Multispecific antibodies and uses thereof

Abstract

To provide antibodies for use in safe and effective therapeutics for numerous diseases characterized by inflammatory responses, that address a broad range of pathogenic mechanisms.SOLUTION: 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 pertains to nucleic acids which encode such antibodies or multispecific antibodies, compositions, and methods for producing and purifying such antibodies and multispecific antibodies, and their use in diagnostics and therapeutics.SELECTED DRAWING: Figure 37

Description

Technical Field

[0001] 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 one of IL-4, IL-13, and 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 diagnostic and therapeutic methods.

[0002] Reference to the Sequence Listing "This application includes a Sequence Listing submitted electronically in.xml format, which is hereby incorporated by reference in its entirety. The.xml file created on February 9, 2023, is named PC072799 Sequence Listing.xml and is 252 KB in size."

Background Art

[0003] Background The present invention relates to antibodies that specifically bind to one or more of IL-4, IL-13, IL-33, TSLP, and p40, and compositions, methods, and uses thereof, including the treatment and prevention of one or more symptoms associated with individual diseases or conditions, such as atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloid, 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, allergy, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloid, systemic lupus erythematosus (SLE), primary biliary cirrhosis, and hidradenitis suppurativa, and includes the use of the antibodies of the present disclosure for treating one or more diseases or conditions selected from the group consisting of.

[0004] IL-4 and IL-13 are important drivers of immune activation and cause inflammation, edema, fibrosis, and itching in atopic disorders (48, 49). IL-4 and IL-13 interact with cells via a common receptor consisting of IL-4Rα and IL-13Rα1 (type II receptor) expressed in monocytes, fibroblasts, keratinocytes, epithelial cells, smooth muscle cells, and other non-lymphoid cell types (29). IL-4 can also activate cells via the IL-4Rα / IL-2Rγ common (type I receptor) expressed in T cells, B cells, and monocytes. Association of IL-4Rα via either receptor activates STAT6 and induces atopy-related genes (29). IL-4 and IL-13 may be involved in common receptors and signaling pathways, but differences in cytokine availability, localization, and receptor binding affinity result in distinct response profiles (49, 50). Further differentiation can result from the type I receptor (IL-4Rα / γc) that drives Th2 differentiation via IL-4 rather than IL-13 (51), and the cell surface "decoy" IL-13Rα2 that mediates neutralization and depletion of IL-13 rather than IL-4 (52, 53).

[0005] The roles of IL-4 and IL-13 in atopic diseases are supported by genetic associations, extensive validation in preclinical models, and clinical efficacy of IL-4 and IL-13 neutralization in a range of atopic indications (48). Dupixent® (dupilumab, Sanofi / Regeneron), an anti-IL-4Rα, 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 the activity of IL-4 and IL-13 in these indications (54 - 56). The anti-IL-13 mAbs lebrikizumab (Lilly) (57) and tralokinumab (Adbry™, Leo Pharma) (58, 59) also have more limited activity in asthma and have demonstrated efficacy in AD (60, 61). The efficacy of anti-IL-13 mAbs in AD suggests a major role for IL-13 neutralization in the efficacy of Dupixent®. Nevertheless, available meta-analyses (62, 63) suggest that Dupixent® has superior activity to lebrikizumab and tralokinumab, consistent with additional benefits of IL-4 blockade.

[0006] IL-33 is released passively during cell necrosis or when tissues are damaged, suggesting that it may function as an alarmin that modifies 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 activation of eosinophils, basophils, mast cells, macrophages, and group 2 innate lymphoid cells (ILC2) associated with allergic inflammation via its receptor ST2 (96).

[0007] Thymic stromal lymphopoietin (TSLP) is an epithelial cytokine important in the initiation and persistence of inflammation. Tezspire® (tezepelumab, Amgen) is a TSLP antibody approved for the treatment of asthma.

[0008] IL-4 and IL-13 are mainly associated with type 2 effector responses. In contrast, IL-12 and IL-23 are involved in type 1 and type 3 (Th17) responses, respectively (77). IL-12 drives helper T1 (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 are involved in a range of human inflammatory and autoimmune diseases. The causal role of IL-12p40-containing cytokines has been established by the approval of numerous drugs (75) (IL-12p40 is simply referred to as p40 hereinafter in this specification). The p40 neutralizing agent Stelara® (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. The IL-23 selective anti-IL-23p19 blocking agents Tremfya® (guselkumab, Janssen), Skyrizi® (risankizumab, Boehringer Ingelheim / AbbVie), and Ilumya® (tildrakizumab, Sun Pharmaceutical) are approved for a range of psoriatic disorders. SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION

[0009] Despite the effectiveness of dupilumab, tezepelumab, guselkumab, risankizumab, and tildrakizumab, there remains an unmet need for safe and effective therapies for numerous diseases characterized by immune responses that address a wide range of pathogenic mechanisms. MEANS FOR SOLVING THE PROBLEMS

[0010] Overview 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 thereof, related nucleic acids, uses, and related methods are provided herein. The disclosure also provides methods for making, preparing, and producing antibodies that bind to one or more of IL-4, IL-13, IL-33, TSLP, and p40. The antibodies of the disclosure are useful for one or more of the diagnosis, prevention, or treatment of disorders or conditions mediated by or associated with one or more of the activities of IL-4, IL-13, IL-33, TSLP, and p40, including, but not limited to, atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloid, 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, allergy, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloid, systemic lupus erythematosus (SLE), primary biliary cirrhosis, and hidradenitis suppurativa. The disclosure further encompasses the expression of the antibodies, as well as the preparation and manufacture of compositions comprising the antibodies of the disclosure, such as medicaments for the use of the antibodies.

[0011] 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 chain and / or light chain of the antibody. Also provided are host cells expressing the antibody. Also provided are methods of treatment using the antibody. Such methods include, but are not limited to, one or more of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloid, 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, allergy, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloid, systemic lupus erythematosus (SLE), primary biliary cirrhosis, and hidradenitis suppurativa, which are related to or mediated by one or more of the expression of IL-4, IL-13, IL-33, TSLP, and p40, and / or one or more of the binding of IL-4, IL-13, IL-33, TSLP, and p40, and methods of treating or preventing one or more of them.

[0012] The present invention can be more readily understood by reference to the following detailed description of embodiments and examples of the invention included herein. It should be understood that the present invention is not limited to the specific methods of manufacture that may be subject to change. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting. One of ordinary skill in the art will recognize or be able to ascertain, using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following embodiments (E).

[0013] E1. An isolated antibody that specifically binds to IL-33, (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 An antibody comprising a heavy chain variable region (IL33-VH) and a light chain variable region (IL33-VL) containing the same.

[0014] An isolated antibody that specifically binds to E2.IL-33, comprising a heavy chain variable region (IL33-VH) and a light chain variable region (IL33-VL) containing 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.

[0015] An isolated antibody that specifically binds to E3.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.

[0016] The antibody according to any one of E1 to E3, 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.

[0017] The antibody according to any one of E1 to E4, comprising an IL33-VH framework sequence derived from the human DP54 germline sequence.

[0018] An antibody according to any one of E1 to E5, comprising an IL33-VL framework sequence derived from a human germline VL sequence selected from the group consisting of E6.DPK1, DPK3, DPK4, DPK5, DPK7, DPK8, and DPK9.

[0019] E7. An antibody according to any one of E1 to E6, comprising an IL33-VL framework sequence derived from the human germline DPK9 sequence.

[0020] E8. An antibody according to any one of E1 to E7, comprising 98%, 99%, or 100% of the sequences of the IL33-VL framework sequence and the IL33-VH framework sequence, wherein one or both of the IL33-VL framework sequence and the IL33-VH framework sequence is at least 66%, 76%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% identical to the human germline sequence from which it is derived.

[0021] E9. An antibody according to any one of E1 to E8, comprising the IL33-VL framework sequence and the IL33-VH framework sequence, wherein one or both of the IL33-VL framework sequence or the IL33-VH framework sequence is identical to the human germline sequence from which it is derived.

