Multispecific antibodies and uses thereof

By developing antibodies that specifically bind IL-4, IL-13, IL-33, TSLP and p40, the problem of insufficient efficacy in the treatment of various inflammatory diseases in the prior art is solved, and effective treatment of various diseases is achieved.

CN119998316APending Publication Date: 2025-05-13PFIZER INC
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Patent Information

Application Number
CN202380037397.9
Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Priority Date
2023-02-03
Filing Date
2023-02-28
Publication Date
2025-05-13

AI Technical Summary

Technical Problem

The prior art has not yet met the need for safe and effective therapeutic agents to address a wide range of pathogenic mechanisms when treating a variety of diseases characterized by inflammatory responses.

Method used

Develop antibodies and compositions specifically binding to IL-4, IL-13, IL-33, TSLP and p40 for the diagnosis and treatment of a variety of diseases including atopic dermatitis, asthma, cancer, etc.

Benefits of technology

By neutralizing cytokines such as IL-4, IL-13, IL-33, TSLP and p40, it can effectively reduce the inflammatory response of related diseases and provide a wider range of therapeutic effects.

✦ Generated by Eureka AI based on patent content.

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Abstract

The present disclosure relates to antibodies that specifically bind to one or more of IL-4, IL-13, IL-33, TSLP, and p40. The present disclosure further relates to antibodies that bind to one of IL-4, IL-13, IL-33, or TSLP. The disclosure further relates to multispecific antibodies that specifically bind to IL-4 and IL-13, as well as at least one other target. The present disclosure relates to multispecific antibodies that bind to one of IL-4, IL-13, and IL-33, TSLP, or p40. The disclosure also relates to related molecules, e.g., nucleic acids encoding such antibodies or multispecific antibodies, compositions and related methods, e.g., methods for producing and purifying such antibodies and multispecific antibodies, and their use in diagnosis and therapy.
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Description

[0001] field

[0002] The present invention relates to antibodies that specifically bind to one or more of IL-4, IL-13, IL-33, TSLP, and p40. The present invention further relates to antibodies that bind to one of IL-4, IL-13, IL-33, or TSLP. The present invention further relates to multispecific antibodies that specifically bind to IL-4 and IL-13 and at least one other target. The present invention relates to multispecific antibodies that bind to IL-4, IL-13, and one of IL-33, TSLP, or p40. The present invention also relates to related molecules, such as nucleic acids encoding such antibodies or multispecific antibodies, compositions, and related methods, such as methods for producing and purifying such antibodies and multispecific antibodies, and their use in diagnosis and therapy.

[0003] References to sequence listings

[0004] “This application contains a Sequence Listing, which has been submitted electronically in .xml format and is hereby incorporated by reference in its entirety. The .xml file, created on February 9, 2023, is named PC072799SequenceListing.xml and is 252KB in size.”

[0005] background

[0006] The present invention relates to antibodies and compositions, methods and uses thereof that specifically bind to one or more of IL-4, IL-13, IL-33, TSLP and p40, including using the antibodies of the present disclosure to treat one or more diseases or conditions selected from the group consisting of atopic dermatitis, atopic dermatitis, asthma, cancer, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPF. , scleroderma and systemic sclerosis, diabetic nephropathy, Behcet's disease, gout, Alzheimer's disease, atherosclerosis, fungal keratitis, non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus (SLE), primary biliary cirrhosis and hidradenitis suppurativa, including the treatment and prevention of one or more symptoms associated with the respective disease or condition.

[0007] IL-4 and IL-13 are key drivers of immune activation, causing the inflammation, edema, fibrosis, and pruritus of atopic conditions (48, 49). IL-4 and IL 13 interact with cells through a common receptor composed of IL-4Rα and IL-13Rα1 (type II receptors) expressed on monocytes, fibroblasts, keratinocytes, epithelial cells, smooth muscle cells, and other non-lymphocyte cell types (29). IL-4 can also activate cells through the IL-4Rα / IL-2Rγ co-expressed on T cells, B cells, and monocytes (type I receptors). Engagement of IL-4Rα with either receptor activates STAT6 to induce atopy-related genes (29). Although IL-4 and IL-13 can engage common receptors and signaling pathways, differences in cytokine availability, localization, and receptor binding affinity result in different response profiles (49, 50). Further differentiation can be triggered by the type I receptor (IL-4Rα / γc), which drives Th2 differentiation by IL-4 but not IL-13 (51) and the cell surface “decoy” IL-13Rα2, which mediates neutralization and depletion of IL-13 but not IL-4 (52, 53).

[0008] The role of IL-4 and IL-13 in atopic disease is supported by genetic associations, extensive validation in preclinical models, and clinical efficacy of IL-4 and IL-13 neutralization across a range of atopic indications (48). (dupirumab; Sanofi / Regeneron) blocks responses to both cytokines and is approved for the treatment of moderate-to-severe atopic dermatitis (AD), asthma, and chronic rhinosinusitis with nasal polyps, demonstrating activity against both IL-4 and IL-13 in these indications (54-56). The anti-IL-13 mAbs nerolizumab (Lilly) (57) and trombopag (Adbry TM ; Leo Pharma) (58, 59) have also demonstrated efficacy in AD and have more limited activity in asthma (60, 61). The effectiveness of anti-IL-13 mAbs in AD suggests that IL-13 neutralization is Nevertheless, available meta-analyses (62, 63) suggest that It had superior activity to neratumumab and troloxetine, consistent with the additive benefit of IL-4 blockade.

[0009] IL-33 is released passively during cell necrosis or when tissue is damaged, suggesting that it may act as an alarmin that alerts the immune system following endothelial or epithelial cell damage during infection, physical stress, or trauma. IL-33 plays an important role in type 2 innate immunity through the activation of allergic inflammation-associated eosinophils, basophils, mast cells, macrophages, and group 2 innate lymphoid cells (ILC2) through its receptor ST2 (96).

[0010] Thymic stromal lymphoprotein (TSLP) is an epithelial cytokine that is crucial for the initiation and perpetuation of inflammation. (tezepelumab, Amgen) is a TSLP antibody approved for the treatment of asthma.

[0011] IL-4 and IL-13 are primarily associated with type 2 effector responses. In contrast, IL-12 and IL-23 have been associated with type 1 and type 3 (Th17) responses, respectively (77). IL-12 drives T helper 1 (Th1) cell differentiation and interferon-γ (IFN-γ) production, while IL-23 promotes the maintenance of Th17 cells that produce IL-17 and other type 3 cytokines. Type 1 and type 3 responses have been associated with a range of human inflammatory and autoimmune diseases. A causal role for IL-12p40-containing cytokines has been established through numerous drug approvals (75) (IL-12p40 will be referred to as p40 in the following). p40 neutralizers (ustekinumab; Janssen) neutralizes both IL-12 and IL-23 and is approved for the treatment of plaque psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis. IL-23-selective anti-IL-23p19 blocker (guselkumab; Janssen), (risankizumab; Boehringer Ingelheim / AbbVie) and (tilatuzumab; Sun Pharmaceutical) is approved for the treatment of a range of psoriatic conditions.

[0012] Despite the efficacy of dupilumab, tezemecumab, guselkumab, risankizumab, and tirazumab, there remains an unmet need for safe and effective therapeutics that address a broad range of pathogenic mechanisms for numerous diseases characterized by inflammatory responses.

[0013] Overview

[0014] Provided herein are antibodies (including antigen-binding fragments thereof) that specifically bind to one or more of IL-4, IL-13, IL-33, TSLP, and p40, as well as monomeric and multimeric antibodies, related nucleic acids, uses, and methods thereof. The present disclosure also provides processes for making, preparing, and generating antibodies that bind to one or more of IL-4, IL-13, IL-33, TSLP, and p40. The antibodies of the present disclosure may be used for one or more of the diagnosis, prevention, or treatment of disorders or conditions mediated by or associated with one or more of IL-4, IL-13, IL-33, TSLP, and p40 activity, including, but not limited to, atopic dermatitis, asthma, cancer, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma and systemic sclerosis, diabetic nephropathy, Behcet's disease, gout, Alzheimer's disease, atherosclerosis, fungal keratitis, nonalcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus (SLE), primary biliary cirrhosis, and hidradenitis suppurativa. The disclosure further encompasses the expression of antibodies and the preparation and manufacture of compositions comprising the antibodies of the disclosure, such as medicaments for use thereof.

[0015] Also provided are polynucleotides encoding antibodies that bind to one or more of IL-4, IL-13, IL-33, TSLP, and p40. Also provided are polynucleotides encoding the heavy or light chain or both of the antibodies. Host cells expressing the antibodies are provided. Methods of treatment using the antibodies are provided. Such methods include, but are not limited to, one or more methods of treating a disease or a method of preventing a disease that is associated with or mediated by one or more of IL-4, IL-13, IL-33, TSLP, and p40 expression and / or is associated with IL-4, IL-13, IL-33, TSLP, and p40 binding atopic dermatitis, atopic dermatitis, asthma, cancer, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, Bullous pemphigoid, chronic urticaria, IPF, scleroderma and systemic sclerosis, diabetic nephropathy, Behcet's disease, gout, Alzheimer's disease, atherosclerosis, fungal keratitis, non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus (SLE), primary biliary cirrhosis and hidradenitis suppurativa are associated with or mediated by one or more of these.

[0016] The present invention can be more easily understood by reference to the following detailed description of embodiments of the present invention and the examples included therein. It should be understood that the present invention is not limited to specific manufacturing methods, which may of course vary. It should also be understood that the terms used herein are only for the purpose of describing specific embodiments and are not intended to be restrictive. Those skilled in the art will recognize or be able to determine many equivalents of the specific embodiments of the present invention described herein using only routine experiments. Such equivalents are intended to be encompassed by the following embodiment (E).

[0017] E1. An isolated antibody that specifically binds to IL-33, comprising a heavy chain variable region (IL33-VH) and a light chain variable region (IL33-VL), comprising

[0018] (i) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 73, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 78;

[0019] (ii) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 63, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 71; or

[0020] (iii) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO: 80, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO: 81.

[0021] E2. An isolated antibody that specifically binds to IL-33, comprising a heavy chain variable region (IL33-VH) and a light chain variable region (IL33-VL) comprising the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 73, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 78.

[0022] E3. An isolated antibody that specifically binds to IL-33, comprising a heavy chain variable region (IL33-VH) and a light chain variable region (IL33-VL), wherein the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 60; the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 61; the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 72; the CDR-L1 comprises the amino acid sequence of SEQ ID NO: 75; the CDR-L2 comprises the amino acid sequence of SEQ ID NO: 76; and the CDR-L3 comprises the amino acid sequence of SEQ ID NO: 77.

[0023] E4. The antibody of any one of E1 to E3, which comprises an IL33-VH framework sequence derived from a human germline VH sequence selected from the group consisting of: DP47, DP48, DP50, DP51, DP54, and DP77.

[0024] E5. The antibody of any one of E1 to E4, which comprises an IL33-VH framework sequence derived from a human DP54 germline sequence.

[0025] E6. The antibody of any one of E1 to E5, which comprises an IL33-VL framework sequence derived from a human germline VL sequence selected from the group consisting of: DPK1, DPK3, DPK4, DPK5, DPK7, DPK8, and DPK9.

[0026] E7. The antibody of any one of E1 to E6, which comprises an IL33-VL framework sequence derived from a human germline DPK9 sequence.

[0027] E8. The antibody of any one of E1 to E7, comprising an IL33-VL framework sequence and an IL33-VH framework sequence 98%, 99% or 100% sequence, and wherein one or both of the IL33-VL framework sequence and the IL33-VH framework sequence are at least 66%, 76%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% identical to the human germline sequence from which they are derived.

[0028] E9. The antibody of any one of E1 to E8, comprising an IL33-VL framework sequence and an IL33-VH framework sequence, and wherein one or both of the IL33-VL framework sequence or the IL33-VH framework sequence are identical to the human germline sequence from which they are derived.

[0029] E10. The antibody of any one of E1 to E9, comprising an IL33-VH sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:73.

[0030] E11. The antibody of any one of E1 to E10, comprising an IL33-VL sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:78.

[0031] E12. The antibody of any one of E1 to E11, comprising

[0032] (i) the IL33-VH sequence of SEQ ID NO: 73 and the IL33-VL sequence of SEQ ID NO: 78; or

[0033] (ii) the IL33-VH sequence of SEQ ID NO: 63 and the IL33-VL sequence of SEQ ID NO: 71; or

[0034] (iii) IL33-VH sequence of SEQ ID NO: 80 and IL33-VL of SEQ ID NO: 81.

[0035] E13. The antibody of any one of E1 to E12, comprising an IL33-VH sequence identical to SEQ ID NO: 73 and an IL33-VL identical to SEQ ID NO: 78.

[0036] E14. The antibody of any one of E1 to E13, comprising the IL33-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 202.

[0037] E15. The antibody of any one of E1 to E14, comprising an IL33-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 203.

[0038] E16. The antibody of any one of E1 to E15, which comprises an IL33-VH sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-127210.

[0039] E17. The antibody of any one of E1 to E16, which comprises an IL33-VL sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-127209.

[0040] E18. An antibody comprising an IL33-VH sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127210, and an IL33-VL sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127209.

[0041] E19. The antibody of E1 to E18, wherein the antibody has a K of less than a value selected from D Binding to human IL-33: 100 pM, 50 pM, 40 pM, 30 pM, 25 pM, 20 pM, 15 pM and 10 pM, 5 pM, 2 pM, 1 pM, 750 fM, 500 fM and 250 fM.

[0042] E20. The antibody of E1 to E19, wherein the antibody has a K of about or less than 15 pM. D Binds human IL-33.

[0043] E21. The antibody of E1 to E20, wherein the antibody has a K of about or less than 1 pM. D Binds human IL-33.

[0044] E22. The antibody of E1 to E21, wherein the antibody has a K of about or less than 250 fM. D Binds human IL-33.

[0045] E23. The antibody of any one of E19 to E22, wherein K D The values ​​were measured by kinetic exclusion assay.

[0046] E24. The antibody of any one of E19 to E22, wherein K D The values ​​were measured by surface plasmon resonance (SPR).

[0047] Antibodies E25.E1 to E24, among which IL-33 neutralization and SEAP assay IL-33IC 50 Less than 20pM.

[0048] Antibodies E26.E1 to E25, among which IL-33 neutralization and SEAP assay IL-33IC 50 Less than 15pM.

[0049] E27.E25 to E26 antibodies, including HEK IL-33 neutralization SEAP assay was performed at 37°C for 20 hours.

[0050] E28. Antibodies to E1 to E27, including IL-33IC 50 Less than 15 pM and calculated by ELISA measurement of IFNγ in human whole blood assays treated with IL-33 and IL-12.

[0051] E29.E28 antibody, wherein the human whole blood assay is performed at 37°C for 22 hours.

[0052] E30. The antibody of E1 to E29, wherein the antibody binds to cynomolgus monkey IL-33.

[0053] E31. Antibodies of E1 to E30, wherein the binding K of the antibody to cynomolgus monkey IL-33 is D The binding K of this antibody to human IL-33 D within 3 orders of magnitude.

[0054] E32. The antibody of E1 to E31, further comprising a constant heavy chain domain (IL33-CH1) and a constant light chain domain (IL33-CL).

[0055] The antibody of E33.E32, wherein IL33-CH1 comprises a sequence selected from the group consisting of SEQ ID NO: 6, SEQ ID NO: 105, and SEQ ID NO: 110.

[0056] E34. The antibody of E32 to E33, wherein IL33-CH1 comprises the sequence according to SEQ ID NO:6.

[0057] E35. The antibody of E32 to E34, wherein IL33-CL comprises a sequence selected from the group consisting of SEQ ID NO: 16, SEQ ID NO: 108 and SEQ ID NO: 113.

[0058] E36. The antibody of E32 to E35, wherein IL33-CL comprises the sequence according to SEQ ID NO:16.

[0059] E37. The antibody of E32 to E36, wherein IL33-CH1 is linked to IL33-VL, and IL33-CL is linked to IL33-VH, forming an IL33-binding domain-exchanged Fab domain (IL33-xFab).

[0060] E38. The antibody of E32 to E37, wherein IL33-CH1 is linked to IL33-VH, and IL33-CL is linked to IL33-VL, forming an IL-33 binding Fab domain (IL33-Fab).

[0061] E39. The antibody of any one of E1 to E38, which comprises an antibody Fc domain comprising a first Fc chain and a second Fc chain.

[0062] The antibody of E40.E39, wherein the Fc domain is an Fc domain of IgA (eg, IgA1 or IgA2), IgD, IgE, IgM, or IgG (eg, IgG1, IgG2, IgG3, or IgG4).

[0063] The antibody of E41.E40, wherein the Fc domain is the Fc domain of IgG1.

[0064] E42. The antibody of E40, wherein the N-terminus of the first Fc chain or the second Fc chain is linked to the C-terminus of the IL33-CH1 domain.

[0065] E43. The antibody of E41 to E42, wherein the first Fc chain and the second Fc chain each comprise, from N-terminus to C-terminus: a hinge region, a CH2 region, and a CH3 region.

[0066] The antibody of E44.E43, wherein the hinge region comprises a sequence selected from the group consisting of SEQ ID NO:7, SEQ ID NO:102, SEQ ID NO:123, SEQ ID NO:126, SEQ ID NO:129 and SEQ ID NO:131.

[0067] E45. The antibody of E44, wherein the hinge region comprises the sequence according to SEQ ID NO:7.

[0068] The antibody of E46.E44, wherein the hinge region on the first Fc chain and the hinge region on the second Fc chain comprise a pair of sequences according to SEQ ID NO: 129 and SEQ ID NO: 131.

[0069] E47. The antibody of E43 to E46, wherein the CH2 region comprises the sequence according to SEQ ID NO:8.

[0070] E48. The antibody of E43 to E47, wherein the CH3 region on the first Fc chain and the CH3 region on the second Fc chain comprise a pair of sequences selected from the group consisting of:

[0071] (i) SEQ ID NO: 9 and SEQ ID NO: 9;

[0072] (ii) SEQ ID NO: 111 and SEQ ID NO: 106;

[0073] (iii) SEQ ID NO: 111 and SEQ ID NO: 114;

[0074] (iv) SEQ ID NO: 114 and SEQ ID NO: 117;

[0075] (v) SEQ ID NO: 124 and SEQ ID NO: 127;

[0076] (vi) SEQ ID NO: 139 and SEQ ID NO: 141; and

[0077] (vii) SEQ ID NO: 147 and SEQ ID NO: 148.

[0078] The antibody of E49.E48, wherein the CH3 region on the first Fc chain and the CH region on the second Fc chain each comprise a sequence according to SEQ ID NO:9.

[0079] The antibody of E50.E48, wherein the CH3 region on the first Fc chain and the CH3 region on the second Fc chain comprise a pair of sequences according to SEQ ID NO: 124 and SEQ ID NO: 127.

[0080] E51. The antibody of any one of E1 to E50, which comprises a polypeptide carrying IL33-VH, which polypeptide comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98%, 99% or 100% identical to a sequence selected from SEQ ID NO: 74, SEQ ID NO: 103, SEQ ID NO: 128, SEQ ID NO: 132, SEQ ID NO: 134, SEQ ID NO: 137, SEQ ID NO: 142 and SEQ ID NO: 143.

[0081] E52. The antibody of any one of E1 to E51, which comprises a polypeptide carrying IL33-VH, the polypeptide comprising an amino acid sequence selected from SEQ ID NO: 74, SEQ ID NO: 103, SEQ ID NO: 128, SEQ ID NO: 132, SEQ ID NO: 134, SEQ ID NO: 137, SEQ ID NO: 142 and SEQ ID NO: 143.

[0082] E53. The antibody of any one of E52 to E53, wherein the polypeptide carrying IL33-VH comprises the sequence according to SEQ ID NO:74.

[0083] E54. The antibody of any one of E52 to E52, wherein the IL33-VH-bearing polypeptide comprises the sequence according to SEQ ID NO: 132.

[0084] E55. The antibody of E32 to E54, wherein IL33-CL comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 16, SEQ ID NO: 108, and SEQ ID NO: 113.

[0085] E56. The antibody of E32 to E55, wherein IL33-CL comprises the amino acid sequence of SEQ ID NO:16.

[0086] E57. The antibody of any one of E1 to 56, comprising a polypeptide carrying IL33-VL comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to a sequence selected from SEQ ID NO: 79, SEQ ID NO: 107, SEQ ID NO: 115, SEQ ID NO: 121, SEQ ID NO: 138, SEQ ID NO: 144 and SEQ ID NO: 145.

[0087] E58. The antibody of any one of E1 to E57, which comprises an IL33-VL-carrying polypeptide comprising the amino acid sequence of SEQ ID NO: 79.

[0088] E59. The antibody of E1 to E58, comprising the polypeptide carrying IL33-VH of SEQ ID NO: 74 and the polypeptide carrying IL33-VL of SEQ ID NO: 79.

[0089] E60. The antibody of E1 to E59, comprising the polypeptide carrying IL33-VH of SEQ ID NO: 132 and the polypeptide carrying IL33-VL of SEQ ID NO: 79.

[0090] E61. The antibody of any one of E1 to E60, which comprises the polypeptide sequence carrying IL33-VH encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127208.

[0091] E62. The antibody of any one of E1 to E61, which comprises the polypeptide sequence carrying IL33-VL encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127207.

[0092] E63. An antibody comprising the polypeptide sequence carrying IL33-VH encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127208, and the polypeptide sequence carrying IL33-VL encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127207.

[0093] E64. An isolated antibody that specifically binds IL-33, comprising the CDRs of an antibody selected from one or more of Tables 82, 85 and 87.

[0094] E65. An isolated antibody that specifically binds to IL-33, comprising the VH and VL of an antibody selected from one or more of Tables 82, 84 and 87.

[0095] E66. An isolated antibody that specifically binds IL-33 selected from one or more of Tables 82, 84 and 87.

[0096] E67. The antibody of any one of E1 to 65 for use as a medicament.

[0097] The antibody of E68.E67, wherein the use is for treating one or more selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, diabetic nephropathy, Behcet's disease, gout, Alzheimer's disease and atherosclerosis.

[0098] E69. The antibody of any one of E67 to E68, wherein the use is for treating one or more selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata and non-alcoholic steatohepatitis (NASH).

[0099] E70. The antibody of any one of E67 to E69, wherein the use is for atopic dermatitis.

[0100] E71. The antibody of any one of E67 to E69, wherein the use is for non-alcoholic steatohepatitis (NASH).

[0101] E72. A pharmaceutical composition comprising a therapeutically effective amount of an antibody from E1 to E71 and a pharmaceutically acceptable carrier.

[0102] E73. A method of treating a medical condition, comprising administering to a subject in need thereof a therapeutically effective amount of the antibody of any one of E1 to E71 or the pharmaceutical composition of E72.

[0103] The method of E74.E73, wherein the condition is selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, diabetic nephropathy, Behcet's disease, gout, Alzheimer's disease and atherosclerosis.

[0104] E75. The method of any one of E73 to E74, comprising administering the antibody or pharmaceutical composition subcutaneously.

[0105] E76. The method of any one of E73 to E75, wherein the antibody or pharmaceutical composition is administered about twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, twice a month, once a month, once every two months, once every three months, or once every four months.

[0106] E77. An isolated antibody that specifically binds to TSLP, comprising a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), comprising

[0107] (i) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 92, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 94;

[0108] (ii) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 92, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 93;

[0109] (iii) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 92, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 213; or

[0110] (iv) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 92, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 214;

[0111] (v) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 221, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 213;

[0112] (vi) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 221, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 94; or

[0113] (vii) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO: 221, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO: 223.

[0114] E78. An isolated antibody that specifically binds to TSLP, comprising a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL) comprising the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO: 92, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO: 94.

[0115] E79. An isolated antibody that specifically binds to TSLP, comprising

[0116] (i) a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), wherein CDR-H1 comprises the amino acid sequence of SEQ ID NO: 82; CDR-H2 comprises the amino acid sequence of SEQ ID NO: 83; CDR-H3 comprises the amino acid sequence of SEQ ID NO: 85; CDR-L1 comprises the amino acid sequence of SEQ ID NO: 86; CDR-L2 comprises the amino acid sequence of SEQ ID NO: 88; and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 90;

[0117] (ii) a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), wherein CDR-H1 comprises the amino acid sequence of SEQ ID NO: 82; CDR-H2 comprises the amino acid sequence of SEQ ID NO: 83; CDR-H3 comprises the amino acid sequence of SEQ ID NO: 85; CDR-L1 comprises the amino acid sequence of SEQ ID NO: 86; CDR-L2 comprises the amino acid sequence of SEQ ID NO: 88; and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 211;

[0118] (iii) a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), wherein CDR-H1 comprises the amino acid sequence of SEQ ID NO: 82; CDR-H2 comprises the amino acid sequence of SEQ ID NO: 83; CDR-H3 comprises the amino acid sequence of SEQ ID NO: 85; CDR-L1 comprises the amino acid sequence of SEQ ID NO: 86; CDR-L2 comprises the amino acid sequence of SEQ ID NO: 88; and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 212;

[0119] (iv) a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), wherein CDR-H1 comprises the amino acid sequence of SEQ ID NO: 82; CDR-H2 comprises the amino acid sequence of SEQ ID NO: 83; CDR-H3 comprises the amino acid sequence of SEQ ID NO: 85; CDR-L1 comprises the amino acid sequence of SEQ ID NO: 86; CDR-L2 comprises the amino acid sequence of SEQ ID NO: 87; and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 211;

[0120] (v) a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), wherein CDR-H1 comprises the amino acid sequence of SEQ ID NO: 82; CDR-H2 comprises the amino acid sequence of SEQ ID NO: 83; CDR-H3 comprises the amino acid sequence of SEQ ID NO: 85; CDR-L1 comprises the amino acid sequence of SEQ ID NO: 86; CDR-L2 comprises the amino acid sequence of SEQ ID NO: 88; and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 90; or

[0121] (vi) a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), wherein CDR-H1 comprises the amino acid sequence of SEQ ID NO: 82; CDR-H2 comprises the amino acid sequence of SEQ ID NO: 83; CDR-H3 comprises the amino acid sequence of SEQ ID NO: 85; CDR-L1 comprises the amino acid sequence of SEQ ID NO: 86; CDR-L2 comprises the amino acid sequence of SEQ ID NO: 87; and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 212.

[0122] E80. The antibody of any one of E77 to E79, which comprises a TSLP-VH framework sequence derived from a human germline VH sequence selected from the group consisting of: DP47, DP49, DP50, DP54 and DP53.

[0123] E81. The antibody of any one of E77 to E80, which comprises a TSLP-VH framework sequence derived from a human DP50 germline sequence.

[0124] E82. The antibody of any one of E77 to E81, comprising a TSLP-VL framework sequence derived from a human germline VL sequence selected from the group consisting of: DPL16, DPL23, V2-6, V2-8, V2-14, and V2-17.

[0125] E83. The antibody of any one of E77 to E82, which comprises a TSLP-VL framework sequence derived from a human germline V2-14 sequence.

[0126] E84. The antibody of any one of E77 to E84, which comprises a TSLP-VL framework sequence and a TSLP-VH framework sequence, and wherein one or both of the TSLP-VL framework sequence or the TSLP-VH framework sequence are at least 66%, 76%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the human germline sequence from which they are derived.

[0127] E85. The antibody of any one of E77 to E84, which comprises a TSLP-VL framework sequence and a TSLP-VH framework sequence, and wherein one or both of the TSLP-VL framework sequence or the TSLP-VH framework sequence are identical to the human germline sequence from which they are derived.

[0128] E86. The antibody of any one of E77 to E85, which comprises a TSLP-VH sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:92.

[0129] E87. The antibody of any one of E77 to E86, which comprises a TSLP-VL sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:94.

[0130] E88. The antibody of any one of E77 to E86, comprising

[0131] (i) TSLP-VH sequence of SEQ ID NO: 92, and TSLP-VL of SEQ ID NO: 94;

[0132] (ii) the TSLP-VH sequence of SEQ ID NO: 92, and the TSLP-VL sequence of SEQ ID NO: 93;

[0133] (iii) TSLP-VH sequence of SEQ ID NO: 92, and TSLP-VL of SEQ ID NO: 213;

[0134] (iv) TSLP-VH sequence of SEQ ID NO: 92, and TSLP-VL of SEQ ID NO: 214;

[0135] (v) TSLP-VH sequence of SEQ ID NO: 221, and TSLP-VL of SEQ ID NO: 215;

[0136] (vi) the TSLP-VH sequence of SEQ ID NO: 221, and the TSLP-VL sequence of SEQ ID NO: 99; or

[0137] (vii) TSLP-VH sequence of SEQ ID NO: 221, and TSLP-VL of SEQ ID NO: 224.

[0138] E89. The antibody of any one of E77 to E88, which comprises a TSLP-VH sequence identical to SEQ ID NO: 92 and a TSLP-VL identical to SEQ ID NO: 94.

[0139] E90. The antibody of any one of E77 to E88, which comprises a TSLP-VH sequence identical to SEQ ID NO: 92 and a TSLP-VL identical to SEQ ID NO: 93.

[0140] E91. The antibody of any one of E77 to E88, which comprises a TSLP-VH sequence identical to SEQ ID NO: 92 and a TSLP-VL identical to SEQ ID NO: 213.

[0141] E92. The antibody of any one of E77 to E88, which comprises a TSLP-VH sequence identical to SEQ ID NO: 92 and a TSLP-VL identical to SEQ ID NO: 214.

[0142] E93. The antibody of any one of E77 to E89, which comprises a TSLP-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 205.

[0143] The antibody of E94.E91, which comprises the TSLP-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 217.

[0144] The antibody of any one of E95.E92, comprising a TSLP-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 218.

[0145] E96. The antibody of any one of E77 to E95, which comprises the TSLP-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 204.

[0146] E97. The antibody of any one of E77 to E96, which comprises a TSLP-VH sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127200.

[0147] E98. The antibody of any one of E77 to E89, which comprises a TSLP-VL sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127199.

[0148] E99. An antibody comprising a TSLP-VH sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127200, and comprising a TSLP-VL sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127199.

[0149] E100. The antibody of any one of E77 to E88, which comprises a TSLP-VL sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-______.

[0150] E101. An antibody comprising a TSLP-VH sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127200, and a TSLP-VL sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-______.

[0151] E102. The antibody of any one of E77 to E88, which comprises a TSLP-VL sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-______.

[0152] E103. An antibody comprising a TSLP-VH sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127200, and a TSLP-VL sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-______.

[0153] E104. The antibody of any one of E77 to E102, wherein the antibody is characterized by an IC of 0.05 in a TARC production bioassay in human peripheral blood mononuclear cells. 50 Less than 10pM.

[0154] E105. The antibody of any one of E77 to E104, wherein the antibody is characterized by an IC of 0.05 in a TARC production bioassay in human peripheral blood mononuclear cells. 50 Less than 7pM.

[0155] E106. The antibody of any one of E77 to E105, wherein the antibody is characterized by an IC of 0.05 in a TARC production bioassay in human peripheral blood mononuclear cells. 50 Less than 6pM.

[0156] E107. The antibody of E77 to E106, wherein the melting temperature of the antibody is 68°C.

[0157] The antibody of E108.E77 to E107, wherein the pH 3.4 retention Δ% HMMS is less than 5, such that the pH 3.4 retention Δ% HMMS is defined as the difference between the percentage of high molecular weight species produced due to degradation after incubation of the antibody at pH 3.4 for 5 hours at room temperature and the percentage of high molecular weight species produced due to degradation after incubation of the antibody at pH 7.2 for 5 hours at room temperature.

[0158] E109. The antibody of E77 to E108, wherein the antibody maintains a Δ% HMMS of less than 1 at low pH 3.4.

[0159] The antibody of E110.E77 to E109, wherein the antibody maintains a Δ% HMMS of less than 0.1 at low pH 3.4.

[0160] The antibody of E111.E77 to E110, further comprising a constant heavy chain domain (TSLP-CH1) and a constant light chain domain (TSLP-CL).

[0161] E112. The antibody of E111, wherein TSLP-CH1 comprises a sequence selected from the group consisting of SEQ ID NO:6, SEQ ID NO:105 and SEQ ID NO:110.

[0162] E113. The antibody of E111 to E112, wherein TSLP-CH1 comprises the sequence according to SEQ ID NO:6.

[0163] E114. The antibody of E111 to E113, wherein TSLP-CL comprises a sequence selected from the group consisting of SEQ ID NO: 16, SEQ ID NO: 95, SEQ ID NO: 108 and SEQ ID NO: 113.

[0164] E115. The antibody of E111 to E114, wherein TSLP-CL comprises the sequence according to SEQ ID NO:95.

[0165] E116. The antibody of E111 to E115, wherein TSLP-CH1 is linked to TSLP-VL, and TSLP-CL is linked to TSLP-VH, forming a TSLP-binding domain-exchanged Fab domain (TSLP-xFab).

