, US 20210363270, and US 20220289864, the contents of each of which are expressly incorporated herein by reference. The generation of such recombinant human hyaluronidases is described in U.S. Patent No.: 7,767,429; U.S. Patent No.: 7,871,607; and US20060104968, the contents of each of which are expressly incorporated herein by reference.

[0271] An exemplary recombinant human hyaluronidase is soluble hyaluronidase provided as a composition designated rHuPH20, i.e., the active ingredient in the commercial product Hylenex® recombinant (hyaluronidase human injection), which is supplied as ENHANZE® drug product. ENHANZE® is a formulation containing rHuPH20 that can be admixed with an antibody prior to subcutaneous injection.

[0272] Hyaluronidases that have altered properties, such as increased stability and / or activity, have been produced and can also be used, including, but not limited to those described in U.S. Pat. No. 9,447,401, U.S. Pat. No. 10,865,400, and U.S. Pat. No.1 1,041,149, the contents of each of which are expressly incorporated herein by reference. These patents provide about 7000 examples in which the effects of replacing each amino acid with 15 other amino acids on activity and stability were identified and described.

[0273] Other variants are known to those of skill in the art including those described, for example, in W02020 / 022791 and W02020197230A, the contents of each of which are expressly incorporated herein by reference. These variant polypeptides include replacements, insertions, and deletions, including one or more amino acid residues S343E, M345T, K349E, L353A, L354I, N356E, and 136 IT. Variants that contain such modifications and others are set forth in SEQ ID NOs: 60-115 from WQ2020 / 022791. W02021 / 150079 also provides variant polypeptides described as having increased stability.

[0274] In one embodiment, the recombinant human hyaluronidase includes a sequence of amino acids in any one of SEQ ID NOs:408-417 and 419-474, or has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity to a sequence of amino acids included in any one of SEQ ID NOs: 408-417 and 419-474 and retains hyaluronidase activity. In one embodiment, the recombinant human hyaluronidase comprises a sequence having at least 95%, 96%, 97%, 98%, or 99% to the amino acid sequence of SEQ ID NO: 408. In one embodiment, the recombinant human hyaluronidase comprises a sequence having at least 95%, 96%, 97%, 98%, or 99% to the amino acid sequence of SEQ ID NO: 410. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:408. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:408. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:409. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:409. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:410. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:410. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:411. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:411. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:412. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:412. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:413. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:413. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:414. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:414. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:415. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:415. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:416. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:416. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:417. In anotherembodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:417. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:419. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:419. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:420. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NQ:420. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:421. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:421. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:422. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:422. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:423. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:423. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:424. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:424. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:425. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:425. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:426. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:426. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:427. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:427. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:428. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:428. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:429. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:429. In another embodiment, therecombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:430. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:430. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:431. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:431. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:432. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:432. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:433. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:433. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:434. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:434. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:435. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:435. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:436. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:436. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:437. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:437. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:438. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:438. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:439. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:439. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:440. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:440. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:441. In another embodiment, the recombinanthuman hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:44I. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:442. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:442. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:443. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:443. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:444. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:444. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:445. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:445. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:446. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:446. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:447. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:447. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:448. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:448. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:449. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:449. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:450. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:450. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:451. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:451. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:452. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:452. In another embodiment, the recombinant humanhyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:453. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:453. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:454. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:454. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:455. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:455. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:456. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO: 456. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:457. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:457. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:458. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:458. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:459. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:459. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:460. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:460. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:461. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:461. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:462. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:462. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:463. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:463. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:464. In another embodiment, the recombinant human hyaluronidaseconsists of the amino acid sequence set forth in SEQ ID NO:464. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:465. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:465. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:466. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:466. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:467. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:467. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:468. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:468. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:469. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:469. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:470. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:470. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:471. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:471. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:472. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:472. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:473. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:473. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:474. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:474.Anti-IL-4Rα AntibodiesAntibody Structure

[0275] The present application provides antibodies and antigen binding fragments thereof and compositions and combinations comprising an antibody, or antigen binding fragment thereof, which binds IL-4 Receptor alpha (IL-4Rα) as well as methods of use thereof. Exemplary anti-IL-4Rα antibodies are described in PCT Publication No. WO2024173847, which is incorporated herein by reference in its entirety. In some embodiments, an anti-IL- 4Rα antibody, or an antigen binding fragment thereof, described herein is selected from an anti-IL-4Rα antibody described in PCT Publication No. WO2024173847.

[0276] The recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon and mu constant region genes, as well as the myriad immunoglobulin variable region genes. Light chains are classified as either kappa or lambda. The “class” of an antibody or immunoglobulin refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called a, 5, a, y, and p, respectively.

[0277] An exemplary immunoglobulin (antibody) structural unit is composed of two pairs of polypeptide chains, each pair having one “light” (about 25 kD) and one “heavy” chain (about 50-70 kD). The N-terminal domain of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms variable light chain (VL) and variable heavy chain (VH) refer to these light and heavy chain domains respectively. The IgGl heavy chain comprises the VH, CHI, CH2, and CH3 domains, respectively, from the N to C-terminus. The light chain comprises the VL and CL domains from N to C terminus. The IgGl heavy chain comprises a hinge between the CHI and CH2 domains. In certain embodiments, the immunoglobulin constructs comprise at least one immunoglobulin domain from IgG, IgM, IgA, IgD, or IgE connected to a therapeutic polypeptide. In some embodiments, the immunoglobulin domain found in an antibody provided herein, is from or is derived from an immunoglobulin-based construct such as a diabody or a nanobody. In certain embodiments, the immunoglobulin constructs described herein comprise at least one immunoglobulin domain from a heavy chain antibody such as a camelid antibody. In certain embodiments, the immunoglobulin constructs provided herein comprise at least one immunoglobulin domain from a mammalian antibody such as a bovine antibody, a human antibody, a camelid antibody, a mouse antibody or any chimeric antibody.

[0278] In some embodiments, the antibodies provided herein comprise a heavy chain. In one embodiment, the heavy chain is an IgA. In one embodiment, the heavy chain is an IgD. In one embodiment, the heavy chain is an IgE. In one embodiment, the heavy chain is an IgG. In one embodiment, the heavy chain is an IgM. In one embodiment, the heavy chain is an IgGl. In one embodiment, the heavy chain is an IgG2. In one embodiment, the heavy chain is an IgG3. In one embodiment, the heavy chain is an IgG4. In one embodiment, the heavy chain is an IgAl. In one embodiment, the heavy chain is an IgA2.

[0279] In some embodiments, an antibody is an IgGl antibody. In some embodiments, an antibody is an IgG3 antibody. In some embodiments, an antibody is an IgG2 antibody. In some embodiments, an antibody is an IgG4 antibody.

[0280] Generally, native four-chain antibodies comprise six HVRs: three in the VH (Hl, H2, H3), and three in the VL (LI, L2, L3). HVRs generally comprise amino acid residues from the hypervariable loops and / or from the complementarity determining regions (CDRs), the latter being of highest sequence variability and / or involved in antigen recognition. With the exception of CDR1 in VH, CDRs generally comprise the amino acid residues that form the hypervariable loops. Hypervariable regions (HVRs) are also referred to as “complementarity determining regions” (CDRs), and these terms are used herein interchangeably in reference to portions of the variable region that form the antigen-binding regions. This particular region has been described by Kabat et al., U.S. Dept, of Health and Human Services, Sequences of Proteins of Immunological Interest (1983) and by Chothia et al. (1987) J Mol Biol 196:901-917, where the definitions include overlapping or subsets of amino acid residues when compared against each other. Nevertheless, application of either definition to refer to a CDR of an antibody or variants thereof is intended to be within the scope of the term as defined and used herein. The exact residue numbers which encompass a particular CDR will vary depending on the sequence and size of the CDR. Those skilled in the art can routinely determine which residues comprise a particular CDR given the variable region amino acid sequence of the antibody.

[0281] The amino acid sequence boundaries of a CDR can be determined by one of skill in the art using any of a number of known numbering schemes, including those described by Kabat et al., supra (“Kabat” numbering scheme); Al-Lazikani et al. (1997) J. Mol. Biol. 273:927-948 (“Chothia” numbering scheme); MacCallum et al. (1996) J. Mol. Biol. 262:732- 745 (“Contact” numbering scheme); Lefranc et al. (2003) Dev. Comp. Immunol. 27:55-77(“IMGT" numbering scheme); and Honegge and Pliickthun, (2001) J. Mol. Biol. 309:657-70 (“AHo” numbering scheme); each of which is incorporated by reference in its entirety.

[0282] TABLE 2 provides the positions of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR- H2, and CDR-H3 as identified by the Kabat and Chothia schemes. For CDR-H1, residue numbering is provided using both the Kabat and Chothia numbering schemes.

[0283] CDRs may be assigned, for example, using antibody numbering software, such as Abnum, available at www.bioinf.org.uk / abs / abnum / , and described in Abhinandan and Martin, (2008) Immunology 45:3832-3839, incorporated by reference in its entirety.TABLE 2. Residues in CDRs according to Kabat and Chothia numbering schemes.*The C-terminus of CDR-H1, when numbered using the Kabat numbering convention, varies between H32 and H34, depending on the length of the CDR.

[0284] The “EU numbering scheme” is generally used when referring to a residue in an antibody heavy chain constant region (e.g., as reported in Kabat et al., supra). Unless stated otherwise, the EU numbering scheme is used to refer to residues in antibody heavy chain constant regions described herein.