[0022] E10. An antibody according to 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.

[0023] E11. An antibody according to 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.

[0024] E12. (i) The IL33-VH sequence of SEQ ID NO: 73, and the IL33-VL 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 of SEQ ID NO: 81 The antibody according to any one of E1 to E11, comprising

[0025] E13. The antibody according to 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.

[0026] E14. The antibody according to any one of E1 to E13, comprising an IL33-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 202.

[0027] E15. The antibody according to any one of E1 to E14, comprising an IL33-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 203.

[0028] E16. The antibody according to any one of E1 to E15, comprising an IL33-VH sequence encoded by a plasmid deposited with the ATCC and having the ATCC accession number PTA-127210.

[0029] E17. The antibody according to any one of E1 to E16, comprising an IL33-VL sequence encoded by a plasmid deposited with the ATCC and having the ATCC accession number PTA-127209.

[0030] E18. An antibody comprising an IL33-VH sequence encoded by a plasmid deposited with the ATCC and having the ATCC accession number PTA-127210, and an IL33-VL sequence encoded by a plasmid deposited with the ATCC and having the ATCC accession number PTA-127209.

[0031] K less than a value selected from the group consisting of 19.100 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 An antibody according to any one of E1 to E18, which binds to human IL-33 at D .

[0032] E20. K of about 15 pM or less D An antibody according to any one of E1 to E19, which binds to human IL-33 at D .

[0033] E21. K of about 1 pM or less D An antibody according to any one of E1 to E20, which binds to human IL-33 at D .

[0034] E22. K of about 250 fM or less D An antibody according to any one of E1 to E21, which binds to human IL-33 at D .

[0035] E23. K D An antibody according to any one of E19 to E22, wherein the value of K is measured by the binding equilibrium exclusion method.

[0036] E24. K D An antibody according to any one of E19 to E22, wherein the value of K is measured by surface plasmon resonance (SPR).

[0037] E25. IC of IL-33 50 An antibody according to any one of E1 to E24, wherein the IC of IL-33 is less than 20 pM in the HEK Blue® IL-33 neutralization SEAP assay.

[0038] E26. IC of IL-33 50 An antibody according to any one of E1 to E25, wherein the IC of IL-33 is less than 15 pM in the HEK Blue® IL-33 neutralization SEAP assay.

[0039] E27. An antibody according to any one of E25 to E26, wherein the HEK Blue® IL-33 neutralization SEAP assay is performed at 37 °C for 20 hours.

[0040] The IC of IL-33 50 is less than 15 pM and is calculated by ELISA measurement of IFNγ in a human whole blood assay treated with IL-33 and IL-12, the antibody according to E1 to E27.

[0041] E29. The antibody according to E28, wherein the human whole blood assay is performed at 37 °C for 22 hours.

[0042] E30. The antibody according to E1 to E29, which binds to cynomolgus monkey IL-33.

[0043] E31. The binding K of the antibody to cynomolgus monkey IL-33 D is within three digits of the binding K of the antibody to human IL-33 D the antibody according to E1 to E30.

[0044] E32. The antibody according to E1 to E31, further comprising a constant heavy domain (IL33-CH1) and a constant light domain (IL33-CL).

[0045] E33. The antibody according to 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.

[0046] E34. The antibody according to E32 to E33, wherein IL33-CH1 comprises the sequence set forth in SEQ ID NO: 6.

[0047] E35. The antibody according to 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.

[0048] E36. The antibody according to E32 to E35, wherein IL33-CL comprises the sequence set forth in SEQ ID NO: 16.

[0049] The antibody according to any one of E32 to E36, wherein E37.IL33-CH1 is connected to IL33-VL, IL33-CL is connected to IL33-VH, and an IL-33-binding domain-swapped Fab domain (IL33-xFab) is formed.

[0050] The antibody according to any one of E32 to E37, wherein E38.IL33-CH1 is connected to IL33-VH, IL33-CL is connected to IL33-VL, and an IL-33-binding Fab domain (IL33-Fab) is formed.

[0051] The antibody according to any one of E1 to E38, comprising an antibody Fc domain comprising a first Fc chain and a second Fc chain.

[0052] The antibody according to E39, wherein E40.the Fc domain is an Fc domain of IgA (e.g., IgA1 or IgA2), IgD, IgE, IgM, or IgG (e.g., IgG1, IgG2, IgG3, or IgG4).

[0053] The antibody according to E40, wherein E41.the Fc domain is an Fc domain of IgG1.

[0054] The antibody according to E40, wherein E42.the N-terminus of the first Fc chain or the second Fc chain is connected to the C-terminus of the IL33-CH1 domain.

[0055] The antibody according to any one of E41 to E42, wherein E43.the first and second Fc chains each comprise a hinge region, a CH2 region, and a CH3 region from the N-terminus to the C-terminus.

[0056] The antibody according to E43, wherein E44.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.

[0057] The antibody according to E44, wherein E45.the hinge region comprises the sequence set forth in SEQ ID NO: 7.

[0058] The antibody according to E44, wherein the hinge region in the first Fc chain and the hinge region in the second Fc chain comprise a pair of sequences set forth in SEQ ID NO: 129 and SEQ ID NO: 131.

[0059] The antibody according to any one of E43 to E46, wherein the CH2 region comprises the sequence set forth in SEQ ID NO: 8.

[0060] E48. The CH3 region in the first Fc chain and the CH3 region in the second Fc chain are (i) SEQ ID NO: 9 and SEQ ID NO: 9, (ii) SEQ ID NO: 111 and SEQ ID NO: 106, (iii) SEQ ID NO: 111 and SEQ ID NO: 114, (iv) SEQ ID NO: 114 and SEQ ID NO: 117, (v) SEQ ID NO: 124 and SEQ ID NO: 127, (vi) SEQ ID NO: 139 and SEQ ID NO: 141, and (vii) SEQ ID NO: 147 and SEQ ID NO: 148 The antibody according to any one of E43 to E47, comprising a pair of sequences selected from the group consisting of

[0061] E49. The antibody according to E48, wherein the CH3 region in the first Fc chain and the CH region in the second Fc chain each comprise the sequence set forth in SEQ ID NO: 9.

[0062] E50. The antibody according to E48, wherein the CH3 region in the first Fc chain and the CH3 region in the second Fc chain comprise a pair of sequences set forth in SEQ ID NO: 124 and SEQ ID NO: 127.

[0063] The antibody according to any one of E1 to E50, comprising a polypeptide having an IL33-VH with 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: 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.

[0064] The antibody according to any one of E1 to E51, comprising a polypeptide having an IL33-VH comprising an amino acid sequence selected from the group consisting of 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.

[0065] The antibody according to any one of E52 to E53, wherein the polypeptide having an IL33-VH comprises the sequence set forth in SEQ ID NO: 74.

[0066] The antibody according to any one of E52 to E52, wherein the polypeptide having an IL33-VH comprises the sequence set forth in SEQ ID NO: 132.

[0067] The antibody according to E32 to E54, wherein the 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.

[0068] The antibody according to E32 to E55, wherein the IL33-CL comprises the amino acid sequence of SEQ ID NO: 16.

[0069] The antibody according to any one of E1 to 56, comprising a polypeptide having an IL33-VL having 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: 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.

[0070] The antibody according to any one of E1 to E57, comprising a polypeptide having an IL33-VL comprising the amino acid sequence of SEQ ID NO: 79.

[0071] The antibody according to any one of E1 to E58, comprising a polypeptide having an IL33-VH of SEQ ID NO: 74 and a polypeptide having an IL33-VL of SEQ ID NO: 79.

[0072] An antibody according to any one of E1 to E59, comprising a polypeptide having IL33-VH of SEQ ID NO: 132 and a polypeptide having IL33-VL of SEQ ID NO: 79.

[0073] An antibody according to any one of E1 to E60, comprising a polypeptide sequence having IL33-VH encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127208.

[0074] An antibody according to any one of E1 to E61, comprising a polypeptide sequence having IL33-VL encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127207.

