Antibodies that bind il-4r alpha and antibodies that bind

Abstract

Described herein are antibodies, or antigen binding fragments thereof, that bind OX40L and IL-4Rα in combination and methods of use thereof. In certain aspects, described herein are methods of inhibiting OX40L and IL-4Rα biological activity. In certain aspects, described herein are pharmaceutical compositions comprising the anti-OX40L and anti-IL-4Rα antibodies, or antigen binding fragments thereof. In certain aspects, the antibodies and methods described herein are used for treatment of an inflammatory disease or disorder (e.g., associated with elevated levels of OX40L and / or IL-4). Also described herein are compositions and combinations comprising an antibody or antigen binding region that binds OX40L, an antibody or antigen binding region that binds IL-4Rα, and a hyaluronidase or variant thereof, as well as related methods of treating an inflammatory disorder or disease in a human patient by administering such compositions and combinations.

Description

ANTIBODIES THAT BIND IL-4R ALPHA AND ANTIBODIES THAT BINDCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to, and the benefit of, U.S. Provisional Application No. 63 / 662,968 (filed June 21, 2024) and U.S. Provisional Application No. 63 / 708,879 (filed October 18, 2024). The entire contents of the aforementioned applications is incorporated herein by reference.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on June 19, 2025, is named AOJ-010PC_SL.txt and is 717,774 bytes in size.BACKGROUND

[0003] An emerging mechanism in treatments for atopic dermatitis (AD) is targeting 0X40 or OX40L. OX40L is the ligand for 0X40. OX40L is expressed on antigen presenting cells and its interaction with 0X40 causes the accumulation of T cells by providing a survival signal. OX40L, by playing a role in activating T cells and reprogramming them into inflammatory subsets, contributes to immune overactivation in AD and other inflammatory conditions. Additionally, OX40L activation of 0X40 inhibits the expression of FOXP3 and the inhibitory function of regulatory T (Treg) cells. Treg cells suppress immune response, which leads to worse symptoms in inflammatory conditions. Therefore, OX40L blockade may lead to clinical benefit in AD and other inflammatory conditions by first suppressing inflammatory T cell activation, and next by increasing the proliferation of Treg cells, which can serve to further reduce inflammatory cells. Amlitelimab, which targets OX40L, and rocatinlimab, which targets 0X40, have both demonstrated promising Phase 2 data in AD.

[0004] 0X40 L is the ligand for 0X40 expressed on antigen presenting cells. Its interaction with 0X40 causes the accumulation of T cells by providing a survival signal. T cells are important types of white blood cells of the immune system that play a central role in the immune response. OX40L, by playing a role in activating T cells and reprogramming them into inflammatory subsets, contributes to immune overactivation in AD and otherinflammatory conditions, such as Systemic Lupus Erythematosus. Additionally, OX40L activation of OX40 inhibits the expression of Foxp3 and the inhibitory function of regulatory T (Treg) cells. Treg cells can suppress the immune response that leads to worsening symptoms in inflammatory conditions.

[0005] Meanwhile, 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) Annu. Rev. Immunol.17:701–738) and (Jensen, P.L. (2000) Stem Cells.18:61–62). IL-4Rα pairs with the common γc 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 IgG1 isotypes by stimulated B cells.

[0006] 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 Th1 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.

[0007] 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.

[0008] In addition, because targeting each of OX40L and IL-4Rα may lead to various clinical benefits in inflammatory conditions, there is a need in the art for improved therapeutics that target both OX40L and IL-4Rα, such as recombinant antibodies and combinations thereof. There is also a need for delivering relatively large doses of these antibodies subcutaneously. SUMMARY

[0009] In a first aspect, disclosed herein is an isolated antibody, or an antigen binding fragment thereof, that binds OX40L, comprising: a) a variable heavy (VH) chain sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and b) a variable light (VL) chain sequence having three light chain CDR sequences, CDR-L1, CDR- L2, and CDR-L3; wherein the antibody, or antigen binding fragment thereof, that binds OX40L comprises: (i) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 2-4; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 5-7; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 8-10; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-14; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 15-16; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 17-18; (ii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 20-22; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-25; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 26-28; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 30-32; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 33-34; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 35-36; (iii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 38-40; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 41-43; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 44-46; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 48-50; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 51-52; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 53-54; or (iv) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 56-58; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 59-61; a CDR-H3 comprising the amino acidsequence set forth in any one of SEQ ID NOs: 62-64; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 66-68; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 69-70; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 71-72; and an isolated antibody that binds IL-4Rα.

[0010] In some embodiments, the isolated antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR- L3 of an antibody selected from dupilumab, stapokibart, and 611.

[0011] In some embodiments, the isolated antibody, or an antigen binding fragment thereof, that binds IL-4Rα comprises: a) a VH chain sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and b) a VL chain sequence having three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein the isolated antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: (i) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 276, 277, and 278; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 285 and 286; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 292 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293; (ii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 283 and 284; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 287 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 291 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293; or (iii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 289 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0012] In another aspect, disclosed herein is an isolated antibody, or an antigen binding fragment thereof, that binds OX40L; and an isolated antibody, or an antigen binding fragmentthereof, that binds IL-4Rα, comprising: a) a variable heavy (VH) chain sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and b) a variable light (VL) chain sequence having three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; wherein the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: (i) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 276, 277, and 278; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR- L1 comprising the sequence set forth in any one of SEQ ID NOs: 285 and 286; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 292 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293; (ii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 283 and 284; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 287 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 291 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293; or (iii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 289 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0013] In some embodiments, the isolated antibody, or antigen binding fragment thereof, that binds OX40L comprises a CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR- L3 of an antibody selected from amlitelimab and oxelumab.

[0014] In some embodiments, the isolated antibody, or antigen binding fragment thereof, that binds OX40L comprises: a) a VH chain sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and b) a VL chain sequence having three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein the isolated antibody, or antigen binding fragment thereof, that binds OX40L comprises: (i) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 2-4; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 5-7; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 8-10; a CDR-L1 comprising theamino acid sequence set forth in any one of SEQ ID NOs: 12-14; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 15-16; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 17-18; (i) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 20-22; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-25; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 26-28; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 30-32; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 33-34; and a CDR- L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 35-36; (iii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 38-40; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 41-43; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 44-46; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 48-50; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 51-52; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 53- 54; or (iv) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 56-58; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 59-61; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 62-64; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 66-68; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 69-70; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 71-72.

[0015] In some embodiments, (a) the antibody, or antigen binding fragment thereof, that binds OX40L comprises: (i) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 2-4; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 5-7; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 8-10; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-14; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 15-16; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 17-18; and (b) the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: (i) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 276, 277, and 278; a CDR-H3 comprising the sequence set forth in any one of SEQ IDNOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 285 and 286; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 292 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0016] In some embodiments, (a) the antibody, or antigen binding fragment thereof, that binds OX40L comprises: (ii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 20-22; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-25; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 26-28; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 30-32; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 33-34; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 35-36; and (b) the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: (i) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 276, 277, and 278; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 285 and 286; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 292 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0017] In some embodiments, (a) the antibody, or antigen binding fragment thereof, that binds OX40L comprises: (iii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 38-40; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 41-43; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 44-46; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 48-50; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 51-52; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 53-54; and (b) the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: (i) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 276, 277, and 278; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 285 and 286; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 292 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0018] In some embodiments, (a) the antibody, or antigen binding fragment thereof, that binds OX40L comprises: (iv) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 56-58; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 59-61; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 62-64; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 66-68; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 69-70; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 71-72; and (b) the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: (i) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 276, 277, and 278; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 285 and 286; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 292 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0019] In some embodiments, (a) the antibody, or antigen binding fragment thereof, that binds OX40L comprises: (i) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 2-4; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 5-7; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 8-10; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-14; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 15-16; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 17-18; and (b) the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: (ii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 283 and 284; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 287 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 291 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0020] In some embodiments, (a) the antibody, or antigen binding fragment thereof, that binds OX40L comprises: (ii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 20-22; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-25; a CDR-H3 comprising the amino acid sequence set forth in anyone of SEQ ID NOs: 26-28; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 30-32; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 33-34; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 35-36; and (b) the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: (ii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 283 and 284; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 287 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 291 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0021] In some embodiments, (a) the antibody, or antigen binding fragment thereof, that binds OX40L comprises: (iii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 38-40; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 41-43; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 44-46; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 48-50; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 51-52; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 53-54; and (b) the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: (ii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 283 and 284; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 287 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 291 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0022] In some embodiments, (a) the antibody, or antigen binding fragment thereof, that binds OX40L comprises: (iv) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 56-58; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 59-61; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 62-64; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 66-68; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 69-70; and a CDR-L3 comprising the amino acid sequence set forth inany one of SEQ ID NOs: 71-72; and (b) the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: (ii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 283 and 284; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 287 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 291 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0023] In some embodiments, (a) the antibody, or antigen binding fragment thereof, that binds OX40L comprises: (i) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 2-4; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 5-7; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 8-10; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-14; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 15-16; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 17-18; and (b) the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: (iii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 289 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0024] In some embodiments, (a) the antibody, or antigen binding fragment thereof, that binds OX40L comprises: (ii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 20-22; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-25; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 26-28; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 30-32; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 33-34; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 35-36; and (b) the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: ((iii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one ofSEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 289 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0025] In some embodiments, (a) the antibody, or antigen binding fragment thereof, that binds OX40L comprises: (iii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 38-40; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 41-43; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 44-46; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 48-50; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 51-52; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 53-54; and (b) the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: (iii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 289 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0026] In some embodiments, (a) the antibody, or antigen binding fragment thereof, that binds OX40L comprises: (iv) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 56-58; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 59-61; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 62-64; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 66-68; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 69-70; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 71-72; and (b) the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: (iii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 289 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290 orthe amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0027] In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L comprises a heavy chain variable domain (VH) sequence comprising the amino acid sequence set forth in any one of SEQ ID NOs: 1, 19, 37, and 55.

[0028] In some embodiments, the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in any one of SEQ ID NOs: 295-297.

[0029] In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L comprises a light chain variable domain (VL) sequence comprising the amino acid sequence set forth in any one of SEQ ID NOs: 11, 29, 47, and 65.

[0030] In some embodiments, the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VL sequence comprising the amino acid sequence set forth in any one of SEQ ID NOs: 298-300.

[0031] In some embodiments, (a) the antibody, or antigen binding fragment thereof, that binds OX40L comprises: (i) a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 1; (ii) a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 19; (iii) a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 37; or (iv) a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 55; and / or (v) a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 11; (vi) a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 29; (vii) a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 47; or (viii) a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 65; and / or (b) the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: (i) a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 295; (ii) a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 296; or (iii) a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 297; and / or (iv) a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 298; (v) a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:299; or (vi) a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:300.

[0032] In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 1; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 11.

[0033] In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 19; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 29.

[0034] In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 37; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 47.

[0035] In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 55; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 65.

[0036] In some embodiments, the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 295; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 298.

[0037] In some embodiments, the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 296; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 299.

[0038] In some embodiments, the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 297; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 300.

[0039] In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 1; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 11; and the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 295; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 298.

[0040] In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 1; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 11; and the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 296; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 299.

[0041] In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 1; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 11; and the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 297; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 300.

[0042] In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 19; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 29; and the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 295; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 298.

[0043] In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 19; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 29; and the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 296; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 299.

[0044] In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 19; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 29; and the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 297; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 300.

[0045] In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 37; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 47; and the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 295; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 298.

[0046] In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 37; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 47;and the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 296; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 299.

[0047] In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 37; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 47; and the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 297; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 300.

[0048] In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 55; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 65; and the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 295; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 298.

[0049] In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 55; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 65; and the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 296; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 299.

[0050] In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 55; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 65; and the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 297; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 300.

[0051] In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα is a humanized, human, or chimeric antibody.

[0052] In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα is a humanized antibody.

[0053] In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a heavy chain human constant region of a class selected from IgG, IgA, IgD, IgE, and IgM.

[0054] In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a human Fc region, and the human Fc region comprises a human heavy chain constant region of the class IgG and a subclass selected from IgG1, IgG2, IgG3, and IgG4.

[0055] In some embodiments, the human Fc region of the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a human IgG1 Fc region.

[0056] In some embodiments, the human Fc region of the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a human IgG4 Fc region.

[0057] In some embodiments, the human Fc region of the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a human IgG2 Fc region.

[0058] In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a heavy chain comprising constant heavy chain sequence selected from the amino acid sequences set forth in any one of SEQ ID NOs: 637-737 and 847-1070.

[0059] In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a light chain comprising constant light chain sequence selected from the sequences set forth in SEQ ID NOs: 738 and 1071.

[0060] In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a heavy chain constant domain having a means for increasing the half-life of the antibody.

[0061] In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises an Fc region comprising one or more amino acid substitutions, wherein the one or more substitutions result in an increase in one or more of antibody half-life, ADCC activity,ADCP activity, or CDC activity compared to an antibody comprising an Fc region without the one or more amino acid substitutions (e.g., a wild-type Fc region).

[0062] In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises an Fc region comprising one or more amino acid substitutions, wherein the one or more substitutions result in a decrease in one or more of, ADCC activity, ADCP activity or CDC activity compared to an antibody comprising an Fc region without the one or more amino acid substitutions, (e.g., a wild-type Fc region).

[0063] In some 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 / Q311V / A378V (QVV), N297A / QVV, D265A / QVV, LALA / QVV, LAGA / QVV, LALAGA / QVV, LALAPG / QVV, DDRVV, N297A / DDRVV, D265A / DDRVV, LALA / DDRVV, LAGA / DDRVV, LALAGA / DDRVV, and LALAPG / DDRVV. In some embodiments, the one or more amino acid substitutions is selected from the group consisting of LS, YTE, 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.

[0064] 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 253 / 255 / 257 or 260 / 262 / 264, respectively. In certain embodiments, an antibody described herein comprises an Fc region with LALA mutations at positions 235 / 236 or 242 / 243, respectively. In certain embodiments, an antibody described herein comprises an Fc region with YTE mutations at positions 253 / 255 / 257 and with LALA mutations at positions 235 / 236. In certain embodiments, an antibody described herein comprises an Fc region with YTE mutations at positions 260 / 262 / 264 and with LALA mutations at positions 242 / 243. In certain embodiments, the OX40L antibody described herein comprises the VH and VL of Construct 114 and an Fc region comprising YTE mutations at positions 253 / 255 / 257, respectively and with LALA mutations at positions 235 / 236, respectively. In certain embodiments, the IL-4Rα antibody described herein comprises the VH and VL of Construct 38 (mAb 471) and an Fc region comprising YTE mutations at positions 260 / 262 / 264, respectively and with LALA mutations at positions 242 / 243, respectively.

[0065] In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 1, a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 11, and a human IgG1 Fc region comprising LALA and YTE mutations. In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 1, a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 11, a constant heavy chain sequence set forth in SEQ ID NO: 651 and / or a constant heavy chain sequence set forth in SEQ ID NO: 973, and a constant light chain sequence set forth in SEQ ID NO: 738. In some embodiments, theantibody, or antigen binding fragment thereof, that binds OX40L comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 1, a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 11, a constant heavy chain sequence set forth in SEQ ID NO: 973, and a constant light chain sequence set forth in SEQ ID NO: 738. In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 1, a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 11, a constant heavy chain sequence set forth in SEQ ID NO: 651, and a constant light chain sequence set forth in SEQ ID NO: 738. In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L comprises a heavy chain sequence set forth in SEQ ID NO: 839 and / or SEQ ID NO: 840 and a light chain sequence set forth in SEQ ID NO: 841. In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L comprises a heavy chain sequence set forth in SEQ ID NO: 839 and a light chain sequence set forth in SEQ ID NO: 841. In some embodiments, the antibody that binds OX40L is Construct 114.

[0066] In some embodiments, the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 297, a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 300, and a human IgG1 Fc region comprising LALA and YTE mutations. In some embodiments, the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 297, a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 300, a constant heavy chain sequence set forth in SEQ ID NO: 651 and / or a constant heavy chain sequence set forth in SEQ ID NO: 973, and a constant light chain sequence set forth in SEQ ID NO: 738. In some embodiments, the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 297, a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 300, a constant heavy chain sequence set forth in SEQ ID NO: 973, and a constant light chain sequence set forth in SEQ ID NO: 738. In some embodiments, the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 297, a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 300, a constant heavy chain sequence set forth in SEQ ID NO: 651, and a constant light chain sequence set forth in SEQ ID NO: 738. In some embodiments, the antibody, or antigen binding fragmentthereof, that binds IL-4Rα comprises a heavy chain sequence set forth in SEQ ID NO: 836 and / or SEQ ID NO: 837 and a light chain sequence set forth in SEQ ID NO: 838. In some embodiments, the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a heavy chain sequence set forth in SEQ ID NO: 836 and a light chain sequence set forth in SEQ ID NO: 838. In some embodiments, the antibody that binds IL-4Rα is Construct 38 (mAb 471).

[0067] In some embodiments, the antibody that binds OX40L is Construct 114 and the antibody that binds IL-4Rα is Construct 38 (mAb 471).

[0068] In some embodiments, the antibody that binds OX40L is Construct 114 and the antibody that binds IL-4Rα is dupilumab, stapokibart, or 611.

[0069] In some embodiments, the antibody that binds OX40L is amlitelimab or oxelumab and the antibody that binds IL-4Rα is Construct 38 (mAb 471).

[0070] In some embodiments, the Fc region of the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα binds to Neonatal Fc receptor (FcRn).

[0071] In some embodiments, the Fc region of the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα binds an FcRn with higher affinity at pH 6.0 compared to an antibody comprising a wild-type Fc region.

[0072] In some embodiments, the Fc region of the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα binds to FcRn with a KD of <1 x 10-7M at pH 6.0.

[0073] In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα is a monoclonal antibody.

[0074] In some embodiments, the antibody, or antigen binding fragment thereof, that binds OX40L binds an OX40L sequence set forth in the amino acid sequence of SEQ ID NO: 739.

[0075] In some embodiments, the antibody, or antigen binding fragment thereof, that binds IL-4Rα binds an IL-4Rα sequence set forth in any one of the amino acid sequences of SEQ ID NOs: 301-303.

[0076] In another aspect, the disclosure relates to the isolated antibodies, or antigen binding fragments thereof, of any one of the preceding aspects or embodiments for use in thetreatment of an inflammatory disorder or disease (e.g., combined in a single formulation or administered in separate formulations).

[0077] In another aspect, the disclosure relates to the isolated antibodies, or antigen binding fragments thereof, of any one of the preceding aspects or embodiments for use in the treatment of atopic dermatitis (AD).

[0078] In some embodiments, the treatment reduces disease severity in a patient and wherein disease severity is assessed by an atopic dermatitis disease severity outcome measure.

[0079] In another aspect, the disclosure relates to the isolated antibodies, or antigen binding fragments thereof, of any one of the preceding aspects or embodiments for use in the treatment of asthma, chronic sinusitis with nasal polyps; Chronic Rhinosinusitis without Nasal Polyps (CRSsNP); eosinophilic esophagitis (EoE); an Eosinophilic gastrointestinal disorder or disease (EGID), such as Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), Eosinophilic Colitis (EoC), or Eosinophilic Gastroenteritis (EGE); 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; hidradenitis suppurativa; celiac disease; systemic sclerosis; idiopathic pulmonary fibrosis; alopecia areata; allergic rhinitis; eosinophilic fasciitis; scleromyxedema; scleredema; or nephrogenic systemic fibrosis.

[0080] In another aspect, disclosed herein is a multi-specific antibody comprising: a first antigen binding region that binds OX40L and comprises: a) a variable heavy (VH) chain sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and b) a variable light (VL) chain sequence having three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; wherein the antigen binding region that binds OX40L comprises: (i) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 2-4; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 5-7; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 8-10; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-14; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 15-16; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 17-18; (ii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 20-22; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-25; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 26-28; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 30-32; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 33-34; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 35-36; (iii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 38-40; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NO: s 41-43; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 44-46; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NO: s 48-50; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 51-52; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 53-54; or (iv) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 56-58; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 59-61; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 62-64; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 66-68; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 69-70; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 71-72; and a second antigen binding region that binds IL-4Rα.

[0081] In some embodiments, the antigen binding region that binds IL-4Rα comprises a CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of an antibody selected from dupilumab, stapokibart, and 611.

[0082] In some embodiments, the antigen binding region that binds IL-4Rα comprises: a) a VH chain sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and b) a VL chain sequence having three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein the antigen binding region that binds IL-4Rα comprises: (i) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 276, 277, and 278; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR- L1 comprising the sequence set forth in any one of SEQ ID NOs: 285 and 286; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 292 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293; (ii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprisingthe sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 283 and 284; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 287 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 291 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293; or (iii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 289 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0083] In another aspect, disclosed herein is a multi-specific antibody comprising: a first antigen binding region that binds OX40L; and a second antigen binding region that binds IL- 4Rα and comprises: a) a variable heavy (VH) chain sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and b) a variable light (VL) chain sequence having three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; wherein the antigen binding region that binds IL-4Rα comprises: (i) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 276, 277, and 278; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 285 and 286; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 292 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293; (ii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 283 and 284; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 287 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 291 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293; or (iii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 289and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0084] In some embodiments, the antigen binding region that binds OX40L comprises a CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of an antibody selected from amlitelimab and oxelumab.

[0085] In some embodiments, the antigen binding region that binds OX40L comprises: a) a VH chain sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and b) a VL chain sequence having three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein the antigen binding region that binds OX40L comprises: (i) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 2-4; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 5-7; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 8-10; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-14; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 15-16; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 17- 18; (ii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 20-22; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-25; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 26-28; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 30-32; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 33-34; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 35-36; (iii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 38-40; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 41-43; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 44-46; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NO: s 48-50; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 51-52; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 53-54; or (iv) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 56-58; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 59-61; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 62-64; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 66-68; a CDR-L2 comprising the amino acid sequence set forth in anyone of SEQ ID NO: 69-70s; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 71-72.