[0285] One example of an antigen-binding domain is an antigen-binding domain formed by a VH-VL dimer of an antibody. Another example of an antigen-binding domain is an antigen-binding domain formed by diversification of certain loops from the tenth fibronectin type III domain of an Adnectin. An antigen-binding domain can include CDRs 1, 2, and 3 from a heavy chain in that order; and CDRs 1 , 2, and 3 from a light chain in that order.

[0286] Epitopes frequently consist of surface-accessible amino acid residues and / or sugar side chains and may have specific three-dimensional structural characteristics, as well as specific charge characteristics. Conformational and non-conformational epitopes are distinguished in that the binding to the former but not the latter may be lost in the presence of denaturing solvents. An epitope may comprise amino acid residues that are directly involvedin the binding, and other amino acid residues, which are not directly involved in the binding. The epitope to which an antibody binds can be determined using known techniques for epitope determination such as, for example, testing for antibody binding to IL-4Rα variants with different point -mutations, or to chimeric IL-4Rα variants.

[0287] To screen for antibodies which bind to an epitope on a target antigen bound by an antibody of interest (e.g., IL-4Rα), a routine cross-blocking assay such as that described in Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory, Ed Harlow and David Lane (1988), can be performed. Alternatively, or additionally, epitope mapping can be performed by methods known in the art.

[0288] 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.

[0289] Human, or fully human, antibodies are antibodies which possess an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or derived from a non-human source that utilizes a human antibody repertoire or human antibody -encoding sequences .e.g., obtained from human sources or designed de novo). Human antibodies specifically exclude humanized antibodies.

[0290] A humanized antibody has a sequence that differs from the sequence of an antibody derived from a non-human species by one or more amino acid substitutions, deletions, and / or additions, such that the humanized antibody is less likely to induce an immune response, and / or induces a less severe immune response, as compared to the non- human species antibody, when it is administered to a human subject. In one embodiment, certain amino acids in the framework and constant domains of the heavy and / or light chains of the non-human species antibody are mutated to produce the humanized antibody. In another embodiment, the constant domain(s) from a human antibody are fused to the variable domain(s) of a non-human species. In another embodiment, one or more amino acid residues in one or more CDR sequences of a non-human antibody are changed to reduce the likely immunogenicity of the non-human antibody when it is administered to a human subject, wherein the changed amino acid residues either are not critical for immunospecific binding of the antibody to its antigen, or the changes to the amino acid sequence that are made are conservative changes, such that the binding of the humanized antibody to the antigen is not significantly worse than the binding of the non-human antibody to the antigen. Examples of how to make humanized antibodies can be found in U.S. Pat. Nos. 6,054,297; 5,886,152; and5,877,293. For further details, see Jones el al. (1986) Nature 321:522-525; Riechmann el 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.

[0291] In some embodiments, an antibody can bind to two or more different epitopes. The two or more different epitopes may 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-4Rot molecule and a non-IL-4Rα molecule). In some aspects, a multi-specific antibody binds two different epitopes (i.e., a “bispecific antibody”). In some aspects, a multi -specific antibody binds three different epitopes i.e., a “trispecific antibody”).

[0292] Anti-IL-4Rα antibodies can include those described herein such as the clones set forth in the drawings and / or tables. In some embodiments, the antibody comprises an alternative scaffold. In some embodiments, the antibody consists of an alternative scaffold. In some embodiments, the antibody consists essentially of an alternative scaffold. In some embodiments, the antibody comprises an antibody fragment. In some embodiments, the antibody consists of an antibody fragment. In some embodiments, the antibody consists essentially of an antibody fragment.

[0293] In some embodiments, the antibodies are monoclonal antibodies.

[0294] In some embodiments, the antibodies are polyclonal antibodies.

[0295] In some embodiments, the antibodies are produced by hybridomas. In other embodiments, the antibodies are produced by recombinant cells engineered to express the desired variable and constant domains.

[0296] In some embodiments, the antibodies may be single chain antibodies or other antibody derivatives retaining the antigen specificity and the lower hinge region or a variant thereof.

[0297] In some embodiments, the antibodies may be polyfunctional antibodies, recombinant antibodies, fully human antibodies, humanized antibodies, fragments or variants thereof. In particular embodiments, the antibody fragment or a derivative thereof is selected from a Fab fragment, a Fab'2 fragment, a CDR and scFv.TABLE 3. Sequences of IL-4Rα Antibody Constructs - vH, vL, and associated CDRsVH Domains

[0298] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a VH sequence selected from any one of SEQ ID NOs: 113-145.

[0299] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to an illustrative VH sequence provided in any one of SEQ ID NOs: 113-145. In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a VH sequence provided in any one of 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. In some aspects, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as “variants.” In some embodiments, such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, randommutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.VL Domains

[0300] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a VL sequence selected from any one of SEQ ID NOs: 146-186.

[0301] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to an illustrative VL sequence provided in any one of SEQ ID NOs: 146-186. In some embodiments, an antibody provided herein comprises a VL sequence provided in any one of 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 a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.VH-VL Combinations

[0302] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a VH sequence selected from any one of SEQ ID NOs: 113-145; and a VL sequence selected from any one of SEQ ID NOs: 146-186.

[0303] In certain aspects, any one of SEQ ID NOs: 113-145 can be combined with any one of SEQ ID NOs: 146-186.

[0304] In certain aspects, an antibody, or antigen binding fragment thereof, provided herein comprises a VH sequence and a VL sequence of a construct provided in TABLE 3 (e.g., a VH sequence and a VL sequence from the same row of Table 3) or a VH sequence and a VL sequence of a construct provided in PCT Publication No. WO2024173847, which is incorporated by reference herein in its entirety. In certain aspects, an antibody, or antigenbinding fragment thereof, provided herein comprises a VH sequence and a VL sequence from Table 2 in PCT Publication No. WO2024173847 (e.g., a VH sequence and a VL sequence from the same row of Table 2).

[0305] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a VH sequence provided in any one of SEQ ID NOs: 1 13-145; 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 any one of SEQ ID NOs: 146-186. In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a VH sequence provided in any one of 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 provided in any one of 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 a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.

[0306] In certain embodiments, the antibody, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof,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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 129 and a VL sequence set forth in SEQID NO: 165. In certain embodiments, the antibody, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof,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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, 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, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 145 and a VL sequence set forth in SEQ ID NO: 186.

[0307] In certain embodiments of any of the antibodies, or antigen binding fragments thereof, described above, the antibody further comprises a heavy chain comprising a human IgG sequence selected from a sequence set forth in any one of SEQ ID NOs: 192-235 and 251-407. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a heavy chain comprising a human IgG sequence set forth in SEQ ID NO: 321 or SEQ ID NO: 205. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a heavy chain comprising a human IgG sequence set forth in SEQ ID NO: 321.

[0308] In certain embodiments, the antibody, or antigen binding fragment thereof, 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 a sequence set forth in any one of SEQ ID NOs: 192-235 and 251- 407. In certain embodiments, the antibody comprises a heavy chain comprising a human IgG sequence selected from a sequence set forth in any one of SEQ ID NOs: 192-234, 251-308, 310-350, and 352-407. In certain embodiments, the antibody does not comprise a heavy chain comprising a human IgG sequence set forth in any of SEQ ID NOs: 235, 309, and 351 (i.e., a human IgG4-SP constant heavy chain region).

[0309] In certain embodiments of any of the antibodies, or antigen binding fragments thereof, described above, the antibody further comprises a constant light chain sequence comprising a sequence set forth in SEQ ID NO: 236.

[0310] In certain embodiments, the antibody, or antigen binding fragment thereof, 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 (e.g., an IgGl constant region) comprising LALA / YTE substitutions, and a human kappa light chain constant region. In certain embodiments, the antibody, or antigen binding fragment thereof, 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 sequence set forth in SEQ ID NO: 205 or SEQ ID NO: 321, and a light chain constant region comprising a sequence set forth in SEQ ID NO: 236. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a VH sequence provided in SEQ ID NO: 134; and a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a VL sequence provided in SEQ ID NO: 178, a heavy chain constant region (e.g., an IgGl constant region) comprising LALA / YTE substitutions, and a human kappa light chain constant region. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a VH sequence provided in SEQ ID NO: 134; and a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a VL sequence provided in SEQ ID NO: 178, a heavy chain constant region comprising a sequence set forth in SEQ ID NO: 205 or SEQ ID NO: 321 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 a 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.

[0311] In certain embodiments, the antibody, or antigen binding fragment thereof, 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 sequence set forth in SEQ ID NO: 321, and a light chain constant region comprising a sequence set forth in SEQ ID NO: 236. In certain embodiments, the antibody, or antigen binding fragment thereof, 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 sequence set forth in SEQ ID NO: 205, and a light chain constant region comprising a sequence set forth in SEQ ID NO: 236.

[0312] In certain embodiments, the antibody, or antigen binding fragment thereof, 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 (e.g., an IgGl constant region) comprising LALA / YTE substitutions, and a human kappa light chain constant region. In certain embodiments, the antibody, or antigen binding fragment thereof, 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 sequence set forth in SEQ ID NO: 205 or SEQ ID NO: 321, and a light chain constant region comprising a sequence set forth in SEQ ID NO: 236. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a VH sequence provided in SEQ ID NO: 130; and a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a VL sequence provided in SEQ ID NO: 166, a heavy chain constant region (e.g., an IgGl constant region) comprising LALA / YTE substitutions, and a human kappa light chain constant region. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a VH sequence provided in SEQ ID NO: 130; and a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a VL sequence provided in SEQ ID NO: 166, a heavy chain constant region comprising a sequence set forth in SEQ ID NO: 205 or SEQ ID NO: 321 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 a 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.