[0166] E117. The antibody of E111 to E115, wherein TSLP-CH1 is linked to TSLP-VH, and TSLP-CL is linked to TSLP-VL, forming a TSLP-binding Fab domain (TSLP-Fab).

[0167] E118. The antibody of any one of E77 to E117, comprising an Fc domain comprising a first Fc chain and a second Fc chain.

[0168] The antibody of E119.E118, wherein the Fc domain is an Fc domain of IgA (eg, IgA1 or IgA2), IgD, IgE, IgM, or IgG (eg, IgG1, IgG2, IgG3, or IgG4).

[0169] E120. The antibody of any one of E118 to E119, wherein the Fc domain is the Fc domain of IgG1.

[0170] E121. The antibody of E118 to E120, wherein the N-terminus of the first Fc chain or the second Fc chain is linked to the C-terminus of the TSLP-CH1 domain.

[0171] E122. The antibody of E118 to E121, wherein the first Fc chain and the second Fc chain each comprise, from N-terminus to C-terminus: a hinge region, a CH2 region, and a CH3 region.

[0172] The antibody of E123.E122, wherein the hinge region comprises a sequence selected from the group consisting of SEQ ID NO:7, SEQ ID NO:102, SEQ ID NO:123, SEQ ID NO:126, SEQ ID NO:129 and SEQ ID NO:131.

[0173] E124. The antibody of E122 to E123, wherein the hinge region comprises the sequence according to SEQ ID NO: 7.

[0174] E125. The antibody of E122 to E123, wherein the hinge region on the first Fc chain and the hinge region on the second Fc chain comprise a pair of sequences according to SEQ ID NO: 129 and SEQ ID NO: 131.

[0175] E126. The antibody of E122 to E123, wherein the CH2 region comprises the sequence according to SEQ ID NO:8.

[0176] E127. The antibody of E122 to E126, wherein the CH3 region on the first Fc chain and the CH3 region on the second Fc chain comprise a pair of sequences selected from the group consisting of:

[0177] (i) SEQ ID NO: 124 and SEQ ID NO: 127;

[0178] (ii) SEQ ID NO: 9 and SEQ ID NO: 9;

[0179] (iii) SEQ ID NO: 111 and SEQ ID NO: 106;

[0180] (iv) SEQ ID NO: 111 and SEQ ID NO: 114;

[0181] (v) SEQ ID NO: 114 and SEQ ID NO: 117;

[0182] (vi) SEQ ID NO: 139 and SEQ ID NO: 141; and

[0183] (vii) SEQ ID NO: 147 and SEQ ID NO: 148.

[0184] E128. The antibody of E127, wherein the CH3 region on the first Fc chain and the CH region on the second Fc chain each comprise a sequence according to SEQ ID NO:9.

[0185] The antibody of E129.E128, wherein the CH3 region on the first Fc chain and the CH region on the second Fc chain comprise a pair of sequences according to SEQ ID NO: 124 and SEQ ID NO: 127.

[0186] The antibody of any one of E130.E77 to E129, which comprises a polypeptide carrying TSLP-VH, which polypeptide comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to a sequence selected from SEQ ID NO: 97, SEQ ID NO: 152, SEQ ID NO: 153, SEQ ID NO: 155, SEQ ID NO: 158, SEQ ID NO: 161, SEQ ID NO: 165, SEQ ID NO: 222.

[0187] E131. The antibody of any one of E77 to E130, which comprises a polypeptide carrying TSLP-VH, which polypeptide comprises an amino acid sequence selected from SEQ ID NO: 97, SEQ ID NO: 152, SEQ ID NO: 153, SEQ ID NO: 155, SEQ ID NO: 158, SEQ ID NO: 161, SEQ ID NO: 165 and SEQ ID NO: 222.

[0188] E132. The antibody of any one of E77 to E131, wherein the TSLP-VH carrying polypeptide comprises the sequence according to SEQ ID NO:97.

[0189] E133. The antibody of any one of E77 to E131, wherein the TSLP-VH carrying polypeptide comprises the sequence according to SEQ ID NO: 165.

[0190] E134. The antibody of any one of E77 to E133, which comprises a polypeptide carrying TSLP-VL, which polypeptide comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to a sequence selected from SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 150, SEQ ID NO: 154, SEQ ID NO: 156, SEQ ID NO: 157, SEQ ID NO: 160, SEQ ID NO: 215, SEQ ID NO: 216 and SEQ ID NO: 224.

[0191] E135. The antibody of any one of E77 to E134, which comprises a polypeptide carrying TSLP-VL, the polypeptide comprising a sequence selected from SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 150, SEQ ID NO: 154, SEQ ID NO: 156, SEQ ID NO: 157, SEQ ID NO: 160, SEQ ID NO: 215, SEQ ID NO: 216 and SEQ ID NO: 224.

[0192] E136. The antibody of any one of E77 to E135, which comprises a TSLP-VL-carrying polypeptide comprising the sequence according to SEQ ID NO:99.

[0193] E137. The antibody of any one of E77 to E135, which comprises a TSLP-VL-carrying polypeptide sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127201.

[0194] E138. The antibody of any one of E77 to E135, which comprises a TSLP-VL-carrying polypeptide sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-_____.

[0195] E139. The antibody of any one of E77 to E135, which comprises a TSLP-VL-carrying polypeptide sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-_____.

[0196] E140. The antibody of any one of E77 to E139, which comprises a TSLP-VH-carrying polypeptide sequence encoded by a plasmid deposited with ATCC and having the deposit number PTA-127202.

[0197] E141. An antibody comprising a polypeptide sequence carrying TSLP-VH encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127202, and a polypeptide sequence carrying TSLP-VL encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127201.

[0198] E142. An antibody comprising a polypeptide sequence carrying TSLP-VH encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127202, and a polypeptide sequence carrying TSLP-VL encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-_____.

[0199] E143. An antibody comprising a polypeptide sequence carrying TSLP-VH encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127202, and a polypeptide sequence carrying TSLP-VL encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-_____.

[0200] E144. An isolated antibody that specifically binds p40 through a p40 binding domain, and wherein the antibody comprises at least one additional antigen binding domain that specifically binds an antigen selected from IL-4, IL-13, IL-33 and TSLP, and wherein the p40 binding domain comprises a heavy chain variable region (p40-VH) and a light chain variable region (p40-VL) comprising the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO: 169, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO: 175.

[0201] E145. An isolated antibody that specifically binds p40 through a p40 binding domain, and wherein the antibody comprises at least one additional antigen binding domain that specifically binds an antigen selected from the group consisting of IL-4, IL-13, IL-33 and TSLP, and wherein the p40 binding domain comprises a heavy chain variable region (p40-VH) and a light chain variable region (p40-VL), wherein CDR-H1 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 166; CDR-H2 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 167; CDR-H3 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 168; CDR-L1 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 171; CDR-L2 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 172, and CDR-L3 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 173.

[0202] E146. The antibody of any one of E144 to E145, wherein the antibody further comprises one or both of an IL-4 binding domain that specifically binds to IL-4 and an IL-13 binding domain that specifically binds to IL-13.

[0203] E147. The antibody of any one of E144 to E146, wherein the p40 binding domain comprises a p40-VH framework sequence derived from a human germline VH sequence selected from the group consisting of DP3, DP7, DP73, DP75, and DP88.

[0204] E148. The antibody of any one of E144 to E147, wherein the p40 binding domain comprises a p40-VH framework sequence derived from a human DP73 germline sequence.

[0205] E149. The antibody of any one of E144 to E148, wherein the p40 binding domain comprises a p40-VL framework sequence derived from a human germline VL sequence selected from the group consisting of DPK4, DPK5, DPK7, DPK8 and DPK9.

[0206] E150. The antibody of any one of E144 to E149, wherein the p40 binding domain comprises a p40-VL framework sequence derived from a human germline DPK7 sequence.

[0207] E151. The antibody of any one of E144 to E150, wherein the p40 binding domain comprises a p40-VL framework sequence and a p40-VH framework sequence, and wherein one or both of the p40 binding domain p40-VL framework sequence or the p40 binding domain p40-VH framework sequence are at least 66%, 76%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the human germline sequence from which they are derived.

[0208] E152. The antibody of any one of E144 to E151, wherein the p40 binding domain comprises a p40-VL framework sequence and a p40-VH framework sequence, and wherein one or both of the p40-VL framework sequence or the p40-VH framework sequence are identical to the human germline sequence from which they are derived.

[0209] E153. The antibody of any one of E144 to E152, wherein the p40 binding domain comprises a p40-VH that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 169.

[0210] E154. The antibody of any one of E144 to E153, wherein the p40 binding domain comprises a p40-VL that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 175.

[0211] E155. The antibody of any one of E144 to E154, wherein the p40 binding domain comprises p40-VH of SEQ ID NO: 169 and p40-VL of SEQ ID NO: 175.

[0212] E156. The antibody of any one of E144 to E155, wherein the p40 binding domain comprises a p40-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 206.

[0213] E157. The antibody of any one of E145 to E156, wherein the p40 binding domain comprises a p40-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 207.

[0214] E158. The antibody of any one of E144 to E157, wherein the p40 binding domain comprises a p40-VH sequence encoded by a plasmid deposited with the ATCC and having accession number PTA-127206.

[0215] E159. The antibody of any one of E144 to E158, wherein the p40 binding domain comprises a p40-VL sequence encoded by a plasmid deposited with the ATCC and having accession number PTA-127205.

[0216] E160. The antibody of E144 to E159, further comprising a constant heavy chain domain (p40-CH1) and a constant light chain domain (p40-CL).

[0217] E161. The antibody of E160, wherein p40-CH1 comprises a sequence selected from the group consisting of SEQ ID NO: 6, SEQ ID NO: 105, and SEQ ID NO: 110.

[0218] E162. The antibody of E160 to E161, wherein p40-CH1 comprises the sequence according to SEQ ID NO:6.

[0219] E163. The antibody of E160 to E162, wherein p40-CL comprises a sequence selected from the group consisting of SEQ ID NO: 16, SEQ ID NO: 108 and SEQ ID NO: 113.

[0220] E164. The antibody of E160 to E163, wherein p40-CL comprises the sequence according to SEQ ID NO:16.

[0221] E165. The antibody of E160 to E164, wherein p40-CH1 is linked to p40-VL, and p40-CL is linked to p40-VH, forming a p40-binding domain-exchanged Fab domain (p40-xFab).

[0222] E166. The antibody of E160 to E164, wherein p40-CH1 is linked to p40-VH, and p40-CL is linked to p40-VL, forming a p40-binding Fab domain (p40-Fab).

[0223] E167. The antibody of any one of E144 to E166, comprising an antibody Fc domain comprising a first Fc chain and a second Fc chain.

[0224] E168. The antibody of E167, wherein the Fc domain is an Fc domain of IgA (eg, IgA1 or IgA2), IgD, IgE, IgM, or IgG (eg, IgG1, IgG2, IgG3, or IgG4).

[0225] The antibody of E169.E168, wherein the Fc domain is the Fc domain of IgG1.

[0226] E170. The antibody of any one of E167 to E169, wherein the N-terminus of the first or second Fc chain is linked to the C-terminus of the p40-CH1 domain.

[0227] E171. The antibody of E167 to E170, wherein the first Fc chain and the second Fc chain each comprise, from N-terminus to C-terminus: a hinge region, a CH2 region, and a CH3 region.

[0228] E172. The antibody of E171, wherein the hinge region comprises a sequence selected from the group consisting of SEQ ID NO:7, SEQ ID NO:102, SEQ ID NO:123, SEQ ID NO:126, SEQ ID NO:129 and SEQ ID NO:131.

[0229] E173. The antibody of E171 to E172, wherein the hinge region on the first Fc chain and the hinge region on the second Fc chain comprise a pair of sequences according to SEQ ID NO: 129 and SEQ ID NO: 131.

[0230] E174. The antibody of E171 to E172, wherein the CH2 region comprises the sequence according to SEQ ID NO:8.

[0231] E175. The antibody of E171 to E174, wherein the CH3 region on the first Fc chain and the CH3 region on the second Fc chain comprise a pair of sequences selected from the group consisting of:

[0232] (i) SEQ ID NO: 9 and SEQ ID NO: 9;

[0233] (ii) SEQ ID NO: 111 and SEQ ID NO: 106;

[0234] (iii) SEQ ID NO: 111 and SEQ ID NO: 114;

[0235] (iv) SEQ ID NO: 114 and SEQ ID NO: 117;

[0236] (v) SEQ ID NO: 124 and SEQ ID NO: 127;

[0237] (vi) SEQ ID NO: 139 and SEQ ID NO: 141; and

[0238] (vii) SEQ ID NO: 147 and SEQ ID NO: 148.

[0239] E176. The antibody of E171 to E175, wherein the CH3 region on the first Fc chain and the CH region on the second Fc chain each comprise a sequence according to SEQ ID NO: 9.

[0240] E177. The antibody of E171 to E176, wherein the CH3 region on the first Fc chain and the CH region on the second Fc chain comprise a pair of sequences according to SEQ ID NO: 124 and SEQ ID NO: 127.

[0241] E178. The antibody of any one of E144 to E177, which comprises a polypeptide carrying p40-VH, which polypeptide comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to a sequence selected from SEQ ID NO: 170, SEQ ID NO: 177, SEQ ID NO: 181, SEQ ID NO: 185 and SEQ ID NO: 186.

[0242] E179. The antibody of any one of E144 to E178, which comprises a polypeptide carrying p40-VH comprising amino acids selected from the group consisting of SEQ ID NO: 170, SEQ ID NO: 177, SEQ ID NO: 181, SEQ ID NO: 185 and SEQ ID NO: 186.

[0243] E180. The antibody of any one of E144 to E179, which comprises a p40-VH-carrying polypeptide comprising the amino acid sequence of SEQ ID NO: 186.

[0244] E181. The antibody of any one of E144 to E180, which comprises a polypeptide carrying p40-VL, which polypeptide comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to a sequence selected from SEQ ID NO: 176, SEQ ID NO: 178, SEQ ID NO: 179, SEQ ID NO: 182 and SEQ ID NO: 183.

[0245] E182. The antibody of any one of E144 to E181, which comprises a p40-VL-carrying polypeptide comprising the amino acid sequence of SEQ ID NO: 176.

[0246] E183. The antibody of any one of E144 to E182, which comprises a polypeptide sequence carrying p40-VH encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127204.

[0247] E184. The antibody of any one of E144 to E183, which comprises a polypeptide sequence carrying p40-VL encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127203.

[0248] E185. An antibody comprising a polypeptide sequence carrying p40-VH encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127204, and a polypeptide sequence carrying p40-VL encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127203.

[0249] E186. An isolated antibody that binds p40 and one or both of IL-4 and IL-13, comprising the CDRs of one or more antibodies selected from Table 86 and Table 87.

[0250] E187. An isolated antibody that binds p40 and one or both of IL-4 and IL-13, comprising the VH and VL of an antibody selected from one or more of Tables 86 and 87.

[0251] E188. An isolated antibody that binds p40 and one or both of IL-4 and IL-13, selected from one or more of Tables 86 and 87.

[0252] E189. The antibody of any one of E144 to E188 for use as a medicament.

[0253] The antibody of E190.E189, wherein the use is for treating one or more selected from the group consisting of: non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, asthma (severe), allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus, primary biliary cirrhosis and hidradenitis suppurativa.

[0254] E191. The antibody of any one of E189 to E190, wherein the use is for treating one or more selected from the group consisting of: non-alcoholic steatohepatitis (NASH), atopic dermatitis, asthma (severe), alopecia, idiopathic pulmonary fibrosis and systemic sclerosis.

[0255] E192. The antibody of any one of E189 to E191, wherein the use is for atopic dermatitis.

[0256] E193. The antibody of any one of E189 to E191, wherein the use is for non-alcoholic steatohepatitis (NASH).

[0257] E194. A pharmaceutical composition comprising a therapeutically effective amount of an antibody of E144 to E193 and a pharmaceutically acceptable carrier.

[0258] E195. A method of treating a medical condition, comprising administering to a subject in need thereof a therapeutically effective amount of an antibody of any one of E144 to E193 or a pharmaceutical composition of E194.

[0259] E196. The method of E195, wherein the condition is selected from the group consisting of: nonalcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, asthma (severe), allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus, primary biliary cirrhosis, and hidradenitis suppurativa.

[0260] E197. The method of any one of E195 to E196, comprising administering the antibody or pharmaceutical composition subcutaneously.

[0261] E198. The method of any one of E195 to E196, wherein the antibody or pharmaceutical composition is administered about twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, twice a month, once a month, once every two months, once every three months, or once every four months.

[0262] E199. An isolated antibody that specifically binds to IL-4, comprising a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL), comprising

[0263] (i) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 22, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 26;

[0264] (ii) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 19, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 20;

[0265] (iii) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 22, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 20;

[0266] (iv) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 28, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 29; or

[0267] (v) CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO: 22, and CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO: 30.

[0268] E200. An isolated antibody that specifically binds to IL-4, comprising a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL) comprising the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO: 22, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO: 26.

[0269] E201. An isolated antibody that specifically binds to IL-4, comprising a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL), wherein the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 18; the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2; the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 3; the CDR-L1 comprises the amino acid sequence of SEQ ID NO: 24; the CDR-L2 comprises the amino acid sequence of SEQ ID NO: 12; and the CDR-L3 comprises the amino acid sequence of SEQ ID NO: 25.

[0270] E202. The antibody of any one of E199 to E201, comprising an IL4-VH framework sequence derived from a human germline VH sequence selected from the group consisting of DP26, DP27, DP28 and DP76.

[0271] E203. The antibody of any one of E199 to E202, comprising an IL4-VH framework sequence derived from a human DP76 germline sequence.

[0272] E204. The antibody of any one of E199 to E203, which comprises an IL4-VL framework sequence derived from a human germline VL sequence selected from the group consisting of: DPK1, DPK3, DPK4, DPK5, DPK7, DPK8, DPK9 and DPK24.

[0273] E205. The antibody of any one of E199 to E204, comprising an IL4-VL framework sequence derived from a human germline DPK9 sequence.

[0274] E206. The antibody of any one of E199 to E205, which comprises an IL4-VL framework sequence and an IL4-VH framework sequence, and wherein one or both of the IL4-VL framework sequence or the IL4-VH framework sequence are at least 66%, 76%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the human germline sequence from which they are derived.

[0275] E207. The antibody of any one of E199 to E206, comprising an IL4-VL framework sequence and an IL4-VH framework sequence, and wherein one or both of the IL4-VL framework sequence or the IL4-VH framework sequence are identical to the human germline sequence from which they are derived.

[0276] E208. The antibody of any one of E199 to E207, which comprises an IL4-VH sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 22.

[0277] E209. The antibody of any one of E199 to E208, which comprises an IL4-VH sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:20.

[0278] E210. The antibody of any one of E199 to E209, comprising

[0279] (i) IL4-VH sequence of SEQ ID NO: 22 and IL4-VL of SEQ ID NO: 26;

[0280] (ii) the IL4-VH sequence of SEQ ID NO: 19 and the IL4-VL sequence of SEQ ID NO: 20;

[0281] (iii) the IL4-VH sequence of SEQ ID NO: 22 and the IL4-VL sequence of SEQ ID NO: 20;

[0282] (iv) the IL4-VH sequence of SEQ ID NO: 28 and the IL4-VL sequence of SEQ ID NO: 29; or

[0283] (v) IL4-VH sequence of SEQ ID NO: 22 and IL4-VL of SEQ ID NO: 30.

[0284] E211. The antibody of any one of E199 to E210, which comprises an IL4-VH sequence identical to SEQ ID NO: 22 and an IL4-VL sequence identical to SEQ ID NO: 26.

[0285] E212. The antibody of any one of E199 to E211, comprising the IL4-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 200.

[0286] E213. The antibody of any one of E199 to E212, comprising an IL4-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 201.

[0287] E214. The antibody of any one of E199 to E213, which comprises an IL4-VH sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127198.

[0288] E215. The antibody of any one of E199 to E214, which comprises an IL4-VL sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127197.

[0289] E216. An antibody comprising an IL4-VH sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127198, and an IL4-VL sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127197.

[0290] E217. The antibody of E199 to E216, wherein the antibody has a K of less than a value selected from about 10 pM, 5 pM, 1 pM and 800 fM. D Binds human IL-4.

[0291] E218. The antibody of E199 to E217, wherein the antibody has a K value of less than about 1 pM D Binds human IL-4.

[0292] E219. The antibody of any one of E199 to E218, wherein K D The values ​​were measured by kinetic exclusion assay.

[0293] E220. The antibody of E199 to E219, wherein the antibody binds to cynomolgus monkey IL-4.

[0294] E221. The antibody of E199 to E220, wherein the antibody does not bind IL-4 from one or more selected from dog, sheep, rabbit, rat and mouse.

[0295] E222. The antibody of E199 to E221, wherein the antibody binds to cynomolgus monkey IL-4 D The binding K of this antibody to human IL-4 D within one order of magnitude.

[0296] E223. The antibody of E199 to E222, wherein the antibody binds to cynomolgus monkey IL-4 D The binding K of this antibody to human IL-4 D within a two-fold difference.

[0297] E224. The antibody of E199 to E223, wherein the antibody is characterized by an IC of 0.05 for IL-4-induced neutralization of CD23 in a human monocyte assay 50 Less than 10pM.

[0298] E225. The antibody of E199 to E224, wherein the antibody is characterized by an IC of 0.05 for cynomolgus monkey IL-4-induced neutralization of CD23 in a human monocyte assay 50 Less than 20pM.

[0299] E226. The antibody of E199 to E225, wherein the viscosity of the antibody at 25°C is 20 cP or less at a concentration of 80 mg / mL in histidine-sucrose pH 5.8 buffer.

[0300] E227. The antibody of E199 to E226, wherein the viscosity of the antibody at 25°C is 20 cP or less at a concentration of 100 mg / mL in histidine-sucrose pH 5.8 buffer.

[0301] E228. The antibody of E199 to E227, wherein the viscosity of the antibody at 25°C is 20 cP or less at a concentration of 120 mg / mL in histidine-sucrose pH 5.8 buffer.

[0302] E229. The antibody of E199 to E228, wherein the antibody comprises a lysine at residue 93 in the light chain.

[0303] E230. The antibody of E199 to E229, further comprising a constant heavy chain domain (IL4-CH1) and a constant light chain domain (IL4-CL).

[0304] E231. The antibody of E230, wherein IL4-CH1 comprises the sequence according to SEQ ID NO:6.

[0305] E232. The antibody of E230 to E231, wherein IL4-CL comprises the sequence according to SEQ ID NO:16.

[0306] E233. The antibody of E230 to E232, wherein IL4-CH1 is linked to IL4-VL, and IL4-CL is linked to IL-4-VH, forming an IL-4-binding domain-exchanged Fab domain (IL4-xFab).

[0307] E234. The antibody of E230 to E232, wherein IL4-CH1 is linked to IL4-VH, and IL4-CL is linked to IL4-VL, forming an IL-4 binding Fab domain (IL4-Fab).

[0308] E235. The antibody of any one of E199 to E234, comprising an Fc domain comprising a first Fc chain and a second Fc chain.

[0309] E236. The antibody of E235, wherein the Fc domain is the Fc domain of IgA (eg, IgA1 or IgA2), IgD, IgE, IgM, or IgG (eg, IgG1, IgG2, IgG3, or IgG4).

[0310] E237. The antibody of E235 to E236, wherein the Fc domain is the Fc domain of IgG1.

[0311] E238. The antibody or antigen-binding fragment thereof of E235 to E237, wherein the N-terminus of the first Fc chain or the second Fc chain is linked to the C-terminus of the IL33-CH1 domain.

[0312] E239. The antibody or antigen-binding fragment thereof of E235 to E238, wherein the first Fc chain and the second Fc chain each comprise, from N-terminus to C-terminus: a hinge region, a CH2 region, and a CH3 region.

[0313] The antibody or antigen-binding fragment thereof of E240.E239, wherein the hinge region comprises a sequence selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 102, SEQ ID NO: 123, SEQ ID NO: 126, SEQ ID NO: 129 and SEQ ID NO: 131.

[0314] E241. The antibody or antigen-binding fragment thereof of E240, wherein the hinge region comprises the sequence according to SEQ ID NO:7.

[0315] E242. The antibody or antigen-binding fragment thereof of E240, wherein the hinge region on the first Fc chain and the hinge region on the second Fc chain comprise a pair of sequences according to SEQ ID NO: 129 and SEQ ID NO: 131.

[0316] E243. The antibody or antigen-binding fragment thereof of E239 to E242, wherein the CH2 region comprises the sequence according to SEQ ID NO: 8.

[0317] E244. The antibody or antigen-binding fragment thereof of E239 to E243, wherein the CH3 region on the first Fc chain and the CH3 region on the second Fc chain comprise a pair of sequences selected from the group consisting of:

[0318] (i) SEQ ID NO: 9 and SEQ ID NO: 9;

[0319] (ii) SEQ ID NO: 111 and SEQ ID NO: 106;

[0320] (iii) SEQ ID NO: 111 and SEQ ID NO: 114;

[0321] (iv) SEQ ID NO: 114 and SEQ ID NO: 117;

[0322] (v) SEQ ID NO: 124 and SEQ ID NO: 127;

[0323] (vi) SEQ ID NO: 139 and SEQ ID NO: 141; and

[0324] (vii) SEQ ID NO: 147 and SEQ ID NO: 148.

[0325] E245. The antibody or antigen-binding fragment thereof of E244, wherein the CH3 region on the first Fc chain and the CH region on the second Fc chain each comprise a sequence according to SEQ ID NO: 9.

[0326] E246. The antibody or antigen-binding fragment thereof of E244, wherein the CH3 region on the first Fc chain and the CH3 region on the second Fc chain comprise a pair of sequences according to SEQ ID NO: 124 and SEQ ID NO: 127.

[0327] E247. The antibody of any one of E199 to E246, which comprises a polypeptide carrying IL4-VH, which polypeptide comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to a sequence selected from the group consisting of SEQ ID NO: 23, SEQ ID NO: 107, SEQ ID NO: 115, SEQ ID NO: 121, SEQ ID NO: 125, SEQ ID NO: 130, SEQ ID NO: 133, SEQ ID NO: 135, SEQ ID NO: 140, SEQ ID NO: 144, SEQ ID NO: 146, SEQ ID NO: 151, SEQ ID NO: 153, SEQ ID NO: 153, SEQ ID NO: 156, SEQ ID NO: 157, SEQ ID NO: 159, SEQ ID NO: 162, SEQ ID NO: 164, SEQ ID NO: 165 NO:179, SEQ ID NO:180 and SEQ ID NO:183.

[0328] E248. The antibody of any one of E199 to E247, which comprises an IL4-VH-carrying polypeptide comprising the amino acid sequence of SEQ ID NO: 23.

[0329] E249. The antibody of any one of E199 to E241, which comprises a polypeptide carrying IL4-VH comprising the amino acid sequence of SEQ ID NO 8:130.

[0330] The antibody of any one of E250.E199 to E249, which comprises a polypeptide carrying IL4-VL, which polypeptide comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to a sequence selected from SEQ ID NO: 27, SEQ ID NO: 109 and SEQ ID NO: 116, SEQ ID NO: 136, SEQ ID NO: 197 and SEQ ID NO: 208.

[0331] E251. The antibody of any one of E199 to E250, which comprises an IL4-VL-carrying polypeptide comprising the amino acid sequence of SEQ ID NO: 27.

[0332] E252. The antibody of any one of E199 to E251, which comprises the polypeptide sequence carrying IL4-VH encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127192.

[0333] E253. The antibody of any one of E199 to E252, which comprises the polypeptide sequence carrying IL4-VL encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127194.

[0334] E254. An antibody comprising a polypeptide sequence carrying IL4-VH encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127192, and a polypeptide sequence carrying IL4-VL encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127194.

[0335] E255. The antibody of any one of E199 to E254 for use as a medicament.

[0336] E256. The antibody of any one of E199 to E255, wherein the use is for treating one or more selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma and systemic sclerosis, diabetic nephropathy, Behcet's disease, gout, Alzheimer's disease, atherosclerosis, fungal keratitis, non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus (SLE), primary biliary cirrhosis and hidradenitis suppurativa.

[0337] E257. The antibody of any one of E199 to 256, wherein the use is for treating one or more selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, non-alcoholic steatohepatitis (NASH), alopecia, idiopathic pulmonary fibrosis and systemic sclerosis.

[0338] E258. The antibody of any one of E199 to 257, wherein the use is for atopic dermatitis.

[0339] E259. The antibody of any one of E199 to 257, wherein the use is for non-alcoholic steatohepatitis (NASH).

[0340] E260. A pharmaceutical composition comprising a therapeutically effective amount of an antibody from E199 to E259 and a pharmaceutically acceptable carrier.

[0341] E261. A method of treating a medical condition, comprising administering to a subject in need thereof a therapeutically effective amount of the antibody of any one of E199 to E259 or the pharmaceutical composition of E260.

[0342] The method of E262.E261, wherein the condition is selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, diabetic nephropathy, Behcet's disease, gout, Alzheimer's disease and atherosclerosis.

[0343] E263. The method of any one of E261 to E262, comprising administering the antibody or pharmaceutical composition subcutaneously.

[0344] E264. The method of any one of E261 to E263, wherein the antibody or pharmaceutical composition is administered about twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, twice a month, once a month, once every two months, once every three months, or once every four months.

[0345] E265. An isolated antibody that specifically binds to IL-13, comprising a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL), comprising

[0346] (i) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 51, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 54;

[0347] (ii) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 44, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 46;

[0348] (iii) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 48, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 49;

[0349] (iv) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 48, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 68; or

[0350] (v) The CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO: 57, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO: 59.

[0351] E266. An isolated antibody that specifically binds to IL-13, comprising a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL) comprising the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO: 51, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO: 54.

[0352] E267. An isolated antibody that specifically binds to IL-13, comprising a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL), wherein the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 41; the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 42; the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 50; the CDR-L1 comprises the amino acid sequence of SEQ ID NO: 53; the CDR-L2 comprises the amino acid sequence of SEQ ID NO: 37; and the CDR-L3 comprises the amino acid sequence of SEQ ID NO: 38.

[0353] E268. The antibody of any one of E265 to E267, comprising an IL13-VH framework sequence derived from a human germline VH sequence selected from the group consisting of: DP7, DP10, DP35, DP47, DP50, DP51, DP54 and DP77.

[0354] E269. The antibody of any one of E265 to E268, comprising an IL13-VH framework sequence derived from a human DP54 germline sequence.

[0355] E270. The antibody of any one of E265 to E269, comprising an IL13-VL framework sequence derived from a human germline VL sequence selected from the group consisting of: DPK3, DPK4, DPK5, DPK8, DPK9, DPK10 and DPK23.

[0356] E271. The antibody of any one of E265 to E270, comprising an IL13-VL framework sequence derived from a human germline DPK9 sequence.

[0357] E272. The antibody of any one of E265 to E271, comprising an IL13-VL framework sequence and an IL13-VH framework sequence, and wherein one or both of the IL13-VL framework sequence or the IL13-VH framework sequence are at least 66%, 76%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the human germline sequence from which they are derived.

[0358] E273. The antibody of any one of E265 to E272, comprising an IL13-VL framework sequence and an IL13-VH framework sequence, and wherein one or both of the IL13-VL framework sequence or the IL13-VH framework sequence are identical to the human germline sequence from which they are derived.

[0359] E274. The antibody of any one of E265 to E273, which comprises an IL13-VH that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:51.

[0360] E275. The antibody of any one of E265 to E274, which comprises an IL13-VL that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:54.

[0361] E276. The antibody of any one of E265 to E275, comprising

[0362] (i) IL13-VH of SEQ ID NO: 51 and IL13-VL of SEQ ID NO: 54;

[0363] (ii) IL13-VH of SEQ ID NO: 44 and IL13-VL of SEQ ID NO: 46;

[0364] (iii) IL13-VH of SEQ ID NO: 48 and IL13-VL of SEQ ID NO: 49;

[0365] (iv) IL13-VH of SEQ ID NO: 48 and IL13-VL of SEQ ID NO: 68; or

[0366] (v) IL13-VH of SEQ ID NO: 57 and IL13-VL of SEQ ID NO: 59.

[0367] E277. The antibody of any one of E265 to E276, which comprises an IL13-VH identical to SEQ ID NO: 51, and an IL13-VL identical to SEQ ID NO: 54.

[0368] E278. The antibody of any one of E265 to E277, comprising a VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 198.

[0369] E279. The antibody of any one of E265 to E278, comprising a VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 199.

[0370] E280. The antibody of any one of E265 to E279, which comprises an IL13-VH sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127196.

[0371] E281. The antibody of any one of E265 to E280, which comprises an IL13-VL sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127195.

[0372] E282. An antibody comprising an IL13-VH sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127196, and an IL13-VL sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127195.