[0086] In some embodiments, (a) the antigen binding region that binds OX40L comprises: (i) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 2-4; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 5-7; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 8-10; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-14; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 15-16; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 17-18; and (b) the antigen binding region that binds IL-4Rα comprises: (i) a CDR- H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR- H2 comprising the sequence set forth in any one of SEQ ID NOs: 276, 277, and 278; a CDR- H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 285 and 286; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 292 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0087] In some embodiments, (a) the antigen binding region that binds OX40L comprises: (ii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 20-22; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-25; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 26-28; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 30-32; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 33-34; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 35-36; and (b) the antigen binding region that binds IL-4Rα comprises: (i) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 276, 277, and 278; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR- L1 comprising the sequence set forth in any one of SEQ ID NOs: 285 and 286; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 292 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0088] In some embodiments, (a) the antigen binding region that binds OX40L comprises: (iii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 38-40; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQID NOs: 41-43; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 44-46; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 48-50; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 51-52; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 53-54; and (b) the antigen binding region that binds IL-4Rα comprises: (i) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 276, 277, and 278; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR- L1 comprising the sequence set forth in any one of SEQ ID NOs: 285 and 286; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 292 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0089] In some embodiments, (a) the antigen binding region that binds OX40L comprises: (iv) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 56-58; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 59-61; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 62-64; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 66-68; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 69-70; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 71-72; and (b) the antigen binding region that binds IL-4Rα comprises: (i) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 276, 277, and 278; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR- L1 comprising the sequence set forth in any one of SEQ ID NOs: 285 and 286; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 292 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0090] In some embodiments, (a) the antigen binding region that binds OX40L comprises: (i) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 2-4; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 5-7; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 8-10; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-14; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 15-16; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 17-18; and (b) the antigen binding region that binds IL-4Rα comprises: (ii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR- H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR- H3 comprising the sequence set forth in any one of SEQ ID NOs: 283 and 284; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 287 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 291 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0091] In some embodiments, (a) the antigen binding region that binds OX40L comprises: (ii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 20-22; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-25; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 26-28; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 30-32; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 33-34; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 35-36; and (b) the antigen binding region that binds IL-4Rα comprises: ((ii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 283 and 284; a CDR- L1 comprising the sequence set forth in any one of SEQ ID NOs: 287 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 291 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0092] In some embodiments, (a) the antigen binding region that binds OX40L comprises: (iii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 38-40; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 41-43; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 44-46; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 48-50; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 51-52; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 53-54; and (b) the antigen binding region that binds IL-4Rα comprises: (ii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 283 and 284; a CDR- L1 comprising the sequence set forth in any one of SEQ ID NOs: 287 and 288; a CDR-L2comprising the sequence set forth in SEQ ID NO: 291 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0093] In some embodiments, (a) the antigen binding region that binds OX40L comprises: (iv) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 56-58; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 59-61; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 62-64; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 66-68; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 69-70; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 71-72; and (b) the antigen binding region that binds IL-4Rα comprises: (ii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 283 and 284; a CDR- L1 comprising the sequence set forth in any one of SEQ ID NOs: 287 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 291 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0094] In some embodiments, (a) the antigen binding region that binds OX40L comprises: (i) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 2-4; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 5-7; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 8-10; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-14; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 15-16; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 17-18; and (b) the antigen binding region that binds IL-4Rα comprises: (iii) a CDR- H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR- H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR- H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 289 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0095] In some embodiments, (a) the antigen binding region that binds OX40L comprises: (ii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 20-22; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQID NOs: 23-25; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 26-28; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 30-32; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 33-34; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 35-36; and (b) the antigen binding region that binds IL-4Rα comprises: (iii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR- L1 comprising the sequence set forth in any one of SEQ ID NOs: 289 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0096] In some embodiments, (a) the antigen binding region that binds OX40L comprises: (iii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 38-40; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 41-43; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 44-46; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 48-50; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 51-52; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 53-54; and (b) the antigen binding region that binds IL-4Rα comprises: (iii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR- L1 comprising the sequence set forth in any one of SEQ ID NOs: 289 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0097] In some embodiments, (a) the antigen binding region that binds OX40L comprises: (iv) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 56-58; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 59-61; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 62-64; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 66-68; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 69-70; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 71-72; and (b) the antigen binding region that binds IL-4Rα comprises: (iii) aCDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR- L1 comprising the sequence set forth in any one of SEQ ID NOs: 289 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0098] In some embodiments, the antigen binding region that binds OX40L comprises a heavy chain variable domain (VH) sequence comprising the amino acid sequence set forth in any one of SEQ ID NOs: 1, 19, 37, and 55.

[0099] In some embodiments, the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in any one of SEQ ID NOs: 295- 297.

[0100] In some embodiments, the antigen binding region that binds OX40L comprises a light chain variable domain (VL) sequence comprising the amino acid sequence set forth in any one of SEQ ID NOs: 11, 29, 47, and 65.

[0101] In some embodiments, the antigen binding region that binds IL-4Rα comprises a VL sequence comprising the amino acid sequence set forth in any one of SEQ ID NOs: 298- 300.

[0102] In some embodiments, (a) the antigen binding region that binds OX40L comprises: (i) a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 1; (ii) a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 19; (iii) a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 37; or (iv) a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 55; and / or (v) a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 11; (vi) a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 29;(vii) a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 47; or (viii) a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 65; and / or (b) the antigen binding region that binds IL-4Rα comprises: (i) a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 295; (ii) a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 296; or (iii) a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 297; and / or (iv) a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 298; (v) a VL sequence comprising the amino acidsequence set forth in SEQ ID NO:299; or (vi) a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:300.

[0103] In some embodiments, the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 1; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 11.

[0104] In some embodiments, the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 19; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 29.

[0105] In some embodiments, the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 37; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 47.

[0106] In some embodiments, the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 55; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 65.

[0107] In some embodiments, the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 295; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 298.

[0108] In some embodiments, the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 296; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 299.

[0109] In some embodiments, the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 297; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 300.

[0110] In some embodiments, the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 1; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 11; and the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 295; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 298.

[0111] In some embodiments, the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 1; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 11; and the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acidsequence set forth in SEQ ID NO: 296; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 299.

[0112] In some embodiments, the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 1; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 11; and the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 297; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 300.

[0113] In some embodiments, the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 19; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 29; and the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 295; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 298.

[0114] In some embodiments, the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 19; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 29; and the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 296; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 299.

[0115] In some embodiments, the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 19; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 29; and the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 297; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 300.

[0116] In some embodiments, the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 37; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 47; and the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 295; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 298.

[0117] In some embodiments, the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 37; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 47; and the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 296; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 299.

[0118] In some embodiments, the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 37; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 47; and the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 297; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 300.

[0119] In some embodiments, the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 55; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 65; and the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 295; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 298.

[0120] In some embodiments, the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 55; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 65; and the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 296; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 299.

[0121] In some embodiments, the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 55; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 65; and the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 297; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 300.

[0122] In some embodiments, the antigen binding region that binds OX40L and / or the antigen binding region that binds IL-4RΑ is humanized, human, or chimeric.

[0123] In some embodiments, the antigen binding region that binds OX40L and / or the antigen binding region that binds IL-4RΑ is humanized.

[0124] In some embodiments, the multi-specific antibody comprises a heavy chain human constant region of a class selected from IgG, IgA, IgD, IgE, and IgM.

[0125] In some embodiments, the multi-specific antibody comprises a human Fc region, and the human Fc region comprises a human heavy chain constant region of the class IgG and a subclass selected from IgG1, IgG2, IgG3, and IgG4.

[0126] In some embodiments, the human Fc region comprises a human IgG1 Fc region.

[0127] In some embodiments, the human Fc region comprises a human IgG4 Fc region.

[0128] In some embodiments, the human Fc region comprises a human IgG2 Fc region.

[0129] In some embodiments, the multi-specific antibody comprises a heavy chain comprising a constant heavy chain sequence selected from the amino acid sequences set forth in any one of SEQ ID NOs: 427, 439, 440, 446, 457, 460, 637-737, and 847-1070.

[0130] In some embodiments, the multi-specific antibody comprises a heavy chain constant domain having a means for increasing the half-life of the antibody.

[0131] In some embodiments, the multi-specific antibody comprises a light chain comprising a constant light chain sequence selected from the sequences set forth in SEQ ID NOs: 469 and 1071.

[0132] In some embodiments, the multi-specific antibody comprises an Fc region comprising one or more amino acid substitutions, wherein the one or more substitutions result in an increase in one or more of antibody half-life, ADCC activity, ADCP activity, or CDC activity compared with the Fc without the one or more substitutions.

[0133] In some embodiments, the multi-specific antibody comprises an Fc region comprising one or more amino acid substitutions, wherein the one or more substitutions result in a decrease in one or more of, ADCC activity, ADCP activity or CDC activity compared to an antibody comprising a wild-type Fc region.

[0134] In some 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 / Q311V / A378V (QVV), N297A / QVV, D265A / QVV, LALA / QVV, LAGA / QVV, LALAGA / QVV, LALAPG / QVV, DDRVV, N297A / DDRVV, D265A / DDRVV, LALA / DDRVV, LAGA / DDRVV, LALAGA / DDRVV, and LALAPG / DDRVV. In some embodiments, the one or more amino acid substitutions is selected from the group consisting of LS, YTE, 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.

[0135] 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 253 / 255 / 257 or 260 / 262 / 264, respectively. In certain embodiments, an antibody described herein comprises an Fc region with LALA mutations at positions 235 / 236 or 242 / 243, respectively. In certain embodiments, an antibody described herein comprises anFc region with YTE mutations at positions 253 / 255 / 257 and with LALA mutations at positions 235 / 236. In certain embodiments, an antibody described herein comprises an Fc region with YTE mutations at positions 260 / 262 / 264 and with LALA mutations at positions 242 / 243. In certain embodiments, the OX40L antibody described herein comprises the VH and VL of Construct 114 and an Fc region comprising YTE mutations at positions 253 / 255 / 257, respectively and with LALA mutations at positions 235 / 236, respectively. In certain embodiments, the IL-4Rα antibody described herein comprises the VH and VL of Construct 38 (mAb 471) and an Fc region comprising YTE mutations at positions 260 / 262 / 264, respectively and with LALA mutations at positions 242 / 243, respectively.

[0136] In some embodiments, the multi-specific antibody comprising an antigen binding region that binds OX40L comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 1, a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 11, a constant heavy chain sequence set forth in any one of SEQ ID NOs: 651 and 973, and a constant light chain sequence set forth in SEQ ID NO: 738.

[0137] In some embodiments, the multi-specific antibody comprising an antigen binding region that binds IL-4Rα comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 297, a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 300, a heavy chain sequence set forth in any one of SEQ ID NOs: 651 and 973, and a light chain sequence set forth in SEQ ID NO: 738.

[0138] In some embodiments, the Fc region of the multi-specific antibody binds to Neonatal Fc receptor (FcRn).

[0139] In some embodiments, the Fc region of the multi-specific antibody binds an FcRn with higher affinity at pH 6.0 compared to an antibody comprising a wild-type Fc region.

[0140] In some embodiments, the Fc region of the multi-specific antibody binds to FcRn with a KDof <1 x 10-7M at pH 6.0.

[0141] In some embodiments, the antigen binding region that binds OX40L and / or the antigen binding region that binds IL-4Rα is monoclonal.

[0142] In some embodiments, the antigen binding region that binds OX40L binds an OX40L sequence set forth in the amino acid sequence of SEQ ID NO: 739.

[0143] In some embodiments, the antigen binding region that binds IL-4Rα binds an IL- 4Rα sequence set forth in any one of the amino acid sequences of SEQ ID NOs: 301-303.

[0144] In another aspect, the disclosure relates to the multi-specific antibodies of any one of the foregoing aspects or embodiments for use in the treatment of an inflammatory disorder or disease.

[0145] In another aspect, the disclosure relates to the multi-specific antibodies of any one of the foregoing aspects or embodiments for use in the treatment of atopic dermatitis (AD).

[0146] In some embodiments, the treatment reduces disease severity in a patient and wherein disease severity is assessed by an atopic dermatitis disease severity outcome measure.

[0147] In another aspect, the disclosure relates to the multi-specific antibodies of any one of the foregoing aspects or embodiments for use in the treatment of asthma; chronic sinusitis with nasal polyps; Chronic Rhinosinusitis without Nasal Polyps (CRSsNP); eosinophilic esophagitis (EoE); an Eosinophilic gastrointestinal disorder or disease (EGID), such as Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), Eosinophilic Colitis (EoC), or Eosinophilic Gastroenteritis (EGE); 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; hidradenitis suppurativa; celiac disease; systemic sclerosis; idiopathic pulmonary fibrosis; alopecia areata; allergic rhinitis; eosinophilic fasciitis; scleromyxedema; scleredema; or nephrogenic systemic fibrosis.

[0148] In another aspect, the disclosure relates to an isolated polynucleotide or set of polynucleotides encoding the isolated antibodies or multi-specific antibodies of any one of the preceding aspects or embodiments, 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.

[0149] In another aspect, the disclosure relates to a vector or set of vectors comprising the polynucleotide or set of polynucleotides of any one of the preceding aspects or embodiments.

[0150] In another aspect, the disclosure relates to a host cell comprising the polynucleotide or set of polynucleotides of any one of the preceding aspects or embodiments or the vector or set of vectors of any one of the preceding aspects or embodiments.

[0151] In another aspect, the disclosure relates to a method of producing one or more of the isolated antibodies or multi-specific antibody of any one of the preceding aspects or embodiments, the method comprising expressing one or more of the isolated antibodies or multi-specific antibody within the host cell of any one of the preceding aspects or embodiments and isolating the one or more expressed antibodies.

[0152] In another aspect, the disclosure relates to a pharmaceutical composition comprising the isolated antibodies or multi-specific antibody of any one of the preceding aspects or embodiments and a pharmaceutically acceptable excipient.

[0153] In another aspect, the disclosure relates to a kit comprising the isolated antibodies or multi-specific antibody of any one of any one of the preceding aspects or embodiments or the pharmaceutical composition of any one of the preceding aspects or embodiments and instructions for use.

[0154] In another aspect, the disclosure relates to a method for treating an inflammatory disorder or disease in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of the isolated antibodies or multi-specific antibody of any one of the preceding aspects or embodiments; a therapeutically effective amount of the pharmaceutical composition of any one of the preceding aspects or embodiments; or a therapeutically effective amount of a pharmaceutical composition comprising an isolated antibody, or an antigen binding fragment thereof, that binds OX40L and a pharmaceutically acceptable excipient and a therapeutically effective amount of a pharmaceutical composition comprising an antibody, or an antigen binding fragment thereof, that binds IL-4RΑ and a pharmaceutically acceptable excipient137.

[0155] In some embodiments, the mammalian subject is a human.

[0156] In some embodiments, the inflammatory disorder or disease is atopic dermatitis.

[0157] In some embodiments, the inflammatory disorder or disease is asthma.

[0158] In some embodiments, the inflammatory disorder or disease is chronic sinusitis with nasal polyps; Chronic Rhinosinusitis without Nasal Polyps (CRSsNP); eosinophilic esophagitis (EoE); an Eosinophilic gastrointestinal disorder or disease (EGID), such as Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), Eosinophilic Colitis (EoC), or Eosinophilic Gastroenteritis (EGE); 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 BronchopulmonaryAspergillosis (ABPA); Chronic Obstructive Pulmonary Disease (COPD); celiac disease; an inflammatory bowel disease, such as Crohn’s disease or ulcerative colitis; lupus; rheumatoid arthritis (RA); psoriasis; hidradenitis suppurativa; systemic sclerosis; idiopathic pulmonary fibrosis; alopecia areata; allergic rhinitis; eosinophilic fasciitis; scleromyxedema; scleredema; or nephrogenic systemic fibrosis.

[0159] In another aspect, the disclosure relates to a method for treating a pathology associated with elevated levels of OX40L and / or IL-4Rα in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount the isolated antibodies or multi-specific antibody of any one of the foregoing aspects or embodiments, the pharmaceutical composition of any one of the foregoing aspects or embodiments, or a therapeutically effective amount of a pharmaceutical composition comprising an isolated antibody, or an antigen binding fragment thereof, that binds OX40L and a pharmaceutically acceptable excipient and a therapeutically effective amount of a pharmaceutical composition comprising an isolated antibody, or an antigen binding fragment thereof, that binds IL-4Rα and a pharmaceutically acceptable excipient.

[0160] In another aspect, the disclosure relates to a method of reducing biological activity of OX40L and / or IL-4RΑ in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount the isolated antibodies or multi-specific antibody of any one of the foregoing aspects or embodiments, the pharmaceutical composition of any one of the foregoing aspects or embodiments, or a therapeutically effective amount of a pharmaceutical composition comprising an isolated antibody, or an antigen binding fragment thereof, that binds OX40L and a pharmaceutically acceptable excipient and a therapeutically effective amount of a pharmaceutical composition comprising an isolated antibody, or an antigen binding fragment thereof, that binds IL-4Rα and a pharmaceutically acceptable excipient.

[0161] In some embodiments, the mammalian subject is a human.

[0162] In another aspect, the disclosure relates to a pharmaceutical composition comprising: an isolated antibody, or an antigen binding fragment thereof, that binds OX40L comprising a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 1, a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 11, a constant heavy chain sequence set forth in any one of SEQ ID NOs: 651 and 973, and a constant light chain sequence set forth in SEQ ID NO: 738; an isolated antibody, or an antigen binding fragment thereof, that binds IL-4Rα comprising a VH domain comprising the amino acidsequence set forth in SEQ ID NO: 297, a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 300, a constant heavy chain sequence set forth in any one of SEQ ID NOs: 651 and 973, and a constant light chain sequence set forth in SEQ ID NO: 738; and a pharmaceutically acceptable excipient.

[0163] In another aspect, the disclosure relates to a pharmaceutical composition comprising: a multi-specific antibody comprising: an antigen binding region that binds OX40L comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 1, a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 11, a constant heavy chain sequence set forth in any one of SEQ ID NOs: 651 and 973, and a constant light chain sequence set forth in SEQ ID NO: 738; an antigen binding region that binds IL-4Rα comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 297, a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 300, a constant heavy chain sequence set forth in any one of SEQ ID NOs: 651 and 973, and a constant light chain sequence set forth in SEQ ID NO: 738; and a pharmaceutically acceptable excipient.

[0164] In some embodiments, the pharmaceutical composition comprises a means for increasing the bioavailability of the isolated antibody, or antigen binding region thereof, that binds OX40L and / or the isolated antibody, or antigen binding region thereof, that binds IL- 4Rα or the multi-specific antibody.

[0165] In certain aspects, described herein are compositions comprising an isolated antibody, or an antigen binding fragment thereof, that binds OX40L, an isolated antibody, or an antigen binding fragment thereof, that binds Interleukin-4 Receptor Alpha (IL-4Rα), and a hyaluronidase or variant thereof. In certain aspects, described herein are compositions comprising any one of the antibodies, or an antigen binding fragment thereof, described herein that binds OX40L, any one of the antibodies, or an antigen binding fragment thereof, described herein that binds IL-4Rα, and any one of the hyaluronidases or variants thereof described herein.

[0166] In certain aspects, described herein are compositions comprising hyaluronidase or a variant thereof and a multi-specific antibody comprising a first antigen binding region that binds OX40L and a second antigen binding region that binds IL-4Rα.

[0167] In certain aspects, described herein are a combination of an antibody, or an antigen binding fragment thereof, that binds OX40L, an antibody, or an antigen binding fragment thereof, that binds IL-4Rα, and a hyaluronidase or variant thereof. In certainaspects, described herein are a combination of any one of the antibodies, or an antigen binding fragment thereof, described herein that binds OX40L, any one of the antibodies, or an antigen binding fragment thereof, described herein that binds IL-4Rα, and a hyaluronidase or a variant thereof.

[0168] In certain aspects, described herein are combinations comprising hyaluronidase or a variant thereof and a multi-specific antibody comprising a first antigen binding region that binds OX40L and a second antigen binding region that binds IL-4Rα.

[0169] 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 isolated antibody, or an antigen binding fragment thereof, that binds OX40L, an isolated antibody, or an antigen binding fragment thereof, that binds IL-4Rα, and a hyaluronidase or a variant thereof. 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 an antigen binding fragment thereof, described herein that binds OX40L, any one of the antibodies, or an antigen binding fragment thereof, described herein that binds IL- 4Rα, and any one of the hyaluronidases or variants thereof described herein.

[0170] In certain aspects, described herein are methods of treating an inflammatory disorder or disease in a human patient comprising co-administering to the patient hyaluronidase or a variant thereof and a multi-specific antibody comprising a first antigen binding region that binds OX40L and a second antigen binding region that binds IL-4Rα. 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 hyaluronidases or variants thereof described herein and any one of the multi-specific antibodies described herein (e.g., comprising a first antigen binding region that binds OX40L and a second antigen binding region that binds IL-4Rα).

[0171] In certain embodiments, the antibody, or an antigen binding fragment thereof, that binds OX40L and / or the antibody, or an antigen binding fragment thereof, that binds IL- 4Rα is a humanized, human, or chimeric antibody. In certain embodiments, the antibody, or an antigen binding fragment thereof, is a monoclonal antibody. In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a heavy chain human constant region of a class selected from IgG, IgA, IgD, IgE, and IgM. In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a human Fc region comprising a human heavy chain constant region of the class IgG and a subclass selected from IgG1, IgG2,IgG3, and IgG4. In certain embodiments, the human Fc region comprises a human IgG1 Fc region

[0172] In certain embodiments the human Fc region comprises a human IgG1 Fc region with LALA mutations. In certain embodiments the human Fc region comprises a human IgG1 Fc region with YTE mutations. In certain embodiments the human Fc region comprises a human IgG1 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 IgG1 Fc region with LALA mutations at L235A / L236A and / or YTE mutations at M253Y / S255T / T257E. In another embodiment, the human Fc region comprises a human IgG1 Fc region with LALA mutations at L242A / L243A and / or YTE mutations at M260Y / S262T / T264E.

[0173] In certain embodiments, the antibody, or an antigen binding fragment thereof, that binds OX40L 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: 5; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 8; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 12; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 15; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 17. In one embodiment, the antibody, or an antigen binding fragment thereof, that binds OX40L comprises a VH sequence set forth in SEQ ID NO: 1 and a VL sequence set forth in SEQ ID NO: 11. In one embodiment, the heavy chain of the antibody that binds OX40L comprises a constant heavy chain sequence set forth in SEQ ID NO: 651. In one embodiment, the heavy chain of the antibody that binds OX40L comprises a constant heavy chain sequence set forth in SEQ ID NO: 973. In one embodiment, the light chain of the antibody, or an antigen binding fragment thereof, that binds OX40L comprises a constant light chain sequence set forth in SEQ ID NO: 738. In one embodiment, the heavy chain of the antibody, or an antigen binding fragment thereof, that binds OX40L comprises a sequence set forth in SEQ ID NO: 839 and / or SEQ ID NO: 840. In one embodiment, the light chain of the antibody, or an antigen binding fragment thereof, that binds OX40L comprises a sequence set forth in SEQ ID NO: 841. In one embodiment, the heavy chain of the antibody, or an antigen binding fragment thereof, that binds OX40L comprises a sequence set forth in SEQ ID NO: 839 and the light chain of the antibody, or antigen binding fragment thereof that binds OX40L, comprises a sequence set forth in SEQ ID NO: 841.