[0075] An antibody comprising a polypeptide sequence having IL33-VH encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127208, and a polypeptide having IL33-VL encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127207.

[0076] An isolated antibody that specifically binds to IL-33, comprising the CDRs of an antibody selected from one or more of Tables 82, 85, and 87.

[0077] 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.

[0078] An isolated antibody that specifically binds to IL-33, which is an antibody selected from one or more of Tables 82, 84, and 87.

[0079] An antibody according to any one of E1 to 65 for use as a medicament.

[0080] The antibody according to E67, wherein the use is for one or more treatments selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloid, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, diabetic kidney disease, Behçet's disease, gout, Alzheimer's disease, and atherosclerosis.

[0081] The antibody according to any one of E67 to E68, wherein the use is for one or more treatments selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, and non-alcoholic steatohepatitis (NASH).

[0082] The antibody according to any one of E67 to E69, wherein the use is for atopic dermatitis.

[0083] The antibody according to any one of E67 to E69, wherein the use is for non-alcoholic steatohepatitis (NASH).

[0084] A pharmaceutical composition comprising a therapeutically effective amount of the antibody according to E1 to E71 and a pharmaceutically acceptable carrier.

[0085] A method of treating a medical condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of the antibody according to any one of E1 to E71 or the pharmaceutical composition according to E72.

[0086] The method according to E73, wherein the condition is selected from atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloid, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, diabetic kidney disease, Behçet's disease, gout, Alzheimer's disease, and atherosclerosis.

[0087] E75. The method according to any one of E73 to E74, comprising subcutaneous administration of the antibody or pharmaceutical composition.

[0088] E76. The method according to any one of E73 to E75, wherein the antibody or pharmaceutical composition is administered 2 times a week, 1 time a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, 2 times a month, 1 time a month, once every 2 months, once every 3 months, or once every 4 months.

[0089] E77. An isolated antibody that specifically binds to TSLP, (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, (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, (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, (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, (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, (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 (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 An antibody comprising a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL) containing the same.

[0090] An isolated antibody that specifically binds to E78.TSLP, comprising a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL) containing 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.

[0091] An isolated antibody that specifically binds to E79.TSLP, (i) 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, a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL); (ii) 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, a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL); (iii) 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, a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL); (iv) The heavy chain variable region (TSLP-VH) and the light chain variable region (TSLP-VL) in which CDR-H1 contains the amino acid sequence of SEQ ID NO: 82, CDR-H2 contains the amino acid sequence of SEQ ID NO: 83, CDR-H3 contains the amino acid sequence of SEQ ID NO: 85, CDR-L1 contains the amino acid sequence of SEQ ID NO: 86, CDR-L2 contains the amino acid sequence of SEQ ID NO: 87, and CDR-L3 contains the amino acid sequence of SEQ ID NO: 211, (v) The heavy chain variable region (TSLP-VH) and the light chain variable region (TSLP-VL) in which CDR-H1 contains the amino acid sequence of SEQ ID NO: 82, CDR-H2 contains the amino acid sequence of SEQ ID NO: 83, CDR-H3 contains the amino acid sequence of SEQ ID NO: 85, CDR-L1 contains the amino acid sequence of SEQ ID NO: 86, CDR-L2 contains the amino acid sequence of SEQ ID NO: 88, and CDR-L3 contains the amino acid sequence of SEQ ID NO: 90, or (vi) The heavy chain variable region (TSLP-VH) and the light chain variable region (TSLP-VL) in which CDR-H1 contains the amino acid sequence of SEQ ID NO: 82, CDR-H2 contains the amino acid sequence of SEQ ID NO: 83, CDR-H3 contains the amino acid sequence of SEQ ID NO: 85, CDR-L1 contains the amino acid sequence of SEQ ID NO: 86, CDR-L2 contains the amino acid sequence of SEQ ID NO: 87, and CDR-L3 contains the amino acid sequence of SEQ ID NO: 212 An antibody comprising

[0092] The antibody according to any one of E77 to E79, comprising a TSLP-VH framework sequence derived from a human germline VH sequence selected from the group consisting of E80.DP47, DP49, DP50, DP54, and DP53.

[0093] The antibody according to any one of E77 to E80, comprising a TSLP-VH framework sequence derived from the human DP50 germline sequence.

[0094] The antibody according to 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 E82.DPL16, DPL23, V2-6, V2-8, V2-14, and V2-17.

[0095] E83. The antibody according to any one of E77 to E82, comprising a TSLP-VL framework sequence derived from the human germline V2-14 sequence.

[0096] E84. The antibody according to any one of E77 to E84, comprising a TSLP-VL framework sequence and a TSLP-VH framework sequence, wherein one or both of the TSLP-VL framework sequence or the TSLP-VH framework sequence is 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 it is derived.

[0097] E85. The antibody according to any one of E77 to E84, comprising a TSLP-VL framework sequence and a TSLP-VH framework sequence, wherein one or both of the TSLP-VL framework sequence or the TSLP-VH framework sequence is identical to the human germline sequence from which it is derived.

[0098] E86. The antibody according to any one of E77 to E85, comprising a TSLP-VH sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 92.

[0099] E87. The antibody according to any one of E77 to E86, comprising a TSLP-VL sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 94.

[0100] E88. (i) The TSLP-VH sequence of SEQ ID NO: 92, and the TSLP-VL of SEQ ID NO: 94 (ii) The TSLP-VH sequence of SEQ ID NO: 92, and the TSLP-VL of SEQ ID NO: 93, (iii) The TSLP-VH sequence of SEQ ID NO: 92, and the TSLP-VL of SEQ ID NO: 213, (iv) The TSLP-VH sequence of SEQ ID NO: 92, and the TSLP-VL of SEQ ID NO: 214, (v) The TSLP-VH sequence of SEQ ID NO: 221, and the TSLP-VL of SEQ ID NO: 215, (vi) The TSLP-VH sequence of SEQ ID NO: 221, and the TSLP-VL of SEQ ID NO: 99, or (vii) The TSLP-VH sequence of SEQ ID NO: 221, and the TSLP-VL of SEQ ID NO: 224 The antibody according to any one of E77 to E86, comprising

[0101] E89. The antibody according to any one of E77 to E88, comprising a TSLP-VH sequence identical to SEQ ID NO: 92 and a TSLP-VL identical to SEQ ID NO: 94.

[0102] E90. The antibody according to any one of E77 to E88, comprising a TSLP-VH sequence identical to SEQ ID NO: 92 and a TSLP-VL identical to SEQ ID NO: 93.

[0103] E91. The antibody according to any one of E77 to E88, comprising a TSLP-VH sequence identical to SEQ ID NO: 92 and a TSLP-VL identical to SEQ ID NO: 213.

[0104] E92. The antibody according to any one of E77 to E88, comprising a TSLP-VH sequence identical to SEQ ID NO: 92 and a TSLP-VL identical to SEQ ID NO: 214.

[0105] E93. The antibody according to any one of E77 to E89, comprising a TSLP-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 205.

[0106] E94. The antibody according to E91, comprising a TSLP-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 217.

[0107] The antibody according to E92, comprising a TSLP-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 218.

[0108] The antibody according to any one of E77 to E95, comprising a TSLP-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 204.

[0109] The antibody according to any one of E77 to E96, comprising a TSLP-VH sequence encoded by a plasmid deposited with ATCC and having an ATCC accession number PTA-127200.

[0110] The antibody according to any one of E77 to E89, comprising a TSLP-VL sequence encoded by a plasmid deposited with ATCC and having an ATCC accession number PTA-127199.

[0111] An antibody comprising a TSLP-VH sequence encoded by a plasmid deposited with ATCC and having an ATCC accession number PTA-127200, and a TSLP-VL sequence encoded by a plasmid deposited with ATCC and having an ATCC accession number PTA-127199.

[0112] The antibody according to any one of E77 to E88, comprising a TSLP-VL sequence encoded by a plasmid deposited with ATCC and having an ATCC accession number PTA-______.

