Trispecific binding proteins that bind interleukin-4 and interleukin-13

Abstract

Provided herein are trispecific binding proteins comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more target proteins, wherein a first pair of polypeptides forming the binding protein possess dual variable domains having a cross-over orientation, and at least two of the antigen binding sites specifically bind an interleukin-4 (IL-4) polypeptide and an interleukin-13 (IL-13) polypeptide, respectively. In some embodiments, the third antigen binding site specifically binds an OX40L polypeptide. The disclosure also relates to nucleic acid molecules, expression vectors, host cells, compositions (e.g., pharmaceutical compositions), methods of production, methods of use, and uses related thereto.

Description

TRISPECIFIC BINDING PROTEINS THAT BIND INTERLEUKIN-4 AND INTERLEUKIN- 13CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the priority benefit of European Patent Application No. EP25305222.9, filed February 19, 2025 and Taiwanese Patent Application No. 115106215, filed February 13, 2026, which is incorporated herein by reference in its entirety.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The content of the electronic sequence listing (183952036641SEQLIST.xml; Size: 103,464 bytes; and Date of Creation: February 6, 2026) is incorporated herein by reference in its entirety.FIELD

[0003] The disclosure relates to trispecific binding proteins comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more target proteins, wherein a first pair of polypeptides forming the binding protein possess dual variable domains having a cross-over orientation, and at least two of the antigen binding sites specifically bind an interleukin-4 (IL-4) polypeptide and an interleukin- 13 (IL-13) polypeptide, respectively. The disclosure also relates to nucleic acid molecules, expression vectors, host cells, compositions (e.g., pharmaceutical compositions), methods of production, methods of use, and uses related thereto.BACKGROUND

[0004] Monoclonal antibody based biotherapeutics have become an important avenue for new drug development. Monoclonal antibody technology offers specific targeting, precise signaling delivery and / or payload to specific cell population, and provides long lasting biological effect through its Fc functions. Efforts in antibody engineering have allowed developing bispecific antibodies combining the specificities of two monoclonal antibodies for various biological applications, expanding the scope of antibody drug development. Newly discovered neutralizing antibodies with improved breadth and potency may provide more options for developing biotherapeutics to treat complexed diseases such as inflammatory diseases or disorders.

[0005] IL-4 and IL- 13 are T helper 2 (Th2) cytokines that play important roles in inflammation (e.g., type II inflammatory responses). Thus, there is a need for effective new molecules targeting these cytokines, e.g., for the treatment of inflammatory diseases or disorders.

[0006] All references cited herein, including patent applications, patent publications, and UniProtKB / Swiss-Prot Accession numbers are herein incorporated by reference in their entirety, as if each individual reference were specifically and individually indicated to be incorporated by reference.BRIEF SUMMARY

[0007] To meet these and other needs, provided herein are binding proteins (e.g., antibodies) that specifically bind IL-4 and / or IL-13. These binding proteins can specifically bind one, two, or three antigen targets or target proteins, such as IL-4, IL-13, and other target proteins such as OX40L. The anti-IL-4 and anti-IL-13 antigen binding sites (as well as binding proteins comprising the same) described herein have advantageous properties such as high affinity binding to human and cynomolgus IL-4 and IL- 13 polypeptides, good manufacturability, strong inhibition of IL-4 and IL-13 signaling, favorable pharmacokinetics, good stability, and low propensity for aggregation / opalescence / viscosity. These antigen binding sites are contemplated for use in a variety of monospecific, bispecific, trispecific, and multispecific binding proteins.

[0008] In some embodiments, provided herein are trispecific and / or trivalent binding proteins comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain of the binding protein comprises a structure represented by the formula:VL2-LI-VLI-L2-CL [I]and a second polypeptide chain of the binding protein comprises a structure represented by the formula:VHI -L3- V H2-L4-CH1 -hinge-CH2-Cu3 [II]and a third polypeptide chain of the binding protein comprises a structure represented by the formula:VH3-Cui-hinge-CH2-CH3 [III]and a fourth polypeptide chain of the binding protein comprises a structure represented by the formula:VL3-CL [IV]wherein:VLI is a first immunoglobulin light chain variable domain;VL2 is a second immunoglobulin light chain variable domain;VL3 is a third immunoglobulin light chain variable domain;VHI is a first immunoglobulin heavy chain variable domain;VH2 is a second immunoglobulin heavy chain variable domain;VH3 is a third immunoglobulin heavy chain variable domain;CL is an immunoglobulin light chain constant domain;CHI is an immunoglobulin CHI heavy chain constant domain;CH2 is an immunoglobulin CH2 heavy chain constant domain;CH3 is an immunoglobulin CH3 heavy chain constant domain;hinge is an immunoglobulin hinge region connecting the CHI and CH2 domains; and Li, L2, L3 and L4 are amino acid linkers;wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair; andwherein VHI and VLI form a binding pair and a first antigen binding site, VH2 and VL2 form a binding pair and a second antigen binding site, and VH3 and VL3 form a binding pair and a third antigen binding site. In some embodiments, the first antigen binding site specifically binds an interleukin-4 (IL-4) polypeptide and the second antigen binding site specifically binds an interleukin- 13 (IL- 13) polypeptide. In some embodiments, the first antigen binding site specifically binds an IL- 13 polypeptide and the second antigen binding site specifically binds an IL-4 polypeptide. In some embodiments, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence selected from the group consisting of SEQ ID NOs:3-5, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6 or 7, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 8 or 9, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10 or 11. In some embodiments, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence selected from the group consisting of SEQ ID NOs:24-27, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6 or 7, a CDR-L2 comprising theamino acid sequence of SEQ ID NO:8 or 9, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10 or 11. In some embodiments, the binding site that specifically binds an IL-13 polypeptide comprises a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 57, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:58, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:59 or 108, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:60, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:61, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:62. In some embodiments, Li, L2, L3 and L4 are each independently amino acid linkers or zero amino acids in length.

[0009] In some embodiments, provided herein are bispecific binding proteins comprising a first antigen binding site specifically binds an interleukin-4 (IL-4) polypeptide and a second antigen binding site specifically binds an interleukin- 13 (IL-13) polypeptide. In some embodiments, the bispecific binding proteins comprise three polypeptide chains that form two antigen binding sites, wherein a first polypeptide chain of the binding protein comprises a structure represented by the formula:VL2-LI-VLI-L2-CL [I]and a second polypeptide chain of the binding protein comprises a structure represented by the formula:Vm -L3- V H2-L4-CH1 -hinge-CH2-Cu3 [II]and a third polypeptide chain of the binding protein comprises a structure represented by the formula:Cm-hinge-CH2-CH3 [V]wherein:VLI is a first immunoglobulin light chain variable domain;VL2 is a second immunoglobulin light chain variable domain;VL3 is a third immunoglobulin light chain variable domain;VHI is a first immunoglobulin heavy chain variable domain;VH2 is a second immunoglobulin heavy chain variable domain;VH3 is a third immunoglobulin heavy chain variable domain;CL is an immunoglobulin light chain constant domain;CHI is an immunoglobulin CHI heavy chain constant domain;CH2 is an immunoglobulin CH2 heavy chain constant domain;CH3 is an immunoglobulin CH3 heavy chain constant domain;hinge is an immunoglobulin hinge region connecting the Cm and Cm domains; and Li, L2, L3 and L4 are amino acid linkers;wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair; and wherein VHI and VLI form a binding pair and a first antigen binding site, and V and VL2 form a binding pair and a second antigen binding site. In some embodiments, the first antigen binding site specifically binds an interleukin-4 (IL-4) polypeptide and the second antigen binding site specifically binds an interleukin- 13 (IL-13) polypeptide. In some embodiments, the first antigen binding site specifically binds an IL- 13 polypeptide and the second antigen binding site specifically binds an IL-4 polypeptide. In some embodiments, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence selected from the group consisting of SEQ ID NOs:3-5, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6 or 7, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8 or 9, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10 or 11. In some embodiments, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence selected from the group consisting of SEQ ID NOs:24-27, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6 or 7, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8 or 9, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10 or 11. In some embodiments, the binding site that specifically binds an IL-13 polypeptide comprises a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:57, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:58, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:59 or 108, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:60, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:61, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:62. In some embodiments, Li, L2, L3 and L4 are each independently amino acid linkers or zero amino acids in length.

[0010] In some embodiments according to any one of the embodiments disclosed herein, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:3, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:3, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11. In some embodiments, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence of SEQ ID NON, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11. In some embodiments, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:5, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11. In some embodiments, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:34 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:35. In some embodiments, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:36 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:37. Insome embodiments, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:38 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:39. In some embodiments, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:40 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:41. In some embodiments, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:42 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43. In some embodiments, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:44 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43. In some embodiments, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:45 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43. In some embodiments, VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:34, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:35. In some embodiments, VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:36, and Vn comprises an amino acid sequence that isat least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:37. In some embodiments, VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:38, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:39. In some embodiments, VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:40, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:41. In some embodiments, VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:42, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43. In some embodiments, VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:44, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43. In some embodiments, VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:45, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43. In some embodiments, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:24, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:24, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, aCDR-L2 comprising the amino acid sequence of SEQ ID NO:9, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11. In some embodiments, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:25, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:25, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11. In some embodiments, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:26, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11. In some embodiments, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:27, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NOV, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11. In some embodiments, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:46 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:47. In some embodiments, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises an amino acid sequence that is at least95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:48 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:39. In some embodiments, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:49 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:41. In some embodiments, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:50 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43. In some embodiments, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:51 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:37. In some embodiments, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 52 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:39. In some embodiments, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:53 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:41. In some embodiments, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 54 and a VL domain thatcomprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43. In some embodiments, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:55 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43. In some embodiments, the binding site that specifically binds an IL-4 polypeptide comprises a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:56 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43. In some embodiments, VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:46, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:47. In some embodiments, VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:48, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:39. In some embodiments, VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:49, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:41. In some embodiments, VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:50, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43. In some embodiments, VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:51, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:37. Insome embodiments, VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:52, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:39. In some embodiments, VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:53, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:41. In some embodiments, VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:54, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43. In some embodiments, VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 55, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43. In some embodiments, VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:56, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ IDNO:43.

[0011] In some embodiments, the binding site that specifically binds an IL- 13 polypeptide comprises a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:57, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:58, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:59, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:60, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:61, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:62. In some embodiments, the binding site that specifically binds an IL- 13 polypeptide comprises a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:70 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:71.In some embodiments, the binding site that specifically binds an IL- 13 polypeptide comprises a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:72 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:73. In some embodiments, the binding site that specifically binds an IL-13 polypeptide comprises a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:74 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 75. In some embodiments, VH2 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:70, and VL2 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:71. In some embodiments, VH2 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:72, and VL2 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:73. In some embodiments, VH2 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:74, and VL2 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 75. In some embodiments, the binding site that specifically binds an IL- 13 polypeptide comprises a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:57, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:58, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 108, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:60, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:61, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:62. In some embodiments, the binding site that specifically binds an IL-13 polypeptide comprises a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:76 and a VL domain that comprises an amino acid sequence that is at least 95%, at least96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:77. In some embodiments, VH2 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:76, and VL2 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:77.

[0012] In some embodiments according to any one of the embodiments disclosed herein, one or more (e.g., one, two, or all three) of the antigen binding sites comprise a pair of reciprocal amino acid substitutions on the VH and VL domains that facilitate heavy-light chain pairing.

[0013] In some embodiments according to any one of the embodiments disclosed herein, VHI comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:3; VLI comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10; VH2 comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:57, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 58, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:59; and VL2 comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:60, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:61, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:62. In some embodiments, VHI comprises the amino acid sequence of SEQ ID NO:34, VLI comprises the amino acid sequence of SEQ ID NO:35, VH2 comprises the amino acid sequence of SEQ ID NO:70, and VL2 comprises the amino acid sequence of SEQ ID NO:71.

[0014] In some embodiments according to any one of the embodiments disclosed herein, the binding protein is capable of inhibiting the function of one or more target proteins. In some embodiments, the binding protein is capable of inhibiting the function of an IL-4 polypeptide and / or an IL- 13 polypeptide.

[0015] In some embodiments according to any one of the embodiments disclosed herein, the third antigen binding site specifically binds an OX40L polypeptide. In some embodiments, the binding protein is capable of inhibiting the function of an OX40L polypeptide. In some embodiments, the binding site that specifically binds an OX40L polypeptide comprises a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:78, a CDR-H2 comprising the amino acid sequence of SEQ IDNO:79, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 80; and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:81, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 82, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 83. In some embodiments, VHS comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:78, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:79, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:80; and Vu comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:81, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:82, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:83. In some embodiments, the binding site that specifically binds an OX40L polypeptide comprises a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:91, and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:92. In some embodiments, the binding site that specifically binds an OX40L polypeptide comprises a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 93, and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:94. In some embodiments, the binding site that specifically binds an OX40L polypeptide comprises a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:95, and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:96. In some embodiments, the binding site that specifically binds an OX40L polypeptide comprises a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 97, and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:96. In some embodiments, VHS comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:91, and Vu comprises an amino acid sequence that is at least 95%, at least96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:92. In some embodiments, VHS comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:93, and VLS comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:94. In some embodiments, VHS comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:95, and VLS comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:96. In some embodiments, VHS comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 97, and Vu comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:96. In some embodiments, the binding site that specifically binds an OX40L polypeptide binds to an epitope of human OX40L that at least partially overlaps with that of human 0X40. In some embodiments, the binding site that specifically binds an OX40L polypeptide binds to an epitope of human OX40L comprising one or more of the following residues (numbering based on SEQ ID NO: 110): Q65, T67, E68, T78, Q80, K106, G107, Y108, F109, SI 10, QI 11, E112, D122, E123, E124, F127, Q128, L129, K130, K131, R133, S134, N136, D156, N157, T158, S159, L160, D161, D162, H164, and N166. In some embodiments, the binding site that specifically binds an OX40L polypeptide binds to an epitope of human OX40L comprising all of the following residues (numbering based on SEQ ID NO: 110): Q65, T67, E68, T78, Q80, K106, G107, Y108, F109, SI 10, QI 11, El 12, D122, E123, E124, F127, Q128, L129, K130, K131, R133, S134, N136, D156, N157, T158, S159, L160, D161, DI 62, Hl 64, and N166. In some embodiments, the binding site that specifically binds an OX40L polypeptide binds to human OX40L with a paratope comprising one or more of the following VH domain residues: F27, T28, N30 / S30, S31, Y32, D50, S52, S54, R56, S57, K98, D99, F102, C103, S104, A106, S107, C108, N109, El 10, and Y113 (consecutive numbering of SEQ ID NO:97 as shown in FIG. 17, which can be converted to other numbering schemes like Kabat or IMGT) and / or one or more of the following VL domain residues: R30, N31, D32, S56, H91, S92, R93, Y94, P95, and W96 (consecutive numbering of SEQ ID NO:96 as shown in FIG. 17, which can be converted to other numbering schemes like Kabat or IMGT). In some embodiments, the binding site thatspecifically binds an OX40L polypeptide binds to human OX40L with a paratope comprising one or more of the following VH domain residues: F27, T28, N30 / S30, S31, Y32, D50, S52, S54, R56, S57, K98, D99, F102, C103, S104, A106, S107, C108, N109, E110, and Y113 (consecutive numbering of SEQ ID NO:97) and one or more of the following VL domain residues: R30, N31, D32, S56, H91, S92, R93, Y94, P95, and W96 (consecutive numbering of SEQ ID NO:96). In some embodiments, the binding site that specifically binds an OX40L polypeptide binds to human OX40L with a paratope comprising all of the following VH domain residues: F27, T28, N30 / S30, S31, Y32, D50, S52, S54, R56, S57, K98, D99, F102, C103, S104, A106, S107, C108, N109, El 10, and Y113 (consecutive numbering of SEQ ID NO:97) and all of the following VL domain residues: R30, N31, D32, S56, H91, S92, R93, Y94, P95, and W96 (consecutive numbering of SEQ ID NO: 96).

[0016] In some embodiments according to any one of the embodiments disclosed herein, VHI comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:3; VLI comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10; VH2 comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:57, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 58, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:59; VL2 comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:60, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:61, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:62; VH3 comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:78, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:79, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:80; and VL3 comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:81, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:82, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:83. In some embodiments, VHI comprises the amino acid sequence of SEQ ID NO:34, VLI comprises the amino acid sequence of SEQ ID NO:35, VH2 comprises the amino acid sequence of SEQ ID NO:70, VL2 comprises the amino acid sequence of SEQ ID NO:71, Vmcomprises the amino acid sequence of SEQ ID NO:91, and VL3 comprises the amino acid sequence of SEQ ID NO:92.

[0017] In some embodiments according to any one of the embodiments disclosed herein, at least one of Li, L2, L3 or L4, is independently 0 amino acids in length. In some embodiments, Li, L2, L3 or L4 are each independently at least one amino acid in length. In some embodiments, (a) Li, L2, L3 and L4 each independently are zero amino acids in length or comprise a sequence selected from the group consisting of GGGGSGGGGS (SEQ ID NO: 102), GGGGSGGGGSGGGGS (SEQ ID NO: 103), S, RT, TKGPS (SEQ ID NO: 104), GQPKAAP (SEQ ID NO: 105), and GGSGSSGSGG (SEQ ID NO: 106); or (b) Li, L2, L3and L4 each independently comprise a sequence selected from the group consisting of GGGGSGGGGS (SEQ ID NO: 102), GGGGSGGGGSGGGGS (SEQ ID NO: 103), S, RT, TKGPS (SEQ ID NO: 104), GQPKAAP (SEQ ID NO: 105), and GGSGSSGSGG (SEQ ID NO: 106). In some embodiments, Li comprises the sequence GQPKAAP (SEQ ID NO: 105), L2 comprises the sequence TKGPS (SEQ ID NO: 104), L3 comprises the sequence S, and L4 comprises the sequence RT. In some embodiments, Li comprises the sequence GGGGSGGGGS (SEQ ID NO: 102), L2comprises the sequence GGGGSGGGGS (SEQ ID NO: 102), L3 is 0 amino acids in length, and L4 is 0 amino acids in length. In some embodiments, Li comprises the sequence GGSGSSGSGG (SEQ ID NO: 106), L2 comprises the sequence GGSGSSGSGG (SEQ ID NO: 106), L3 is 0 amino acids in length, and L4 is 0 amino acids in length. In some embodiments, Li comprises the sequence GGGGSGGGGSGGGGS (SEQ ID NO: 103), L2 is 0 amino acids in length, L3 comprises the sequence GGGGSGGGGSGGGGS (SEQ ID NO: 103), and L4 is 0 amino acids in length.

[0018] In some embodiments according to any one of the embodiments disclosed herein, the CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgGl or IgG4 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgGl or IgG4 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V. In some embodiments, the CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgGl or IgG4 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgGl or IgG4 according to EU Index, wherein the amino acid substitutions are S354C andT366W. In some embodiments, the CH3 domains of the second and the third polypeptide chains are human IgGl or IgG4 CH3 domains, and wherein only one of the CH3 domains comprises amino acid substitutions at positions corresponding to positions 435 and 436 of human IgGl or IgG4 according to EU Index, wherein the amino acid substitutions are H435R and Y436F. In some embodiments, the CH3 domains of the second and the third polypeptide chains are human IgGl CH3 domains, and wherein the CH3 domains each comprise amino acid substitutions at positions corresponding to positions 234 and 235 of human IgGl according to EU Index, wherein the amino acid substitutions are L234A and L235A.

[0019] In some embodiments according to any one of the embodiments disclosed herein, the first polypeptide chain of the binding protein comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 98, the second polypeptide chain of the binding protein comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 99, the third polypeptide chain of the binding protein comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 100, and the fourth polypeptide chain of the binding protein comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 101.

[0020] Further provided herein is a kit of polynucleotides, comprising a first polynucleotide that encodes a first polypeptide chain of the binding protein according to any one of the above embodiments, a second polynucleotide that encodes a second polypeptide chain of the binding protein according to any one of the above embodiments, a third polynucleotide that encodes a third polypeptide chain of the binding protein according to any one of the above embodiments, and a fourth polynucleotide that encodes a fourth polypeptide chain of the binding protein according to any one of the above embodiments.

[0021] Further provided herein are antibodies that specifically bind an IL-4 polypeptide, wherein the antibody comprises a heavy chain variable (VH) domain and a light chain variable (VH) domain; wherein the VH domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence selected from the group consisting of SEQ ID NOs:3-5; and wherein the VL domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6 or 7, a CDR-L2comprising the amino acid sequence of SEQ ID NO:8 or 9, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10 or 11. Further provided herein are antibodies that specifically bind an IL-4 polypeptide, wherein the antibody comprises a heavy chain variable (VH) domain and a light chain variable (VH) domain; wherein the VH domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence selected from the group consisting of SEQ ID NOs:24-27; and wherein the VL domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6 or 7, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8 or 9, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10 or 11. In some embodiments, the VH domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:3, and the VL domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the VH domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:3, and the VL domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11. In some embodiments, the VH domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence of SEQ ID NON, and the VL domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11. In some embodiments, the VH domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:1, a CDR-H2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:5, and the VL domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11. In some embodiments, the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acidsequence of SEQ ID NO:34, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:35. In some embodiments, the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:36, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:37. In some embodiments, the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:38, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:39. In some embodiments, the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:40, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:41. In some embodiments, the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:42, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43. In some embodiments, the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:44, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43. In some embodiments, the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:45, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43. In some embodiments, the VH domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:24, and the VL domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6, a CDR-L2 comprising the amino acid sequence ofSEQ ID N0:8, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the VH domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:24, and the VL domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:9, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11. In some embodiments, the VH domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:25, and the VL domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the VH domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:25, and the VL domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11. In some embodiments, the VH domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:26, and the VL domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11. In some embodiments, the VH domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:27, and the VL domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NOV, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11. In some embodiments, the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:46, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:47. In some embodiments, the VH domain comprisesan amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:48, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:39. In some embodiments, the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:49, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:41. In some embodiments, the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:50, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43. In some embodiments, the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:51, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:37. In some embodiments, the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:52, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:39. In some embodiments, the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:53, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:41. In some embodiments, the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:54, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43. In some embodiments, the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:55, and the VL domain comprises an amino acid sequence that isat least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43. In some embodiments, the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:56, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43. In some embodiments, the antibody is a monospecific antibody. In some embodiments, the antibody is a bispecific or multispecific antibody.