[0174] In certain embodiments, the antibody, or an antigen binding fragment thereof, that binds IL-4Rα comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 273; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 279; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 281; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 289; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290; and a CDR- L3 comprising the sequence set forth in SEQ ID NO: 293. In one embodiment, the antibody, or an antigen binding fragment thereof, that binds IL-4Rα comprises a VH sequence set forth in SEQ ID NO: 297 and a VL sequence set forth in SEQ ID NO: 300. In one embodiment, the heavy chain of the antibody, or an antigen binding fragment thereof, that binds IL-4Rα comprises a constant heavy chain sequence set forth in SEQ ID NO: 651. In one embodiment, the heavy chain of the antibody, or an antigen binding fragment thereof, that binds IL-4Rα comprises a constant heavy chain sequence set forth in SEQ ID NO: 973. In one embodiment, the light chain of the antibody, or an antigen binding fragment thereof, that binds IL-4Rα comprises a constant light chain sequence set forth in SEQ ID NO: 738. In one embodiment, the heavy chain of the antibody, or an antigen binding fragment thereof, that binds IL-4Rα comprises a sequence set forth in SEQ ID NO: 836 and / or SEQ ID NO: 837. In one embodiment, the light chain of the antibody, or an antigen binding fragment thereof, that binds IL-4Rα comprises a sequence set forth in SEQ ID NO: 838. In one embodiment, the heavy chain of the antibody, or an antigen binding fragment thereof, that binds IL-4Rα comprises a sequence set forth in SEQ ID NO: 836 and the light chain of the antibody, or antigen binding fragment thereof that binds IL-4Rα, comprises a sequence set forth in SEQ ID NO: 838.

[0175] In certain embodiments, a multi-specific antibody comprising a first antigen binding region that binds OX40L and a second antigen binding region that binds IL-4Rα is provided. In one embodiment, the antigen binding region that binds OX40L 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: 5; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 8; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 12; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 15; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 17. In one embodiment, the antigen binding region that binds OX40L comprises a VH sequence set forth in SEQ ID NO: 1 and a VL sequence set forth in SEQ ID NO: 11.In another embodiment, the antigen binding region that binds IL- 4Rα comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 273; a CDR-H2comprising the sequence set forth in SEQ ID NO: 279; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 281; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 289; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293. In one embodiment, the antibody that binds IL-4Rα comprises a VH sequence set forth in SEQ ID NO: 297 and a VL sequence set forth in SEQ ID NO: 300.

[0176] In certain embodiments, the antibody or antigen binding region that binds OX40L and / or the antibody or antigen binding region that binds IL-4Rα 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 region that binds OX40L and / or the antibody or antigen binding region that binds IL-4Rα comprises a human Fc region, and the human Fc region comprises a human heavy chain constant region of the class IgG and a subclass selected from IgG1, IgG2, IgG3, and IgG4. In certain embodiments, the human Fc region of the antibody that binds OX40L and / or the antibody that binds IL-4Rα comprises a human IgG1 Fc region. In certain embodiments, the human Fc region of the antibody that binds OX40L and / or the antibody that binds IL-4Rα comprises a human IgG4 Fc region. In certain embodiments, the human Fc region of the antibody or antigen binding region that binds OX40L and / or the antibody or antigen binding region that binds IL-4Rα comprises a human IgG2 Fc region.

[0177] In certain embodiments the human Fc region comprises a human IgG1 Fc region with LALA mutations. In certain embodiments the human Fc region comprises a human IgG1 Fc region with YTE mutations. In certain embodiments the human Fc region comprises a human IgG1 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 IgG1 Fc region with LALA mutations at L235A / L236A and / or YTE mutations at M253Y / S255T / T257E. In another embodiment, the human Fc region comprises a human IgG1 Fc region with LALA mutations at L242A / L243A and / or YTE mutations at M260Y / S262T / T264E.

[0178] In certain embodiments, the Fc region of the antibody or antigen binding region that binds OX40L and / or the antibody or antigen binding region that binds IL-4Rα binds to Neonatal Fc receptor (FcRn). In certain embodiments, the Fc region of the antibody or antigen binding region that binds OX40L and / or the antibody or antigen binding region thatbinds IL-4Rα 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 of the antibody or antigen binding region that binds OX40L and / or the antibody or antigen binding region that binds IL-4Rα binds to FcRn with a KDof <1 x 10-7M at pH 6.0.

[0179] In certain embodiments, the antibody or antigen binding region that binds OX40L and / or the antibody or antigen binding region that binds IL-4Rα is a monoclonal antibody.

[0180] In certain embodiments, the antibody or antigen binding region that binds OX40L binds an OX40L sequence set forth in the amino acid sequence of SEQ ID NO: 739. In certain embodiments, the antibody or antigen binding region that binds IL-4Rα binds an IL- 4Rα sequence set forth in any one of the amino acid sequences of SEQ ID NOs: 301-303.

[0181] Any suitable hyaluronidase or variant thereof can be used in the compositions, combinations, and methods described herein. 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: 1076- 1085 and 1087-1142. In certain embodiments, the recombinant human hyaluronidase is rHuPH20. In certain embodiments, the rHuPH20 formulation is ENHANZE®.

[0182] In one embodiment, the recombinant human hyaluronidase includes a sequence of amino acids in any one of SEQ ID NOs: 1076-1085 and 1087-1142, or has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 97%, 98%, or 99% sequence identity to a sequence of amino acids included in any one of SEQ ID NO: 1076-1085 and 1087-1142 and retains hyaluronidase activity. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1076. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1076. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1078. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1078. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1079. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1079. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1080. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1080. In another embodiment, the recombinant human hyaluronidase comprises theamino acid sequence set forth in SEQ ID NO:1081. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1081. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1082. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1082. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1083. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1083. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1084. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1084. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1085. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1085. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1087. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1087. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1088. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1088. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1089. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1089. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1090. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1090. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1091. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1091. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1093. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1093. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1094. In another embodiment, the recombinant human hyaluronidase consists of the amino acidsequence set forth in SEQ ID NO:1094. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1095. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1095. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1096. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1096. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1097. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1097. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1098. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1098. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1099. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1099. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1100. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1100. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1101. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1101. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1102. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1102. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1103. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1103. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1104. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1104. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1105. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1105. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence setforth in SEQ ID NO:1106. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1106. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1107. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1107. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1108. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1108. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1109. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1109. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1110. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1110. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1111. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1111. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1112. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1112. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1113. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1113. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1114. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1114. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1115. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1115. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1116. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1116. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1117. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQID NO:1117. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1118. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1118. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1119. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1119. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1120. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1120. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1121. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1121. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1122. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1122. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1123. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1123. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1124. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1124. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1125. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1125. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1126. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1126. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1127. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1127. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1128. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1128. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1129. Inanother embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1129. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1130. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1130. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1131. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1131. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1132. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1132. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1133. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1133. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1134. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1134. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1135. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1135. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1136. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1136. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1137. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1137. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1138. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1138. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1139. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1139. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1140. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1140. In anotherembodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1141. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1141. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1142. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1142.

[0183] In certain embodiments, the hyaluronidase or variant thereof and antibodies (i.e., anti- IL-4Rα antibody, or antigen binding fragment thereof, and anti-OX40L antibody, or antigen binding fragment thereof) or multi-specific antibody (i.e., comprising a first antigen binding region that binds OX40L and a second antigen binding region that binds IL-4Rα) are administered in separate formulations. In certain embodiments, the hyaluronidase or variant thereof and antibodies or multi-specific antibody are administered simultaneously in separate formulations. In certain embodiments, the hyaluronidase or variant thereof is administered to the patient prior to administration of the antibodies or multi-specific antibody. In certain embodiments, the hyaluronidase or variant thereof is administered to the patient after administration of the antibodies or multi-specific antibody. In certain embodiments, the hyaluronidase or variant thereof is administered to the patient after administration of one of the antibodies (either the OX40L antibody or the IL-4Rα antibody) but is administered before the administration of the second of the antibodies (either the OX40L antibody or the IL-4Rα antibody). In certain embodiments, the hyaluronidase or variant thereof and the antibodies or multi-specific antibody are mixed and administered in a single formulation. In certain embodiments, the hyaluronidase or variant thereof and the antibodies or multi-specific antibody are administered by subcutaneous injection. In certain embodiments, the hyaluronidase or variant thereof and the antibodies or multi-specific antibody are administered by intravenous injection.

[0184] In certain embodiments, the hyaluronidase is rHuPH20 (ENHANZE®) 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.

[0185] 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 that bind OX40L described herein and any one of theantibodies that bind IL-4Rα described herein in combination with a hyaluronidase or variant thereof. 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 multi-specific antibodies described herein in combination with 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 disease severity is assessed by an atopic dermatitis disease severity outcome measure. In certain embodiments, the inflammatory disorder or disease is asthma; chronic sinusitis with nasal polyps; Chronic Rhinosinusitis without Nasal Polyps (CRSsNP); eosinophilic esophagitis (EoE); an Eosinophilic gastrointestinal disorder or disease (EGID), such as Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), Eosinophilic Colitis (EoC), or Eosinophilic Gastroenteritis (EGE); 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; ulcerative colitis; hidradenitis suppurativa; celiac disease; systemic sclerosis; idiopathic pulmonary fibrosis; alopecia areata; allergic rhinitis; eosinophilic fasciitis; scleromyxedema; scleredema; or nephrogenic systemic fibrosis.

[0186] In certain aspects, described herein are compositions comprising an isolated antibody, or antigen binding region thereof, that binds OX40L, an isolated antibody, or antigen binding region thereof, that binds IL-4Rα, and a hyaluronidase or variant thereof.

[0187] In certain aspects, described herein are compositions comprising an isolated antibody, or antigen binding region thereof, that binds OX40L, an isolated antibody, or antigen binding region thereof, that binds IL-4Rα, and a hyaluronidase or variant thereof, wherein the antibody that binds OX40L 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: 5; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 8; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 12; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 15; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 17.

[0188] In certain aspects, described herein are compositions comprising an isolated antibody, or antigen binding region thereof, that binds OX40L, an isolated antibody, orantigen binding region thereof, that binds IL-4Rα, and a hyaluronidase or variant thereof, wherein the antibody that binds OX40L comprises a VH sequence set forth in SEQ ID NO: 1 and a VL sequence set forth in SEQ ID NO: 11.

[0189] In certain aspects, described herein are compositions comprising an isolated antibody, or antigen binding region thereof, that binds OX40L, an isolated antibody, or antigen binding region thereof, that binds IL-4Rα, and a hyaluronidase or variant thereof, wherein the antibody that binds IL-4Rα comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 273; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 279; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 281; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 289; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0190] In certain aspects, described herein are compositions comprising an isolated antibody, or antigen binding region thereof, that binds OX40L, an isolated antibody, or antigen binding region thereof, that binds IL-4Rα, and a hyaluronidase or variant thereof, wherein the antibody that binds IL-4Rα comprises a VH sequence set forth in SEQ ID NO: 297 and a VL sequence set forth in SEQ ID NO: 300.

[0191] In certain aspects, described herein are compositions comprising an isolated antibody, or an antigen binding fragment thereof, that binds OX40L, an isolated antibody, or an antigen binding fragment thereof, that binds IL-4Rα, and a hyaluronidase or variant thereof, wherein the antibody, or an antigen binding fragment thereof, that binds OX40L 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: 5; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 8; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 12; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 15; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 17, and wherein the antibody, or an antigen binding fragment thereof, that binds IL-4Rα comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 273; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 279; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 281; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 289; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0192] In certain aspects, described herein are compositions comprising an isolated antibody, or an antigen binding fragment thereof, that binds OX40L, an isolated antibody, or an antigen binding fragment thereof, that binds IL-4Rα, and a hyaluronidase or variantthereof, wherein the antibody, or an antigen binding fragment thereof, that binds OX40L comprises a VH sequence set forth in SEQ ID NO: 1 and a VL sequence set forth in SEQ ID NO: 11; and wherein the antibody, or an antigen binding fragment thereof, that binds IL-4Rα comprises a VH sequence set forth in SEQ ID NO: 297 and a VL sequence set forth in SEQ ID NO: 300.

[0193] In certain aspects, described herein are compositions comprising hyaluronidase or a variant thereof and a multi-specific antibody comprising a first antigen binding region that binds OX40L and a second antigen binding region that binds IL-4Rα, wherein the antigen binding region that binds OX40L 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: 5; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 8; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 12; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 15; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 17, and wherein the antigen binding region that binds IL-4Rα comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 273; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 279; a CDR- H3 comprising the sequence set forth in SEQ ID NO: 281; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 289; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0194] In certain aspects, described herein are compositions comprising hyaluronidase or a variant thereof and a multi-specific antibody comprising a first antigen binding region that binds OX40L and a second antigen binding region that binds IL-4Rα, wherein the antigen binding region that binds OX40L comprises a VH sequence set forth in SEQ ID NO: 1 and a VL sequence set forth in SEQ ID NO: 11; and wherein the antigen binding region that binds IL-4Rα comprises a VH sequence set forth in SEQ ID NO: 297 and a VL sequence set forth in SEQ ID NO: 300.

[0195] In certain aspects, described herein are combinations comprising an isolated antibody, or an antigen binding fragment thereof, that binds OX40L, an isolated antibody, or an antigen binding fragment thereof, that binds IL-4Rα, and a hyaluronidase or variant thereof, wherein the antibody, or an antigen binding fragment thereof, that binds OX40L 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: 5; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 8; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 12; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 15; and a CDR-L3 comprising thesequence set forth in SEQ ID NO: 17, and wherein the antibody, or an antigen binding fragment thereof, that binds IL-4Rα comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 273; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 279; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 281; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 289; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293

[0196] In certain aspects, described herein are combinations comprising an isolated antibody, or an antigen binding fragment thereof, that binds OX40L, an isolated antibody, or an antigen binding fragment thereof, that binds IL-4Rα, and a hyaluronidase or variant thereof, wherein the antibody, or an antigen binding fragment thereof, that binds OX40L comprises a VH sequence set forth in SEQ ID NO: 1 and a VL sequence set forth in SEQ ID NO: 11; and wherein the antibody, or an antigen binding fragment thereof, that IL-4Rα comprises a VH sequence set forth in SEQ ID NO: 297 and a VL sequence set forth in SEQ ID NO: 300.

[0197] In certain aspects, described herein are combinations comprising hyaluronidase or a variant thereof and a multi-specific antibody comprising a first antigen binding region that binds OX40L and a second antigen binding region that binds IL-4Rα, wherein the antigen binding region that binds OX40L 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: 5; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 8; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 12; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 15; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 17, and wherein the antigen binding region that binds IL-4Rα comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 273; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 279; a CDR- H3 comprising the sequence set forth in SEQ ID NO: 281; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 289; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0198] In certain aspects, described herein are combinations comprising hyaluronidase or a variant thereof and a multi-specific antibody comprising a first antigen binding region that binds OX40L and a second antigen binding region that binds IL-4Rα, wherein the antigen binding region that binds OX40L comprises a VH sequence set forth in SEQ ID NO: 1 and a VL sequence set forth in SEQ ID NO: 11; and wherein the antigen binding region that bindsIL-4Rα comprises a VH sequence set forth in SEQ ID NO: 297 and a VL sequence set forth in SEQ ID NO: 300.

[0199] In certain aspects, described herein are methods of treating an inflammatory disorder or disease in a human patient comprising administering to the patient an isolated antibody, or an antigen binding fragment thereof, that binds OX40L, an isolated antibody, or an antigen binding fragment thereof, that binds IL-4Rα, and a hyaluronidase or a variant thereof, wherein the antibody, or an antigen binding fragment thereof, that binds OX40L 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: 5; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 8; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 12; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 15; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 17, and wherein the antibody, or an antigen binding fragment thereof, that binds IL-4Rα comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 273; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 279; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 281; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 289; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0200] In certain aspects, described herein are methods of treating an inflammatory disorder or disease in a human patient comprising administering to the patient an isolated antibody, or an antigen binding fragment thereof, that binds OX40L, an isolated antibody, or an antigen binding fragment thereof, that binds IL-4Rα, and a hyaluronidase or a variant thereof, wherein the antibody, or an antigen binding fragment thereof, that binds OX40L comprises a VH sequence set forth in SEQ ID NO: 1 and a VL sequence set forth in SEQ ID NO: 11; and wherein the antibody, or an antigen binding fragment thereof, that binds IL-4Rα comprises a VH sequence set forth in SEQ ID NO: 297 and a VL sequence set forth in SEQ ID NO: 300.

[0201] In certain aspects, described herein are methods of treating an inflammatory disorder or disease in a human patient comprising administering to the patient hyaluronidase or a variant thereof and a multi-specific antibody comprising a first antigen binding region that binds OX40L and a second antigen binding region that binds IL-4Rα, wherein the antigen binding region that binds OX40L 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: 5; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 8; a CDR-L1 comprising thesequence set forth in SEQ ID NO: 12; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 15; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 17, and wherein the antigen binding region that binds IL-4Rα comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 273; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 279; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 281; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 289; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

[0202] In certain aspects, described herein are methods of treating an inflammatory disorder or disease in a human patient comprising administering to the patient hyaluronidase or a variant thereof and a multi-specific antibody comprising a first antigen binding region that binds OX40L and a second antigen binding region that binds IL-4Rα, wherein the antigen binding region that binds OX40L comprises a VH sequence set forth in SEQ ID NO: 1 and a VL sequence set forth in SEQ ID NO: 11; and wherein the antigen binding region that binds IL-4Rα comprises a VH sequence set forth in SEQ ID NO: 297 and a VL sequence set forth in SEQ ID NO: 300.

[0203] 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: 1076-1142 and 1087-1142. In certain embodiments, the recombinant human hyaluronidase is rHuPH20. In certain embodiments, the rHuPH20 formulation is ENHANZE®.

[0204] In certain embodiments, the antibodies or multi-specific antibody and hyaluronidase or a variant thereof are 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 asthma; chronic sinusitis with nasal polyps; Chronic Rhinosinusitis without Nasal Polyps (CRSsNP); eosinophilic esophagitis (EoE); an Eosinophilic gastrointestinal disorder or disease (EGID), such as Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), Eosinophilic Colitis (EoC), or Eosinophilic Gastroenteritis (EGE); 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 BronchopulmonaryAspergillosis (ABPA); Chronic Obstructive Pulmonary Disease (COPD); an inflammatory bowel disease, such as Crohn’s disease or ulcerative colitis; lupus; rheumatoid arthritis (RA); psoriasis; hidradenitis suppurativa; celiac disease; systemic sclerosis; idiopathic pulmonary fibrosis; alopecia areata; allergic rhinitis; eosinophilic fasciitis; scleromyxedema; scleredema; or nephrogenic systemic fibrosis. BRIEF DESCRIPTION OF THE FIGURES

[0205] FIGURE 1 is a graph showing the ability of exemplary anti-hOX40L antibodies to bind to hOX40L-expressing CHO cells.

[0206] FIGURE 2 is a graph showing the OD450-540 value with increasing concentration of the indicated antibody in the presence of hOX40L to determine the ability of the indicated antibodies to block the binding of hOX40L to hOX40.

[0207] FIGURE 3 is a graph showing the luminescence units (RLU) with increasing concentration of the indicated antibody in the presence of cells that express hOX40 to determine the ability of the indicated antibodies to block the binding of hOX40L to hOX40.

[0208] FIGURE 4A and FIGURE 4B are graphs showing the percent inhibition of OX40L and OX40L binding by the indicated antibody compared to a positive control.

[0209] FIGURE 5A - FIGURE 5C are graphs showing inhibition of IFNgamma response in PBMC-CD4 T cell mixed lymphocyte reaction (MLR) with 100 nM, 20 nM and 4 nM concentrations of indicated antibodies.

[0210] FIGURE 6A and FIGURE 6B are a set of graphs showing the concentration of the indicated antibody over time in the serum of cynomolgus monkeys after receiving a single dose of the indicated antibody.

[0211] FIGURE 7A and FIGURE 7B show the ability of exemplary antibodies and dupilumab to inhibit IL-4 and IL-13 binding.

[0212] FIGURE 8A and FIGURE 8B show the ability of exemplary antibodies and dupilumab to inhibit IL-4-induced and IL-13-induced STAT6 phosphorylation (pSTAT6).

[0213] FIGURE 9A and FIGURE 9B show the ability of exemplary antibodies and dupilumab to inhibit IL-4- and / or IL-13-induced TARC secretion.

[0214] FIGURE 10A and FIGURE 10B show the ability of exemplary antibodies and dupilumab to inhibit IL-4-induced and IL-13-induced proliferation of TF-1 cells.

[0215] FIGURE 11A and FIGURE 11B show the serum concentration of exemplary antibodies (Construct 13 (mAb422), Construct 38 (mAb471), and dupilumab) over time aftera single intravenous (FIGURE 11A) or subcutaneous (FIGURE 11B) administration of 25 mg / kg in non-human primates.

[0216] FIGURE 12 is a heatmap depicting the changes in cytokine / chemokine levels of thymus and activation regulated chemokine (TARC), macrophage-derived chemokine (MDC), interleukin (IL)-13, IL-5, interferon gamma (IFNg), tumor necrosis factor alpha (TNFa), IL-31, and granulocyte-macrophage colony-stimulating factor (GM-CSF) in allogeneic lymphocyte reaction experiments performed on myeloid dendritic cells (mDCs) primed with recombinant human TSLP and allogeneic CD4-positive cells from four healthy volunteers treated with test article, Construct 38, Construct 114, a combination of Construct 38 and Construct 114, dupilumab, or amlitelimab, or unstimulated. Values are normalized to isotype control. DETAILED DESCRIPTION Definitions

[0217] 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 4thed. (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.

[0218] As used herein, the singular forms “a”, “an”, and “the” include plural references unless indicated otherwise.

[0219] It is understood that aspects and embodiments of the invention described herein include “comprising,” “consisting,” and “consisting essentially of” aspects and embodiments.