[0113] An antibody comprising a TSLP-VH sequence encoded by a plasmid deposited with ATCC and having an ATCC accession number PTA-127200, and a TSLP-VL sequence encoded by a plasmid deposited with ATCC and having an ATCC accession number PTA-______.

[0114] An antibody according to any one of E77 to E88, comprising a TSLP-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-______.

[0115] E103. An antibody comprising a TSLP-VH sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127200, and comprising a TSLP-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-______.

[0116] E104. An IC of less than 10 pM in a TARC production bioassay in human peripheral blood monocytes 50 characterizing the antibody according to any one of E77 to E102.

[0117] E105. An IC of less than 7 pM in a TARC production bioassay in human peripheral blood monocytes 50 characterizing the antibody according to any one of E77 to E104.

[0118] E106. An IC of less than 6 pM in a TARC production bioassay in human peripheral blood monocytes 50 characterizing the antibody according to any one of E77 to E105.

[0119] E107. An antibody according to any one of E77 to E106, having a melting temperature of 68°C.

[0120] E108. The pH 3.4 hold ΔHMMS% is defined as the difference between the percentage of high molecular weight species due to the degradation of the antibody after 5 hours of incubation at pH 3.4 at room temperature and the percentage of high molecular weight species due to the degradation of the antibody after 5 hours of incubation at pH 7.2 at room temperature. An antibody according to any one of E77 to E107, wherein the pH 3.4 hold ΔHMMS% is less than 5.

[0121] An antibody according to any one of E77 to E108, having a low pH 3.4 hold ΔHMMS% of less than E109.1.

[0122] An antibody according to any one of E77 to E109, having a low pH 3.4 hold ΔHMMS% of less than E110.0.1.

[0123] An antibody according to any one of E77 to E110, further comprising a constant heavy domain (TSLP-CH1) and a constant light domain (TSLP-CL).

[0124] An antibody according to 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.

[0125] An antibody according to any one of E111 to E112, wherein TSLP-CH1 comprises the sequence set forth in SEQ ID NO: 6.

[0126] An antibody according to any one 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.

[0127] An antibody according to any one of E111 to E114, wherein TSLP-CL comprises the sequence set forth in SEQ ID NO: 95.

[0128] An antibody according to any one of E111 to E115, wherein TSLP-CH1 is connected to TSLP-VL, TSLP-CL is connected to TSLP-VH, and a TSLP-binding domain-swapped Fab domain (TSLP-xFab) is formed.

[0129] An antibody according to any one of E111 to E115, wherein TSLP-CH1 is connected to TSLP-VH, TSLP-CL is connected to TSLP-VL, and a TSLP-binding Fab domain (TSLP-Fab) is formed.

[0130] An antibody according to any one of E77 to E117, comprising an Fc domain comprising a first Fc chain and a second Fc chain.

[0131] E119. The antibody according to E118, wherein the Fc domain is an Fc domain of IgA (e.g., IgA1 or IgA2), IgD, IgE, IgM, or IgG (e.g., IgG1, IgG2, IgG3, or IgG4).

[0132] E120. The antibody according to any one of E118 to E119, wherein the Fc domain is an Fc domain of IgG1.

[0133] E121. The antibody according to any one of E118 to E120, wherein the N-terminus of the first Fc chain or the second Fc chain is connected to the C-terminus of the TSLP-CH1 domain.

[0134] E122. The antibody according to any one of E118 to E121, wherein the first Fc chain and the second Fc chain each comprise a hinge region, a CH2 region, and a CH3 region from the N-terminus to the C-terminus.

[0135] E123. The antibody according to 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.

[0136] E124. The antibody according to any one of E122 to E123, wherein the hinge region comprises the sequence set forth in SEQ ID NO: 7.

[0137] E125. The antibody according to any one of E122 to E123, wherein the hinge region in the first Fc chain and the hinge region in the second Fc chain comprise a pair of the sequences set forth in SEQ ID NO: 129 and SEQ ID NO: 131.

[0138] E126. The antibody according to any one of E122 to E123, wherein the CH2 region comprises the sequence set forth in SEQ ID NO: 8.

[0139] The CH3 region in the first Fc chain and the CH3 region in the second Fc chain are (i) SEQ ID NO: 124 and SEQ ID NO: 127, (ii) SEQ ID NO: 9 and SEQ ID NO: 9, (iii) SEQ ID NO: 111 and SEQ ID NO: 106, (iv) SEQ ID NO: 111 and SEQ ID NO: 114, (v) SEQ ID NO: 114 and SEQ ID NO: 117, (vi) SEQ ID NO: 139 and SEQ ID NO: 141, and (vii) SEQ ID NO: 147 and SEQ ID NO: 148 The antibody according to any one of E122 to E126, comprising a pair of sequences selected from the group consisting of

[0140] E128. The antibody according to E127, wherein the CH3 region in the first Fc chain and the CH region in the second Fc chain each contain the sequence set forth in SEQ ID NO: 9.

[0141] E129. The antibody according to E128, wherein the CH3 region in the first Fc chain and the CH region in the second Fc chain contain a pair of sequences set forth in SEQ ID NO: 124 and SEQ ID NO: 127.

[0142] E130. The antibody according to any one of E77 to E129, comprising a polypeptide having a TSLP-VH with 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: 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.

[0143] E131. The antibody according to any one of E77 to E130, comprising a polypeptide having a TSLP-VH containing an amino acid sequence selected from the group consisting of 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.

[0144] The antibody according to any one of E77 to E131, wherein the polypeptide having E132.TSLP-VH comprises the sequence set forth in SEQ ID NO: 97.

[0145] The antibody according to any one of E77 to E131, wherein the polypeptide having E133.TSLP-VH comprises the sequence set forth in SEQ ID NO: 165.

[0146] The antibody according to any one of E77 to E133, comprising a polypeptide having TSLP-VL with 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: 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.

[0147] The antibody according to any one of E77 to E134, comprising a polypeptide having TSLP-VL comprising a sequence selected from the group consisting of 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.

[0148] The antibody according to any one of E77 to E135, comprising a polypeptide having TSLP-VL comprising the sequence set forth in SEQ ID NO: 99.

[0149] The antibody according to any one of E77 to E135, comprising a polypeptide sequence having TSLP-VL encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127201.

[0150] The antibody according to any one of E77 to E135, comprising a polypeptide sequence having TSLP-VL encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-_____.

[0151] An antibody according to any one of E77 to E135, comprising a polypeptide sequence of TSLP-VL encoded by a plasmid deposited with ATCC and having an ATCC accession number PTA-_____.

[0152] An antibody according to any one of E77 to E139, comprising a polypeptide sequence of TSLP-VH encoded by a plasmid deposited with ATCC and having an ATCC accession number PTA-127202.

[0153] An antibody comprising a polypeptide sequence of TSLP-VH encoded by a plasmid deposited with ATCC and having an ATCC accession number PTA-127202, and a polypeptide sequence of TSLP-VL encoded by a plasmid deposited with ATCC and having an ATCC accession number PTA-127201.

[0154] An antibody comprising a polypeptide sequence of TSLP-VH encoded by a plasmid deposited with ATCC and having an ATCC accession number PTA-127202, and a polypeptide sequence of TSLP-VL encoded by a plasmid deposited with ATCC and having an ATCC accession number PTA-_____.

[0155] An antibody comprising a polypeptide sequence of TSLP-VH encoded by a plasmid deposited with ATCC and having an ATCC accession number PTA-127202, and a polypeptide sequence of TSLP-VL encoded by a plasmid deposited with ATCC and having an ATCC accession number PTA-_____.

[0156] An isolated antibody that specifically binds to p40 via an E144.p40 binding domain and comprises at least one additional antigen-binding domain that specifically binds to an antigen selected from the group consisting of IL-4, IL-13, IL-33, and TSLP, 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.

[0157] An isolated antibody that specifically binds to p40 via an E145.p40 binding domain and comprises at least one additional antigen-binding domain that specifically binds to an antigen selected from the group consisting of IL-4, IL-13, IL-33, and TSLP, wherein the p40 binding domain comprises a heavy chain variable region (p40-VH) and a light chain variable region (p40-VL), the CDR-H1 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 166, the CDR-H2 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 167, the CDR-H3 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 168, the CDR-L1 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 171, the CDR-L2 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 172, and the CDR-L3 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 173.