[0373] E283. The antibody of E265 to E282, wherein the antibody has a K of less than a value selected from D Binding to human IL-13: 10 nM, 5 nM, 2 nM, 1 nM, 900 pM, 800 pM, 700 pM, 600 pM, 500 pM, 400 pM, 300 pM, 250 pM, 200 pM, 150 pM, 100 pM and 60 pM.

[0374] The antibody of E284.E265 to E276, wherein the antibody has a K of less than 60 pM D Binds human IL-13.

[0375] E285. The antibody of any one of E283 to E284, wherein K D The values ​​were measured by kinetic exclusion assay.

[0376] E286. The antibody of any one of E283 to E285, wherein K D The values ​​were measured by SPR.

[0377] E287. The antibody of E265 to E286, wherein the antibody binds to cynomolgus monkey IL-13.

[0378] E288. The antibody of E265 to E287, wherein the antibody does not bind IL-13 from one or more species selected from dog, rabbit and mouse.

[0379] E289. The antibody of E265 to E288, wherein the antibody binds to cynomolgus monkey IL-13 D The binding K of this antibody to human IL-13 D within one order of magnitude.

[0380] The antibody of E290.E265 to E289, wherein the antibody binds to cynomolgus monkey IL-13 with a K D The binding K of this antibody to human IL-13 D within five times the difference.

[0381] E291. The antibody of E265 to E290, wherein the antibody binds to cynomolgus monkey IL-13 D The binding K of this antibody to human IL-13 D within a two-fold difference.

[0382] E292. Antibodies of E265 to E291, wherein IL-13 IC is expressed as measured by neutralization of IL-13pSTAT6 phosphorylation in HT-29 cells. 50 Less than 100pM.

[0383] E293. Antibodies to E265 to E292, wherein the IL-13 IC neutralizes IL-13 induction of CD23 as measured in a human monocyte assay 50 Less than 20pM.

[0384] E294. Antibodies to E265 to E293, wherein the IL-13 IC neutralizes IL-13 induction of CD23 as measured in a human monocyte assay 50 Less than 15pM.

[0385] E295. Antibodies to E265 to E294, wherein the IL-13 IC neutralizes IL-13 induction of CD23 as measured in a human monocyte assay 50 Less than 12pM.

[0386] E296. The antibody of E265 to E295, further comprising a constant heavy chain domain (IL13-CH1) and a constant light chain domain (IL13-CL).

[0387] E297. The antibody of E296, wherein IL13-CH1 comprises a sequence selected from the group consisting of SEQ ID NO: 6, SEQ ID NO: 105 and SEQ ID NO: 110.

[0388] E298. The antibody of E296 to E297, wherein IL13-CH1 comprises the sequence according to SEQ ID NO:6.

[0389] E299. The antibody of E296 to E298, wherein IL13-CL comprises a sequence selected from the group consisting of SEQ ID NO: 16, SEQ ID NO: 108 and SEQ ID NO: 113.

[0390] E300. The antibody of E296 to E299, wherein IL13-CL comprises the sequence according to SEQ ID NO:16.

[0391] E301. The antibody of E296 to E300, wherein IL13-CH1 is linked to IL13-VL, and IL13-CL is linked to IL13-VH, forming an IL-13-binding domain-exchanged Fab domain (IL13-xFab).

[0392] E302. The antibody of E296 to E301, wherein IL13-CH1 is linked to IL13-VH, and IL13-CL is linked to IL33-VL, forming an IL-13 binding Fab domain (IL13-Fab).

[0393] E303. The antibody of any one of E265 to E302, comprising an Fc domain comprising a first Fc chain and a second Fc chain.

[0394] E304. The antibody of E303, wherein the Fc domain is the Fc domain of IgA (eg, IgA1 or IgA2), IgD, IgE, IgM, or IgG (eg, IgG1, IgG2, IgG3, or IgG4).

[0395] E305. The antibody of E303 to E304, wherein the Fc domain is the Fc domain of IgG1.

[0396] E306. The antibody of E303 to E305, wherein the N-terminus of the first Fc chain or the second Fc chain is linked to the C-terminus of the IL13-CH1 domain.

[0397] E307. The antibody of E303 to E306, wherein the first Fc chain and the second Fc chain each comprise, from N-terminus to C-terminus: a hinge region, a CH2 region, and a CH3 region.

[0398] E308. The antibody of E307, wherein the hinge region comprises a sequence selected from the group consisting of SEQ ID NO:7, SEQ ID NO:102, SEQ ID NO:123, SEQ ID NO:126, SEQ ID NO:129 and SEQ ID NO:131.

[0399] E309. The antibody of E307 to E308, wherein the hinge region comprises the sequence according to SEQ ID NO: 7.

[0400] E310. The antibody of E307 to E309, wherein the hinge region comprises the sequence according to SEQ ID NO: 102.

[0401] E311. The antibody of E307 to E310, wherein the CH2 region comprises the sequence according to SEQ ID NO:8.

[0402] E312. The antibody of E307 to E311, wherein the CH3 region on the first Fc chain and the CH3 region on the second Fc chain comprise a pair of sequences selected from the group consisting of:

[0403] (i) SEQ ID NO: 124 and SEQ ID NO: 127;

[0404] (ii) SEQ ID NO: 9 and SEQ ID NO: 9;

[0405] (iii) SEQ ID NO: 111 and SEQ ID NO: 106;

[0406] (iv) SEQ ID NO: 111 and SEQ ID NO: 114;

[0407] (v) SEQ ID NO: 114 and SEQ ID NO: 117;

[0408] (vi) SEQ ID NO: 139 and SEQ ID NO: 141; and

[0409] (vii) SEQ ID NO: 147 and SEQ ID NO: 148.

[0410] E313. The antibody of E307 to E312, wherein the CH3 region on the first Fc chain and the CH region on the second Fc chain each comprise a sequence according to SEQ ID NO: 9.

[0411] E314. The antibody of E307 to E312, wherein the CH3 region on the first Fc chain and the CH region on the second Fc chain comprise a pair of sequences according to SEQ ID NO: 124 and SEQ ID NO: 127.

[0412] E315. The antibody of any one of E265 to E314, which comprises a polypeptide carrying IL13-VH, which polypeptide comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to a sequence selected from SEQ ID NO: 52, SEQ ID NO: 66, SEQ ID NO: 112, SEQ ID NO: 118, SEQ ID NO: 121, SEQ ID NO: 122, SEQ ID NO: 130, SEQ ID NO: 145, SEQ ID NO: 149, SEQ ID NO: 152, SEQ ID NO: 154, SEQ ID NO: 160, SEQ ID NO: 162, SEQ ID NO: 164 and SEQ ID NO: 209.

[0413] E316. The antibody of any one of E265 to E315, which comprises a polypeptide carrying IL13-VH consisting of SEQ ID NO: 52, SEQ ID NO: 66, SEQ ID NO: 112, SEQ ID NO: 118, SEQ ID NO: 121, SEQ ID NO: 122, SEQ ID NO: 130, SEQ ID NO: 145, SEQ ID NO: 149, SEQ ID NO: 152, SEQ ID NO: 154, SEQ ID NO: 160, SEQ ID NO: 162, SEQ ID NO: 164 and SEQ ID NO: 209.

[0414] E317. The antibody of any one of E264 to E316, which comprises a polypeptide carrying IL13-VH comprising the amino acid sequence of SEQ ID NO: 52.

[0415] E318. The antibody of any one of E265 to E316, which comprises a polypeptide carrying IL13-VH comprising the amino acid sequence of SEQ ID NO: 122.

[0416] E319. The antibody of any one of E265 to E318, which comprises a polypeptide carrying IL13-VL, which polypeptide comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to a sequence selected from SEQ ID NO: 55, SEQ ID NO: 163 and SEQ ID NO: 196.

[0417] E320. The antibody of any one of E265 to E319, which comprises a polypeptide carrying IL13-VL, the polypeptide comprising an amino acid sequence selected from the group consisting of: SEQ ID NO: 55, SEQ ID NO: 119, SEQ ID NO: 120, SEQ ID NO: 125, SEQ ID NO: 130, SEQ ID NO: 133, SEQ ID NO: 135, SEQ ID NO: 140, SEQ ID NO: 163, SEQ ID NO: 164 and SEQ ID NO: 196.

[0418] E321. The antibody of any one of E265 to E320, which comprises an IL13-VL-carrying polypeptide comprising the amino acid sequence of SEQ ID NO: 55.

[0419] E322. The antibody of any one of E265 to E321, which comprises an IL13-VL-carrying polypeptide comprising the amino acid sequence of SEQ ID NO: 130.

[0420] E323. The antibody of any one of E265 to E322, which comprises the polypeptide sequence carrying IL13-VH encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127193.

[0421] E324. The antibody of any one of E265 to E323, which comprises the polypeptide sequence carrying IL13-VL encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127192.

[0422] E325. An antibody comprising a polypeptide sequence carrying IL13-VH encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127193, and a polypeptide sequence carrying IL13-VL encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127192.

[0423] E326. The antibody of any one of E265 to E325 for use as a medicament.

[0424] The antibody of E327.E326, wherein the use is for treating one or more selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma and systemic sclerosis, diabetic nephropathy, Behcet's disease, gout, Alzheimer's disease, atherosclerosis, fungal keratitis, non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus (SLE), primary biliary cirrhosis and hidradenitis suppurativa.

[0425] E328. The antibody of any one of E326 to E327, wherein the use is for treating one or more selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, non-alcoholic steatohepatitis (NASH), alopecia, idiopathic pulmonary fibrosis and systemic sclerosis.

[0426] E329. The antibody of any one of E326 to E328, wherein the use is for atopic dermatitis.

[0427] E330. The antibody of any one of E326 to E329, wherein the use is for non-alcoholic steatohepatitis (NASH).

[0428] E331. A pharmaceutical composition comprising a therapeutically effective amount of an antibody from E265 to E330 and a pharmaceutically acceptable carrier.

[0429] E332. A method of treating a medical condition, comprising administering to a subject in need thereof a therapeutically effective amount of the antibody of any one of E265 to E330 or the pharmaceutical composition of E331.

[0430] E333. The method of E332, wherein the condition is selected from: non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, asthma (severe), allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus, primary biliary cirrhosis and hidradenitis suppurativa.

[0431] E334. The method of any one of E332 to E333, comprising administering the antibody or pharmaceutical composition subcutaneously.

[0432] E335. The method of any one of E332 to E334, wherein the antibody or pharmaceutical composition is administered about twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, twice a month, once a month, once every two months, once every three months, or once every four months.

[0433] E336. An isolated antibody that specifically binds IL-33, specifically binds IL-4 and specifically binds IL-13, comprising an IL-33 binding domain, an IL-4 binding domain and an IL-13 binding domain.

[0434] E337. The antibody of E336, wherein specific binding to IL-33 is through the antibody of any one of E1 to E71.

[0435] E338. The antibody of E336 to E337, wherein specific binding to IL-4 is through the antibody of any one of E199 to E259.

[0436] E339. The antibody of E336 to E338, wherein specific binding to IL-13 is through the antibody of any one of E265 to E330.

[0437] E340. The antibody of any one of E336 to E339, wherein

[0438] (i) the IL-33 binding domain comprises a heavy chain variable region (IL33-VH) and a light chain variable region (IL33-VL), wherein CDR-H1 of the IL-33 binding domain comprises the amino acid sequence of SEQ ID NO: 60; CDR-H2 of the IL-33 binding domain comprises the amino acid sequence of SEQ ID NO: 61; CDR-H3 of the IL-33 binding domain comprises the amino acid sequence of SEQ ID NO: 72; CDR-L1 of the IL-33 binding domain comprises the amino acid sequence of SEQ ID NO: 75; CDR-L2 of the IL-33 binding domain comprises the amino acid sequence of SEQ ID NO: 76; and CDR-L3 of the IL-33 binding domain comprises the amino acid sequence of SEQ ID NO: 77; and

[0439] (ii) the IL-4 binding domain comprises a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL), wherein CDR-H1 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 18; CDR-H2 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 2; CDR-H3 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 3; CDR-L1 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 24; CDR-L2 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 12, and CDR-L3 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 25, and

[0440] (iii) the IL-13 binding domain comprises a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL), wherein CDR-H1 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 41; CDR-H2 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 42; CDR-H3 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 50; CDR-L1 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 53; CDR-L2 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 37, and CDR-L3 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 38.

[0441] E341. The antibody of E336 to E340, wherein

[0442] (i) the IL-33 binding domain comprises IL33-VH of SEQ ID NO: 73 and IL33-VL of SEQ ID NO: 78;

[0443] (i) the IL-4 binding domain comprises IL4-VH of SEQ ID NO: 22 and IL4-VL of SEQ ID NO: 26; and

[0444] (ii) The IL-13 binding domain comprises IL13-VH of SEQ ID NO: 51 and IL13-VL of SEQ ID NO: 54.

[0445] E342. The antibody of E336 to 341, wherein

[0446] (i) the IL-33 binding domain comprises an IL33-VH sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127210, and an IL33-VL sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127209;

[0447] (ii) the IL-4 binding domain comprises an IL4-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC deposit number PTA-127198, and an IL4-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC deposit number PTA-127197; and

[0448] (iii) the IL-13 binding domain comprises the IL13-VH sequence encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127196, and the IL13-VL sequence encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127195.

[0449] E343. The antibody of E336 to E342, wherein the IL-33 binding domain is fused to the IL-13 binding domain with or without a linker.

[0450] E344. The antibody of E336 to E342, wherein the IL-33 binding domain is fused to the IL-4 binding domain with or without a linker.

[0451] E345. The antibody of E336 to E342, wherein the IL-13 binding domain is fused to the IL-4 binding domain with or without a linker.

[0452] E346. The antibody of any one of E343 to E345, wherein the fusion has a linker.

[0453] E347. The antibody of any one of E336 to E346, wherein the IL-13 binding domain is fused to the IL-4 binding domain with a linker.

[0454] E348. The antibody of E343 to E347, wherein the linker comprises SEQ ID NO: 104.

[0455] E349. The antibody of any one of E336 to E348, wherein the antibody comprises a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, such that

[0456] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising a first antigen binding site;

[0457] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising a second antigen binding site;

[0458] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a third antigen binding site.

[0459] The antibody of E350.E349, wherein the first polypeptide chain and the second polypeptide chain associate together to form an antibody comprising two arms; a dual Fab arm comprising the first Fab domain and the second Fab domain, and a single Fab arm comprising the third Fab domain.

[0460] E351. The antibody of E349 to E350, wherein the fifth polypeptide chain comprises the sequence EPKSC (SEQ ID NO: 122) at the C-terminus.

[0461] E352. The antibody of E349 to E351, wherein the first antigen binding site specifically binds IL-13, the second antibody binding site specifically binds IL-4, and the third antigen binding site specifically binds IL-33.

[0462] E353. The antibody of E349 to E352, wherein the first Fab domain, the second Fab domain and the third Fab domain each comprise a different option selected from the following (i), (ii) and (iii):

[0463] (i) IL33-Fab of E38;

[0464] (ii) IL4-Fab of E234; and

[0465] (iii) IL13-Fab of E302.

[0466] E354. The antibody of E349 to E353, wherein the first Fab domain is the IL13-Fab of E302, the second Fab domain is the IL4-Fab of E234, and the third Fab domain is the IL33-Fab of E38.

[0467] E355. The antibody of E349 to E354, wherein the first polypeptide comprises a first Fc chain and the second polypeptide comprises a second Fc chain.

[0468] E356. The antibody of E355, wherein the first Fc chain and the second Fc chain each contain one or more amino acid modifications that promote association of the first Fc chain with the second Fc chain.

[0469] E357. The antibody of E349 to E356, wherein the first Fc chain comprises a first CH3 domain, and the second Fc chain comprises a second CH3 domain, and the first CH3 domain and the second CH3 domain each comprise different and complementary sequences, and the different and complementary sequences are one selected from the following pairs of different and complementary sequences:

[0470] (i) SEQ ID NO: 111 and SEQ ID NO: 106;

[0471] (ii) SEQ ID NO: 111 and SEQ ID NO: 114;

[0472] (iii) SEQ ID NO: 114 and SEQ ID NO: 117;

[0473] (iv) SEQ ID NO: 124 and SEQ ID NO: 127;

[0474] (v) SEQ ID NO: 139 and SEQ ID NO: 141; and

[0475] (vi) SEQ ID NO: 147 and SEQ ID NO: 148.

[0476] E358. The antibody of E357, wherein the first CH3 domain and the second CH3 domain comprise SEQ ID NO: 124 and SEQ ID NO: 127.

[0477] E359. The antibody of E349 to E358, wherein the properties of the first polypeptide chain, the second polypeptide chain, the third polypeptide chain, the fourth polypeptide chain, and the fifth polypeptide chain are selected from the group consisting of:

[0478] (i) the first polypeptide chain comprises SEQ ID NO: 132, the second polypeptide chain comprises SEQ ID NO: 130, the third polypeptide chain comprises SEQ ID NO: 79, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122;

[0479] (ii) the first polypeptide chain comprises SEQ ID NO: 146, the second polypeptide chain comprises SEQ ID NO: 145, the third polypeptide chain comprises SEQ ID NO: 109, the fourth polypeptide chain comprises SEQ ID NO: 196, and the fifth polypeptide chain comprises SEQ ID NO: 103;

[0480] (iii) the first polypeptide chain comprises SEQ ID NO: 112, the second polypeptide chain comprises SEQ ID NO: 107, the third polypeptide chain comprises SEQ ID NO: 196, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 103;

[0481] (iv) the first polypeptide chain comprises SEQ ID NO: 118, the second polypeptide chain comprises SEQ ID NO: 115, the third polypeptide chain comprises SEQ ID NO: 119, the fourth polypeptide chain comprises SEQ ID NO: 116, and the fifth polypeptide chain comprises SEQ ID NO: 103;

[0482] (v) the first polypeptide chain comprises SEQ ID NO: 118, the second polypeptide chain comprises SEQ ID NO: 115, the third polypeptide chain comprises SEQ ID NO: 120, the fourth polypeptide chain comprises SEQ ID NO: 116, and the fifth polypeptide chain comprises SEQ ID NO: 103;

[0483] (vi) the first polypeptide chain comprises SEQ ID NO: 209, the second polypeptide chain comprises SEQ ID NO: 121, the third polypeptide chain comprises SEQ ID NO: 196, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 103;

[0484] (vii) the first polypeptide chain comprises SEQ ID NO: 128, the second polypeptide chain comprises SEQ ID NO: 125, the third polypeptide chain comprises SEQ ID NO: 79, the fourth polypeptide chain comprises SEQ ID NO: 208, and the fifth polypeptide chain comprises SEQ ID NO: 122;

[0485] (viii) the first polypeptide chain comprises SEQ ID NO: 134, the second polypeptide chain comprises SEQ ID NO: 133, the third polypeptide chain comprises SEQ ID NO: 79, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122;

[0486] (ix) the first polypeptide chain comprises SEQ ID NO: 121, the second polypeptide chain comprises SEQ ID NO: 144, the third polypeptide chain comprises SEQ ID NO: 196, the fourth polypeptide chain comprises SEQ ID NO: 136, and the fifth polypeptide chain comprises SEQ ID NO: 143;

[0487] (x) the first polypeptide chain comprises SEQ ID NO: 137, the second polypeptide chain comprises SEQ ID NO: 135, the third polypeptide chain comprises SEQ ID NO: 138, the fourth polypeptide chain comprises SEQ ID NO: 136, and the fifth polypeptide chain comprises SEQ ID NO: 122;

[0488] (xi) the first polypeptide chain comprises SEQ ID NO: 142, the second polypeptide chain comprises SEQ ID NO: 140, the third polypeptide chain comprises SEQ ID NO: 79, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122.

[0489] E360. The antibody of any one of E349 to E359, wherein the first polypeptide chain comprises SEQ ID NO: 132, the second polypeptide chain comprises SEQ ID NO: 130, the third polypeptide chain comprises SEQ ID NO: 79, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122.

[0490] E361. An isolated antibody that specifically binds IL-33, specifically binds IL-4, and specifically binds IL-13, comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein

[0491] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site;

[0492] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site;

[0493] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising an IL-33 binding site; and

[0494] wherein the first polypeptide chain comprises SEQ ID NO: 132, the second polypeptide chain comprises SEQ ID NO: 130, the third polypeptide chain comprises SEQ ID NO: 79, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122.

[0495] E362. An isolated antibody that specifically binds IL-33, specifically binds IL-4, and specifically binds IL-13, comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein

[0496] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site;

[0497] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site;

[0498] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising an IL-33 binding site; and

[0499] wherein the first polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127208; the second polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127192; the third polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127207; the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127194; and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127193.

[0500] E363. The antibody of E336 to E362, wherein the antibody has a viscosity of less than 20 cP at a concentration of at least 50 mg / mL in a buffer of 20 mM histidine, 8.5% sucrose, 0.05 mg / mL EDTA pH 6.0.

[0501] E364. The antibody of E336 to E363, wherein the viscosity of the antibody is less than 15 cP at a concentration of at least 90 mg / mL in a buffer of 20 mM histidine, 8.5% sucrose, 0.05 mg / mL EDTA pH 6.0.

[0502] E365. The antibody of E336 to E364, wherein the antibody has a terminal half-life of at least 12 days in cynomolgus monkeys.

[0503] E366. The antibody of E330 to E365, wherein the antibody has a terminal half-life of at least 16 days in TG32 mice.

[0504] E367. The antibody of E330 to E366, wherein the antibody binds human IL-4 with a binding affinity of less than 220 nM as measured by SPR.

[0505] E368. The antibody of E330 to E367, wherein the antibody binds human IL-13 with a binding affinity of less than 220 nM as measured by SPR.

[0506] E369. The antibody of E336 to E368, wherein the antibody binds human IL-4 with a binding affinity of less than 1 pM as measured by KinExA immobilized antigen assay in PBS.

[0507] E370. The antibody of E336 to E369, wherein the antibody binds cynomolgus monkey IL-4 with a binding affinity of less than 5 pM as measured by KinExA immobilized antigen assay in PBS.

[0508] E371. The antibody of E336 to E370, wherein the antibody binds human IL-13 with a binding affinity of less than 1 pM as measured by KinExA immobilized antigen assay in PBS.

[0509] E372. The antibody of E336 to E371, wherein the antibody binds cynomolgus monkey IL-13 with a binding affinity of less than 1 pM as measured by KinExA immobilized antigen assay in PBS.

[0510] E373. The antibody of E336 to E372, wherein the antibody is characterized by an IC of 0.001 for IL-4-induced neutralization of CD23 in a human monocyte assay 50 Less than 20nM.

[0511] E374. Antibodies of E336 to E373, wherein the antibodies are characterized by an IC of 0.000 for IL-13-induced neutralization of CD23 in a human monocyte assay 50 Less than 20nM.

[0512] The antibody of E375.E336 to E374, wherein the antibody is characterized by an IC in a wild-type IL-33 neutralization HEK-BlueSEAP assay 50 Less than 30nM.

[0513] E376. The antibody of E336 to E375, wherein the antibody is characterized by an IC of 0.05 in a recombinant constitutively active IL-33 neutralization HEK-Blue SEAP assay. 50 Less than 15pM.

[0514] E377. The antibody of any one of E336 to E376 for use as a medicament.

[0515] The antibody of E378.E377, wherein the use is for treating one or more selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, diabetic nephropathy, Behcet's disease, gout, Alzheimer's disease and atherosclerosis.

[0516] E379. The antibody of any one of E377 to 378, wherein the use is for treating one or more selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata and non-alcoholic steatohepatitis (NASH).

[0517] E380. The antibody of any one of E377 to E379, wherein the use is for atopic dermatitis.

[0518] E381. The antibody of any one of E377 to E379, wherein the use is for non-alcoholic steatohepatitis (NASH).

[0519] E382. A pharmaceutical composition comprising a therapeutically effective amount of an antibody from E336 to E381 and a pharmaceutically acceptable carrier.

[0520] E383. A method of treating a medical condition comprising administering to a subject in need thereof a therapeutically effective amount of the antibody of any one of E336 to E381 or the pharmaceutical composition of E382.

[0521] The method of E384.E383, wherein the condition is selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, diabetic nephropathy, Behcet's disease, gout, Alzheimer's disease and atherosclerosis.

[0522] E385. The method of any one of E383 to E384, comprising administering the antibody or pharmaceutical composition subcutaneously.

[0523] E386. The method of any one of E383 to E385, wherein the antibody or pharmaceutical composition is administered about twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, twice a month, once a month, once every two months, once every three months, or once every four months.

[0524] E387. An isolated antibody that specifically binds TSLP, specifically binds IL-4 and specifically binds IL-13, comprising a TSLP binding domain, an IL-4 binding domain and an IL-13 binding domain.

[0525] E388. The antibody of E387, wherein the specific binding to TSLP is through the antibody of any one of E77 to E143.

[0526] E389. The antibody of E387 to E388, wherein specific binding to IL-4 is through the antibody of any one of E199 to E259.

[0527] E390. The antibody of E387 to E389, wherein specific binding to IL-13 is through the antibody of any one of E265 to E330.

[0528] E391. The antibody of any one of E381 to E384, wherein

[0529] (i) the TSLP binding domain comprises a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), wherein the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 82; the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 83; the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 85; the CDR-L1 comprises the amino acid sequence of SEQ ID NO: 86; the CDR-L2 comprises the amino acid sequence of SEQ ID NO: 88; and the CDR-L3 comprises the amino acid sequence of SEQ ID NO: 90; and

[0530] (ii) the IL-4 binding domain comprises a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL), wherein the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 18; the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2; the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 3; the CDR-L1 comprises the amino acid sequence of SEQ ID NO: 24; the CDR-L2 comprises the amino acid sequence of SEQ ID NO: 12; and the CDR-L3 comprises the amino acid sequence of SEQ ID NO: 25, and

[0531] (iii) the IL-13 binding domain comprises a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL), wherein the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 41; the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 42; the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 50; the CDR-L1 comprises the amino acid sequence of SEQ ID NO: 53; the CDR-L2 comprises the amino acid sequence of SEQ ID NO: 37; and the CDR-L3 comprises the amino acid sequence of SEQ ID NO: 38.

[0532] E392. The antibody of E387 to E391, wherein

[0533] (i) the TSLP binding portion comprises TSLP-VH of SEQ ID NO: 92 and TSLP-VL of SEQ ID NO: 94;

[0534] (ii) the IL-4 binding portion comprises IL4-VH of SEQ ID NO: 22 and IL4-VL of SEQ ID NO: 26; and

[0535] (iii) the IL-13 binding portion comprises IL13-VH of SEQ ID NO: 51 and IL13-VL of SEQ ID NO: 54.

[0536] E393. The antibody of E387 to E392, wherein

[0537] (i) the TSLP binding domain comprises a TSLP-VH sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127200, and a TSLP-VL sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA0-127199;

[0538] (ii) the IL-4 binding domain comprises an IL4-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC deposit number PTA-127198, and an IL4-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC deposit number PTA-127197; and

[0539] (iii) the IL-13 binding domain comprises the IL13-VH sequence encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127196, and the IL13-VL sequence encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127195.

[0540] E394. The antibody of E387 to E393, wherein the TSLP binding domain is fused to the IL-13 binding domain with or without a linker.

[0541] E395. The antibody of E387 to E393, wherein the TSLP binding domain is fused to the IL-4 binding domain with or without a linker.

[0542] E396. The antibody of E387 to E393, wherein the IL-13 binding domain is fused to the IL-4 binding domain with or without a linker.

[0543] E397. The antibody of any one of E394 to E396, wherein the fusion has a linker.

[0544] E398. The antibody of any one of E394 to E397, wherein the IL-13 binding domain is fused to the IL-4 binding domain with a linker.

[0545] E399. The antibody of E394 to E398, wherein the linker comprises SEQ ID NO:104.

[0546] E400. The antibody of any one of E387 to E399, wherein the antibody comprises a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, such that

[0547] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising a first antigen binding site;

[0548] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising a second antigen binding site;

[0549] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a third antigen binding site.

[0550] The antibody of E401.E400, wherein the first polypeptide chain and the second polypeptide chain associate together to form an antibody comprising two arms; a dual Fab arm comprising the first Fab domain and the second Fab domain, and a single Fab arm comprising the third Fab domain.

[0551] E402. The antibody of E400 to E401, wherein the fifth polypeptide chain comprises the sequence EPKSC (SEQ ID NO: 122) at the C-terminus.

[0552] E403. The antibody of E400 to E402, wherein the first antigen binding site specifically binds IL-13, the second antibody binding site specifically binds IL-4, and the third antigen binding site specifically binds TSLP.

[0553] E404. The antibody of E400 to E403, wherein the first Fab domain, the second Fab domain and the third Fab domain each comprise a different option selected from the following (i), (ii) and (iii):

[0554] (i) TSLP-Fab of E117;

[0555] (ii) IL4-Fab of E234;

[0556] (iii) IL13-Fab of E302.

[0557] E405. The antibody of E400 to E406, wherein the first Fab domain is the IL13-Fab of E302, the second Fab domain is the IL4-Fab of E234, and the third Fab domain is the TSLP-Fab of E117.

[0558] E406. The antibody of E400 to E405, wherein the first polypeptide comprises a first Fc chain and the second polypeptide comprises a second Fc chain.

[0559] E407. The antibody of E406, wherein the first Fc chain and the second Fc chain each contain one or more amino acid modifications that promote association of the first Fc chain with the second Fc chain.

[0560] E408. The antibody of E400 to E407, wherein the first Fc chain comprises a first CH3 domain, and the second Fc chain comprises a second CH3 domain, and the first CH3 domain and the second CH3 domain each comprise different and complementary sequences, and the different and complementary sequences are one selected from the following pairs of different and complementary sequences:

[0561] (i) SEQ ID NO: 111 and SEQ ID NO: 106;

[0562] (ii) SEQ ID NO: 111 and SEQ ID NO: 114;

[0563] (iii) SEQ ID NO: 114 and SEQ ID NO: 117;

[0564] (iv) SEQ ID NO: 124 and SEQ ID NO: 127;

[0565] (v) SEQ ID NO: 139 and SEQ ID NO: 141; and

[0566] (vi) SEQ ID NO: 147 and SEQ ID NO: 148.

[0567] E409. The antibody of E408, wherein the first CH3 domain and the second CH3 domain comprise SEQ ID NO: 124 and SEQ ID NO: 127.

[0568] E410. The antibody of E400 to E409, wherein the properties of the first polypeptide chain, the second polypeptide chain, the third polypeptide chain, the fourth polypeptide chain, and the fifth polypeptide chain are selected from the group consisting of:

[0569] (i) the first polypeptide chain comprises SEQ ID NO: 165, the second polypeptide chain comprises SEQ ID NO: 130, the third polypeptide chain comprises SEQ ID NO: 99, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122;

[0570] (ii) the first polypeptide chain comprises SEQ ID NO: 146, the second polypeptide chain comprises SEQ ID NO: 149, the third polypeptide chain comprises SEQ ID NO: 109, the fourth polypeptide chain comprises SEQ ID NO: 196, and the fifth polypeptide chain comprises SEQ ID NO: 150;

[0571] (iii) the first polypeptide chain comprises SEQ ID NO: 112, the second polypeptide chain comprises SEQ ID NO: 151, the third polypeptide chain comprises SEQ ID NO: 196, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 150;

[0572] (iv) the first polypeptide chain comprises SEQ ID NO: 112, the second polypeptide chain comprises SEQ ID NO: 159, the third polypeptide chain comprises SEQ ID NO: 196, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 150;

[0573] (v) the first polypeptide chain comprises SEQ ID NO: 161, the second polypeptide chain comprises SEQ ID NO: 162, the third polypeptide chain comprises SEQ ID NO: 98, the fourth polypeptide chain comprises SEQ ID NO: 197, and the fifth polypeptide chain comprises SEQ ID NO: 163;

[0574] (vi) the first polypeptide chain comprises SEQ ID NO: 146, the second polypeptide chain comprises SEQ ID NO: 154, the third polypeptide chain comprises SEQ ID NO: 109, the fourth polypeptide chain comprises SEQ ID NO: 196, and the fifth polypeptide chain comprises SEQ ID NO: 155;

[0575] (vii) the first polypeptide chain comprises SEQ ID NO: 112, the second polypeptide chain comprises SEQ ID NO: 156, the third polypeptide chain comprises SEQ ID NO: 196, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 155;

[0576] (viii) the first polypeptide chain comprises SEQ ID NO: 146, the second polypeptide chain comprises SEQ ID NO: 152, the third polypeptide chain comprises SEQ ID NO: 109, the fourth polypeptide chain comprises SEQ ID NO: 196, and the fifth polypeptide chain comprises SEQ ID NO: 98;

[0577] (ix) the first polypeptide chain comprises SEQ ID NO: 112, the second polypeptide chain comprises SEQ ID NO: 153, the third polypeptide chain comprises SEQ ID NO: 196, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 98;

[0578] (x) the first polypeptide chain comprises SEQ ID NO: 112, the second polypeptide chain comprises SEQ ID NO: 157, the third polypeptide chain comprises SEQ ID NO: 196, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 158;

[0579] (xi) the first polypeptide chain comprises SEQ ID NO: 146, the second polypeptide chain comprises SEQ ID NO: 160, the third polypeptide chain comprises SEQ ID NO: 109, the fourth polypeptide chain comprises SEQ ID NO: 196, and the fifth polypeptide chain comprises SEQ ID NO: 158; and

[0580] (xii) the first polypeptide chain comprises SEQ ID NO: 161, the second polypeptide chain comprises SEQ ID NO: 164, the third polypeptide chain comprises SEQ ID NO: 98, the fourth polypeptide chain comprises SEQ ID NO: 197, and the fifth polypeptide chain comprises SEQ ID NO: 122;

[0581] (xiii) the first polypeptide chain comprises SEQ ID NO: 165, the second polypeptide chain comprises SEQ ID NO: 130, the third polypeptide chain comprises SEQ ID NO: 215, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122; and

[0582] (xiv) the first polypeptide chain comprises SEQ ID NO: 165, the second polypeptide chain comprises SEQ ID NO: 130, the third polypeptide chain comprises SEQ ID NO: 216, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122.