[0220] For all compositions described herein, and all methods using a composition described herein, the compositions can either comprise the listed components or steps, or can “consist essentially of” the listed components or steps. When a composition is described as“consisting essentially of” the listed components, the composition contains the components listed, and may contain other components which do not substantially affect the condition being treated, but do not contain any other components which substantially affect the condition being treated other than those components expressly listed; or, if the composition does contain extra components other than those listed which substantially affect the condition being treated, the composition does not contain a sufficient concentration or amount of the extra components to substantially affect the condition being treated. When a method is described as “consisting essentially of” the listed steps, the method contains the steps listed, and may contain other steps that do not substantially affect the condition being treated, but the method does not contain any other steps which substantially affect the condition being treated other than those steps expressly listed. As a non-limiting specific example, when a composition is described as ‘consisting essentially of’ a component, the composition may additionally contain any amount of pharmaceutically acceptable carriers, vehicles, or diluents and other such components which do not substantially affect the condition being treated.

[0221] The term “vector,” as used herein, refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes the vector as a self- replicating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as “expression vectors.”

[0222] The terms “host cell,” “host cell line,” and “host cell culture” are used interchangeably 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.

[0223] 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.

[0224] As used herein, the term “prokaryote” refers to prokaryotic organisms. For example, a non-eukaryotic organism can belong to the Eubacteria (including but not limited to, Escherichia coli, Thermus thermophilus, Bacillus stearothermophilus, Pseudomonas fluorescens, Pseudomonas aeruginosa, Pseudomonas putida, etc.) phylogenetic domain, or the Archaea (including but not limited to, Methanococcus jannaschii, Methanobacterium thermoautotrophicum, Halobacterium such as Haloferax volcanii and Halobacterium species NRC-1, Archaeoglobus fulgidus, Pyrococcus furiosus, Pyrococcus horikoshii, Aeuropyrum pernix, etc.) phylogenetic domain.

[0225] An “effective amount” or “therapeutically effective amount” as used herein refers to an amount of therapeutic compound, such as an anti-OX40L antibody, or an antigen binding fragment thereof, or an anti-IL-4Rα antibody, or an antigen binding fragment thereof, administered to an individual, either as a single dose or as part of a series of doses, which is effective to produce or contribute to a desired therapeutic effect, either alone or in combination with another therapeutic modality. Examples of a desired therapeutic effect are reducing an aberrant immune response, slowing or delaying disease development; stabilization of disease; and amelioration of one or more symptoms. An effective amount may be given in one or more dosages.

[0226] The term “treating” (and variations thereof such as “treat” or “treatment”) refers to clinical intervention in an attempt to alter the natural course of a disease or condition in a subject in need thereof. Treatment can be performed during the course of clinical pathology. Desirable effects of treatment include preventing recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.

[0227] 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.

[0228] As used herein, the term “subject,” “patient,” or “individual” means a mammalian subject. Exemplary subjects include humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, goats, rabbits, and sheep. In certain embodiments, the subject is a human. In 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.

[0229] 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.

[0230] The term “in vivo” refers to processes that occur in a living organism.

[0231] 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.

[0232] The term “pharmaceutical composition” refers to a preparation which is in such form as to permit the biological activity of one or more active ingredient(s) contained therein to be effective in treating a subject.

[0233] 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.

[0234] 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.

[0235] The terms “modulate” and “modulation” refer to reducing or inhibiting or, alternatively, activating or increasing, a recited variable.

[0236] 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.

[0237] 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.

[0238] The term “about” indicates and encompasses an indicated value and a range above and below that value. In certain embodiments, the term “about” indicates the designated value ± 10%, ± 5%, or ± 1%. In certain embodiments, where applicable, the term “about” indicates the designated value(s) ± one standard deviation of that value(s).

[0239] 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.

[0240] 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.

[0241] For any of the structural and functional characteristics described herein, methods of determining these characteristics are known in the art.

[0242] The term “optionally” is meant, when used sequentially, to include from one to all of the enumerated combinations and contemplates all sub-combinations.

[0243] The term “amino acid” refers to the twenty common naturally occurring amino acids. Naturally occurring amino acids include alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartic acid (Asp; D), cysteine (Cys; C); glutamic acid (Glu; E), glutamine (Gln; Q), Glycine (Gly; G); histidine (His; H), isoleucine (Ile; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Val; V).

[0244] 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).

[0245] 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.

[0246] The term “ka” (M-1×sec-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.

[0247] The term “KD” (M), as used herein, refers to the dissociation equilibrium constant of a particular antibody-antigen interaction. KD = kd / ka. In some embodiments, the affinity of an antibody is described in terms of the KD for an interaction between such antibody and its antigen. For clarity, as known in the art, a smaller KD value indicates a higher affinity interaction, while a larger KD value indicates a lower affinity interaction.

[0248] The term “KA” (M-1), as used herein, refers to the association equilibrium constant of a particular antibody-antigen interaction. KA = ka / kd.

[0249] As used herein, “administration” refers to providing or giving a subject a therapeutic agent (e.g., an anti-OX40L antibody, or an antigen binding fragment thereof, or 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.

[0250] 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.

[0251] 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.

[0252] 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 acids Amino Acid 3 Letter 1 Letter Side-chain Electrostatic Steric Code Code Polarity character at Volume†te te te te te te te teFrom this table 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 and W. 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).

[0253] 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.

[0254] A “anti-OX40L antibody,” “OX40L antibody,” or “OX40L specific antibody” is an antibody, as provided herein, which specifically binds to the antigen OX40L.

[0255] A “OX40L antigen binding region,” “anti-OX40L antigen binding region,” or “OX40L-specific antigen binding region” is an antigen binding region of a multi-specific antibody, as provided herein, which specifically binds to the antigen OX40L. In some embodiments, the OX40L antigen binding region binds the extracellular domain of OX40L.

[0256] 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 IL-4Rα.

[0257] A “IL-4Rα antigen binding region,” “anti-IL-4Rα antigen binding region,” or “IL- 4Rα-specific antigen binding region” is an antigen binding region of a multi-specific antibody, as provided herein, which specifically binds to the antigen IL-4Rα.

[0258] The term “multi-specific antibody” is used herein in its broadest sense to include molecules comprising polypeptides that have the capability of binding to two or more distinct antigens. Multi-specific antibodies include antibodies comprising two or more antigen binding domains that have affinity to one or more antigens, such as, for example, a bispecific antibody.

[0259] The term “epitope” means a portion of an antigen that specifically binds to an antibody.

[0260] 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”).

[0261] The term “antigen-binding domain” means the portion of an antibody that is capable of specifically binding to an antigen or epitope.

[0262] 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.

[0263] The term “human antibody” refers to an antibody which possesses an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or derived from a non-human source that utilizes a human antibody repertoire or human antibody-encoding sequences (e.g., obtained from human sources or designed de novo). Human antibodies specifically exclude humanized antibodies.

[0264] 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.

[0265] 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.

[0266] 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.

[0267] 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.

[0268] The term “single-chain” refers to a molecule comprising amino acid monomers linearly linked by peptide bonds. In a particular such embodiment, the C-terminus of the Fab light chain is connected to the N-terminus of the Fab heavy chain in the single-chain Fab molecule. As described in more detail herein, an scFv has a variable domain of light chain (VL) connected from its C-terminus to the N-terminal end of a variable domain of heavy chain (VH) by a polypeptide chain. Alternately the scFv comprises of polypeptide chain where in the C-terminal end of the VH is connected to the N-terminal end of VL by a polypeptide chain.

[0269] The “Fab fragment” (also referred to as fragment antigen-binding) contains the constant domain (CL) of the light chain and the first constant domain (CH1) of the heavy chain along with the variable domains VL and VH on the light and heavy chains respectively. The variable domains comprise the complementarity determining loops (CDR, also referred to as hypervariable region) that are involved in antigen-binding. Fab′ fragments differ from Fab fragments by the addition of a few residues at the carboxy terminus of the heavy chain CH1 domain including one or more cysteines from the antibody hinge region.

[0270] “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 ß-mercaptoethanol.

[0271] “Fv” fragments comprise a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain.

[0272] “Single-chain Fv” or “sFv” or “scFv” includes the VH and VL domains of an antibody, wherein these domains are present in a single polypeptide chain. In one embodiment, the Fv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the scFv to form the desired structure for antigen-binding. For a review of scFv see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol.113, Rosenburg and Moore eds., Springer-Verlag, New York, pp.269-315 (1994). HER2 antibody scFv fragments are described in WO93 / 16185; U.S. Pat. No.5,571,894; and U.S. Pat. No. 5,587,458.

[0273] “scFv-Fc” fragments comprise an scFv attached to an Fc domain. For example, an Fc domain may be attached to the C-terminal of the scFv. The Fc domain may follow the VH or VL, depending on the orientation of the variable domains in the scFv (i.e., VH-VL or VL-VH). Any suitable Fc domain known in the art or described herein may be used. In some cases, the Fc domain comprises an IgG4 Fc domain.

[0274] 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., FEBS Letters, 1998, 414:521-526 and Muyldermans et al., Trends in Biochem. Sci., 2001, 26:230-245, each of which is incorporated by reference in its entirety. Single domain antibodies are also known as sdAbs or nanobodies. SdAbs are fairly stable and easy to express as fusion partner with the Fc chain of an antibody (Harmsen MM, De Haard HJ (2007). “Properties, production, and applications of camelid single-domain antibody fragments”. Appl. Microbiol Biotechnol.77(1): 13-22).

[0275] 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.

[0276] 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.

[0277] 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.

[0278] 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 a 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.

[0279] 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 specifiedpercentage 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.

[0280] For sequence comparison, typically one sequence acts as a reference sequence to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are input into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. The sequence comparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters.

[0281] Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith & Waterman, Adv. Appl. Math.2:482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol.48:443 (1970), by the search for similarity method of Pearson & Lipman, Proc. Nat’l. Acad. Sci. USA 85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by visual inspection (see generally Ausubel et al., infra).

[0282] 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.

[0283] 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.

[0284] The term "atopic dermatitis disease severity outcome measure" refers to a determination of certain signs, symptoms, features or parameters that have been associated with atopic dermatitis and that can be quantitatively or qualitatively assessed. Exemplary atopic dermatitis disease severity outcome measures include "Eczema Area and Severity Index" (EASI), "Severity Scoring of Atopic Dermatitis" (SCORAD), "Validated Investigator Global Assessment-Atopic Dermatitis" (vIGA-AD), "Investigator Global Assessment of Signs" (IGSA), Rajka / Langeland Atopic Dermatitis Severity Score, “Body Surface Area” (BSA), and Patient-Reported Outcomes including Pruritus Visual Analog Scale (an aspect of disease severity assessed as part of SCORAD), Sleep Loss Visual Analog Scale (an aspect of disease severity assessed as part of SCORAD), Atopic Dermatitis Symptom Diary (ADSD), Atopic Dermatitis Impact Questionnaire (ADIQ), Dermatology Life Quality Index (DLQI) (Finlay and Khan, Clin Exper Dermatol 1994;19:210), 5-D Itch Scale (Elman et al., Br J Dermatol 2010;162(3):587-593), Itch Numeric Rating Scale (I-NRS) (see Naegeli et al., International Journal of Dermatology.2015;54(6):715-722; and Newton L, et al., J. Patient Rep. Outcomes.2019;3(1):42), and the Patient-Oriented Eczema Measure (POEM) (www.nottingham.ac.uk / research / groups / cebd / resources / poem.aspx).

[0285] Hyaluronidases

[0286] 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.

[0287] 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).

[0288] 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-β-N-acetylhexosaminidases that break down β-1,4 glycosidic linkages to form tetrasaccharides. Second, leech / hookworm hyaluronidases are endo-β-D- glucuronidases that break down β-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 β-elimination reaction at β-1,4 glycosidic linkage.

[0289] 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). Acid- active hyaluronidases are activated at a pH of 3 to 4. Neutral-active hyaluronidases, which include 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).

[0290] 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.

[0291] Examples 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).

[0292] 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 mammalian- type 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 (SEQ ID 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 NO:30 of US Patent No.: 8,568,713), Arthrobacter sp. (strain FB24) (SEQ ID NO:67 of US Patent No.: 8,568,713), Bdellovibrio bacteriovorus (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 Ia (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); serotypeM4, strain MGAS10750 (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 / ES114 (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, HYAL1 (SEQ ID NO:36 of US Patent No.: 8,568,713), HYAL2 (SEQ ID NO:37 of US 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 are Vitrase® (ovine hyaluronidase) and Amphadase ® (bovine hyaluronidase).

[0293] 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:1076-1085 and 1087-1142. 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.

[0294] 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-114 solution warmed to 37 ºC. (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 intothe 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.

[0295] 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.

[0296] 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 ºC (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 (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.

[0297] 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 abilityof 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.

[0298] 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:1076; 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:1077. 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:1076. Thus, a 474 amino acid GPI-anchored mature polypeptide with an amino acid sequence set forth in SEQ ID NO:1077 is produced.

[0299] The amino acid sequence of the human PH20 precursor polypeptide (SEQ ID NO: 1076; 509 amino acids) is as follows: MGVLKFKHIFFRSFVKSSGVSQIVFTFLLIPCCLTLNFRAPPVIPNVPFLWAWNAPSEF CLGKFDEPLDMSLFSFIGSPRINATGQGVTIFYVDRLGYYPYIDSITGVTVNGGIPQKIS LQDHLDKAKKDITFYMPVDNLGMAVIDWEEWRPTWARNWKPKDVYKNRSIELVQ QQNVQLSLTEATEKAKQEFEKAGKDFLVETIKLGKLLRPNHLWGYYLFPDCYNHHY KKPGYNGSCFNVEIKRNDDLSWLWNESTALYPSIYLNTQQSPVAATLYVRNRVREAI RVSKIPDAKSPLPVFAYTRIVFTDQVLKFLSQDELVYTFGETVALGASGIVIWGTLSIM RSMKSCLLLDNYMETILNPYIINVTLAAKMCSQVLCQEQGVCIRKNWNSSDYLHLNP DNFAIQLEKGGKFTVRGKPTLEDLEQFSEKFYCSCYSTLSCKEKADVKDTDAVDVCI ADGVCIDAFLKPPMETEEPQIFYN ASPSTLSATMFIVSILFLIISSVASL.

[0300] The amino acid sequence of the mature PH20 polypeptide (SEQ ID NO: 1077; 474 amino acids) is as follows:LNFRAPPVIPNVPFLWAWNAPSEFCLGKFDEPLDMSLFSFIGSPRINATGQGVTIFYVD RLGYYPYIDSITGVTVNGGIPQKISLQDHLDKAKKDITFYMPVDNLGMAVIDWEEWR PTWARNWKPKDVYKNRSIELVQQQNVQLSLTEATEKAKQEFEKAGKDFLVETIKLG KLLRPNHLWGYYLFPDCYNHHYKKPGYNGSCFNVEIKRNDDLSWLWNESTALYPSI YLNTQQSPVAATLYVRNRVREAIRVSKIPDAKSPLPVFAYTRIVFTDQVLKFLSQDEL VYTFGETVALGASGIVIWGTLSIMRSMKSCLLLDNYMETILNPYIINVTLAAKMCSQV LCQEQGVCIRKNWNSSDYLHLNPDNFAIQLEKGGKFTVRGKPTLEDLEQFSEKFYCS CYSTLSCKEKADVKDTDAVDVCIADGVCIDAFLKPPMETEEPQIFYNASPSTLSATMF IVSILFLIISSVASL.

[0301] 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:1077 and positions 142-172 of the precursor polypeptide set forth in SEQ ID NO:1076, 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:1077) 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)

[0302] The Peptide 3 region, which corresponds to amino acid positions 242-262 of the mature polypeptide set forth in SEQ ID NO:1077, and positions 277-297 of the precursor polypeptide set forth in SEQ ID NO:1076, 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).

[0303] 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 IDNO:1076 and positions 170-200 of the mature polypeptide set forth in SEQ ID NO:1077. 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:1077) 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).

[0304] 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:1076. Because amino acids 36 to 464 of SEQ ID NO:1076 appear to contain the minimally active human 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:1076 (corresponding to residues C25 and C316, and C189 and C203 of the mature polypeptide set forth in SEQ ID NO:1077, 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: 1076 (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:1077, respectively).

[0305] 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.

[0306] Soluble rHuPH20 is encoded by a nucleic acid that includes the signal sequence and is set forth in SEQ ID NO:1086. 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. Accordingly, exemplary sHuPH20 polypeptides include mature polypeptides having an amino acid sequence set forth in any one of SEQ ID NOs:1078-1085 and 1087-1142. Other variants can have 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to any of SEQ ID NOs: 1078-1085 and 1087-1142, as long they retain a hyaluronidase activity and are soluble. Corresponding allelic variants and other variants alsoare included, including those corresponding to the precursor human PH20 polypeptide set forth in SEQ ID NO: 1076 and the mature human PH20 polypeptide set forth in SEQ ID NO: 1077.

[0307] 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).

[0308] rHuPH20 is a glycosylated single chain protein with up to 447 amino acids, synthesized in CHO cells. 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.

[0309] Any suitable hyaluronidase (e.g., a recombinant human hyaluronidase) can be used in the methods 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 Patent No.: 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.

[0310] An exemplary recombinant human hyaluronidase is rHuPH20, i.e., the active ingredient in the commercial product Hylenex® recombinant (hyaluronidase human injection), which is supplied as ENHANZE® drug product.

[0311] 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. 11,041,149, 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.

[0312] Other variants are known to those of skill in the art including those described, for example, in WO2020 / 022791 and WO2020197230A, 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 WO2020 / 022791. WO2021 / 150079 also provides variant polypeptides described as having increased stability.

[0313] In one embodiment, the recombinant human hyaluronidase includes a sequence of amino acids in any one of SEQ ID NOs: 1076-1085 and 1087-1142, or has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 97%, 98%, or 99% sequence identity to a sequence of amino acids included in SEQ ID NO: 1076- 1085 and 1087-1142 and retains hyaluronidase activity.

[0314] In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1076. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1076. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1078. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1078. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1079. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1079. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQID NO:1080. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1080. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1081. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1081. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1082. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1082. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1083. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1083. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1084. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1084. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1085. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1085. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1087. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1087. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1088. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1088. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1089. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1089. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1090. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1090. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1091. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1091. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1092. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1092. Inanother embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1093. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1093. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1094. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1094. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1095. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1095. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1096. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1096. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1097. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1097. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1098. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1098. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1099. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1099. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1100. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1100. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1101. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1101. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1102. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1102. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1103. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1103. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1104. In anotherembodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1104. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1105. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1105. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1106. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1106. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1107. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1107. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1108. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1108. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1109. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1109. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1110. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1110. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1111. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1111. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1112. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1112. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1113. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1113. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1114. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1114. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1115. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1115. In another embodiment,the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1116. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1116. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1117. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1117. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1118. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1118. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1119. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1119. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1120. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1120. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1121. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1121. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1122. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1122. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1123. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1123. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1124. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1124. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1125. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1125. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1126. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1126. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1127. In another embodiment, the recombinanthuman hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1127. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1128. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1128. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1129. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1129. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1130. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1130. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1131. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1131. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1132. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1132. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1133. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1133. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1134. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1134. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1135. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1135. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1136. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1136. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1137. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1137. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1138. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1138. In another embodiment, the recombinant humanhyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1139. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1139. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1140. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1140. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1141. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1141. In another embodiment, the recombinant human hyaluronidase comprises the amino acid sequence set forth in SEQ ID NO:1142. In another embodiment, the recombinant human hyaluronidase consists of the amino acid sequence set forth in SEQ ID NO:1142. Antibodies

[0315] 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., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0316] 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 IgG1 heavy chain comprises of the VH, CH1, CH2 and CH3 domains respectively from the N to C-terminus. The light chain comprises of the VL and CL domains from N to C terminus. The IgG1 heavy chain comprises a hinge between the CH1 and CH2 domains. In certain embodiments, the immunoglobulin constructs comprise at least one immunoglobulin domain from IgG, IgM, IgA, IgD, or IgE connected to a therapeutic polypeptide. In some embodiments, the immunoglobulin domain found in an antibody provided herein, is from or derived from an immunoglobulin-based construct such as adiabody, 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.

[0317] 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 IgG1. 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 IgA1. In one embodiment, the heavy chain is an IgA2.

[0318] In some embodiments, an antibody is an IgG1 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.

[0319] Generally, native four-chain antibodies comprise six HVRs; three in the VH (H1, H2, H3), and three in the VL (L1, 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., J Mol Biol 196:901-917 (1987), where the definitions include overlapping or subsets of amino acid residues when compared against each other. Nevertheless, application of either definition to refer to a CDR of an antibody or variants thereof is intended to be within the scope of the term as defined and used herein. The exact residue numbers which encompass a particular CDR will vary depending on the sequence and size of the CDR. Those skilled in the art can routinely determine which residues comprise a particular CDR given the variable region amino acid sequence of the antibody.

[0320] The amino acid sequence boundaries of a CDR can be determined by one of skill in the art using any of a number of known numbering schemes, including those described by Kabat et al., supra (“Kabat” numbering scheme); Al-Lazikani et al., 1997, J. Mol. Biol., 273:927-948 (“Chothia” numbering scheme); MacCallum et al., 1996, J. Mol. Biol.262:732- 745 (“Contact” numbering scheme); Lefranc et al., Dev. Comp. Immunol., 2003, 27:55-77 (“IMGT” numbering scheme); and Honegge and Plückthun, J. Mol. Biol., 2001, 309:657-70 (“aHo” numbering scheme); each of which is incorporated by reference in its entirety.

[0321] 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.

[0322] CDRs may be assigned, for example, using antibody numbering software, such as Abnum, available at www.bioinf.org.uk / abs / abnum / , and described in Abhinandan and Martin, Immunology, 2008, 45:3832-3839, incorporated by reference in its entirety. TABLE 2. Residues in CDRs according to Kabat and Chothia numbering schemes CDR Kabat Chothiaconvention, varies between H32 and H34, depending on the length of the CDR.

[0323] 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.

[0324] 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.

[0325] Epitopes frequently consist of surface-accessible amino acid residues and / or sugar side chains and may have specific three-dimensional structural characteristics, as well as specific charge characteristics. Conformational and non-conformational epitopes are distinguished in that the binding to the former but not the latter may be lost in the presence of denaturing solvents. An epitope may comprise amino acid residues that are directly involved in the binding, and other amino acid residues, which are not directly involved in the binding. The epitope to which an antibody binds can be determined using known techniques for epitope determination such as, for example, testing for antibody binding to OX40L or IL- 4Rα, to OX40L or IL-4Rα variants with different point-mutations, or to chimeric OX40L or IL-4Rα variants.