[0158] The antibody according to any one of E144 to E145, further comprising 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.

[0159] The antibody according to 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.

[0160] The antibody according to any one of E144 to E147, wherein the p40 binding domain comprises a p40-VH framework sequence derived from a human DP73 germline sequence.

[0161] The antibody according to 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.

[0162] The antibody according to any one of E144 to E149, wherein the p40 binding domain comprises a p40-VL framework sequence derived from a human germline DPK7 sequence.

[0163] The antibody according to any one of E144 to E150, wherein the p40 binding domain comprises a p40-VL framework sequence and a p40-VH framework sequence, and one or both of the p40 binding domain p40-VL framework sequence and 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 it is derived.

[0164] The antibody according to any one of E144 to E151, wherein the p40 binding domain comprises a p40-VL framework sequence and a p40-VH framework sequence, and one or both of the p40-VL framework sequence or the p40-VH framework sequence are identical to the human germline sequence from which it is derived.

[0165] The antibody according to 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.

[0166] The antibody according to any one of E144 to E153, wherein the E154.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.

[0167] The antibody according to any one of E144 to E154, wherein the E155.p40 binding domain comprises the p40-VH of SEQ ID NO: 169 and the p40-VL of SEQ ID NO: 175.

[0168] The antibody according to any one of E144 to E155, wherein the E156.p40 binding domain comprises a p40-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 206.

[0169] The antibody according to any one of E145 to E156, wherein the E157.p40 binding domain comprises a p40-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 207.

[0170] The antibody according to any one of E144 to E157, wherein the E158.p40 binding domain comprises a p40-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127206.

[0171] The antibody according to any one of E144 to E158, wherein the E159.p40 binding domain comprises a p40-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127205.

[0172] The antibody according to any one of E144 to E159, further comprising a constant heavy domain (p40-CH1) and a constant light domain (p40-CL).

[0173] The antibody according to E160, wherein the p40-CH1 comprises a sequence selected from the group consisting of SEQ ID NO: 6, SEQ ID NO: 105, and SEQ ID NO: 110.

[0174] The antibody described in E160 to E161, wherein E162.p40-CH1 contains the sequence described in SEQ ID NO: 6.

[0175] The antibody described in E160 to E162, wherein E163.p40-CL contains a sequence selected from the group consisting of SEQ ID NO: 16, SEQ ID NO: 108, and SEQ ID NO: 113.

[0176] The antibody described in E160 to E163, wherein E164.p40-CL contains the sequence described in SEQ ID NO: 16.

[0177] The antibody described in E160 to E164, wherein E165.p40-CH1 is connected to p40-VL, p40-CL is connected to p40-VH, and a p40-binding domain-swap Fab domain (p40-xFab) is formed.

[0178] The antibody described in E160 to E164, wherein E166.p40-CH1 is connected to p40-VH, p40-CL is connected to p40-VL, and a p40-binding Fab domain (p40-Fab) is formed.

[0179] The antibody according to any one of E144 to E166, comprising an antibody Fc domain containing a first Fc chain and a second Fc chain.

[0180] The antibody according to E167, wherein the Fc domain is an Fc domain of IgA (e.g., IgA1 or IgA2), IgD, IgE, IgM, or IgG (e.g., IgG1, IgG2, IgG3, or IgG4).

[0181] The antibody according to E168, wherein the Fc domain is an Fc domain of IgG1.

[0182] The antibody according to any one of E167 to E169, wherein the N-terminus of the first Fc chain or the second Fc chain is connected to the C-terminus of the p40-CH1 domain.

[0183] The antibody according to E167 to E170, wherein the first and second Fc chains each contain a hinge region, a CH2 region, and a CH3 region from the N-terminus to the C-terminus.

[0184] E172. The antibody according to E171, wherein the hinge region contains 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.

[0185] E173. The antibody according to E171 to E172, wherein the hinge region in the first Fc chain and the hinge region in the second Fc chain contain a pair of the sequences described in SEQ ID NO: 129 and SEQ ID NO: 131.

[0186] E174. The antibody according to E171 to E172, wherein the CH2 region contains the sequence described in SEQ ID NO: 8.

[0187] E175. The CH3 region in the first Fc chain and the CH3 region in the second Fc chain are (i) SEQ ID NO: 9 and SEQ ID NO: 9, (ii) SEQ ID NO: 111 and SEQ ID NO: 106, (iii) SEQ ID NO: 111 and SEQ ID NO: 114, (iv) SEQ ID NO: 114 and SEQ ID NO: 117, (v) SEQ ID NO: 124 and SEQ ID NO: 127, (vi) SEQ ID NO: 139 and SEQ ID NO: 141, and (vii) SEQ ID NO: 147 and SEQ ID NO: 148 The antibody according to E171 to E174, which contains a pair of sequences selected from the group consisting of.

[0188] E176. The antibody according to E171 to E175, wherein the CH3 region in the first Fc chain and the CH region in the second Fc chain each contain the sequence described in SEQ ID NO: 9.

[0189] The antibody according to any one of E171 to E176, wherein the CH3 region in the first Fc chain and the CH region in the second Fc chain include a pair of sequences described in SEQ ID NO: 124 and SEQ ID NO: 127.

[0190] The antibody according to any one of E144 to E177, comprising a polypeptide having a p40-VH with 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: 170, SEQ ID NO: 177, SEQ ID NO: 181, SEQ ID NO: 185, and SEQ ID NO: 186.

[0191] The antibody according to any one of E144 to E178, comprising a polypeptide having a p40-VH containing an amino acid 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.

[0192] The antibody according to any one of E144 to E179, comprising a polypeptide having a p40-VH containing the amino acid sequence of SEQ ID NO: 186.

[0193] The antibody according to any one of E144 to E180, comprising a polypeptide having a p40-VL with 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: 176, SEQ ID NO: 178, SEQ ID NO: 179, SEQ ID NO: 182, and SEQ ID NO: 183.

[0194] The antibody according to any one of E144 to E181, comprising a polypeptide having a p40-VL containing the amino acid sequence of SEQ ID NO: 176.

[0195] An antibody according to any one of E144 to E182, comprising a polypeptide sequence having p40-VH encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127204.

[0196] An antibody according to any one of E144 to E183, comprising a polypeptide sequence having p40-VL encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127203.

[0197] An antibody comprising a polypeptide sequence having p40-VH encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127204, and a polypeptide sequence having p40-VL encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127203.

[0198] An isolated antibody that binds to p40 and one or both of IL-4 and IL-13, comprising the CDRs of an antibody selected from one or more of Tables 86 and 87.

[0199] An isolated antibody that binds to 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.

[0200] An isolated antibody that binds to p40 and one or both of IL-4 and IL-13, which is an antibody selected from one or more of Tables 86 and 87.

[0201] An antibody according to any one of E144 to E188 for use as a medicament.

[0202] The antibody according to E189, wherein the use is for one or more treatments selected from the group consisting of non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, atopic dermatitis, Crohn's disease, ulcerative colitis, asthma (severe), allergy, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloid, systemic lupus erythematosus, primary biliary cirrhosis, and hidradenitis suppurativa.

[0203] The antibody according to any one of E189 to E190, wherein the use is for one or more treatments selected from the group consisting of non-alcoholic steatohepatitis (NASH), atopic dermatitis, asthma (severe), alopecia, idiopathic pulmonary fibrosis, and systemic sclerosis.

[0204] The antibody according to any one of E189 to E191, wherein the use is for atopic dermatitis.

[0205] The antibody according to any one of E189 to E191, wherein the use is for non-alcoholic steatohepatitis (NASH).

[0206] A pharmaceutical composition comprising a therapeutically effective amount of the antibody according to E144 to E193 and a pharmaceutically acceptable carrier.

[0207] A method of treating a medical condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of the antibody according to any one of E144 to E193 or the pharmaceutical composition according to E194.