[0583] E411. The antibody of any one of E411 to E410, wherein the first polypeptide chain comprises SEQ ID NO: 165, the second polypeptide chain comprises SEQ ID NO: 130, the third polypeptide chain comprises SEQ ID NO: 99, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122.

[0584] E412. An isolated antibody that specifically binds to TSLP, specifically binds to IL-4, and specifically binds to IL-13, comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein

[0585] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site;

[0586] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site;

[0587] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a TSLP binding site; and

[0588] wherein the first polypeptide chain comprises SEQ ID NO: 165, the second polypeptide chain comprises SEQ ID NO: 130, the third polypeptide chain comprises SEQ ID NO: 99, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122.

[0589] E413. An isolated antibody that specifically binds to TSLP, specifically binds to IL-4, and specifically binds to IL-13, comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein

[0590] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site;

[0591] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site;

[0592] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a TSLP binding site, and

[0593] wherein the first polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127202; the second polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127192; the third polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127201; the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127194; and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127193.

[0594] E414. The antibody of any one of E387 to E413, wherein the antibody has a terminal half-life of at least 14 days in cynomolgus monkeys.

[0595] E415. The antibody of any one of E387 to E414, wherein the antibody has a terminal half-life of at least 18 days in TG32 mice.

[0596] E416. The antibody of any one of E387 to E415, characterized by an IC of anti-TSLP bioactivity as measured by a TARC production bioassay in human primary PBMCs. 50 Less than 10pM.

[0597] E417. The antibody of any one of E387 to E416, characterized by a viscosity of 20 cP at a concentration of at least 100 mg / mL in a buffer of 20 mM histidine, 8.5% sucrose, 0.05 mg / mL EDTA pH 6.0.

[0598] E418. The antibody of any one of E387 to E417, characterized in that the score for high molecular weight species is less than 2% when determined by analytical size exclusion chromatography (aSEC).

[0599] E419. The antibody of any one of E387 to E418, characterized by a score of less than 12 in an affinity capture self-interacting nanoparticle spectroscopy (AC SINS) assay.

[0600] E420. The antibody of any one of E387 to E419, wherein the antibody binds human IL-4 with a binding affinity of less than 1 pM as measured by KinExA immobilized antigen assay in PBS.

[0601] E421. The antibody of any one of E387 to E420, wherein the antibody binds cynomolgus monkey IL-4 with a binding affinity of less than 1 pM as measured by KinExA immobilized antigen assay in PBS.

[0602] E422. The antibody of any one of E387 to E421, wherein the antibody binds human IL-13 with a binding affinity of less than 1 pM as measured by KinExA immobilized antigen assay in PBS.

[0603] E423. The antibody of any one of E387 to E422, wherein the antibody binds cynomolgus monkey IL-13 with a binding affinity of less than 1 pM as measured by KinExA immobilized antigen assay in PBS.

[0604] E424. The antibody of any one of E387 to E423, wherein the antibody binds human TSLP with a binding affinity of less than 5 pM as measured by KinExA immobilized antigen assay in PBS.

[0605] E425. The antibody of any one of E387 to E424, wherein the antibody binds cynomolgus monkey IL-13 with a binding affinity of less than 20 pM as measured by KinExA immobilized antigen assay in PBS.

[0606] E426. The antibody of any one of E387 to E425, wherein the antibody is characterized by an IC of 0.05 for IL-4-induced neutralization of CD23 in a human monocyte assay 50 Less than 25pM.

[0607] E427. The antibody of any one of E387 to E426, wherein the antibody is characterized by an IC of 0.05 for IL-4-induced neutralization of CD23 in a human monocyte assay 50 Less than 15pM.

[0608] E428. The antibody of any one of E387 to E427, wherein the antibody is characterized by an IC of 0.05 for cynomolgus IL-4-induced neutralization of CD23 in a human monocyte assay 50 Less than 60pM.

[0609] E429. The antibody of any one of E387 to E428, wherein the antibody is characterized by an IC of 0.05 for neutralization of human TSLP in a TARC production bioassay in human primary PBMCs 50 Less than 15pM.

[0610] E430. The antibody of any one of E387 to E429, wherein the antibody is characterized by an IC in a cynomolgus monkey TSLP neutralization assay 50 Less than 35pM.

[0611] E431. The antibody of any one of E387 to 430 for use as a medicament.

[0612] The antibody of E432.E431, wherein the use is for treating one or more selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis and fungal keratitis.

[0613] E433. The antibody of any one of E431 to E432, wherein the use is for treating one or more selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata and non-alcoholic steatohepatitis (NASH).

[0614] E434. The antibody of any one of E431 to 433, wherein the use is for atopic dermatitis.

[0615] E435. The antibody of any one of E431 to 433, wherein the use is for non-alcoholic steatohepatitis (NASH).

[0616] E436. A pharmaceutical composition comprising a therapeutically effective amount of an antibody from E387 to E435 and a pharmaceutically acceptable carrier.

[0617] E437. A method of treating a medical condition comprising administering to a subject in need thereof a therapeutically effective amount of the antibody of any one of E387 to E435 or the pharmaceutical composition of E436.

[0618] E438. The method of E437, wherein the condition is selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, and fungal keratitis.

[0619] E439. The method of any one of E437 to E438, comprising administering the antibody or pharmaceutical composition subcutaneously.

[0620] E440. The method of any one of E437 to E439, wherein the antibody or pharmaceutical composition is administered about twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, twice a month, once a month, once every two months, once every three months, or once every four months.

[0621] E445. An isolated antibody that specifically binds p40, specifically binds IL-4 and specifically binds IL-13, comprising a p40 binding domain, an IL-4 binding domain and an IL-13 binding domain.

[0622] E446. The antibody of E445, wherein specific binding to p40 is through the antibody of any one of E144 to E193.

[0623] E447. The antibody of E445 to E446, wherein specific binding to IL-4 is through the antibody of any one of E199 to E259.

[0624] E448. The antibody of any one of E445 to E447, wherein specific binding to IL-13 is through the antibody of any one of E265 to E330.

[0625] E449. The antibody of any one of E445 to E448, wherein

[0626] (i) the p40 binding domain comprises a heavy chain variable region (p40-VH) and a light chain variable region (p40-VL), wherein CDR-H1 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 166; CDR-H2 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 167; CDR-H3 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 168; CDR-L1 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 171; CDR-L2 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 172, and CDR-L3 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 173; and

[0627] (ii) the IL-4 binding domain comprises a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL), wherein CDR-H1 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 18; CDR-H2 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 2; CDR-H3 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 3; CDR-L1 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 24; CDR-L2 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 12, and CDR-L3 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 25, and

[0628] (iii) the IL-13 binding domain comprises a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL), wherein CDR-H1 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 41; CDR-H2 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 42; CDR-H3 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 50; CDR-L1 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 53; CDR-L2 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 37, and CDR-L3 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 38.

[0629] E450. The antibody of E445 to 449, wherein

[0630] (i) the p40 binding domain comprises p40-VH of SEQ ID NO: 169 and p40-VL of SEQ ID NO: 175;

[0631] (ii) the IL-4 binding domain comprises IL4-VH of SEQ ID NO: 22 and IL4-VL of SEQ ID NO: 26;

[0632] (iii) the IL-13 binding domain comprises IL13-VH of SEQ ID NO: 51 and IL13-VL of SEQ ID NO: 54.

[0633] E451. The antibody of E445 to 450, wherein

[0634] (i) the p40 binding domain comprises a p40-VH sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127206, and a p40-VL sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127205;

[0635] (ii) the IL-4 binding domain comprises an IL4-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC deposit number PTA-127198, and an IL4-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC deposit number PTA-127197; and

[0636] (iii) the IL-13 binding domain comprises the IL13-VH sequence encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127196, and the IL13-VL sequence encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127195.

[0637] E452. The antibody of E445 to E451, wherein the p40 binding domain is fused to the IL-13 binding domain with or without a linker.

[0638] E453. The antibody of E445 to E451, wherein the p40 binding domain is fused to the IL-4 binding domain with or without a linker.

[0639] E454. The antibody of E445 to E451, wherein the IL-13 binding domain is fused to the IL-4 binding domain with or without a linker.

[0640] E455. The antibody of any one of E452 to E454, wherein the fusion has a linker.

[0641] E456. The antibody of any one of E452 to E455, wherein the IL-13 binding domain is fused to the IL-4 binding domain with a linker.

[0642] E457. The antibody of E456, wherein the linker comprises SEQ ID NO:104.

[0643] E458. The antibody of any one of E445 to E457, wherein the antibody comprises a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, such that

[0644] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising a first antigen binding site;

[0645] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising a second antigen binding site;

[0646] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a third antigen binding site.

[0647] The antibody of E459.E458, wherein the first polypeptide chain and the second polypeptide chain associate together to form an antibody comprising two arms; a dual Fab arm comprising the first Fab domain and the second Fab domain, and a single Fab arm comprising the third Fab domain.

[0648] E460. The antibody of E458 to E459, wherein the fifth polypeptide chain comprises the sequence EPKSC (SEQ ID NO: 122) at the C-terminus.

[0649] E461. The antibody of E458 to E460, wherein the first antigen binding site specifically binds IL-13, the second antibody binding site specifically binds IL-4, and the third antigen binding site specifically binds p40.

[0650] E462. The antibody of E458 to E461, wherein the first Fab domain, the second Fab domain and the third Fab domain each comprise a different option selected from the following (i), (ii) and (iii):

[0651] (i) p40-Fab of E166,

[0652] (ii) IL4-Fab of E234, and

[0653] (iii) IL13-Fab of E302.

[0654] E463. The antibody of E458 to E462, wherein the first Fab domain is the IL13-Fab of E302, the second Fab domain is the IL4-Fab of E234, and the third Fab domain is the p40-Fab of E166.

[0655] E464. The antibody of E458 to E463, wherein the first polypeptide comprises a first Fc chain and the second polypeptide comprises a second Fc chain.

[0656] E465. The antibody of E464, wherein the first Fc chain and the second Fc chain each contain one or more amino acid modifications that promote association of the first Fc chain with the second Fc chain.

[0657] E466. The antibody of E464 to E465, wherein the first Fc chain comprises a first CH3 domain, and the second Fc chain comprises a second CH3 domain, and the first CH3 domain and the second CH3 domain each comprise different and complementary sequences, and the different and complementary sequences are one selected from the following pairs of different and complementary sequences:

[0658] (i) SEQ ID NO: 106 and SEQ ID NO: 111;

[0659] (ii) SEQ ID NO: 147 and SEQ ID NO: 148; and

[0660] (iii) SEQ ID NO: 124 and SEQ ID NO: 127.

[0661] E467. The antibody of E466, wherein the first CH3 domain and the second CH3 domain comprise SEQ ID NO: 124 and SEQ ID NO: 127.

[0662] E468. The antibody of E458 to E467, wherein the characteristics of the first polypeptide chain, the second polypeptide chain, the third polypeptide chain, the fourth polypeptide chain, and the fifth polypeptide chain are selected from the group consisting of:

[0663] (i) the first polypeptide chain comprises SEQ ID NO: 186, the second polypeptide chain comprises SEQ ID NO: 130, the third polypeptide chain comprises SEQ ID NO: 176, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122;

[0664] (ii) the first polypeptide chain comprises SEQ ID NO: 146, the second polypeptide chain comprises SEQ ID NO: 178, the third polypeptide chain comprises SEQ ID NO: 109, the fourth polypeptide chain comprises SEQ ID NO: 196, and the fifth polypeptide chain comprises SEQ ID NO: 177;

[0665] (iii) the first polypeptide chain comprises SEQ ID NO: 112, the second polypeptide chain comprises SEQ ID NO: 179, the third polypeptide chain comprises SEQ ID NO: 196, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 177;

[0666] (iv) the first polypeptide chain comprises SEQ ID NO: 181, the second polypeptide chain comprises SEQ ID NO: 180, the third polypeptide chain comprises SEQ ID NO: 182, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 122;

[0667] (v) the first polypeptide chain comprises SEQ ID NO: 118, the second polypeptide chain comprises SEQ ID NO: 183, the third polypeptide chain comprises SEQ ID NO: 120, the fourth polypeptide chain comprises SEQ ID NO: 116, and the fifth polypeptide chain comprises SEQ ID NO: 177;

[0668] (vi) the first polypeptide chain comprises SEQ ID NO: 185, the second polypeptide chain comprises SEQ ID NO: 125, the third polypeptide chain comprises SEQ ID NO: 176, the fourth polypeptide chain comprises SEQ ID NO: 207, and the fifth polypeptide chain comprises SEQ ID NO: 122; and

[0669] (vii) the first polypeptide chain comprises SEQ ID NO: 185, the second polypeptide chain comprises SEQ ID NO: 125, the third polypeptide chain comprises SEQ ID NO: 176, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122.

[0670] E469. The antibody of any one of E458 to E468, wherein the first polypeptide chain comprises SEQ ID NO: 186, the second polypeptide chain comprises SEQ ID NO: 130, the third polypeptide chain comprises SEQ ID NO: 176, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122.

[0671] E470. An isolated antibody that specifically binds p40, specifically binds IL-4, and specifically binds IL-13, comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein

[0672] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site;

[0673] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site;

[0674] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a p40 binding site, and wherein

[0675] The first polypeptide chain comprises SEQ ID NO: 186, the second polypeptide chain comprises SEQ ID NO: 130, the third polypeptide chain comprises SEQ ID NO: 176, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122.

[0676] E471. An isolated antibody that specifically binds p40, specifically binds IL-4, and specifically binds IL-13, comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein

[0677] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site;

[0678] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site;

[0679] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a p40 binding site, and

[0680] wherein the first polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127204; the second polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127192; the third polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127203; the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127194; and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127193.

[0681] E472. The antibody of E445 to E471, wherein the viscosity of the antibody is less than 20 cP at a concentration of at least 100 mg / mL in a buffer of 20 mM histidine, 8.5% sucrose, 0.05 mg / mL EDTA pH 6.0.

[0682] E473. The antibody of E445 to E472, wherein the antibody has a viscosity of less than 12 cP at a concentration of at least 50 mg / mL in a buffer of 20 mM histidine, 8.5% sucrose, 0.05 mg / mL EDTA pH 6.0.

[0683] E474. The antibody of E445 to E473, wherein the antibody has a terminal half-life of at least 12 days in cynomolgus monkeys.

[0684] E475. The antibody of E445 to E474, wherein the antibody has a terminal half-life of at least 18 days in TG-32 mice.

[0685] E476. The antibody of E445 to E475, wherein the antibody binds human IL-4 with an affinity constant of less than 220 pM as measured by SPR.

[0686] E477. The antibody of E445 to E476, wherein the antibody binds human IL-13 with an affinity constant of less than 220 pM as measured by SPR.

[0687] E478. The antibody of E445 to E477, wherein the antibody binds human IL-12 with an affinity constant of less than 130 pM as measured by SPR.

[0688] E479. The antibody of E445 to E478, wherein the antibody binds human IL-23 with an affinity constant of less than 100 pM as measured by SPR.

[0689] E480. The antibody of E445 to E479, wherein the antibody binds human IL-4 with a binding affinity of less than 1 pM as measured by KinExA immobilized antigen assay in PBS.

[0690] E481. The antibody of E445 to E480, wherein the antibody binds cynomolgus monkey IL-13 with a binding affinity of less than 2 pM as measured by KinExA immobilized antigen assay in PBS.

[0691] E482. The antibody of E445 to E481, wherein the antibody is characterized by an IC of 0.05 for IL-4-induced neutralization of CD23 as measured in a human monocyte assay 50 Less than 12pM.

[0692] E483. The antibody of E445 to E482, wherein the antibody is characterized by an IC of 0.05 for cynomolgus monkey IL-4-induced neutralization of CD23 as measured in a human monocyte assay 50 Less than 12pM.

[0693] E484. The antibody of E445 to E483, wherein the antibody is characterized by an IC of 0.05 for cynomolgus monkey IL-13-induced neutralization of CD23 as measured in a human monocyte assay 50 Less than 12pM.

[0694] E485. The antibody of E445 to E484, wherein the antibody is characterized by an IC of 0.05 for IL-13-induced neutralization of CD23 as measured in a human monocyte assay 50 Less than 45pM.

[0695] E486. The antibody of E445 to E485, wherein the antibody is characterized by an IC of 0.05 in a human IL-12 neutralization and Kit-225 assay on human peripheral blood mononuclear cells. 50 Less than 600pM.

[0696] E487. The antibody of E445 to E486, wherein the antibody is characterized by an IC in a cynomolgus monkey IL-23Kit-225 neutralization assay on human peripheral blood mononuclear cells 50 Less than 2100pM.

[0697] E488. The antibody of E445 to E487, wherein the antibody is characterized by an IC in a human IL-12 neutralization assay in human whole blood 50 Less than 400pM.

[0698] E489. The antibody of E445 to E488, wherein the antibody is characterized by an IC in a cynomolgus monkey IL-23 neutralization assay in human whole blood 50 Less than 10,000pM.

[0699] E490. The antibody of any one of E445 to 489 for use as a medicament.

[0700] The antibody of E491.E490, wherein the use is for treating one or more selected from the group consisting of: non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, atopic dermatitis, Crohn's disease, ulcerative colitis, asthma (severe), allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus, primary biliary cirrhosis and hidradenitis suppurativa.

[0701] E492. The antibody of any one of E490 to E491, wherein the use is for treating one or more selected from the group consisting of: non-alcoholic steatohepatitis (NASH), atopic dermatitis, asthma (severe), alopecia, idiopathic pulmonary fibrosis and systemic sclerosis.

[0702] E483. The antibody of any one of E490 to E482, wherein the use is for atopic dermatitis.

[0703] E484. The antibody of any one of E490 to E483, wherein the use is for non-alcoholic steatohepatitis (NASH).

[0704] E495. A pharmaceutical composition comprising a therapeutically effective amount of an antibody from E445 to E484 and a pharmaceutically acceptable carrier.

[0705] E496. A method of treating a medical condition, comprising administering to a subject in need thereof a therapeutically effective amount of an antibody of any one of E445 to E494 or a pharmaceutical composition of E495.

[0706] E497. The method of E496, wherein the condition is selected from: non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, asthma (severe), allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus, primary biliary cirrhosis and hidradenitis suppurativa.

[0707] E498. The method of any one of E496 to E497, comprising administering the antibody or pharmaceutical composition subcutaneously.

[0708] E499. The method of any one of E496 to E498, wherein the antibody or pharmaceutical composition is administered about twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, twice a month, once a month, once every two months, once every three months, or once every four months.

[0709] E500. An antibody comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain and a fifth polypeptide chain, such that

[0710] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising a first antigen binding site;

[0711] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising a second antigen binding site;

[0712] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a third antigen binding site.

[0713] The antibody of E501.E500, wherein the first polypeptide chain and the second polypeptide chain associate together to form an antibody comprising two arms; a dual Fab arm comprising the first Fab domain and the second Fab domain, and a single Fab arm comprising the third Fab domain.

[0714] E502. The antibody of E501, wherein the first Fab comprises a first antigen-related VH (VH-1), a first antigen-related VL (VL-1), a first antigen-related CL (CL-1) and a first antigen-related CH1 (CH1-1).

[0715] The antibody of E503.E504, wherein the C-terminus of VH-1 is covalently fused to the N-terminus of CH1-1 via a peptide bond.

[0716] E504. The antibody of E502 to E503, wherein the C-terminus of VL-1 is covalently fused to the N-terminus of CL-1 via a peptide bond.

[0717] E505. The antibody of E501 to E504, wherein the second Fab comprises a second antigen-related VH (VH-2), a second antigen-related VL (VL-2), a second antigen-related CL (CL-2) and a second antigen-related CH1 (CH1-2).

[0718] The antibody of E506.E505, wherein the C-terminus of VH-2 is covalently fused to the N-terminus of CH1-2 via a peptide bond.

[0719] E507. The antibody of E505 to E506, wherein the C-terminus of VL-2 is covalently fused to the N-terminus of CL-2 via a peptide bond.

[0720] E508. The antibody of E501 to E507, wherein the third Fab comprises a third antigen-related VH (VH-3), a first antigen-related VL (VL-3), a first antigen-related CL (CL-3) and a first antigen-related CH1 (CH1-3).

[0721] The antibody of E509.E508, wherein the C-terminus of VH-3 is covalently fused to the N-terminus of CH1-3 via a peptide bond.

[0722] E510. The antibody of E508 to E509, wherein the C-terminus of VL-3 is covalently fused to the N-terminus of CL-3 via a peptide bond.

[0723] E511. The antibody of E500 to 510, wherein the second polypeptide comprises (VL-1)-(CL-1)-(linker)-(VH-2)-(CH1-2)-(second hinge)-(second CH2)-(second CH3) from N-terminus to C-terminus; the fifth polypeptide comprises (VH1)-(CL-1) from N-terminus to C-terminus; and the fourth polypeptide comprises (VL-2)-(CL-2).

[0724] E512. The antibody of E500 to E511, wherein the first polypeptide comprises (VH-3)-(CH1-3)-(first hinge)-(first CH2)-(first CH3) from N-terminus to C-terminus; and the third polypeptide comprises (VL-3)-(CL-3).

[0725] E513. The antibody of E508 to E512, wherein one or more of the CH1-1 domain, the CH1-2 domain and the CH1-3 domain may comprise a sequence selected from SEQ ID NO: 6, SEQ ID NO: 105 and SEQ ID NO: 110.

[0726] E514. The antibody of E508 to E513, wherein one or more of the CL-1 domain, CL-2 domain and CL-3 domain comprises a sequence selected from SEQ ID NO: 16, SEQ ID NO: 95, SEQ ID NO: 108 and SEQ ID NO: 113.

[0727] E515. The antibody of E512 to E514, wherein the first hinge region and the second hinge region comprise a pair of sequences according to SEQ ID NO: 129 and SEQ ID NO: 131.

[0728] E516. The antibody of E512 to E515, wherein one or both of the first CH2 domain and the second CH2 domain comprises the sequence according to SEQ ID NO:8.

[0729] The antibody of E517.E512 to E516, wherein the first CH3 domain and the second CH3 domain each comprise different and complementary sequences, and the different and complementary sequences are one selected from the following different and complementary sequence pairs:

[0730] (i) SEQ ID NO: 111 and SEQ ID NO: 106;

[0731] (ii) SEQ ID NO: 111 and SEQ ID NO: 114;

[0732] (iii) SEQ ID NO: 114 and SEQ ID NO: 117;

[0733] (iv) SEQ ID NO: 124 and SEQ ID NO: 127;

[0734] (v) SEQ ID NO: 139 and SEQ ID NO: 141; and

[0735] (vi) SEQ ID NO: 147 and SEQ ID NO: 148.

[0736] E518. Antibodies of E512 to E517, wherein

[0737] (i) the CL-1 comprises the sequence according to SEQ ID NO: 16, the linker comprises the sequence according to SEQ ID NO: 104, the CH1-2 comprises the sequence according to SEQ ID NO: 6, the second hinge comprises the sequence according to SEQ ID NO: 129, the second CH2 comprises the sequence according to SEQ ID NO: 8, and the second CH3 comprises the sequence according to SEQ ID NO: 124;

[0738] (ii) the CH1-1 comprises the sequence according to SEQ ID NO: 6; and

[0739] (iii) the CL-2 comprises the sequence according to SEQ ID NO:16.

[0740] E519. The antibody of E508 to 518, wherein CL-3 comprises a sequence selected from the group consisting of SEQ ID NO: 16, SEQ ID NO: 95, SEQ ID NO: 108, SEQ ID NO: 113.

[0741] E520. The antibody of E508 to E519, wherein CL-3 comprises the sequence according to SEQ ID NO:95.

[0742] E521. The antibody of E508 to E519, wherein CL-3 comprises the sequence according to SEQ ID NO:16.

[0743] E522. The antibody of E508 to E521, wherein CH1-3 comprises the sequence according to SEQ ID NO:6.

[0744] E523. The antibody of E512 to E522, wherein the first hinge comprises the sequence according to SEQ ID NO: 131.

[0745] E524. The antibody of E512 to E523, wherein the first CH2 comprises the sequence according to SEQ ID NO:8.

[0746] E525. The antibody of E512 to E524, wherein the first CH3 comprises the sequence according to SEQ ID NO: 127.

[0747] E526. An isolated antibody of any one of E500 to E525, which specifically binds IL-4 and specifically binds IL-13, comprising an IL-4 binding domain and an IL-13 binding domain.

[0748] E527. An isolated antibody of any one of E1 to E525, which specifically binds IL-4 and specifically binds IL-13, comprising an IL-4 binding domain and an IL-13 binding domain.

[0749] E528. An isolated antibody that specifically binds IL-4 and specifically binds IL-13, comprising an IL-4 binding domain and an IL-13 binding domain.

[0750] E529. The antibody of E526 to E528, wherein specific binding to IL-4 is through the antibody of any one of E199 to E259.

[0751] E530. The antibody of any one of E526 to E529, wherein specific binding to IL-13 is through the antibody of any one of E265 to E330.

[0752] E531. The antibody of any one of E526 to E530, wherein the antibody comprises at least one additional antigen binding domain that binds to at least one target different from both IL-4 and IL-13.

[0753] The antibody of E532.E531, wherein the at least one different target is selected from IL-33, TSLP and p40, and wherein when the target is IL-33, it may optionally further comprise antibodies from E1 to E71, and wherein when the target is TSLP, it may optionally further comprise antibodies from E77 to E143, and wherein when the target is p40, it may optionally further comprise antibodies from E144 to E193.

[0754] E533. The antibody of E531, wherein the at least one different target is not IL-33.

[0755] E534. The antibody of E531, wherein the at least one different target is not TSLP.

[0756] E535. The antibody of E531, wherein the at least one different target is not p40.

[0757] E536. The antibody of any one of E526 to E535, wherein

[0758] (i) the IL-4 binding domain comprises a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL), wherein CDR-H1 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 18; CDR-H2 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 2; CDR-H3 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 3; CDR-L1 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 24; CDR-L2 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 12, and CDR-L3 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 25, and

[0759] (ii) the IL-13 binding domain comprises a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL), wherein CDR-H1 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 41; CDR-H2 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 42; CDR-H3 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 50; CDR-L1 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 53; CDR-L2 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 37, and CDR-L3 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 38.

[0760] E537. Antibodies of E526 to E536, wherein

[0761] (i) the IL-4 binding domain comprises IL4-VH of SEQ ID NO: 22 and IL4-VL of SEQ ID NO: 26;

[0762] (ii) the IL-13 binding domain comprises IL13-VH of SEQ ID NO: 51 and IL13-VL of SEQ ID NO: 54;

[0763] E538. The antibody of E531 to E537, wherein the additional antigen binding domain is fused to the IL-13 binding domain with or without a linker.

[0764] E539. The antibody of E531 to E537, wherein the additional antigen binding domain is fused to the IL-4 binding domain with or without a linker.

[0765] E540. The antibody of E531 to E537, wherein the IL-13 binding domain is fused to the IL-4 binding domain with or without a linker.

[0766] E541. The antibody of any one of E538 to E540, wherein the fusion has a linker.

[0767] E542. The antibody of any one of E540 to E541, wherein the IL-13 binding domain is fused to the IL-4 binding domain with a linker.

[0768] E543. The antibody of E542, wherein the linker comprises SEQ ID NO:104.

[0769] E544. The antibody of any one of E526 to E543, wherein the antibody comprises a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, such that

[0770] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising a first antigen binding site;

[0771] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising a second antigen binding site;

[0772] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a third antigen binding site.

[0773] The antibody of E545.E544, wherein the first polypeptide chain and the second polypeptide chain associate together to form an antibody comprising two arms; a dual Fab arm comprising the first Fab domain and the second Fab domain, and a single Fab arm comprising the third Fab domain.

[0774] E546. Antibodies of E526 to E545, wherein

[0775] (i) the first antigen binding site specifically binds IL-13, the second antibody binding site specifically binds IL-4, and the third antigen binding site specifically binds the at least one additional target;

[0776] (ii) the first antigen binding site specifically binds IL-4, the second antibody binding site specifically binds IL-13, and the third antigen binding site specifically binds the at least one additional target;

[0777] (iii) the first antigen binding site specifically binds IL-4, the second antibody binding site specifically binds the at least one additional target, and the third antigen binding site specifically binds IL-13;

[0778] (iv) wherein the first antigen binding site specifically binds IL-13, the second antibody binding site specifically binds the at least one additional target, and the third antigen binding site specifically binds IL-4;

[0779] (v) the first antigen binding site specifically binds to the at least one additional target, the second antibody binding site specifically binds to IL-13, and the third antigen binding site specifically binds to IL-4; or

[0780] (vi) the first antigen binding site specifically binds to the at least one additional target, the second antibody binding site specifically binds to IL-4, and the third antigen binding site specifically binds to IL-13.

[0781] E547. The antibody of E544 to E546, wherein the first Fab domain is the IL13-Fab of E302, the second Fab domain is the IL4-Fab of E234, and the third Fab domain is an additional target-Fab.

[0782] E548. The antibody of E44 to E547, wherein the fifth polypeptide chain comprises the sequence EPKSC (SEQ ID NO: 122) at the C-terminus.

[0783] E549. The antibody of E544 to E548, wherein the first polypeptide comprises a first Fc chain and the second polypeptide comprises a second Fc chain.

[0784] The antibody of E550.E549, wherein the first Fc chain and the second Fc chain each contain one or more amino acid modifications that promote association of the first Fc chain with the second Fc chain.

[0785] The antibody of E551.E544 to E550, wherein the first Fc chain comprises a first CH3 domain, and the second Fc chain comprises a second CH3 domain, and the first CH3 domain and the second CH3 domain each comprise different and complementary sequences, and the different and complementary sequences are one selected from the following pairs of different and complementary sequences:

[0786] (i) SEQ ID NO: 111 and SEQ ID NO: 106;

[0787] (ii) SEQ ID NO: 111 and SEQ ID NO: 114;

[0788] (iii) SEQ ID NO: 114 and SEQ ID NO: 117;

[0789] (iv) SEQ ID NO: 124 and SEQ ID NO: 127;

[0790] (v) SEQ ID NO: 139 and SEQ ID NO: 141; and

[0791] (vi) SEQ ID NO: 147 and SEQ ID NO: 148.

[0792] E552. The antibody of E551, wherein the first CH3 domain and the second CH3 domain comprise SEQ ID NO: 124 and SEQ ID NO: 127.