[0022] Further provided herein are antibodies that specifically bind an IL- 13 polypeptide, wherein the antibody comprises a heavy chain variable (VH) domain and a light chain variable (VH) domain; wherein the VH domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:57, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:58, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:59, and the VL domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:60, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:61, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:62. In some embodiments, the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:70, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:71. In some embodiments, the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:72, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:73. In some embodiments, the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:74, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:75. In some embodiments, the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:76, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:77. Insome embodiments, the antibody is a monospecific antibody. In some embodiments, the antibody is a bispecific or multispecific antibody.

[0023] Further provided herein are antibodies that specifically bind an OX40L polypeptide, wherein the antibody comprises a heavy chain variable (VH) domain and a light chain variable (VH) domain; wherein the VH domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:78, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:79, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:80, and the VL domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:81, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:82, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:83. In some embodiments, the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:91, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:92. In some embodiments, the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:93, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 94. In some embodiments, the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:95, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:96. In some embodiments, the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:97, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 96. In some embodiments, the antibody is a monospecific antibody. In some embodiments, the antibody is a bispecific or multispecific antibody.

[0024] Further provided herein are nucleic acid molecules (e.g., isolated nucleic acid molecules) comprising a nucleotide sequence encoding the antibody or binding protein of any one of the above embodiments. Further provided herein are vectors (e.g., expression vectors) comprising the nucleic acid molecules of any one of the above embodiments.Further provided herein are host cells (e.g., isolated host cells) comprising the kit of polynucleotides, nucleic acid molecules, or vector of any one of the above embodiments. In some embodiments, the host cell is a mammalian or insect cell.

[0025] Further provided herein are pharmaceutical compositions comprising the antibody or binding protein of any one of the above embodiments and a pharmaceutically acceptable carrier.

[0026] Further provided herein are methods of preventing and / or treating an inflammatory disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of at least one binding protein, antibody, or pharmaceutical composition of any one of the above embodiments. In some embodiments, the inflammatory disease or disorder is atopic dermatitis. In some embodiments, the patient is a human.

[0027] Further provided herein is the binding protein, antibody, or pharmaceutical composition of any one of the above embodiments for use in a method of preventing and / or treating an inflammatory disease or disorder in a patient. In some embodiments, the inflammatory disease or disorder is atopic dermatitis. In some embodiments, the patient is a human.

[0028] Further provided herein is the use of a binding protein, antibody, or pharmaceutical composition of any one of the above embodiments in the manufacture of a medicament for preventing and / or treating an inflammatory disease or disorder in a patient. In some embodiments, the inflammatory disease or disorder is atopic dermatitis. In some embodiments, the patient is a human.

[0029] It is to be understood that one, some, or all of the properties of the various embodiments described herein may be combined to form other embodiments of the present invention. These and other aspects of the invention will become apparent to one of skill in the art. These and other embodiments of the invention are further described by the detailed description that follows.BRIEF DESCRIPTION OF THE DRAWINGS

[0030] FIG. 1 shows a schematic of the exemplary bivalent bispecific antibody which includes one cross-over dual variable (CODV) arm targeting IL-4 and IL-13.

[0031] FIGS. 2A & 2B show the binding affinity of a molecule comprising a CODV arm with antigen binding domains ADI-46659 (anti-IL-4) and CL-203143 (anti-IL-13) to human and cyno IL-4 and IL- 13 (FIG. 2A), compared to a molecule with another moleculecomprising comparator antigen binding domains (FIG. 2B). It was found that kD was higher for the molecule with ADI-46659 (anti-IL-4) and CL-203143 (anti-IL-13).

[0032] FIG. 3 shows purity and titer of various CODV antibodies as shown in FIG. 1 which comprise different VH / VL domains binding to IL-4 and IL-13. Two antigen binding domains binding to IL-4 (ADI-46653 and ADI-466659) were tested and combined with various antigen binding domains binding IL-13. Both IL-4 antigen binding domains were tested in the outer position (VH most N-terminal on the heavy chain) as well as in the inner position (VH C-terminal from another VH on the heavy chain) position. The left graph indicates the purity as determined by aSEC, the right graph indicates the titer, and the numbers above the columns indicate how many different constructs could be expressed. Surprisingly, the outer position was strongly favored by both ADI-46653 and ADI-466659. The among of constructs which could be expressed was almost three times as high as for the inner position. Moreover, the titer and the purity very on average better for constructs which had ADI-46653 or ADI-466659 in the outer position.

[0033] FIG. 4 shows a schematic of the exemplary trivalent, trispecific antibody C. The antibody includes one cross-over dual variable (CODV) arm targeting IL-4 and IL- 13, and one Fab arm targeting OX40L. The backbone is IgGl. Key indicates the domains in which charge mutations (CM1, CM2, CR3, and NN3) and mutations improving properties as measured by Kd-DLS (such as viscosity; V2) are located.

[0034] FIG. 5A shows a schematic depicting IL-2 release induced by the interaction between OX40+peripheral blood mononuclear cells (PBMCs) and OX40L+Chinese hamster ovary (CHO) cells.

[0035] FIG. 5B shows inhibition of OX40L-induced IL-2 production by PBMCs using trispecific antibody C.

[0036] FIG. 6 shows a schematic depicting thymus- and activation-regulated chemokine (TARC) release induced by type I IL-4 receptor (IL-4RI) stimulation mediated by IL-4 binding, and Eotaxin-3 release induced by type II IL-4 receptor (IL-4RII) stimulation mediated by IL-4 or IL- 13 binding.

[0037] FIGs. 7A-7B show trispecific antibody inhibition of IL-4 (FIG. 7A) and IL-13-mediated (FIG. 7B) TARC release by IL-4RI+PBMCs. Shown are the results for trispecific antibodies B and C and for a comparator bispecific anti-IL-4 / IL-13 antibody.

[0038] FIGs. 7C-7D show trispecific antibody inhibition of IL-4 and IL- 13 -mediated Eotaxin-3 release by IL-4RII+ A549 epithelial cells. Shown are the results for trispecific antibodies B and C and for a comparator bispecific anti-IL-4 / IL-13 antibody.

[0039] FIG. 8 shows a schematic depicting exogenous IL-4, IL- 13 and allergen Dermatophagoides pteronyssinus (der p) added to tissue, stimulating the release of TARC, IL-5 and Eotaxin-3.

[0040] FIGs. 9A-9C show the inhibition of IL-5 (FIG. 9A), TARC (FIG. 9B), and Eotaxin-3 (FIG. 9C) production in an allergen-driven tissue-mimic assay by the indicated trispecific, bispecific, or monospecific antibodies. Shown are the results for trispecific antibody C, for a comparator monospecific anti-OX40L antibody, for a comparator bispecific anti-IL-4 / IL-13 antibody, and for a comparator bispecific anti-IL-13 / OX40L VHH antibody.

[0041] FIG. 10 shows results from a T-cell-dependent antibody response (TDAR) assay induced by the antigen KLH. X-axis (left to right): -KLH, +KLH, lOmg / kg anti-OX40L Ab, lOmg / kg trispecific antibody B, 3mg / kg trispecific antibody B, LOmg / kg trispecific antibody B, 0.3mg / kg trispecific antibody B. * indicates a p-value less than 0.05. ** indicates a p-value less than 0.01.

[0042] FIGS. 11A-11D show eosinophil numbers (FIG. HA), CD4+memory cells (FIG. 11B), eotaxin-3 levels (FIG. 11C), and TARC levels (FIG. 11D) in lungs of quintuple knock-in mice upon antigen exposure. Shown are results for treatment with the trispecific antibodies, for a comparator monospecific anti-OX40L antibody, and for a comparator bispecific anti-IL-4 / IL-13 antibody.

[0043] FIG. HE shows pathological changes, visualized by Periodic acid-Schiff (PAS) staining, in lungs of quintuple knock-in mice upon antigen exposure. Shown are results for treatment with the trispecific antibodies, for a comparator monospecific anti-OX40L antibody, and for a comparator bispecific anti-IL-4 / IL-13 antibody.

[0044] FIG. HF shows pharmacokinetic properties (z.e., concentration overtime) of trispecific antibodies in hFcRn Tg32 mice following intravenous injection at a dose of 5 mg / kg.

[0045] FIG. 12A shows the isoelectric point data for trispecific antibodies E, B, and C.

[0046] FIG. 12B shows the poly dispersity of trispecific antibodies E, B, and C as measured by dynamic light scattering (DLS).

[0047] FIG. 12C shows kD-DLS values for trispecific antibodies E, B, and C as measured by DLS.

[0048] FIG. 12D shows the viscosity of trispecific antibodies E, B, and C.

[0049] FIG. 12E shows the turbidity of trispecific antibodies E, B, and C.

[0050] FIG. 13 shows the aggregation profiles of trispecific antibodies E, B, and C after three weeks at 40°C. TO represents time 0, T1 represents week 1, T2 represents week 2, and T3 represents week 3.

[0051] FIG. 14 shows the structure of the anti-OX40L (MM25PL3A2) Fab: OX40L complex, as determined by CryoEM. Shown are the OX40L trimer bound to 3 MM25PL3 A2 Fabs (at a), top view (at b), and side view (at c).

[0052] FIG. 15 shows top and bottom views of the CryoEM map of the anti-OX40L (MM25PL3A2) Fab: OX40L complex at a resolution of 3.94A.

[0053] FIG. 16 depicts the structures of the OX40:OX40L complex (at a), the anti-OX40L (MM25PL3A2) Fab: OX40L complex (at b), and an overlay (at c), showing partial overlap of the Fab and 0X40 epitopes on OX40L.

[0054] FIG. 17 shows the anti-OX40L (MM25PL3 A2) Fab (SEQ ID NO: 111) epitope mapped onto the human OX40L amino acid sequence (SEQ ID NO: 110; at a) and the anti-OX40L (MM25PL3A2) Fab paratope residues mapped onto the VH (SEQ ID NO:97) and VL (SEQ ID NO:96) domain sequences after energy minimization of the CDR loops fitted in the 3.94A CryoEM map (at b). Sequences in (b) correspond to SEQ ID Nos: 112 (upper) and 113 (lower), respectively. For the epitope mapping at a, Fab:OX40L interactions are highlighted as indicated (in the upper OX40L sequence, labelled “MM25”, * orAindicating the OX40L monomer the Fab interacts with). Furthermore, the OX40L residues binding to 0X40 are shown in gray (in the lower OX40L sequence labelled “0X40”).

[0055] FIG. 18A shows a schematic of an exemplary trispecific binding protein with 3 antigen binding sites that specifically bind IL-4, IL-13, and IL-17, respectively. The arm with anti -IL-4 and anti-IL-13 binding sites is configured as a cross-over dual variable (CODV) arm, while the arm with the anti -IL- 17 binding site is configured as a traditional Fab arm.

[0056] FIG. 18B shows a schematic of an exemplary trispecific binding protein with 3 antigen binding sites that specifically bind IL-4, IL-13, and IL-17, respectively. Positions of mutations to promote association of the two heavy chains (knobs-into-holes or KiH mutations), mutations to promote purification of the assembled binding protein (RF mutation), Fc silencing mutations (LALA), mutations to promote circulation half-life (DQ), and mutations to promote proper chain pairing (CM1, CM2, CR3, and NN3), are depicted.

[0057] FIGS. 19A-4E show stability of trispecific binding protein C (see Table 18) at pH 5 (circles) or pH 8 (squares) over time, including protein concentration (FIG. 19A), diffusion coefficient (FIG. 19B), % low molecular weight species (left panel in FIG. 19C),% high molecular weight species (right panel in FIG. 19C), size exclusion chromatography (SEC) total area (FIG. 19D), and fragmentation (FIG. 19E).

[0058] FIG. 20 shows a diagram of a surface plasmon resonance assay to measure single antigen binding of individual antigen binding domains with a CODV-based trispecific binding protein (as shown in FIG. 18A).

[0059] FIG. 21A shows a schematic of an exemplary trispecific binding protein with 3 antigen binding sites that specifically bind IL-4, IL-13, and NKG2D, respectively. The arm with anti -IL-4 and anti-IL-13 binding sites is configured as a cross-over dual variable (CODV) arm, while the arm with the anti-NKG2D binding site is configured as a traditional Fab arm.

[0060] FIG. 21B shows a schematic of an exemplary trispecific binding protein with 3 antigen binding sites that specifically bind IL-4, IL-13, and NKG2D, respectively.Positions of mutations to promote association of the two heavy chains (knobs-into-holes or KiH mutations), mutations to promote purification of the assembled binding protein (RF mutation), mutations to promote proper chain pairing (CM1, CM2, CR3, and NN3), mutations to reduce effector function (LALA), and mutations to extend half-life (HLE) are depicted.

[0061] FIG. 22A details the characterization of the top 10 anti-IL4 / IL-13 / NKG2D trispecific binding proteins. Antigen binding domains for each of the three domains for each molecule are as indicated. SEC: size exclusion chromatography; HIC: hydrophobic interaction chromatography; DSF: differential scanning fluorimetry; cIEF: capillary isoelectric focusing.

[0062] FIG. 22B details the binding of the top 10 anti-IL4 / IL-13 / NKG2D trispecific binding proteins to all three targets. cIL13: cynomolgus IL-13; hIL13: human IL-13; cIL4: cynomolgus IL-4; hIL4: human IL-4; cNKG2D: cynomolgus NKG2D; hNKG2D: human NKG2D; DSF: differential scanning fluorimetry; SPR: surface plasmon resonance.DETAILED DESCRIPTION

[0063] The disclosure relates to trispecific binding proteins comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more target proteins, wherein a first pair of polypeptides forming the binding protein possess dual variable domains having a cross-over orientation, and at least two of the antigen binding sites specifically bind an interleukin-4 (IL-4) polypeptide and an interleukin- 13 (IL-13) polypeptide, respectively. In some embodiments, the third antigen binding site specificallybinds an OX40L polypeptide. The disclosure also provides monospecific and multispecific binding proteins that specifically bind an IL-4, IL-13, or OX40L polypeptide. The disclosure also relates to nucleic acid molecules, expression vectors, host cells, compositions (e.g., pharmaceutical compositions), methods of production, methods of use, and uses related thereto.General Definitions

[0064] As utilized in accordance with the present disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0065] It is understood that aspects and embodiments of the disclosure described herein include “comprising,” “consisting,” and “consisting essentially of’ aspects and embodiments.

[0066] The term "polynucleotide" as used herein refers to single-stranded or doublestranded nucleic acid polymers of at least 10 nucleotides in length. In certain embodiments, the nucleotides comprising the polynucleotide can be ribonucleotides or deoxyribonucleotides or a modified form of either type of nucleotide. Such modifications include base modifications such as bromuridine, ribose modifications such as arabinoside and 2', 3 '-dideoxyribose, and internucleotide linkage modifications such as phosphorothioate, phosphorodithioate, phosphoroselenoate, phosphorodiselenoate, phosphoroanilothioate, phoshoraniladate and phosphoroamidate. The term "polynucleotide" specifically includes single-stranded and double-stranded forms of DNA.

[0067] An "isolated polynucleotide" is a polynucleotide of genomic, cDNA, or synthetic origin or some combination thereof, which: (1) is not associated with all or a portion of a polynucleotide in which the isolated polynucleotide is found in nature, (2) is linked to a polynucleotide to which it is not linked in nature, or (3) does not occur in nature as part of a larger sequence.

[0068] An "isolated polypeptide" is one that: (1) is free of at least some other polypeptides with which it would normally be found, (2) is essentially free of other polypeptides from the same source, e.g., from the same species, (3) is expressed by a cell from a different species, (4) has been separated from at least about 50 percent of polynucleotides, lipids, carbohydrates, or other materials with which it is associated in nature, (5) is not associated (by covalent or noncovalent interaction) with portions of apolypeptide with which the "isolated polypeptide" is associated in nature, (6) is operably associated (by covalent or noncovalent interaction) with a polypeptide with which it is not associated in nature, or (7) does not occur in nature. Such an isolated polypeptide can be encoded by genomic DNA, cDNA, mRNA or other RNA, of synthetic origin, or any combination thereof. Preferably, the isolated polypeptide is substantially free from polypeptides or other contaminants that are found in its natural environment that would interfere with its use (therapeutic, diagnostic, prophylactic, research or otherwise).

[0069] Naturally occurring antibodies typically comprise a tetramer. Each such tetramer is typically composed of two identical pairs of polypeptide chains, each pair having one full-length "light" chain (typically having a molecular weight of about 25 kDa) and one full-length "heavy" chain (typically having a molecular weight of about 50-70 kDa). The terms "heavy chain" and "light chain" as used herein refer to any immunoglobulin polypeptide having sufficient variable domain sequence to confer specificity for a target antigen. The amino-terminal portion of each light and heavy chain typically includes a variable domain of about 100 to 110 or more amino acids that typically is responsible for antigen recognition. The carboxy-terminal portion of each chain typically defines a constant domain responsible for effector function. Thus, in a naturally occurring antibody, a full-length heavy chain immunoglobulin polypeptide includes a variable domain (VH) and three constant domains (CHI, CH2, and Cm), wherein the VH domain is at the amino-terminus of the polypeptide and the CH3 domain is at the carboxyl-terminus, and a full-length light chain immunoglobulin polypeptide includes a variable domain (VL) and a constant domain (CL), wherein the VL domain is at the amino-terminus of the polypeptide and the CL domain is at the carboxyl-terminus.

[0070] Human light chains are typically classified as kappa and lambda light chains, and human heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. IgG has several subclasses, including, but not limited to, IgGl, IgG2, IgG3, and IgG4. IgM has subclasses including, but not limited to, IgMl and IgM2. IgA is similarly subdivided into subclasses including, but not limited to, IgAl and IgA2. Within full-length light and heavy chains, the variable and constant domains typically are joined by a "J" region of about 12 or more amino acids, with the heavy chain also including a "D" region of about 10 more amino acids. See, e.g., FUNDAMENTAL IMMUNOLOGY (Paul, W ., ed., Raven Press, 2nd ed., 1989), which is incorporated by reference in its entirety for all purposes. The variable regions of each light / heavy chain pair typically form an antigen binding site. The variable domains ofnaturally occurring antibodies typically exhibit the same general structure of relatively conserved framework regions (FR) joined by three hypervariable regions, also called complementarity determining regions or CDRs. The CDRs from the two chains of each pair typically are aligned by the framework regions, which may enable binding to a specific epitope. From the amino-terminus to the carboxyl-terminus, both light and heavy chain variable domains typically comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0071] The term "CDR set" refers to a group of three CDRs that occur in a single variable region capable of binding the antigen. The exact boundaries of these CDRs have been defined differently according to different systems. The system described by Kabat (Kabat et al., SEQUENCES OF PROTEINS OF IMMUNOLOGICAL INTEREST (National Institutes of Health, Bethesda, Md. (1987) and (1991)) not only provides an unambiguous residue numbering system applicable to any variable region of an antibody, but also provides precise residue boundaries defining the three CDRs. These CDRs may be referred to as Kabat CDRs. Chothia and coworkers (Chothia and Lesk, 1987, J. Mol. Biol. 196: 901-17; Chothia etal., 1989, Nature 342: 877-83) found that certain sub-portions within Kabat CDRs adopt nearly identical peptide backbone conformations, despite having great diversity at the level of amino acid sequence. These sub-portions were designated as LI, L2, and L3 or Hl, H2, and H3 where the "L" and the "H" designates the light chain and the heavy chain regions, respectively. These regions may be referred to as Chothia CDRs, which have boundaries that overlap with Kabat CDRs. Other boundaries defining CDRs overlapping with the Kabat CDRs have been described by Padlan, 1995, FASEB J. 9: 133-39; MacCallum, 1996, J. Mol. Biol. 262(5): 732-45; and Lefranc, 2003, Dev. Comp.Immunol. 27: 55-77. Another system for defining CDRs is the IMGT definition, (see, e.g., imgt.org / IMGTScientificChart / Nomenclature / IMGT-FRCDRdefmition.html). Still other CDR boundary definitions may not strictly follow one of the herein systems, but will nonetheless overlap with the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues or even entire CDRs do not significantly impact antigen binding. The methods used herein may utilize CDRs defined according to any of these systems, although certain embodiments use Kabat or IMGT defined CDRs. Identification of predicted CDRs using the amino acid sequence is well known in the field, such as in Martin, A.C. "Protein sequence and structure analysis of antibody variable domains," In Antibody Engineering, Vol. 2. Kontermann R., Diibel S., eds. Springer-Verlag, Berlin, p. 33-51 (2010). The amino acid sequence of theheavy and / or light chain variable domain may be also inspected to identify the sequences of the CDRs by other conventional methods, e.g., by comparison to known amino acid sequences of other heavy and light chain variable regions to determine the regions of sequence hypervariability. The numbered sequences may be aligned by eye, or by employing an alignment program such as one of the CLUSTAL suite of programs, as described in Thompson, 1994, Nucleic Acids Res. 22: 4673-80. Molecular models are conventionally used to correctly delineate framework and CDR regions and thus correct the sequence-based assignments.