[0326] To screen for antibodies which bind to an epitope on a target antigen bound by an antibody of interest (e.g., OX40L or 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. Anti-OX40L Antibodies

[0327] The present application provides antibodies or antigen binding fragments thereof and compositions comprising an antibody, or an antigen binding fragment thereof, which binds OX40L. In some embodiments, an anti-OX40L antibody, or an antigen binding fragment thereof, described herein is selected from amlitelimab and oxelumab. In some embodiments, amlitelimab comprises a variable heavy (VH) chain sequence having the amino acid sequence of SEQ ID NO: 832 and a variable light (VL) chain sequence having the amino acid sequence of SEQ ID NO: 833. In some embodiments, oxelumab comprises a VH chain sequence having the amino acid sequence of SEQ ID NO: 834 and a VL chain sequence having the amino acid sequence of SEQ ID NO: 835. In some embodiments, amlitelimab comprises a heavy chain having the amino acid sequence of SEQ ID NO: 842 and a light chain sequence having the amino acid sequence of SEQ ID NO: 843. In some embodiments, oxelumab comprises a heavy chain having the amino acid sequence of SEQ ID NO: 1072 and a light chain sequence having the amino acid sequence of SEQ ID NO: 1073, or a VH and / or VL therein. See also PCT Application No. PCT / US2024 / 026854 (corresponding to PCT Publication No. WO2024227174), which is incorporated herein by reference in its entirety. In some embodiments, an anti-OX40L antibody, or an antigenbinding fragment thereof, described herein is selected from an anti-OX40L antibody described therein.

[0328] Anti-OX40L antibodies or an antigen binding fragments thereof 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.

[0329] In some embodiments, the antibodies are monoclonal antibodies.

[0330] In some embodiments, the antibodies are polyclonal antibodies.

[0331] 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.

[0332] 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.

[0333] In some embodiments, the antibodies may be polyfunctional antibodies, recombinant antibodies, human antibodies, humanized antibodies, fragments or variants thereof. In particular embodiments, the antibody fragment or a derivative thereof is selected from a Fab fragment, a Fab′2 fragment, a CDR and ScFv.

[0334] In some embodiments, the antibodies are capable of forming an immune complex.

[0335] For sequence comparison, typically one sequence acts as a reference sequence to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are input into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. The sequence comparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters.

[0336] Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith & Waterman, Adv. Appl. Math.2:482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol.48:443 (1970), by the search for similarity method of Pearson & Lipman, Proc. Nat’l. Acad. Sci. USA 85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, andTFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by visual inspection (see generally Ausubel et al., infra).

[0337] 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., J. Mol. Biol.215:403-410 (1990). Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (www.ncbi.nlm.nih.gov / ). Sequences of OX40L Antibodies TABLE 3. Sequences of OX40L antibody constructs – VH, VL, and associated CDRs Identifier VH and Heavy Chain CDRs VL and Light Chain CDRs 114 VH SE ID NO 1 VL SE ID NO 11Identifier VH and Heavy Chain CDRs VL and Light Chain CDRs IMGT (SEQ ID NO: 25) IMGT (SEQ ID NO: 34)Identifier VH and Heavy Chain CDRs VL and Light Chain CDRs Oxelumab VH (SEQ ID NO: 834) VL (SEQ ID NO: 835)

[0338] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a VH sequence selected from any one of SEQ ID NOs: 1, 19, 37, and 55.

[0339] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to an illustrative VH sequence selected from any one of SEQ ID NOs: 1, 19, 37, and 55. In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a VH sequence selected from any one of SEQ ID NOs: 1, 19, 37, and 55, 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. Anti-OX40L VL Domains

[0340] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a VL sequence selected from any one of SEQ ID NOs: 11, 29, 47, and 65.

[0341] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a VL sequence selected from any one of SEQ ID NOs: 11, 29, 47, and 65. In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a VL sequence selected from any one of SEQ ID NOs: 11, 29, 47, and 65, 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 areconservative 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. Anti-OX40L VH-VL Combinations

[0342] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a VH sequence selected from any one of SEQ ID NOs: 1, 19, 37, and 55; and a VL sequence selected from any one of SEQ ID NOs: 11, 29, 47, and 65.

[0343] In certain aspects, a VH sequence selected from any one of SEQ ID NOs: 1, 19, 37, and 55 can be combined with a VL sequence selected from any one of SEQ ID NOs: 11, 29, 47, and 65.

[0344] In certain aspects, an antibody, or an antigen binding fragment thereof, provided herein comprises a VH sequence and a VL sequence of a construct provided in TABLE 3 (e.g., a VH sequence and a VL sequence from the same row of TABLE 3) or in PCT Application No. PCT / US2024 / 026854 (corresponding to PCT Publication No. WO2024227174), incorporated by reference herein in its entirety. In certain aspects, an antibody, or antigen binding fragment thereof, provided herein comprises a VH sequence and a VL sequence from Table 2 in PCT Application No. PCT / US2024 / 026854 (e.g., a VH sequence and a VL sequence from the same row of Table 2).

[0345] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a VH sequence selected from any one of SEQ ID NOs: 1, 19, 37, and 55; 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 selected from any one of SEQ ID NOs: 11, 29, 47, and 65. In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a VH sequence selected from any one of SEQ ID NOs: 1, 19, 37, and 55, 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 selected from any one of SEQ ID NOs: 11, 29, 47, and 65, 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.

[0346] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 1 and a VL sequence set forth in SEQ ID NO: 11.

[0347] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 19 and a VL sequence set forth in SEQ ID NO: 29.

[0348] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 37 and a VL sequence set forth in SEQ ID NO: 47.

[0349] In certain embodiments, the antibody, or an antigen binding fragment thereof, comprises a VH sequence set forth in SEQ ID NO: 55 and a VL sequence set forth in SEQ ID NO: 65.

[0350] In certain embodiments, an antibody, or an antigen binding fragment thereof, comprises any of the VH and VL combinations described above and further comprises a heavy chain comprising a human IgG sequence selected from a sequence set forth in any one of SEQ ID NOs: 637-737 and SEQ ID NOs: 847-1070 or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto. In certain embodiments, an antibody comprises any of the VH and VL combinations described above and further comprises a heavy chain comprising a constant heavy chain sequence set forth in SEQ ID NO: 651 or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto. In certain embodiments, an antibody comprises any of the VH and VL combinations described above and further comprises a constant heavy chain comprising a constant heavy chain sequence set forth in SEQ ID NO: 973 or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto. In certain embodiments, an antibody comprises any of the VH and VLcombinations described above and further comprises a human constant light chain sequence set forth in SEQ ID NO: 738 or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto. In certain embodiments, an antibody comprises any of the VH and VL combinations described above and further comprises a constant heavy chain sequence set forth in SEQ ID NO: 651 or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto and a human constant light chain sequence set forth in SEQ ID NO: 738 or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto. In certain embodiments, an antibody comprises any of the VH and VL combinations described above and further comprises a constant heavy chain sequence set forth in SEQ ID NO: 973 or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto and a human constant light chain sequence set forth in SEQ ID NO: 738 or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto.

[0351] 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: 959-1070), 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: 637-737 and 847-958). 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: 959-1070), a human IgG sequence lacking a C-terminal lysine (e.g., any one of SEQ ID NOs: 637-737 and 847-958), or a mixture thereof (e.g., a mixture of the same heavy chain constant sequence with and without a C-terminal lysine, such as a mixture of SEQ ID NO: 973 and SEQ ID NO: 651). Anti-OX40L CDRs

[0352] In some embodiments, disclosed herein is an antibody, or an antigen binding fragment thereof, comprising 1, 2, 3, 4, 5, or 6 of the CDRs of TABLE 3. In some embodiments, disclosed herein is an antibody, or an antigen binding fragment thereof, comprising 6 of the Kabat CDRs of TABLE 3. In some embodiments, disclosed herein is an antibody, or an antigen binding fragment thereof, comprising 1, 2, 3, 4, 5, or 6 of the Chothia CDRs of TABLE 3. In some embodiments, disclosed herein is an antibody, or an antigen binding fragment thereof, comprising 1, 2, 3, 4, 5, or 6 of the IMGT CDRs of TABLE 3. Insome 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).

[0353] In some embodiments, disclosed herein is an antibody, or an antigen binding fragment thereof, comprising 1, 2, 3, 4, 5, or 6 of the CDRs of an antibody provided in PCT Application No. PCT / US2024 / 026854 (corresponding to PCT Publication No. WO2024227174, incorporated by reference herein in its entirety, such as 1, 2, 3, 4, 5, or 6 of the CDRs in Table 2 in PCT Application No. PCT / US2024 / 026854. In some embodiments, disclosed herein is an antibody, or an antigen binding fragment thereof, comprising 1, 2, 3, 4, 5, or 6 of the Kabat CDRs of an antibody, or an antigen binding fragment thereof, provided in PCT Application No. PCT / US2024 / 026854. In some embodiments, disclosed herein is an antibody, or an antigen binding fragment thereof, comprising 1, 2, 3, 4, 5, or 6 of the Chothia CDRs of an antibody, or an antigen binding fragment thereof, provided in PCT Application No. PCT / US2024 / 026854. In some embodiments, disclosed herein is an antibody, or an antigen binding fragment thereof, comprising 1, 2, 3, 4, 5, or 6 of the IMGT CDRs of an antibody provided in PCT Application No. PCT / US2024 / 026854. 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 in in PCT Application No. PCT / US2024 / 026854 (e.g., 6 CDRs from the same antibody).

[0354] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises three CDRs of a VH domain selected from SEQ ID NOs: 1, 19, 37, and 55. 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.

[0355] In some embodiments, the CDRs are CDRs having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to a CDR-H1, CDR-H2, or CDR-H3 selected from SEQ ID NOs: 2-10, 12-18, 20-28, 30-36, 38-46, 48-54, 56-64, and 66-72. In some embodiments, the CDR-H1 is a CDR-H1 of a VH domain selected from SEQ ID NOs: 1, 19, 37, and 55, with up to 1, 2, 3, 4, or 5 amino acid substitutions. In some embodiments, the CDR-H2 is a CDR-H2 of a VH domain selected from SEQ ID NOs: 1, 19, 37, and 55, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the CDR-H3 is a CDR-H3 of a VH domain selected from SEQ ID NOs: 1, 19, 37, and 55,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.

[0356] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises three CDRs of a VL domain selected from SEQ ID NOs: 11, 29, 47, and 65. 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.

[0357] In some embodiments, the CDRs are CDRs having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to a CDR-L1, CDR-L2, or CDR-L3 selected from SEQ ID NOs: 2-10, 12-18, 20-28, 30-36, 38-46, 48-54, 56-64, and 66- 72, In some embodiments, the CDR-L1 is a CDR-L1 of a VL domain selected from SEQ ID NOs: 11, 29, 47, and 65, with up to 1, 2, 3, 4, or 5 amino acid substitutions. In some embodiments, the CDR-L2 is a CDR-L2 of a VL domain selected from SEQ ID NOs: 11, 29, 47, and 65, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the CDR-L3 is a CDR-L3 of a VL domain selected from SEQ ID NOs: 11, 29, 47, and 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.

[0358] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises three CDRs of a VH domain selected from SEQ ID NOs: 1, 19, 37, and 55 and three CDRs of a VL domain selected from SEQ ID NOs: 11, 29, 47, and 65.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.

[0359] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H3 selected from SEQ ID NOs: 8-10, 26-28, 44-46, and 62-64. In some aspects, the CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a CDR-H3 selected from SEQ ID NOs: 8-10, 26-28, 44-46, and 62-64. In some embodiments, the CDR-H3 is a CDR-H3 selected from SEQ ID NOs: 8-10, 26-28, 44-46, and 62-64, 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.

[0360] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 selected from SEQ ID NOs: 2-4, 20-22, 38-40, and 56- 58. In some aspects, the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a CDR-H1 selected from SEQ ID NOs: 2-4, 20-22, 38-40, and 56-58. In some embodiments, the CDR-H1 is a CDR-H1 selected from SEQ ID NOs: 2- 4, 20-22, 38-40, and 56-58, 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.

[0361] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H2 selected from SEQ ID NOs: 5-7, 23-25, 41-43, and 59-61. In some aspects, the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a CDR-H2 selected from SEQ ID NOs: 5-7, 23-25, 41-43, and 59-61. In some embodiments, the CDR-H2 is a CDR-H2 selected from SEQ ID NOs: 5- 7, 23-25, 41-43, and 59-61, 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.

[0362] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-L3 selected from SEQ ID NOs: 17-18, 35-36, 53-54, and 71-72. In some aspects, the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a CDR-L3 selected from SEQ ID NOs: 17-18, 35- 36, 53-54, and 71-72. In some embodiments, the CDR-L3 is a CDR-L3 selected from SEQ ID NOs: 17-18, 35-36, 53-54, and 71-72, 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.

[0363] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-L2 selected from SEQ ID NOs: 15-16, 33-34, 51-52, and 69-70. In some aspects, the CDR-L2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a CDR-L2 selected from SEQ ID NOs: 15-16, 33- 34, 51-52, and 69-70. In some embodiments, the CDR-L2 is a CDR-L2 selected from SEQ ID NOs: 15-16, 33-34, 51-52, and 69-70, 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 toherein 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.

[0364] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-L1 selected from SEQ ID NOs: 12-14, 30-32, 48-50, and 66-68. In some aspects, the CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a CDR-L1 selected from SEQ ID NOs: 12-14, 30- 32, 48-50, and 66-68. In some embodiments, the CDR-L1 is a CDR-L1 selected from SEQ ID NOs: 12-14, 30-32, 48-50, and 66-68, 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.

[0365] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2; a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 5; a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 8; a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 12; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 15; and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 17.

[0366] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 3; a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 6; a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 9; a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 13; a CDR-L2 comprising theamino acid sequence set forth in SEQ ID NO: 16; and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 18.

[0367] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 4; a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 7; a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 10; a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 14; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 16; and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 17.

[0368] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 20; a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 23; a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 26; a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 30; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 33; and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 35.

[0369] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 21; a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 24; a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 27; a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 31; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 34; and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 36.

[0370] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 22; a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 25; a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 27; a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 32; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 34; and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 35.

[0371] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 38; a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 41; aCDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 44; a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 48; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 51; and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 53.

[0372] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 39; a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 42; a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 45; a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 49; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 52; and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 54.

[0373] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 40; a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 43; a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 46; a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 50; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 52; and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 53.

[0374] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 56; a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 59; a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 62; a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 66; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 69; and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 71.

[0375] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 57; a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 60; a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 63; a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 67; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 70; and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 72.

[0376] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein comprises a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 58; a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 61; a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 64; a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 68; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 70; and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 71.

[0377] In certain embodiments, any of the antibodies or antigen binding fragments thereof described above further comprises a heavy chain comprising a human IgG sequence selected from a sequence set forth in any one of SEQ ID NOs: 637-737 and SEQ ID NOs: 847-1070 or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto. In certain embodiments, any of the antibodies described above further comprises a constant heavy chain sequence set forth in SEQ ID NO: 651 or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto. In certain embodiments, any of the antibodies described above further comprises a constant heavy chain sequence set forth in SEQ ID NO: 973 or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto. In certain embodiments, any of the antibodies described above further comprises a human constant light chain sequence set forth in SEQ ID NO: 738 or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto. In certain embodiments, any of the antibodies described above further comprises a constant heavy chain sequence set forth in SEQ ID NO: 651 or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto and a human constant light chain sequence set forth in SEQ ID NO: 738 or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto. In certain embodiments, any of the antibodies described above further comprises a constant heavy chain sequence set forth in SEQ ID NO: 973 or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto and a human constant light chain sequence set forth in SEQ ID NO: 738 or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto.

[0378] 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 IDNOs: 959-1070), 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: 637-737 and 847-958). 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: 959-1070), a human IgG sequence lacking a C-terminal lysine (e.g., any one of SEQ ID NOs: 637-737 and 847-958), or a mixture thereof (e.g., a mixture of the same heavy chain constant sequence with and without a C-terminal lysine, such as a mixture of SEQ ID NO: 973 and SEQ ID NO: 651).

[0379] In some aspects, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this disclosure are referred to herein as “variants” or “clones”. In some embodiments, such variants or clones are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants or cones are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies. Fc Region

[0380] The structures of the Fc regions of various immunoglobulins, and the glycosylation sites contained therein, are known in the art. See Schroeder et al. (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.

[0381] 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., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.

[0382] 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 FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternatively spliced forms of these receptors. FcγRII receptors include FcγRIIA (an “activating receptor”) and FcγRIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in 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 FcγRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. Inhibiting receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain (reviewed in Daëron, Annu. Rev. Immunol.15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med.126:330-41 (1995). Other FcRs, including those to be identified in the future, are encompassed by the term “FcR” herein. The term also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol.117:587 (1976); and Kim et al., J. Immunol.24:249 (1994)).

[0383] Modifications in the CH2 domain can affect the binding of FcRs to the Fc. A number of amino acid modifications in the Fc region are known that can selectively alter the affinity of the Fc for different Fcgamma receptors. In some aspects, the Fc comprises one or more modifications designed to promote selective binding of Fc-gamma receptors.

[0384] Exemplary mutations that may alter the binding of FcRs to the Fc are listed below (in EU numbering format): • S298A / E333A / K334A, S298A / E333A / K334A / K326A (Lu Y, Vernes JM, Chiang N, et al., J Immunol Methods.2011 Feb 28;365(1-2):132-41); • F243L / R292P / Y300L / V305I / P396L, F243L / R292P / Y300L / L235V / P396L (Stavenhagen JB, Gorlatov S, Tuaillon N, et al., Cancer Res.2007 Sep 15;67(18):8882-90; Nordstrom JL, Gorlatov S, Zhang W, et al., Breast Cancer Res. 2011 Nov 30;13(6):R123); • F243L (Stewart R, Thom G, Levens M, et al., Protein Eng Des Sel.2011 Sep;24(9):671-8.), S298A / E333A / K334A (Shields RL, Namenuk AK, Hong K, et al., J Biol Chem.2001 Mar 2;276(9):6591-604);• S239D / I332E / A330L, S239D / I332E (Lazar et al., (2006) Proc Natl Acad Sci U S A. 103(11):4005-10); • S239D / S267E, S267E / L328F (Chu et al., (2008) Mol Immunol.45(15):3926-33); • S239D / D265S / S298A / I332E, S239E / S298A / K326A / A327H, G237F / S298A / A330L / I 332E, S239D / I332E / S298A, S239D / K326E / A330L / I332E / S298A, G236A / S239D / D2 70L / 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 1907568379, Oct 2012) lists mutations on page 283.

[0385] In some embodiments, any of the antibodies or antigen binding fragments thereof described above further comprises a heavy chain comprising a constant heavy chain sequence selected from an amino acid sequence set forth in any one of SEQ ID NOs: 637-737 and SEQ ID NOs: 847-1070, or an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

[0386] In some embodiments, an antibody, or an antigen binding fragment thereof, described herein includes modifications designed 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 C1q for CDC. The following TABLE 4 summarizes various designs reported in the literature for effector function engineering.

[0387] 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 GlymaxX® technology (ProBioGen AG) is based on the introduction of a gene for an enzyme which deflects the cellular pathway of fucose biosynthesis into cells used for antibody production. This prevents the addition of the sugar “fucose” to the N-linked antibody carbohydrate part by antibody-producing cells (von Horsten et al. (2010) Glycobiology.2010 Dec; 20 (12):1607-18). Examples of cell lines capable of producing defucosylated antibody include CHO-DG44 with stable overexpression of the bacterial oxidoreductase GDP-6-deoxy-D-lyxo-4-hexylose reductase (RMD) (see von Horsten et al. (2010) supra) or Lec13 CHO cells, which are deficient in protein fucosylation (see Ripka et al. (1986) Arch. Biochem. Biophys.249:533-545; U.S. Pat. Pub. No.2003 / 0157108; WO2004 / 056312; each of which is incorporated by reference in its entirety), and knockout cell lines, such as alpha-1,6-fucosyltransferase gene or FUT8 knockout CHO cells (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.

[0388] 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.

[0389] In some aspects, an antibody, or an antigen binding fragment thereof, provided herein comprises an IgG1 domain with reduced fucose content at position Asn 297 compared to a naturally occurring IgG1 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.

[0390] 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.

[0391] 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.

[0392] 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.

[0393] 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 Reference Mutations Effect C C C C C C C C C C C

[0394] Fc modifications designed to reduce FcgR and / or complement binding and / or effector function are known in the art. Recent publications describe strategies that have been used to engineer antibodies with reduced or silenced effector activity (see Strohl, WR (2009) Curr Opin Biotech 20:685-691, and Strohl, WR and Strohl LM, “Antibody Fc engineering for optimal antibody performance” In Therapeutic Antibody Engineering, Cambridge: Woodhead Publishing (2012), pp 225-249). These strategies include reduction of effector function through modification of glycosylation, use of IgG2 / IgG4 scaffolds, or the introduction of mutations in the hinge or CH2 regions of the Fc. For example, U.S. Patent Publication No.2011 / 0212087 (Strohl), International Patent Publication No. WO 2006 / 105338 (Xencor), U.S. Patent Publication No.2012 / 0225058 (Xencor), U.S. Patent Publication No.2012 / 0251531 (Genentech), and Strop et al., ((2012) J. Mol. Biol.420: 204- 219), each of which is incorporated by reference in its entirety, describe specific modifications designed to reduce FcgR or complement binding to the Fc.

[0395] Specific, non-limiting examples of amino acid modifications designed 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 MutationsMutations

[0396] In some emboe s, a a o y, o a a ge ding fragment thereof, provided herein comprises one or more alterations that is designed to improve or diminish C1q 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.

[0397] In certain embodiments, the heavy chain comprises a constant heavy chain sequence selected from the sequences set forth in SEQ ID NOs: 637-737 and SEQ ID NOs: 847-1070.

[0398] In certain embodiments, the Fc region comprises one or more amino acid substitutions, wherein the one or more substitutions result in an increase in one or more of antibody half-life, ADCC activity, ADCP activity, or CDC activity compared with the Fc without the one or more substitutions. In certain embodiments, the one or more amino acid substitutions results in increased antibody half-life at pH 6.0 compared to an antibody comprising a wild-type Fc region. In certain embodiments, the antibody has an increased half-life that is about 10,000-fold, 1,000-fold, 500-fold, 100-fold, 50-fold, 20-fold, 10-fold, 9- fold, 8-fold, 7-fold, 6-fold, 5-fold, 4.5-fold, 4-fold, 3.5-fold, 3-fold, 2.5-fold, 2-fold, 1.95- fold, 1.9-fold, 1.85-fold, 1.8-fold, 1.75-fold, 1.7-fold, 1.65-fold, 1.6-fold, 1.55-fold, 1.50-fold, 1.45-fold, 1.4-fold, 1.35-fold, 1.3-fold, 1.25-fold, 1.2-fold, 1.15-fold, 1.1-fold, or 1.05-fold longer compared to an antibody comprising a wild-type Fc region. In certain embodiments, the antibody has an increased half-life that is about 10,000-fold, 1,000-fold, 500-fold, 100- fold, 50-fold, 20-fold, 10-fold, 9-fold, 8-fold, 7-fold, 6-fold, 5-fold, 4.5-fold, 4-fold, 3.5-fold,3-fold, 2.5-fold, 2-fold, 1.95-fold, 1.9-fold, 1.85-fold, 1.8-fold, 1.75-fold, 1.7-fold, 1.65-fold, 1.6-fold, 1.55-fold, 1.50-fold, 1.45-fold, 1.4-fold, 1.35-fold, 1.3-fold, 1.25-fold, 1.2-fold, 1.15-fold, 1.1-fold, or 1.05-fold longer compared to amlitelimab.