[0793] E553. The antibody of E544 to E552, wherein the properties of the second polypeptide chain, the fourth polypeptide chain, and the fifth polypeptide chain are selected from the group consisting of:

[0794] (i) the second polypeptide chain comprises SEQ ID NO: 145, the fourth polypeptide chain comprises SEQ ID NO: 196, and the fifth polypeptide chain comprises SEQ ID NO: 103;

[0795] (ii) the second polypeptide chain comprises SEQ ID NO: 107, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 103;

[0796] (iii) the second polypeptide chain comprises SEQ ID NO: 115, the fourth polypeptide chain comprises SEQ ID NO: 116, and the fifth polypeptide chain comprises SEQ ID NO: 103;

[0797] (iv) the second polypeptide chain comprises SEQ ID NO: 121, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 103;

[0798] (v) the second polypeptide chain comprises SEQ ID NO: 125, the fourth polypeptide chain comprises SEQ ID NO: 208, and the fifth polypeptide chain comprises SEQ ID NO: 122;

[0799] (vi) the second polypeptide chain comprises SEQ ID NO: 130, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122;

[0800] (vii) the second polypeptide chain comprises SEQ ID NO: 133, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122;

[0801] (viii) the second polypeptide chain comprises SEQ ID NO: 144, the fourth polypeptide chain comprises SEQ ID NO: 136, and the fifth polypeptide chain comprises SEQ ID NO: 143;

[0802] (ix) the second polypeptide chain comprises SEQ ID NO: 135, the fourth polypeptide chain comprises SEQ ID NO: 136, and the fifth polypeptide chain comprises SEQ ID NO: 122;

[0803] (x) the second polypeptide chain comprises SEQ ID NO: 140, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122;

[0804] (xi) the second polypeptide chain comprises SEQ ID NO: 149, the fourth polypeptide chain comprises SEQ ID NO: 196, and the fifth polypeptide chain comprises SEQ ID NO: 150;

[0805] (xii) the second polypeptide chain comprises SEQ ID NO: 151, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 150;

[0806] (xiii) the second polypeptide chain comprises SEQ ID NO: 159, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 150;

[0807] (xiv) the second polypeptide chain comprises SEQ ID NO: 162, the fourth polypeptide chain comprises SEQ ID NO: 197, and the fifth polypeptide chain comprises SEQ ID NO: 163;

[0808] (xv) the second polypeptide chain comprises SEQ ID NO: 154, the fourth polypeptide chain comprises SEQ ID NO: 196, and the fifth polypeptide chain comprises SEQ ID NO: 155;

[0809] (xvi) the second polypeptide chain comprises SEQ ID NO: 156, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 155;

[0810] (xvii) the second polypeptide chain comprises SEQ ID NO: 152, the fourth polypeptide chain comprises SEQ ID NO: 196, and the fifth polypeptide chain comprises SEQ ID NO: 98;

[0811] (xviii) the second polypeptide chain comprises SEQ ID NO: 153, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 98;

[0812] (xix) the second polypeptide chain comprises SEQ ID NO: 157, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 158;

[0813] (xx) the second polypeptide chain comprises SEQ ID NO: 160, the fourth polypeptide chain comprises SEQ ID NO: 196, and the fifth polypeptide chain comprises SEQ ID NO: 158;

[0814] (xxi) the second polypeptide chain comprises SEQ ID NO: 164, the fourth polypeptide chain comprises SEQ ID NO: 197, and the fifth polypeptide chain comprises SEQ ID NO: 122; and

[0815] (xxii) the second polypeptide chain comprises SEQ ID NO: 178, the fourth polypeptide chain comprises SEQ ID NO: 196, and the fifth polypeptide chain comprises SEQ ID NO: 177;

[0816] (xxiii) the second polypeptide chain comprises SEQ ID NO: 179, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 177;

[0817] (xxiv) the second polypeptide chain comprises SEQ ID NO: 180, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 122;

[0818] (xxv) the second polypeptide chain comprises SEQ ID NO: 183, the fourth polypeptide chain comprises SEQ ID NO: 116, and the fifth polypeptide chain comprises SEQ ID NO: 177;

[0819] (xxvi) the second polypeptide chain comprises SEQ ID NO: 125, the fourth polypeptide chain comprises SEQ ID NO: 207, and the fifth polypeptide chain comprises SEQ ID NO: 122;

[0820] (xxvii) the second polypeptide chain comprises SEQ ID NO: 125, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122.

[0821] E554. The antibody of any one of E544 to E553, wherein the second polypeptide chain comprises SEQ ID NO: 130, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122.

[0822] E555. An isolated antibody that specifically binds IL-4 and specifically binds IL-13 and at least one additional target, comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein

[0823] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site;

[0824] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site;

[0825] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising at least one additional target binding site; and

[0826] wherein the second polypeptide chain comprises SEQ ID NO: 130, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122.

[0827] E556. An antibody comprising an antibody Fc domain, the antibody Fc domain comprising a first Fc chain and a second Fc chain, wherein the first Fc chain and the second Fc chain each contain two amino acid modifications that promote association of the first Fc chain with the second Fc chain, characterized in that

[0828] (i) the first Fc chain comprises D(H232)R and K(H440)R, and the second Fc chain comprises D(H232)E and L(H391)E; or

[0829] (ii) the first Fc chain comprises D(H232)E and K(H440)R, and the second Fc chain comprises L(H391)R and D(H232)E.

[0830] The antibody of E557.E556, wherein the first Fc chain comprises, in N-terminus to C-terminus, a first hinge region connected to a first CH2 region connected to a first CH3 region, and herein the second Fc chain comprises, in N-terminus to C-terminus, a second hinge region connected to a second CH2 region connected to a second CH3 region, and wherein the first hinge region and the second hinge region comprise a pair of sequences according to SEQ ID NO: 129 and SEQ ID NO: 131, and the first CH3 region and the second CH3 region comprise either of the following two pairs of sequences: SEQ ID NO: 124 and SEQ ID NO: 127; or SEQ ID NO: 147 and SEQ ID NO: 148.

[0831] E558. The antibody of any one of E556 to E557, further comprising an antibody of one or more of E1 to E71, E77 to E143, E144 to E193, E199 to E259, E265 to E330, E336 to E381, E387 to E435, E445 to E484 and E500 to E557.

[0832] E559. An isolated antibody comprising the CDRs of an antibody selected from one or more of Tables 80, 81, 82, 83, 84, 85, 86 and 87.

[0833] E560. An isolated antibody comprising the VH and VL of an antibody selected from one or more of Tables 80, 81, 82, 83, 84, 85, 86 and 87.

[0834] E561. An isolated antibody selected from one or more of Tables 80, 81, 82, 83, 84, 85, 86 and 87.

[0835] E562. An isolated polynucleotide comprising one or more nucleotide sequences encoding an antibody of any one of E1 to E71, E77 to E143, E144 to E193, E199 to E259, E265 to E330, E336 to E381, E387 to E435, E445 to E484 and E500 to E561.

[0836] E563. The polynucleotide of E562, wherein the polynucleotide is RNA.

[0837] E564. The polynucleotide of E562 to E563, wherein the polynucleotide comprises at least one chemical modification.

[0838] The polynucleotide of E565.E564, wherein the chemical modification is selected from pseudouridine, 1-methylpseudouridine, N1-methylpseudouridine, N1-ethylpseudouridine, 2-thiouridine, 4'-thiouridine, 5-methylcytosine, 2-thiol-1-methyl-1-deaza-pseudouridine, 2-thiol-1-methyl-pseudouridine, 2-thiol-5-aza-uridine, 2-thiol-dihydropseudouridine, 2-thiol-dihydrouridine, 2-thiol-pseudouridine, 4-methoxy-2-thiol-pseudouridine, 4-methoxy-pseudouridine, 4-thiol-1-methyl-pseudouridine, 4-thiol-pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methyluridine, 5-methoxyuridine and 2'-O-methyluridine.

[0839] E566. The polynucleotide of E562 to E563, wherein the polynucleotide does not comprise a chemical modification.

[0840] E567. An isolated polynucleotide encoding the VH, VL, or both of an antibody that binds to IL-33, wherein the nucleic acid comprises: the nucleic acid sequence of SEQ ID NO: 202, the nucleic acid sequence of SEQ ID NO: 203, or both.

[0841] E568. An isolated polynucleotide encoding a VH-carrying polypeptide and a VL-carrying polypeptide, or both, of an antibody that binds to IL-33, wherein the nucleic acid comprises the nucleic acid sequence of SEQ ID NO: 190, the nucleic acid sequence of SEQ ID NO: 191, or both.

[0842] E569. An isolated polynucleotide encoding the VH, VL, or both of an antibody that binds IL-33, wherein the nucleic acid comprises the nucleic acid sequence of an insert of a plasmid deposited with ATCC and having accession number PTA-127209, the nucleic acid sequence of an insert of a plasmid deposited with ATCC and having accession number PTA-127210, or both.

[0843] E570. An isolated polynucleotide encoding a VH-carrying polypeptide and a VL-carrying polypeptide, or both, of an antibody that binds IL-33, wherein the nucleic acid comprises the nucleic acid sequence of an insert of a plasmid deposited with ATCC and having accession number PTA-127207, the nucleic acid sequence of an insert of a plasmid deposited with ATCC and having accession number PTA-127208, or both.

[0844] E571. An isolated polynucleotide encoding the VH, VL, or both of an antibody that binds to TSLP, wherein the nucleic acid comprises: the nucleic acid sequence of SEQ ID NO: 204, the nucleic acid sequence of SEQ ID NO: 205, or both.

[0845] E572. An isolated polynucleotide encoding a VH-carrying polypeptide and a VL-carrying polypeptide, or both, of an antibody that binds to TSLP, wherein the nucleic acid comprises the nucleic acid sequence of SEQ ID NO: 192, the nucleic acid sequence of SEQ ID NO: 193, or both.

[0846] E573. An isolated polynucleotide encoding the VH, VL, or both of an antibody that binds to TSLP, wherein the nucleic acid comprises the nucleic acid sequence of an insert of a plasmid deposited with ATCC and having accession number PTA-127200, the nucleic acid sequence of an insert of a plasmid deposited with ATCC and having accession number PTA-127199, or both.

[0847] E574. An isolated polynucleotide encoding a VH-carrying polypeptide and a VL-carrying polypeptide, or both, of an antibody that binds to TSLP, wherein the nucleic acid comprises the nucleic acid sequence of an insert of a plasmid deposited with ATCC and having accession number PTA-127202, the nucleic acid sequence of an insert of a plasmid deposited with ATCC and having accession number PTA-127201, or both.

[0848] E575. An isolated polynucleotide encoding a VH-carrying polypeptide and a VL-carrying polypeptide, or both, of an antibody that binds to P40, wherein the nucleic acid comprises the nucleic acid sequence of SEQ ID NO: 194, the nucleic acid sequence of SEQ ID NO: 195, or both.

[0849] E576. An isolated polynucleotide encoding a VH-carrying polypeptide and a VL-carrying polypeptide, or both, of an antibody that binds to p40, wherein the nucleic acid comprises the nucleic acid sequence of an insert of a plasmid deposited with ATCC and having accession number PTA-127204, the nucleic acid sequence of an insert of a plasmid deposited with ATCC and having accession number PTA-127203, or both.

[0850] E577. An isolated polynucleotide encoding the VH, VL, or both of an antibody that binds to IL-4, wherein the nucleic acid comprises: the nucleic acid sequence of SEQ ID NO: 200, the nucleic acid sequence of SEQ ID NO: 201, or both.

[0851] E578. An isolated polynucleotide encoding a VH-carrying polypeptide and a VL-carrying polypeptide, or both, of an antibody that binds to IL-4, wherein the nucleic acid comprises the nucleic acid sequence of SEQ ID NO: 188, the nucleic acid sequence of SEQ ID NO: 189, or both.

[0852] E579. An isolated polynucleotide encoding the VH, VL, or both of an antibody that binds to IL-4, wherein the nucleic acid comprises the nucleic acid sequence of an insert of a plasmid deposited with ATCC and having accession number PTA-127198, the nucleic acid sequence of an insert of a plasmid deposited with ATCC and having accession number PTA-127197, or both.

[0853] E580. An isolated polynucleotide encoding a VH-carrying polypeptide and a VL-carrying polypeptide, or both, of an antibody that binds to IL-4, wherein the nucleic acid comprises the nucleic acid sequence of an insert of a plasmid deposited with ATCC and having accession number PTA-127192, the nucleic acid sequence of an insert of a plasmid deposited with ATCC and having accession number PTA-127194, or both.

[0854] E581. An isolated polynucleotide encoding the VH, VL, or both of an antibody that binds to IL-13, wherein the nucleic acid comprises: the nucleic acid sequence of SEQ ID NO: 196, the nucleic acid sequence of SEQ ID NO: 195, or both.

[0855] E582. An isolated polynucleotide encoding a VH-carrying polypeptide and a VL-carrying polypeptide, or both, of an antibody that binds IL-13, wherein the nucleic acid comprises the nucleic acid sequence of SEQ ID NO: 187, the nucleic acid sequence of SEQ ID NO: 188, or both.

[0856] E583. An isolated polynucleotide encoding the VH, VL, or both of an antibody that binds IL-13, wherein the nucleic acid comprises the nucleic acid sequence of an insert of a plasmid deposited with ATCC and having accession number PTA-127196, the nucleic acid sequence of an insert of a plasmid deposited with ATCC and having accession number PTA-127195, or both.

[0857] E584. An isolated polynucleotide encoding a VH-carrying polypeptide and a VL-carrying polypeptide, or both, of an antibody that binds IL-13, wherein the nucleic acid comprises the nucleic acid sequence of an insert of a plasmid deposited with ATCC and having accession number PTA-127193, the nucleic acid sequence of an insert of a plasmid deposited with ATCC and having accession number PTA-127192, or both.

[0858] E585. An isolated polynucleotide encoding one or more of the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide or the fifth polypeptide of an anti-IL-4 / IL-13 / IL-33 antibody, comprising

[0859] (i) the IL33-VH sequence encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127210, and the IL33-VL sequence encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127209;

[0860] (ii) the IL4-VH sequence encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127198, and the IL4-VL sequence encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127197; and

[0861] (iii) the IL13-VH sequence encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127196, and the IL13-VL sequence encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127195.

[0862] E586. An isolated polynucleotide encoding one or more of a first polypeptide, a second polypeptide, a third polypeptide, a fourth polypeptide, or a fifth polypeptide of an anti-IL-4 / IL-13 / IL-33 antibody, wherein the isolated antibody specifically binds to IL-33, specifically binds to IL-4, and specifically binds to IL-13, comprises a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein

[0863] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site;

[0864] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site;

[0865] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising an IL-33 binding site; and

[0866] wherein the first polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127208; the second polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127192; the third polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127207; the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127194; and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127193.

[0867] E587. An isolated polynucleotide encoding one or more of a first polypeptide, a second polypeptide, a third polypeptide, a fourth polypeptide, or a fifth polypeptide of an anti-IL-4 / IL-13 / TSLP antibody, wherein the antibody comprises

[0868] (i) the TSLP-VH sequence encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127200, and the TSLP-VL sequence encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA0-127199;

[0869] (ii) the IL4-VH sequence encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127198, and the IL4-VL sequence encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127197; and

[0870] (iii) the IL13-VH sequence encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127196, and the IL13-VL sequence encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127195.

[0871] E588. An isolated polynucleotide encoding one or more of a first polypeptide, a second polypeptide, a third polypeptide, a fourth polypeptide, or a fifth polypeptide of an anti-IL-4 / IL-13 / TSLP antibody, wherein the antibody comprises a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein

[0872] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site;

[0873] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site;

[0874] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a TSLP binding site, and

[0875] wherein the first polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127202; the second polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127192; the third polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127201; the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127194; and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127193.

[0876] E589. An isolated polynucleotide encoding one or more of a first polypeptide, a second polypeptide, a third polypeptide, a fourth polypeptide, or a fifth polypeptide of an anti-IL-4 / IL-13 / p40 antibody, wherein the antibody comprises

[0877] (i) the p40-VH sequence encoded by the plasmid deposited with ATCC and having ATCC Accession No. PTA-127206, and the p40-VL sequence encoded by the plasmid deposited with ATCC and having ATCC Accession No. PTA-127205;

[0878] (ii) the IL4-VH sequence encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127198, and the IL4-VL sequence encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127197; and

[0879] (iii) the IL13-VH sequence encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127196, and the IL13-VL sequence encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127195.

[0880] E590. An isolated polynucleotide encoding one or more of a first polypeptide, a second polypeptide, a third polypeptide, a fourth polypeptide, or a fifth polypeptide of an anti-IL-4 / IL-13 / p40 antibody, wherein the antibody comprises a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein

[0881] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site;

[0882] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site;

[0883] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a p40 binding site, and

[0884] wherein the first polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127204; the second polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127192; the third polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127203; the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127194; and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127193.

[0885] E591. A vector comprising the polynucleotides E562 to E590.

[0886] E592. An isolated host cell comprising the polynucleotides of E562 to E590 or the vector of E591.

[0887] E593. A method of producing an isolated antibody, comprising culturing a host cell of E592 under conditions that result in production of the antibody and recovering the antibody.

[0888] E594. A pharmaceutical composition comprising a therapeutically effective amount of an antibody of any one of E1 to E71, E77 to E143, E144 to E193, E199 to E259, E265 to E330, E336 to E381, E387 to E435, E445 to E484 and E500 to E557 and a pharmaceutically acceptable carrier.

[0889] E595. A method for producing a heterotrimeric antibody comprising a dual Fab arm and a single Fab arm, wherein the dual Fab arm comprises a first Fab domain connected to a second Fab domain connected to a first Fc domain, and the single Fab arm comprises a third Fab domain connected to the second Fc domain, and the method comprises

[0890] (i) a first preassembly step, wherein the bis-Fab arm is incubated in a first preassembly adjustment buffer at a temperature of 2°C to 10°C and wherein the pH of the first preassembly adjustment buffer is 1 to 3 units lower than the isoelectric point (pi) of the bis-Fab arm; and

[0891] (ii) a second preassembly step, wherein the single Fab arm is incubated in a second preassembly adjustment buffer at a temperature of 2°C to 10°C and wherein the pH of the second preassembly adjustment buffer is 1 to 3 units lower than the isoelectric point (pi) of the single Fab arm; and

[0892] (iii) a third assembly step, wherein the dual Fab arm and the single Fab arm from steps (i) and (ii) are mixed together in assembly buffer for 1 to 24 hours.

[0893] E596. An isolated antibody that specifically binds to TSLP, comprising the CDRs of an antibody selected from one or more of Tables 83, 84 and 87.

[0894] E597. An isolated antibody that specifically binds to TSLP, comprising the VH and VL of an antibody selected from one or more of Tables 83, 84 and 87.

[0895] E598. An isolated antibody that specifically binds to TSLP selected from one or more of Tables 83, 84 and 87.

[0896] E599. The antibody of any one of E381 to E384, wherein

[0897] (i) the TSLP binding domain comprises a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), wherein the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 82; the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 83; the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 85; the CDR-L1 comprises the amino acid sequence of SEQ ID NO: 86; the CDR-L2 comprises the amino acid sequence of SEQ ID NO: 87; and the CDR-L3 comprises the amino acid sequence of SEQ ID NO: 211; and

[0898] (ii) the IL-4 binding domain comprises a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL), wherein the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 18; the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2; the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 3; the CDR-L1 comprises the amino acid sequence of SEQ ID NO: 24; the CDR-L2 comprises the amino acid sequence of SEQ ID NO: 12; and the CDR-L3 comprises the amino acid sequence of SEQ ID NO: 25, and

[0899] (iii) the IL-13 binding domain comprises a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL), wherein the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 41; the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 42; the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 50; the CDR-L1 comprises the amino acid sequence of SEQ ID NO: 53; the CDR-L2 comprises the amino acid sequence of SEQ ID NO: 37; and the CDR-L3 comprises the amino acid sequence of SEQ ID NO: 38.

[0900] E600. The antibody of E387 to E390 or E599, wherein

[0901] (i) the TSLP binding portion comprises TSLP-VH of SEQ ID NO: 92 and TSLP-VL of SEQ ID NO: 213;

[0902] (ii) the IL-4 binding portion comprises IL4-VH of SEQ ID NO: 22 and IL4-VL of SEQ ID NO: 26; and

[0903] (iii) the IL-13 binding portion comprises IL13-VH of SEQ ID NO: 51 and IL13-VL of SEQ ID NO: 54.

[0904] E601. The antibody of E387 to E390 or E599 to E600, wherein

[0905] (i) The TSLP binding domain comprises a TSLP-VH sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127200, and a TSLP-VL sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-_____.

[0906] (ii) the IL-4 binding domain comprises an IL4-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC deposit number PTA-127198, and an IL4-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC deposit number PTA-127197; and

[0907] (iii) the IL-13 binding domain comprises the IL13-VH sequence encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127196, and the IL13-VL sequence encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127195.

[0908] E602. An isolated antibody that specifically binds to TSLP, specifically binds to IL-4, and specifically binds to IL-13, comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein

[0909] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site;

[0910] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site;

[0911] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a TSLP binding site; and

[0912] wherein the first polypeptide chain comprises SEQ ID NO: 165, the second polypeptide chain comprises SEQ ID NO: 130, the third polypeptide chain comprises SEQ ID NO: 215, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122.

[0913] E603. An isolated antibody that specifically binds to TSLP, specifically binds to IL-4, and specifically binds to IL-13, comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein

[0914] (iv) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site;

[0915] (v) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site;

[0916] (vi) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a TSLP binding site, and

[0917] wherein the first polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127202; the second polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127192; the third polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-_____; the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127194; and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127193.

[0918] E604. The antibody of any one of E381 to E390, wherein

[0919] (i) the TSLP binding domain comprises a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), wherein the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 82; the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 83; the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 85; the CDR-L1 comprises the amino acid sequence of SEQ ID NO: 86; the CDR-L2 comprises the amino acid sequence of SEQ ID NO: 87; and the CDR-L3 comprises the amino acid sequence of SEQ ID NO: 212; and

[0920] (ii) the IL-4 binding domain comprises a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL), wherein the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 18; the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2; the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 3; the CDR-L1 comprises the amino acid sequence of SEQ ID NO: 24; the CDR-L2 comprises the amino acid sequence of SEQ ID NO: 12; and the CDR-L3 comprises the amino acid sequence of SEQ ID NO: 25, and

[0921] (iii) the IL-13 binding domain comprises a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL), wherein the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 41; the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 42; the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 50; the CDR-L1 comprises the amino acid sequence of SEQ ID NO: 53; the CDR-L2 comprises the amino acid sequence of SEQ ID NO: 37; and the CDR-L3 comprises the amino acid sequence of SEQ ID NO: 38.

[0922] E605. The antibody of E387 to E390 or E604, wherein

[0923] (i) the TSLP binding portion comprises TSLP-VH of SEQ ID NO: 92 and TSLP-VL of SEQ ID NO: 214;

[0924] (ii) the IL-4 binding portion comprises IL4-VH of SEQ ID NO: 22 and IL4-VL of SEQ ID NO: 26; and

[0925] (iii) the IL-13 binding portion comprises IL13-VH of SEQ ID NO: 51 and IL13-VL of SEQ ID NO: 54.

[0926] E606. The antibody of E387 to E390 or E602 to E603, wherein

[0927] (i) The TSLP binding domain comprises a TSLP-VH sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127200, and a TSLP-VL sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA0-_____.

[0928] (ii) the IL-4 binding domain comprises an IL4-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC deposit number PTA-127198, and an IL4-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC deposit number PTA-127197; and

[0929] (iii) the IL-13 binding domain comprises the IL13-VH sequence encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127196, and the IL13-VL sequence encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127195.

[0930] E607. An isolated antibody that specifically binds to TSLP, specifically binds to IL-4, and specifically binds to IL-13, comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein

[0931] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site;

[0932] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site;

[0933] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a TSLP binding site; and

[0934] wherein the first polypeptide chain comprises SEQ ID NO: 165, the second polypeptide chain comprises SEQ ID NO: 130, the third polypeptide chain comprises SEQ ID NO: 216, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122.

[0935] E608. An isolated antibody that specifically binds to TSLP, specifically binds to IL-4, and specifically binds to IL-13, comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein

[0936] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site;

[0937] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site;

[0938] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a TSLP binding site, and

[0939] wherein the first polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127202; the second polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127192; the third polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-_____; the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127194; and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127193.

[0940] E609. The antibody of any one of E77 to E143 or E596 to E608 for use as a medicament.

[0941] The antibody of E610.E609, wherein the use is for treating one or more selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis and fungal keratitis.

[0942] E611. The antibody of any one of E147 to E148 or E596 to E610, wherein the use is for treating one or more selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata and non-alcoholic steatohepatitis (NASH).

[0943] E612. The antibody of any one of E147 to E149 or E596 to E611, wherein the use is for atopic dermatitis.

[0944] E613. The antibody of any one of E147 to E149 or E596 to E612, wherein the use is for non-alcoholic steatohepatitis (NASH).

[0945] E614. A pharmaceutical composition comprising a therapeutically effective amount of an antibody of E77 to E143 or E596 to E608 and a pharmaceutically acceptable carrier.

[0946] E615. A method of treating a medical condition comprising administering to a subject in need thereof a therapeutically effective amount of the antibody of any one of E77 to E143 or E596 to E608 or the pharmaceutical composition of E614.

[0947] E616. The method of E615, wherein the condition is selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, and fungal keratitis.

[0948] E617. The method of any one of E615 to E616, comprising administering the antibody or pharmaceutical composition subcutaneously.

[0949] E618. The method of any one of E615 to E617, wherein the antibody or pharmaceutical composition is administered about twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, twice a month, once a month, once every two months, once every three months, or once every four months.

[0950] E619. An antibody of any one of E1 to E71, E77 to E143, E144 to E193, E199 to E259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, E500 to E557, or E596 to E612 for use in inhibiting tumor growth.

[0951] E620. An antibody of any one of E1 to E71, E77 to E143, E144 to E193, E199 to E259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, E500 to E557, E596 to E612 or E619 for use in inhibiting the progression of malignant cell growth in a patient.

[0952] E621. An antibody of any one of E1 to E71, E77 to E143, E144 to E193, E199 to E259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, E500 to E557, E596 to E612, or E619 to E620, for use in inhibiting metastasis of malignant cells in a patient.

[0953] E622. An antibody of any one of E1 to E71, E77 to E143, E144 to E193, E199 to E259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, E500 to E557, E596 to E612, or E619 to E621, for use in inducing tumor regression in a patient.

[0954] E623. An antibody of any one of E1 to E71, E77 to E143, E144 to E193, E199 to E259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, E500 to E557, E596 to E612, or E619 to E622 for use in treating a cancer presenting with a solid tumor.

[0955] The antibody of any one of E624.E1 to E71, E77 to E143, E144 to E193, E199 to E259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, E500 to E557, E596 to E612, or E619 to E623, wherein the use is for the treatment of one or more selected from the group consisting of bladder cancer, breast cancer, clear cell renal carcinoma, head / neck squamous cell carcinoma, lung squamous cell carcinoma, malignant melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma carcinoma, small cell lung cancer (SCLC), triple-negative breast cancer, urothelial carcinoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin's lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL), or small lymphocytic lymphoma (SLL).

[0956] The antibody of any one of E625.E1 to E71, E77 to E143, E144 to E193, E199 to E259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, E500 to E557, E596 to E612 or E619 to E624, wherein the use is for the treatment of one or more selected from the group consisting of: renal cell carcinoma (RCC), bladder cancer, breast cancer, clear cell renal carcinoma, squamous cell carcinoma of the head / neck (SCCHN), squamous cell carcinoma of the lung, malignant melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, small cell lung cancer (SCLC) or triple-negative breast cancer.

[0957] The antibody of any one of E626.E1 to E71, E77 to E143, E144 to E193, E199 to E259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, E500 to E557, E596 to E612, or E619 to E625, wherein the use is for the treatment of one or more selected from heme malignancies, and in some embodiments, the heme malignancies are acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic Lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), EBV-positive DLBCL, primary mediastinal large B-cell lymphoma, T-cell / histiocyte-rich large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL), or small lymphocytic lymphoma (SLL).

[0958] E627. A method of treating cancer in a subject, comprising administering to the subject a combination therapy comprising a first anti-cancer therapeutic and a second anti-cancer therapeutic, wherein the first anti-cancer therapeutic is an antibody to one or more of IL-4, IL-13 and TSLP, and wherein the second anti-cancer therapeutic is selected from an anti-OX40 antibody, an anti-4-1BB antibody, an anti-HER2 antibody, a PD-1 pathway antagonist, an anti-PD-1 antibody, an anti-PD-L1 antibody, a TLR3 agonist, a TLR 7 / 8 agonist, a TLR9 agonist, a bispecific anti-CD47 / anti-PD-L1 antibody and a bispecific anti-P-cadherin / anti-CD3 antibody.

[0959] E628. The method of E627, wherein the first anti-cancer therapeutic comprises an anti-IL-4 antibody.

[0960] E629. The method of E627 to E628, wherein the first anti-cancer therapeutic comprises the anti-IL-4 antibody of any one of E199 to E259.

[0961] E630. The method of E627 to E631, wherein the first anti-cancer therapeutic comprises an anti-IL-13 antibody.

[0962] E631. The method of E627 to E630, wherein the first anti-cancer therapeutic comprises the anti-IL-13 antibody of any one of E265 to E330.

[0963] E632. The method of E627 to E631, wherein the first anti-cancer therapeutic comprises an anti-TSLP antibody.

[0964] E633. The method of E627 to E632, wherein the first anti-cancer therapeutic comprises the anti-TSLP antibody of any one of E77 to E143 or E596 to E598.

[0965] E634. The method of E627 to E633, wherein the first anti-cancer therapeutic comprises an IL-4 / IL-13 antibody.

[0966] E635. The method of E627 to E634, wherein the first anti-cancer therapeutic comprises an IL-4 / IL-13 antibody, and wherein the IL-4 / IL-13 antibody comprises the IL-4 / IL-13 antibody of any one of E526 to E558.

[0967] E636. The method of E627 to E635, wherein the first anti-cancer therapeutic comprises an IL-4 / IL-13 / TSLP antibody.

[0968] E637. The method of E627 to E636, wherein the first anti-cancer therapeutic comprises an IL-4 / IL-13 / TSLP antibody, and wherein the IL-4 / IL-13 / TSLP antibody comprises the antibody of any one of E387 to E435 or E599 to E613.

[0969] E638. The method of E627 to E637, wherein the first anti-cancer therapeutic comprises an IL-4 / IL-13 / TSLP antibody, and wherein the IL-4 / IL-13 / TSLP antibody comprises the antibody of any one of E412.

[0970] E639. The method of E627 to E637, wherein the first anti-cancer therapeutic comprises an IL-4 / IL-13 / TSLP antibody, and wherein the IL-4 / IL-13 / TSLP antibody comprises the antibody of any one of E603.

[0971] E640. The method of E627 to E637, wherein the first anti-cancer therapeutic comprises an IL-4 / IL-13 / TSLP antibody, and wherein the IL-4 / IL-13 / TSLP antibody comprises the antibody of any one of E607.

[0972] E641. The method of E627 to E640, wherein the second anti-cancer therapeutic agent is a PD-1 pathway antagonist.

[0973] E642. The method of E627 to E641, wherein the second anti-cancer therapeutic agent is a PD-1 antagonist.

[0974] The method of E643.E627 to E642, wherein the second anticancer therapeutic agent is a PD-1 antagonist, and the PD-1 antagonist is selected from: sasanlimab, BCD-100, camrelizumab, cemiplimab, genolimzumab, MEDI0680, nivolumab, pembrolizumab, sintilimab, spartalizumab, STI-A1110, tislelizumab, atezolizumab, durvalumab, BMS-936559 (MDX-1105), LY3300054, TSR-042.

[0975] E644. The method of E627 to E643, wherein the second anti-cancer therapeutic agent is a PD-1 antagonist, and the PD-1 antagonist is an antibody comprising the VH shown in SEQ ID NO: 4 and the VL shown in SEQ ID NO: 8 of US10155037.

[0976] E644. The method of E627 to E643, wherein the second anti-cancer therapeutic is a PD-1 antagonist, and the PD-1 antagonist is sazanalizumab.

[0977] E645. The method of E627 to E646, wherein the second anticancer agent is a PD-1 antagonist, and the PD-1 antagonist is sazanlimab, and is an antibody comprising a HC and a light chain, the HC comprising a sequence according to SEQ ID NO: 225, and the light chain comprising a sequence according to SEQ ID NO: 226.

[0978] E646. A method of treating cancer in a subject, comprising administering to the subject a combination therapy comprising a first anti-cancer therapeutic and a second anti-cancer therapeutic, wherein the first anti-cancer therapeutic is the IL-4 / IL-13 / TSLP antibody of E412 and the second anti-cancer therapeutic is a PD-1 antagonist antibody comprising a HC and a light chain, the HC comprising a sequence according to SEQ ID NO: 225, and the light chain comprising a sequence according to SEQ ID NO: 226.

[0979] E647. A method of treating cancer in a subject, comprising administering to the subject a combination therapy comprising a first anti-cancer therapeutic and a second anti-cancer therapeutic, wherein the first anti-cancer therapeutic is the IL-4 / IL-13 / TSLP antibody of E603 and the second anti-cancer therapeutic is a PD-1 antagonist antibody comprising a HC and a light chain, the HC comprising a sequence according to SEQ ID NO: 225, the light chain comprising a sequence according to SEQ ID NO: 226.

[0980] E648. A method of treating cancer in a subject, comprising administering to the subject a combination therapy comprising a first anti-cancer therapeutic and a second anti-cancer therapeutic, wherein the first anti-cancer therapeutic is the IL-4 / IL-13 / TSLP antibody of E607 and the second anti-cancer therapeutic is a PD-1 antagonist antibody comprising a HC and a light chain, the HC comprising a sequence according to SEQ ID NO: 225, and the light chain comprising a sequence according to SEQ ID NO: 226.

[0981] E649. A medicament comprising a first anticancer agent and a second anticancer agent, wherein the first anticancer therapeutic agent is the IL-4 / IL-13 / TSLP antibody of E412, and the second anticancer therapeutic agent is a PD-1 antagonist antibody comprising a HC and a light chain, the HC comprising a sequence according to SEQ ID NO: 225, and the light chain comprising a sequence according to SEQ ID NO: 226.