[0072] The term "Fc" as used herein refers to a molecule comprising the sequence of a non-antigen-binding fragment resulting from digestion of an antibody or produced by other means, whether in monomeric or multimeric form, and can contain the hinge region. The original immunoglobulin source of the native Fc is preferably of human origin and can be any of the immunoglobulins, although IgGl and IgG2 are preferred. Fc molecules are made up of monomeric polypeptides that can be linked into dimeric or multimeric forms by covalent (z.e., disulfide bonds) and non-covalent association. The number of intermolecular disulfide bonds between monomeric subunits of native Fc molecules ranges from 1 to 4 depending on class (e.g., IgG, IgA, and IgE) or subclass (e.g., IgGl, IgG2, IgG3, IgAl, and IgGA2). One example of a Fc is a disulfide-bonded dimer resulting from papain digestion of an IgG. The term "native Fc" as used herein is generic to the monomeric, dimeric, and multimeric forms.

[0073] A F(ab) fragment typically includes one light chain and the VH and CHI domains of one heavy chain, wherein the VH-CHI heavy chain portion of the F(ab) fragment cannot form a disulfide bond with another heavy chain polypeptide. As used herein, a F(ab) fragment can also include one light chain containing two variable domains separated by an amino acid linker and one heavy chain containing two variable domains separated by an amino acid linker and a CHI domain.

[0074] A F(ab') fragment typically includes one light chain and a portion of one heavy chain that contains more of the constant region (between the CHI and CH2 domains), such that an interchain disulfide bond can be formed between two heavy chains to form a F(ab')2 molecule.

[0075] The term "binding protein" as used herein refers to a non-naturally occurring (or recombinant or engineered) molecule that specifically binds to at least one target antigen. A trispecific binding protein of the present disclosure, unless otherwise specified, typicallycomprises four polypeptide chains that form at least three antigen binding sites, wherein a first polypeptide chain has a structure represented by the formula:VL2- LI-VLI- L2-CL[I]and a second polypeptide chain has a structure represented by the formula:VHI -L3- V H2-L4-CH1 -hinge-CH2-Cu3 [II]and a third polypeptide chain has a structure represented by the formula:VH3-CHI [III]and a fourth polypeptide chain has a structure represented by the formula:VL3-CL [IV]wherein:VLI is a first immunoglobulin light chain variable domain;VL2 is a second immunoglobulin light chain variable domain;VL3 is a third immunoglobulin light chain variable domain;VHI is a first immunoglobulin heavy chain variable domain;VH2 is a second immunoglobulin heavy chain variable domain;VH3 is a third immunoglobulin heavy chain variable domain;CL is an immunoglobulin light chain constant domain;CHI is the immunoglobulin CHI heavy chain constant domain; andhinge is an immunoglobulin hinge region connecting the CHI and CH2 domains;Li, L2, L3 and L4 are amino acid linkers;and wherein the polypeptide of formula I and the polypeptide of formula II form a crossover light chain-heavy chain pair.

[0076] A "recombinant" molecule is one that has been prepared, expressed, created, or isolated by recombinant means.

[0077] One embodiment of the disclosure provides binding proteins having biological and immunological specificity to three target antigens. Another embodiment of the disclosure provides nucleic acid molecules comprising nucleotide sequences encoding polypeptide chains that form such binding proteins. Another embodiment of the disclosure provides expression vectors comprising nucleic acid molecules comprising nucleotide sequences encoding polypeptide chains that form such binding proteins. Yet another embodiment of the disclosure provides host cells that express such binding proteins (z.e., comprising nucleic acid molecules or vectors encoding polypeptide chains that form such binding proteins).

[0078] The term "swapability" as used herein refers to the interchangeability of variable domains within the binding protein format and with retention of folding and ultimate binding affinity. "Full swapability" refers to the ability to swap the order of both VHI and VH2 domains, and therefore the order of VLI and VL2 domains, in the polypeptide chain of formula I or the polypeptide chain of formula II (z.e., to reverse the order) while maintaining full functionality of the binding protein as evidenced by the retention of binding affinity. Furthermore, it should be noted that the designations VH and VL refer only to the domain's location on a particular protein chain in the final format. For example, VHI and VH2 could be derived from VLI and VL2 domains in parent antibodies and placed into the VHI and VH2 positions in the binding protein. Likewise, VLI and VL2 could be derived from VHI and VH2 domains in parent antibodies and placed in the VHI and VH2 positions in the binding protein. Thus, the VH and VL designations refer to the present location and not the original location in a parent antibody. VH and VL domains are therefore "swappable."

[0079] The term "antigen" or "target antigen" or "antigen target" as used herein refers to a molecule or a portion of a molecule that is capable of being bound by a binding protein. A target antigen may have one or more epitopes.

[0080] The term "trispecific binding protein" refers to a binding protein that specifically binds to three different antigen targets.

[0081] The term "trivalent binding protein" refers to a binding protein that has three binding sites. In particular embodiments the trivalent binding protein can bind to one antigen target. In other embodiments, the trivalent binding protein can bind to two antigen targets. In other embodiments, the trivalent binding protein can bind to three antigen targets.

[0082] An "isolated" binding protein is one that has been identified and separated and / or recovered from a component of its natural environment. Contaminant components of its natural environment are materials that would interfere with diagnostic or therapeutic uses for the binding protein, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In some embodiments, the binding protein will be purified: (1) to greater than 95% by weight of antibody as determined by the Lowry method, and most preferably more than 99% by weight, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or nonreducing conditions using Coomassie blue or, preferably, silver stain. Isolated binding proteins include the bindingprotein in situ within recombinant cells since at least one component of the binding protein's natural environment will not be present.

[0083] The terms "substantially pure" or "substantially purified" as used herein refer to a compound or species that is the predominant species present (z.e., on a molar basis it is more abundant than any other individual species in the composition). In some embodiments, a substantially purified fraction is a composition wherein the species comprises at least about 50% (on a molar basis) of all macromolecular species present. In other embodiments, a substantially pure composition will comprise more than about 80%, 85%, 90%, 95%, or 99% of all macromolar species present in the composition. In still other embodiments, the species is purified to essential homogeneity (contaminant species cannot be detected in the composition by conventional detection methods) wherein the composition consists essentially of a single macromolecular species.

[0084] The term "epitope" includes any determinant, preferably a polypeptide determinant, capable of specifically binding to an immunoglobulin or T-cell receptor. In certain embodiments, epitope determinants include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and, in certain embodiments, may have specific three-dimensional structural characteristics and / or specific charge characteristics. An epitope is a region of an antigen that is bound by an antibody or binding protein. In certain embodiments, a binding protein is said to specifically bind an antigen when it preferentially recognizes its target antigen in a complex mixture of proteins and / or macromolecules. In some embodiments, a binding protein is said to specifically bind an antigen when the equilibrium dissociation constant is < 10'8M, more preferably when the equilibrium dissociation constant is < 10'9M, and most preferably when the dissociation constant is < 10'10M.

[0085] The dissociation constant (KD) of a binding protein can be determined, for example, by surface plasmon resonance. Generally, surface plasmon resonance analysis measures real-time binding interactions between ligand (a target antigen on a biosensor matrix) and analyte (a binding protein in solution) by surface plasmon resonance (SPR) using the BIAcore system (Pharmacia Biosensor; Piscataway, NJ). Surface plasmon analysis can also be performed by immobilizing the analyte (binding protein on a biosensor matrix) and presenting the ligand (target antigen). The term "KD," as used herein refers to the dissociation constant of the interaction between a particular binding protein and a target antigen.

[0086] The term "specifically binds" as used herein refers to the ability of a binding protein or an antigen-binding fragment thereof to bind to an antigen containing an epitopewith an Kd of at least about 1 x 10'6M, 1 x 10'7M, 1 x 10'8M, 1 x 10'9M, 1 x IO'10M, 1 x 10'11M, l x IO’12M, or more, and / or to bind to an epitope with an affinity that is at least twofold greater than its affinity for a nonspecific antigen.

[0087] The term "linker" as used herein refers to one or more amino acid residues inserted between immunoglobulin domains to provide sufficient mobility for the domains of the light and heavy chains to fold into cross over dual variable region immunoglobulins. A linker is inserted at the transition between variable domains or between variable and constant domains, respectively, at the sequence level. The transition between domains can be identified because the approximate size of the immunoglobulin domains are well understood. The precise location of a domain transition can be determined by locating peptide stretches that do not form secondary structural elements such as beta-sheets or alpha-helices as demonstrated by experimental data or as can be assumed by techniques of modeling or secondary structure prediction. The linkers described herein are referred to as Li, which is located on the light chain between the C-terminus of the VL2 and the N-terminus of the VLI domain; and L2, which is located on the light chain between the C-terminus of the VLI and the N-terminus of the CL domain. The heavy chain linkers are known as L3, which is located between the C-terminus of the VHI and the N-terminus of the VH2 domain; and L4, which is located between the C-terminus of the VH2 and the N-terminus of the CHI domain.

[0088] The term "vector" as used herein refers to any molecule (e.g., nucleic acid, plasmid, or virus) that is used to transfer coding information to a host cell. The term "vector" includes a nucleic acid molecule that is capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid," which refers to a circular doublestranded DNA molecule into which additional DNA segments may be inserted. Another type of vector is a viral vector, wherein additional DNA segments may be inserted into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of a host cell upon introduction into the host cell and thereby are replicated along with the host genome. In addition, certain vectors are capable of directing the expression of genes to which they are operatively linked. Such vectors are referred to herein as "recombinant expression vectors" (or simply, "expression vectors"). In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. The terms "plasmid" and "vector" may be used interchangeably herein, as a plasmid is the most commonly used form of vector. However, the disclosure is intended toinclude other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses, and adeno-associated viruses), which serve equivalent functions.

[0089] The phrase "recombinant host cell" (or "host cell") as used herein refers to a cell into which a recombinant expression vector has been introduced. A recombinant host cell or host cell is intended to refer not only to the particular subject cell, but also to the progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but such cells are still included within the scope of the term "host cell" as used herein. A wide variety of host cell expression systems can be used to express the binding proteins, including bacterial, yeast, baculoviral, and mammalian expression systems (as well as phage display expression systems). An example of a suitable bacterial expression vector is pUC19. To express a binding protein recombinantly, a host cell is transformed or transfected with one or more recombinant expression vectors carrying DNA fragments encoding the polypeptide chains of the binding protein such that the polypeptide chains are expressed in the host cell and, preferably, secreted into the medium in which the host cells are cultured, from which medium the binding protein can be recovered.

[0090] The term "transformation" as used herein refers to a change in a cell's genetic characteristics, and a cell has been transformed when it has been modified to contain a new DNA. For example, a cell is transformed where it is genetically modified from its native state. Following transformation, the transforming DNA may recombine with that of the cell by physically integrating into a chromosome of the cell, or may be maintained transiently as an episomal element without being replicated, or may replicate independently as a plasmid. A cell is considered to have been stably transformed when the DNA is replicated with the division of the cell. The term "transfection" as used herein refers to the uptake of foreign or exogenous DNA by a cell, and a cell has been "transfected" when the exogenous DNA has been introduced inside the cell membrane. A number of transfection techniques are well known in the art. Such techniques can be used to introduce one or more exogenous DNA molecules into suitable host cells.

[0091] The term "naturally occurring" as used herein and applied to an object refers to the fact that the object can be found in nature and has not been manipulated by man. For example, a polynucleotide or polypeptide that is present in an organism (including viruses) that can be isolated from a source in nature and that has not been intentionally modified by man is naturally-occurring. Similarly, "non-naturally occurring" as used herein refers to anobject that is not found in nature or that has been structurally modified or synthesized by man.

[0092] As used herein, the twenty conventional amino acids and their abbreviations follow conventional usage. Stereoisomers (e.g., D-amino acids) of the twenty conventional amino acids; unnatural amino acids and analogs such as a-, a-di substituted amino acids, N-alkyl amino acids, lactic acid, and other unconventional amino acids may also be suitable components for the polypeptide chains of the binding proteins. Examples of unconventional amino acids include: 4-hydroxyproline, y-carboxyglutamate, s-N,N,N-trimethyllysine, s-N-acetyllysine, O-phosphoserine, N-acetylserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, o-N-methylarginine, and other similar amino acids and imino acids (e.g., 4-hydroxyproline). In the polypeptide notation used herein, the left-hand direction is the amino terminal direction and the right-hand direction is the carboxyl-terminal direction, in accordance with standard usage and convention.

[0093] Naturally occurring residues may be divided into classes based on common side chain properties:(1) hydrophobic: Met, Ala, Vai, Leu, He, Phe, Trp, Tyr, Pro;(2) polar hydrophilic: Arg, Asn, Asp, Gin, Glu, His, Lys, Ser, Thr ;(3) aliphatic: Ala, Gly, He, Leu, Vai, Pro;(4) aliphatic hydrophobic: Ala, He, Leu, Vai, Pro;(5) neutral hydrophilic: Cys, Ser, Thr, Asn, Gin;(6) acidic: Asp, Glu;(7) basic: His, Lys, Arg;(8) residues that influence chain orientation: Gly, Pro;(9) aromatic: His, Trp, Tyr, Phe; and(10) aromatic hydrophobic: Phe, Trp, Tyr.

[0094] Conservative amino acid substitutions may involve exchange of a member of one of these classes with another member of the same class. Non-conservative substitutions may involve the exchange of a member of one of these classes for a member from another class.

[0095] The term "patient" as used herein includes human and animal subjects.

[0096] The terms "treatment" or "treat" as used herein refer to therapeutic treatment and / or alleviating symptoms, e.g., in those in need thereof. Those in need of treatment include those having a disorder. In particular embodiments, binding proteins can be used to treat humans with an inflammatory disease or disorder, or an inflammatory disease ordisorder in a human subject. In particular embodiments, the inflammatory disease or disorder is atopic dermatitis.

[0097] The terms “prevention” or “prevent” as used herein refer to prophylactic or preventative measures. Those in need of prevention include those prone to have the disorder or those in which the disorder is to be prevented. In particular embodiments, binding proteins can be used to prevent humans prone to have an inflammatory disease or disorder, or humans susceptible to an inflammatory disease or disorder. The binding proteins can also be used to prevent an inflammatory disease or disorder in a human patient. In particular embodiments, the inflammatory disease or disorder is atopic dermatitis.

[0098] The terms "pharmaceutical composition" or "therapeutic composition" as used herein refer to a compound or composition capable of inducing a desired therapeutic effect when properly administered to a patient.

[0099] The term "pharmaceutically acceptable carrier" or "physiologically acceptable carrier" as used herein refers to one or more formulation materials suitable for accomplishing or enhancing the delivery of a binding protein.

[0100] The terms "effective amount" and "therapeutically effective amount" when used in reference to a pharmaceutical composition comprising one or more binding proteins refer to an amount or dosage sufficient to produce a desired therapeutic result. More specifically, a therapeutically effective amount may be an amount of a binding protein sufficient to inhibit, for some period of time, one or more of the clinically defined pathological processes associated with the condition being treated. The effective amount may vary depending on the specific binding protein that is being used, and also depends on a variety of factors and conditions related to the patient being treated and the severity of the disorder. For example, if the binding protein is to be administered in vivo, factors such as the age, weight, and health of the patient as well as dose response curves and toxicity data obtained in preclinical animal work may be among those factors considered.

[0101] One embodiment of the disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a binding protein.Trispecific Binding Proteins

[0102] Certain aspects of the present disclosure relate to trispecific and / or trivalent binding proteins comprising four polypeptide chains that form three antigen binding sites that specifically bind to one or more target proteins, wherein a first pair of polypeptides formingthe binding protein possess dual variable domains having a cross-over orientation (e.g., a CODV arm) and wherein a second pair of polypeptides forming the binding protein possess a single variable domain (e.g., a Fab arm). Any of the CDRs or variable domains of any of the antigen binding proteins described herein may find use in a trispecific binding protein of the present disclosure.

[0103] In some embodiments, each of the three antigen binding sites binds a different target (e.g., polypeptide antigen). In some embodiments, the trispecific binding protein comprises four polypeptide chains that form the three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula:VL2-LI-VLI-L2-CL [I]and a second polypeptide chain comprises a structure represented by the formula:VHI -L3- V H2-L4-CH1 -hinge-CH2-Cu3 [II]and a third polypeptide chain comprises a structure represented by the formula:VH3-Cui-hinge-CH2-CH3 [III]and a fourth polypeptide chain comprises a structure represented by the formula:VL3-CL [IV]wherein:VLI is a first immunoglobulin light chain variable domain;VL2 is a second immunoglobulin light chain variable domain;VL3 is a third immunoglobulin light chain variable domain;VHI is a first immunoglobulin heavy chain variable domain;VH2 is a second immunoglobulin heavy chain variable domain;VH3 is a third immunoglobulin heavy chain variable domain;CL is an immunoglobulin light chain constant domain;CHI is an immunoglobulin CHI heavy chain constant domain;CH2 is an immunoglobulin CH2 heavy chain constant domain;CH3 is an immunoglobulin CH3 heavy chain constant domain;hinge is an immunoglobulin hinge region connecting the CHI and CH2 domains; and Li, L2, L3 and L4 are amino acid linkers;wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.

[0104] In some embodiments, a trispecific binding protein of the present disclosure comprises a VHI and VLI domain pair that form a first antigen binding site, a VH2 and VL2domain pair that form a second antigen binding site, and a VH3 and VL3 domain pair that form a third antigen binding site. It is contemplated that any of the antigen binding sites described herein may find use in a trispecific binding protein of the present disclosure, e.g., comprising four polypeptide chains having the structures described supra. In some embodiments, a trispecific binding protein of the present disclosure comprises a VHI and VLI domain pair that form a first antigen binding site that specifically binds an IL-4 polypeptide, a VH2 and VL2 domain pair that form a second antigen binding site that specifically binds an IL- 13 polypeptide, and a VH3 and VL3 domain pair that form a third antigen binding site that specifically binds a third target antigen. In some embodiments, the third target antigen is not an IL-4 polypeptide or an IL- 13 polypeptide. In some embodiments, a trispecific binding protein of the present disclosure comprises a VHI and VLI domain pair that form a first antigen binding site that specifically binds an IL-4 polypeptide, a VH2 and VL2 domain pair that form a second antigen binding site that specifically binds an IL- 13 polypeptide, and a VH3 and VL3 domain pair that form a third antigen binding site that specifically binds an OX40L polypeptide.

[0105] In some embodiments, a trispecific binding protein of the present disclosure comprises a VHI and VLI domain pair that form a first antigen binding site that specifically binds an IL- 13 polypeptide, a VH2 and VL2 domain pair that form a second antigen binding site that specifically binds an IL-4 polypeptide, and a VH3 and VL3 domain pair that form a third antigen binding site that specifically binds a third target antigen. In some embodiments, the third target antigen is not an IL-4 polypeptide or an IL-13 polypeptide. In some embodiments, a trispecific binding protein of the present disclosure comprises a VHI and VLI domain pair that form a first antigen binding site that specifically binds an IL-13 polypeptide, a VH2 and VL2 domain pair that form a second antigen binding site that specifically binds an IL-4 polypeptide, and a VH3 and VL3 domain pair that form a third antigen binding site that specifically binds an OX40L polypeptide.

[0106] In some embodiments, a trispecific binding protein of the present disclosure is capable of inhibiting the function of one or more target proteins. In some embodiments, a trispecific binding protein of the present disclosure is capable of inhibiting the function of an IL-4 polypeptide and / or an IL-13 polypeptide. In some embodiments, a trispecific binding protein of the present disclosure is capable of inhibiting the function of an IL-4 polypeptide and an IL-13 polypeptide. In some embodiments, a trispecific binding protein of the present disclosure is capable of inhibiting the function of an OX40L polypeptide.

[0107] In some embodiments, a trispecific binding protein of the present disclosure comprises a VHI and VLI domain pair that form a first antigen binding site that specificallybinds an IL-4 polypeptide, a VH2 and VL2 domain pair that form a second antigen binding site that specifically binds an IL- 13 polypeptide, and a VH3 and VL3 domain pair that form a third antigen binding site that specifically binds an OX40L polypeptide. Any of the anti-IL-4 binding sites described below (e.g., in Table 1), anti-IL-13 binding sites described below (e.g., in Table 2), or anti-OX40L binding sites described below (e.g., in Table 3) may be used in a trispecific binding protein of the present disclosure.