[0313] In certain embodiments, the antibody, or antigen binding fragment thereof, 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 sequence set forth in SEQ ID NO: 321, and a light chain constant region comprising a sequence set forth in SEQ ID NO: 236. In certain embodiments, the antibody, or antigen binding fragment thereof, 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 sequence set forth in SEQ ID NO: 205, and a light chain constant region comprising a sequence set forth in SEQ ID NO: 236.

[0314] In certain embodiments, the antibody, or antigen binding fragment thereof, 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 (e.g., an IgGl constant region) comprising LALA / YTE substitutions, and a human kappa light chain constant region. In certain embodiments, the antibody, or antigen binding fragment thereof, 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 sequence set forth in SEQ ID NO: 205 or SEQ ID NO: 321, and a light chain constant region comprising a sequence set forth in SEQ ID NO: 236. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a VH sequence provided in SEQ ID NO: 121; and a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a VL sequence provided in SEQ ID NO: 158, a heavy chain constant region (e.g., an IgGl constant region) comprising LALA / YTE substitutions, and a human kappa light chain constant region. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a VH sequence provided in SEQ ID NO: 121; and a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a VL sequence provided in SEQ ID NO: 158, a heavy chain constant region comprising a sequence set forth in SEQ ID NO: 205 or SEQ ID NO: 321 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 a 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.

[0315] In certain embodiments, the antibody, or antigen binding fragment thereof, 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 sequence set forth in SEQ ID NO: 321, and a light chain constant region comprising a sequence set forth in SEQ ID NO: 236. In certain embodiments, the antibody, or antigen binding fragment thereof, 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 sequence set forth in SEQ ID NO: 205, and a light chain constant region comprising a sequence set forth in SEQ ID NO: 236.

[0316] Although a C-terminal lysine may be present in the corresponding coding sequence of the constant heavy chain region (e.g., in a sequence encoding any one of SEQ ID NOs: 307-407), it may be cleaved off during manufacture or after administration (resulting in, e.g., a constant heavy chain sequence of any one of SEQ ID NOs: 192-235 and 251-306). Accordingly, any of the antibodies or antigen binding fragments thereof described above may comprise a human IgG sequence containing a C-terminal lysine (e.g., any one of SEQ ID NOs: 307-407), a human IgG sequence lacking a C-terminal lysine (e.g., any one of SEQ ID NOs: 1 2-235 and 251-306), or a mixture thereof (e.g., mixture of the same heavy chain constant region sequence with and without a C-terminal lysine, such as a mixture of SEQ ID NO: 321 and SEQ ID NO: 205).CDRs

[0317] In some embodiments, disclosed herein is an antibody, or antigen binding fragment thereof, comprising 1, 2, 3, 4, 5, or 6 of the CDRs of TABLE 3. In some embodiments, disclosed herein is an antibody, or antigen binding fragment thereof, comprising 6 of the Kabat CDRs of TABLE 3, 6 of the Chothia CDRs of TABLE 3, or 6 of the IMGT CDRs of TABLE 3. In some embodiments, the antibody, or an antigen binding fragment thereof, comprises 6 of the Kabat CDRs, 6 of the Chothia CDRs, or 6 of the IMGT CDRs from a single row of TABLE 3 (e.g., 6 CDRs from the same antibody).

[0318] In some embodiments, disclosed herein is an antibody, or antigen binding fragment thereof, comprising 1, 2, 3, 4, 5, or 6 of the CDRs of an antibody provided in PCT Publication No. WO2024173847, which is incorporated by reference herein in its entirety. In some embodiments, disclosed herein is an antibody, or antigen binding fragment thereof, comprising 1, 2, 3, 4, 5, or 6 of the Kabat CDRs of an antibody provided in PCT Publication No. WO2024173847. In some embodiments, disclosed herein is an antibody, or antigen binding fragment thereof, comprising 1, 2, 3, 4, 5, or 6 of the Chothia CDRs of an antibody provided in PCT Publication No. WO2024173847. In some embodiments, disclosed herein is an antibody, or antigen binding fragment thereof, comprising 1, 2, 3, 4, 5, or 6 of the IMGT CDRs of an antibody provided in PCT Publication No. WO2024173847. In some embodiments, the antibody, or an antigen binding fragment thereof, comprises 6 of the Kabat CDRs, 6 of the Chothia CDRs, or 6 of the IMGT CDRs from a single row of Table 2 of PCT Publication No. WO2024173847 (e.g., 6 CDRs from the same antibody).

[0319] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises one to three CDRs of a VH domain selected from any one of SEQ ID NOs: 1 13-145. In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises two to three CDRs of a VH domain selected from any one of SEQ ID NOs: 113-145. In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises three CDRs of a VH domain selected from any one of 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.

[0320] In some embodiments, the CDRs are CDRs having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to a CDR-H1, CDR-H2, or CDR-H3 of SEQ ID NOs: 1-25, 66-99, and 187-191. In some embodiments, the CDR-H1 is a CDR-H1 of a VH domain selected from any one of SEQ ID NOs: 113-145, with up to 1, 2, 3, 4, or 5 amino acid substitutions. In some embodiments, the CDR-H2 is a CDR-H2 of a VH domain of any one of SEQ ID NO: 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 any one of 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 a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.

[0321] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises one to three CDRs of a VL domain selected from any one of SEQ ID NOs: 146-186. In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises two to three CDRs of a VL domain selected from any one of SEQ ID NOs: 146-186. In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises three CDRs of a VL domain selected from any one of SEQ ID NOs: 146- 186. In some aspects, the CDRs are Exemplary CDRs. In some aspects, the CDRs are KabatCDRs. 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.

[0322] In some embodiments, the CDRs are CDRs having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to a CDR-L1, CDR-L2, or CDR-L3 of SEQ ID NOs: 26-65, 100-107, and amino acid sequences LG, KG, EG, SA, and LS. In some embodiments, the CDR-L1 is a CDR-L1 of a VL domain selected from any one of SEQ ID NOs: 146-186, with up to 1, 2, 3, 4, or 5 amino acid substitutions. In some embodiments, the CDR-L2 is a CDR-L2 of a VL domain selected from any one of SEQ ID NOs: 146-186, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the CDR-L3 is a CDR-L3 of a VL domain selected from any one of SEQ ID NO: 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 a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.

[0323] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises one to three CDRs of a VH domain selected from any one of SEQ ID NOs: 113-145 and one to three CDRs of a VL domain selected from any one of SEQ ID NOs: 146- 186. In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises two to three CDRs of a VH domain selected from any one of SEQ ID NOs: 1 13- 145 and two to three CDRs of a VL domain selected from any one of SEQ ID NOs: 146-186. In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises three CDRs of a VH domain selected from any one of SEQ ID NOs: 113-145 and three CDRs of a VL domain selected from any one 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.

[0324] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H3 selected from any one of SEQ ID NOs: 17-25 and 92-99. Insome aspects, the CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a CDR-H3 selected from any one of SEQ ID NOs: 17-25 and 92-99. In some embodiments, the CDR-H3 is a CDR-H3 selected from any one of SEQ ID NO: 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 a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.

[0325] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 selected from any one of 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 any one of SEQ ID NOs: 1-4, 66-70, and 187-191. In some embodiments, the CDR-H1 is a CDR-H1 selected from any one of SEQ ID NO: 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 a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.

[0326] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H2 selected from any one of 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 any one of SEQ ID NOs: 5-16 and 71-90. In some embodiments, the CDR-H2 is a CDR-H2 selected from any one of 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 someembodiments, such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.

[0327] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-L3 selected from any one of 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 a CDR-L3 of any one of SEQ ID NOs: 53-65. In some embodiments, the CDR-L3 is a CDR-L3 selected from any one of 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 a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.

[0328] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-L2 selected from any one of SEQ ID NOs: 41-52 and amino acid sequences LG, KG, EG, SA, and LS. In some aspects, the CDR-L2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a CDR-L2 selected from any one of SEQ ID NOs: 41-52 and amino acid sequences LG, KG, EG, SA, and LS. In some embodiments, the CDR-L2 is a CDR-L2 selected from any one of SEQ ID NOs: 41-52 and amino acid sequences LG, KG, EG, SA and LS, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as “variants.” In some embodiments, such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.

[0329] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-L1 selected from any one of 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 any one of SEQ ID NOs: 26-40 and 100-107. In some embodiments, the CDR-L1 is a CDR-L1 selected from any one of 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 a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.

[0330] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H3 selected from any one of SEQ ID NOs: 17-25 and 92-99, a CDR-H2 selected from any one of SEQ ID NOs: 5-16 and 71-90, a CDR-H1 selected from any one of SEQ ID NOs: 1-4, 66-70, and 187-191, a CDR-L3 selected from any one of SEQ ID NOs: 53-65, a CDR-L2 selected from any one of SEQ ID NOs: 41-52 and amino acid sequences LG, KG, EG, SA and LS, and a CDR-L1 selected from any one of 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 any one of 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 selected from any one of SEQ ID NOs: 5-16 and 71-90, the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a CDR-H1 selected from any one of SEQ ID NOs: 1-4, 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 any one of SEQ ID NOs: 53-65, 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 any one of SEQ ID NOs: 41-52 and amino acid sequences LG, KG, EG, SA, and LS, and the CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a CDR-L1 selected from any one of SEQ ID NOs: 26-40 and 100-107. In some embodiments, the CDR-H3 is a CDR-H3 selected from any one of 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 selected from any one of SEQ ID NOs: 5-16 and 71-90, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H1 is a CDR-H1 selected from any one of 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 a CDR-L3 selected from any one of SEQ ID NOs: 53-65, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L2 is a CDR-L2 selected from any one of SEQ ID NOs: 41-52 and amino acid sequences LG, KG, EG, SA, and LS, with up to 1, 2, 3, or 4 amino acid substitutions; and the CDR-L1 is a CDR- L1 selected from any one of SEQ ID NOs: 26-40 and 100-107, with up to 1, 2, 3, 4, 5, or 6 amino acid substitutions.