[0982] E649. A medicament comprising a first anticancer agent and a second anticancer agent, wherein the first anticancer therapeutic agent is the IL-4 / IL-13 / TSLP antibody of E603, and the second anticancer therapeutic agent is a PD-1 antagonist antibody comprising a HC and a light chain, the HC comprising a sequence according to SEQ ID NO: 225, and the light chain comprising a sequence according to SEQ ID NO: 226.

[0983] E649. A medicament comprising a first anticancer agent and a second anticancer agent, wherein the first anticancer therapeutic agent is the IL-4 / IL-13 / TSLP antibody of E607, and the second anticancer therapeutic agent is a PD-1 antagonist antibody comprising a HC and a light chain, the HC comprising a sequence according to SEQ ID NO: 225, and the light chain comprising a sequence according to SEQ ID NO: 226.

[0984] E650. The method or medicament as described in any one of E627 to E649, wherein the cancer presents as a solid tumor.

[0985] E651. The method or medicament as described in any one of E627 to E650, wherein the cancer is selected from one or more of the following: bladder cancer, breast cancer, clear cell renal carcinoma, head / neck squamous cell carcinoma, lung squamous cell carcinoma, malignant melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, small cell lung cancer (SCLC), triple-negative breast cancer, urothelial carcinoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin's lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL) or small lymphocytic lymphoma (SLL).

[0986] E652. The method or medicament as described in any one of E627 to E651, wherein the cancer is selected from one or more of the following: renal cell carcinoma (RCC), bladder cancer, breast cancer, clear cell renal carcinoma, head / neck squamous cell carcinoma (SCCHN), lung squamous cell carcinoma, malignant melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, small cell lung cancer (SCLC) or triple-negative breast cancer.

[0987] E653. The method or medicament as described in any one of E627 to E652, wherein the cancer is one or more selected from heme malignancies, and in some embodiments, the heme malignancies are acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), EBV-positive DLBCL, primary mediastinal large B-cell lymphoma, T cell / histiocyte-rich large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL) or small lymphocytic lymphoma (SLL).

[0988] E654. The antibody, method or medicament for use as described in any one of E1 to E653, wherein at least one of the therapeutic agents is administered to the subject at an interval of once a day, once every two days, once every three days, once a week, once every two weeks, once every three weeks, once every four weeks, once every 30 days, once every five weeks, once every six weeks, once a month, once every two months, once every three months or once every four months.

[0989] Use of any one of the antibodies E656.E1 to E71, E77 to E143, E144 to E193, E199 to E259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, E500 to E557, E596 to E612, or E619 to E625 for the manufacture of a medicament for treating one or more of: atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata , nonalcoholic steatohepatitis (NASH), prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, fungal keratitis, bladder cancer, breast cancer, clear cell renal cell carcinoma, head / neck squamous cell carcinoma, lung squamous cell carcinoma, malignant melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, small cell lung cancer (SCLC), triple-negative breast cancer, urothelial carcinoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic CLL, CML, Diffuse Large B-Cell Lymphoma (DLBCL), Follicular Lymphoma, Hodgkin's Lymphoma (HL), Mantle Cell Lymphoma (MCL), Multiple Myeloma (MM), Myeloid Cell Leukemia-1 Protein (Mcl-1), Myelodysplastic Syndrome (MDS), Non-Hodgkin's Lymphoma (NHL) or Small Lymphocytic Lymphoma (SLL), Heme Malignancies, Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Lymphocytic Leukemia (CLL), The following are listed as potential targets for this indication: chronic myeloid leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), EBV-positive DLBCL, primary mediastinal large B-cell lymphoma, T-cell / histiocyte-rich large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL), and small lymphocytic lymphoma (SLL).

[0990] E657. A pharmaceutical composition for treating one or more of the following: atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, nonalcoholic steatohepatitis (NASH), prurigo nodularis, keloid, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, fungal keratitis, bladder cancer, breast cancer, clear cell renal carcinoma, head / neck squamous cell carcinoma, lung squamous cell carcinoma, malignant melanoma, non-small cell lung cancer (NSCLC) ), ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, small cell lung cancer (SCLC), triple-negative breast cancer, urothelial carcinoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin's lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), DS), non-Hodgkin's lymphoma (NHL) or small lymphocytic lymphoma (SLL), heme malignancies, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), EBV-positive DLBCL, primary mediastinal large B-cell lymphoma, T cell / histiocyte-rich large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma (HL), mantle cell lymphoma (MCL), Multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL) and small lymphocytic lymphoma (SLL), the pharmaceutical composition comprises an antibody of any one of E1 to E71, E77 to E143, E144 to E193, E199 to E259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, E500 to E557, E596 to E612 or E619 to E625.

[0991] E658. An anti-disease agent comprising an antibody of any one of E1 to E71, E77 to E143, E144 to E193, E199 to E259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, E500 to E557, E596 to E612, or E619 to E625, wherein the disease is one or more selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, Alopecia areata, non-alcoholic steatohepatitis (NASH), prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, fungal keratitis, bladder cancer, breast cancer, clear cell renal cell carcinoma, head / neck squamous cell carcinoma, lung squamous cell carcinoma, malignant melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, small cell lung cancer (SCLC), triple-negative breast cancer, urothelial carcinoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), CLL, CML, Diffuse Large B-Cell Lymphoma (DLBCL), Follicular Lymphoma, Hodgkin's Lymphoma (HL), Mantle Cell Lymphoma (MCL), Multiple Myeloma (MM), Myeloid Cell Leukemia-1 Protein (Mcl-1), Myelodysplastic Syndrome (MDS), Non-Hodgkin's Lymphoma (NHL) or Small Lymphocytic Lymphoma (SLL), Heme Malignancies, Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Lymphoma The patients were classified as follows: CLL, chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), EBV-positive DLBCL, primary mediastinal large B-cell lymphoma, T-cell / histiocyte-rich large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL), and small lymphocytic lymphoma (SLL).

[0992] BRIEF DESCRIPTION OF THE DRAWINGS

[0993] Figure 1ADepicted are exemplary sequences illustrating the Pfabat numbering of the light chain portions of anti-IL-13 and anti-IL-4 binding arms. Position names appear vertically in a single row, and dashes ("-") indicate gaps in alignment. For example, residue L27D of anti-IL-13 CDR-L1 is His, and the equivalent residue in the anti-IL-4 binding arm is Glu. Positions considered as part of a CDR are shown in bold text, and the corresponding amino acids are bolded and underlined.

[0994] Figure 1B Depicted are exemplary sequences showing the Pfabat numbering of the heavy chain portions of the anti-IL-13, anti-IL-4, and anti-IL-33 binding arms. Position names appear vertically in a single row, and dashes ("-") indicate gaps in the alignment. For example, residue H100C of the anti-IL-4 CDR-L1 is Phe, and the anti-IL-13 binding arm with the shorter CDRH3 has no corresponding residue. Positions considered to be part of the CDR are shown in bold text, and the corresponding amino acids are bolded and underlined. The anti-IL-13 heavy chain fragments used in most multispecific antibody sequences do not contain a complete hinge or Fc. The Pfabat algorithm numbers the sequences as separate Fab domains and does not number the small upper hinge fragment ("EPKSC" (SEQ ID NO: 102)), although it is manually included here (lowercase letters, positions H226-H230) for reference.

[0995] Figure 2 Depicted is a diagram summarizing the results of LC / MS analysis of the IL4-1285 antibody. It was revealed that the post-translational modification is located on the light chain. Mass spectrometry analysis of peak 1 (P1) relative to peak 2 (P2) showed an 80 Dalton (Da) substance, with a mass of 23755.0 Da present in P2. P1 refers to the "main peak" substance that was separated when analyzed by the ion exchange purification method and also detected by using light chain LC / MS analysis (after LysC+TCEP). P2 refers to "peak 2" that was separated by the ion exchange purification method and also detected by using light chain LC / MS analysis (after LysC+TCEP). Peak 2 has additional sulfation on Tyr (L27a), so it has an 80 Da shift in MS.

[0996] Figure 3 Depicted are graphs comparing LC / MS analysis of IL4-1346 (hu3B9-VLv2.8) [lower two graphs] and IL4-1285 (hu3B9-VLv2.0) antibody light chains [upper two graphs]. Light chain CDR1 peptide (DRVTITCKASQSVD Y ) were identified by LC / MS analysis and Y(L27d) F mutation removes heterogeneity. The left figure at top and bottom is peptide level illustrative plate data (AspN enzyme). The right figure at top and bottom is the subunit using LysC method. Peptide spectrum (AspN digestion) is presented in the upper left spectrum, and wherein DFD light chain does not contain sulfation and DYD light chain does have some sulfation (+79.9568Da). Subunit analysis shows that DFD light chain does not have sulfation substance (upper right spectrum) and DYD light chain has some sulfation Da substances (lower right spectrum).

[0997] Figure 4 Depicted are changes incorporated into the IL4-1359 (VH1 G07_VLv2.9) VH CDRH1 that contribute to improved affinity for IL-4.

[0998] Figure 5 Depicted are changes at Tyr(L27d)E that may be made to remove the O-sulfation post-translational modification and further stabilize the IL-4 / IL4-1285 (RA1-2 or hu3B9-VLv2.0) interface.

[0999] Figure 6 Depicted is an alignment of the IL-13 complex demonstrating the binding orientation of IL13-1283 (IMA-638 or hu13.2) relative to IL13-1307 (hu13.4).

[1000] Figure 7 Depicted are CDRL1 differences in IL13-1307 (hu13.4) relative to IL13-1283 (IMA-638 or hu13.2) that contribute to the increased affinity for human IL-13.

[1001] Figure 8 Depicted are CDRH3 amino acid differences between IL13-1307 (hu13.4) and IL13-1283 (IMA-638 or hu13.2) that contribute to the improved affinity for IL-13.

[1002] Figure 9 Depicted is how the presence of serine at residue 30 in IL13-1307 (hu13.4) CDRH1 contributes to increased affinity for IL-13 relative to IL13-1283 (IMA-638 or hu13.2).

[1003] Figure 10 Depicted is how the aspartic acid at position 55 in the CDRH2 of IL13-1307 (hu13.4), but not the glycine at this position in IL13-1283, contributes to increased affinity for IL-13 relative to IL13-1283 (IMA-638 or hu13.2).

[1004] Figure 11 Depicted is how changes incorporated into the IL13-0001 (1RVHC9-VLA4) VH CDRH3 contribute to improved affinity for IL-13.

[1005] Figure 12 Depicted is how changes incorporated into IL13-0001 (1RVHC9-VLA4) VL CDRL1 contribute to improved affinity for IL-13.

[1006] Figure 13 Depicted are graphs showing how increased efficacy of IL-33 neutralization correlates with increased polyresponsiveness.

[1007] Figure 14 depicts a high throughput off-rate screen of anti-TSLP variants. Figure 14A Figure 2: Dissociation rate screening sensor plot. R represents the response (nM). t0, t240, and t640 represent time points. Association index = sample (Rt240 - Rt0) / TSLP-0001 (Rt240 - Rt0). Dissociation index = sample (Rt640 - Rt240) / TSLP-0001 (Rt640 - Rt240). Figure 14B : Spotfire plot of association index and dissociation index. Variants inside the squares are hits that meet the selection criteria.

[1008] Figure 15 Depicts the electrostatic surface map of the TSLP-0260Fv region. Electrostatic surface maps were determined using a Poisson Boltzmann calculator (Delphi). Here, positive charge potentials are shown in white and negative charge potentials in black. The areas of focus for reducing viscosity are the negatively charged patches outlined by the black dotted circles. These three patches contain a portion of the CDRs L1-L2, L3-H2-H3, and H2, respectively.

[1009] Figure 16 Details of the antibody:TSLP interface are depicted. The VH-E99Y mutation potentially introduces a new hydrogen-bonding network at the TSLP-Ab interface. Selected interface residues are labeled and shown as sticks. N71 and R149 are from TSLP. Dashed lines represent salt bridges and hydrogen bonds. Light grey with α-helical structure: TSLP. Dark grey: Antibody. This also increases overall packing.

[1010] Figure 17 Depicted is a graph showing viscosity analysis of anti-TSLP variants. Viscosity was measured by a DLS bead-based method.

[1011] Figure 18A 、 Figure 18B 、 Figure 18C 、 Figure 18D 、 Figure 18E 、 Figure 18F 、 Figure 18G 、 Figure 18H and Figure 18I Depicted is a general schematic diagram and nomenclature of trispecific Tri-Fab-Fc and Fab domains. Figure 18A Depicted is a schematic diagram of Tri-Fab-Fc showing that domains Fab1, Fab2 and Fab3 and single Fab (SFab) and double Fab (DFab) arms are expressed in separate cells. Figure 18: Depicted is a schematic diagram of a conventional Fab. Figure 18C A schematic diagram of the modified Fd is depicted. Figure 18D A schematic diagram of VH-VL swapping is depicted. Figure 18E A schematic diagram of S1 is depicted. Figure 18F A schematic diagram of S1Rev is depicted. Figure 18G A schematic diagram of CH-Ck exchange is depicted. Figure 18H A schematic diagram of the CH-Cl exchange is depicted. Figure 18 depicts an exploded view of Tri-Fab-Fc, indicating the individual protein chains: SFab HC (3) and SFab LC (3) chains, which together make up the SFab arm; and DFab LC (1)-HC (2), modified Fd (1), and DFab LC (2) chains, which together make up the DFab arm. Note: VL represents the light chain variable domain; VH represents the heavy chain variable domain; Ck represents the kappa constant light chain domain, Cl represents the lambda constant light chain domain; CH1 represents the heavy chain constant domain 1. EPKSC (SEQ ID NO: 102): A stretch of amino acids from the hinge region of IgG1 is fused to the C-terminus of CH1, forming a disulfide bond with CL (Fab1).

[1012] Figure 19 depicts the configuration and features of Tri-Fab-Fc with native chain pairing in the Fab1 position. Figure 19A and Figure 19B Depicted are the configurations of two native chain-pairing Tri-Fab-Fc variants, in which all three Fabs have conventional chain pairing. S1: S1 mutation on CH1 / CK. S1rev: S1rev mutation on CH1 / CK. Positively charged (+) mutations are solid black circles. Negatively charged (+) mutations are dashed black circles. Figure 19C Depicted are graphs showing analytical SEC of IL413TSLP-0003 and IL413TSLP-0004 after Mab Select SuRe elution and after prepSEC superdex 200 purification. Figure 19D and Figure 19EDepicted are graphs showing LCMS analysis of IL413TSLP-0003 and IL413TSLP-0004, respectively. The table lists each chain of the trispecific and the corresponding theoretical chain mass. A number from 1 to 5 is placed in front of each chain to provide a shorthand description of the chain composition of the major peak in LCMS.

[1013] Figure 20A 、 Figure 20B 、 Figure 20C 、 Figure 20D 、 Figure 20E and Figure 20F Depicted is a sketch showing the configuration of CλS, CκS, and VDS Tri-Fab-Fc variants, in which the Fab1 domain (anti-TSLP) contains the C1 domain fused to the C-terminus of the VH1 domain, and the CH1 domain fused to the C-terminus of the VL1 domain. Figure 20A ) and IL413TSLP-0002( Figure 20B ) has a Fab1 light chain with structures VL-CH1 and VH-Cl at the N-terminus of the double Fab arm. Figure 20C ) and IL413TSLP-0008( Figure 20D ) has Fab1 Vl-CH1 and VH-Cl Fab1 light chains at the N-terminus of the dual Fab chains. Figure 20E ) shows a CkS configuration with Fab1 and Fab3 carrying S1 and S1 rev mutations, respectively, Fab2 containing a VL-CH1 structure and VH-CL fused to the N-terminus of Fc. Figure 20F ) shows a CkS configuration with Fab1 and Fab3 carrying S1 and S1 rev mutations, respectively, Fab2 containing a VL-CH1 structure including an SS elbow between the VL and CH1 domains, and VH-CL fused to the N-terminus of the Fc.

[1014] Figure 21 Depicted is a graph showing the effect of domain geometry on Tri-Fab-Fc binding activity assessed by bridging ELISA. TPP-9662 is an IL-4 / IL-13 bispecific antibody with S1 / S1rev and KiH. mab8.8 is a negative control antibody.

[1015] FIG22 depicts improvement of Tri-Fab-Fc chain pairing by adjusting DNA ratios in transient transfection. Figure 22A Depicted is a NuPAGE Bis-tris gel analysis. R: reducing. NR: non-reducing. Figure 22B Depicted are graphs showing aSEC analysis.

[1016] Figure 23 depicts a schematic of a Tri-Fab-Fc variant engineered using modified Fd formats and S1 / S1rev complementing mutations.

[1017] Figure 24 Depicted are non-reducing and reducing stain free SDS-PAGE analysis of stable CHO produced Tri-Fab-Fc.

[1018] Figure 25 depicts a schematic representation of a representative Tri-Fab-Fc trispecific configuration using charge-based heterodimerization, Fab1 paired with either CκS or mFd. RRR or EEE charge mutations: two RR / EE in the hinge region and one R / E in CH3. The anti-IL-13 domain was designed as either CκS (exemplified by IL413TSLP-0251) or mFd (exemplified by IL413TSLP-0252).

[1019] Figure 26 Depicted is a draft of the anti-IL-13 / IL-4 dual Fab EEE arm design, with the anti-IL-13 domain as the mFd at the Fab1 position and the anti-IL-4 domain at the Fab2 position.

[1020] Figure 27 Depicted is a draft of the anti-IL-13 / IL-4 dual Fab EEE arm design, with the anti-IL-4 binding domain as the mFd at the Fab1 position and the anti-IL-13 domain at the Fab2 position.

[1021] Figure 28 depicts a sketch of the anti-IL-13 / IL-4 dual Fab EEE arm design with CKS at the Fab 1 position.

[1022] Figure 29 depicts a graph showing that Tri-Fab-Fc IL13433-0006 can simultaneously bind human IL-4, IL-13, and IL-33.

[1023] Figure 30 Depicted are SPR sensorgrams of IL413p40-0705 and human IL-4, IL-13, and IL-23 injected in various orders.

[1024] Figure 31 depicts a dual-cell design Tri-Fab-Fc variant with mFd format and S1-S1rev complementing mutations.

[1025] Figure 32 Depicted are Tri-Fab-Fc engineered with a modified Fd format and produced using a single-cell process.

[1026] Figure 33Depicted is a graph showing the viscosity of IL413p40-0698 and IL413p40-0700 measured by differential light scattering (DLS).

[1027] Figure 34 Depicts anti-IL-4 / 13 / 33 Tri-Fab-Fc IV pharmacokinetics in Tg32 mice. Antibody names are abbreviated to their four-digit references as follows: 1042 refers to IL13433-1042, 1258 refers to IL13433-1258, 1261 refers to IL13433-1261, 1270 refers to IL13433-1270, 1275 refers to IL13433-1275, and anti-IL-33 Ab LS refers to IL33-0232 VH and VL, wherein the Fc domain further comprises LS mutations as described herein.

[1028] Figure 35 depicts a graph showing binding of trispecifics to human, cynomolgus monkey, mouse, and rat IL-4 by surface plasmon resonance. Trispecifics: (A) IL13433-1258, (B) IL413TSLP-1024, (C) IL413P40-0705 were immobilized on a CM5 sensor chip, and binding of 200 nM human (hu), cynomolgus monkey (cy), mouse (mu), rabbit (rb), or rat (rt) IL-4 was measured by surface plasmon resonance.

[1029] Figure 36 depicts a graph showing binding of trispecifics to human, cynomolgus monkey, mouse, and rat IL-13 by surface plasmon resonance. Trispecifics: (A) IL13433-1258, (B) IL413TSLP-1024, (C) IL413P40-0705 were immobilized on a CM5 sensor chip, and binding of 200 nM human (hu), cynomolgus monkey (cy), mouse (mu), rabbit (rb), or rat (rt) IL-13 was measured by surface plasmon resonance.

[1030] Figure 37 Figure 2 is a schematic depicting the different Fab positions within the Tri-Fab-Fc construct with a modified Fd (mFd) design.

[1031] Figure 38 Depicted are the SPR sensor profiles of Tri-Fab-Fc IL413p40-0705 with human (hu), cynomolgus monkey (cy), mouse (mu), rat (rt), and rabbit (rb) IL-12, IL-23, IL-4, and IL-13.

[1032] Figure 39Depicted are graphs showing species specificity of IL-33 binding to the trispecific IL13433-1258 by surface plasmon resonance.

[1033] Figure 40 Depicted are graphs showing binding of short and long forms of TSLP to TSLP-0001, mAb TSLP-0875, and the trispecific IL413 TSLP-1024 by surface plasmon resonance.

[1034] Figure 41 Depicted is a diagram showing the biological activity of short and long forms of TSLP in inducing monocyte TARC production. Monocytes isolated from human peripheral blood were incubated overnight at 37°C with 0.31pg / mL-20ng / ml recombinant human TSLP (Pfizer), short form TSLP (TSLPlf Avi V5 His 10 biotin) or long form TSLP (TSLPlf Avi V5 His 10 biotin). TARC production in the cell supernatant was quantified by MSD. Data are presented as mean ± SD. The EC50 values ​​for hTSLP, sfTSLP, and lfTSLP were 0.3680, N / A, and 7.472ng / mL, respectively.

[1035] Figure 42 Depicted is a graph showing binding of human, cynomolgus monkey, mouse, and rat TSLP to the trispecific IL413TSLP-1024 by surface plasmon resonance. Biotinylated human (hu), cynomolgus monkey (cy), mouse (mu), or rat (rt) TSLP was captured on a biotin CAP sensor chip, and binding of the IL413TSLP-1024 trispecific was determined by surface plasmon resonance.

[1036] Figure 43 Depicted are graphs showing simultaneous binding of IL-4, IL-13, and TSLP to IL413TSLP-1024 by surface plasmon resonance.

[1037] Figure 44 depicts a graph showing mean CT26 tumor volume over time and at the end of the study. Results of a study in which Balb / c mice bearing CT26 tumors were dosed with the compounds listed in Table 88. (A) Mean volume (mm3) and standard error of the mean of implanted tumors over time for each treatment group, starting on day 9 (first day of drug injection). (B) Volume (mm3) of implanted tumors on day 22 post-implantation (last day of the study). The bars and whiskers represent the mean and standard deviation for each treatment group. Each point represents the final tumor volume for each mouse in that treatment group. Treatment with anti-PD-1 antibody, anti-IL-4 antibody plus mIL13Ra2-mFc, or anti-IL-4 antibody plus mIL13Ra2-mFc plus anti-PD-1 antibody did not significantly alter tumor growth characteristics compared to isotype-treated animals. In contrast, mice treated with anti-IL-4 plus anti-TSLP antibody plus mIL13Ra2-mFc (40% tumor growth inhibition, p = 0.043) or anti-IL-4 plus anti-TSLP plus anti-PD-1 antibody plus mIL13Ra2-mFc (54% tumor growth inhibition, p = 0.002) exhibited significant tumor growth inhibition relative to the isotype.

[1038] Figure 45 Depicted is a graph showing the volume of CT26 tumors over time for each mouse in each treatment group. Volume (in mm3) of subcutaneously implanted CT26 tumors over time for individual mice in each treatment group starting on day 9 (first day of drug injection).

[1039] Figure 46 depicts graphs showing that neutralization of IL-4 with mAb IL4-1040 or TSLP with mAb TSLP-0875 inhibits interferon gamma secretion by primary human tumor-reactive T cells. Interferon gamma secretion from primary A375-reactive human T cells polarized and restimulated with the treatments listed in Table 2 as described in Example 87. (A) shows interferon gamma secretion from six different donors tested over multiple days. T cells were polarized and restimulated with isotype antibody alone, isotype antibody and 0.8 ng / mL recombinant human IL-4, or mAb IL4-1040 and 0.8 ng / mL recombinant human IL-4. (B) shows interferon gamma secretion from the same six donors as in (A) that were polarized and restimulated with isotype antibody, isotype antibody and 0.8 ng / mL recombinant human TSLP, or mAb TSLP-0875 and 0.8 ng / mL recombinant human TSLP. Data in (A and B) are presented as mean and standard deviation. Statistical tests in (A and B) are ANOVA, and the data shown above the bars are from post hoc P value for multiple comparison test.

[1040] Figure 47 depicts a graph showing that neutralization of IL-4 with mAb IL4-1040 and / or TSLP with mAb TSLP-0875 improves T cell-mediated control of human A375 cancer cell growth in vitro, which correlates with interferon gamma secretion. Primary human T cells were polarized and restimulated as described in Example 87. Growth curves of A375 tumor cells during T cell restimulation were generated as described in Example 88. (A) Primary human T cells were polarized and restimulated with: (A) isotype antibody alone, isotype antibody and 0.8 ng / mL recombinant human IL-4, or mAb IL4-1040 and 0.8 ng / mL recombinant human IL-4; (B) isotype antibody alone, isotype antibody and 0.8 ng / mL recombinant human TSLP, or mAb TSLP-0875 and 0.8 ng / mL recombinant human TSLP; (C) isotype antibody alone, isotype antibody and 0.8 ng / mL each of recombinant human IL-4 and TSLP, or mAb 1040, mAb and 0.8 ng / mL each of recombinant human IL-4 and TSLP. (D) Interferon gamma was quantified in conditioned media collected on day 5 of restimulation as described in Example 87. The level of secreted interferon gamma was correlated with the normalized A375 AUC from the same wells. (A-C) Data from donor 1923 and (D) from donor 8385. The data in (AC) are presented as the mean and standard deviation of six technical replicates and illustrate data from three different donors. The data in (D) are presented as the mean of six technical replicates and illustrate data from four donors.

[1041] Figure 48 Depicted is a graph showing that recombinant human IL-4 or a combination of IL-4 and TSLP reduces the frequency of A375 polarized primary human CD8 T cells expressing both perforin and granzyme B. The proportion of A375 polarized CD8 T cells expressing both perforin and granzyme B was determined by flow cytometry as described in Example 89. Data are presented as the mean and standard deviation of three technical replicates and represent data from two different donors.

[1042] Figure 49 depicts a graph showing the neutralization of IL4- and IL13-induced CCL17 secretion from the human clear cell renal cell carcinoma cell line 769-P by trispecific IL413TSLP-1028 and IL413TSLP-1037. 769-P human clear cell renal cell carcinoma cells were incubated with recombinant human IL-4 (A) or IL-13 (B) along with dilutions of trispecific IL413TSLP-1028 or IL413TSLP-1037 at 37°C for approximately 20 hours. CCL17 secretion was quantified by Legendplex and concentrations were extrapolated from the standard curve.

[1043] Detailed description

[1044] Provided herein are antibodies that specifically bind to IL-4, antibodies that specifically bind to IL-13, antibodies that specifically bind to IL-33, antibodies that specifically bind to TSLP, and multispecific antibodies that specifically bind to IL-4 and IL-13, along with one of IL-33, TSLP, and p40. Also provided herein are related nucleic acids, compositions, and methods of making and using the antibodies.

[1045] General techniques

[1046] All references (including patent applications, patent publications, UniProtKB accession numbers) cited herein are hereby incorporated by reference to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference in its entirety.

[1047] The techniques and procedures described or referred to herein are generally well understood by those skilled in the art and are routinely employed using conventional methods, such as the widely used methods described in Sambrook et al., Molecular Cloning: A Laboratory Manual 3rd edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY CURRENT PROTOCOLS IN MOLECULAR BIOLOGY (FM Ausubel et al. eds., (2003)); METHODS IN ENZYMOLOGY (Academic Press, Inc.): PCR 2: A PRACTICAL APROACH (MJ MacPherson, BD Hames and GR Taylor eds. (1995)), Harlow and Lane, eds. (1988) ANTIBODIES, A LABORATORY MANUAL, and ANIMAL CELL CULTURE (RI Freshney, ed. (1987)); Oligonucleotide Synthesis (MJGait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (JECellis, ed., 1998) Academic Press; Animal Cell Culture (RI Freshney), ed., 1987); Introduction to Cell and Tissue Culture (JPMather and PERoberts, 1998) Plenum Press; Cell and Tissue Culture Laboratory Procedures (A.Doyle, JBGriffiths, and DGNewell, eds., 1993-8) J.Wiley and Sons; Handbook of Experimental Immunology (DMWeir and CCBlackwell, eds); Gene Transfer Vectors for Mammalian Cells (JMMiller and MPCalos, eds., 1987); PCR: The PolymeraseChain Reaction, (Mullis et al., eds., 1994); Current Protocols in Immunology (JEColigan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (CA Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: A Practical Approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999)); The Antibodies (M. Zanetti and JD Capra, eds., Harwood Academic Publishers, 1995); and updated editions.

[1048] definition

[1049] Unless otherwise defined, all technical terms, symbols, and other scientific terms or terminology used herein are intended to have the meanings commonly understood by those skilled in the art to which the present invention relates. For example, the term "and / or" used herein in phrases such as "A and / or B" is intended to include A and B; A or B, A (alone); and B (alone). Similarly, the term "and / or" used in phrases such as "A, B, and / or C" is intended to cover each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone). In some cases, for clarity and / or ease of reference, terms with commonly understood meanings are defined herein, and the inclusion of such definitions herein should not necessarily be interpreted as indicating a substantial difference from what is generally understood in the art.

[1050] As used herein, the singular forms "a," "an," and "the" include their plural referents unless the context clearly dictates otherwise.

[1051] As used herein, numerical ranges are inclusive of the numbers defining the range.

[1052] Mention herein that the value or parameter of " about " includes (and describes) for the value or parameter itself and for the embodiment of the value or parameter that is lower or higher by up to 10% of the stated numerical value of the comparable parameter. For example, a dosage of " about 5 mg / kg " includes 5 mg / kg and also includes any value between 4.5 mg / kg and 5.5 mg / kg. When the term " about " is used in the context of a time period (year, month, week, day, etc.), the term " about " means a subsequent secondary time period of a time period plus or minus an amount (e.g., about 1 year means 11-13 months; about 6 months means 6 months plus or minus 1 week; about 1 week means 6-8 days, etc.), or within 10% of the specified value, whichever is greater.

[1053] "Antibody" refers to an immunoglobulin molecule that is capable of specifically binding to a target, such as a polypeptide, carbohydrate, polynucleotide, lipid, etc., through at least one antigen binding site located in the variable region of the immunoglobulin molecule. As used herein, the term "antibody" can encompass any type of antibody (e.g., monospecific, bispecific, trispecific, multispecific), and includes portions of intact antibodies that retain the ability to bind to a given antigen (e.g., "antigen-binding fragments") and any other modified configuration of an immunoglobulin molecule that contains an antigen binding site.

[1054] Antibodies include antibodies of any class, such as IgG, IgA or IgM (or subclasses thereof), and the antibodies do not need to be of any particular class. Immunoglobulins can be classified into different classes depending on the antibody amino acid sequence of the constant region of their heavy chains (HC). There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG and IgM, and several of these classes can be further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. The heavy chain constant regions corresponding to the different classes of immunoglobulins are referred to as α, δ, ε, γ and μ, respectively. The subunit structures and three-dimensional configurations of the different classes of immunoglobulins are well known.

[1055] Examples of antibody antigen-binding fragments and modified configurations include (i) Fab fragments (monovalent fragments consisting of VL, VH, CL and CH1 domains); (ii) F(ab')2 fragments (divalent fragments comprising two Fab fragments connected by a disulfide bridge at the hinge region); and (iii) Fv fragments consisting of the VL and VH domains of a single arm of an antibody. In addition, although the two domains VL and VH of the Fv fragment are encoded by separate genes, they can be joined using recombinant methods by a synthetic linker that enables them to become a single protein chain in which the VL and VH regions pair to form a monovalent molecule (called single-chain Fv (scFv)); see, for example, Bird et al., Science 1988; 242: 423-426 and Huston et al., Proc. Natl. Acad. Sci. 1988 USA 85: 5879-5883. Other forms of single-chain antibodies, such as diabodies, are also encompassed.

[1056] In addition, antibodies are further encompassed in which the C-terminal lysine (K) amino acid residue on the heavy chain polypeptide is missing (e.g., human IgG1 heavy chains contain a terminal lysine). As is known in the art, the C-terminal lysine is sometimes cleaved during antibody production, resulting in antibodies whose heavy chains lack the C-terminal lysine. Alternatively, the antibody heavy chain can be produced using a nucleic acid that does not include a C-terminal lysine.

[1057] The "variable region" of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. As known in the art, the variable regions of the heavy and light chains are each composed of four framework regions (FRs) connected by three complementary determining regions (CDRs), also referred to as hypervariable regions; and promote the formation of the antigen binding site of the antibody. If a variant of the variable region is required (especially in amino acid residues outside the CDR regions (i.e., in the framework regions) with substitutions), appropriate amino acid substitutions, preferably conservative amino acid substitutions, can be identified by comparing the variable region to the variable region of other antibodies (which contain CDR1 and CDR2 sequences in the same typical class as the variable region being tested). (Chothia and Lesk, J Mol Biol 196 (4): 901-917, 1987).