[0108] In some embodiments, VHI comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:3; VLI comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8, and a CDR-L3 comprising the amino acid sequence of SEQ ID NOTO; VH2 comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:57, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:58, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:59; VL2 comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:60, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:61, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:62; VH3 comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:78, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:79, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:80; and VL3 comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:81, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:82, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:83. In some embodiments, VHI comprises the amino acid sequence of SEQ ID NO:34, VLI comprises the amino acid sequence of SEQ ID NO:35, VH2 comprises the amino acid sequence of SEQ ID NOTO, VL2 comprises the amino acid sequence of SEQ ID NO:71, VH3 comprises the amino acid sequence of SEQ ID NO:91, and VL3 comprises the amino acid sequence of SEQ ID NO:92.

[0109] In some embodiments, a binding protein of the present disclosure comprises four polypeptide chains that form three antigen binding sites, wherein the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:98 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:98; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:99 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 99; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 100 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 100; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 101 or an amino acid sequence thatis at least 95% identical to the amino acid sequence of SEQ ID NO: 101. In some embodiments, a binding protein of the present disclosure comprises four polypeptide chains that form three antigen binding sites, wherein the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:98; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:99; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 100; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 101.

[0110] Table 4 indicates the sequences of four chains of an exemplary trispecific binding protein. In some embodiments, a binding protein of the present disclosure comprises one, two, three, or all four polypeptide chains of a single binding protein described in Table 4. In some embodiments, a binding protein of the present disclosure comprises one, two, three, or four polypeptide chains that are at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to one, two, three, or all four polypeptide chains of a single binding protein described in Table 4.Table 4. Exemplary trispecific binding protein sequences.Anti-IL-4 Binding Sites[OHl] Certain aspects of the present disclosure relate to binding proteins that comprise an antigen binding site that binds (e.g., specifically binds) an IL-4 polypeptide. In some embodiments, the IL-4 polypeptide is a human IL-4 polypeptide, also known as IL4, BSF1, BSF-1, BCGF1, and BCGF-1. Human IL-4 polypeptides are known in the art and include, without limitation, the polypeptide represented by NCBI Accession Number NP_000580.1, or a polypeptide produced from NCBI Gene ID Number 3565, which are incorporated herein by reference.

[0112] In some embodiments, a binding protein comprising an antigen binding site that binds an IL-4 polypeptide is monospecific and / or monovalent, bispecific and / or bivalent, trispecific and / or trivalent, or multispecific and / or multivalent.

[0113] In some embodiments, any of the CDRs and / or variable domains of the anti -IL-4 binding sites described below can be used in a monospecific antibody. In some embodiments, the monospecific antibody is a monoclonal antibody.

[0114] In some embodiments, any of the CDRs and / or variable domains of the anti-IL-4 binding sites described below can be used in a bispecific or multispecific antibody.

[0115] In some embodiments, any of the CDRs and / or variable domains of the anti-IL-4 binding sites described below (e.g., in Table 1) can be used in any binding site of a trispecific binding protein comprising four polypeptides that form three antigen binding sites, e.g., as described supra. In certain embodiments, a binding protein that comprises an antigen binding site that binds an IL-4 polypeptide is a trispecific binding protein comprising four polypeptides that form three antigen binding sites as described supra. In some embodiments, the VHI and VLI domains pair and form a first antigen binding site that binds an IL-4 polypeptide.

[0116] In some embodiments, a binding site that binds IL-4 comprises: an antibody heavy chain variable (VH) domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence selected from the group consisting of SEQ ID NOs:3-5, and an antibody light chain variable (VL) domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6 or 7, a CDR-L2 comprising the amino acid sequence ofSEQ ID NOV or 9, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10 or 11.

[0117] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:3, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10.

[0118] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:3, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11.

[0119] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence of SEQ ID NON, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11.

[0120] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:5, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11.

[0121] In some embodiments, a binding site that binds IL-4 comprises: an antibody heavy chain variable (VH) domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 12, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 13, and a CDR-H3 comprising the amino acid sequence selected from the group consisting of SEQ ID NOs: 14-16, and an antibody light chain variable (VL) domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 17 or 18, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 19, and a CDR-L3 comprising the amino acid sequence of SEQ ID NOVO or 21.

[0122] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 12, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 13, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 14, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 17, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 19, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:20.

[0123] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 12, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 13, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 14, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 18, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 19, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:21.

[0124] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 12, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 13, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 15, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 18, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 19, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:21.

[0125] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 12, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 13, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 16, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 18, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 19, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:21.

[0126] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:34 and / or a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:35. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:34 and / or a VL domain that comprises the amino acid sequence of SEQ ID NO:35. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:34 and a VL domain that comprises the amino acid sequence of SEQ ID NO:35. In some embodiments, abinding site that binds IL-4 comprises: a VH domain that comprises 1, 2, or all 3 CDRs from a VH domain comprising the amino acid sequence of SEQ ID NO:34 and / or a VL domain that comprises 1, 2, or all 3 CDRs from a VL domain comprising the amino acid sequence of SEQ ID NO:35.

[0127] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:36 and / or a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:37. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:36 and / or a VL domain that comprises the amino acid sequence of SEQ ID NO:37. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:36 and a VL domain that comprises the amino acid sequence of SEQ ID NO:37. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises 1, 2, or all 3 CDRs from a VH domain comprising the amino acid sequence of SEQ ID NO:36 and / or a VL domain that comprises 1, 2, or all 3 CDRs from a VL domain comprising the amino acid sequence of SEQ ID NO:37.

[0128] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:38 and / or a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:39. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:38 and / or a VL domain that comprises the amino acid sequence of SEQ ID NO:39. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:38 and a VL domain that comprises the amino acid sequence of SEQ ID NO:39. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises 1, 2, or all 3 CDRs from a VH domain comprising the amino acid sequence of SEQ ID NO:38 and / or a VL domain that comprises 1, 2, or all 3 CDRs from a VL domain comprising the amino acid sequence of SEQ ID NO:39.

[0129] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:40 and / or a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:41. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:40 and / or a VL domain that comprises the amino acid sequence of SEQ ID NO:41. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:40 and a VL domain that comprises the amino acid sequence of SEQ ID NO:41. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises 1, 2, or all 3 CDRs from a VH domain comprising the amino acid sequence of SEQ ID NO:40 and / or a VL domain that comprises 1, 2, or all 3 CDRs from a VL domain comprising the amino acid sequence of SEQ ID NO:41.

[0130] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:42 and / or a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:42 and / or a VL domain that comprises the amino acid sequence of SEQ ID NO:43. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:42 and a VL domain that comprises the amino acid sequence of SEQ ID NO:43. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises 1, 2, or all 3 CDRs from a VH domain comprising the amino acid sequence of SEQ ID NO:42 and / or a VL domain that comprises 1, 2, or all 3 CDRs from a VL domain comprising the amino acid sequence of SEQ ID NO:43.

[0131] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:44 and / or a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:44 and / or a VL domain that comprises the amino acid sequence of SEQ ID NO:43. In some embodiments, a binding site that binds IL-4comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:44 and a VL domain that comprises the amino acid sequence of SEQ ID NO:43. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises 1, 2, or all 3 CDRs from a VH domain comprising the amino acid sequence of SEQ ID NO:44 and / or a VL domain that comprises 1, 2, or all 3 CDRs from a VL domain comprising the amino acid sequence of SEQ ID NO:43.

[0132] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:45 and / or a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:45 and / or a VL domain that comprises the amino acid sequence of SEQ ID NO:43. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:45 and a VL domain that comprises the amino acid sequence of SEQ ID NO:43. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises 1, 2, or all 3 CDRs from a VH domain comprising the amino acid sequence of SEQ ID NO:45 and / or a VL domain that comprises 1, 2, or all 3 CDRs from a VL domain comprising the amino acid sequence of SEQ ID NO:43.

[0133] In some embodiments, a binding site that binds IL-4 comprises: an antibody heavy chain variable (VH) domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence selected from the group consisting of SEQ ID NOs:24-27, and an antibody light chain variable (VL) domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6 or 7, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8 or 9, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:10 or 11.

[0134] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:24, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10.

[0135] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:24, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:9, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11.

[0136] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:25, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10.

[0137] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:25, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11.

[0138] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:26, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11.

[0139] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:27, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NOV, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11.

[0140] In some embodiments, a binding site that binds IL-4 comprises: an antibody heavy chain variable (VH) domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:28, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:29, and a CDR-H3 comprising the amino acid sequence selected from the group consisting of SEQ IDNOs:30-33, and an antibody light chain variable (VL) domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 17 or 18, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 19, and a CDR-L3 comprising the amino acid sequence of SEQ IDNO:20 or 21.

[0141] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:28, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:29, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:30, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 17, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 19, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:20.

[0142] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:28, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:29, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:30, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 18, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 19, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:21.

[0143] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:28, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:29, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:31, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 17, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 19, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:20.

[0144] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:28, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:29, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:31, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 18, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 19, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:21.

[0145] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:28, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:29, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:32, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 18, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 19, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:21.

[0146] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:28, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:29, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:33, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 18, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 19, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:21.

[0147] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:46 and / or a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:47. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:46 and / or a VL domain that comprises the amino acid sequence of SEQ ID NO:47. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:46 and a VL domain that comprises the amino acid sequence of SEQ ID NO:47. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises 1, 2, or all 3 CDRs from a VH domain comprising the amino acid sequence of SEQ ID NO:46 and / or a VL domain that comprises 1, 2, or all 3 CDRs from a VL domain comprising the amino acid sequence of SEQ ID NO:47.

[0148] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:48 and / or a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:39. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:48 and / or a VL domain that comprises the amino acid sequence of SEQ ID NO:39. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:48 and a VL domain that comprises the amino acid sequence of SEQ ID NO:39. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises 1, 2, or all 3 CDRs from a VH domain comprising the amino acid sequence of SEQ ID NO:48 and / or a VL domain that comprises 1, 2, or all 3 CDRs from a VL domain comprising the amino acid sequence of SEQ ID NO:39.

[0149] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:49 and / or a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:41. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:49 and / or a VL domain that comprises the amino acid sequence of SEQ ID NO:41. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:49 and a VL domain that comprises the amino acid sequence of SEQ ID NO:41. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises 1, 2, or all 3 CDRs from a VH domain comprising the amino acid sequence of SEQ ID NO:49 and / or a VL domain that comprises 1, 2, or all 3 CDRs from a VL domain comprising the amino acid sequence of SEQ ID NO:41.

[0150] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:50 and / or a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO: 50 and / or a VL domain that comprises the amino acid sequence of SEQ ID NO:43. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:50 and a VL domain that comprises the amino acid sequence of SEQ ID NO:43. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises 1, 2, or all 3 CDRs from a VH domain comprising the amino acid sequence of SEQ ID NO:50 and / or a VL domain that comprises 1, 2, or all 3 CDRs from a VL domain comprising the amino acid sequence of SEQ ID NO:43.

[0151] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:51 and / or a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:37. In some embodiments, a binding site that binds IL-4 comprises: a VH domain thatcomprises the amino acid sequence of SEQ ID NO: 51 and / or a VL domain that comprises the amino acid sequence of SEQ ID NO:37. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:51 and a VL domain that comprises the amino acid sequence of SEQ ID NO:37. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises 1, 2, or all 3 CDRs from a VH domain comprising the amino acid sequence of SEQ ID NO:51 and / or a VL domain that comprises 1, 2, or all 3 CDRs from a VL domain comprising the amino acid sequence of SEQ ID NO:37.

[0152] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:52 and / or a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:39. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO: 52 and / or a VL domain that comprises the amino acid sequence of SEQ ID NO:39. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:52 and a VL domain that comprises the amino acid sequence of SEQ ID NO:39. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises 1, 2, or all 3 CDRs from a VH domain comprising the amino acid sequence of SEQ ID NO:52 and / or a VL domain that comprises 1, 2, or all 3 CDRs from a VL domain comprising the amino acid sequence of SEQ ID NO:39.

[0153] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:53 and / or a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:41. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO: 53 and / or a VL domain that comprises the amino acid sequence of SEQ ID NO:41. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:53 and a VL domain that comprises the amino acid sequence of SEQ ID NO:41. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises 1, 2, or all 3 CDRs from a VH domain comprising the amino acid sequence of SEQ ID NO:53 and / or a VL domainthat comprises 1, 2, or all 3 CDRs from a VL domain comprising the amino acid sequence of SEQ ID NO:4L

[0154] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:54 and / or a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO: 54 and / or a VL domain that comprises the amino acid sequence of SEQ ID NO:43. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:54 and a VL domain that comprises the amino acid sequence of SEQ ID NO:43. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises 1, 2, or all 3 CDRs from a VH domain comprising the amino acid sequence of SEQ ID NO:54 and / or a VL domain that comprises 1, 2, or all 3 CDRs from a VL domain comprising the amino acid sequence of SEQ ID NO:43.

[0155] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:55 and / or a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO: 55 and / or a VL domain that comprises the amino acid sequence of SEQ ID NO:43. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:55 and a VL domain that comprises the amino acid sequence of SEQ ID NO:43. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises 1, 2, or all 3 CDRs from a VH domain comprising the amino acid sequence of SEQ ID NO:55 and / or a VL domain that comprises 1, 2, or all 3 CDRs from a VL domain comprising the amino acid sequence of SEQ ID NO:43.

[0156] In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:56 and / or a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO: 56 and / or a VL domain that comprises the amino acid sequence of SEQ ID NO:43. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:56 and a VL domain that comprises the amino acid sequence of SEQ ID NO:43. In some embodiments, a binding site that binds IL-4 comprises: a VH domain that comprises 1, 2, or all 3 CDRs from a VH domain comprising the amino acid sequence of SEQ ID NO:56 and / or a VL domain that comprises 1, 2, or all 3 CDRs from a VL domain comprising the amino acid sequence of SEQ ID NO:43.

[0157] Sequences of exemplary anti-IL-4 antigen binding sites are provided in Table 1. In some embodiments, a binding protein comprising an anti-IL-4 antigen binding site of the present disclosure comprises 1, 2, 3, 4, 5, or all 6 CDR sequences of an anti-IL-4 antibody described in Table 1. In some embodiments, a binding protein comprising an anti-IL-4 antigen binding site of the present disclosure comprises a VH domain sequence and / or VL domain sequence of an anti-IL-4 antibody described in Table 1.Table 1. Anti-IL-4 binding protein sequences.Anti-IL-13 Binding Sites

[0158] Certain aspects of the present disclosure relate to binding proteins that comprise an antigen binding site that binds (e.g., specifically binds) an IL- 13 polypeptide. In some embodiments, the IL-13 polypeptide is a human IL-13 polypeptide, also known as IL13 and P600. Human IL- 13 polypeptides are known in the art and include, without limitation, the polypeptide represented by NCBI Accession Number NP_001341920.1, or a polypeptide produced from NCBI Gene ID Number 3596, which are incorporated herein by reference.

[0159] In some embodiments, a binding protein comprising an antigen binding site that binds an IL-13 polypeptide is monospecific and / or monovalent, bispecific and / or bivalent, trispecific and / or trivalent, or multispecific and / or multivalent.

[0160] In some embodiments, any of the CDRs and / or variable domains of the anti-IL-13 binding sites described below can be used in a monospecific antibody. In some embodiments, the monospecific antibody is a monoclonal antibody.

[0161] In some embodiments, any of the CDRs and / or variable domains of the anti-IL-13 binding sites described below can be used in a bispecific or multispecific antibody.

[0162] In some embodiments, any of the CDRs and / or variable domains of the anti-IL-13 binding sites described below (e.g., in Table 2) can be used in any binding site of a trispecific binding protein comprising four polypeptides that form three antigen binding sites, e.g., as described supra. In certain embodiments, a binding protein that comprises an antigen binding site that binds an IL- 13 polypeptide is a trispecific binding protein comprising four polypeptides that form three antigen binding sites as described supra. In some embodiments, the VH2 and VL2 domains pair and form a second antigen binding site that binds an IL-13 polypeptide.

[0163] In some embodiments, a binding site that binds IL-13 comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:57, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:58, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:59 or 108, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:60, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:61, and a CDR-L3 comprising the amino acid sequence of SEQ IDNO:62.

[0164] In some embodiments, a binding site that binds IL-13 comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:57, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:58, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:59, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:60, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:61, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:62.

[0165] In some embodiments, a binding site that binds IL-13 comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:57, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:58, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 108, and a VL domain that comprises a CDR-L1 comprisingthe amino acid sequence of SEQ ID NO:60, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:61, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:62.

[0166] In some embodiments, a binding site that binds IL-13 comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:63, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:64, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:65 or 66, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:67, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:68, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:69. In some embodiments, a binding site that binds IL-13 comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:63, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:64, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:65, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:67, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:68, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:69. In some embodiments, a binding site that binds IL-13 comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:63, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:64, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:66, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:67, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:68, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:69.

[0167] In some embodiments, a binding site that binds IL-13 comprises: a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:70 and / or a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:71. In some embodiments, a binding site that binds IL-13 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:70 and / or a VL domain that comprises the amino acid sequence of SEQ ID NO:71. In some embodiments, a binding site that binds IL-13 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:70 and a VL domain that comprises the amino acid sequence of SEQ ID NO:71. In some embodiments, a binding site that binds IL-13 comprises: a VH domain that comprises 1, 2, or all 3 CDRs from a VH domain comprising the amino acid sequence of SEQ ID NO:70 and / or a VL domain that comprises 1, 2, or all 3 CDRs from a VL domain comprising the amino acid sequence of SEQ ID NO:71.

[0168] In some embodiments, a binding site that binds IL-13 comprises: a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:72 and / or a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:73. In some embodiments, a binding site that binds IL-13 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:72 and / or a VL domain that comprises the amino acid sequence of SEQ ID NO: 73. In some embodiments, a binding site that binds IL-13 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:72 and a VL domain that comprises the amino acid sequence of SEQ ID NO:73. In some embodiments, a binding site that binds IL-13 comprises: a VH domain that comprises 1, 2, or all 3 CDRs from a VH domain comprising the amino acid sequence of SEQ ID NO:72 and / or a VL domain that comprises 1, 2, or all 3 CDRs from a VL domain comprising the amino acid sequence of SEQ ID NO: 73.

[0169] In some embodiments, a binding site that binds IL-13 comprises: a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:74 and / or a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:75. In some embodiments, a binding site that binds IL-13 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:74 and / or a VL domain that comprises the amino acid sequence of SEQ ID NO: 75. In some embodiments, a binding site that binds IL-13 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:74 and a VL domain that comprises the amino acid sequence of SEQ ID NO:75. In some embodiments, a binding site that binds IL-13 comprises: a VH domain that comprises 1, 2, or all 3 CDRs from a VH domain comprising the amino acid sequence of SEQ ID NO:74 and / or a VL domain that comprises 1, 2, or all 3 CDRs from a VL domain comprising the amino acid sequence of SEQ ID NO: 75.

[0170] In some embodiments, a binding site that binds IL-13 comprises: a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:76 and / or a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:77. In some embodiments, a binding site that binds IL-13 comprises: a VH domain thatcomprises the amino acid sequence of SEQ ID NO:76 and / or a VL domain that comprises the amino acid sequence of SEQ ID NO:77. In some embodiments, a binding site that binds IL-13 comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:76 and a VL domain that comprises the amino acid sequence of SEQ ID NO:77. In some embodiments, a binding site that binds IL-13 comprises: a VH domain that comprises 1, 2, or all 3 CDRs from a VH domain comprising the amino acid sequence of SEQ ID NO:76 and / or a VL domain that comprises 1, 2, or all 3 CDRs from a VL domain comprising the amino acid sequence of SEQ ID NO:77.

[0171] Sequences of exemplary anti-IL-13 antigen binding sites are provided in Table 2. In some embodiments, a binding protein comprising an anti-IL-13 antigen binding site of the present disclosure comprises 1, 2, 3, 4, 5, or all 6 CDR sequences of an anti-IL-13 antibody described in Table 2. In some embodiments, a binding protein comprising an anti-IL-13 antigen binding site of the present disclosure comprises a VH domain sequence and / or VL domain sequence of an anti-IL-13 antibody described in Table 2.Table 2. Anti-IL-13 binding protein sequences.Anti-OX40L Binding Sites

[0172] Certain aspects of the present disclosure relate to binding proteins that comprise an antigen binding site that binds (e.g., specifically binds) an OX40L polypeptide. In some embodiments, the OX40L polypeptide is a human OX40L polypeptide, also known as tumor necrosis factor (TNF) superfamily member 4 (TNFSF4), GP34, CD252, TXGP1, CD134L, OX-40L, and TNLG2B. Human OX40L polypeptides are known in the art and include, without limitation, the polypeptide represented by NCBI Accession NumberNP 001284491.1, or a polypeptide produced from NCBI Gene ID Number 7292. In some embodiments, the OX40L polypeptide comprises the amino acid sequence MERVQPLEENVGNAARPRFERNKLLLVASVIQGLGLLLCFTYICLHFSALQVSHRYP RIQSIKVQFTEYKKEKGFILTSQKEDEIMKVQNNSVIINCDGFYLISLKGYFSQEVNISL HYQKDEEPLFQLKKVRSVNSLMVASLTYKDKVYLNVTTDNTSLDDFHVNGGELILI HQNPGEFCVL (SEQ ID NO: 110).

[0173] In some embodiments, a binding protein comprising an antigen binding site that binds an OX40L polypeptide is monospecific and / or monovalent, bispecific and / or bivalent, trispecific and / or trivalent, or multispecific and / or multivalent.