[0208] The method according to E195, wherein the condition is selected from the group consisting of non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, atopic dermatitis, Crohn's disease, ulcerative colitis, asthma (severe), allergy, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloid, systemic lupus erythematosus, primary biliary cirrhosis, and hidradenitis suppurativa.

[0209] The method according to any one of E195 to E196, comprising subcutaneous administration of said antibody or pharmaceutical composition.

[0210] E198. The method according to any one of E195 to E196, wherein said antibody, or pharmaceutical composition, is administered 2 times a week, 1 time a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, 2 times a month, 1 time a month, once every 2 months, once every 3 months, or once every 4 months.

[0211] E199. An isolated antibody that specifically binds to IL-4, (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 An antibody comprising a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL) comprising the same.

[0212] 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) containing 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.

[0213] 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 CDR-H1 comprises the amino acid sequence of SEQ ID NO: 18, CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2, CDR-H3 comprises the amino acid sequence of SEQ ID NO: 3, CDR-L1 comprises the amino acid sequence of SEQ ID NO: 24, CDR-L2 comprises the amino acid sequence of SEQ ID NO: 12, and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 25.

[0214] The antibody according to 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.

[0215] The antibody according to any one of E199 to E202, comprising an IL4-VH framework sequence derived from the human DP76 germline sequence.

[0216] The antibody according to any one of E199 to E203, comprising 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.

[0217] The antibody according to any one of E199 to E204, comprising an IL4-VL framework sequence derived from the human germline DPK9 sequence.

[0218] An antibody according to any one of E199 to E205, comprising an IL4-VL framework sequence and an IL4-VH framework sequence, wherein one or both of the IL4-VL framework sequence or the IL4-VH framework sequence is 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 it is derived.

[0219] An antibody according to any one of E199 to E206, comprising an IL4-VL framework sequence and an IL4-VH framework sequence, wherein one or both of the IL4-VL framework sequence or the IL4-VH framework sequence is identical to the human germline sequence from which it is derived.

[0220] An antibody according to any one of E199 to E207, comprising 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.

[0221] An antibody according to any one of E199 to E208, comprising an IL4-VL sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 20.

[0222] E210. (i) The IL4-VH sequence of SEQ ID NO: 22, and the IL4-VL of SEQ ID NO: 26, (ii) The IL4-VH sequence of SEQ ID NO: 19, and the IL4-VL of SEQ ID NO: 20, (iii) The IL4-VH sequence of SEQ ID NO: 22, and the IL4-VL of SEQ ID NO: 20, (iv) The IL4-VH sequence of SEQ ID NO: 28, and the IL4-VL of SEQ ID NO: 29, or (v) The IL4-VH sequence of SEQ ID NO: 22, and the IL4-VL of SEQ ID NO: 30 An antibody according to any one of E199 to E209, comprising:

[0223] An antibody according to any one of E199 to E210, comprising an IL4-VH sequence identical to SEQ ID NO: 22 and an IL4-VL sequence identical to SEQ ID NO: 26.

[0224] An antibody according to any one of E199 to E211, comprising an IL4-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 200.

[0225] An antibody according to any one of E199 to E212, comprising an IL4-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 201.

[0226] An antibody according to any one of E199 to E213, comprising an IL4-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127198.

[0227] An antibody according to any one of E199 to E214, comprising an IL4-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127197.

[0228] An antibody comprising an IL4-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127198, and an IL4-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127197.

[0229] E217. An antibody according to E199 to E216, having a K less than a value selected from the group consisting of about 10 pM, 5 pM, 1 pM, and 800 fM D that binds to human IL-4.

[0230] E218. An antibody according to E199 to E217, having a K less than a value of about 1 pM D that binds to human IL-4.

[0231] E219.K D An antibody according to any one of E199 to E218, wherein the value is measured by the binding equilibrium exclusion method.

[0232] An antibody according to any one of E199 to E219, which binds to cynomolgus monkey IL-4.

[0233] An antibody according to any one of E199 to E220, which does not bind to IL-4 derived from one or more selected from the group consisting of dog, sheep, rabbit, rat, and mouse.

[0234] E222. Binding K of the antibody to cynomolgus monkey IL-4 D is within one digit of the binding K of the antibody to human IL-4 D An antibody according to any one of E199 to E221.

[0235] E223. Binding K of the antibody to cynomolgus monkey IL-4 D is within twice the difference of the binding K of the antibody to human IL-4 D An antibody according to any one of E199 to E222.

[0236] E224. IC less than 10 pM in a human monocyte assay for neutralization of IL-4 induction of CD23 50 An antibody according to any one of E199 to E223, characterized thereby.

[0237] E225. IC less than 20 pM in a human monocyte assay for neutralization of cynomolgus monkey IL-4 induction of CD23 50 An antibody according to any one of E199 to E224, characterized thereby.

[0238] E226. An antibody according to any one of E199 to E225, having a viscosity of 20 cP or less at 25 °C at a concentration of 80 mg / mL in a buffer of histidine-sucrose pH 5.8.

[0239] The antibody described in any one of E199 to E226, having a viscosity of 20 cP or less at 25°C at a concentration of 100 mg / mL in a buffer of histidine-sucrose pH 5.8.

[0240] E228. The antibody described in any one of E199 to E227, having a viscosity of 20 cP or less at 25°C at a concentration of 120 mg / mL in a buffer of histidine-sucrose pH 5.8.

[0241] E229. The antibody described in any one of E199 to E228, wherein residue 93 in the light chain contains lysine.

[0242] E230. The antibody described in any one of E199 to E229, further comprising a constant heavy domain (IL4-CH1) and a constant light domain (IL4-CL).

[0243] E231. The antibody described in E230, wherein IL4-CH1 contains the sequence described in SEQ ID NO: 6.

[0244] E232. The antibody described in any one of E230 to E231, wherein IL4-CL contains the sequence described in SEQ ID NO: 16.

[0245] E233. The antibody described in any one of E230 to E232, wherein IL4-CH1 is connected to IL4-VL, IL4-CL is connected to IL-4-VH, and an IL-4-binding domain-swap Fab domain (IL4-xFab) is formed.

[0246] E234. The antibody described in any one of E230 to E232, wherein IL4-CH1 is connected to IL4-VH, IL4-CL is connected to IL4-VL, and an IL-4-binding Fab domain (IL4-Fab) is formed.

[0247] E235. The antibody described in any one of E199 to E234, comprising an Fc domain containing a first Fc chain and a second Fc chain.

[0248] The antibody according to E235, wherein the Fc domain of E236 is the Fc domain of IgA (e.g., IgA1 or IgA2), IgD, IgE, IgM, or IgG (e.g., IgG1, IgG2, IgG3, or IgG4).

[0249] The antibody according to E235 to E236, wherein the Fc domain of E237 is the Fc domain of IgG1.

[0250] The antibody or antigen-binding fragment thereof according to E235 to E237, wherein the N-terminus of the first Fc chain or the second Fc chain is connected to the C-terminus of the IL33-CH1 domain.

[0251] The antibody or antigen-binding fragment thereof according to E235 to E238, wherein the first and second Fc chains each contain a hinge region, a CH2 region, and a CH3 region from the N-terminus to the C-terminus.

[0252] The antibody or antigen-binding fragment thereof according to E239, wherein the hinge region contains 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.

[0253] The antibody or antigen-binding fragment thereof according to E240, wherein the hinge region contains the sequence set forth in SEQ ID NO: 7.

[0254] The antibody or antigen-binding fragment thereof according to E240, wherein the hinge region in the first Fc chain and the hinge region in the second Fc chain contain a pair of the sequences set forth in SEQ ID NO: 129 and SEQ ID NO: 131.

[0255] The antibody or antigen-binding fragment thereof according to E239 to E242, wherein the CH2 region contains the sequence set forth in SEQ ID NO: 8.