[0399] In certain embodiments, the Fc region comprises one or more amino acid substitutions, wherein the one or more substitutions result in a decrease in one or more of ADCC activity, ADCP activity, or CDC activity compared with the Fc without the one or more substitutions.

[0400] 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 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.

[0401] 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 YTEmutations at positions 253, 255 and 257. In certain embodiments, an antibody described herein comprises an Fc region with LALA mutations at positions 235 and 236, respectively. In certain embodiments, an antibody described herein comprises an Fc region with YTE mutations at positions 253, 255 and 257 and with LALA mutations at positions 235 and 236. In certain embodiments, the OX40L antibody described herein comprises the heavy and light chain variable regions of Construct 114 and an Fc region comprising YTE mutations at positions 253, 255 and 257, respectively and with LALA mutations at positions 235 and 236, respectively (e.g., as shown in the heavy chain sequences of SEQ ID NOs: 839 and 840).

[0402] In certain embodiments the human Fc region comprises a human IgG1 Fc with LALA mutations. In certain embodiments, the human Fc region comprises a human IgG1 Fc with YTE mutations. In certain embodiments, the human Fc region comprises a human IgG1 Fc with LALA and YTE mutations. In certain embodiments, when direct numbering is used, “YTE” and “LALA” mutations can be located at different amino acid position numbers. For example, a human Fc region can comprise a human IgG1 Fc with LALA mutations at L235A / L236A and / or YTE mutations at M253Y / S255T / T257E.

[0403] In some embodiments, the OX40L antibody, or antigen binding fragment thereof, comprises a heavy chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:1, a constant heavy chain sequence set forth in SEQ ID NO: 651, a light chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:11, and a constant light chain sequence set forth in SEQ ID NO: 738. In some embodiments, the OX40L antibody, or antigen binding fragment thereof, comprises a heavy chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:1, a constant heavy chain sequence set forth in SEQ ID NO: 973, a light chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:11, and a constant light chain sequence set forth in SEQ ID NO: 738.

[0404] The C-terminal Lys330 of the constant heavy chain sequence of SEQ ID NO: 973 may or may not be present. The disclosure specifically contemplates SEQ ID NO: 973 that does not include the C-terminal Lys corresponding to Lys330 (as set forth in SEQ ID NO: 651). A polypeptide comprising SEQ ID NO: 973 (e.g., the polypeptide of SEQ ID NO: 839) may be expressed including a C-terminal Lys330 which then may be proteolytically cleaved upon expression of the polypeptide (e.g., a polypeptide comprising SEQ ID NO: 973 is expressed using a nucleic acid construct encoding the polypeptide including a C-terminal lysine residue, which may then be removed via cleavage to produce a polypeptide in whichthe constant heavy chain has the sequence of SEQ ID NO: 651, such as the polypeptide of SEQ ID NO: 840). Accordingly, the OX40L antibody that is administered can have the constant heavy chain sequence of SEQ ID NO: 973, SEQ ID NO: 651, or a mixture thereof.

[0405] In some embodiments, the OX40L antibody comprises a light chain comprising the sequence set forth in SEQ ID NO: 841. In some embodiments, the OX40L antibody comprises a heavy chain comprising the sequence set forth in SEQ ID NO: 839 or SEQ ID NO: 840. In some embodiments, the OX40L antibody comprises a heavy chain comprising the sequence set forth in SEQ ID NO: 839. In some embodiments, the OX40L antibody comprises a heavy chain comprising the sequence set forth in SEQ ID NO: 840.

[0406] In some embodiments, the OX40L antibody comprises a light chain comprising the sequence set forth in SEQ ID NO: 841 and a heavy chain comprising the sequence set forth in SEQ ID NO: 839. In some embodiments, the OX40L antibody comprises a light chain comprising the sequence set forth in SEQ ID NO: 841 and a heavy chain comprising the sequence set forth in SEQ ID NO: 840.

[0407] In certain embodiments, the Fc region binds an Fcγ Receptor selected from the group consisting of: FcγRI, FcγRIIa, FcγRIIb, FcγRIIc, FcγRIIIa, and FcγRIIIb. In certain embodiments, the Fc region binds an Fcγ Receptor with higher affinity at pH 6.0 compared to an antibody comprising a wild-type Fc region. Binding

[0408] 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®).

[0409] With regard to the binding of an antibody to a target molecule, the terms “bind,” “specific binding,” “specifically binds to,” “specific for,” “selectively binds,” and “selective for” a particular antigen (e.g., a polypeptide target) or an epitope on a particular antigen mean binding that is measurably different from a non-specific or non-selective interaction (e.g., with a non-target molecule). Specific binding can be measured, for example, by measuring binding to a target molecule (i.e., OX40L) and comparing it to binding to a non-target molecule. Specific binding can also be determined by competition with a control moleculethat mimics the epitope recognized on the target molecule. In that case, specific binding is indicated if the binding of the antibody to the target molecule is competitively inhibited by the control molecule. In some embodiments, the affinity of an anti-OX40L antibody, or an antigen binding fragment thereof, for a non-target molecule is less than about 50% of the affinity for OX40L. In some embodiments, the affinity of an anti-OX40L antibody, or an antigen binding fragment thereof, for a non-target molecule is less than about 40% of the affinity for OX40L. In some embodiments, the affinity of an anti-OX40L antibody, or an antigen binding fragment thereof, for a non-target molecule is less than about 30% of the affinity for OX40L. In some embodiments, the affinity of an anti-OX40L antibody, or an antigen binding fragment thereof, for a non-target molecule is less than about 20% of the affinity for OX40L. In some embodiments, the affinity of an anti-OX40L antibody, or an antigen binding fragment thereof, for a non-target molecule is less than about 10% of the affinity for OX40L. In some embodiments, the affinity of an anti-OX40L antibody, or an antigen binding fragment thereof, for a non-target molecule is less than about 1% of the affinity for OX40L. In some embodiments, the affinity of an anti-OX40L antibody, or an antigen binding fragment thereof, for a non-target molecule is less than about 0.1% of the affinity for OX40L.

[0410] In certain embodiments, the antibody, or an antigen binding fragment thereof, binds an OX40L sequence set forth in SEQ ID NO: 739.

[0411] In certain embodiments, the antibody, or an antigen binding fragment thereof, binds to an OX40L sequence set forth in SEQ ID NO: 739 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 an antigen binding fragment thereof, binds to an OX40L sequence set forth in SEQ ID NO: 739 with a KD of less than or equal to about 1 x 10-10M, as measured by surface plasmon resonance (SPR). In certain embodiments, the antibody, or an antigen binding fragment thereof, binds to human OX40L with a KD of less than or equal to about 1 x 10-9M, as measured by surface plasmon resonance (SPR).

[0412] In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein binds OX40L with a KDof less than or equal to about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.95, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 x 10-8M, as measured by ELISA or any other suitable method known in the art. In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein binds OX40L with a KDof less than orequal to about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.95, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 x 10-9M, as measured by ELISA or any other suitable method known in the art.

[0413] In some embodiments, the KDof the antibody, or an antigen binding fragment thereof, provided herein for the binding of OX40L is between about 0.001-0.01, 0.01-0.1, 0.01-0.05, 0.05-0.1, 0.1-0.5, 0.5-1, 0.25-0.75, 0.25-0.5, 0.5-0.75, 0.75-1, 0.75-2, 1.1-1.2, 1.2- 1.3, 1.3-1.4, 1.4-1.5, 1.5-1.6, 1.6-1.7, 1.7-1.8, 1.8-1.9, 1.9-2, 1-2, 1-5, 2-7, 3-8, 3-5, 4-6, 5-7, 6-8, 7-9, 7-10, or 5-10 x 10-8M, as measured by ELISA or any other suitable method known in the art. In some embodiments, an antibody, or an antigen binding fragment thereof, provided herein binds OX40L with a KDof less than or equal to about 1 x 10-8M, or less than or equal to about 1 x 10-9M as measured by ELISA or any other suitable method known in the art.

[0414] In some embodiments, the antibody, or an antigen binding fragment thereof, provided herein binds OX40L with a KD of less than or equal to about 10, 9, 8, 7, 6, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.98, 1.95, 1.9, 1.85, 1.8, 1.75, 1.7, 1.65, 1.6, 1.55, 1.50, 1.45, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.85, 0.8, 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, 0.05, 0.01, 0.005, 0.001, 0.0005, or 0.0001 x 10-8M, or less, as measured by ELISA or any other suitable method known in the art . In some embodiments, the antibody, or an antigen binding fragment thereof, provided herein binds OX40L with a KD between 5-3, 4-2, 3-1, 1.9-1.8, 1.8-1.7, 1.7-1.6, 1.6-1.5, 1.9-1.5, 1.5-1, 1-0.8, 1-0.5, 0.9-0.6, 0.7-0.4, 0.6-0.2, 0.5-0.3, 0.3-0.2, 0.2-0.1, 0.1-0.01, 0.01-0.001, or 0.001-0.0001 x 10-8M as measured by ELISA or any other suitable method known in the art.

[0415] In some embodiments, the antibody, or an antigen binding fragment thereof, provided herein binds FcRn with an affinity at pH 7.4 compared to pH 6.0 at a ratio (pH 7.4 / pH 6.0) of about 10,000, 1,000, 500, 100, 50, 20, 10, 9, 8, 7, 6, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.95, 1.9, 1.85, 1.8, 1.75, 1.7, 1.65, 1.6, 1.55, 1.50, 1.45, 1.4, 1.3, 1.2, 1.1, or 1.05, as measured by ELISA or any other suitable method known in the art. In some embodiments, the antibody, or an antigen binding fragment thereof, provided herein binds FcRn with an affinity at pH 6.0 compared to pH 7.4 at a ratio (pH 6.0 / pH 7.4) of about 1-0.8, 1-0.5, 0.9-0.6, 0.7-0.4, 0.6-0.2, 0.5-0.3, 0.3-0.2, 0.2-0.1, 0.1-0.01, 0.01-0.001, or 0.001-0.0001 x 10-8M as measured by ELISA or any other suitable method known in the art.Function

[0416] “Effector functions” refer to those biological activities mediated by the Fc region of an antibody, which activities may vary depending on the antibody isotype. Examples of antibody effector functions include receptor ligand blocking, agonism, or antagonism, C1q binding to activate complement dependent cytotoxicity (CDC), Fc receptor binding to activate antibody-dependent cellular cytotoxicity (ADCC), and antibody dependent cellular phagocytosis (ADCP). Anti-IL-4Rα Antibodies

[0417] The present application provides antibodies, or antigen binding fragments thereof, and compositions comprising an antibody, or an antigen binding fragment thereof, which binds IL-4Rα. See also PCT Application No. PCT / US2024 / 016235 (corresponding to 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 therein.

[0418] In some embodiments, an anti-IL-4Rα antibody, or an antigen binding fragment thereof, described herein is selected from dupilumab, stapokibart, and 611. In some embodiments, dupilumab comprises a variable heavy (VH) chain sequence having the amino acid sequence of SEQ ID NO: 113 and a variable light (VL) chain sequence having the amino acid sequence of SEQ ID NO: 146. In some embodiments, dupilumab comprises a heavy chain having the amino acid sequence of SEQ ID NO: 147 and a light chain sequence having the amino acid sequence of SEQ ID NO: 148. In some embodiments, stapokibart comprises a heavy chain having the amino acid sequence of SEQ ID NO: 1074 and a light chain sequence having the amino acid sequence of SEQ ID NO: 1075, or a VH and / or VL therein (e.g., a VH having the sequence of SEQ ID NO: 844 and a VL having the sequence of SEQ ID NO: 845).

[0419] 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 sca...

Claims

CLAIMS 1. An isolated antibody, or an antigen binding fragment thereof, that binds OX40L, comprising: a) a variable heavy (VH) chain sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and b) a variable light (VL) chain sequence having three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; wherein the antibody, or an antigen binding fragment thereof, that binds OX40L comprises: (i) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 2-4; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 5-7; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 8-10; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-14; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 15-16; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 17-18; (ii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 20-22; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-25; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 26-28; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 30-32; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 33-34; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 35-36; (iii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 38-40; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 41-43; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 44-46; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 48-50; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 51-52; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 53-54; or (iv) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 56-58; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 59-61; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 62-64; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 66-68; a CDR-L2 comprising the amino acid sequence set forth inany one of SEQ ID NOs: 69-70; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 71-72; and an isolated antibody, or an antigen binding fragment thereof, that binds IL-4Rα.

2. The isolated antibodies of claim 1, wherein the isolated antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR- L2, and CDR-L3 of an antibody selected from dupilumab, stapokibart, and 611.

3. The isolated antibodies of claim 1, wherein the isolated antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: a) a VH chain sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and b) a VL chain sequence having three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein the isolated antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: (i) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 276, 277, and 278; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 285 and 286; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 292 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293; (ii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 283 and 284; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 287 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 291 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293; or (iii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 289 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

4. An isolated antibody that binds OX40L, or an antigen binding fragment thereof; and an isolated antibody that binds IL-4Rα, or an antigen binding fragment thereof, comprising: a) a variable heavy (VH) chain sequence having three heavy chain CDR sequences, CDR-H1, CDR- H2, and CDR-H3; and b) a variable light (VL) chain sequence having three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; wherein the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: (i) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 276, 277, and 278; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 285 and 286; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 292 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293; (ii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 283 and 284; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 287 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 291 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293; or (iii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 289 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

5. The isolated antibodies of claim 4, wherein the isolated antibody, or antigen binding fragment thereof, that binds OX40L comprises a CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR- L2, and CDR-L3 of an antibody selected from amlitelimab and oxelumab.

6. The isolated antibodies of claim 4, wherein the isolated antibody, or antigen binding fragment thereof, that binds OX40L comprises: a) a VH chain sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and b) a VL chain sequence having three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein the isolated antibody, or antigen binding fragment thereof, that binds OX40L comprises: (i) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 2-4; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 5-7; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 8-10; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-14; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 15-16; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 17-18; (i) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 20-22; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-25; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 26-28; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 30-32; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 33-34; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 35-36; (iii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 38-40; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 41-43; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 44-46; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 48-50; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 51-52; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 53-54; or (iv) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 56-58; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 59-61; a CDR-H3 comprising the amino acid sequence set forth in any oneof SEQ ID NOs: 62-64; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 66-68; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 69-70; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 71-72.

7. The isolated antibodies of claim 3 or 6, wherein: (a) the antibody, or antigen binding fragment thereof, that binds OX40L comprises: (i) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 2-4; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 5-7; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 8-10; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-14; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 15-16; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 17-18; and (b) the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: (i) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 276, 277, and 278; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 285 and 286; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 292 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

8. The isolated antibodies of claim 3 or 6, wherein: (a) the antibody, or antigen binding fragment thereof, that binds OX40L comprises: (ii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 20-22; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-25; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 26-28; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 30-32; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 33-34; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 35-36; and (b) the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises:(i) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 276, 277, and 278; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 285 and 286; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 292 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

9. The isolated antibodies of claim 3 or 6, wherein: (a) the antibody, or antigen binding fragment thereof, that binds OX40L comprises: (iii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 38-40; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 41-43; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 44-46; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 48-50; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 51-52; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 53-54; and (b) the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: (i) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 276, 277, and 278; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 285 and 286; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 292 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

10. The isolated antibodies of claim 3 or 6, wherein: (a) the antibody, or antigen binding fragment thereof, that binds OX40L comprises: (iv) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 56-58; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 59-61; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 62-64; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 66-68; a CDR-L2 comprising the amino acid sequence set forth inany one of SEQ ID NOs: 69-70; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 71-72; and (b) the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: (i) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 276, 277, and 278; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 285 and 286; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 292 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

11. The isolated antibodies of claim 3 or 6, wherein: (a) the antibody, or antigen binding fragment thereof, that binds OX40L comprises: (i) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 2-4; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 5-7; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 8-10; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-14; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 15-16; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 17-18; and (b) the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: (ii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 283 and 284; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 287 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 291 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

12. The isolated antibodies of claim 3 or 6, wherein: (a) the antibody, or antigen binding fragment thereof, that binds OX40L comprises: (ii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 20-22; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-25; a CDR-H3 comprising the amino acid sequence set forth in any oneof SEQ ID NOs: 26-28; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 30-32; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 33-34; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 35-36; and (b) the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: (ii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 283 and 284; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 287 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 291 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

13. The isolated antibodies of claim 3 or 6, wherein: (a) the antibody, or antigen binding fragment thereof, that binds OX40L comprises: (iii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 38-40; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 41-43; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 44-46; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 48-50; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 51-52; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 53-54; and (b) the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: (ii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 283 and 284; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 287 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 291 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

14. The isolated antibodies of claim 3 or 6, wherein: (a) the antibody, or antigen binding fragment thereof, that binds OX40L comprises:(iv) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 56-58; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 59-61; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 62-64; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 66-68; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 69-70; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 71-72; and (b) the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: (ii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 283 and 284; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 287 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 291 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

15. The isolated antibodies of claim 3 or 6, wherein: (a) the antibody, or antigen binding fragment thereof, that binds OX40L comprises: (i) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 2-4; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 5-7; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 8-10; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-14; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 15-16; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 17-18; and (b) the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: (iii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 289 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

16. The isolated antibodies of claim 3 or 6, wherein: (a) the antibody, or antigen binding fragment thereof, that binds OX40L comprises: (ii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 20-22; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-25; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 26-28; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 30-32; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 33-34; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 35-36; and (b) the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: (iii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 289 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

17. The isolated antibodies of claim 3 or 6, wherein: (a) the antibody, or antigen binding fragment thereof, that binds OX40L comprises: (iii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 38-40; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 41-43; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 44-46; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 48-50; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 51-52; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 53-54; and (b) the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: (iii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 289 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

18. The isolated antibodies of claim 3 or 6, wherein: (a) the antibody, or antigen binding fragment thereof, that binds OX40L comprises: (iv) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 56-58; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 59-61; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 62-64; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 66-68; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 69-70; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 71-72; and (b) the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: (iii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 289 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

19. The isolated antibodies of any one of the preceding claims, wherein the antibody, or antigen binding fragment thereof, that binds OX40L comprises a heavy chain variable domain (VH) sequence comprising the amino acid sequence set forth in any one of SEQ ID NOs: 1, 19, 37, and 55.

20. The isolated antibodies of any one of the preceding claims, wherein the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in any one of SEQ ID NOs: 295-297.

21. The isolated antibodies of any one of the preceding claims, wherein the antibody, or antigen binding fragment thereof, that binds OX40L comprises a light chain variable domain (VL) sequence comprising the amino acid sequence set forth in any one of SEQ ID NOs: 11, 29, 47, and 65.

22. The isolated antibodies of any one of the preceding claims, wherein the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VL sequence comprising the amino acid sequence set forth in any one of SEQ ID NOs: 298-300.

23. The isolated antibodies of any one of claims 19-22, wherein: (a) the antibody, or antigen binding fragment thereof, that binds OX40L comprises: (i) a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 1; (ii) a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 19; (iii) a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 37; or (iv) a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 55; and / or (v) a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 11; (vi) a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 29; (vii) a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 47; or (viii) a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 65; and / or (b) the antibody that binds IL-4Rα comprises: (i) a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 295; (ii) a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 296; or (iii) a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 297; and / or (iv) a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 298;(v) a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:299; or (vi) a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

300.

24. The isolated antibodies of claim 23, wherein the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 1; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

11.

25. The isolated antibodies of claim 23, wherein the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 19; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

29.

26. The isolated antibodies of claim 23, wherein the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 37; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

47.

27. The isolated antibodies of claim 23, wherein the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 55; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

65.

28. The isolated antibodies of claim 23, wherein the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 295; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

298.

29. The isolated antibodies of claim 23, wherein the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence setforth in SEQ ID NO: 296; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

299.

30. The isolated antibodies of claim 23, wherein the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 297; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

300.

31. The isolated antibodies of claim 23, wherein the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 1; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 11; and wherein the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 295; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

298.

32. The isolated antibodies of claim 23, wherein the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 1; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 11; and wherein the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 296; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

299.

33. The isolated antibodies of claim 23, wherein the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 1; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 11; and wherein the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 297; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

300.

34. The isolated antibodies of claim 23, wherein the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 19; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 29; and wherein the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 295; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

298.

35. The isolated antibodies of claim 23, wherein the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 19; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 29; and wherein the antibody, or antigen binding fragment thereof, that binds IL- 4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 296; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

299.

36. The isolated antibodies of claim 23, wherein the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 19; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 29; and wherein the antibody, or antigen binding fragment thereof, that binds IL- 4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 297; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

300.

37. The isolated antibodies of claim 23, wherein the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 37; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 47; and wherein the antibody, or antigen binding fragment thereof, that binds IL- 4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 295; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

298.

38. The isolated antibodies of claim 23, wherein the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 37; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 47; and wherein the antibody, or antigen binding fragment thereof, that binds IL- 4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 296; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

299.

39. The isolated antibodies of claim 23, wherein the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 37; and a VL sequence comprising the amino acid sequence set forth inSEQ ID NO: 47; and wherein the antibody, or antigen binding fragment thereof, that binds IL- 4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 297; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

300.

40. The isolated antibodies of claim 23, wherein the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 55; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 65; and wherein the antibody, or antigen binding fragment thereof, that binds IL- 4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 295; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

298.

41. The isolated antibodies of claim 23, wherein the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 55; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 65; and wherein the antibody, or antigen binding fragment thereof, that binds IL- 4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 296; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

299.

42. The isolated antibodies of claim 23, wherein the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 55; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 65; and wherein the antibody, or antigen binding fragment thereof, that binds IL- 4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 297; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

300.