[1058] In certain embodiments, the deterministic description of CDR and the identification of the residues comprising the binding site of the antibody are realized by resolving the structure of the antibody or the structure of the antibody-ligand complex. In certain embodiments, it can be realized by any of the various techniques well known to those skilled in the art, such as X-ray crystallography. In certain embodiments, various analytical methods can be adopted to identify or estimate CDR districts. In certain embodiments, various analytical methods can be adopted to identify or estimate CDR districts. The example of this type of method includes but is not limited to the Pfabat numbering method set forth in Kabat definition, Chothia definition, AbM definition, contact definition, conformational definition and Example 1.

[1059] The Kabat definition is a standard for numbering residues in antibodies and is often used to identify CDR regions. See, e.g., Johnson & Wu, 2000, Nucleic Acids Res., 28:214-8. The Chothia definition is similar to the Kabat definition, but the Chothia definition takes into account the position of certain structural loop regions. See, e.g., Chothia et al., 1986, J. Mol. Biol., 196:901-17; Chothia et al., 1989, Nature, 342:877-83. The AbM definition uses an integrated suite of computer programs produced by the Oxford Molecular Group that model antibody structures. See, e.g., Martin et al., 1989, Proc Natl Acad Sci (USA), 86:9268-9272; "AbM TM, A Computer Program for Modeling Variable Regions of Antibodies," Oxford, UK; Oxford Molecular, Ltd. The AbM definition models the tertiary structure of an antibody from the primary sequence using a combination of knowledge databases and ab initio computational methods, such as those described in Samudrala et al., 1999, "Ab Initio Protein Structure Prediction Using a Combined Hierarchical Approach," in PROTEINS, Structure, Function and Genetics Suppl., 3:194-198. Contact definitions are based on analysis of available complex crystal structures. See, e.g., MacCallum et al., 1996, J. Mol. Biol., 5:732-45. In another approach, referred to herein as "conformational definition" of the CDRs, the positions of the CDRs can be identified as residues that contribute enthalpy to antigen binding. See, e.g., Makabe et al., 2008, Journal of Biological Chemistry, 283: 1156-1166. Although other CDR boundary definitions may not strictly follow one of the above methods, they will still overlap with at least a portion of the Kabat CDRs, although they may be shortened or lengthened based on predictions or experimental findings that specific residues or groups of residues do not significantly affect antigen binding. The numbering system used in this application is the Kabat numbering method described in Example 1.

[1060] As used herein, CDR may refer to a CDR defined by any method known in the art, including a combination of methods. Methods used herein can utilize CDRs defined according to any of these methods. For any given embodiment containing more than one CDR, CDR may be defined according to any one of Kabat, Chothia, expansion, AbM, contact, conformational definition or Pfabat methods. The antibodies of the present application are numbered according to a modified version of the Kabat numbering system and are described in more detail in Example 1.

[1061] As used herein, the term "hinge region" includes the meaning known in the art, which is shown in, for example, Janeway et al., ImmunoBiology: the immune system in health and disease, Elsevier Science Ltd., NY (4th ed., 1999); Bloom et al., Protein Science, 6:407-415, 1997; and Humphreys et al., J. Immunol. Methods, 209:193-202, 1997.

[1062] The "constant region" of an antibody refers to the constant region of the antibody light chain or the constant region of the antibody heavy chain, alone or in combination. The IgG heavy chain constant region contains three sequential immunoglobulin domains (CH1, CH2, and CH3), with a hinge region located between the CH1 and CH2 domains. The IgG light chain constant region contains a single immunoglobulin domain (CL).

[1063] "Fc domain" refers to the portion of an immunoglobulin (Ig) molecule that is associated with the crystallizable fragment obtained by papain digestion of the Ig molecule. As used herein, the term relates to the 2-chain constant region of an antibody, each chain excluding the first constant region immunoglobulin domain. Within the Fc domain, there are two "Fc chains" (e.g., "first Fc chain" and "second Fc chain"). "Fc chain" generally refers to the C-terminal portion of an antibody heavy chain. Therefore, the Fc chain refers to the last two constant region immunoglobulin domains (CH2 and CH3) of IgA, IgD, and IgG heavy chains, and the last three constant region immunoglobulin domains of IgE and IgM heavy chains, and optionally the flexible hinge at the N-termini of these domains.

[1064] Although the boundaries of the Fc chain can vary, a human IgG heavy chain Fc chain is generally defined to include residues C226 or P230 relative to its carboxyl terminus, where numbering is according to the EU index of Edelman et al., Proc. Natl. Acad. Sci. USA 1969; 63(1):78-85 and as described in Kabat et al., 1991. Typically, an Fc chain comprises about amino acid residues 236 to about 447 of the human IgG1 heavy chain constant region. "Fc chain" can refer to this polypeptide alone or in a larger molecule (e.g., an antibody heavy chain or an Fc fusion protein).

[1065] A "functional" Fc domain refers to an Fc domain that has at least one effector function of a native sequence Fc domain. Exemplary "effector functions" include C1q binding; complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g., B cell receptors); and B cell activation, among others. Such effector functions generally require an Fc domain in combination with a binding domain (e.g., an antibody variable region) and can be assessed using various assays known in the art for assessing such antibody effector functions.

[1066] A "native sequence" Fc chain or "wild-type Fc chain" refers to an Fc chain comprising an amino acid sequence identical to the amino acid sequence of an Fc chain found in nature. A "variant" Fc chain comprises an amino acid sequence that differs from the amino acid sequence of a native sequence Fc chain by virtue of at least one amino acid modification, but retains at least one effector function of the wild-type Fc chain. In some embodiments, the variant Fc chain has at least one amino acid substitution in the wild-type Fc chain, e.g., about one to about ten amino acid substitutions, and preferably about one to about five amino acid substitutions, compared to the wild-type Fc chain. The variant Fc chain herein will preferably have at least about 80% sequence identity with the wild-type Fc chain, and most preferably at least about 90% sequence identity therewith, more preferably at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity therewith. In some embodiments, the Fc chain comprises part or all of the wild-type hinge region (generally at its N-terminus). In some embodiments, the Fc polypeptide does not contain a functional or wild-type hinge region.

[1067] Nomenclature

[1068] The antibody domains disclosed herein may be prefixed with an indicator of the respective target antigen to which the domain is most closely associated. The prefixes are added merely to provide clarification of the abbreviated form of the different domains described throughout this disclosure and do not replace the actual function of the various domains or conflict with the structure of the various domains. For example, IL4-VH refers to the variable heavy chain domain of an antibody comprising CDRs that specifically bind to IL-4. IL4-CH1 refers to the CH1 domain located at the C-terminus of the IL-4 variable domain, regardless of whether the variable domain is a variable light chain domain (IL4-VL) or a variable heavy chain domain (IL4-VH). As described throughout this disclosure, the domains of the antibodies of the present disclosure may be combined or fused with domains from other antibodies. Thus, for example, IL4-VH and IL13-VL may be present on a single polypeptide chain, and each may be present independently or together in the same antibody, and the polypeptides may be referred to as both IL4-VH and IL13-VL (see Figure 18). Again, as an example, a polypeptide carrying IL4-VH is any polypeptide comprising an IL4-VH domain, i.e., a VH domain comprising CDRs that specifically bind to IL-4. A polypeptide carrying IL4-VH may comprise a hinge region, a CH1 domain, a CH2 domain, and a CH3 domain, as in a standard IgG format, or may comprise various domains as described herein, such as IL13-VL, together with CH1 and CL domains fused to IL4-VH or IL13-VL (see Figure 18 for an illustration of different combinations of antibody domains). For example, the DFab LC(1)-HC(2) arms of IL41333-1258, IL413TSLP-1024, and IL413P40-0705 (see Figure 18I ) each comprises, from N-terminus to C-terminus, IL13-VL, CL, linker, IL4-VH, CHI, CH2, and CH3, and can be referred to as both a polypeptide carrying IL4-VH and a polypeptide carrying IL13-VL. Furthermore, framework regions can be referred to by the target to which their CDRs are specific. For example, the framework regions of the IL-4 antibodies of the present disclosure can be referred to as the IL4-VL framework or the IL4-VH framework. Those skilled in the art will appreciate that these designations neither confer nor imply any relationship between the framework regions and the targets to which the CDRs specifically bind. Thus, the IL4-VL framework region can be derived from a human germline DPK9 sequence identical to the known human DPK9 germline sequence. This nomenclature is not limited to the specific antibodies exemplified in this paragraph and applies to all possible antibodies and antibody combinations within the present disclosure.

[1069] Antibodies IL13433-1258, IL134TSLP-1024, and IL134p40-0705 can each be described as comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, wherein the second polypeptide comprises, from N-terminus to C-terminus, (VL-1)-(CL-1)-(linker)-(VH-2)-(CH1-2)-(second hinge)-(second CH2)-(second CH3); and the fifth polypeptide comprises, from N-terminus to C-terminus, (VH1)-(CL-1); and the fourth polypeptide comprises (VL-2)-(CL-2); the first polypeptide comprises, from N-terminus to C-terminus, (VH-3)-(CH1-3)-(first hinge)-(first CH2)-(first CH3); and the third polypeptide comprises (VL-3)-(CL-3). In each case, VL-1 and VH-1 are IL13-VL and IL13-VH; VL-2 and VH-2 are IL4-VL and IL4-VH, and VH-3 and VL-3 are IL33-VH and IL33-VL; or TSLP-VH and TSLP-VL; or p40-VH and p40-VL.

[1070] "Monoclonal antibody" (mAb) refers to an antibody derived from a single copy or clone (including, for example, any eukaryotic, prokaryotic or phage clone). Monoclonal antibodies are highly specific, being directed against a single antigenic site. In addition, in contrast to polyclonal antibody preparations that typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. The modifier "monoclonal" indicates that the antibody is characterized by being obtained from a substantially homogeneous antibody population and should not be construed as requiring the antibody to be produced by any ad hoc method. For example, the monoclonal antibody used in accordance with the present invention can be manufactured by the hybridoma method described first in Kohler and Milstein, 1975, Nature 256: 495, or can be manufactured by the recombinant DNA method described in, for example, U.S. Patent No. 4,816,567. In another example, monoclonal antibodies can also be separated from phage libraries, for example, using the phage libraries generated by the technology described in McCafferty et al., 1990, Nature 348: 552-554.

[1071] A "human antibody" refers to an antibody having an amino acid sequence that corresponds to the amino acid sequence of an antibody produced by a human or prepared using any technique for preparing fully human antibodies. For example, fully human antibodies can be obtained by using commercially available mice that have been engineered to express specific human immunoglobulins or by library (e.g., phage, yeast, or ribosome) display technology for preparing fully human antibodies. This definition of a human antibody specifically excludes humanized antibodies that comprise non-human antigen-binding residues.

[1072] A "chimeric antibody" refers to an antibody in which the variable region sequence is derived from one species and the constant region sequence is derived from another species, for example, an antibody in which the variable region sequence is derived from a mouse antibody and the constant region sequence is derived from a human antibody.

[1073] "Humanized" antibodies refer to non-human (e.g., murine) antibodies that are chimeric antibodies containing minimal sequence derived from non-human immunoglobulins. Preferably, humanized antibodies are human immunoglobulins (recipient antibody) with the desired specificity, affinity, and capacity in which residues from the CDRs of the recipient are replaced with residues from the CDRs of a non-human species (donor antibody) such as mouse, rat, or rabbit. Humanized antibodies may contain residues that are found neither in the recipient antibody nor in the imported CDR or framework sequences but are included to further refine and optimize antibody performance.

[1074] "Antigen" refers to a molecular entity used to immunize an immunocompetent vertebrate to produce antibodies that recognize the antigen or to screen expression libraries (e.g., phage, yeast, or ribosome display libraries) for antibody selection. As used herein, antigen is a broader term and is generally intended to include target molecules specifically recognized by antibodies, and thus includes fragments or mimetics of such molecules that are used in immunization methods to generate antibodies or in library screening to select antibodies.

[1075] "Epitope" refers to an area or region of an antigen to which an antibody specifically binds, such as an area or region comprising residues that interact with an antibody, as determined by any method well known in the art. Many methods for locating and characterizing epitope positions on proteins are known in the art, including crystal structure analysis of antibody-antigen complexes, competitive assays, gene fragment expression assays, epitope mapping, and synthetic peptide-based assays, such as those described in Chapter 11 of Harlow and Lane, Using Antibodies, a Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1999. Additionally or alternatively, during the exploratory process, the generation and characterization of antibodies can elucidate information about the desired epitope. Based on this information, antibodies that bind to the same epitope can then be competitively screened.

[1076] As used herein, the term "binding affinity" refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y can generally be expressed by the dissociation constant (K D ). The affinity of a molecule X for its partner Y can generally be represented by a dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein. Low-affinity antibodies generally bind antigen slowly and tend to dissociate easily, while high-affinity antibodies generally bind antigen faster and tend to remain bound longer. Various methods for measuring binding affinity are known in the art, any of which can be used for the purposes of the present invention. Specifically, the term "binding affinity" is intended to refer to the dissociation rate of a particular antigen-antibody interaction. K D is the rate of dissociation (also called the off-rate (k off )") and the association rate (or "on-rate (k on )”). Therefore, K D Equal to k off / k on And it is expressed as molar concentration (M). So K D The smaller the value, the stronger the binding affinity. D Compared with 1 μM K D Indicates weak binding affinity. The K of the antibody D The value can be determined using methods well established in the art. D A method is by using surface plasmon resonance (SPR), typically using a biosensor system such as a BIACORE system. BIACORE kinetic analysis involves analyzing the binding and dissociation of an antigen to a chip having an immobilized molecule (e.g., a molecule comprising an epitope binding domain) on the surface. Surface plasmon resonance-based biosensors can be used, for example, to characterize analyte / ligand interactions under conditions where the analyte is monovalent with respect to binding to a ligand immobilized on the sensor surface by a capture reagent at low capacity, to determine the association and dissociation rate constants, k, respectively. on and k off , to determine K Dand other ratios. The analysis can be performed, for example, using a kinetic titration method as described in Karlsson et al., Anal. Biochem 349, 136-147, 2006 or using multi-cycle kinetic analysis. The sensor chip, capture reagent, and assay buffer used for a given assay are selected to allow stable capture of the ligand onto the sensor surface, minimize nonspecific binding of the analyte to the surface, and produce an analyte binding reaction suitable for kinetic analysis according to the recommendations in Myszka, J. Mol. Recognit 12, 279-284, 1999. The assay binding reaction based on the analyte / ligand interaction is double referenced and fitted to a 1:1 Langmuir "mass transport limited model" where k a 、k d and R max is a global parameter as described in Myszka & Morton et al., Biophys. Chem 64, 127-137 (1997). Equilibrium dissociation constant K D Deduced from the ratio of the kinetic rate constants, K D =k off / k on Such assays are preferably performed at 25°C or 37°C. Typically, rate constants (k on or k a and k off or k d ) and equilibrium dissociation constant. Another method for determining the K D The method is to use biolayer interferometry, usually using Technology (Octet QK e System, ForteBio). Alternatively or additionally, the KinExA (Kinetic Exclusion Assay) assay, available from Sapidyne Instruments (Boise, ID), can also be used.

[1077] As used herein, the terms "immunospecific binding," "immunospecific recognition," "specific binding," "specific recognition," and similar terms refer to a molecule, such as a binding domain, that specifically binds to an antigen (e.g., an epitope or immune complex) and does not specifically bind to another molecule. A molecule that specifically binds to an antigen may bind to other peptides or polypeptides with lower affinity, as determined by assays known in the art (e.g., immunoassays, BIACORE assays, and the like). TM Preferably, the molecule that specifically binds to the antigen does not cross-react with other proteins.

[1078] When used in reference to the interaction of an antibody with a protein or peptide, the term "specific binding" or "specifically binds" refers to an interaction that is dependent on the presence of a specific structure (i.e., an antigenic determinant or epitope) on the protein; in other words, the antibody recognizes and binds to a specific protein structure rather than proteins in general. For example, if the antibody is specific for epitope "A," the presence of a protein containing epitope A (or free, unlabeled A) in a reaction containing labeled "A" and the antibody will reduce the amount of labeled A bound to the antibody.

[1079] In certain embodiments, "specific binding" means, for example, that an antibody binds to an antibody with a K of about 0.1 nM or less, but more typically less than about 1 μM. D In certain embodiments, "specifically binds" means that the antibody sometimes binds with a K of at least about 0.1 μM or less, at other times at least about 0.01 μM or less, and at other times at least about 1 nM or less. D Binding target. Because of the sequence identity between homologous proteins in different species, specific binding may include antibodies that recognize one protein in more than one species. Similarly, due to the homology within certain regions of the polypeptide sequences of different proteins, specific binding may include antibodies that recognize more than one protein. It should be understood that in certain embodiments, an antibody or binding portion that specifically binds to a first target may or may not specifically bind to a second target. Therefore, "specific binding" does not necessarily require (although it may include) exclusive binding, i.e., binding to a single target. Therefore, in some embodiments, an antibody can specifically bind to more than one target. In certain embodiments, multiple targets can bind to the same antigen binding site on an antibody. For example, an antibody may, in some cases, comprise two identical antigen binding sites, each of which specifically binds to the same epitope on two or more proteins. In certain alternative embodiments, an antibody can be multispecific and comprise at least two antigen binding sites with different specificities. As a non-limiting example, a bispecific antibody may comprise an antigen binding site that recognizes an epitope on a protein and further comprise a second, different antigen binding site that recognizes a different epitope on a second protein. Generally, but not necessarily, reference to binding means specific binding.

[1080] An antibody that specifically binds to an antigen may bind to other peptides or polypeptides with lower affinity, as determined by assays known in the art, such as immunoassays, BIACORE TM Preferably, an antibody that specifically binds to an antigen does not cross-react with other proteins.

[1081] The term "nonspecific binding" or "background binding" when used in reference to the interaction of an antibody with a protein or peptide refers to interactions that are not dependent on the presence of a specific structure (i.e., the antibody binds to the protein generally, not to a specific structure such as an epitope).

[1082] Neutralizing or "blocking" antibodies are antibodies whose binding to one or more of IL-4, IL-13, IL-33, TSLP, and p40 results in one or both of the following: (i) interfering with, limiting, or inhibiting the interaction between IL-4, IL-13, IL-33, TSLP, and p40 and a suitable ligand, respectively; or (ii) resulting in inhibition of at least one biological function to which IL-4, IL-13, IL-33, TSLP, or p40 is bound, as desired. Assays for determining neutralization by the antibodies of the present disclosure are well known in the art.

[1083] As used herein, "antibody that binds to a target"; "antibody that recognizes a target"; "antibody that specifically binds to a target"; "anti-target antibody"; "anti-target antibody molecule"; "target antibody" and the like include molecules that contain at least one binding domain that specifically binds to a target.

[1084] A "monospecific antibody" refers to an antibody that contains one or more antigen-binding sites per molecule such that any and all binding sites of the antibody specifically recognize the same epitope on the antigen. Thus, where a monospecific antibody has more than one antigen-binding site, the binding sites compete with each other for binding to one antigen molecule.

[1085] "Bispecific antibodies" refer to molecules that have binding specificities for at least two different epitopes. In some embodiments, bispecific antibodies can bind to two different antigens simultaneously. In other embodiments, the two different epitopes can be present on the same antigen.

[1086] As used herein, a "trispecific antibody" is an antibody that has binding specificity for three different epitopes. In some embodiments, a trispecific antibody can bind to three different antigens simultaneously. In other embodiments, the three different epitopes can be present on the same antigen.

[1087] As used herein, a "multispecific antibody" is an antibody that has binding specificity for at least two different epitopes. In some embodiments, a multispecific antibody can simultaneously bind to at least two different antigens. In other embodiments, at least two different epitopes can be present on the same antigen.

[1088] As used herein, the term "IL-4 / IL-13 / IL-33 trispecific antibody" or "IL-4 / IL-13 / IL-33 multispecific antibody" refers to a molecule designed to specifically bind to IL-4, IL-13, and IL-33. As used herein, the term "IL-4 / IL-13 / TSLP trispecific antibody" or "IL-4 / IL-13 / TSLP multispecific antibody" refers to a molecule designed to specifically bind to IL-4, IL-13, and TSLP. As used herein, the term "IL-4 / IL-13 / p40 trispecific antibody" or "IL-4 / IL-13 / p40 multispecific antibody" refers to a molecule designed to specifically bind to IL-4, IL-13, and p40.

[1089] The term "half maximal effective concentration (EC 50 )” refers to the concentration of therapeutic agent that elicits a response halfway between baseline and maximum after a specified exposure time. Therapeutic agents can cause either inhibition or stimulation. EC 50 The value is commonly used and is used herein as a measure of efficacy.

[1090] The term "inhibitory concentration (IC 50 )" refers to the concentration of inhibitor that achieves 50% inhibition in its activity. Therapeutic agents can cause inhibition or stimulation. IC 50 The value is commonly used and is used herein as a measure of efficacy.

[1091] "Agonist" refers to a substance that promotes (ie, induces, causes, enhances, or increases) the biological activity or action of another molecule. The term agonist encompasses substances (eg, antibodies) that bind to a molecule to promote the activity of that molecule.

[1092] "Antagonist" refers to a substance that prevents, blocks, inhibits, neutralizes, or reduces the biological activity or effect of another molecule (e.g., a receptor). The term antagonist encompasses substances (e.g., antibodies) that bind to a molecule to prevent or reduce the activity of that molecule.

[1093] As used herein with respect to the term "competition" means that the first antibody binds to an epitope in a manner sufficiently similar to the binding of the second antibody, such that the result of the binding of the second antibody to its cognate epitope in the presence of the first antibody is detectably reduced compared to the binding of the second antibody in the absence of the first antibody. An alternative may exist but need not be so, i.e., the binding of the first antibody to its epitope in the presence of the second antibody may also be detectably reduced. That is, in the case where the second antibody does not inhibit the binding of the first antibody to its corresponding epitope, the first antibody may inhibit the binding of the second antibody to its epitope. However, when each antibody detectably inhibits the binding of another antibody to its cognate epitope or ligand to the same, greater or lesser extent, the antibodies are referred to as "cross-competing" with each other in conjunction with their respective epitopes. The present invention encompasses both competition and cross-competing antibodies. Regardless of the mechanism (such as steric hindrance, conformational change, or binding to a common epitope or portion thereof) of the competition or cross-competition, those skilled in the art will understand based on the teachings provided herein that such competition or cross-competing antibodies are encompassed in and can be used in the methods disclosed herein.

[1094] "Host cell" refers to an individual cell or cell culture that can be or has been a recipient of one or more vectors for incorporating a polynucleotide insert. Host cells include the progeny of a single host cell, and the progeny may not necessarily be completely identical (in morphology or genomic DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation. Host cells include cells transfected in vivo with a polynucleotide of the invention.

[1095] "Vector" refers to a construct that can deliver and preferably express one or more related genes or sequences (e.g., antibody encoding genes) in a host cell. Examples of vectors include, but are not limited to, plasmids and viral vectors, and may include naked nucleic acids, or may include nucleic acids associated with delivery auxiliary materials (e.g., cationic condensing agents, liposomes, etc.). A vector may include DNA or RNA. As used herein, "expression vector" refers to a vector comprising at least one polypeptide encoding gene, at least one regulatory element (e.g., a promoter sequence, a poly (A) sequence) associated with the transcription or translation of a gene. Typically, the vector used herein contains at least one antibody encoding gene, and one or more regulatory elements or selective markers. Vector components may include, for example, one or more of the following: a signal sequence; an origin of replication; one or more marker genes; suitable transcription control elements (e.g., promoters, enhancers, and terminators). For translation, one or more translation control elements may also be included, such as a ribosome binding site, a translation initiation site, and a stop codon.

[1096] An "isolated" molecule (e.g., an isolated antibody) is one that, by virtue of its source or source of derivation, (1) is not associated with naturally associated components with which it naturally accompanies it; (2) is substantially free of other molecules from the same source (e.g., species, cell expressing it, library, etc.); (3) is expressed by a cell from a different species; or (4) does not occur in nature. Thus, a molecule that is chemically synthesized or expressed in a cellular system different from that in which it is naturally derived will be "isolated" from its naturally associated components. A molecule can also be rendered substantially free of naturally associated components by isolation using purification techniques well known in the art.

[1097] As used herein, the term "linker" refers to an amino acid sequence of two or more amino acids in length. The linker can be composed of neutral polar or non-polar amino acids. The length of the linker can be, for example, 2 to 100 amino acids, for example, between 2 and 50 amino acids in length, for example, 3, 4, 5, 6, 8, 10, 12, 15, 20, 25, 30, 35, 40, 45 or 50 amino acids in length. The linker can be "cleavable", for example, by self-cleavage or enzymatic cleavage or chemical cleavage. The cleavage sites in the amino acid sequence and the enzymes and chemicals that cleave at such sites are well known in the art and are also described herein. In some aspects, the linker comprises one or more repeating units of a sequence comprising glycine and serine residues. In some aspects, the linker comprises one or more G4S repeating units. In some aspects, the linker comprises (G4S) 1-3 In some aspects, the linker is GGGGS (SEQ ID NO: 10).

[1098] As used herein, the term "disulfide bond" or "cysteine-cysteine ​​disulfide bond" refers to a covalent interaction between two cysteines, wherein the sulfur atoms of the cysteines are oxidized to form a disulfide bond. The average bond energy of a disulfide bond is approximately 60 kcal / mol, compared to 1-2 kcal / mol for a hydrogen bond. In the context of the present invention, the cysteines that form the disulfide bond are located within the framework region of the single-chain antibody and serve to stabilize the antibody conformation. Cysteine ​​residues can be introduced, for example, by site-directed mutagenesis, such that a stable disulfide bond can be generated within the molecule.

[1099] As used herein, the terms "linked," "fused," and "fusion" are used interchangeably to refer to the joining together of two or more elements or components by any means including chemical conjugation or recombinant means.

[1100] As used herein, the term "covalently linked" means that the specified moieties are covalently bound to each other directly, or indirectly through one or more intervening moieties (eg, linker peptides or moieties).

[1101] As used herein, the term "linked to" refers to the colinear, covalent connection or attachment of two or more proteins, polypeptides, or fragments thereof through their individual peptide backbones. For example, one polypeptide can be linked to another polypeptide by genetic expression of a single polynucleotide molecule encoding both polypeptides in-frame. Such gene fusions result in the expression of a single, continuous protein comprising both polypeptides.

[1102] As used herein, the term "modification" refers to an amino acid substitution, insertion or deletion in a polypeptide sequence; a change in a portion chemically attached to a protein; or a modification of a protein (e.g., an antibody) function. For example, a modification may be a changed antibody function or a changed carbohydrate structure attached to a protein. As used herein, "amino acid modification" refers to a mutation (substitution), insertion (addition) or deletion of one or more amino acid residues in an antibody. The term "amino acid mutation" represents the replacement of at least one existing amino acid residue with another different amino acid residue (e.g., a replacement amino acid residue). The term "amino acid deletion" represents the removal of at least one amino acid residue at a predetermined position in an amino acid sequence. For example, the mutation L234A represents that the amino acid residue lysine at position 234 in the Fc region of an antibody is replaced by the amino acid residue alanine (replacing lysine with alanine) (numbering is according to the EU index numbering system).

[1103] The term "agent" is used herein to refer to a biomacromolecule, an extract made from biological material, a mixture of biomacromolecules, a compound, a mixture of compounds, or a mixture of a compound and a biomacromolecule. The term "therapeutic agent" refers to an agent that has biological activity.

[1104] "Polypeptide" or "protein" (used interchangeably herein) refers to an amino acid chain of any length. The chain can be straight or branched. The chain can contain one or more modified amino acids. The term also encompasses amino acid chains that have been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other adjustment or modification, such as conjugation with a labeling component. The definition also includes, for example, polypeptides containing one or more analogs of an amino acid (including, for example, unnatural amino acids), as well as other modifications known in the art. It should be understood that a polypeptide can appear as a single chain or in associated chains.

[1105] As used herein, a "first polypeptide" is any polypeptide that will associate with a second polypeptide. The first polypeptide and the second polypeptide meet at an interface. In addition to the interface, the first polypeptide may comprise one or more additional domains, such as a "binding domain" (e.g., an antibody variable domain, a receptor binding domain, a ligand binding domain, or an enzyme domain) or an antibody constant domain (or portion thereof) comprising a CH2, CH1, and CL domain. Typically, the first polypeptide will comprise at least one domain derived from an antibody. This domain is suitably a constant domain, such as the CH3 domain of an antibody and can form the interface of the first polypeptide. Exemplary first polypeptides include antibody heavy chain polypeptides, chimeras combining antibody constant domains with binding domains of heterologous polypeptides, receptor polypeptides, ligand polypeptides, and antibody variable domain polypeptides (e.g., bispecific antibodies).

[1106] In addition to the interface, the second polypeptide may also comprise additional domains, such as a "binding domain" (e.g., an antibody variable domain, a receptor binding domain, a ligand binding domain, or an enzyme domain), or an antibody constant domain (or portion thereof) comprising a CH2, CH1, and CL domain. Typically, the second polypeptide will comprise at least one domain derived from an antibody. This domain is suitably a constant region, such as a CH3 domain of an antibody and may form the interface of the second polypeptide. Exemplary second polypeptides include antibody heavy chain polypeptides, chimeras combining antibody constant domains with binding domains of heterologous polypeptides, and antibody variable domain polypeptides (e.g., bispecific antibodies).

[1107] "Polynucleotide" or "nucleic acid" (used interchangeably herein) refers to a chain of nucleotides of any length and includes DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases or their analogs, or any substrate that can be incorporated into the chain by DNA or RNA polymerase. The polynucleotide may contain modified nucleotides, such as methylated nucleotides and their analogs. If present, the nucleotide structure may be modified before or after chain assembly. The nucleotide sequence may be interrupted by non-nucleotide components. The polynucleotide may be further modified after polymerization, for example, by conjugation with a labeling component. Other types of modifications include, for example, "capping"; substitution of one or more naturally occurring nucleotides with analogs; internucleotide modifications, such as those with uncharged linkages (e.g., methylphosphonates, phosphotriesters, phosphoramidates, carbamates, etc.) and those with charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.), those containing side moieties such as proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), those with intercalators (e.g., acridine, psoralen, etc.), those containing chelators (e.g., metals, radioactive metals, boron, oxidized metals, etc.), those containing alkylating agents, those with modified linkages (e.g., α-mutarotomer nucleic acids, etc.), and unmodified forms of polynucleotides. In addition, any hydroxyl group typically present in the sugar can be replaced, for example, by a phosphonate group, a phosphate group, protected by standard protecting groups, or activated to prepare additional linkages to additional nucleotides, or can be conjugated to a solid support. The 5' and 3' end OH groups may be phosphorylated or substituted with amine or organic end-capping groups of 1 to 20 carbon atoms. Other hydroxyl groups may also be derived into standard protecting groups. Polynucleotides may also contain ribose or deoxyribose in similar forms generally known in the art, including, for example, 2'-O-methyl-, 2'-O-allyl, 2'-fluoro- or 2'-azido-ribose, carbocyclic sugar analogs, α- or β-anomeric sugars, epimeric sugars (e.g., arabinose, xylose, or lyxose); pyranose, furanose, sedoheptulose, acyclic analogs, and abasic nucleoside analogs (e.g., methyl nucleosides).

[1108] As used herein, nucleic acids are written from left to right in a 5' to 3' orientation; amino acid sequences are written from left to right in an amino to carboxyl orientation, respectively. For definitions and terminology in this field, practitioners are particularly referred to Sambrook et al., 1989 and Ausubel FM et al., 1993. It should be understood that this invention is not limited to the particular methodology, protocols, and reagents described, as these may vary.

[1109] The present invention also encompasses polynucleotides complementary to any such sequences. Polynucleotides can be single-stranded (coding or antisense) or double-stranded and can be DNA (genomic, cDNA or synthetic) or RNA molecules. RNA molecules include mature and immature mRNAs, such as precursor mRNA (pre-mRNA) or heterogeneous nuclear mRNA (hnRNA) and mature mRNA. Additional coding or non-coding sequences may (but not necessarily) be present in the polynucleotides of the present invention, and the polynucleotides may (but not necessarily) be linked to other molecules or support materials.

[1110] It will be appreciated by those skilled in the art that due to the degeneracy of the genetic code, there are many nucleotide sequences encoding the amino acid sequences provided herein. The present invention particularly contemplates polynucleotides that vary due to differences in codon usage.