[0331] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 1, 66, and 187; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 5, 71, and 79; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 17 and 91; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 26 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 41 or amino acid sequence LG: and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 53. In some embodiments, the CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a CDR-H3 selected from any one of SEQ ID NOs: 17 and 91, the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a CDR-H2 selected from any one of SEQ ID NOs: 5, 71, and 79, the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a CDR-H1 selected from any one of SEQ ID NOs: 1, 66, and 187, the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a CDR-L3 of SEQ ID NO: 53, the CDR-L2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a CDR-L2 of SEQ ID NO: 41 or the amino acid sequence LG, and the CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a CDR-L1 selected from any one of SEQ ID NOs: 26 and 100. In some embodiments, the CDR-H3 is a CDR-H3 selected from any one of SEQ ID NOs: 17 and 91, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H2 is a CDR-H2 selected from any one of SEQ ID NOs: 5, 71, and 79, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H1 is a CDR-H1 selected from any one of SEQ ID NOs: 1, 66, and 187, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L3 is a CDR-L3 of SEQ ID NO: 53 with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L2 is a CDR-L2 of SEQID NO: 41 or the amino acid sequence LG, with up to 1, 2, 3, or 4 amino acid substitutions; and the CDR-L1 is a CDR-L1 selected from any one of SEQ ID NOs: 26 and 100, with up to 1, 2, 3, 4, 5, or 6 amino acid substitutions.

[0332] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 18 and 92; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 27 and 101; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 42 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 54.

[0333] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 62, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 18 and 92; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 28 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 42 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 55.

[0334] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 7, 72, and 81; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 22 and 93; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 29 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 55.

[0335] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 18 and 92; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 28 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 45 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 55.

[0336] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2,67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 8, 73, and 82; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 19 and 94; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 30 and 102; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 56.

[0337] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 8, 73, and 82; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 20 and 95; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 31 and 103; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 57.

[0338] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 17 and 91; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 32 and 102; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 46 or the amino acid sequence KG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 58.

[0339] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2,67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 8, 73, and 82; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 20 and 95; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 32 and 102; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 45 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 59.

[0340] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2,68, and 189; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 20 and 95; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 32 and 102; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 45 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 60.

[0341] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 9, 77, and 83; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 18 and 92; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 29 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 60.

[0342] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 9, 77, and 83; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 18 and 92; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 27 and 101; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 57.

[0343] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 18 and 92; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 27 and 101; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0344] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 10, 71, and 84; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 20 and 95; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 27 and 101; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0345] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 18 and 92; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 28 and 100; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0346] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 3, 69, and 190; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 8, 73, and 82; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 21 and 96; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 28 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0347] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 7, 72, and 81; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 20 and 95; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 28 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 42 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 62.

[0348] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 11, 73, and 85; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 18 and 92; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 33 and 102; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0349] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 23, 69, and 190; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 11, 73, and 85; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 19 and 94; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 34 and 100; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 60.

[0350] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 11, 73,and 85; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 22 and 93; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 34 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 56.

[0351] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 3, 69, and 190; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 23 and 97; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 28 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 42 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0352] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 7, 72, and 81; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 20, 18, and 95; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 27 and 101; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0353] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 7, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 18 and 92; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 27 and 101; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0354] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 24 and 98; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 36 and 102; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 45 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0355] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 8, 73, and 82; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 18 and 92; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 37 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 47 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0356] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 12, 74, and 86; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 24 and 98; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 28 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0357] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 189; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 13, 71, and 87; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 20 and 95; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 28 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0358] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 10, 71, and 84; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 20 and 95; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 34 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 57.

[0359] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 20 and 95; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 34 and 100; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0360] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 1,66, and 187; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 5, 71, and 79; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 17 and 91; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 38 and 105; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 48 or the amino acid sequence SA; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 63.

[0361] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2,67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 20 and 95; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 39 and 106; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 41 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 64.

[0362] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 14, 75, and 88; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 20 and 95; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 39 and 106; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 49 or the amino acid sequence LS; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 63.

[0363] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 19 and 94; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 28 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 42 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 60.

[0364] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 8, 73,and 82; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 18 and 92; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 31 and 103; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 58.

[0365] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 3, 69, and 190; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 5, 71, and 79; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 19 and 94; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 33 and 102; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 50 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0366] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 18 and 92; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 30 and 101; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 51 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0367] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 3, 67, and 190; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 15, 76, and 89; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 20 and 95; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 40 and 107; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 52 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0368] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 20 and 95; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 30 and 102; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 47 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0369] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 4, 70, and 191; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 11, 73, and 85; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 22, 18, and 93; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 30 and 102; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 60.

[0370] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 14, 75, and 88; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 18 and 92; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 27 and 101; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 65.

[0371] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 15, 76, and 89; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 19 and 94; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 28 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 62.

[0372] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 3, 69, and 190; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 9, 77, and 83; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 19 and 94; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 28 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 55.

[0373] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 15, 76, and 89; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 24 and 98; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 34 and 100; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 42 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0374] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 18 and 92; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 32 and 102; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 51 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

[0375] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 16, 78, and 90; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 19 and 94; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 28 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 45 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 57.

[0376] In some embodiments, an antibody, or antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 4, 70, and 191; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 16, 78, and 90; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 25 and 99; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 34 and 100; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 53.

[0377] In some embodiments, the CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a CDR-H3 of TABLE 3; the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a CDR-H2 of TABLE 3, the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a CDR-H1 of TABLE 3, the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a CDR-L3 of TABLE 3, the CDR-L2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a CDR-L2 of TABLE 3, and the CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a CDR-L1 of TABLE 3. In some embodiments, the CDR-H3 is a CDR-H3 of TABLE 3, with up to 1, 2, 3,4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H2 is a CDR-H2 of TABLE 3, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H1 is a CDR-H1 of TABLE 3, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L3 is a CDR-L3 of TABLE 3, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L2 is a CDR-L2 of TABLE 3, with up to 1. 2, 3, or 4 amino acid substitutions; and the CDR-L1 is a CDR-L1 of TABLE 3, with up to 1, 2, 3, 4, 5, or 6 amino acid substitutions.

[0378] In certain embodiments of any of the antibodies or antigen binding fragments thereof described above, the antibody further comprises a heavy chain comprising a human IgG sequence selected from a sequence set forth in any one of SEQ ID NOs: 192-235 and 251-407. In certain embodiments of any of the antibodies or antigen binding fragments thereof described above, the antibody further comprises a constant light chain sequence comprising a sequence set forth in SEQ ID NO: 236. In certain embodiments of any of the antibodies or antigen binding fragments thereof described above, the antibody further comprises a heavy chain comprising a human IgG sequence selected from SEQ ID NO: 205 and SEQ ID NO: 321 and a constant light chain sequence comprising a sequence set forth in SEQ ID NO: 236.

[0379] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 10, 71, and 84; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 20 and 95; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 27 and 101; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; 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 IgGl constant region) comprising LALA / YTE substitutions. In certain embodiments, the antibody comprises a heavy chain comprising a heavy chain constant region selected from SEQ ID NO: 205 and SEQ ID NO: 321. In certain embodiments, the antibody comprises a heavy chain comprising a heavy chain constant region set forth in SEQ ID NO: 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 a sequence set forth in SEQ ID NO: 236.

[0380] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67,and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71. and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 24 and 98; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 36 and 102; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 45 or the amino acid sequence LG; 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 IgGl constant region) comprising LALA / YTE substitutions. In certain embodiments, the antibody comprises a heavy chain comprising a heavy chain constant region selected from SEQ ID NO: 205 and SEQ ID NO: 321. In certain embodiments, the antibody comprises a heavy chain comprising a heavy chain constant region set forth in SEQ ID NO: 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 a sequence set forth in SEQ ID NO: 236.

[0381] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 2, 67, and 188; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 6, 71, and 80; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 20 and 95; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 30 and 102; a CDR- L2 comprising the sequence set forth in SEQ ID NO: 47 or the amino acid sequence EG; 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 IgGl constant region) comprising LALA / YTE substitutions. In certain embodiments, the antibody comprises a heavy chain comprising a heavy chain constant region selected from SEQ ID NO: 205 and SEQ ID NO: 321. In certain embodiments, the antibody comprises a heavy chain comprising a heavy chain constant region set forth in SEQ ID NO: 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 a sequence set forth in SEQ ID NO: 236.

[0382] Although a C-terminal lysine may be present in the corresponding coding sequence of the constant heavy chain region (e.g., in a sequence encoding any one of SEQ ID NOs: 307-407), it may be cleaved off during manufacture or after administration (resulting in, e.g., a constant heavy chain sequence of any one of SEQ ID NOs: 192-235 and 251-306). Accordingly, any of the antibodies or antigen binding fragments thereof described above maycomprise a human IgG sequence containing a C-terminal lysine (e.g., any one of SEQ ID NOs: 307-407), a human IgG sequence lacking a C-terminal lysine (e.g., any one of SEQ ID NOs: 192-235 and 251-306), or a mixture thereof (e.g., a mixture of the same heavy chain constant region sequence with and without a C-terminal lysine, such as a mixture of SEQ ID NO: 321 and SEQ ID NO: 205).