[0174] In some embodiments, any of the CDRs and / or variable domains of the anti-OX40L binding sites described below can be used in a monospecific antibody. In some embodiments, the monospecific antibody is a monoclonal antibody.

[0175] In some embodiments, any of the CDRs and / or variable domains of the anti-OX40L binding sites described below can be used in a bispecific or multispecific antibody.

[0176] In some embodiments, any of the CDRs and / or variable domains of the anti-OX40L binding sites described below (e.g., in Table 3) can be used in any binding site of a trispecific binding protein comprising four polypeptides that form three antigen binding sites, e.g., as described supra. In certain embodiments, a binding protein that comprises an antigen binding site that binds an OX40L polypeptide is a trispecific binding protein comprising four polypeptides that form three antigen binding sites as described supra. In some embodiments, the VH3 and VL3 domains pair and form a third antigen binding site that binds an OX40L polypeptide.

[0177] In some embodiments, the binding site that specifically binds an OX40L polypeptide binds to an epitope of human OX40L that at least partially overlaps with that of human 0X40. In some embodiments, the binding site that specifically binds an OX40L polypeptide binds to an epitope of human OX40L comprising one or more of the following residues (numbering based on SEQ ID NO: 110): Q65, T67, E68, T78, Q80, K106, G107, Y108, F109, SI 10, QI 11, E112, D122, E123, E124, F127, Q128, L129, K130, K131, R133, S134, N136, D156, N157, T158, S159, L160, D161, D162, H164, and N166. In some embodiments, the binding site that specifically binds an OX40L polypeptide binds to an epitope of human OX40L comprising all of the following residues (numbering based on SEQ ID NO: 110): Q65, T67, E68, T78, Q80, K106, G107, Y108, F109, SI 10, QI 11, El 12, D122, E123, E124, F127, Q128, L129, K130, K131, R133, S134, N136, D156, N157, T158, S159, L160, D161, D162, H164, andN166. In some embodiments, residues Q65, T67, E68, T78, Q80, K106, G107, Y108, F109, SI 10, Qlll, E112, K131, R133, S134, N136 D156, N157, T158, S159, L160, D161, D162, H164, and N166 are part of a first OX40L monomer, and residues D122, E123, E124, F127, Q128, L129, and K130 are part of a second OX40L monomer.

[0178] In some embodiments, the binding site that specifically binds an OX40L polypeptide binds to human OX40L with a paratope comprising one or more of the followingVH domain residues: F27, T28, N30 / S30, S31, Y32, D50, S52, S54, R56, S57, K98, D99, F102, C103, S104, A106, S107, C108, N109, El 10, and Y113 (consecutive numbering of SEQ ID NO:97) and / or one or more of the following VL domain residues: R30, N31, D32, S56, H91, S92, R93, Y94, P95, and W96 (consecutive numbering of SEQ ID NO:96). In some embodiments, the binding site that specifically binds an OX40L polypeptide binds to human OX40L with a paratope comprising one or more of the following VH domain residues: F27, T28, N30 / S30, S31, Y32, D50, S52, S54, R56, S57, K98, D99, F102, C103, SI 04, Al 06, SI 07, Cl 08, N109, El 10, and Y113 (consecutive numbering of SEQ ID NO :97) and one or more of the following VL domain residues: R30, N31, D32, S56, H91, S92, R93, Y94, P95, and W96 (consecutive numbering of SEQ ID NO:96). In some embodiments, the binding site that specifically binds an OX40L polypeptide binds to human OX40L with a paratope comprising all of the following VH domain residues: F27, T28, N30 / S30, S31, Y32, D50, S52, S54, R56, S57, K98, D99, F102, C103, S104, A106, S107, C108, N109, El 10, and Y113 (consecutive numbering of SEQ ID NO:97) and all of the following VL domain residues: R30, N31, D32, S56, H91, S92, R93, Y94, P95, and W96 (consecutive numbering of SEQ ID NO: 96).

[0179] In some embodiments, a binding site that binds OX40L comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:78, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:79, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:80, and VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:81, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:82, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:83.

[0180] In some embodiments, a binding site that binds OX40L comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:84 or 85, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:86, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:87, and VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:88, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:89, and a CDR-L3 comprising the amino acid sequence of SEQ ID NOVO. In some embodiments, a binding site that binds OX40L comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:84, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 86, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:87, and VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:88, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:89, and a CDR-L3 comprising the amino acid sequence of SEQ ID NOVO. Insome embodiments, a binding site that binds OX40L comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:85, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 86, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:87, and VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:88, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:89, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:90.

[0181] In some embodiments, a binding site that binds OX40L comprises: a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:91 and / or a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:92. In some embodiments, a binding site that binds OX40L comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:91 and / or a VL domain that comprises the amino acid sequence of SEQ ID NO:92. In some embodiments, a binding site that binds OX40L comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:91 and a VL domain that comprises the amino acid sequence of SEQ ID NO:92. In some embodiments, a binding site that binds OX40L comprises: a VH domain that comprises 1, 2, or all 3 CDRs from a VH domain comprising the amino acid sequence of SEQ ID NO:91 and / or a VL domain that comprises 1, 2, or all 3 CDRs from a VL domain comprising the amino acid sequence of SEQ ID NO:92.

[0182] In some embodiments, a binding site that binds OX40L comprises: a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:93 and / or a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:94. In some embodiments, a binding site that binds OX40L comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:93 and / or a VL domain that comprises the amino acid sequence of SEQ ID NO:94. In some embodiments, a binding site that binds OX40L comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:93 and a VL domain that comprises the amino acid sequence of SEQ ID NO:94. In some embodiments, a binding site that binds OX40L comprises: a VH domain that comprises 1, 2, or all 3 CDRs from a VH domain comprising the amino acid sequence of SEQ ID NO:93 and / or a VL domain that comprises 1, 2, or all 3 CDRs from a VL domain comprising the amino acid sequence of SEQ ID NO:94.

[0183] In some embodiments, a binding site that binds OX40L comprises: a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:95 and / or a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:96. In some embodiments, a binding site that binds OX40L comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:95 and / or a VL domain that comprises the amino acid sequence of SEQ ID NO:96. In some embodiments, a binding site that binds OX40L comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:95 and a VL domain that comprises the amino acid sequence of SEQ ID NO:96. In some embodiments, a binding site that binds OX40L comprises: a VH domain that comprises 1, 2, or all 3 CDRs from a VH domain comprising the amino acid sequence of SEQ ID NO:95 and / or a VL domain that comprises 1, 2, or all 3 CDRs from a VL domain comprising the amino acid sequence of SEQ ID NO:96.

[0184] In some embodiments, a binding site that binds OX40L comprises: a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:97 and / or a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:96. In some embodiments, a binding site that binds OX40L comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:97 and / or a VL domain that comprises the amino acid sequence of SEQ ID NO:96. In some embodiments, a binding site that binds OX40L comprises: a VH domain that comprises the amino acid sequence of SEQ ID NO:97 and a VL domain that comprises the amino acid sequence of SEQ ID NO:96. In some embodiments, a binding site that binds OX40L comprises: a VH domain that comprises 1, 2, or all 3 CDRs from a VH domain comprising the amino acid sequence of SEQ ID NO:97 and / or a VL domain that comprises 1, 2, or all 3 CDRs from a VL domain comprising the amino acid sequence of SEQ ID NO:96.

[0185] Sequences of exemplary anti-OX40L antigen binding sites are provided in Table 3. In some embodiments, a binding protein comprising an anti-OX40L antigen binding site of the present disclosure comprises 1, 2, 3, 4, 5, or all 6 CDR sequences of an anti-OX40L antibody described in Table 3. In some embodiments, a binding protein comprising an anti-OX40L antigen binding site of the present disclosure comprises a VH domain sequence and / or VL domain sequence of an anti-OX40L antibody described in Table 3.Table 3. Anti-OX40L binding protein sequences.Chain pairing

[0186] In some embodiments, a binding protein of the present disclosure may comprise one or more amino acid substitutions, e.g, within a VH and / or VL domain, to facilitate heavy-light chain pairing. For example, a binding protein such as a bispecific, trispecific, or multispecific binding protein of the present disclosure comprising two or more distinct species of heavy and cognate light chains may comprise one or more substitutions in the pairing heavy and light chains (e.g., in the VH and VL domains) that promote proper pairing of the correct, cognate heavy and light chains. One example of such technology is the DuetMab concept, in which native disulfide bonds in only one arm of a bispecific antibody are removed and replaced by non-natural disulfide bonds at different positions (e.g., through reciprocal removal of native cysteine residues from the heavy and light chain and introduction of non-native cysteine residues at other positions in the heavy and light chain). See, e.g, Mazor, Y. et al. (2015)AL4fe 7(2):377-389.

[0187] In some embodiments, a binding protein of the present disclosure may comprise pair of reciprocal amino acid substitutions on the VH and VL domains that facilitate heavylight chain pairing. In some embodiments, one, two, or all three antigen binding domains of a trispecific binding protein of the present disclosure may comprise pair of reciprocal amino acid substitutions on the VH and VL domains that facilitate heavy -light chain pairing. In some embodiments, one or both antigen binding domain(s) of a bispecific binding protein of the present disclosure may comprise pair of reciprocal amino acid substitutions on the VH and VL domains that facilitate heavy -light chain pairing. Amino acid substitutions of VH and VL domains that facilitate heavy -light chain pairing (e.g, promote correct heavy-light chain pairing) are known in the art; see, e.g., Dillon, M. et al. (2017) MAbs 9(2):213-230 and Bagert, J.D. el al. (2023) MAbs 15(1):2273449.Linkers

[0188] In some embodiments, the linkers Li, L2, L3, and L4 range from no amino acids (length=O) to about 100 amino acids long, or less than 100, 50, 40, 30, 20, or 15 amino acids or less. The linkers can also be 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acids long. Li, L2, L3, and L4 in one binding protein may all have the same amino acid sequence or may all have different amino acid sequences.

[0189] Examples of suitable linkers include, for example, GGGGSGGGGS (SEQ ID NO: 102), GGGGSGGGGSGGGGS (SEQ ID NO: 103), S, RT, TKGPS (SEQ ID NO: 104), GQPKAAP (SEQ ID NO: 105), GGSGSSGSGG (SEQ ID NO: 106), and DKTHT (SEQ ID NO: 109), as well as those disclosed in International Publication Nos. WO2017 / 074878, W02017 / 180913, and W02020 / 210392. The examples listed above are not intended to limit the scope of the disclosure in any way, and linkers comprising randomly selected amino acids selected from the group consisting of valine, leucine, isoleucine, serine, threonine, lysine, arginine, histidine, aspartate, glutamate, asparagine, glutamine, glycine, and proline have been shown to be suitable in the binding proteins.

[0190] The identity and sequence of amino acid residues in the linker may vary depending on the type of secondary structural element necessary to achieve in the linker. For example, glycine, serine, and alanine are best for linkers having maximum flexibility. Some combination of glycine, proline, threonine, and serine are useful if a more rigid and extended linker is necessary. Any amino acid residue may be considered as a linker in combination with other amino acid residues to construct larger peptide linkers as necessary depending on the desired properties.

[0191] In some embodiments, the length of Li is at least twice the length of L3. In some embodiments, the length of L2 is at least twice the length of L4. In some embodiments, the length of Li is at least twice the length of L3, and the length of L2 is at least twice the length of L4. In some embodiments, Li is 3 to 12 amino acid residues in length, L2 is 3 to 14 amino acid residues in length, L3 is 1 to 8 amino acid residues in length, and L4 is 1 to 3 amino acid residues in length. In some embodiments, Li is 5 to 10 amino acid residues in length, L2 is 5 to 8 amino acid residues in length, L3 is 1 to 5 amino acid residues in length, and L4 is 1 to 2 amino acid residues in length. In some embodiments, Li is 7 amino acid residues in length, L2 is 5 amino acid residues in length, L3 is 1 amino acid residue in length, and L4 is 2 amino acid residues in length.

[0192] In some embodiments, Li, L2, L3 and L4 each independently are zero amino acids in length or comprise a sequence selected from the group consisting of GGGGSGGGGS (SEQ ID NO: 102), GGGGSGGGGSGGGGS (SEQ ID NO: 103), S, RT, TKGPS (SEQ ID NO: 104), GQPKAAP (SEQ ID NO: 105), and GGSGSSGSGG (SEQ ID NO: 106). In some embodiments, Li, L2, L3 and L4 each independently comprise a sequence selected from the group consisting of GGGGSGGGGS (SEQ ID NO: 102), GGGGSGGGGSGGGGS (SEQ ID NO: 103), S, RT, TKGPS (SEQ ID NO: 104), GQPKAAP (SEQ ID NO: 105), and GGSGSSGSGG (SEQ ID NO: 106). In some embodiments, Li comprises the sequence GQPKAAP (SEQ ID NO: 105), L2comprises the sequence TKGPS (SEQ ID NO: 104), L3comprises the sequence S, and L4 comprises the sequence RT.

[0193] In some embodiments, at least one of Li, L2, L3 or L4 comprises the sequence DKTHT (SEQ ID NO: 109). In some embodiments, Li, L2, L3 and L4 comprise the sequence DKTHT (SEQ ID NO: 109).Fc regions and constant domains

[0194] In some embodiments, a binding protein of the present disclosure comprises a second polypeptide chain further comprising an Fc region linked to CHI, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains. In some embodiments, a binding protein of the present disclosure comprises a third polypeptide chain further comprising an Fc region linked to CHI, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains. In some embodiments, a binding protein of the present disclosure comprises a second polypeptide chain further comprising an Fc region linked to CHI, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, and a third polypeptide chain further comprising an Fc region linked to CHI, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains.

[0195] In some embodiments, a binding protein of the present disclosure comprises a full-length antibody heavy chain or a polypeptide chain comprising an Fc region. In some embodiments, the Fc region is a human Fc region, e.g., a human IgGl, IgG2, IgG3, or IgG4 Fc region. In some embodiments, the antibody constant region includes an antibody hinge, CHI, CH2, CH3, and optionally CH4 domains. In some embodiments, the Fc region includes antibody CH2, CH3, and optionally CH4 domains. In some embodiments, the Fc region is a human IgGl Fc region. In some embodiments, the Fc region is a human IgG4 Fc region. Insome embodiments, the Fc region includes one or more of the mutations described infra. In some embodiments, the Fc region is an Fc region of one of the heavy chain polypeptides (e.g., polypeptide 2 or 3) of a binding protein shown in Table 4. In some embodiments, the heavy chain constant region is a constant region of one of the heavy chain polypeptides (e.g., polypeptide 2 or 3) of a binding protein shown in Table 4. In some embodiments, the light chain constant region is a constant region of one of the light chain polypeptides (e.g., polypeptide 1 or 4) of a binding protein shown in Table 4.

[0196] In some embodiments, a binding protein of the present disclosure includes one or two Fc variants. The term "Fc variant" as used herein refers to a molecule or sequence that is modified from a native Fc but still comprises a binding site for the salvage receptor, FcRn (neonatal Fc receptor). Exemplary Fc variants, and their interaction with the salvage receptor, are known in the art. Thus, the term "Fc variant" can comprise a molecule or sequence that is humanized from a non-human native Fc. Furthermore, a native Fc comprises regions that can be removed because they provide structural features or biological activity that are not required for the antibody -like binding proteins of the invention. Thus, the term "Fc variant" comprises a molecule or sequence that lacks one or more native Fc sites or residues, or in which one or more Fc sites or residues has be modified, that affect or are involved in: (1) disulfide bond formation, (2) incompatibility with a selected host cell, (3) N-terminal heterogeneity upon expression in a selected host cell, (4) glycosylation, (5) interaction with complement, (6) binding to an Fc receptor other than a salvage receptor, or (7) antibodydependent cellular cytotoxicity (ADCC).

[0197] In some embodiments, a binding protein of the present disclosure (e.g., a trispecific binding protein) comprises a “knob” mutation on the second polypeptide chain and a “hole” mutation on the third polypeptide chain. In some embodiments, a binding protein of the present disclosure comprises a “knob” mutation on the third polypeptide chain and a “hole” mutation on the second polypeptide chain. In some embodiments, the “knob” mutation comprises substitution(s) at positions corresponding to positions 354 and / or 366 of human IgGl or IgG4 according to EU Index. In some embodiments, the amino acid substitutions are S354C, T366W, T366Y, S354C and T366W, or S354C and T366Y. In some embodiments, the “knob” mutation comprises substitutions at positions corresponding to positions 354 and 366 of human IgGl or IgG4 according to EU Index. In some embodiments, the amino acid substitutions are S354C and T366W. In some embodiments, the “hole” mutation comprises substitution(s) at positions corresponding to positions 407 and, optionally, 349, 366, and / or 368 and of human IgGl or IgG4 according to EU Index. In some embodiments, the amino acid substitutions areY407V or Y407T and optionally Y349C, T366S, and / or L368A. In some embodiments, the “hole” mutation comprises substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgGl or IgG4 according to EU Index. In some embodiments, the amino acid substitutions are Y349C, T366S, L368A, and Y407V.

[0198] In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CHI, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitution(s) at positions corresponding to positions 366 and optionally 354 of human IgGl or IgG4 according to EU Index, wherein the amino acid substitutions are T366W or T366Y and optionally S354C; and wherein the third polypeptide chain further comprises a second Fc region linked to CHI, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitution(s) at positions corresponding to positions 407 and optionally 349, 366, and / or 368 and of human IgGl or IgG4 according to EU Index, wherein the amino acid substitutions are Y407V or Y407T and optionally Y349C, T366S, and / or L368A.

[0199] In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CHI, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitution(s) at positions corresponding to positions 407 and optionally 349, 366, and / or 368 and of human IgGl or IgG4 according to EU Index, wherein the amino acid substitutions are Y407V or Y407T and optionally Y349C, T366S, and / or L368A; and wherein the third polypeptide chain further comprises a second Fc region linked to CHI, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitution(s) at positions corresponding to positions 366 and optionally 354 of human IgGl or IgG4 according to EU Index, wherein the amino acid substitutions are T366W or T366Y and optionally S354C.

[0200] In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CHI, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitution at position corresponding to position 366 of human IgGl or IgG4 according to EU Index, wherein the amino acid substitution is T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to CHI, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chainconstant domains, wherein the second Fc region comprises amino acid substitution(s) at positions corresponding to positions 366, 368, and / or 407 and of human IgGl or IgG4 according to EU Index, wherein the amino acid substitutions are T366S, L368A, and / or Y407V.

[0201] In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CHI, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitution(s) at positions corresponding to positions 366, 368, and / or 407 and of human IgGl or IgG4 according to EU Index, wherein the amino acid substitutions are T366S, L368A, and / or Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to CHI, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitution at position corresponding to position 366 of human IgGl or IgG4 according to EU Index, wherein the amino acid substitution is T366W.

[0202] In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CHI, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgGl or IgG4 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to CHI, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgGl or IgG4 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CHI, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgGl or IgG4 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to CHI, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgGl or IgG4 according to EU Index, wherein the amino acid substitutions areS354C and T366W. In some embodiments, the first and / or second Fc regions are human IgGl Fc regions. In some embodiments, the first and / or second Fc regions are human IgG4 Fc regions.

[0203] In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CHI, wherein the first Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 228, 354, 366, and 409 of human IgG4 according to EU Index, wherein the amino acid substitutions are S228P, S354C, T366W, and R409K; and wherein the third polypeptide chain further comprises a second Fc region linked to CHI, wherein the second Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 228, 349, 366, 368, 407, and 409 of human IgG4 according to EU Index, wherein the amino acid substitutions are S228P, Y349C, T366S, L368A, Y407V, and R409K. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CHI, wherein the first Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 228, 349, 366, 368, 407, and 409 of human IgG4 according to EU Index, wherein the amino acid substitutions are S228P, Y349C, T366S, L368A, Y407V, and R409K; and wherein the third polypeptide chain further comprises a second Fc region linked to CHI, wherein the second Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 228, 354, 366, and 409 of human IgG4 according to EU Index, wherein the amino acid substitutions are S228P, S354C, T366W, and R409K.

[0204] In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CHI, wherein the first Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 234, 235, 354, and 366 of human IgG4 according to EU Index, wherein the amino acid substitutions are F234A, L235A, S354C, and T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to CHI, wherein the second Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 234, 235, 349, 366, 368, and 407 of human IgG4 according to EU Index, wherein the amino acid substitutions are F234A, L235A, Y349C, T366S, L368A, and Y407V. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CHI, wherein the first Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 234, 235, 349, 366, 368, and 407 of human IgG4 according to EU Index, wherein the amino acid substitutions are F234A, L235A, Y349C, T366S, L368A, and Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to CHI, wherein the second Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 234, 235, 354, and 366 of human IgG4 according to EU Index, wherein the amino acid substitutions are F234A, L235A, S354C, and T366W.