43. The isolated antibodies of any one of the preceding claims, wherein the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα is a humanized, human, or chimeric antibody.

44. The isolated antibodies of any one of the preceding claims, wherein the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα is a humanized antibody.

45. The isolated antibodies of any one of the preceding claims, wherein the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a heavy chain human constant region of a class selected from IgG, IgA, IgD, IgE, and IgM.

46. The isolated antibodies of any one of the preceding claims, wherein the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a human Fc region, and wherein the human Fc region comprises a human heavy chain constant region of the class IgG and a subclass selected from IgG1, IgG2, IgG3, and IgG4.

47. The isolated antibodies of claim 46, wherein the human Fc region of the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a human IgG1 Fc region.

48. The isolated antibodies of claim 46, wherein the human Fc region of the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a human IgG4 Fc region.

49. The isolated antibodies of claim 46, wherein the human Fc region of the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a human IgG2 Fc region.

50. The isolated antibodies of any one of the preceding claims, wherein the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a heavy chain comprising a constant heavy chain sequence selected from the amino acid sequences set forth in any one of SEQ ID NOs: 637-737 and 847-1070.

51. The isolated antibodies of any one of the preceding claims, wherein the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a light chain comprising a constant light chain sequence selected from the sequences set forth in SEQ ID NOs: 738 and 1071.

52. The isolated antibodies of any one of the preceding claims, wherein the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises an Fc region comprising one or more amino acid substitutions, wherein the one or more substitutions result in an increase in one or more of antibody half-life, ADCC activity, ADCP activity, or CDC activity compared with the Fc without the one or more substitutions.

53. The isolated antibodies of any one of the preceding claims, wherein the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises an Fc region comprising one or more amino acid substitutions, wherein the one or more substitutions result in a decrease in one or more of, ADCC activity, ADCP activity or CDC activity compared to an antibody comprising a wild-type Fc region.

54. The isolated antibodies of claim 52 or 53, wherein 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 / 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.

55. The isolated antibodies of any one of the preceding claims, wherein the antibody, or antigen binding fragment thereof, that binds OX40L comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 1, a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 11, a constant heavy chain sequence set forth in any one of SEQ ID NOs: 651 and 973, and a constant light chain sequence set forth in SEQ ID NO:

738.

56. The isolated antibodies of any one of the preceding claims, wherein the antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 297, a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 300, a constant heavy chain sequence set forth in any one of SEQ ID NOs: 651 and 973, and a constant light chain sequence set forth in SEQ ID NO:

738.

57. The isolated antibodies of any one of the preceding claims, wherein the Fc region of the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα binds to Neonatal Fc receptor (FcRn).

58. The isolated antibodies of claim 57, wherein the Fc region of the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα binds an FcRn with higher affinity at pH 6.0 compared to an antibody comprising a wild-type Fc region.

59. The isolated antibodies of claim 57 or 58, wherein the Fc region of the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα binds to FcRn with a KD of <1 x 10-7M at pH 6.

0.

60. The isolated antibodies of any one of the preceding claims, wherein the antibody, or antigen binding fragment thereof, that binds OX40L and / or the antibody, or antigen binding fragment thereof, that binds IL-4Rα is a monoclonal antibody.

61. The isolated antibodies of any one of the preceding claims, wherein the antibody, or antigen binding fragment thereof, that binds OX40L binds an OX40L sequence set forth in the amino acid sequence of SEQ ID NO:

739.

62. The isolated antibodies of any one of the preceding claims, wherein the antibody, or antigen binding fragment thereof, that binds IL-4Rα binds an IL-4Rα sequence set forth in any one of the amino acid sequences of SEQ ID NOs: 301-303.

63. The isolated antibodies of any one of the preceding claims for use in the treatment of an inflammatory disorder or disease.

64. The isolated antibodies of claim 63 for use in the treatment of atopic dermatitis (AD).

65. The isolated antibodies of claim 64, wherein the treatment reduces disease severity in a patient and wherein disease severity is assessed by an atopic dermatitis disease severity outcome measure.

66. The isolated antibodies of claim 63, for use in the treatment of asthma; chronic sinusitis with nasal polyps; Chronic Rhinosinusitis without Nasal Polyps (CRSsNP); eosinophilic esophagitis (EoE); 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); 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); Crohn’s disease; lupus; rheumatoid arthritis (RA); psoriasis; ulcerative colitis; hidradenitis suppurativa; celiac disease; systemic sclerosis; idiopathic pulmonary fibrosis; alopecia areata, allergic rhinitis; eosinophilic fasciitis; scleromyxedema; scleredema; or nephrogenic systemic fibrosis.

67. A multi-specific antibody comprising: a first antigen binding region that binds OX40L and comprises: a) a variable heavy (VH) chain sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3;and b) a variable light (VL) chain sequence having three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; wherein the antigen binding region that binds OX40L comprises: (i) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 2-4; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 5-7; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 8-10; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-14; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 15-16; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 17-18; (ii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 20-22; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-25; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 26-28; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 30-32; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 33-34; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 35-36; (iii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 38-40; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NO: s 41-43; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 44-46; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NO: s 48-50; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 51-52; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 53-54; or (iv) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 56-58; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 59-61; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 62-64; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 66-68; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 69-70; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 71-72; and a second antigen binding region that binds IL-4Rα.

68. The multi-specific antibody of claim 67, wherein the antigen binding region that binds IL- 4Rα comprises a CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of an antibody selected from dupilumab, stapokibart, and 611.

69. The multi-specific antibody of claim 67, wherein the antigen binding region that binds IL- 4Rα comprises: a) a VH chain sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and b) a VL chain sequence having three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein the antigen binding region that binds IL-4Rα comprises: (i) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 276, 277, and 278; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 285 and 286; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 292 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293; (ii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 283 and 284; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 287 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 291 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293; or (iii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 289 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

70. A multi-specific antibody comprising: a first antigen binding region that binds OX40L; anda second antigen binding region that binds IL-4Rα and comprises: a) a variable heavy (VH) chain sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR- H3; and b) a variable light (VL) chain sequence having three light chain CDR sequences, CDR- L1, CDR-L2, and CDR-L3; wherein the antigen binding region that binds IL-4Rα comprises: (i) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 276, 277, and 278; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 285 and 286; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 292 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293; (ii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 283 and 284; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 287 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 291 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293; or (iii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 289 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

71. The multi-specific antibody of claim 70, wherein the antigen binding region that binds OX40L comprises a CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of an antibody selected from amlitelimab and oxelumab.

72. The multi-specific antibody of claim 70, wherein the antigen binding region that binds OX40L comprises: a) a VH chain sequence having three heavy chain CDR sequences, CDR-H1,CDR-H2, and CDR-H3; and b) a VL chain sequence having three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein the antigen binding region that binds OX40L comprises: (i) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 2-4; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 5-7; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 8-10; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-14; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 15-16; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 17-18; (ii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 20-22; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-25; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 26-28; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 30-32; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 33-34; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 35-36; (iii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 38-40; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 41-43; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 44-46; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NO: s 48-50; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 51-52; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 53-54; or (iv) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 56-58; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 59-61; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 62-64; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 66-68; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NO: 69-70s; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 71-72.

73. The multi-specific antibody of claim 69 or 72, wherein: (a) the antigen binding region that binds OX40L comprises:(i) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 2-4; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 5-7; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 8-10; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-14; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 15-16; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 17-18; and (b) the antigen binding region that binds IL-4Rα comprises: (i) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 276, 277, and 278; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 285 and 286; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 292 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

74. The multi-specific antibody of claim 69 or 72, wherein: (a) the antigen binding region that binds OX40L comprises: (ii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 20-22; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-25; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 26-28; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 30-32; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 33-34; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 35-36; and (b) the antigen binding region that binds IL-4Rα comprises: (i) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 276, 277, and 278; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 285 and 286; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 292 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

75. The multi-specific antibody of claim v, wherein: (a) the antigen binding region that binds OX40L comprises: (iii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 38-40; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 41-43; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 44-46; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 48-50; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 51-52; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 53-54; and (b) the antigen binding region that binds IL-4Rα comprises: (i) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 276, 277, and 278; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 285 and 286; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 292 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

76. The multi-specific antibody of claim 69 or 72, wherein: (a) the antigen binding region that binds OX40L comprises: (iv) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 56-58; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 59-61; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 62-64; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 66-68; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 69-70; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 71-72; and (b) the antigen binding region that binds IL-4Rα comprises: (i) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 276, 277, and 278; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 285 and 286; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 292 orthe amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

77. The multi-specific antibody of claim 69 or 72, wherein: (a) the antigen binding region that binds OX40L comprises: (i) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 2-4; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 5-7; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 8-10; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-14; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 15-16; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 17-18; and (b) the antigen binding region that binds IL-4Rα comprises: (ii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 283 and 284; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 287 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 291 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

78. The multi-specific antibody of claim 69 or 72, wherein: (a) the antigen binding region that binds OX40L comprises: (ii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 20-22; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-25; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 26-28; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 30-32; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 33-34; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 35-36; and (b) the antigen binding region that binds IL-4Rα comprises: (ii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ IDNOs: 283 and 284; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 287 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 291 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

79. The multi-specific antibody of claim 69 or 72, wherein: (a) the antigen binding region that binds OX40L comprises: (iii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 38-40; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 41-43; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 44-46; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 48-50; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 51-52; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 53-54; and (b) the antigen binding region that binds IL-4Rα comprises: (ii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 283 and 284; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 287 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 291 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

80. The multi-specific antibody of claim 69 or 72, wherein: (a) the antigen binding region that binds OX40L comprises: (iv) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 56-58; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 59-61; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 62-64; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 66-68; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 69-70; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 71-72; and (b) the antigen binding region that binds IL-4Rα comprises:(ii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 283 and 284; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 287 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 291 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

81. The multi-specific antibody of claim 69 or 72, wherein: (a) the antigen binding region that binds OX40L comprises: (i) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 2-4; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 5-7; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 8-10; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-14; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 15-16; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 17-18; and (b) the antigen binding region that binds IL-4Rα comprises: (iii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 289 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

82. The multi-specific antibody of claim 69 or 72, wherein: (a) the antigen binding region that binds OX40L comprises: (ii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 20-22; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-25; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 26-28; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 30-32; a CDR-L2 comprising the amino acid sequence set forth inany one of SEQ ID NOs: 33-34; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 35-36; and (b) the antigen binding region that binds IL-4Rα comprises: (iii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 289 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

83. The multi-specific antibody of claim 69 or 72, wherein: (a) the antigen binding region that binds OX40L comprises: (iii) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 38-40; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 41-43; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 44-46; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 48-50; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 51-52; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 53-54; and (b) the antigen binding region that binds IL-4Rα comprises: (iii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 289 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

84. The multi-specific antibody of claim 69 or 72, wherein: (a) the antigen binding region that binds OX40L comprises: (iv) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 56-58; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 59-61; a CDR-H3 comprising the amino acid sequence set forth in any oneof SEQ ID NOs: 62-64; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 66-68; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 69-70; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 71-72; and (b) the antigen binding region that binds IL-4Rα comprises: (iii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 289 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

85. The multi-specific antibody of any one of claims 67-84, wherein the antigen binding region that binds OX40L comprises a heavy chain variable domain (VH) sequence comprising the amino acid sequence set forth in any one of SEQ ID NOs: 1, 19, 37, and 55.

86. The multi-specific antibody of any one of claims 67-85, wherein the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in any one of SEQ ID NOs: 295-297.

87. The multi-specific antibody of any one of claims 67-86, wherein the antigen binding region that binds OX40L comprises a light chain variable domain (VL) sequence comprising the amino acid sequence set forth in any one of SEQ ID NOs: 11, 29, 47, and 65.

88. The multi-specific antibody of any one of claims 67-87, wherein the antigen binding region that binds IL-4Rα comprises a VL sequence comprising the amino acid sequence set forth in any one of SEQ ID NOs: 298-300.

89. The multi-specific antibody of any one of claims 85-88, wherein: (a) the antigen binding region that binds OX40L comprises: (i) a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 1;(ii) a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 19; (iii) a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 37; or (iv) a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 55; and / or (v) a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 11; (vi) a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 29; (vii) a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 47; or (viii) a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 65; and / or (b) the antigen binding region that binds IL-4Rα comprises: (i) a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 295; (ii) a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 296; or (iii) a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 297; and / or (iv) a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 298; (v) a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:299; or (vi) a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

300.

90. The multi-specific antibody of claim 89, wherein the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 1; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 11.

91. The multi-specific antibody of claim 89, wherein the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 19; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

29.

92. The multi-specific antibody of claim 89, wherein the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 37; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

47.

93. The multi-specific antibody of claim 89, wherein the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 55; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

65.

94. The multi-specific antibody of claim 89, wherein the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 295; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

298.

95. The multi-specific antibody of claim 89, wherein the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 296; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

299.

96. The multi-specific antibody of claim 89, wherein the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 297; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

300.

97. The multi-specific antibody of claim 89, wherein the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 1; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 11; and wherein the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 295; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

298.

98. The multi-specific antibody of claim 89, wherein the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 1; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 11; andwherein the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 296; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

299.

99. The multi-specific antibody of claim 89, wherein the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 1; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 11; and wherein the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 297; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

300.

100. The multi-specific antibody of claim 89, wherein the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 19; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 29; and wherein the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 295; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

298.

101. The multi-specific antibody of claim 89, wherein the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 19; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 29; and wherein the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 296; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

299.

102. The multi-specific antibody of claim 89, wherein the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 19; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 29; and wherein the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 297; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

300.

103. The multi-specific antibody of claim 89, wherein the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO:37; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 47; and wherein the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 295; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

298.

104. The multi-specific antibody of claim 89, wherein the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 37; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 47; and wherein the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 296; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

299.

105. The multi-specific antibody of claim 89, wherein the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 37; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 47; and wherein the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 297; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

300.

106. The multi-specific antibody of claim 89, wherein the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 55; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 65; and wherein the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 295; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

298.

107. The multi-specific antibody of claim 89, wherein the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 55; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 65; and wherein the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 296; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 299.

108. The multi-specific antibody of claim 89, wherein the antigen binding region that binds OX40L comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 55; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO: 65; and wherein the antigen binding region that binds IL-4Rα comprises a VH sequence comprising the amino acid sequence set forth in SEQ ID NO: 297; and a VL sequence comprising the amino acid sequence set forth in SEQ ID NO:

300.

109. The multi-specific antibody of any one of claims 67-108, wherein the antigen binding region that binds OX40L and / or the antigen binding region that binds IL-4Rα is humanized, human, or chimeric.

110. The multi-specific antibody of any one of claims 67-109, wherein the antigen binding region that binds OX40L and / or the antigen binding region that binds IL-4Rα is humanized.

111. The multi-specific antibody of any one of claims 67-110, wherein the multi-specific antibody comprises a heavy chain human constant region of a class selected from IgG, IgA, IgD, IgE, and IgM.

112. The multi-specific antibody of any one of claims 67-111, wherein the multi-specific antibody comprises a human Fc region, and wherein the human Fc region comprises a human heavy chain constant region of the class IgG and a subclass selected from IgG1, IgG2, IgG3, and IgG4.

113. The multi-specific antibody of claim 112, wherein the human Fc region comprises a human IgG1 Fc region.

114. The multi-specific antibody of claim 112, wherein the human Fc region comprises a human IgG4 Fc region.

115. The multi-specific antibody of claim 112, wherein the human Fc region comprises a human IgG2 Fc region.

116. The multi-specific antibody of any one of claims 67-115, wherein the multi-specific antibody comprises a heavy chain comprising a constant heavy chain sequence selected from the amino acid sequences set forth in any one of SEQ ID NOs: 637-737 and 847-1070.

117. The multi-specific antibody of any one of claims 67-116, wherein the multi-specific antibody comprises a light chain comprising a constant light chain sequence selected from the sequences set forth in SEQ ID NOs: 738 and 1071.

118. The multi-specific antibody of any one of claims 67-117, wherein the multi-specific antibody comprises an Fc region comprising one or more amino acid substitutions, wherein the one or more substitutions result in an increase in one or more of antibody half-life, ADCC activity, ADCP activity, or CDC activity compared with the Fc without the one or more substitutions.

119. The multi-specific antibody of any one of claims 67-118, wherein the multi-specific antibody comprises an Fc region comprising one or more amino acid substitutions, wherein the one or more substitutions result in a decrease in one or more of, ADCC activity, ADCP activity or CDC activity compared to an antibody comprising a wild-type Fc region.

120. The multi-specific antibody of claim 118 or 119, wherein 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 / 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.

121. The multi-specific antibody of any one of claims 67-120, wherein the antigen binding region that binds OX40L comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 1, a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 11, a constant heavy chain sequence set forth in any one of SEQ ID NOs: 651 and 973, and a constant light chain sequence set forth in SEQ ID NO:

738.

122. The multi-specific antibody of any one of claims 67-121, wherein the antigen binding region that binds IL-4Rα comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 297, a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 300, a constant heavy chain sequence set forth in any one of SEQ ID NOs: 651 and 973, and a constant light chain sequence set forth in SEQ ID NO:

738.

123. The multi-specific antibody of any one of claims 67-122, wherein the Fc region binds to Neonatal Fc receptor (FcRn).

124. The multi-specific antibody of claim 123, wherein the Fc region binds an FcRn with higher affinity at pH 6.0 compared to an antibody comprising a wild-type Fc region.

125. The multi-specific antibody of claim 123 or 124, wherein the Fc region binds IL-4Rα binds to FcRn with a KD of <1 x 10-7M at pH 6.

0.

126. The multi-specific antibody of any one of claims 67-125, wherein the antigen binding region that binds OX40L and / or the antigen binding region that binds IL-4Rα is a monoclonal antigen binding region.

127. The multi-specific antibody of any one of claims 67-126, wherein the antigen binding region that binds OX40L binds an OX40L sequence set forth in the amino acid sequence of SEQ ID NO:

739.

128. The multi-specific antibody of any one of claims 67-127, wherein the antigen binding region that binds IL-4Rα binds an IL-4Rα sequence set forth in any one of the amino acid sequences of SEQ ID NOs: 301-303.

129. The multi-specific antibody of any one of claims 67-128 for use in the treatment of an inflammatory disorder or disease.

130. The multi-specific antibody of claim 129 for use in the treatment of atopic dermatitis (AD).

131. The multi-specific antibody of claim 130, wherein the treatment reduces disease severity in a patient and wherein disease severity is assessed by an atopic dermatitis disease severity outcome measure.

132. The multi-specific antibody of claim 129, , for use in the treatment of asthma; chronic sinusitis with nasal polyps; Chronic Rhinosinusitis without Nasal Polyps (CRSsNP); eosinophilic esophagitis (EoE); 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); 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); Crohn’s disease; lupus; rheumatoid arthritis (RA); psoriasis; ulcerative colitis; hidradenitis suppurativa; celiac disease; systemic sclerosis; idiopathic pulmonary fibrosis; alopecia areata, allergic rhinitis; eosinophilic fasciitis; scleromyxedema; scleredema; or nephrogenic systemic fibrosis.

133. An isolated polynucleotide or set of polynucleotides encoding the isolated antibodies or multi-specific antibodies of any one of the preceding claims, a VH thereof, a VL thereof, a lightchain thereof, a heavy chain thereof, or an antigen-binding portion thereof, optionally, wherein the polynucleotide or set of polynucleotides comprises cDNA.

134. A vector or set of vectors comprising the polynucleotide or set of polynucleotides of claim 133.

135. A host cell comprising the polynucleotide or set of polynucleotides of claim 133 or the vector or set of vectors of claim 134.

136. A method of producing one or more of the isolated antibodies or multi-specific antibodies of any one of the preceding claims, the method comprising expressing one or more of the isolated antibodies or multi-specific antibodies within the host cell of claim 135 and isolating the one or more expressed antibodies.

137. A pharmaceutical composition comprising the isolated antibodies or multi-specific antibodies of any one of claims 1-62 and 67-128 and a pharmaceutically acceptable excipient.

138. A kit comprising the isolated antibodies or multi-specific antibodies of any one of claims 1-62 and 67-128 or the pharmaceutical composition of claim 137 and instructions for use.

139. A method for treating an inflammatory disorder or disease in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of the isolated antibodies or multi-specific antibodies of any one of claims 1-62 and 67-128; a therapeutically effective amount of the pharmaceutical composition of claim 137; or a therapeutically effective amount of a pharmaceutical composition comprising an isolated antibody, or antigen binding fragment thereof, that binds OX40L and a pharmaceutically acceptable excipient and a therapeutically effective amount of a pharmaceutical composition comprising an antibody, or antigen binding fragment thereof, that binds IL-4Rα and a pharmaceutically acceptable excipient137.

140. The method of claim 139, wherein the mammalian subject is a human.

141. The method of claim 139 or 140, wherein the inflammatory disorder or disease is atopic dermatitis.

142. The method of claim 139 or 140, wherein the inflammatory disorder or disease is asthma.

143. The method of claim 139 or 140, wherein the inflammatory disorder or disease is chronic sinusitis with nasal polyps; Chronic Rhinosinusitis without Nasal Polyps (CRSsNP); eosinophilic esophagitis (EoE); an Eosinophilic gastrointestinal disorder or disease (EGID) selected from the group consisting of Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), Eosinophilic Colitis (EoC), and Eosinophilic Gastroenteritis (EGE); Churg-Strauss syndrome / Eosinophilic granulomatosis with polyangiitis (EGPA); Prurigo Nodularis (PN); 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); celiac disease; Crohn’s disease; lupus; rheumatoid arthritis (RA); psoriasis; ulcerative colitis; hidradenitis suppurativa; systemic sclerosis; idiopathic pulmonary fibrosis; alopecia areata, allergic rhinitis; eosinophilic fasciitis; scleromyxedema; scleredema; or nephrogenic systemic fibrosis.

144. A method for treating a pathology associated with elevated levels of OX40L and / or IL-4 in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount the isolated antibodies or multi-specific antibodies of any one of claims 1-62 and 67-128; the pharmaceutical composition of claim 137; or a therapeutically effective amount of a pharmaceutical composition comprising an isolated antibody, or antigen binding fragment thereof, that binds OX40L and a pharmaceutically acceptable excipient and a therapeutically effective amount of a pharmaceutical composition comprising an antibody, or antigen binding fragment thereof, that binds IL-4Rα and a pharmaceutically acceptable excipient.