[0256] E244. The CH3 regions in the first Fc chain and the second Fc chain are (i) SEQ ID NO: 9 and SEQ ID NO: 9, (ii) A pair of sequences selected from the group consisting of SEQ ID NO: 111 and SEQ ID NO: 106, (iii) A pair of sequences selected from the group consisting of SEQ ID NO: 111 and SEQ ID NO: 114, (iv) A pair of sequences selected from the group consisting of SEQ ID NO: 114 and SEQ ID NO: 117, (v) A pair of sequences selected from the group consisting of SEQ ID NO: 124 and SEQ ID NO: 127, (vi) A pair of sequences selected from the group consisting of SEQ ID NO: 139 and SEQ ID NO: 141, and (vii) A pair of sequences selected from the group consisting of SEQ ID NO: 147 and SEQ ID NO: 148 An antibody or an antigen-binding fragment thereof as described in E239 to E243, comprising a pair of sequences selected from the group consisting of.

[0257] E245. An antibody or an antigen-binding fragment thereof as described in E244, wherein the CH3 region in the first Fc chain and the CH region in the second Fc chain each comprise the sequence described in SEQ ID NO: 9.

[0258] E246. An antibody or an antigen-binding fragment thereof as described in E244, wherein the CH3 region in the first Fc chain and the CH3 region in the second Fc chain comprise a pair of sequences described in SEQ ID NO: 124 and SEQ ID NO: 127.

[0259] E247. An antibody according to any one of E199 to E246, comprising a polypeptide having an IL4-VH with 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: 156, SEQ ID NO: 157, SEQ ID NO: 159, SEQ ID NO: 162, and SEQ ID NO: 164, SEQ ID NO: 179, SEQ ID NO: 180, and SEQ ID NO: 183.

[0260] E248. An antibody according to any one of E199 to E247, comprising a polypeptide having an IL4-VH comprising the amino acid sequence of SEQ ID NO: 23.

[0261] The antibody according to any one of E199 to E241, comprising a polypeptide having an IL4-VH containing the amino acid sequence of SEQ ID NO: 8:130.

[0262] E250. The antibody according to any one of E199 to E249, comprising a polypeptide having an IL4-VL having 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: 27, SEQ ID NO: 109, and SEQ ID NO: 116, SEQ ID NO: 136, SEQ ID NO: 197, and SEQ ID NO: 208.

[0263] E251. The antibody according to any one of E199 to E250, comprising a polypeptide having an IL4-VL containing the amino acid sequence of SEQ ID NO: 27.

[0264] E252. The antibody according to any one of E199 to E251, comprising a polypeptide sequence having an IL4-VH encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127192.

[0265] E253. The antibody according to any one of E199 to E252, comprising a polypeptide sequence having an IL4-VL encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127194.

[0266] E254. An antibody comprising a polypeptide sequence having an IL4-VH encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127192, and a polypeptide sequence having an IL4-VL encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127194.

[0267] E255. The antibody according to any one of E199 to E254 for use as a medicament.

[0268] The antibody according to any one of E199 to E255, for use in one or more treatments selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloid, 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, allergy, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloid, systemic lupus erythematosus (SLE), primary biliary cirrhosis, and hidradenitis suppurativa.

[0269] The antibody according to any one of E199 to E256, for use in one or more treatments selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, non-alcoholic steatohepatitis (NASH), alopecia, idiopathic pulmonary fibrosis, and systemic sclerosis.

[0270] The antibody according to any one of E199 to E257, for use in the treatment of atopic dermatitis.

[0271] The antibody according to any one of E199 to E257, for use in the treatment of non-alcoholic steatohepatitis (NASH).

[0272] A pharmaceutical composition comprising a therapeutically effective amount of the antibody according to E199 to E259 and a pharmaceutically acceptable carrier.

[0273] A method of treating a medical condition, comprising administering to a subject in need thereof a therapeutically effective amount of the antibody according to any one of E199 to E259, or the pharmaceutical composition according to E260.

[0274] The method according to E261, wherein the condition is selected from atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloid, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, diabetic kidney disease, Behcet's disease, gout, Alzheimer's disease, and atherosclerosis.

[0275] The method according to any one of E261 to E262, comprising subcutaneous administration of the antibody or pharmaceutical composition.

[0276] The method according to any one of E261 to E263, wherein the antibody or pharmaceutical composition is administered 2 times per week, 1 time per week, 1 time every 2 weeks, 1 time every 3 weeks, 1 time every 4 weeks, 1 time every 5 weeks, 1 time every 6 weeks, 1 time every 7 weeks, 1 time every 8 weeks, 1 time every 9 weeks, 1 time every 10 weeks, 2 times per month, 1 time per month, 1 time every 2 months, 1 time every 3 months, or 1 time every 4 months.

[0277] An isolated antibody that specifically binds to IL-13, (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 An antibody comprising a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL) containing the same.

[0278] An isolated antibody that specifically binds to E266.IL-13, comprising a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL) containing 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.

[0279] An isolated antibody that specifically binds to E267.IL-13, comprising a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL), wherein CDR-H1 contains the amino acid sequence of SEQ ID NO: 41, CDR-H2 contains the amino acid sequence of SEQ ID NO: 42, CDR-H3 contains the amino acid sequence of SEQ ID NO: 50, CDR-L1 contains the amino acid sequence of SEQ ID NO: 53, CDR-L2 contains the amino acid sequence of SEQ ID NO: 37, and CDR-L3 contains the amino acid sequence of SEQ ID NO: 38.

[0280] The antibody according to 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 E268.DP7, DP10, DP35, DP47, DP50, DP51, DP54, and DP77.

[0281] The antibody according to any one of E265 to E268, comprising an IL13-VH framework sequence derived from the human DP54 germline sequence.

[0282] The antibody according to 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 E270.DPK3, DPK4, DPK5, DPK8, DPK9, DPK10, and DPK23.

[0283] An antibody according to any one of E265 to E270, comprising an IL13-VL framework sequence derived from a human germline DPK9 sequence.

[0284] An antibody according to any one of E265 to E271, comprising an IL13-VL framework sequence and an IL13-VH framework sequence, wherein one or both of the IL13-VL framework sequence or the IL13-VH framework sequence is 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 it is derived.

[0285] An antibody according to any one of E265 to E272, comprising an IL13-VL framework sequence and an IL13-VH framework sequence, wherein one or both of the IL13-VL framework sequence or the IL13-VH framework sequence is identical to the human germline sequence from which it is derived.

[0286] An antibody according to any one of E265 to E273, comprising 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.

[0287] An antibody according to any one of E265 to E274, comprising 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.

[0288] E276. (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, or (v) IL13-VH of SEQ ID NO: 57, and IL13-VL of SEQ ID NO: 59 The antibody according to any one of E265 to E275, comprising

[0289] E277. The antibody according to any one of E265 to E276, comprising an IL13-VH identical to SEQ ID NO: 51 and an IL13-VL identical to SEQ ID NO: 54.

[0290] E278. The antibody according to any one of E265 to E277, comprising a VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 198.

[0291] E279. The antibody according to any one of E265 to E278, comprising a VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 199.

[0292] E280. The antibody according to any one of E265 to E279, comprising an IL13-VH sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127196.

[0293] E281. The antibody according to any one of E265 to E280, comprising an IL13-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127195.

[0294] E282. An antibody comprising an IL13-VH sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127196, and an IL13-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127195.

[0295] K less than a value selected from the group consisting of 283.10 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 An antibody according to any one of E265 to E282, which binds to human IL-13 at D .

[0296] K less than 60 pM D An antibody according to any one of E265 to E276, which binds to human IL-13 at D .

[0297] E285. K D An antibody according to any one of E283 to E284, wherein the value is measured by the binding equilibrium exclusion method.

[0298] E286. K D An antibody according to any one of E283 to E285, wherein the value is measured by SPR.

[0299] E287. An antibody according to any one of E265 to E286, which binds to cynomolgus monkey IL-13.

[0300] E288. An antibody according to any one of E265 to E287, which does not bind to IL-13 derived from one or more species selected from the group consisting of dog, rabbit, and mouse.

[0301] E289. The binding K of the antibody to cynomolgus monkey IL-13 D is within one digit of the binding K of the antibody to human IL-13 D An antibody according to any one of E265 to E288.