[0205] In some embodiments, a binding protein of the present disclosure comprises one or more mutations to reduce effector function, e.g., Fc receptor-mediated antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), and / or antibodydependent cellular cytotoxicity (ADCC). In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CHI, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains; wherein the third polypeptide chain further comprises a second Fc region linked to CHI, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains; wherein the first and second Fc regions are human IgGl Fc regions; and wherein the first and the second Fc regions each comprise amino acid substitutions at positions corresponding to positions 234 and 235 of human IgGl according to EU Index, wherein the amino acid substitutions are L234A and L235A. In some embodiments, the Fc regions of the second and the third polypeptide chains are human IgGl Fc regions, and wherein the Fc regions each comprise amino acid substitutions at positions corresponding to positions 234 and 235 of human IgGl according to EU Index, wherein the amino acid substitutions are L234A and L235A. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CHI, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains; wherein the third polypeptide chain further comprises a second Fc regionlinked to CHI, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains; wherein the first and second Fc regions are human IgGl Fc regions; and wherein the first and the second Fc regions each comprise amino acid substitutions at positions corresponding to positions 234, 235, and 329 of human IgGl according to EU Index, wherein the amino acid substitutions are L234A, L235A, and P329A. In some embodiments, the Fc regions of the second and the third polypeptide chains are human IgGl Fc regions, and wherein the Fc regions each comprise amino acid substitutions at positions corresponding to positions 234, 235, and 329 of human IgGl according to EU Index, wherein the amino acid substitutions are L234A, L235A, and P329A. In some embodiments, the Fc regions of the second and the third polypeptide chains are human IgG4 Fc regions, and the Fc regions each comprise amino acid substitutions at positions corresponding to positions 234 and 235 of human IgG4 according to EU Index, wherein the amino acid substitutions are F234A and L235A. In some embodiments, the binding protein comprises a second polypeptide chain further comprising a first Fc region linked to CHI, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, and a third polypeptide chain further comprising a second Fc region linked to CHI, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains; and wherein the first and the second Fc regions each comprise amino acid substitutions at positions corresponding to positions 234 and 235 of human IgG4 according to EU Index, wherein the amino acid substitutions are F234A and L235A.

[0206] In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CHI, wherein the first Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 228, 234, 235, 354, 366, and 409 of human IgG4 according to EU Index, wherein the amino acid substitutions are S228P, F234A, L235A, S354C, T366W, and R409K; and wherein the third polypeptide chain further comprises a second Fc region linked to CHI, wherein the second Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 228, 234, 235, 349, 366, 368, 407, and 409 of human IgG4 according to EU Index, wherein the amino acid substitutions are S228P, F234A, L235A, Y349C, T366S, L368A, Y407V, and R409K. In some embodiments, the second polypeptidechain further comprises a first Fc region linked to CHI, wherein the first Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 228, 234, 235, 349, 366, 368, 407, and 409 of human IgG4 according to EU Index, wherein the amino acid substitutions are S228P, F234A, L235A, Y349C, T366S, L368A, Y407V, and R409K; and wherein the third polypeptide chain further comprises a second Fc region linked to CHI, wherein the second Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 228, 234, 235, 354, 366, and 409 of human IgG4 according to EU Index, wherein the amino acid substitutions are S228P, F234A, L235A, S354C, T366W, and R409K.

[0207] In some embodiments, the Fc region is a human IgG4 Fc region comprising one or more mutations that reduce or eliminate Fcyl and / or Fcyll binding. In some embodiments, the Fc region is a human IgG4 Fc region comprising one or more mutations that reduce or eliminate Fcyl and / or Fcyll binding but do not affect FcRn binding. In some embodiments, the Fc region is a human IgG4 Fc region comprising amino acid substitutions at positions corresponding to positions 228 and / or 409 of human IgG4 according to EU Index. In some embodiments, the amino acid substitutions are S228P and / or R409K. In some embodiments, the Fc region is a human IgG4 Fc region comprising amino acid substitutions at positions corresponding to positions 234 and / or 235 of human IgG4 according to EU Index. In some embodiments, the amino acid substitutions are F234A and / or L235A. In some embodiments, the Fc region is a human IgG4 Fc region comprising amino acid substitutions at positions corresponding to positions 228, 234, 235, and / or 409 of human IgG4 according to EU Index. In some embodiments, the amino acid substitutions are S228P, F234A, L235A, and / or R409K. In some embodiments, the Fc region is a human IgG4 Fc region comprising amino acid substitutions at positions corresponding to positions 233-236 of human IgG4 according to EU Index. In some embodiments, the amino acid substitutions are E233P, F234V, L235A, and a deletion at 236. In some embodiments, the Fc region is a human IgG4 Fc region comprising amino acid mutations at substitutions corresponding to positions 228, 233-236, and / or 409 of human IgG4 according to EU Index. In some embodiments, the amino acid mutations are S228P; E233P, F234V, L235A, and a deletion at 236; and / or R409K.

[0208] In some embodiments, the Fc region comprises one or more mutations that reduce or eliminate Fc receptor binding and / or effector function of the Fc region (e.g., Fc receptor-mediated antibody -dep endent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), and / or antibody-dependent cellular cytotoxicity (ADCC)).

[0209] In some embodiments, the Fc region is a human IgGl Fc region comprising one or more amino acid substitutions at positions corresponding to positions 234, 235, and / or 329 of human IgGl according to EU Index. In some embodiments, the amino acid substitutions are L234A, L235A, and / or P329A. In some embodiments, the Fc region is a human IgGl Fc region comprising amino acid substitutions at positions corresponding to positions 298, 299, and / or 300 of human IgGl according to EU Index. In some embodiments, the amino acid substitutions are S298N, T299A, and / or Y300S. In some embodiments, the Fc region is a human IgGl Fc region comprising one or more amino acid substitutions at positions corresponding to positions 256 and / or 307 of human IgGl according to EU Index. In some embodiments, the amino acid substitutions are T256D and / or T307Q.

[0210] In some embodiments, a binding protein of the present disclosure comprises one or more mutations to improve purification, e.g., by modulating the affinity for a purification reagent. For example, it is known that heterodimeric binding proteins can be selectively purified away from their homodimeric forms if one of the two Fc regions of the heterodimeric form contains mutation(s) that reduce or eliminate binding to Protein A, because the heterodimeric form will have an intermediate affinity for Protein A-based purification than either homodimeric form and can be selectively eluted from Protein A, e.g., by use of a different pH (See e.g., Smith, E.J. et al. (2015) Sci. Rep. 5: 17943). In some embodiments, the mutation comprises substitutions at positions corresponding to positions 435 and 436 of human IgGl or IgG4 according to EU Index, wherein the amino acid substitutions are H435R and Y436F. In some embodiments, the binding protein comprises a second polypeptide chain further comprising a first Fc region linked to CHI, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, and a third polypeptide chain further comprising a second Fc region linked to CHI, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains; and wherein only one of the first and the second Fc regions comprises amino acid substitutions at positions corresponding to positions 435 and 436 of human IgGl or IgG4 according to EU Index, wherein the amino acid substitutions are H435R and Y436F. In some embodiments, a binding protein of the present disclosure comprises knob and hole mutations and one or more mutations to improvepurification. In some embodiments, the first and / or second Fc regions are human IgGl Fc regions. In some embodiments, the first and / or second Fc regions are human IgG4 Fc regions.

[0211] In some embodiments, a binding protein of the present disclosure comprises one or more mutations to improve stability, e.g., of the hinge region and / or dimer interface of IgG4 (See e.g., Spiess, C. et al. (2013) J. Biol. Chem. 288:26583-26593). In some embodiments, the mutation comprises substitutions at positions corresponding to positions 228 and 409 of human IgG4 according to EU Index, wherein the amino acid substitutions are S228P and R409K. In some embodiments, the binding protein comprises a second polypeptide chain further comprising a first Fc region linked to CHI, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, and a third polypeptide chain further comprising a second Fc region linked to CHI, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains; wherein the first and second Fc regions are human IgG4 Fc regions; and wherein the first and the second Fc regions each comprise amino acid substitutions at positions corresponding to positions 228 and 409 of human IgG4 according to EU Index, wherein the amino acid substitutions are S228P and R409K. In some embodiments, a binding protein of the present disclosure comprises knob and hole mutations and one or more mutations to improve stability. In some embodiments, the first and / or second Fc regions are human IgG4 Fc regions.

[0212] In some embodiments, the Fc region is a human IgGl Fc region comprising one or more amino acid substitutions at positions corresponding to positions 234, 235, and / or 329 of human IgGl according to EU Index. In some embodiments, the amino acid substitutions are L234A, L235A, and / or P329A. In some embodiments, the Fc region is a human IgGl Fc region comprising amino acid substitutions at positions corresponding to positions 298, 299, and / or 300 of human IgGl according to EU Index. In some embodiments, the amino acid substitutions are S298N, T299A, and / or Y300S.Nucleic acids

[0213] Other aspects of the present disclosure relate to isolated nucleic acid molecules comprising a nucleotide sequence encoding any of the binding proteins described herein, including monospecific / monovalent, bispecific / bivalent, trispecific / trivalent, or multispecific / multivalent binding proteins, e.g., as described supra.

[0214] Other aspects of the present disclosure relate to kits of polynucleotides, e.g., that encode one or more polypeptides of a binding protein as described herein. For example, in some embodiments, the kits comprise a first polynucleotide that encodes a first polypeptide of a trispecific binding protein of the present disclosure, a second polynucleotide that encodes a second polypeptide of a trispecific binding protein of the present disclosure, a third polynucleotide that encodes a third polypeptide of a trispecific binding protein of the present disclosure, and a fourth polynucleotide that encodes a fourth polypeptide of a trispecific binding protein of the present disclosure. In some embodiments, the kits comprise a first polynucleotide that encodes a heavy chain polypeptide of an antibody of the present disclosure, and a second polynucleotide that encodes a light chain polypeptide of an antibody of the present disclosure.

[0215] Other aspects of the present disclosure relate to a vector system comprising one or more vectors encoding a first, second, third, and fourth polypeptide chain of any of the binding proteins described herein. In some embodiments, the vector system comprises a first vector encoding the first polypeptide chain of the binding protein, a second vector encoding the second polypeptide chain of the binding protein, a third vector encoding the third polypeptide chain of the binding protein, and a fourth vector encoding the fourth polypeptide chain of the binding protein. In some embodiments, the vector system comprises a first vector that encodes a heavy chain polypeptide of an antibody of the present disclosure, and a second vector that encodes a light chain polypeptide of an antibody of the present disclosure.

[0216] Standard recombinant DNA methodologies are used to construct the polynucleotides that encode the polypeptides which form the binding proteins, incorporate these polynucleotides into recombinant expression vectors, and introduce such vectors into host cells. See e.g., Sambrook et al., 2001, MOLECULAR CLONING: A LABORATORY M NUAL (Cold Spring Harbor Laboratory Press, 3rd ed.). Enzymatic reactions and purification techniques may be performed according to manufacturer's specifications, as commonly accomplished in the art, or as described herein. Unless specific definitions are provided, the nomenclature utilized in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art. Similarly, conventional techniques may be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, delivery, and treatment of patients.

[0217] In some embodiments, the isolated nucleic acid is operably linked to a heterologous promoter to direct transcription of the binding protein-coding nucleic acid sequence. Apromoter may refer to nucleic acid control sequences which direct transcription of a nucleic acid. A first nucleic acid sequence is operably linked to a second nucleic acid sequence when the first nucleic acid sequence is placed in a functional relationship with the second nucleic acid sequence. For instance, a promoter is operably linked to a coding sequence of a binding protein if the promoter affects the transcription or expression of the coding sequence.Examples of promoters may include, but are not limited to, promoters obtained from the genomes of viruses (such as polyoma virus, fowlpox virus, adenovirus (such as Adenovirus 2), bovine papillomavirus, avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis-B virus, Simian Virus 40 (SV40), and the like), from heterologous eukaryotic promoters (such as the actin promoter, an immunoglobulin promoter, from heat-shock promoters, and the like), the CAG-promoter (Niwa et al., Gene 108(2): 193-9, 1991), the phosphoglycerate kinase (PGK)-promoter, a tetracycline-inducible promoter (Masui et al., Nucleic Acids Res.33:e43, 2005), the lac system, the trp system, the tac system, the trc system, major operator and promoter regions of phage lambda, the promoter for 3 -phosphoglycerate kinase, the promoters of yeast acid phosphatase, and the promoter of the yeast alpha-mating factors. Polynucleotides encoding binding proteins of the present disclosure may be under the control of a constitutive promoter, an inducible promoter, or any other suitable promoter described herein or other suitable promoter that will be readily recognized by one skilled in the art.

[0218] In some embodiments, the protein(s) to be expressed (e.g., a polypeptide belonging to an antibody or binding protein of the present disclosure) comprise a leader sequence that allows the protein to be secreted from a cell and is cleaved afterwards. An exemplary leader peptide sequence is MGWSCIILFLVATATGVHS (SEQ ID NO: 107).

[0219] In some embodiments, the isolated nucleic acid is incorporated into a vector. In some embodiments, the vector is an expression vector. Expression vectors may include one or more regulatory sequences operatively linked to the polynucleotide to be expressed. The term "regulatory sequence" includes promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Examples of suitable enhancers may include, but are not limited to, enhancer sequences from mammalian genes (such as globin, elastase, albumin, a-fetoprotein, insulin and the like), and enhancer sequences from a eukaryotic cell virus (such as SV40 enhancer on the late side of the replication origin (bp 100-270), the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, adenovirus enhancers, and the like). Examples of suitable vectors may include, for example, plasmids, cosmids, episomes, transposons, and viral vectors (e.g., adenoviral, vaccinia viral, Sindbis-viral, measles, herpes viral, lentiviral, retroviral, adeno-associated viral vectors, etc.).Expression vectors can be used to transfect host cells, such as, for example, bacterial cells, yeast cells, insect cells, and mammalian cells. Biologically functional viral and plasmid DNA vectors capable of expression and replication in a host are known in the art, and can be used to transfect any cell of interest.Host cells

[0220] Other aspects of the present disclosure relate to a host cell (e.g., an isolated host cell) comprising one or more isolated polynucleotides, vectors, and / or vector systems described herein. In some embodiments, an isolated host cell of the present disclosure is cultured in vitro. In some embodiments, the host cell is a bacterial cell (e.g., an E. coli cell). In some embodiments, the host cell is a yeast cell (e.g., an S. cerevisiae cell). In some embodiments, the host cell is an insect cell. Examples of insect host cells may include, for example, Drosophila cells (e.g., S2 cells), Trichoplusia ni cells (e.g., High Five™ cells), and Spodoptera frugiperda cells (e.g., Sf21 or Sf9 cells). In some embodiments, the host cell is a mammalian cell. Examples of mammalian host cells may include, for example, human embryonic kidney cells (e.g., 293 or 293 cells subcloned for growth in suspension culture), Expi293™ cells, CHO cells, baby hamster kidney cells e.g., BHK, ATCC CCL 10), mouse sertoli cells e.g., TM4 cells), monkey kidney cells e.g., CV1 ATCC CCL 70), African green monkey kidney cells e.g., VERO-76, ATCC CRL-1587), human cervical carcinoma cells e.g., HELA, ATCC CCL 2), canine kidney cells e.g., MDCK, ATCC CCL 34), buffalo rat liver cells e.g., BRL 3A, ATCC CRL 1442), human lung cells e.g., W138, ATCC CCL 75), human liver cells e.g., Hep G2, HB 8065), mouse mammary tumor cells e.g., MMT 060562, ATCC CCL51), TRI cells, MRC 5 cells, FS4 cells, a human hepatoma line e.g., Hep G2), and myeloma cells e.g., NS0 and Sp2 / 0 cells).

[0221] Other aspects of the present disclosure relate to a method of producing any of the binding proteins described herein. In some embodiments, the method includes a) culturing a host cell e.g., any of the host cells described herein) comprising an isolated nucleic acid, vector, and / or vector system e.g., any of the isolated nucleic acids, vectors, and / or vector systems described herein) under conditions such that the host cell expresses the binding protein; and b) isolating the binding protein from the host cell. Methods of culturing host cells under conditions to express a protein are well known to one of ordinary skill in the art. Methods of isolating proteins from cultured host cells are well known to one of ordinary skill in the art, including, for example, by affinity chromatography (e.g., two step affinitychromatography comprising protein A affinity chromatography followed by size exclusion chromatography).Pharmaceutical Compositions

[0222] Therapeutic or pharmaceutical compositions comprising binding proteins are within the scope of the disclosure. Such therapeutic or pharmaceutical compositions can comprise a therapeutically effective amount of a binding protein, or binding protein-drug conjugate, in admixture with a pharmaceutically or physiologically acceptable formulation agent selected for suitability with the mode of administration.

[0223] Acceptable formulation materials are nontoxic to recipients at the dosages and concentrations employed.

[0224] The pharmaceutical composition can contain formulation materials for modifying, maintaining, or preserving, for example, the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption, or penetration of the composition. Suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine, or lysine), antimicrobials, antioxidants (such as ascorbic acid, sodium sulfite, or sodium hydrogen-sulfite), buffers (such as borate, bicarbonate, Tris-HCl, citrates, phosphates, or other organic acids), bulking agents (such as mannitol or glycine), chelating agents (such as ethylenediamine tetraacetic acid (EDTA)), complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin, or hydroxypropyl-beta-cyclodextrin), fillers, monosaccharides, disaccharides, and other carbohydrates (such as glucose, mannose, or dextrins), proteins (such as serum albumin, gelatin, or immunoglobulins), coloring, flavoring and diluting agents, emulsifying agents, hydrophilic polymers (such as polyvinylpyrrolidone), low molecular weight polypeptides, salt-forming counterions (such as sodium), preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid, or hydrogen peroxide), solvents (such as glycerin, propylene glycol, or polyethylene glycol), sugar alcohols (such as mannitol or sorbitol), suspending agents, surfactants or wetting agents (such as pluronics; PEG; sorbitan esters; polysorbates such as polysorbate 20 or polysorbate 80; triton; tromethamine; lecithin; cholesterol or tyloxapal), stability enhancing agents (such as sucrose or sorbitol), tonicity enhancing agents (such as alkali metal halides - e.g., sodium or potassium chloride - or mannitol sorbitol), delivery vehicles, diluents, excipients and / or pharmaceutical adjuvants (see, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES (18th Ed., A.R. Gennaro, ed., Mack PublishingCompany 1990), and subsequent editions of the same, incorporated herein by reference for any purpose).

[0225] The optimal pharmaceutical composition will be determined by a skilled artisan depending upon, for example, the intended route of administration, delivery format, and desired dosage. Such compositions can influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the binding protein.

[0226] The primary vehicle or carrier in a pharmaceutical composition can be either aqueous or non-aqueous in nature. For example, a suitable vehicle or carrier for injection can be water, physiological saline solution, or artificial cerebrospinal fluid, possibly supplemented with other materials common in compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. Other exemplary pharmaceutical compositions comprise Tris buffer of about pH 7.0-8.5, or acetate buffer of about pH 4.0-5.5, which can further include sorbitol or a suitable substitute. In one embodiment of the disclosure, binding protein compositions can be prepared for storage by mixing the selected composition having the desired degree of purity with optional formulation agents in the form of a lyophilized cake or an aqueous solution. Further, the binding protein can be formulated as a lyophilizate using appropriate excipients such as sucrose.

[0227] The pharmaceutical compositions of the disclosure can be selected for parenteral delivery or subcutaneous. Alternatively, the compositions can be selected for inhalation or for delivery through the digestive tract, such as orally. The preparation of such pharmaceutically acceptable compositions is within the skill of the art.

[0228] The formulation components are present in concentrations that are acceptable to the site of administration. For example, buffers are used to maintain the composition at physiological pH or at a slightly lower pH, typically within a pH range of from about 5 to about 8.

[0229] When parenteral administration is contemplated, the therapeutic compositions for use can be in the form of a pyrogen-free, parenterally acceptable, aqueous solution comprising the desired binding protein in a pharmaceutically acceptable vehicle. A particularly suitable vehicle for parenteral injection is sterile distilled water in which a binding protein is formulated as a sterile, isotonic solution, properly preserved. Yet another preparation can involve the formulation of the desired molecule with an agent, such as injectable microspheres, bio-erodible particles, polymeric compounds (such as polylactic acid or polyglycolic acid), beads, or liposomes, that provides for the controlled or sustainedrelease of the product which can then be delivered via a depot injection. Hyaluronic acid can also be used, and this can have the effect of promoting sustained duration in the circulation. Other suitable means for the introduction of the desired molecule include implantable drug delivery devices.

[0230] In one embodiment, a pharmaceutical composition can be formulated for inhalation. For example, a binding protein can be formulated as a dry powder for inhalation. Binding protein inhalation solutions can also be formulated with a propellant for aerosol delivery. In yet another embodiment, solutions can be nebulized.

[0231] It is also contemplated that certain formulations can be administered orally. In one embodiment of the disclosure, binding proteins that are administered in this fashion can be formulated with or without those carriers customarily used in the compounding of solid dosage forms such as tablets and capsules. For example, a capsule can be designed to release the active portion of the formulation at the point in the gastrointestinal tract where bioavailability is maximized and pre-systemic degradation is minimized. Additional agents can be included to facilitate absorption of the binding protein. Diluents, flavorings, low melting point waxes, vegetable oils, lubricants, suspending agents, tablet disintegrating agents, and binders can also be employed.

[0232] Another pharmaceutical composition can involve an effective quantity of binding proteins in a mixture with non-toxic excipients that are suitable for the manufacture of tablets. By dissolving the tablets in sterile water, or another appropriate vehicle, solutions can be prepared in unit-dose form. Suitable excipients include, but are not limited to, inert diluents, such as calcium carbonate, sodium carbonate or bicarbonate, lactose, or calcium phosphate; or binding agents, such as starch, gelatin, or acacia; or lubricating agents such as magnesium stearate, stearic acid, or talc.