145. A method of reducing biological activity of OX40L and / or IL-4Rα in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount the isolated antibodies or multi-specific antibodies of any one of claims 1-62 and 67-128; the pharmaceutical composition of claim 137; or a therapeutically effective amount of a pharmaceutical composition comprising an isolated antibody, or antigen binding fragment thereof, that binds OX40L and a pharmaceutically acceptable excipient and a therapeutically effective amount of a pharmaceutical composition comprising an antibody, orantigen binding fragment thereof, that binds IL-4Rα and a pharmaceutically acceptable excipient.

146. The method of any one of claims 139-127, wherein the mammalian subject is a human.

147. A pharmaceutical composition comprising: an isolated antibody, or antigen binding fragment thereof, that binds OX40L comprising a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 1, a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 11, a constant heavy chain sequence set forth in any one of SEQ ID NOs: 651 and 973, and a constant light chain sequence set forth in SEQ ID NO: 738; an isolated antibody, or antigen binding fragment thereof, that binds IL-4Rα comprising a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 297, a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 300, a constant heavy chain sequence set forth in any one of SEQ ID NOs: 651 and 973, and a constant light chain sequence set forth in SEQ ID NO: 738; and a pharmaceutically acceptable excipient.

148. A pharmaceutical composition comprising: a multi-specific antibody comprising: an antigen binding region that binds OX40L comprising a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 1, a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 11, a constant heavy chain sequence set forth in any one of SEQ ID NOs: 651 and 973, and a constant light chain sequence set forth in SEQ ID NO: 738; an antigen binding region that binds IL-4Rα comprising a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 297, a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 300, a constant heavy chain sequence set forth in any one of SEQ ID NOs: 651 and 973, and a constant light chain sequence set forth in SEQ ID NO: 738; and a pharmaceutically acceptable excipient.

149. A composition comprising an isolated antibody, or antigen binding region thereof, that binds OX40L, an isolated antibody, or antigen binding region thereof, that binds Interleukin-4 Receptor Alpha (IL-4Rα), and a hyaluronidase or variant thereof.

150. A composition comprising an isolated antibody, or antigen binding region thereof, that binds OX40L, an isolated antibody, or antigen binding region thereof, that binds Interleukin-4 Receptor Alpha (IL-4Rα), and a hyaluronidase or variant thereof, wherein the antibody, or antigen binding region thereof, that binds OX40L 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: 5; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 8; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 12; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 15; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

17.

151. A composition comprising an isolated antibody, or antigen binding region thereof, that binds OX40L, an isolated antibody, or antigen binding region thereof, that binds Interleukin-4 Receptor Alpha (IL-4Rα), and a hyaluronidase or variant thereof, wherein the antibody, or antigen binding region thereof, that binds OX40L comprises a VH sequence set forth in SEQ ID NO: 1 and a VL sequence set forth in SEQ ID NO:

11.

152. A composition comprising an isolated antibody, or antigen binding region thereof, that binds OX40L, an isolated antibody, or antigen binding region thereof, that binds Interleukin-4 Receptor Alpha (IL-4Rα), and a hyaluronidase or variant thereof, wherein the antibody, or antigen binding region thereof, that binds IL-4Rα comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 273; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 279; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 281; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 289; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

153. A composition comprising an isolated antibody, or antigen binding region thereof, that binds OX40L, an isolated antibody, or antigen binding region thereof, that binds Interleukin-4 Receptor Alpha (IL-4Rα), and a hyaluronidase or variant thereof, wherein the antibody, or antigen binding region thereof, that binds IL-4Rα comprises a VH sequence set forth in SEQ ID NO: 297 and a VL sequence set forth in SEQ ID NO:

300.

154. A composition comprising an isolated antibody, or antigen binding region thereof, that binds OX40L, an isolated antibody, or antigen binding region thereof, that binds Interleukin-4 Receptor Alpha (IL-4Rα), and a hyaluronidase or variant thereof,wherein the antibody, or antigen binding region thereof, that binds OX40L 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: 5; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 8; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 12; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 15; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 17, and wherein the antibody, or antigen binding region thereof, that binds IL-4Rα comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 273; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 279; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 281; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 289; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

155. A composition comprising an isolated antibody, or antigen binding region thereof, that binds OX40L, an isolated antibody, or antigen binding region thereof, that binds IL-4Rα, and a hyaluronidase or variant thereof, wherein the antibody, or antigen binding region thereof, that binds OX40L comprises a VH sequence set forth in SEQ ID NO: 1 and a VL sequence set forth in SEQ ID NO: 11; and wherein the antibody, or antigen binding region thereof, that binds IL-4Rα comprises a VH sequence set forth in SEQ ID NO: 297 and a VL sequence set forth in SEQ ID NO:

300.

156. A composition comprising hyaluronidase or variant thereof and a multi-specific antibody comprising a first antigen binding region that binds OX40L and a second antigen binding region that binds IL-4Rα, wherein the antigen binding region that binds OX40L 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: 5; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 8; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 12; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 15; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 17, and wherein the antigen binding region that binds IL-4Rα comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 273; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 279; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 281; a CDR-L1comprising the sequence set forth in SEQ ID NO: 289; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

157. A composition comprising hyaluronidase or variant thereof and a multi-specific antibody comprising a first antigen binding region that binds OX40L and a second antigen binding region that binds IL-4Rα, wherein the antigen binding region that binds OX40L comprises a VH sequence set forth in SEQ ID NO: 1 and a VL sequence set forth in SEQ ID NO: 11; and wherein the antigen binding region that binds IL-4Rα comprises a VH sequence set forth in SEQ ID NO: 297 and a VL sequence set forth in SEQ ID NO:

300.

158. A combination comprising an isolated antibody, or antigen binding region thereof, that binds OX40L, an isolated antibody, or antigen binding region thereof, that binds IL-4Rα, and a hyaluronidase or variant thereof, wherein the antibody, or antigen binding region thereof, that binds OX40L 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: 5; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 8; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 12; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 15; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 17, and wherein the antibody, or antigen binding region thereof, that binds IL-4Rα comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 273; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 279; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 281; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 289; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

159. A combination comprising an isolated antibody, or antigen binding region thereof, that binds OX40L, an isolated antibody, or antigen binding region thereof, that binds IL-4Rα, and a hyaluronidase or variant thereof, wherein the antibody, or antigen binding region thereof, that binds OX40L comprises a VH sequence set forth in SEQ ID NO: 1 and a VL sequence set forth in SEQ ID NO: 11; and wherein the antibody, or antigen binding region thereof, that binds IL-4Rα comprises a VH sequence set forth in SEQ ID NO: 297 and a VL sequence set forth in SEQ ID NO: 300.

160. A combination comprising hyaluronidase or variant thereof and a multi-specific antibody comprising a first antigen binding region that binds OX40L and a second antigen binding region that binds IL-4RΑ, wherein the antigen binding region that binds OX40L 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: 5; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 8; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 12; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 15; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 17, and wherein the antigen binding region that binds IL-4Rα comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 273; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 279; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 281; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 289; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

161. A combination comprising hyaluronidase or variant thereof and a multi-specific antibody comprising a first antigen binding region that binds OX40L and a second antigen binding region that binds IL-4Rα, wherein the antigen binding region that binds OX40L comprises a VH sequence set forth in SEQ ID NO: 1 and a VL sequence set forth in SEQ ID NO: 11; and wherein the antigen binding region that binds IL-4Rα comprises a VH sequence set forth in SEQ ID NO: 297 and a VL sequence set forth in SEQ ID NO:

300.

162. A method of treating an inflammatory disorder or disease in a human patient comprising administering to the patient an isolated antibody, or antigen binding region thereof, that binds OX40L, an isolated antibody, or antigen binding region thereof, that binds IL-4Rα, and a hyaluronidase or variant thereof, wherein the antibody, or antigen binding region thereof, that binds OX40L 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: 5; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 8; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 12; a CDR-L2 comprisingthe sequence set forth in SEQ ID NO: 15; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 17; and wherein the antibody, or antigen binding region thereof, that binds IL-4Rα comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 273; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 279; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 281; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 289; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290; and a CDR-L3 comprising the sequence set forth in SEQ ID NO:

293.

163. A method of treating an inflammatory disorder or disease in a human patient comprising administering to the patient an isolated antibody, or antigen binding region thereof, that binds OX40L, an isolated antibody, or antigen binding region thereof, that binds IL-4Rα, and a hyaluronidase or variant thereof, wherein the antibody, or antigen binding region thereof, that binds OX40L comprises a VH sequence set forth in SEQ ID NO: 1 and a VL sequence set forth in SEQ ID NO: 11; and wherein the antibody, or antigen binding region thereof, that binds IL-4Rα comprises a VH sequence set forth in SEQ ID NO: 297 and a VL sequence set forth in SEQ ID NO:

300.

164. A method of treating an inflammatory disorder or disease in a human patient comprising administering to the patient hyaluronidase or variant thereof and a multi-specific antibody comprising a first antigen binding region that binds OX40L and a second antigen binding region that binds IL-4Rα, wherein the antigen binding region that binds OX40L 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: 5; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 8; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 12; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 15; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 17, and wherein the antigen binding region that binds IL-4Rα comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 273; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 279; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 281; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 289; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293.

165. A method of treating an inflammatory disorder or disease in a human patient comprising administering to the patient hyaluronidase or variant thereof and a multi-specific antibody comprising a first antigen binding region that binds OX40L and a second antigen binding region that binds IL-4Rα, wherein the antigen binding region that binds OX40L comprises a VH sequence set forth in SEQ ID NO: 1 and a VL sequence set forth in SEQ ID NO: 11; and wherein the antigen binding region that binds IL-4Rα comprises a VH sequence set forth in SEQ ID NO: 297 and a VL sequence set forth in SEQ ID NO:

300.

166. The composition of any one of claims 149-157, the combination of any one of claims 158-161, or the method of any one of claims 162-165, wherein the antibody or antigen binding region that binds OX40L and / or the antibody or antigen binding region that binds IL-4Rα is a humanized, human, or chimeric antibody.

167. The composition of any one of claims 149-157, the combination of any one of claims 158-161, or the method of any one of claims 162-165, wherein the antibody or antigen binding region that binds OX40L and / or the antibody or antigen binding region that binds IL-4Rα is a humanized antibody.

168. The composition of any one of claims 149-157, the combination of any one of claims 158-161, or the method of any one of claims 162-165, wherein the antibody or antigen binding region that binds OX40L and / or the antibody or antigen binding region that binds IL-4Rα comprises a heavy chain human constant region of a class selected from IgG, IgA, IgD, IgE, and IgM.

169. The composition of any one of claims 149-157, the combination of any one of claims 158-161, or the method of any one of claims 162-165, wherein the antibody or antigen binding region that binds OX40L and / or the antibody or antigen binding region that binds IL-4Rα comprises a human Fc region, and wherein the human Fc region comprises a human heavy chain constant region of the class IgG and a subclass selected from IgG1, IgG2, IgG3, and IgG4.

170. The composition of any one of claims 149-157, the combination of any one of claims 158-161, or the method of any one of claims 162-165, wherein the antibody or antigen binding region that binds OX40L and / or the antibody or antigen binding region that binds IL-4Rαcomprises a human Fc region, and wherein the human Fc region comprises a human IgG1 Fc region.

171. The composition of any one of claims 149-157, the combination of any one of claims 158-161, or the method of any one of claims 162-165, wherein the antibody or antigen binding region that binds OX40L and / or the antibody or antigen binding region that binds IL-4Rα comprises a human Fc region, and wherein the human Fc region comprises a human IgG4 Fc region.

172. The composition of any one of claims 149-157, the combination of any one of claims 158-161, or the method of any one of claims 162-165, wherein the antibody or antigen binding region that binds OX40L and / or the antibody or antigen binding region that binds IL-4Rα comprises a human Fc region, and wherein the human Fc region comprises a human IgG2 Fc region.

173. The composition of any one of claims 149-157, the combination of any one of claims 158-161, or the method of any one of claims 162-165, wherein the antibody or antigen binding region that binds OX40L and / or the antibody or antigen binding region that binds IL-4Rα comprises a human IgG1 Fc region with LALA and YTE mutations.

174. The composition of any one of claims 149-157, the combination of any one of claims 158-161, or the method of any one of claims 162-165, wherein the antibody or antigen binding region that binds OX40L and / or the antibody or antigen binding region that binds IL-4Rα comprises a human Fc region, and wherein the human Fc region of the antibody or antigen binding region that binds OX40L comprises a human IgG1 Fc with LALA mutations (L235A / L236A by direct numbering) and YTE mutations (M253Y / S255T / T257E by direct numbering) and / or the human Fc region of the antibody or antigen binding region that binds IL- 4Rα comprises a human IgG1 Fc with LALA mutations (L242A / L243A by direct numbering) and YTE mutations (M260Y / S262T / T264E by direct numbering).

175. The composition of any one of claims 149-157, the combination of any one of claims 158-161, or the method of any one of claims 162-165, wherein the antibody or antigen binding region that binds OX40L and / or the antibody or antigen binding region that binds IL-4Rα comprises an Fc region that binds to Neonatal Fc receptor (FcRn).

176. The composition of any one of claims 149-157, the combination of any one of claims 158-161, or the method of any one of claims 162-165, wherein the antibody or antigen binding region that binds OX40L and / or the antibody or antigen binding region that binds IL-4Rα comprises an Fc region that binds an FcRn with higher affinity at pH 6.0 compared to an antibody comprising a wild-type Fc region.

177. The composition of any one of claims 149-157, the combination of any one of claims 158-161, or the method of any one of claims 162-165, wherein the antibody or antigen binding region that binds OX40L and / or the antibody or antigen binding region that binds I IL-4Rα comprises an Fc region that binds to FcRn with a KDof <1 x 10-7M at pH 6.

0.

178. The composition of any one of claims 149-157, the combination of any one of claims 158-161, or the method of any one of claims 162-165, wherein the antibody or antigen binding region that binds OX40L and / or the antibody or antigen binding region that binds IL-4Rα is a monoclonal antibody.

179. The composition of any one of claims 149-157, the combination of any one of claims 158-161, or the method of any one of claims 162-165, wherein the antibody or antigen binding region that binds OX40L binds an OX40L sequence set forth in the amino acid sequence of SEQ ID NO:

739.

180. The composition of any one of claims 149-157, the combination of any one of claims 158-161, or the method of any one of claims 162-165, wherein the antibody or antigen binding region that binds IL-4Rα binds an IL-4Rα sequence set forth in any one of the amino acid sequences of SEQ ID NOs: 301-303.

181. The composition of any one of claims 149-157, the combination of any one of claims 158-161, or the method of any one of claims 162-165, wherein the antibody or antigen binding region that binds OX40L comprises a heavy chain comprising a constant heavy chain sequence set forth in SEQ ID NO: 651 or SEQ ID NO:

973.

182. The composition of any one of claims 149-157, the combination of any one of claims 158-161, or the method of any one of claims 162-165, wherein the antibody or antigen bindingregion that binds OX40L comprises a light chain comprising a constant light chain sequence set forth in SEQ ID NO:

738.

183. The composition of any one of claims 149-157, the combination of any one of claims 158-161, or the method of any one of claims 162-165, wherein the antibody or antigen binding region that binds IL-4Rα comprises a heavy chain comprising a constant heavy chain sequence set forth in SEQ ID NO: 651 or SEQ ID NO:

973.

184. The composition of any one of claims 149-157, the combination of any one of claims 158-161, or the method of any one of claims 162-165, wherein the antibody or antigen binding region that binds IL-4Rα comprises a light chain comprising a constant light chain sequence set forth in SEQ ID NO:

738.

185. The composition of any one of claims 149-157, the combination of any one of claims 158-161, or the method of any one of claims 162-165, wherein the hyaluronidase is a recombinant human hyaluronidase.

186. The composition, combination, or method of claim 185, wherein the recombinant human hyaluronidase comprises the amino acid sequence set forth in any one of SEQ ID NOs: 1076- 1085 and 1087-1142.

187. The composition, combination, or method of claim 185, wherein the recombinant human hyaluronidase is rHuPH20.

188. The composition, combination, or method of claim 187, wherein the rHuPH20 formulation is ENHANZE®.

189. The composition of any one of claims 149-157, the combination of any one of claims 158-161, or the method of any one of claims 162-165, wherein the hyaluronidase and antibody or antibodies are administered in separate formulations.

190. The composition of any one of claims 149-157, the combination of any one of claims 158-161, or the method of any one of claims 162-165, wherein the hyaluronidase and antibody or antibodies are administered simultaneously in separate formulations.

191. The composition, combination, or method of claim 189, wherein the hyaluronidase is administered to the patient prior to administration of the antibody or antibodies.

192. The composition, combination, or method of claim 189, wherein the hyaluronidase is administered to the patient after administration of the antibody or antibodies.

193. The composition, combination, or method of claim 189, wherein the hyaluronidase is administered to the patient after administration of one of the antibodies, but before administration of the other antibody.

194. The composition of any one of claims 149-157, the combination of any one of claims 158-161, or the method of any one of claims 162-165, wherein the hyaluronidase and antibody or antibodies are administered in a single formulation.

195. The composition of any one of claims 149-157, the combination of any one of claims 158-161, or the method of any one of claims 162-165, wherein the hyaluronidase and antibody or antibodies are administered by subcutaneous injection.

196. The composition of any one of claims 149-157, the combination of any one of claims 158-161, or the method of any one of claims 162-165, wherein the hyaluronidase and antibody or antibodies are administered by intravenous injection.

197. The composition of any one of claims 149-157, the combination of any one of claims 158-161, or the method of any one of claims 162-165, wherein the hyaluronidase is rHuPH20 (ENHANZE®) 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.

198. The method of any one of claims 162-165, wherein the inflammatory disorder or disease is atopic dermatitis.

199. The method of claim 198, wherein the treatment reduces disease severity in the patient and wherein disease severity is assessed by an atopic dermatitis disease severity outcome measure.

200. The method of any one of claims 162-165, wherein the inflammatory disorder or disease is asthma; chronic sinusitis with nasal polyps; Chronic Rhinosinusitis without Nasal Polyps (CRSsNP); eosinophilic esophagitis (EoE); 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); 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); Crohn’s disease; lupus; rheumatoid arthritis (RA); psoriasis; ulcerative colitis; hidradenitis suppurativa; celiac disease; systemic sclerosis; idiopathic pulmonary fibrosis; alopecia areata, allergic rhinitis; eosinophilic fasciitis; scleromyxedema; scleredema; or nephrogenic systemic fibrosis.

201. A kit for treating an inflammatory disorder or disease in a human patient, the kit comprising: (a) a dose of an antibody, or antigen binding fragment thereof, that binds OX40L, wherein the antibody comprises a VH sequence set forth in SEQ ID NO: 1 and a VL sequence set forth in SEQ ID NO: 11; (b) a dose of an antibody, or antigen binding fragment thereof, that binds IL-4Rα, wherein the antibody comprises a VH sequence set forth in SEQ ID NO: 297 and a VL sequence set forth in SEQ ID NO: 300; (c) a dose of a hyaluronidase or variant thereof; and (d) instructions.

202. The kit of claim 201, wherein the hyaluronidase is a recombinant human hyaluronidase.

203. The kit of claim 202, wherein the recombinant human hyaluronidase comprises the amino acid sequence set forth in any one of SEQ ID NOs: 1076-1085 and 1087-1142.

204. The kit of claim 202, wherein the recombinant human hyaluronidase is rHuPH20.

205. The kit of claim 204, wherein the rHuPH20 formulation is ENHANZE®.

206. The kit of claim 202, for use in treating an inflammatory disorder or disease.

207. The kit of claim 206, wherein the inflammatory disorder or disease is atopic dermatitis.

208. The kit of claim 206, wherein the inflammatory disorder or disease is asthma; chronic sinusitis with nasal polyps; Chronic Rhinosinusitis without Nasal Polyps (CRSsNP); eosinophilic esophagitis (EoE); 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); 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); Crohn’s disease; lupus; rheumatoid arthritis (RA); psoriasis; ulcerative colitis; hidradenitis suppurativa; celiac disease; systemic sclerosis; idiopathic pulmonary fibrosis; alopecia areata, allergic rhinitis; eosinophilic fasciitis; scleromyxedema; scleredema; or nephrogenic systemic fibrosis.

209. An isolated antibody, or an antigen binding fragment thereof, that binds OX40L, comprising: a) a variable heavy (VH) chain sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and b) a variable light (VL) chain sequence having three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; wherein the antibody, or antigen binding fragment thereof, that binds OX40L comprises: (i) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 2-4; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 5-7; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 8-10; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-14; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 15-16; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 17-18; andan isolated antibody, or an antigen binding fragment thereof, that binds IL-4Rα, wherein the isolated antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: a) a VH chain sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and b) a VL chain sequence having three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein the isolated antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises: (iii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 289 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293, wherein the isolated antibody, or antigen binding fragment thereof, that binds OX40L and / or the isolated antibody, or antigen binding fragment thereof, that binds IL-4Rα comprises a heavy chain comprising a heavy chain constant region having a means for extending the half-life of the isolated antibody.

210. A multi-specific antibody comprising: a first antigen binding region that binds OX40L, comprising: a) a VH chain sequence having three heavy chain CDR sequences, CDR-H1, CDR- H2, and CDR-H3; and b) a VL chain sequence having three light chain CDR sequences, CDR- L1, CDR-L2, and CDR-L3; wherein the antigen binding region that binds OX40L comprises: (i) a CDR-H1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 2-4; a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 5-7; a CDR-H3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 8-10; a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-14; a CDR-L2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 15-16; and a CDR-L3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 17-18; and a second antigen binding region that binds IL-4Rα comprising: a) a VH chain sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and b) a VL chain sequence having three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein the antigen binding region that binds IL-4Rα comprises:(iii) a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 273, 274, and 275; a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 279, 277, and 280; a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 281 and 282; a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 289 and 288; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293, wherein the multi-specific antibody comprises a heavy chain constant region having a means for extending the half-life of the multi-specific antibody.

211. A composition comprising an isolated antibody, or antigen binding region thereof, that binds OX40L and an isolated antibody, or antigen binding region thereof, that binds IL-4Rα, wherein the antibody, or antigen binding region thereof, that binds OX40L 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: 5; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 8; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 12; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 15; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 17, and wherein the antibody, or antigen binding region thereof, that binds IL-4Rα comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 273; a CDR-H2 comprising the sequence set forth in SEQ ID NO: 279; a CDR-H3 comprising the sequence set forth in SEQ ID NO: 281; a CDR-L1 comprising the sequence set forth in SEQ ID NO: 289; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 290; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 293, wherein the composition further comprises a means for increasing the bioavailability of the isolated antibody, or antigen binding region thereof, that binds OX40L and / or the isolated antibody, or antigen binding region thereof, that binds IL-4Rα.

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