[0383] In some aspects, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this disclosure are referred to herein as “variants” or “clones”. In some embodiments, such variants or clones are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants or clones are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.Fc Region

[0384] The structures of the Fc regions of various immunoglobulins, and the glycosylation sites contained therein, are known in the art. See Schroeder and Cavacini, J. (2010) Allergy Clin. Immunol. 125:S41-52, incorporated by reference in its entirety. The Fc region may be a naturally occurring Fc region, or an Fc region modified as described in the art or elsewhere in this disclosure.

[0385] Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al. Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991. An "Fc polypeptide" of a dimeric Fc as used herein refers to one of the two polypeptides forming the dimeric Fc domain, i.e. a polypeptide comprising C-terminal constant regions of an immunoglobulin heavy chain, capable of stable self-association. For example, an Fc polypeptide of a dimeric IgG Fc comprises an IgG CH2 and an IgG CH3 constant domain sequence. An Fc can be of the class IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGi, IgG2, IgGs, IgG4, IgAi, and IgA2.

[0386] In certain embodiments, provided human IgGl Fc regions include an SRDEL (SEQ ID NO: 478) allotype or an SREEM (SEQ ID NO: 479) allotype.

[0387] The terms “Fc receptor” and “FcR” are used to describe a receptor that binds to the Fc region of an antibody. For example, an FcR can be a native sequence human FcR. Generally, an FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the FcyRI, FcyRII, and FcyRIII subclasses, including allelic variants and alternatively spliced forms of these receptors. FcyRII receptors include FcyRIIA (an “activating receptor”) and FcyRIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof. Immunoglobulins of other isotypes can also be bound by certain FcRs (see, e.g., Janeway et al., Immuno Biology: the immune system in health and disease, (Elsevier Science Ltd., NY) (4th ed., 1999)).Activating receptor FcyRIIA contains an immunoreceptor tyrosine-based activation motif (IT AM) in its cytoplasmic domain. Inhibiting receptor FcyRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain (reviewed in Daeron, (1997) Anna. Rev. Immunol. 15:203-234). FcRs are reviewed in Ravetch and Kinet, (1991) Atinu. Rev. Immunol 9:457-92: Capel el al. (1994) Immunomethods 4:25-34; and de Haas el al. (1995) J. Lab. Clin. Med. 126:330-41. Other FcRs, including those to be identified in the future, are encompassed by the term “FcR” herein. The term also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al. (1976) J. Immunol. 117:587; and Kim et al. (1994) J. Immunol. 24:249).

[0388] Modifications in the CH2 domain can affect the binding of FcRs to the Fc. A number of amino acid modifications in the Fc region are known in the art for selectively altering the affinity of the Fc for different Fcgamma receptors. In some aspects, the Fc comprises one or more modifications to promote selective binding of Fc-gamma receptors.

[0389] Exemplary mutations that may alter the binding of FcRs to the Fc are listed below (in EU numbering format):• S298A / E333A / K334A, S298A / E333A / K334A / K326A (Lu et al., (2011) J ImmunolMet / zods 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 Sei. 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 U SA. 103(l l):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 / D270 L / I332E, S239E / S267E / H268D, L234F / S267E / N325L, G237F / V266L / S267D and other mutations listed in WO2011 / 120134 and WO2011 / 120135, herein incorporated by reference. Therapeutic Antibody Engineering (by William R. Strohl and Lila M. Strohl, Woodhead Publishing series in Biomedicine No 11, ISBN 1 907568 37 9, Oct 2012) lists mutations on page 283.

[0390] In some embodiments, an antibody described herein includes modifications intended to improve its ability to mediate effector function. Such modifications that can have this effect are known in the art and include afucosylation, or engineering of the affinity of the Fc towards an activating receptor, mainly FCGR3a for ADCC, and towards Clq for GDC. The following TABLE 4 summarizes various designs reported in the literature for effector function engineering.

[0391] Methods of producing antibodies with little or no fucose on the Fc glycosylation site (Asn 297 EU numbering) without altering the amino acid sequence are well known in the art. The GlymaX® technology (ProBioGen AG) is based on the introduction of a gene for an enzyme which deflects the cellular pathway of fucose biosynthesis into cells used for antibody production. This prevents the addition of the sugar “fucose” to the N-linked antibody carbohydrate part by antibody -producing cells, (von Horsten et al. (2010) Glycobiology. 2010 Dec; 20 (12): 1607-18). Examples of cell lines capable of producing defucosylated antibody include CHO-DG44 with stable overexpression of the bacterial oxidoreductase GDP-6-deoxy-D-lyxo-4-hexylose reductase (RMD) (see von Horsten et al. (2010) supra) or Lee 13 CHO cells, which are deficient in protein fucosylation (see Ripka et al. (1986) Arch. Biochem. Biophys. 249:533-545; U.S. Pat. Pub. No. 2003 / 0157108; WO 2004 / 056312; each of which is incorporated by reference in its entirety), and knockout cell lines, such as alpha- 1,6-fucosyltransferase gene or FUT8 knockout CHO cells (see Yamane- Ohnuki et al. (2004) Biotech. Bioeng. 87: 614-622; Kanda et al. (2006) Biotechnol. Bioeng. 94:680-688; and WO 2003 / 085107; each of which is incorporated by reference in its entirety). Another approach to obtaining antibodies with lowered levels of fucosylation can be found in U.S. Patent No. 8,409,572, which teaches selecting cell lines for antibody production for their ability to yield lower levels of fucosylation on antibodies.

[0392] Antibodies can be fully afucosylated (meaning they contain no detectable fucose) or they can be partially afucosylated, meaning that the isolated antibody contains less than 95%, less than 85%, less than 75%, less than 65%, less than 55%, less than 45%, less than 35%, less than 25%, less than 15% or less than 5% of the amount of fucose normally detected for a similar antibody produced by a mammalian expression system.

[0393] In some aspects, an antibody, or an antigen binding fragment thereof, provided herein comprises an IgGl domain with reduced fucose content at position Asn 297 compared to a naturally occurring IgGl domain. Such Fc domains can have improved ADCC. See Shields et al. (2002) J. Biol. Chem. 277:26733-26740, incorporated by reference in its entirety. In some aspects, such antibodies do not comprise any fucose at position Asn 297. The amount of fucose may be determined using any suitable method, for example as described in WO 2008 / 077546, incorporated by reference in its entirety.

[0394] In certain embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises an Fc region with one or more amino acid substitutions which improve ADCC, such as a substitution at one or more of positions 298, 333, and 334 of the Fc region. In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises an Fc region with one or more amino acid substitutions at positions 239, 332, and 330, as described in Lazar et al. (2006) Proc. Natl. Acad. Sci. USA 103:4005-4010, incorporated by reference in its entirety.

[0395] Other illustrative glycosylation variants which may be incorporated into the antibodies provided herein are described, for example, in U.S. Pat. Pub. Nos. 2003 / 0157108, 2004 / 0093621, 2003 / 0157108, 2003 / 0115614, 2002 / 0164328, 2004 / 0093621, 2004 / 0132140, 2004 / 0110704, 2004 / 0110282, 2004 / 0109865; International Pat. Pub. Nos. 2000 / 61739, 2001 / 29246, 2003 / 085119, 2003 / 084570, 2005 / 035586, 2005 / 035778; 2005 / 053742, 2002 / 031140; Okazaki et al., J. Mol. Biol., 2004, 336: 1239-1249; and Yamane-Ohnuki et al. (2004) supra; each of which is incorporated by reference in its entirety.

[0396] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises an Fc region with at least one galactose residue in the oligosaccharide attached to the Fc region. Such antibody variants may have improved CDC function. Examples of such antibody variants are described, for example, in WO 1997 / 30087; WO 1998 / 58964; and WO 1999 / 22764; each of which is incorporated by reference in its entirety.

[0397] Thus, in one embodiment, an antibody described herein can include a dimeric Fc that comprises one or more amino acid modifications as noted in TABLE 4 that may confer improved effector function. In another embodiment, the antibody can be afucosylated to improve effector function.TABLE 4. CH2 domains and effector function engineering

[0398] Fc modifications intended to reduce FcgR and / or complement binding and / or effector function are known in the art. Recent publications describe strategies that have been used to engineer antibodies with reduced or silenced effector activity (see Strohl, WR (2009), Curr Opin Biotech 20:685-691, and Strohl, WR and Strohl LM, “Antibody Fc engineering foroptimal antibody performance" In Therapeutic Antibody Engineering, Cambridge: Woodhead Publishing (2012), pp 225-249). These strategies include reduction of effector function through modification of glycosylation, use of IgG2 / IgG4 scaffolds, or the introduction of mutations in the hinge or CH2 regions of the Fc. For example, U.S. Patent Publication No. 2011 / 0212087 (Strohl), International Patent Publication No. WO 2006 / 105338 (Xencor), U.S. Patent Publication No. 2012 / 0225058 (Xencor), U.S. Patent Publication No. 2012 / 0251531 (Genentech), and Strop et al. ((2012) J. Mol. Biol. 420: 204- 219), each of which is incorporated by reference in its entirety, describe specific modifications designed to reduce FcgR or complement binding to the Fc.