[0233] Additional pharmaceutical compositions of the disclosure will be evident to those skilled in the art, including formulations involving binding proteins in sustained- or controlled-delivery formulations. Techniques for formulating a variety of other sustained- or controlled-delivery means, such as liposome carriers, bio-erodible microparticles or porous beads and depot injections, are also known to those skilled in the art. Additional examples of sustained-release preparations include semipermeable polymer matrices in the form of shaped articles, e.g. films, or microcapsules. Sustained release matrices can include polyesters, hydrogels, polylactides, copolymers of L-glutamic acid and gamma ethyl -L-glutamate, poly(2 -hydroxy ethyl -methacrylate), ethylene vinyl acetate, or poly-D(-)-3 -hydroxybutyricacid. Sustained-release compositions can also include liposomes, which can be prepared by any of several methods known in the art.

[0234] Pharmaceutical compositions to be used for in vivo administration typically must be sterile. This can be accomplished by filtration through sterile filtration membranes.Where the composition is lyophilized, sterilization using this method can be conducted either prior to, or following, lyophilization and reconstitution. The composition for parenteral administration can be stored in lyophilized form or in a solution. In addition, parenteral compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

[0235] Once the pharmaceutical composition has been formulated, it can be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or as a dehydrated or lyophilized powder. Such formulations can be stored either in a ready -to-use form or in a form (e.g., lyophilized) requiring reconstitution prior to administration.

[0236] The disclosure also encompasses kits for producing a single-dose administration unit. The kits can each contain both a first container having a dried protein and a second container having an aqueous formulation. Also included within the scope of this disclosure are kits containing single and multi -chambered pre-filled syringes (e.g., liquid syringes and lyosyringes).

[0237] The effective amount of a binding protein pharmaceutical composition to be employed therapeutically will depend, for example, upon the therapeutic context and objectives. One skilled in the art will appreciate that the appropriate dosage levels for treatment will thus vary depending, in part, upon the molecule delivered, the indication for which the binding protein is being used, the route of administration, and the size (body weight, body surface, or organ size) and condition (the age and general health) of the patient. Accordingly, the clinician can titer the dosage and modify the route of administration to obtain the optimal therapeutic effect.

[0238] Dosing frequency will depend upon the pharmacokinetic parameters of the binding protein in the formulation being used. Typically, a clinician will administer the composition until a dosage is reached that achieves the desired effect. The composition can therefore be administered as a single dose, as two or more doses (which may or may not contain the same amount of the desired molecule) over time, or as a continuous infusion via an implantation device or catheter. Further refinement of the appropriate dosage is routinely made by those of ordinary skill in the art and is within the ambit of tasks routinely performedby them. Appropriate dosages can be ascertained through use of appropriate dose-response data.

[0239] The route of administration of the pharmaceutical composition is in accord with known methods, e.g., orally; through injection by subcutaneous, intravenous, intraperitoneal, intracerebral (intraparenchymal), intracerebroventricular, intramuscular, intraocular, intraarterial, intraportal, or intralesional routes; by sustained release systems; or by implantation devices. Where desired, the compositions can be administered by bolus injection or continuously by infusion, or by implantation device.

[0240] The composition can also be administered locally via implantation of a membrane, sponge, or other appropriate material onto which the desired molecule has been absorbed or encapsulated. Where an implantation device is used, the device can be implanted into any suitable tissue or organ, and delivery of the desired molecule can be via diffusion, timed-release bolus, or continuous administration.

[0241] The disclosure also relates to a kit comprising a binding protein and other reagents useful for detecting target antigen levels in biological samples. Such reagents can include a detectable label, blocking serum, positive and negative control samples, and detection reagents. In some embodiments, the kit comprises a composition comprising any binding protein, polynucleotide, vector, vector system, and / or host cell described herein. In some embodiments, the kit comprises a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc. The containers may be formed from a variety of materials such as glass or plastic. The container holds a composition which is by itself or combined with another composition effective for treating, preventing and / or diagnosing a condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). In some embodiments, the label or package insert indicates that the composition is used for preventing, diagnosing, and / or treating the condition of choice. Alternatively, or additionally, the article of manufacture or kit may further comprise a second (or third) container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.Methods and Uses for Binding Proteins

[0242] Certain aspects of the present disclosure relate to methods for preventing and / or treating an inflammatory disease or disorder (e.g., atopic dermatitis) in a patient, e.g., in need thereof. In some embodiments, the methods comprise administering to the patient a therapeutically effective amount of a binding protein or pharmaceutical composition of the present disclosure. In some embodiments, the patient is a human.

[0243] Also provided herein is a binding protein or pharmaceutical composition of the present disclosure for use in preventing and / or treating an inflammatory disease or disorder (e.g., atopic dermatitis) in a patient. In some embodiments, the binding protein or pharmaceutical composition for its uses comprises administering to the patient a therapeutically effective amount of a binding protein or pharmaceutical composition of the present disclosure. In some embodiments, the patient is a human.

[0244] Also provided herein is use of a binding protein or pharmaceutical composition of the present disclosure in the manufacture of a medicament for preventing and / or treating an inflammatory disease or disorder (e.g., atopic dermatitis) in a patient. In some embodiments, the patient is a human.

[0245] Any of the binding proteins described herein may find use in the methods or uses of the present disclosure.

[0246] The binding proteins can be employed in any known assay method, such as competitive binding assays, direct and indirect sandwich assays, and immunoprecipitation assays for the detection and quantitation of one or more target antigens. The binding proteins will bind the one or more target antigens with an affinity that is appropriate for the assay method being employed.

[0247] For diagnostic applications, in certain embodiments, binding proteins can be labeled with a detectable moiety. The detectable moiety can be any one that is capable of producing, either directly or indirectly, a detectable signal. For example, the detectable moiety can be a radioisotope, such as3H,14C,32P,35S,125I, "Tc,niIn, or67Ga; a fluorescent or chemiluminescent compound, such as fluorescein isothiocyanate, rhodamine, or luciferin; or an enzyme, such as alkaline phosphatase, P-galactosidase, or horseradish peroxidase.

[0248] The binding proteins are also useful for in vivo imaging. A binding protein labeled with a detectable moiety can be administered to an animal, preferably into the bloodstream, and the presence and location of the labeled antibody in the host assayed. The binding protein can be labeled with any moiety that is detectable in an animal, whether by nuclear magnetic resonance, radiology, or other detection means known in the art.

[0249] For clinical or research applications, in certain embodiments, binding proteins can be conjugated to a cytotoxic agent. A variety of antibodies coupled to cytotoxic agents (i.e., antibody-drug conjugates) have been used to target cytotoxic payloads to specific tumor cells. Cytotoxic agents and linkers that conjugate the agents to an antibody are known in the art; see, e.g., Parslow, A.C. etal. (2016) Biomedicines 4:14 and Kalim, M. et al. (2017) Drug Des. Devel. Ther. 11:2265-2276.

[0250] Therapeutic or pharmaceutical compositions comprising binding proteins are within the scope of the disclosure. Such therapeutic or pharmaceutical compositions can comprise a therapeutically effective amount of a binding protein, or binding protein-drug conjugate, in admixture with a pharmaceutically or physiologically acceptable formulation agent selected for suitability with the mode of administration. These pharmaceutical compositions may find use in any of the methods and uses described herein e.g., ex vivo, in vitro, and / or in vivo).

[0251] Acceptable formulation materials preferably are nontoxic to recipients at the dosages and concentrations employed.

[0252] The pharmaceutical composition can contain formulation materials for modifying, maintaining, or preserving, for example, the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption, or penetration of the composition.

[0253] The optimal pharmaceutical composition will be determined by a skilled artisan depending upon, for example, the intended route of administration, delivery format, and desired dosage. Such compositions can influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the binding protein.

[0254] The primary vehicle or carrier in a pharmaceutical composition can be either aqueous or non-aqueous in nature. For example, a suitable vehicle or carrier for injection can be water, physiological saline solution, or artificial cerebrospinal fluid, possibly supplemented with other materials common in compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. Other exemplary pharmaceutical compositions comprise Tris buffer of about pH 7.0-8.5, or acetate buffer of about pH 4.0-5.5, which can further include sorbitol or a suitable substitute. In one embodiment of the disclosure, binding protein compositions can be prepared for storage by mixing the selected composition having the desired degree of purity with optional formulation agents in the form of a lyophilized cake or an aqueous solution. Further, thebinding protein can be formulated as a lyophilizate using appropriate excipients such as sucrose.

[0255] The pharmaceutical compositions of the disclosure can be selected for parenteral delivery or subcutaneous. Alternatively, the compositions can be selected for inhalation or for delivery through the digestive tract, such as orally. The preparation of such pharmaceutically acceptable compositions is within the skill of the art.

[0256] The formulation components are present in concentrations that are acceptable to the site of administration. For example, buffers are used to maintain the composition at physiological pH or at a slightly lower pH, typically within a pH range of from about 5 to about 8.

[0257] When parenteral administration is contemplated, the therapeutic compositions for use can be in the form of a pyrogen-free, parenterally acceptable, aqueous solution comprising the desired binding protein in a pharmaceutically acceptable vehicle. A particularly suitable vehicle for parenteral injection is sterile distilled water in which a binding protein is formulated as a sterile, isotonic solution, properly preserved. Yet another preparation can involve the formulation of the desired molecule with an agent, such as injectable microspheres, bio-erodible particles, polymeric compounds (such as polylactic acid or polyglycolic acid), beads, or liposomes, that provides for the controlled or sustained release of the product which can then be delivered via a depot injection. Hyaluronic acid can also be used, and this can have the effect of promoting sustained duration in the circulation. Other suitable means for the introduction of the desired molecule include implantable drug delivery devices.

[0258] In one embodiment, a pharmaceutical composition can be formulated for inhalation. For example, a binding protein can be formulated as a dry powder for inhalation. Binding protein inhalation solutions can also be formulated with a propellant for aerosol delivery. In yet another embodiment, solutions can be nebulized.

[0259] It is also contemplated that certain formulations can be administered orally. In one embodiment of the disclosure, binding proteins that are administered in this fashion can be formulated with or without those carriers customarily used in the compounding of solid dosage forms such as tablets and capsules. For example, a capsule can be designed to release the active portion of the formulation at the point in the gastrointestinal tract when bioavailability is maximized and pre-systemic degradation is minimized. Additional agents can be included to facilitate absorption of the binding protein. Diluents, flavorings, lowmelting point waxes, vegetable oils, lubricants, suspending agents, tablet disintegrating agents, and binders can also be employed.

[0260] Another pharmaceutical composition can involve an effective quantity of binding proteins in a mixture with non-toxic excipients that are suitable for the manufacture of tablets. By dissolving the tablets in sterile water, or another appropriate vehicle, solutions can be prepared in unit-dose form. Suitable excipients include, but are not limited to, inert diluents, such as calcium carbonate, sodium carbonate or bicarbonate, lactose, or calcium phosphate; or binding agents, such as starch, gelatin, or acacia; or lubricating agents such as magnesium stearate, stearic acid, or talc.

[0261] Additional pharmaceutical compositions of the disclosure will be evident to those skilled in the art, including formulations involving binding proteins in sustained- or controlled-delivery formulations. Techniques for formulating a variety of other sustained- or controlled-delivery means, such as liposome carriers, bio-erodible microparticles or porous beads and depot injections, are also known to those skilled in the art. Additional examples of sustained-release preparations include semipermeable polymer matrices in the form of shaped articles, e.g. films, or microcapsules. Sustained release matrices can include polyesters, hydrogels, polylactides, copolymers of L-glutamic acid and gamma ethyl -L-glutamate, poly(2 -hydroxy ethyl -methacrylate), ethylene vinyl acetate, or poly-D(-)-3 -hydroxybutyric acid. Sustained-release compositions can also include liposomes, which can be prepared by any of several methods known in the art.

[0262] Pharmaceutical compositions to be used for in vivo administration typically must be sterile. This can be accomplished by filtration through sterile filtration membranes.Where the composition is lyophilized, sterilization using this method can be conducted either prior to, or following, lyophilization and reconstitution. The composition for parenteral administration can be stored in lyophilized form or in a solution. In addition, parenteral compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

[0263] Once the pharmaceutical composition has been formulated, it can be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or as a dehydrated or lyophilized powder. Such formulations can be stored either in a ready -to-use form or in a form (e.g., lyophilized) requiring reconstitution prior to administration.

[0264] The disclosure also relates to a kit comprising a binding protein and other reagents useful for detecting target antigen levels in biological samples. Such reagents can include adetectable label, blocking serum, positive and negative control samples, and detection reagents. In some embodiments, the kit comprises a composition comprising any binding protein, polynucleotide, vector, vector system, and / or host cell described herein. In some embodiments, the kit comprises a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc. The containers may be formed from a variety of materials such as glass or plastic. The container holds a composition which is by itself or combined with another composition effective for treating, preventing and / or diagnosing a condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). In some embodiments, the label or package insert indicates that the composition is used for preventing, diagnosing, and / or treating the condition of choice. Alternatively, or additionally, the article of manufacture or kit may further comprise a second (or third) container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0265] The disclosure also encompasses kits for producing a single-dose administration unit. The kits can each contain both a first container having a dried protein and a second container having an aqueous formulation. Also included within the scope of this disclosure are kits containing single and multi -chambered pre-filled syringes (e.g., liquid syringes and lyosyringes).

[0266] The effective amount of a binding protein pharmaceutical composition to be employed therapeutically will depend, for example, upon the therapeutic context and objectives. One skilled in the art will appreciate that the appropriate dosage levels for treatment will thus vary depending, in part, upon the molecule delivered, the indication for which the binding protein is being used, the route of administration, and the size (body weight, body surface, or organ size) and condition (the age and general health) of the patient. Accordingly, the clinician can titer the dosage and modify the route of administration to obtain the optimal therapeutic effect.

[0267] Dosing frequency will depend upon the pharmacokinetic parameters of the binding protein in the formulation being used. Typically, a clinician will administer the composition until a dosage is reached that achieves the desired effect. The composition can therefore be administered as a single dose, as two or more doses (which may or may notcontain the same amount of the desired molecule) over time, or as a continuous infusion via an implantation device or catheter. Further refinement of the appropriate dosage is routinely made by those of ordinary skill in the art and is within the ambit of tasks routinely performed by them. Appropriate dosages can be ascertained through use of appropriate dose-response data.

[0268] The route of administration of the pharmaceutical composition is in accord with known methods, e.g., orally; through injection by intravenous, intraperitoneal, intracerebral (intraparenchymal), intracerebroventricular, intramuscular, intraocular, intraarterial, intraportal, or intralesional routes; by sustained release systems; or by implantation devices. Where desired, the compositions can be administered by bolus injection or continuously by infusion, or by implantation device.

[0269] The composition can also be administered locally via implantation of a membrane, sponge, or other appropriate material onto which the desired molecule has been absorbed or encapsulated. Where an implantation device is used, the device can be implanted into any suitable tissue or organ, and delivery of the desired molecule can be via diffusion, timed-release bolus, or continuous administration.Exemplary Embodiments