[1111] "Conservative substitutions" refer to the replacement of one amino acid with a biologically, chemically, or structurally similar residue. Biologically similar means that the substitution does not destroy biological activity. Structurally similar means that the side chains of the amino acids have similar lengths (e.g., alanine, glycine, and serine) or are of similar size. Chemically similar means that the residues have the same charge or are both hydrophilic or hydrophobic. Specific examples include replacing one hydrophobic residue (e.g., isoleucine, valine, leucine, or methionine) with another, or replacing one polar residue with another, such as arginine for lysine, glutamic acid for aspartic acid, glutamine for asparagine, serine for threonine, etc. Specific examples of conservative substitutions include replacing one hydrophobic residue (e.g., isoleucine, valine, leucine, or methionine) with another, or replacing one polar residue with another, such as arginine for lysine, glutamic acid for aspartic acid, or glutamine for asparagine, etc. Conservative amino acid substitutions generally include, for example, substitutions within the following groups: glycine, alanine, valine, isoleucine, and leucine; aspartic acid and glutamic acid; asparagine and glutamine; serine and threonine; lysine and arginine; and phenylalanine and tyrosine.

[1112] The present invention also encompasses modifications of the antibodies provided herein, including functionally equivalent antibodies that do not significantly affect their properties and variants with enhanced or reduced activity or affinity. For example, the amino acid sequence can be mutated to obtain an antibody with the desired binding affinity for IL-4, IL-13, IL-33, TSLP or p40. Examples of modified polypeptides include polypeptides with conservative substitutions of amino acid residues, one or more deletions or additions of amino acids that do not significantly and adversely alter the functional activity or mature (enhance) the affinity of the polypeptide for its ligand, or the use of chemical analogs.

[1113] Amino acid sequence insertions include amino-terminal or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing one hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include antibodies with an N-terminal methionyl residue or antibodies fused to epitope tags. Other insertional variants of antibody molecules include fusions of the N-terminus or C-terminus of an antibody with an enzyme or polypeptide that increases the half-life of the antibody in the blood circulation.

[1114] The substitution variant removes at least one amino acid residue in the antibody molecule and inserts a different residue into its position. The most interesting substitution type mutagenesis site includes a hypervariable region, but FR changes are also considered. Conservative substitutions are shown below as residues in the same numbered group (1 to 6). If this type of substitution causes a change in biological activity, more substantial changes as further described below about amino acid classes, which are named "exemplary substitutions," can be introduced, and the product can be screened.

[1115] Substantial changes in the biological properties of the antibody are achieved by selecting substitutions that differ significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of ​​the substitution, such as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain. Based on common side chain properties, naturally occurring amino acid residues are divided into the following groups:

[1116] (1) Non-polar: norleucine, Met, Ala, Val, Leu, Ile;

[1117] (2) Polar, uncharged: Cys, Ser, Thr, Asn, Gln;

[1118] (3) Acidic (negatively charged): Asp, Glu;

[1119] (4) Basic (positively charged): Lys, Arg;

[1120] (5) Residues that affect chain orientation: Gly, Pro; and

[1121] (6) Aromatic: Trp, Tyr, Phe, His.

[1122] Non-conservative substitutions are made by exchanging a member of one of these classes for another class.

[1123] Any cysteine ​​residues not involved in maintaining the proper conformation of the antibody may also be substituted with serine to improve the oxidative stability of the molecule and prevent abnormal cross-linking. Conversely, particularly when the antibody is an antibody fragment such as an Fv fragment, cysteine ​​bonds may be added to the antibody to improve its stability.

[1124] Amino acid modifications can range from changing or modifying one or more amino acids to completely redesigning a region, such as a variable region. Changes in the variable region can alter binding affinity and / or specificity. In some embodiments, no more than one to five conservative amino acid substitutions are made within the CDR domain. In other embodiments, no more than one to three conservative amino acid substitutions are made within the CDR domain. In other embodiments, the CDR domain is either or both of a VH CDR3 or a VL CDR3.

[1125] Modifications also include glycosylated and non-glycosylated polypeptides, as well as polypeptides with other post-translational modifications such as glycosylation using different sugars, acetylation, and phosphorylation. Antibodies are glycosylated at conserved positions in their constant regions (Jefferis and Lund, Chem. Immunol. 65: 111-128, 1997; Wright and Morrison, TibTECH 15: 26-32, 1997). The oligosaccharide side chains of immunoglobulins affect protein function (Boyd et al., Mol. Immunol. 32: 1311-1318, 1996; Wittwe and Howard, Biochem. 29: 4175-4180, 1990) and intramolecular interactions between the various parts of the glycoprotein, which can affect the conformation and the three-dimensional surface presented by the glycoprotein (Jefferis and Lund, supra; Wyss and Wagner, Current Opin. Biotech. 7: 409-416, 1996). Oligosaccharides can also be used to target specific glycoproteins to certain molecules based on specific recognition structures. Glycosylation of antibodies has also been reported to affect antibody-dependent cellular cytotoxicity (ADCC). Specifically, CHO cells with tetracycline-regulated expression of β(1,4)-N-acetylglucosaminyltransferase III (GnTIII), a glycosyltransferase that catalyzes the formation of bisecting GlcNAc, were reported to have enhanced ADCC activity (Umana et al., Mature Biotech. 17:176-180, 1999).

[1126] The glycosylation of antibodies is typically N-connected or O-connected. N-connection refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine, asparagine-X-threonine, and asparagine-X-cysteine ​​(wherein X is any amino acid except proline) are recognition sequences for the enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Therefore, the presence of any of these tripeptide sequences in a polypeptide creates a potential glycosylation site. The glycosylation O-connections refers to the attachment of one of sugar N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, but 5-hydroxyproline or 5-hydroxylysine can also be used.

[1127] Addition of glycosylation sites to the antibody is conveniently accomplished by altering the amino acid sequence such that it contains one or more of the above-described tripeptide sequences (for N-linked glycosylation sites). The alteration may also be made by adding or substituting one or more serine or threonine residues to the sequence of the original antibody (for O-linked glycosylation sites).

[1128] The glycosylation pattern of the antibody can also be altered without changing the basic nucleotide sequence. Glycosylation depends largely on the host cell used to express the antibody. Because the cell types used for expression of recombinant glycoproteins such as antibodies as potential therapeutic agents are rarely naive cells, changes in the glycosylation pattern of the antibody can be expected (see, for example, Hse et al., J. Biol. Chem. 272: 9062-9070, 1997).

[1129] The term "identity" or "same as" refers to the overall relatedness between polymeric molecules, such as nucleic acid molecules (e.g., DNA molecules or RNA molecules) or polypeptide molecules. "Identity" measures the percentage of identical matches between two or more sequences with gapped alignments addressed by a specific mathematical model (e.g., an "algorithm") of a computer program, which is well known in the art.

[1130] The terms "increase," "enhance," "decrease," or "reduce" refer to values ​​relative to a baseline measurement, such as a measurement in the same individual before starting a treatment described herein, or a measurement in a control individual or subject (or multiple control individuals or subjects) in the absence of a treatment described herein. In some embodiments, a "control individual" is an individual with the same form of disease or injury as the individual being treated. In some embodiments, a "control individual" is an individual who does not have the same form of disease or injury as the individual being treated.

[1131] The term "excipient" refers to any material that allows the active ingredient to retain bioactivity in combination with an active ingredient of interest (e.g., an antibody). The selection of excipient will depend to a great extent on factors such as mode of administration, the impact of the excipient on solubility and stability, and the properties of the formulation. As used herein, "excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents, carriers, diluents, and the like that are compatible physiologically. The example of excipient includes one or more and combinations thereof in water, saline, phosphate buffered saline (PBS), dextrose, glycerol, ethanol, and the like, and in the composition, an isotonic agent may be included, such as sugar, sodium chloride, or a polyol (e.g., mannitol) or sorbitol.

[1132] The terms "cancer", "cancerous" or "malignant" refer to or describe a physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include, but are not limited to, carcinomas, lymphomas, leukemias, blastomas, and sarcomas. More specific examples of the cancer include squamous cell carcinoma, myeloma, small cell lung cancer, non-small cell lung cancer, glioma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myeloid leukemia (AML), multiple myeloma, gastrointestinal (tract) cancer, kidney cancer, ovarian cancer, liver cancer, lymphoblastic leukemia, lymphocytic leukemia, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, brain cancer, stomach cancer, bladder cancer, liver cancer, breast cancer, colon cancer, and head and neck cancer. Another specific example of cancer includes renal cell carcinoma.

[1133] "Chemotherapeutic agents" are compounds that can be used to treat cancer. Classes of chemotherapeutic agents include, but are not limited to, alkylating agents, antimetabolites, kinase inhibitors, spindle poison alkaloids, cytotoxic / antitumor antibiotics, topoisomerase inhibitors, photosensitizers, antiestrogens and selective estrogen receptor modulators (SERMs), antiprogestins, estrogen receptor downregulators (ERDs), estrogen receptor antagonists, luteinizing hormone-releasing hormone agonists, antiandrogens, aromatase inhibitors, EGFR inhibitors, VEGF inhibitors, and antisense oligonucleotides that inhibit the expression of genes associated with abnormal cell proliferation or tumor growth. Chemotherapeutic agents that can be used in the methods of treatment of the present invention include cytostatic and / or cytotoxic agents. Chemotherapeutic agents are further described elsewhere herein.

[1134] As used herein, "RECIST 1.1 response criteria" means the definitions set forth in Eisenhauer et al., EA et al., Eur. J Cancer 45:228-247 (2009) for target lesions or non-target lesions, as appropriate based on the context in which the response is measured.

[1135] "Sustained response" means a sustained therapeutic effect after cessation of treatment with a therapeutic agent or combination therapy described herein. In some embodiments, a sustained response has a duration that is at least the same as the duration of treatment or at least 1.5, 2.0, 2.5, or 3 times longer than the duration of treatment.

[1136] "Tissue section" refers to a single portion or piece of a tissue sample, eg, a thin section of tissue cut from a sample of normal tissue or a tumor.

[1137] As used herein, "treat" or "treating" cancer means administering a combination therapy of at least one first therapeutic agent and a second therapeutic agent to a subject having or diagnosed with cancer to achieve at least one positive therapeutic effect, such as a decrease in the number of cancer cells, a decrease in tumor size, a decrease in the rate of cancer cell infiltration into peripheral organs, or a decrease in tumor metastasis or tumor growth rate. Positive therapeutic effects in cancer can be measured in a variety of ways (see WA Weber, J. Nucl. Med. 50: 1S-10S (2009)). For example, with respect to tumor growth inhibition, according to the National Cancer Institute (NCI) criteria, a T / C of less than or equal to 42% is the lowest level of anti-tumor activity. T / C < 10% is considered a high level of anti-tumor activity, where T / C (%) = median tumor volume of treated tumors / median tumor volume of controls × 100. In some embodiments, the treatment achieved by the combination of the present invention is any one of ...

Claims

1. An isolated antibody that specifically binds to IL-33, comprising a heavy chain variable region (IL33-VH) and a light chain variable region (IL33-VL), comprising (i) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO: 73, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO: 78; (ii) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO: 63, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO: 71; or (iii) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO: 80, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO:

81.

2. An isolated antibody that specifically binds to IL-33, comprising a heavy chain variable region (IL33-VH) and a light chain variable region (IL33-VL), wherein CDR-H1 comprises the amino acid sequence of SEQ ID NO: 60; CDR-H2 comprises the amino acid sequence of SEQ ID NO: 61; CDR-H3 comprises the amino acid sequence of SEQ ID NO: 72; CDR-L1 comprises the amino acid sequence of SEQ ID NO: 75; CDR-L2 comprises the amino acid sequence of SEQ ID NO: 76; and CDR-L3 comprises the amino acid sequence of SEQ ID NO:

77.

3. The antibody of any one of claims 1 to 3, comprising an IL33-VH framework sequence derived from a human germline VH sequence selected from the group consisting of DP47, DP48, DP50, DP51, DP54 and DP77, and optionally further comprising an IL33-VL framework sequence derived from a human germline VL sequence selected from the group consisting of DPK1, DPK3, DPK4, DPK5, DPK7, DPK8 and DPK9.

4. The antibody according to any one of claims 1 to 4, comprising (i) the IL33-VH sequence of SEQ ID NO: 73 and the IL33-VL sequence of SEQ ID NO: 78; or (ii) the IL33-VH sequence of SEQ ID NO: 63 and the IL33-VL of SEQ ID NO: 71; or (iii) the IL33-VH sequence of SEQ ID NO: 80 and the IL33-VL sequence of SEQ ID NO: 81; or (iv) an IL33-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 202, and an IL33-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 203; (v) a polypeptide sequence carrying IL33-VH encoded by the nucleic acid sequence of SEQ ID NO: 190, and a polypeptide sequence carrying IL33-VL encoded by the nucleic acid sequence of SEQ ID NO: 191; (vi) an IL33-VH sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127210, and an IL33-VL sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127209; or (vii) the polypeptide sequence carrying IL33-VH encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127208, and the polypeptide sequence carrying IL33-VL encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127207.

5. An isolated antibody that specifically binds to IL-33, specifically binds to IL-4, and specifically binds to IL-13, comprising the IL-33 binding domain, IL-4 binding domain, and IL-13 binding domain contained in the antibody of any one of claims 1 to 4.

6. The antibody of claim 5, wherein the IL-4 binding domain comprises a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL), comprising (i) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO: 22, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO: 26; (ii) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO: 19, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO: 20; (iii) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO: 22, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO: 20; (iv) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO: 28, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO: 29; or (v) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO: 22, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO:

30.

7. The antibody of any one of claims 5 to 6, wherein the IL-4 binding domain comprises a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL), wherein the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 18; the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2; the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 3; the CDR-L1 comprises the amino acid sequence of SEQ ID NO: 24; the CDR-L2 comprises the amino acid sequence of SEQ ID NO: 12; and the CDR-L3 comprises the amino acid sequence of SEQ ID NO:

25.

8. The antibody of any one of claims 5 to 7, wherein the IL-4 binding domain comprises (i) the IL4-VH sequence of SEQ ID NO: 22 and the IL4-VL sequence of SEQ ID NO: 26; (ii) the IL4-VH sequence of SEQ ID NO: 19 and the IL4-VL sequence of SEQ ID NO: 20; (iii) the IL4-VH sequence of SEQ ID NO: 22 and the IL4-VL sequence of SEQ ID NO: 20; (iv) the IL4-VH sequence of SEQ ID NO: 28 and the IL4-VL sequence of SEQ ID NO: 29; or (v) the IL4-VH sequence of SEQ ID NO: 22 and the IL4-VL sequence of SEQ ID NO: 30; (vi) an IL4-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 200, and an IL4-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 201; (vii) a polypeptide sequence carrying IL4-VH encoded by the nucleic acid sequence of SEQ ID NO: 188, and a polypeptide sequence carrying IL4-VL encoded by the nucleic acid sequence of SEQ ID NO: 189; (viii) an IL4-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC deposit number PTA-127198, and an IL4-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC deposit number PTA-127197; (ix) the polypeptide sequence carrying IL4-VH encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127192, and the polypeptide sequence carrying IL4-VL encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127194.

9. The antibody of any one of claims 5 to 8, wherein the IL-4 binding domain is characterized by one or more of the following: (i) with a K value less than a value selected from about 10 pM, 5 pM, 1 pM and 800 fM D Binds to human IL-4; (ii) binding to cynomolgus monkey IL-4; (iii) does not bind to IL-4 from one or more selected from dog, sheep, rabbit, rat and mouse; (iv) Binding K to cynomolgus monkey IL-4 D The binding K of the antibody to human IL-4 D within 1 order of magnitude; (v) IC of IL-4-induced neutralization of CD23 in human monocyte assay 50 Less than 10pM; (vi) a viscosity of 20 cP or less at 25°C at a concentration of 80 mg / mL in histidine-sucrose pH 5.8 buffer; (vii) Lysine at residue 93 in the light chain.

10. The antibody of any one of claims 5 to 9, wherein the IL-13 binding domain comprises a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL), comprising (i) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO:51, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO:54; (ii) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO:44, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO:46; (iii) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO: 48, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO: 49; (iv) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO:48, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO:68; or (v) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO:57, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO:

59.

11. The antibody of any one of claims 5 to 10, wherein the IL-13 binding domain comprises a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL), wherein the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 41; the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 42; the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 50; the CDR-L1 comprises the amino acid sequence of SEQ ID NO: 53; the CDR-L2 comprises the amino acid sequence of SEQ ID NO: 37; and the CDR-L3 comprises the amino acid sequence of SEQ ID NO:

38.

12. The antibody of any one of claims 5 to 11, wherein the IL-13 binding domain comprises (i) IL13-VH of SEQ ID NO: 51 and IL13-VL of SEQ ID NO: 54; (ii) IL13-VH of SEQ ID NO: 44 and IL13-VL of SEQ ID NO: 46; (iii) IL13-VH of SEQ ID NO: 48 and IL13-VL of SEQ ID NO: 49; (iv) IL13-VH of SEQ ID NO: 48 and IL13-VL of SEQ ID NO: 68; (v) IL13-VH of SEQ ID NO: 57 and IL13-VL of SEQ ID NO: 59; (vi) an IL13-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 198, and an IL13-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 199; (vii) a polypeptide sequence carrying IL13-VH encoded by the nucleic acid sequence of SEQ ID NO: 187, and a polypeptide sequence carrying IL13-VL encoded by the nucleic acid sequence of SEQ ID NO: 188; (viii) an IL13-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127196, and an IL13-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127195; or (ix) the polypeptide sequence carrying IL13-VH encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127193, and the polypeptide sequence carrying IL13-VL encoded by the plasmid deposited with ATCC and having ATCC deposit number PTA-127192.

13. The antibody according to any one of claims 5 to 12, characterized in that One or more of: (i) the antibody has a K of less than a value selected from 10 nM, 5 nM, 2 nM, 1 nM, 900 pM, 800 pM, 700 pM, 600 pM, 500 pM, 400 pM, 300 pM, 250 pM, 200 pM, 150 pM, 100 pM and 60 pM; D Binds to human IL-13; (ii) the antibody optionally has a binding K of the antibody to human IL-13 D Binds to cynomolgus monkey IL-13 within 1 order of magnitude of (iii) IL-13 IC as measured by neutralization of IL-13pSTAT6 phosphorylation in HT-29 cells 50 Less than 100 pM; (iv) IL-13 IC neutralizing IL-13-induced CD23 as measured in a human monocyte assay 50 Less than 20pM; (v) the antibody has a terminal half-life of at least 14 days in cynomolgus monkeys; (vi) the antibody has a terminal half-life of at least 18 days in TG32 mice; (vii) the antibody does not bind to IL-13 from one or more species selected from dog, rabbit and mouse.

14. The antibody of any one of claims 5 to 13, wherein (i) the IL-33 binding domain comprises a heavy chain variable region (IL33-VH) and a light chain variable region (IL33-VL), wherein CDR-H1 of the IL-33 binding domain comprises the amino acid sequence of SEQ ID NO: 60; CDR-H2 of the IL-33 binding domain comprises the amino acid sequence of SEQ ID NO: 61; CDR-H3 of the IL-33 binding domain comprises the amino acid sequence of SEQ ID NO: 72; CDR-L1 of the IL-33 binding domain comprises the amino acid sequence of SEQ ID NO: 75; CDR-L2 of the IL-33 binding domain comprises the amino acid sequence of SEQ ID NO: 76; and CDR-L3 of the IL-33 binding domain comprises the amino acid sequence of SEQ ID NO: 77; and (ii) the IL-4 binding domain comprises a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL), wherein CDR-H1 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 18; CDR-H2 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 2; CDR-H3 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 3; CDR-L1 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 24; CDR-L2 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 12, and CDR-L3 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 25, and (iii) the IL-13 binding domain comprises a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL), wherein CDR-H1 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 41; CDR-H2 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 42; CDR-H3 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 50; CDR-L1 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 53; CDR-L2 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 37, and CDR-L3 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO:

38.

15. The antibody of any one of claims 5 to 14, wherein (i) the IL-33 binding domain comprises IL33-VH of SEQ ID NO: 73 and IL33-VL of SEQ ID NO: 78; (ii) the IL-4 binding domain comprises IL4-VH of SEQ ID NO: 22 and IL4-VL of SEQ ID NO: 26; and (iii) the IL-13 binding domain comprises IL13-VH of SEQ ID NO: 51 and IL13-VL of SEQ ID NO:

54.

16. An isolated antibody that specifically binds to IL-33, specifically binds to IL-4, and specifically binds to IL-13, comprising an IL-33 binding domain, an IL-4 binding domain, and an IL-13 binding domain, wherein (i) the IL-33 binding domain comprises an IL33-VH sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127210, and an IL33-VL sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127209; (ii) the IL-4 binding domain comprises an IL4-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC deposit number PTA-127198, and an IL4-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC deposit number PTA-127197; and (iii) the IL-13 binding domain comprises an IL13-VH sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127196, and an IL13-VL sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127195.

17. The antibody of any one of claims 5 to 16, wherein the antibody comprises a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain and a fifth polypeptide chain, such that (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising a first antigen binding site; (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising a second antigen binding site; (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a third antigen binding site.

18. The antibody of claim 17, wherein the properties of the first polypeptide chain, the second polypeptide chain, the third polypeptide chain, the fourth polypeptide chain, and the fifth polypeptide chain are selected from the group consisting of: (i) the first polypeptide chain comprises SEQ ID NO: 132, the second polypeptide chain comprises SEQ ID NO: 130, the third polypeptide chain comprises SEQ ID NO: 79, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122; (ii) the first polypeptide chain comprises SEQ ID NO: 146, the second polypeptide chain comprises SEQ ID NO: 145, the third polypeptide chain comprises SEQ ID NO: 109, the fourth polypeptide chain comprises SEQ ID NO: 196, and the fifth polypeptide chain comprises SEQ ID NO: 103; (iii) the first polypeptide chain comprises SEQ ID NO: 112, the second polypeptide chain comprises SEQ ID NO: 107, the third polypeptide chain comprises SEQ ID NO: 196, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 103; (iv) the first polypeptide chain comprises SEQ ID NO: 118, the second polypeptide chain comprises SEQ ID NO: 115, the third polypeptide chain comprises SEQ ID NO: 119, the fourth polypeptide chain comprises SEQ ID NO: 116, and the fifth polypeptide chain comprises SEQ ID NO: 103; (v) the first polypeptide chain comprises SEQ ID NO: 118, the second polypeptide chain comprises SEQ ID NO: 115, the third polypeptide chain comprises SEQ ID NO: 120, the fourth polypeptide chain comprises SEQ ID NO: 116, and the fifth polypeptide chain comprises SEQ ID NO: 103; (vi) the first polypeptide chain comprises SEQ ID NO:209, the second polypeptide chain comprises SEQ ID NO:121, the third polypeptide chain comprises SEQ ID NO:196, the fourth polypeptide chain comprises SEQ ID NO:109, and the fifth polypeptide chain comprises SEQ ID NO:103; (vii) the first polypeptide chain comprises SEQ ID NO: 128, the second polypeptide chain comprises SEQ ID NO: 125, the third polypeptide chain comprises SEQ ID NO: 79, the fourth polypeptide chain comprises SEQ ID NO: 208, and the fifth polypeptide chain comprises SEQ ID NO: 122; (viii) the first polypeptide chain comprises SEQ ID NO: 134, the second polypeptide chain comprises SEQ ID NO: 133, the third polypeptide chain comprises SEQ ID NO: 79, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122; (ix) the first polypeptide chain comprises SEQ ID NO: 121, the second polypeptide chain comprises SEQ ID NO: 144, the third polypeptide chain comprises SEQ ID NO: 196, the fourth polypeptide chain comprises SEQ ID NO: 136, and the fifth polypeptide chain comprises SEQ ID NO: 143; (x) the first polypeptide chain comprises SEQ ID NO: 137, the second polypeptide chain comprises SEQ ID NO: 135, the third polypeptide chain comprises SEQ ID NO: 138, the fourth polypeptide chain comprises SEQ ID NO: 136, and the fifth polypeptide chain comprises SEQ ID NO: 122; (xi) the first polypeptide chain comprises SEQ ID NO: 142, the second polypeptide chain comprises SEQ ID NO: 140, the third polypeptide chain comprises SEQ ID NO: 79, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122; (xii) the first polypeptide chain comprises a sequence encoded by a nucleic acid according to SEQ ID NO: 190, the second polypeptide chain comprises a sequence encoded by a nucleic acid according to SEQ ID NO: 188, the third polypeptide chain comprises a sequence encoded by a nucleic acid according to SEQ ID NO: 191, the fourth polypeptide chain comprises a sequence encoded by a nucleic acid according to SEQ ID NO: 187, and the fifth polypeptide chain comprises a sequence encoded by a nucleic acid according to SEQ ID NO: 122; and (xiii) wherein the first polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having an ATCC deposit number of PTA-127208; the second polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having an ATCC deposit number of PTA-127192; the third polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having an ATCC deposit number of PTA-127207; the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having an ATCC deposit number of PTA-127194; and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having an ATCC deposit number of PTA-127193.

19. The antibody of any one of claims 17 to 18, wherein the first polypeptide chain comprises SEQ ID NO: 132, the second polypeptide chain comprises SEQ ID NO: 130, the third polypeptide chain comprises SEQ ID NO: 79, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO:

122.

20. An isolated antibody that specifically binds IL-33, specifically binds IL-4, and specifically binds IL-13, comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site; (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site; (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising an IL-33 binding site; and Wherein the first polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having the ATCC deposit number PTA-127208; the second polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having the ATCC deposit number PTA-127192; the third polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having the ATCC deposit number PTA-127207; the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having the ATCC deposit number PTA-127194; and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having the ATCC deposit number PTA-127193.

21. The antibody of any one of claims 1 to 20, wherein the antibody is characterized by one or more of the following: (i) with a K value less than 100 pM, 50 pM, 40 pM, 30 pM, 25 pM, 20 pM, 15 pM and 10 pM, 5 pM, 2 pM, 1 pM, 750 fM, 500 fM and 250 fM D Binds to human IL-33; (ii) In HEK In the IL-33 neutralization SEAP assay, IC 50 Less than 20pM; (iii) binding to cynomolgus monkey IL-33; (iv) Binding K of the Antibody to Cynomolgus Monkey IL-33 D The binding K of the antibody to human IL-33 D within 3 orders of magnitude; (v) a viscosity of less than 20 cP at a concentration of at least 50 mg / mL in a 20 mM histidine, 8.5% sucrose, 0.05 mg / mL EDTA buffer, pH 6.0; (vi) a viscosity of less than 15 cP at a concentration of at least 90 mg / mL in a 20 mM histidine, 8.5% sucrose, 0.05 mg / mL EDTA buffer, pH 6.0; (vii) a terminal half-life of at least 12 days in cynomolgus monkeys; (viii) a terminal half-life of at least 16 days in TG32 mice; (ix) binds to one or both of human IL-4 and human IL-13 with a binding affinity of less than 220 nM as measured by SPR; (x) binds to one or both of human IL-4 and human IL-13 with a binding affinity of less than 1 pM as measured by KinExA immobilized antigen assay in PBS; (xi) IC of IL-4-induced neutralization of CD23 in human monocyte assay 50 Less than 20nM; (xii) IC of IL-13-induced neutralization of CD23 in human monocyte assay 50 Less than 20nM; (xiii) In the wild-type IL-33 neutralization HEK-Blue SEAP assay, IC 50 Less than 30nM; (xiv) In the recombinant constitutively active IL-33 neutralization HEK-Blue SEAP assay, IC 50 Less than 15pM.

22. The antibody of any one of claims 1 to 21 for use in treating one or more selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, diabetic nephropathy, Behcet's disease, gout, Alzheimer's disease, atherosclerosis, and non-alcoholic steatohepatitis (NASH).

23. A pharmaceutical composition comprising a therapeutically effective amount of the antibody of any one of claims 1 to 22 and a pharmaceutically acceptable carrier.

24. A method of treating a medical condition comprising administering to a subject in need thereof a therapeutically effective amount of the antibody of any one of claims 1 to 22 or the pharmaceutical composition of claim 23.

25. The method of any one of claims 1 to 24, comprising administering the antibody or the pharmaceutical composition subcutaneously.

26. The method of claim 25, wherein the antibody or the pharmaceutical composition is administered about twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, twice a month, once a month, once every two months, once every three months, or once every four months.

27. An isolated polynucleotide comprising one or more nucleotide sequences encoding the antibody of any one of claims 1 to 22.

28. The isolated polynucleotide of claim 27, comprising one or more of: (i) a nucleotide sequence encoding VH, VL, or both of an antibody that binds to IL-33, wherein the nucleic acid comprises the nucleic acid sequence of SEQ ID NO: 202, the nucleic acid sequence of SEQ ID NO: 203, or both; (ii) a nucleotide sequence encoding a polypeptide carrying VH and a polypeptide carrying VL, or both, of an antibody that binds to IL-33, wherein the nucleic acid comprises the nucleic acid sequence of SEQ ID NO: 190, the nucleic acid sequence of SEQ ID NO: 191, or both; (iii) a nucleotide sequence encoding VH, VL, or both of an antibody that binds to IL-33, wherein the nucleic acid comprises the nucleic acid sequence of an insert of a plasmid deposited with the ATCC and having a deposit number of PTA-127209, and the nucleic acid sequence of an insert of a plasmid deposited with the ATCC and having a deposit number of PTA-127210, or both; (iv) a nucleotide sequence encoding VH, VL, or both of an antibody that binds to IL-33, wherein the nucleic acid comprises the nucleic acid sequence of an insert of a plasmid deposited with the ATCC and having a deposit number of PTA-127209, and the nucleic acid sequence of an insert of a plasmid deposited with the ATCC and having a deposit number of PTA-127210, or both; (v) a nucleotide sequence encoding one or more of the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide or the fifth polypeptide of the anti-IL-4 / IL-13 / IL-33 antibody, comprising (iv) the IL33-VH sequence according to SEQ ID NO: 202 and the IL33-VH sequence according to SEQ ID NO: IL33-VL sequence of 203; (v) the IL4-VH sequence according to SEQ ID NO: 200 and the IL4-VH sequence according to SEQ ID NO: 201 IL4-VL sequence; and (vi) the IL13-VH sequence according to SEQ ID NO: 198 and the IL13-VH sequence according to SEQ ID NO: IL13-VL sequence of 199; (vi) a nucleotide sequence encoding one or more of the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide or the fifth polypeptide of the anti-IL-4 / IL-13 / IL-33 antibody, comprising a) a polypeptide carrying IL33-VH encoded by the sequence of SEQ ID NO: 190, and a polypeptide carrying IL33-VL encoded by the sequence of SEQ ID NO: 191; b) a polypeptide carrying IL4-VH encoded by the sequence according to SEQ ID NO: 188; and a polypeptide carrying IL4-VL encoded by the sequence according to SEQ ID NO: 189; and c) a polypeptide carrying IL13-VH encoded by the sequence according to SEQ ID NO: 187; and a polypeptide carrying IL13-VL encoded by the sequence according to SEQ ID NO: 188; (vii) a nucleotide sequence encoding one or more of the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide or the fifth polypeptide of the anti-IL-4 / IL-13 / IL-33 antibody, comprising a) an IL33-VH sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127210, and an IL33-VL sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127209; b) an IL4-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC deposit number PTA-127198, and an IL4-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC deposit number PTA-127197; and c) an IL13-VH sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127196, and an IL13-VL sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127195; (viii) a nucleotide sequence encoding one or more of the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide or the fifth polypeptide of the anti-IL-4 / IL-13 / IL-33 antibody, comprising a) a polypeptide carrying IL33-VH encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127208, and a polypeptide carrying IL33-VL encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127207; b) a polypeptide carrying IL4-VH encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127192, and a polypeptide carrying IL4-VL encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127194; and c) a polypeptide carrying IL13-VH encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127193, and a polypeptide carrying IL13-VL encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127192.

29. A vector comprising the polynucleotide of any one of claims 27 to 28.

30. An isolated host cell comprising the polynucleotide of any one of claims 27 to 28 or the vector of claim 29.

31. A method of producing an isolated antibody comprising culturing the host cell of claim 30 under conditions which result in production of the antibody and recovering the antibody.

32. The method of claim 31, wherein the isolated antibody is a heterotrimeric antibody comprising a dual Fab arm and a single Fab arm, wherein the dual Fab arm comprises a first Fab domain connected to a second Fab domain connected to a first Fc domain, and the single Fab arm comprises a third Fab domain connected to the second Fc domain, and the method comprises (i) a first preassembly step, wherein the bis-Fab arms are incubated in a first preassembly adjustment buffer at a temperature of 2°C to 10°C and wherein the pH of the first preassembly adjustment buffer is 1 to 3 units lower than the isoelectric point (pI) of the bis-Fab arms; and (ii) a second preassembly step, wherein the single Fab arm is incubated in a second preassembly adjustment buffer at a temperature of 2°C to 10°C and wherein the pH of the second preassembly adjustment buffer is 1 to 3 units lower than the isoelectric point (pi) of the single Fab arm; and (iii) a third assembly step, wherein the dual Fab arm and the single Fab arm from steps (i) and (ii) are mixed together in assembly buffer for 1 to 24 hours.

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