[0399] Specific, non-limiting examples of amino acid modifications intended to reduce FcgR or complement binding to the Fc include those identified in the following TABLE 5:TABLE 5. Modifications designed to reduce FcgR or complement binding to the Fc

[0400] In some embodiments, an antibody provided herein comprises one or more alterations that is designed to improve or diminish Clq binding and / or CDC. See U.S. Pat. No. 6,194,551; WO 99 / 51642; and Idusogie et al. (2000) J. Immunol., 164:4178-4184; each of which is incorporated by reference in its entirety.

[0401] In certain embodiments, an antibody provided herein comprises a heavy chain comprising a constant heavy chain sequence selected from a sequence set forth in any one of 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). Although a C- terminal lysine may be present in the corresponding coding sequence of the constant heavy chain region, it may be cleaved off during manufacture or after administration. Accordingly, sequences of heavy chain constant regions with and without the C-terminal lysine are provided herein. Consequently, a composition resulting from the manufacture of an antibody comprising a C-terminal lysine in the corresponding coding sequence of the constant heavy chain region (e.g., an antibody with a coding sequence that encodes any one of SEQ ID NOs: 307-407) may comprise antibodies having a constant heavy chain sequence containing a C- terminal lysine (e.g., selected from SEQ ID NOs: 307-407), antibodies having a constant heavy chain sequence lacking a C-terminal lysine (e.g., the corresponding sequence of any one of SEQ ID NOs: 192-235 and 251 -306), or a mixture thereof. For example, a composition comprising an antibody comprising the constant heavy chain sequence of SEQ ID NO: 321 that is administered to a subject may comprise antibodies having the constant heavy chain sequence set forth in SEQ ID NO: 321 or SEQ ID NO: 205, or a mixture thereof (e.g., a mixture of antibodies having either a constant heavy chain sequence of SEQ ID NO: 321 or a constant heavy chain sequence of SEQ ID NO: 205 and / or antibodies containingboth constant heavy chain sequences (e.g., in a single antibody containing two constant heavy chain sequences)).

[0402] In certain embodiments, an antibody provided herein comprises a VH sequence and a VL sequence provided in TABLE 3 (e.g., a VH sequence and a VL sequence from the same row of TABLE 3), together with a heavy chain constant region selected from a sequence set forth in any one of SEQ ID NOs: 192-235 and 251-407. In certain embodiments, an antibody provided herein comprises a VH sequence and a VL sequence provided in TABLE 3, together with a heavy chain constant region selected from a sequence set forth in any one of SEQ ID NOs: 192-235 and 251-407 and a light chain constant region set forth in SEQ ID NO: 236.

[0403] 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: 146; and a constant heavy chain comprising a human IgG sequence selected from a sequence set forth in any one of SEQ ID NOs: 192-235 and 251-407. In certain embodiments, the antibody comprises a constant heavy chain comprising a human IgG sequence selected from a sequence set forth in any one of SEQ ID NOs: 192-234, 251-308, 310-350, and 352-407. In certain embodiments, the antibody does not comprise a constant heavy chain comprising a human IgG sequence set forth in any of SEQ ID NOs: 235, 309, and 351 (i.e., a human IgG4-SP constant heavy chain region).

[0404] In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 134 and a VL sequence set forth in SEQ ID NO: 178; and the constant heavy chain comprises a human IgG sequence selected from a sequence set forth in any one of SEQ ID NOs: 192-235 and 251-407 (e.g., SEQ ID NO: 321 or SEQ ID NO: 205). In certain embodiments, the antibody, or antigen binding fragment thereof, comprises a light chain constant region set forth in SEQ ID NO: 236.

[0405] In certain embodiments, the anti-IL-4Rα antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 475 and / or SEQ ID NO: 476. In certain embodiments, the anti-IL-4Rα antibody comprises a light chain comprising an amino acid sequence set forth in SEQ ID NO: 477. In certain embodiments, the anti-IL-4Rα antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 475 and a light chain comprising an amino acid sequence set forth in SEQ ID NO: 477. The heavy chain sequence of SEQ ID NO: 475 contains a C-terminal lysine, which may be cleaved off during manufacture or after administration, resulting in an antibody containingthe heavy chain sequence of SEQ ID NO: 476. In certain embodiments, the anti-IL-4Rα antibody comprises a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 476 and a light chain comprising an amino acid sequence set forth in SEQ ID NO: 477.

[0406] In certain embodiments, the Fc region comprises one or more amino acid substitutions, wherein the one or more amino acid substitutions result in an increase in one or more of antibody half-life, ADCC activity, ADCP activity, or CDC activity compared with the Fc region without the one or more amino acid substitutions. In certain embodiments, the one or more amino acid substitutions results in increased antibody half-life at pH 6.0 compared to an antibody comprising a wild-type Fc region. In certain embodiments, the antibody has an increased half-life that is about 10,000-fold, 1,000-fold, 500-fold, 100-fold, 50-fold, 20-fold, 10-fold, 9-fold, 8-fold. 7-fold, 6-fold, 5-fold, 4.5-fold, 4-fold, 3.5-fold, 3- fold, 2.5-fold, 2-fold, 1.95-fold, 1.9-fold, 1.85-fold, 1.8-fold, 1.75-fold, 1.7-fold, 1.65-fold, 1.6-fold, 1.55-fold, 1.50-fold, 1.45-fold, 1.4-fold, 1.35-fold, 1.3-fold, 1.25-fold, 1.2-fold, 1.15-fold, 1.1 -fold, or 1.05-fold longer compared to an antibody comprising a wild-type Fc region. In certain embodiments, the antibody has an increased half-life that is about 10,000- fold, 1,000-fold, 500-fold, 100-fold, 50-fold, 20-fold, 10-fold, 9-fold, 8-fold, 7-fold, 6-fold, 5-fold, 4.5-fold, 4-fold, 3.5-fold, 3-fold, 2.5-fold, 2-fold, 1.95-fold, 1.9-fold, 1.85-fold, 1.8- fold, 1.75-fold, 1.7-fold, 1.65-fold, 1.6-fold, 1.55-fold, 1.50-fold, 1.45-fold, 1.4-fold, 1.35- fold, 1.3-fold, 1.25-fold, 1.2-fold, 1.15-fold, 1.1-fold, or 1.05-fold longer compared to dupilumab. In certain embodiments, the antibody has an increased half-life that is about 2.5- fold, 2.4-fold, 2.3-fold, 2.2-fold, 2.1 -fold, 2.0-fold, 1.9-fold, or 1.8-fold longer compared to dupilumab.

[0407] In certain embodiments, an antibody described herein comprises a heavy chain constant domain having a means for increasing the half-life of the antibody.

[0408] In certain embodiments, the Fc region comprises one or more amino acid substitutions, wherein the one or more amino acid substitutions result in a decrease in one or more of ADCC activity, ADCP activity, or CDC activity compared with the Fc region without the one or more amino acid substitutions.

[0409] In certain embodiments, the one or more amino acid substitutions is selected from the group consisting of S228P (SP), M252Y, S254T, T256E, T256D, T250Q, H285D, T307A, T307Q, T307R, T307W, L309D, Q411H, Q311V, A378V, E380A, M428L, N434A, N434S, N297A, D265A, L234A, L235A, and N434W. In certain embodiments, the one or more amino acid substitutions comprises a specific combination of amino acid substitutionsselected from the group consisting of M428L / N434S (LS), M252Y / S254T / T256E (YTE), T250Q / M428L, T307A / E380A / N434A, T256D / T307Q (DQ), T256D / T307W (DW), M252Y / T256D (YD), T307Q / Q311V / A378V (QVV), T256D / H285D / T307R / Q311V / A378V (DDRVV), L309D / Q311H / N434S (DHS), S228P / L235E (SPLE), L234A / L235A (LALA), M428L / N434A (LA), L235A / G237A (LAGA), L234A / L235A / G237A (LALAGA), L234A / L235A / P329G (LALAPG), D265A / YTE, LALA / YTE, LAGA / YTE, LALAGA / YTE, LALAPG / YTE, N297A / LS, D265A / LS, LALA / LS, LALAGA / LS, LALAPG / LS, N297A / DHS, D265A / DHS, LALA / DHS, LAGA / DHS, LALAGA / DHS, LALAPG / DHS, SP / YTE, SPLE / YTE, SP / LS, SPLE / LS, SP / DHS, SPLE / DHS, N297A / LA, D265A / LA, LALA / LA, LAGA / LA, LALAGA / LA, LALAPG / LA, N297A / N434A, D265A / N434A, LALA / N434A, LAGA / N434A, LALAGA / N434A, LALAPG / N434A, N297A / N434W, D265A / N434W, LALA / N434W, LAGA / N434W, LALAGA / N434W, LALAPG / N434W, N297A / DQ, D265A / DQ, LALA / DQ, LAGA / DQ, LALAGA / DQ, LALAPG / DQ, N297A / DW, D265A / DW, LALA / DW, LAGA / DW, LALAGA / DW, LALAPG / DW, N297A / YD, D265A / YD, LALA / YD, LAGA / YD, LALAGA / YD, LALAPG / YD, T307Q / Q311V / A378V (QVV), N297A / QVV, D265A / QVV, LALA / QVV, LAGA / QVV, LALAGA / QVV, LALAPG / QVV, DDRVV, N297A / DDRVV, D265A / DDRVV, LALA / DDRVV, LAGA / DDRVV, LALAGA / DDRVV, and LALAPG / DDRVV.