[0270] The following exemplary embodiments are representative of some aspects of the invention:Embodiment 1. A trispecific binding protein comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain of the binding protein comprises a structure represented by the formula:VL2-LI-VLI-L2-CL [I]and a second polypeptide chain of the binding protein comprises a structure represented by the formula:VHI -L3- V H2-L4-CH1 -hinge-CH2-Cu3 [II]and a third polypeptide chain of the binding protein comprises a structure represented by the formula:VH3-Cui-hinge-CH2-CH3 [III]and a fourth polypeptide chain of the binding protein comprises a structure represented by the formula:VL3-CL [IV]wherein:VLI is a first immunoglobulin light chain variable domain;VL2 is a second immunoglobulin light chain variable domain;VL3 is a third immunoglobulin light chain variable domain;VHI is a first immunoglobulin heavy chain variable domain;VH2 is a second immunoglobulin heavy chain variable domain;VH3 is a third immunoglobulin heavy chain variable domain;CL is an immunoglobulin light chain constant domain;CHI is an immunoglobulin CHI heavy chain constant domain;CH2 is an immunoglobulin CH2 heavy chain constant domain;CH3 is an immunoglobulin CH3 heavy chain constant domain;hinge is an immunoglobulin hinge region connecting the CHI and CH2 domains; and Li, L2, L3 and L4 are each independently amino acid linkers or zero amino acids in length;wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair of the binding protein; andwherein VHI and VLI form a binding pair and a first antigen binding site, VH2 and VL2 form a binding pair and a second antigen binding site, and VH3 and VL3 form a binding pair and a third antigen binding site;wherein the first antigen binding site specifically binds an interleukin-4 (IL-4) polypeptide and the second antigen binding site specifically binds an interleukin- 13 (IL-13) polypeptide, or the first antigen binding site specifically binds an IL- 13 polypeptide and the second antigen binding site specifically binds an IL-4 polypeptide;wherein the binding site that specifically binds an IL-4 polypeptide comprises:(a) a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CORED comprising the amino acid sequence selected from the group consisting of SEQ ID NOs:3-5, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6 or 7, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8 or 9, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10 or 11, or(b) a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence selected from the group consisting of SEQ ID NOs:24-27, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6 or 7, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8 or 9, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10 or 11; andwherein the binding site that specifically binds an IL-13 polypeptide comprises a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:57, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:58, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:59 or 108, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:60, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:61, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:62.Embodiment 2. The binding protein of embodiment 1, wherein the first binding site specifically binds the IL-4 polypeptide, and the second binding site specifically binds the IL-13 polypeptide.Embodiment s. The binding protein of embodiment 1 or embodiment 2, wherein the binding site that specifically binds an IL-4 polypeptide comprises:(a) a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:3, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10;(b) a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:3, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11;(c) a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CORED comprising the amino acid sequence of SEQ ID NO:4, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:9, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11; or(d) a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:5, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:1LEmbodiment 4. The binding protein of embodiment 3, wherein the binding site that specifically binds an IL-4 polypeptide comprises:(a) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:34 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:35;(b) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:36 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 37;(c) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:38 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 39;(d) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:40 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:41;(e) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:42 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43;(f) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:44 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43; or(g) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:45 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43.Embodiment 5. The binding protein of embodiment 4, wherein:(a) VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:34, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO 35;(b) VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:36, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:37;(c) VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:38, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:39;(d) VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:40, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:41;(e) VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:42, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43;(f) VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:44, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43; or(g) VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:45, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43.Embodiment 6. The binding protein of embodiment 1 or embodiment 2, wherein the binding site that specifically binds an IL-4 polypeptide comprises:(a) a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:24, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10;(b) a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:24, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11;(c) a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:25, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10;(d) a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:25, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11;(e) a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:26, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NOV, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11; or(f) a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:27, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:9, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:1LEmbodiment 7. The binding protein of embodiment 6, wherein the binding site that specifically binds an IL-4 polypeptide comprises:(a) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:46 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:47;(b) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:48 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 39;(c) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:49 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:41;(d) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:50 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43;(e) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence ofSEQ ID NO:51 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 37;(f) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 52 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 39;(g) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:53 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:41;(h) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 54 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43;(i) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 55 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43; or(j) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:56 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43.Embodiment 8. The binding protein of embodiment 7, wherein:(a) VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:46, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:47;(b) VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:48, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:39;(c) VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:49, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:41;(d) VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:50, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43;(e) VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:51, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:37;(f) VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:52, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:39;(g) VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:53, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:41;(h) VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:54, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43;(i) VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:55, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43; or(j) VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:56, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43.Embodiment 9. The binding protein of any one of embodiments 1-8, wherein the binding site that specifically binds an IL-13 polypeptide comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:57, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:58, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:59, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:60, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:61, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:62.Embodiment 10. The binding protein of embodiment 9, wherein the binding site that specifically binds an IL-13 polypeptide comprises:(a) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:70 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:71;(b) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 72 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 73; or(c) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 74 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 75.Embodiment 11. The binding protein of embodiment 10, wherein:(a) VH2 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:70, and VL2 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:71;(b) VH2 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:72, and VL2 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:73; or(c) VH2 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:74, and VL2 comprises an amino acid sequence that is at least 95%, at least 96%, at least97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:75.Embodiment 12. The binding protein of any one of embodiments 1-8, wherein the binding site that specifically binds an IL-13 polypeptide comprises: a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:57, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:58, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 108, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ IDNO:60, aCDR-L2 comprising the amino acid sequence of SEQIDNO:61, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:62.Embodiment 13. The binding protein of embodiment 12, wherein the binding site that specifically binds an IL- 13 polypeptide comprises a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:76 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:77.Embodiment 14. The binding protein of embodiment 13, wherein VH2 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:76, and VL2 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:77.Embodiment 15. The binding protein of embodiment 1 or embodiment 2, wherein one, two, or all three of the antigen binding sites comprise a pair of reciprocal amino acid substitutions on the VH and VL domains that facilitate heavy-light chain pairing.Embodiment 16. The binding protein of embodiment 1, wherein VHI comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:3; VLI comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8, and a CDR-L3 comprising the amino acid sequence of SEQ ID NOTO; VH2 comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:57, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:58, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:59; and VL2 comprises aCDR-L1 comprising the amino acid sequence of SEQ ID NO:60, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:61, and a CDR-L3 comprising the amino acid sequence of SEQ IDNO:62.Embodiment 17. The binding protein of embodiment 1, wherein VHI comprises the amino acid sequence of SEQ ID NO:34, VLI comprises the amino acid sequence of SEQ ID NO:35, VH2 comprises the amino acid sequence of SEQ ID NO:70, and VL2 comprises the amino acid sequence of SEQ ID NO:71.Embodiment 18. The binding protein of any one of embodiments 1-17, wherein the binding protein is capable of inhibiting the function of one or more target proteins.Embodiment 19. The binding protein of embodiment 18, wherein the binding protein is capable of inhibiting the function of an IL-4 polypeptide and / or an IL-13 polypeptide.Embodiment 20. The binding protein of any one of embodiments 1-19, wherein the third antigen binding site specifically binds an OX40L polypeptide.Embodiment 21. The method of embodiment 20, wherein the binding protein is capable of inhibiting the function of an OX40L polypeptide.Embodiment 22. The binding protein of embodiment 20 or embodiment 21, wherein VH3 comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:78, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:79, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:80; and VL3 comprises a CDR-L1 comprising the amino acid sequence of SEQ IDNO:81, aCDR-L2 comprising the amino acid sequence of SEQIDNO:82, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:83.Embodiment 23. The binding protein of embodiment 22, wherein:(a) VH3 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:91, and VL3 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 92;(b) VH3 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:93, and VL3 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 94;(c) VH3 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:95, and VL3 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:96; or(d) VH3 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:97, and VL3 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:96.Embodiment 24. The binding protein of embodiment 1, wherein VHI comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:3; VLI comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8, and a CDR-L3 comprising the amino acid sequence of SEQ ID NOTO; VH2 comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:57, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:58, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:59; VL2 comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:60, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:61, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:62; VH3 comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:78, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:79, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:80; and VL3 comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:81, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:82, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:83.IllEmbodiment 25. The binding protein of embodiment 1, wherein VHI comprises the amino acid sequence of SEQ ID NO:34, VLI comprises the amino acid sequence of SEQ ID NO:35, VH2 comprises the amino acid sequence of SEQ ID NO:70, VL2 comprises the amino acid sequence of SEQ ID NO:71, VH3 comprises the amino acid sequence of SEQ ID NO:91, and VL3 comprises the amino acid sequence of SEQ ID NO:92.Embodiment 26. The binding protein of any one of embodiments 1-25, wherein at least one of Li, L2, L3 or L4, is independently 0 amino acids in length.Embodiment 27. The binding protein of any one of embodiments 1-25, wherein Li, L2, L3 or L4 are each independently at least one amino acid in length.Embodiment 28. The binding protein of any one of embodiments 1-25, wherein (a) Li, L2, L3 and L4 each independently are zero amino acids in length or comprise a sequence selected from the group consisting of GGGGSGGGGS (SEQ ID NO: 102), GGGGSGGGGSGGGGS (SEQ ID NO: 103), S, RT, TKGPS (SEQ ID NO: 104), GQPKAAP (SEQ ID NO: 105), and GGSGSSGSGG (SEQ ID NO: 106); or (b) Li, L2, L3 and L4 each independently comprise a sequence selected from the group consisting of GGGGSGGGGS (SEQ ID NO: 102), GGGGSGGGGSGGGGS (SEQ ID NO: 103), S, RT, TKGPS (SEQ ID NO: 104), GQPKAAP (SEQ ID NO: 105), and GGSGSSGSGG (SEQ ID NO: 106).Embodiment 29. The binding protein of any one of embodiments 1-25, wherein:(a) Li comprises the sequence GQPKAAP (SEQ ID NO: 105), L2 comprises the sequence TKGPS (SEQ ID NO: 104), L3 comprises the sequence S, and L4 comprises the sequence RT;(b) Li comprises the sequence GGGGSGGGGS (SEQ ID NO: 102), L2 comprises the sequence GGGGSGGGGS (SEQ ID NO: 102), L3 is 0 amino acids in length, and L4 is 0 amino acids in length;(c) Li comprises the sequence GGSGSSGSGG (SEQ ID NO: 106), L2 comprises the sequence GGSGSSGSGG (SEQ ID NO: 106), L3 is 0 amino acids in length, and L4 is 0 amino acids in length; or(d) Li comprises the sequence GGGGSGGGGSGGGGS (SEQ ID NO: 103), L2 is 0 amino acids in length, L3 comprises the sequence GGGGSGGGGSGGGGS (SEQ ID NO: 103), and L4 is 0 amino acids in length.Embodiment 30. The binding protein of any one of embodiments 1-29, wherein the CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgGl or IgG4 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgGl or IgG4 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.Embodiment 31. The binding protein of any one of embodiments 1-29, wherein the CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgGl or IgG4 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgGl or IgG4 according to EU Index, wherein the amino acid substitutions are S354C and T366W.Embodiment 32. The binding protein of any one of embodiments 1-31, wherein the CH3 domains of the second and the third polypeptide chains are human IgGl or IgG4 CH3 domains, and wherein only one of the CH3 domains comprises amino acid substitutions at positions corresponding to positions 435 and 436 of human IgGl or IgG4 according to EU Index, wherein the amino acid substitutions are H435R and Y436F.Embodiment 33. The binding protein of any one of embodiments 1-32, wherein the CH3 domains of the second and the third polypeptide chains are human IgGl CH3 domains, and wherein the CH3 domains each comprise amino acid substitutions at positions corresponding to positions 234 and 235 of human IgGl according to EU Index, wherein the amino acid substitutions are L234A and L235A.Embodiment 34. The binding protein of embodiment 1, wherein the first polypeptide chain of the binding protein comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:98, the second polypeptide chain of the binding protein comprises an amino acidsequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 99, the third polypeptide chain of the binding protein comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 100, and the fourth polypeptide chain of the binding protein comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 101.Embodiment 35. A kit of polynucleotides, comprising a first polynucleotide that encodes a first polypeptide chain of the binding protein according to any one of embodiments 1-34, a second polynucleotide that encodes a second polypeptide chain of the binding protein according to any one of embodiments 1-34, a third polynucleotide that encodes a third polypeptide chain of the binding protein according to any one of embodiments 1-34, and a fourth polynucleotide that encodes a fourth polypeptide chain of the binding protein according to any one of embodiments 1-34.Embodiment 36. An isolated nucleic acid molecule comprising a nucleotide sequence encoding the binding protein of any one of embodiments 1-34.Embodiment 37. An expression vector comprising the nucleic acid molecule of embodiment 36.Embodiment 38. An isolated host cell comprising the kit of polynucleotides of embodiment 35, the nucleic acid molecule of embodiment 36, or the expression vector of embodiment 37.Embodiment 39. The isolated host cell of embodiment 38, wherein the host cell is a mammalian or insect cell.Embodiment 40. A method of producing a binding protein, comprising culturing the host cell of embodiment 38 or embodiment 39 such that the binding protein is produced.Embodiment 41. The method of embodiment 40, further comprising recovering the binding protein from the host cell.Embodiment 42. A pharmaceutical composition comprising the binding protein of any one of embodiments 1-34 and a pharmaceutically acceptable carrier.Embodiment 43. A method of preventing and / or treating an inflammatory disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of at least one binding protein of any one of embodiments 1-34 or the pharmaceutical composition of embodiment 42.Embodiment 44. The method of embodiment 43, wherein the inflammatory disease or disorder is atopic dermatitis.Embodiment 45. The method of embodiment 43 or embodiment 44, wherein the patient is a human.Embodiment 46. The binding protein of any one of embodiments 1-34 or the pharmaceutical composition of embodiment 42 for use in preventing and / or treating an inflammatory disease or disorder in a patient.Embodiment 47. The binding protein or pharmaceutical composition for use of embodiment 46, wherein the inflammatory disease or disorder is atopic dermatitis.Embodiment 48. Use of the binding protein of any one of embodiments 1-34 or the pharmaceutical composition of embodiment 42 in the manufacture of a medicament for preventing and / or treating an inflammatory disease or disorder in a patient.Embodiment 49. The use of embodiment 48, wherein the inflammatory disease or disorder is atopic dermatitis.Embodiment 50. An antibody that specifically binds an IL-4 polypeptide, wherein the antibody comprises a heavy chain variable (VH) domain and a light chain variable (VH) domain; wherein the VH domain comprises:(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence selected from the group consisting of SEQ ID NOs:3-5; or(b) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence selected from the group consisting of SEQ ID NOs:24-27; andwherein the VL domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6 or 7, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8 or 9, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10 or 11.Embodiment 51. The antibody of embodiment 50, wherein:(a) the VH domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:3, and the VL domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10;(b) the VH domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:3, and the VL domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11;(c) the VH domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence of SEQ ID NON, and the VL domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11; or(d) the VH domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:1, a CDR-H2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:5, and the VL domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ IDNO:11.Embodiment 52. The antibody of embodiment 51, wherein:(a) the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:34, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:35;(b) the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:36, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:37;(c) the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:38, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:39;(d) the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:40, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:41;(e) the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:42, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43;(f) the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:44, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43; or(g) the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:45, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43.Embodiment 53. The antibody of embodiment 50, wherein:(a) the VH domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:24, and the VL domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10;(b) the VH domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:24, and the VL domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11;(c) the VH domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:25, and the VL domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10;(d) the VH domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:25, and the VL domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11;(e) the VH domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:26, and the VL domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:9, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11; or(f) the VH domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:27, and the VL domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ IDNO:11.Embodiment 54. The antibody of embodiment 53, wherein:(a) the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:46, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:47;(b) the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:48, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:39;(c) the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:49, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:41;(d) the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQID NO:50, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43;(e) the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:51, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:37;(f) the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:52, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:39;(g) the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:53, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:41;(h) the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:54, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43;(i) the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:55, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43; or(j) the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQID NO:56, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43.Embodiment 55. An antibody that specifically binds an IL- 13 polypeptide, wherein the antibody comprises a heavy chain variable (VH) domain and a light chain variable (VH) domain; wherein the VH domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:57, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:58, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:59, and the VL domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:60, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:61, and a CDR-L3 comprising the amino acid sequence of SEQ IDNO:62.Embodiment 56. The antibody of embodiment 55, wherein:(a) the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:70, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:71;(b) the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:72, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:73;(c) the VH domain comprises an amino acid sequence that is at least 95%, at least 96...

Claims

CLAIMSWhat is claimed is:

1. A trispecific binding protein comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain of the binding protein comprises a structure represented by the formula:VL2-LI-VLI-L2-CL [I]and a second polypeptide chain of the binding protein comprises a structure represented by the formula:VHI -L3- V H2-L4-CH1 -hinge-CH2-Cu3 [II]and a third polypeptide chain of the binding protein comprises a structure represented by the formula:VH3-Cui-hinge-CH2-CH3 [III]and a fourth polypeptide chain of the binding protein comprises a structure represented by the formula:VL3-CL [IV]wherein:VLI is a first immunoglobulin light chain variable domain;VL2 is a second immunoglobulin light chain variable domain;VL3 is a third immunoglobulin light chain variable domain;VHI is a first immunoglobulin heavy chain variable domain;VH2 is a second immunoglobulin heavy chain variable domain;VH3 is a third immunoglobulin heavy chain variable domain;CL is an immunoglobulin light chain constant domain;CHI is an immunoglobulin CHI heavy chain constant domain;CH2 is an immunoglobulin CH2 heavy chain constant domain;CH3 is an immunoglobulin CH3 heavy chain constant domain;hinge is an immunoglobulin hinge region connecting the CHI and CH2 domains; and Li, L2, L3 and L4 are each independently amino acid linkers or zero amino acids in length;wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair of the binding protein; andwherein VHI and VLI form a binding pair and a first antigen binding site, VH2 and VL2 form a binding pair and a second antigen binding site, and VH3 and VL3 form a binding pair and a third antigen binding site;wherein the first antigen binding site specifically binds an interleukin-4 (IL-4) polypeptide and the second antigen binding site specifically binds an interleukin- 13 (IL-13) polypeptide, or the first antigen binding site specifically binds an IL- 13 polypeptide and the second antigen binding site specifically binds an IL-4 polypeptide;wherein the binding site that specifically binds an IL-4 polypeptide comprises:(a) a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CORED comprising the amino acid sequence selected from the group consisting of SEQ ID NOs:3-5, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6 or 7, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 8 or 9, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10 or 11, or(b) a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence selected from the group consisting of SEQ ID NOs:24-27, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6 or 7, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 8 or 9, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10 or 11; andwherein the binding site that specifically binds an IL-13 polypeptide comprises a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 57, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 58, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:59 or 108, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:60, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:61, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:62.

2. The binding protein of claim 1, wherein the first binding site specifically binds the IL-4 polypeptide, and the second binding site specifically binds the IL- 13 polypeptide.

3. The binding protein of claim 1 or claim 2, wherein the binding site that specifically binds an IL-4 polypeptide comprises:(a) a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CORED comprising the amino acid sequence of SEQ ID NOD, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6, a CDR-L2 comprising the amino acid sequence of SEQ ID NOD, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10;(b) a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NOD, and a CDR-H3 comprising the amino acid sequence of SEQ ID NOD, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:9, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11;(c) a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NOD, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:4, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NOD, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:9, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11;(d) a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NOD, and a CDR-H3 comprising the amino acid sequence of SEQ ID NOD, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NOD, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:9, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11;(e) a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:24, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NOD, a CDR-L2 comprising theamino acid sequence of SEQ ID NO:8, and a CDR-L3 comprising the amino acid sequence of SEQ ID NOVO;(f) a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:24, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:9, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11;(g) a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:25, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10;(h) a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:25, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11;(i) a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:26, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:7, a CDR-L2 comprising the amino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11; or(j) a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:27, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NOV, a CDR-L2 comprising theamino acid sequence of SEQ ID NOV, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 11;optionally wherein the binding site that specifically binds an IL-4 polypeptide comprises:(a) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:34 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:35, optionally VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:34, and VLI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO 35;(b) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:36 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:37, optionally VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 36, and Vn comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:37;(c) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:38 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:39, optionally VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:38, and Vncomprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:39;(d) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:40 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:41, optionally VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:40, and Vn comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:41;(e) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:42 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43, optionally VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:42, and Vn comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43;(f) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:44 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43, optionally VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:44, and Vn comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43;(g) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:45 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43, optionally VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:45, and Vn comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43;(h) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:46 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:47, optionally VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:46, and Vn comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:47;(i) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:48 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:39, optionally VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:48, and Vn comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:39;\T1(j) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:49 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:41, optionally VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:49, and Vn comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:41;(k) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 50 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43, optionally VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:50, and Vn comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43;(l) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:51 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:37, optionally VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:51, and Vn comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:37;(m) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acidsequence of SEQ ID NO: 52 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:39, optionally VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 52, and Vn comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:39;(n) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 53 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:41, optionally VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:53, and Vn comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:41;(o) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 54 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43, optionally VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 54, and Vn comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43;(p) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:55 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%identical to the amino acid sequence of SEQ ID NO:43, optionally VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 55, and Vn comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43; or(q) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 56 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43, optionally VHI comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:56, and Vn comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:43.

4. The binding protein of any one of claims 1-3, wherein the binding site that specifically binds an IL-13 polypeptide comprises:(a) a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:57, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:58, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 59, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:60, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:61, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 62; or(b) a VH domain that comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:57, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:58, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 108, and a VL domain that comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:60, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:61, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 62;optionally wherein the binding site that specifically binds an IL-13 polypeptide comprises:180(a) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:70 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:71, optionally VH2 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:70, and VL2 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:71;(b) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 72 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:73, optionally VH2 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:72, and VL2 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 73;(c) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 74 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:75, optionally VH2 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:74, and VL2 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 75; or(d) a VH domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:76 and a VL domain that comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:77, optionally VH2 comprises an amino acid sequence that is at least18195%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:76, and VL2 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:77.

5. The binding protein of claim 1 , wherein VHI compri ses a CDR-H 1 compri sing the amino acid sequence of SEQ ID NO:1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:3; VLI comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10; VH2 comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:57, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:58, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 59; and VL2 comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:60, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:61, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 62;optionally wherein VHI comprises the amino acid sequence of SEQ ID NO:34, VLI comprises the amino acid sequence of SEQ ID NO:35, VH2 comprises the amino acid sequence of SEQ ID NO:70, and VL2 comprises the amino acid sequence of SEQ ID NO:71.

6. The binding protein of any one of claims 1-5, wherein the third antigen binding site specifically binds an OX40L polypeptide.

7. The binding protein of claim 6, wherein VH3 comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:78, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:79, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 80; and VL3 comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:81, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 82, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 83; optionally wherein:(a) VH3 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:91, and VL3 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 92;182(b) VHS comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:93, and VLS comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 94;(c) VHS comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:95, and VL3 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:96; or(d) VH3 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:97, and VL3 comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:96.

8. The binding protein of claim 1, wherein VHI comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:3; VLI comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:6, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10; VH2 comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:57, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:58, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 59; VL2 comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:60, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:61, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:62; VH3 comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:78, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:79, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 80; and VL3 comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 81 , a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 82, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:83;183optionally wherein VHI comprises the amino acid sequence of SEQ ID NO:34, VLI comprises the amino acid sequence of SEQ ID NO:35, VH2 comprises the amino acid sequence of SEQ ID NO:70, VL2 comprises the amino acid sequence of SEQ ID NO:71, Vm comprises the amino acid sequence of SEQ ID NO : 91 , and V LS comprises the ammo acid sequence of SEC) ID bIO.92.

9. The binding protein of any one of claims 1-8, wherein at least one of Li, L2, L3 or L4, is independently 0 amino acids in length or Li, L2, L3 or L4 are each independently at least one amino acid in length; optionally wherein:(a) Li, L2, L3 and L4 each independently are zero amino acids in length or comprise a sequence selected from the group consisting of GGGGSGGGGS (SEQ ID NO: 102), GGGGSGGGGSGGGGS (SEQ ID NO: 103), S, RT, TKGPS (SEQ ID NO: 104), GQPKAAP (SEQ ID NO: 105), and GGSGSSGSGG (SEQ ID NO: 106);(b) Li, L2, L3 and L4 each independently comprise a sequence selected from the group consisting of GGGGSGGGGS (SEQ ID NO: 102), GGGGSGGGGSGGGGS (SEQ ID NO: 103), S, RT, TKGPS (SEQ ID NO: 104), GQPKAAP (SEQ ID NO: 105), and GGSGSSGSGG (SEQ ID NO: 106);(c) Li comprises the sequence GQPKAAP (SEQ ID NO: 105), L2 comprises the sequence TKGPS (SEQ ID NO: 104), L3 comprises the sequence S, and L4 comprises the sequence RT;(d) Li comprises the sequence GGGGSGGGGS (SEQ ID NO: 102), L2 comprises the sequence GGGGSGGGGS (SEQ ID NO: 102), L3 is 0 amino acids in length, and L4 is 0 amino acids in length;(e) Li comprises the sequence GGSGSSGSGG (SEQ ID NO: 106), L2 comprises the sequence GGSGSSGSGG (SEQ ID NO: 106), L3 is 0 amino acids in length, and L4 is 0 amino acids in length; or(f) Li comprises the sequence GGGGSGGGGSGGGGS (SEQ ID NO: 103), L2 is 0 amino acids in length, L3 comprises the sequence GGGGSGGGGSGGGGS (SEQ ID NO: 103), and L4 is 0 amino acids in length.

10. The binding protein of any one of claims 1-9, wherein:184(a) the CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgGl or IgG4 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgGl or IgG4 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; or(b) the CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgGl or IgG4 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgGl or IgG4 according to EU Index, wherein the amino acid substitutions are S354C and T366W.

11. The binding protein of any one of claims 1-10, wherein:(a) the CH3 domains of the second and the third polypeptide chains are human IgGl or IgG4 CH3 domains, and wherein only one of the CH3 domains comprises amino acid substitutions at positions corresponding to positions 435 and 436 of human IgGl or IgG4 according to EU Index, wherein the amino acid substitutions are H435R and Y436F; and / or(b) the CH3 domains of the second and the third polypeptide chains are human IgGl CH3 domains, and wherein the CH3 domains each comprise amino acid substitutions at positions corresponding to positions 234 and 235 of human IgGl according to EU Index, wherein the amino acid substitutions are L234A and L235A.

12. The binding protein of claim 1, wherein the first polypeptide chain of the binding protein comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 98, the second polypeptide chain of the binding protein comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:99, the third polypeptide chain of the binding protein comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 100, and the fourth polypeptide chain of the binding protein comprises an amino acid sequence that is at least 95%,185at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO : 101.

13. A pharmaceutical composition comprising the binding protein of any one of claims 1-12 and a pharmaceutically acceptable carrier.

14. The binding protein of any one of claims 1-12 or the pharmaceutical composition of claim 13 for use in preventing and / or treating an inflammatory disease or disorder in a patient; optionally wherein the inflammatory disease or disorder is atopic dermatitis; and / or optionally wherein the patient is a human.

15. An antibody that specifically binds an OX40L polypeptide, wherein the antibody comprises a heavy chain variable (VH) domain and a light chain variable (VH) domain; wherein the VH domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:78, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:79, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:80, and the VL domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO:81, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:82, and a CDR-L3 comprising the amino acid sequence of SEQ IDNO:83;optionally wherein:(a) the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:91, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 92;(b) the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:93, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 94;(c) the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:95, and the VL domain comprises an amino acid sequence that is at least 95%, at least18696%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 96; or(d) the VH domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:97, and the VL domain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:96.187

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