[0410] Although the EU numbering system is typically used to identify the positions of the various Fc mutations described herein, direct numbering can also be used. For example, in certain embodiments, an antibody described herein comprises an Fc region with YTE mutations at positions 260, 262, and 264, respectively. In certain embodiments, an antibody described herein comprises an Fc region with LALA mutations at positions 242 and 243, respectively. In certain embodiments, an antibody described herein comprises an Fc region e.g., a human IgGl Fc region) with YTE mutations at positions 260, 262, and 264 and with LALA mutations at positions 242 and 243, respectively. In certain embodiments, an antibody described herein comprises the VH and VL of mAb471 (Construct 38) and an Fc region comprising YTE mutations at positions 260, 262, and 264 (M260Y / S262T / T264E), respectively and with LALA mutations at positions 242 and 243 (L242A / L243A), respectively (e.g., as shown in the heavy chain sequences of SEQ ID NOs: 475 and 476).

[0411] In certain embodiments the human Fc region comprises a human IgG 1 Fc region with LALA mutations. In certain embodiments, the human Fc region comprises a human IgGl Fc region with YTE mutations. In certain embodiments, the human Fc regioncomprises a human IgGl Fc region with LALA and YTE mutations. In certain embodiments, when direct numbering is used, “YTE” and “LALA” mutations can be located at different amino acid position numbers. For example, a human Fc region can comprise a human IgGl Fc region with LALA mutations at L242A / L243A and / or YTE mutations at M260Y / S262T / T264E.

[0412] In certain embodiments, the Fc region binds an Fey Receptor selected from the group consisting of: FcyRI, FcyRIIa, FcyRIIb, FcyRIIc, FcyRIIIa, and FcyRIIIb. In certain embodiments, the Fc region binds an Fey Receptor with higher affinity at pH 6.0 compared to an antibody comprising a wild-type Fc region.Binding

[0413] The affinity of a molecule X for its partner Y can be represented by the dissociation equilibrium constant (KD). The kinetic components that contribute to the dissociation equilibrium constant are described in more detail below. Affinity can be measured by common methods known in the art, including those described herein, such as surface plasmon resonance (SPR) technology (e.g., BIACORE®) or biolayer interferometry (e.g., FORTEBIO®).

[0414] With regard to the binding of an antibody to a target molecule, the terms “bind,” “specific binding,” “specifically binds to,” “specific for,” “selectively binds,” and “selective for” a particular antigen (e.g., a polypeptide target) or an epitope on a particular antigen mean binding that is measurably different from a non-specific or non-selective interaction (e.g., with a non-target molecule). Specific binding can be measured, for example, by measuring binding to a target molecule (z.e., IL-4Rα) and comparing it to binding to a non-target molecule. Specific binding can also be determined by competition with a control molecule that mimics the epitope recognized on the target m...

Claims

CLAIMS1. A composition comprising an isolated antibody, or antigen binding fragment thereof, that binds Interleukin (IL)-4 Receptor alpha (IL-4Rα) and a hyaluronidase, wherein the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO:2; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 6: a CDR-H3 comprising the sequence set forth in SEQ ID NO: 20; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 30; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 47; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

2. A composition comprising an isolated antibody, or antigen binding fragment thereof, that binds Interleukin (IL)-4 Receptor alpha (IL-4Rα) and a hyaluronidase, wherein the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 1; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 5; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 17; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 26; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 41; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 53.

3. A composition comprising an isolated antibody, or antigen binding fragment thereof, that binds Interleukin (IL)-4 Receptor alpha (IL-4Rα) and a hyaluronidase, wherein the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 134 and a VL sequence set forth in SEQ ID NO: 178.

4. A composition comprising an isolated antibody, or antigen binding fragment thereof, that binds Interleukin (IL)-4 Receptor alpha (IL-4Rα) and a hyaluronidase, wherein the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 113 and a VL sequence set forth in SEQ ID NO: 146.

5. A combination comprising an isolated antibody, or antigen binding fragment thereof, that binds Interleukin (IL)-4 Receptor alpha (IL-4Rα) and a hyaluronidase, wherein the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO:2; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 6; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 20; a CDR-L1 comprising thesequence set forth in SEQ ID NO: 30; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 47: and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

6. A combination comprising an isolated antibody, or antigen binding fragment thereof, that binds Interleukin (IL)-4 Receptor alpha (IL-4Rα) and a hyaluronidase, wherein the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 1; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 5; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 17; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 26; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 41; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 53.

7. A combination comprising an isolated antibody, or antigen binding fragment thereof, that binds Interleukin (IL)-4 Receptor alpha (IL-4Rα) and a hyaluronidase, wherein the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 134 and a VL sequence set forth in SEQ ID NO: 178.

8. A combination comprising an isolated antibody, or antigen binding fragment thereof, that binds Interleukin (IL)-4 Receptor alpha (IL-4Rα) and a hyaluronidase, wherein the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 113 and a VL sequence set forth in SEQ ID NO: 146.

9. A method of treating an inflammatory disorder or disease in a human patient comprising administering to the patient an isolated antibody, or antigen binding fragment thereof, that binds Interleukin (IL)-4 Receptor alpha (IL-4Rα) and a hyaluronidase, wherein the antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO:2; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 6; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 20; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 30; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 47; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.

10. A method of treating an inflammatory disorder or disease in a human patient comprising administering to the patient an isolated antibody, or antigen binding fragment thereof, that binds Interleukin (IL)-4 Receptor alpha (IL-4Rα) and a hyaluronidase, whereinthe antibody, or antigen binding fragment thereof, comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 1; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 5; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 17; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 26; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 41; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 53.

11. A method of treating an inflammatory disorder or disease in a human patient comprising administering to the patient an isolated antibody, or antigen binding fragment thereof, that binds Interleukin (IL)-4 Receptor alpha (IL-4Rα) and a hyaluronidase, wherein the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 134 and a VL sequence set forth in SEQ ID NO: 178.

12. A method of treating an inflammatory disorder or disease in a human patient comprising administering to the patient an isolated antibody, or antigen binding fragment thereof, that binds Interleukin (IL)-4 Receptor alpha (IL-4Rα) and a hyaluronidase, wherein the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 113 and a VL sequence set forth in SEQ ID NO: 146.

13. The composition of any one of claims 1-4, the combination of any one of claims 5-8, or the method of any one of claims 9-12, wherein the antibody, or antigen binding fragment thereof, is a humanized, human, or chimeric antibody.

14. The composition of any one of claims 1-4, the combination of any one of claims 5-8, or the method of any one of claims 9-12, wherein the antibody, or antigen binding fragment thereof, is a humanized antibody.

15. The composition of any one of claims 1-4, the combination of any one of claims 5-8, or the method of any one of claims 9-12, wherein the antibody, or antigen binding fragment thereof, comprises a heavy chain human constant region of a class selected from IgG, IgA, IgD, IgE, and IgM.

16. The composition of any one of claims 1-4, the combination of any one of claims 5-8, or the method of any one of claims 9-12, wherein the antibody, or antigen binding fragment thereof, comprises a human Fc region comprising a human heavy chain constant region of the class IgG and a subclass selected from IgGl, IgG2, IgG3, and IgG4.

17. The composition of any one of claims 1-4, the combination of any one of claims 5-8, or the method of any one of claims 9-12, wherein the antibody, or antigen binding fragment thereof, comprises a human IgGl Fc region.

18. The composition of any one of claims 1-4, the combination of any one of claims 5-8, or the method of any one of claims 9-12, wherein the antibody, or antigen binding fragment thereof, comprises a human IgGl Fc region with LALA and YTE mutations.

19. The composition of any one of claims 1-4, the combination of any one of claims 5-8, or the method of any one of claims 9-12, wherein the antibody, or antigen binding fragment thereof, comprises a human IgGl Fc region with LALA mutations at positions 242 and 243 (L242A / L243A) and YTE mutations at positions 260, 262, and 264 (M260Y / S262T / T264E) by direct numbering.

20. The composition of any one of claims 1-4, the combination of any one of claims 5-8, or the method of any one of claims 9-12, wherein the antibody, or antigen binding fragment thereof, comprises a human Fc region comprising a human IgG sequence selected from a sequence set forth in any one of SEQ ID NOs: 192-235 and 251-407.

21. The composition of any one of claims 1-4, the combination of any one of claims 5-8, or the method of any one of claims 9-12, wherein the antibody, or antigen binding fragment thereof, comprises a heavy chain comprising a constant heavy chain region having a means for extending the half-life of the antibody.

22. The composition of any one of claims 1-4, the combination of any one of claims 5-8, or the method of any one of claims 9-12, wherein the antibody, or antigen binding fragment thereof, comprises a heavy chain comprising a constant heavy chain sequence set forth in SEQ ID NO: 321.

23. The composition of any one of claims 1-4, the combination of any one of claims 5-8, or the method of any one of claims 9-12, wherein antibody, or antigen binding fragment thereof, comprises a the light chain comprising a constant light chain sequence set forth in SEQ ID NO: 236.

24. The composition of claim 1 or 3, the combination of claim 5 or 7, or the method of claim 9 or 11, wherein the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 134, a VL sequence set forth in SEQ ID NO: 178, a constant heavy chain sequence set forth in SEQ ID NO: 321, and a constant light chain sequence set forth in SEQ ID NO: 236.

25. The composition of any one of claims 1-4, the combination of any one of claims 5-8, or the method of any one of claims 9-12, wherein the Fc region of the antibody binds to Neonatal Fc receptor (FcRn).

26. The composition of any one of claims 1-4, the combination of any one of claims 5-8, or the method of any one of claims 9-12, wherein the Fc region of the antibody binds an FcRn with higher affinity at pH 6.0 compared to an antibody comprising a wild-type Fc region.

27. The composition of any one of claims 1-4, the combination of any one of claims 5-8, or the method of any one of claims 9-12, wherein the Fc region of the antibody binds to FcRn with a KD of <1 x 10'7M at pH 6.0.

28. The composition of any one of claims 1-4, the combination of any one of claims 5-8, or the method of any one of claims 9-12, wherein the antibody, or antigen binding fragment thereof, is a monoclonal antibody.

29. The composition of any one of claims 1-4, the combination of any one of claims 5-8, or the method of any one of claims 9-12, wherein the antibody, or antigen binding fragment thereof, binds an IL-4Rα sequence set forth in any one of SEQ ID NOs: 237-240.

30. The composition of any one of claims 1-4, the combination of any one of claims 5-8, or the method of any one of claims 9-12, wherein the antibody, or antigen binding fragment thereof, binds to an IL-4Rα sequence set forth in any one of SEQ ID NOs: 237-240 with a KD of less than or equal to about 1, 2, 3, 4, 5, 6, 7, 8, or 9 x 10’9M, as measured by surface plasmon resonance (SPR).

31. The composition of any one of claims 1-4, the combination of any one of claims 5-8, or the method of any one of claims 9-12, wherein the antibody, or antigen binding fragment thereof, binds to an IL-4Rα sequence set forth in any one of SEQ ID NOs: 237-240 with a KD of less than or equal to about 1 x 10'10M, as measured by surface plasmon resonance (SPR).

32. The composition of any one of claims 1-4, the combination of any one of claims 5-8, or the method of any one of claims 9-12, wherein the antibody, or antigen binding fragment thereof, binds to human IL-4Rα with a KD of less than or equal to about 1 x 10'9M, as measured by surface plasmon resonance (SPR).

33. The composition of any one of claims 1-4, the combination of any one of claims 5-8, or the method of any one of claims 9-12, wherein the antibody exhibits a melting temperature greater than 68°C as measured by Differential Scanning Fluorometry (DSF).

34. The composition of any one of claims 1-4, the combination of any one of claims 5-8, or the method of any one of claims 9-12, wherein the antibody exhibits a melting temperature greater than 75°C as measured by Differential Scanning Fluorometry (DSF).

35. The composition of any one of claims 1-4, the combination of any one of claims 5-8, or the method of any one of claims 9-12, wherein the antibody exhibits an aggregation temperature equal to or greater than 71 ,2°C as measured by Differential Scanning The composition, the combination, or the method of claim 28, Fluorometry (DSF).

36. The composition of any one of claims 1-4, the combination of any one of claims 5-8, or the method of any one of claims 9-12, wherein the antibody has a retention time of 15.2 minutes or less as measured by hydrophobic interaction chromatography.

37. The composition of any one of claims 1-4, the combination of any one of claims 5-8, or the method of any one of claims 9-12, wherein the hyaluronidase is a recombinant human hyaluronidase.

38. The composition, the combination, or the method of claim 37, wherein the recombinant human hyaluronidase comprises the amino acid sequence set forth in any one of SEQ ID NOs: 408-417 and 419-474.

39. The composition, the combination, or the method of claim 37, wherein the recombinant human hyaluronidase is rHuPH20.

40. The composition, the combination, or the method of claim 39, wherein the rHuPH20 formulation is ENHANZE®.

41. The combination of any one of claims 5-8 or the method of any one of claims 9-12, wherein the hyaluronidase and antibody, or antigen binding fragment thereof, are administered in separate formulations.

42. The combination or the method of claim 41, wherein the hyaluronidase and antibody, or antigen binding fragment thereof, are administered simultaneously in separate formulations.

43. The combination or the method of claim 41, wherein the hyaluronidase is administered to the patient prior to administration of the antibody, or antigen binding fragment thereof.

44. The combination or the method of claim 41, wherein the hyaluronidase is administered to the patient after administration of the antibody, or antigen binding fragment thereof.

45. The composition of any one of claims 1-4, the combination of any one of claims 5-8, or the method of any one of claims 9-12, wherein the hyaluronidase and the antibody, or antigen binding fragment thereof, are mixed and administered in a single formulation.

46. The composition of any one of claims 1-4, the combination of any one of claims 5-8, or the method of any one of claims 9-12, wherein the hyaluronidase and the antibody, or antigen binding fragment thereof, are administered by subcutaneous injection.

47. The composition of any one of claims 1-4, the combination of any one of claims 5-8, or the method of any one of claims 9-12, wherein the hyaluronidase and the antibody, or antigen binding fragment thereof, are administered by intravenous injection.

48. The composition of any one of claims 1-4, the combination of any one of claims 5-8, or the method of any one of claims 9-12, wherein the hyaluronidase is rHuPH20 administered at a concentration of 5,000, 6,000, 7,000, 8,000, 9,000, 10,000, 11,000, 12,000, 13,000, 14,000, 15,000, 16,000, 17,000, 18,000, 19,000, 20,000, 21,000, 22,000, 23,000, 24,000, 25,000. 26,000, 27,000, 28,000, 29,000, 30,000. 31,000, 32,000, 33,000, 34,000, 35,000. 36.

000. 37.000, 38,000, 39,000, or 40,000 units.

49. The method of any one of claims 9-12, wherein the inflammatory disorder or disease is atopic dermatitis.

50. The method of claim 49, wherein the treatment reduces disease severity in the patient and wherein disease severity is assessed by an atopic dermatitis disease severity outcome measure.

51. The method of any one of claims 9-12, wherein the inflammatory disorder or disease is selected from the group consisting of asthma, chronic sinusitis with nasal polyps, Chronic Rhinosinusitis without Nasal Polyps (CRSsNP), eosinophilic esophagitis (EoE), Churg- Strauss syndrome / Eosinophilic granulomatosis with polyangiitis (EGPA), Prurigo Nodularis (PN), Chronic Spontaneous Urticaria (CSU), Chronic Pruritis of Unknown Origin (CPUO), Bullous Pemphigoid (BP), Cold Inducible Urticaria (ColdU), Allergic Fungal Rhinosinusitis (AFRS), Allergic Bronchopulmonary Aspergillosis (ABPA), Chronic Obstructive Pulmonary Disease (COPD), an inflammatory bowel disease, lupus, rheumatoid arthritis, idiopathic pulmonary fibrosis, alopecia areata, psoriasis, celiac disease, hidradenitis suppurativa, and systemic sclerosis.

52. The method of claim 51, wherein the inflammatory bowel disease is Crohn’s disease or ulcerative colitis.

53. The method of any one of claims 9-12, wherein the inflammatory disorder or disease is an Eosinophilic gastrointestinal disorder or disease (EGID) selected from the group consisting of Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), Eosinophilic Colitis (EoC), and Eosinophilic Gastroenteritis (EGE).

54. A kit for treating an inflammatory disorder or disease in a human patient, the kit comprising:(a) a dose of an isolated antibody, or antigen binding fragment thereof, that binds Interleukin (IL)-4 Receptor alpha (IL-4Rα), wherein the antibody comprises a VH sequence set forth in SEQ ID NO: 134 and a VL sequence set forth in SEQ ID NO: 178;(b) a dose of a hyaluronidase; and(c) instmctions.

55. The kit of claim 54, wherein the hyaluronidase is a recombinant human hyaluronidase.

56. The kit of claim 55, wherein the recombinant human hyaluronidase comprises the amino acid sequence set forth in any one of SEQ ID NOs: 408-417 and 419-474.

57. The kit of claim 55, wherein the recombinant human hyaluronidase is rHuPH20.

58. The kit of claim 57, wherein the rHuPH20 formulation is ENHANZE®.

59. The kit of claim 54 for use in treating an inflammatory disorder or disease.

60. The kit of claim 59, wherein the inflammatory disorder or disease is atopic dermatitis.

61. The kit of claim 59, wherein the inflammatory disorder or disease is selected from the group consisting of asthma, chronic sinusitis with nasal polyps, Chronic Rhinosinusitiswithout Nasal Polyps (CRSsNP), eosinophilic esophagitis (EoE), Churg-Strauss syndrome / Eosinophilic granulomatosis with polyangiitis (EGPA), Prurigo Nodularis (PN), Chronic Spontaneous Urticaria (CSU), Chronic Pruritis of Unknown Origin (CPUO), Bullous Pemphigoid (BP), Cold Inducible Urticaria (ColdU), Allergic Fungal Rhinosinusitis (AFRS), Allergic Bronchopulmonary Aspergillosis (ABPA), Chronic Obstructive Pulmonary Disease (COPD), an inflammatory bowel disease, lupus, rheumatoid arthritis, idiopathic pulmonary fibrosis, alopecia areata, psoriasis, celiac disease, hidradenitis suppurativa, and systemic sclerosis.

62. The kit of claim 61, wherein the inflammatory bowel disease is Crohn’s disease or ulcerative colitis.

63. The kit of claim 59, wherein the inflammatory disorder or disease is an Eosinophilic gastrointestinal disorder or disease (EGID) selected from the group consisting of Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), Eosinophilic Colitis (EoC), and Eosinophilic Gastroenteritis (EGE).

64. The kit of any one of claims 54-63, wherein the antibody, or antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 134, a VL sequence set forth in SEQ ID NO: 178, a constant heavy chain sequence set forth in SEQ ID NO: 321, and a constant light chain sequence set forth in SEQ ID NO: 236.