[0302] E290. The binding K of the antibody to cynomolgus monkey IL-13 D is within a five-fold difference of the binding K of the antibody to human IL-13 D An antibody according to any one of E265 to E289.

[0303] E291. The binding K of the antibody to cynomolgus monkey IL-13 Dis within two-fold difference of the binding K of the antibody to human IL-13, the antibody described in E265 to E290. D is within two-fold difference of the binding K of the antibody to human IL-13, the antibody described in E265 to E290.

[0304] The IC of E292.IL-13 50 is less than 100 pM as measured by neutralization of IL-13 pSTAT6 phosphorylation in HT-29 cells, the antibody described in E265 to E291.

[0305] The IC of E293.IL-13 50 is less than 20 pM as measured in a human monocyte assay for neutralization of IL-13-induced CD23, the antibody described in E265 to E292.

[0306] The IC of E294.IL-13 50 is less than 15 pM as measured in a human monocyte assay for neutralization of IL-13-induced CD23, the antibody described in E265 to E293.

[0307] The IC of E295.IL-13 50 is less than 12 pM as measured in a human monocyte assay for neutralization of IL-13-induced CD23, the antibody described in E265 to E294.

[0308] The antibody described in E265 to E295, further comprising a constant heavy domain (IL13-CH1) and a constant light domain (IL13-CL).

[0309] The antibody described in 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.

[0310] The antibody described in E296 to E297, wherein IL13-CH1 comprises the sequence described in SEQ ID NO: 6.

[0311] The antibody described in 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.

[0312] Antibody according to any one of E296 to E299, wherein E300.IL13-CL comprises the sequence set forth in SEQ ID NO: 16.

[0313] Antibody according to any one of E296 to E300, wherein E301.IL13-CH1 is connected to IL13-VL, E301.IL13-CL is connected to IL13-VH, and an IL-13-binding domain-swapped Fab domain (IL13-xFab) is formed.

[0314] Antibody according to any one of E296 to E301, wherein E302.IL13-CH1 is connected to IL13-VH, E302.IL13-CL is connected to IL33-VL, and an IL-13-binding Fab domain (IL13-Fab) is formed.

[0315] Antibody according to any one of E265 to E302, comprising an Fc domain comprising a first Fc chain and a second Fc chain.

[0316] Antibody according to E303, wherein the Fc domain is an Fc domain of IgA (e.g., IgA1 or IgA2), IgD, IgE, IgM, or IgG (e.g., IgG1, IgG2, IgG3, or IgG4).

[0317] Antibody according to any one of E303 to E304, wherein the Fc domain is an Fc domain of IgG1.

[0318] Antibody according to any one of E303 to E305, wherein the N-terminus of the first Fc chain or the second Fc chain is connected to the C-terminus of the IL13-CH1 domain.

[0319] Antibody according to any one of E303 to E306, wherein the first Fc chain and the second Fc chain each comprise a hinge region, a CH2 region, and a CH3 region from the N-terminus to the C-terminus.

[0320] The antibody according to 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.

[0321] The antibody according to E307 to E308, wherein the hinge region comprises the sequence set forth in SEQ ID NO: 7.

[0322] The antibody according to E307 to E309, wherein the hinge region comprises the sequence set forth in SEQ ID NO: 102.

[0323] The antibody according to E307 to E310, wherein the CH2 region comprises the sequence set forth in SEQ ID NO: 8.

[0324] E312. The CH3 region in the first Fc chain and the CH3 region in the second Fc chain are (i) SEQ ID NO: 124 and SEQ ID NO: 127, (ii) SEQ ID NO: 9 and SEQ ID NO: 9, (iii) SEQ ID NO: 111 and SEQ ID NO: 106, (iv) SEQ ID NO: 111 and SEQ ID NO: 114, (v) SEQ ID NO: 114 and SEQ ID NO: 117, (vi) SEQ ID NO: 139 and SEQ ID NO: 141, and (vii) SEQ ID NO: 147 and SEQ ID NO: 148 The antibody according to E307 to E311, comprising a pair of sequences selected from the group consisting of

[0325] E313. The antibody according to E307 to E312, wherein the CH3 region in the first Fc chain and the CH region in the second Fc chain each comprise the sequence set forth in SEQ ID NO: 9.

[0326] E314. The antibody according to E307 to E312, wherein the CH3 region in the first Fc chain and the CH region in the second Fc chain comprise a pair of sequences set forth in SEQ ID NO: 124 and SEQ ID NO: 127.

[0327] The antibody according to any one of E265 to E314, comprising a polypeptide having an IL13-VH with 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: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.

[0328] The antibody according to any one of E265 to E315, comprising a polypeptide having an 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.

[0329] The antibody according to any one of E264 to E316, comprising a polypeptide having an IL13-VH comprising the amino acid sequence of SEQ ID NO:52.

[0330] The antibody according to any one of E265 to E316, comprising a polypeptide having an IL13-VH comprising the amino acid sequence of SEQ ID NO:122.

[0331] The antibody according to any one of E265 to E318, comprising a polypeptide having an IL13-VL with 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:55, SEQ ID NO:163, and SEQ ID NO:196.

[0332] An antibody according to any one of E265 to E319, comprising a polypeptide having an IL13-VL 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.

[0333] An antibody according to any one of E265 to E320, comprising a polypeptide having an IL13-VL comprising the amino acid sequence of SEQ ID NO: 55.

[0334] An antibody according to any one of E265 to E321, comprising a polypeptide having an IL13-VL comprising the amino acid sequence of SEQ ID NO: 130.

[0335] An antibody according to any one of E265 to E322, comprising a polypeptide sequence having an IL13-VH encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127193.

[0336] An antibody according to any one of E265 to E323, comprising a polypeptide sequence having an IL13-VL encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127192.

[0337] An antibody comprising an IL13-VH polypeptide sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127193, and a polypeptide sequence having an IL13-VL encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127192.

[0338] An antibody according to any one of E265 to E325 for use as a medicament.

[0339] The antibody according to E326, for use in one or more treatments selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloid, bullous pemphigoid, chronic urticaria, IPF, scleroderma, and systemic sclerosis, diabetic nephropathy, Behçet's disease, gout, Alzheimer's disease, atherosclerosis, fungal keratitis, non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, allergy, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloid, systemic lupus erythematosus (SLE), primary biliary cirrhosis, and hidradenitis suppurativa.

[0340] The antibody according to any one of E326 to E327, for use in one or more treatments selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, non-alcoholic steatohepatitis (NASH), alopecia, idiopathic pulmonary fibrosis, and systemic sclerosis.

[0341] The antibody according to any one of E326 to E328, for use in the treatment of atopic dermatitis.

[0342] The antibody according to any one of E326 to E329, for use in the treatment of non-alcoholic steatohepatitis (NASH).

[0343] A pharmaceutical composition comprising a therapeutically effective amount of the antibody according to E265 to E330 and a pharmaceutically acceptable carrier.

[0344] A method of treating a medical condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of the antibody according to any one of E265 to E330 or the pharmaceutical composition according to E331.

[0345] The method according to E332, wherein the condition is selected from the group consisting of non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, atopic dermatitis, Crohn's disease, ulcerative colitis, asthma (severe), allergy, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloid, systemic lupus erythematosus, primary biliary cirrhosis, and hidradenitis suppurativa.

[0346] E334. The method according to any one of E332 to E333, comprising subcutaneous administration of the antibody or pharmaceutical composition.

[0347] E335. The method according to any one of E332 to E334, wherein the antibody or pharmaceutical composition is administered 2 times per week, 1 time per week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, 2 times per month, 1 time per month, once every 2 months, once every 3 months, or once every 4 months.

[0348] E336. An isolated antibody that specifically binds to IL-33, specifically binds to IL-4, and specifically binds to IL-13, the antibody comprising an IL-33 binding domain, an IL-4 binding domain, and an IL-13 binding domain.

[0349] E337. The antibody according to E336, wherein the specific binding to IL-33 is mediated by the antibody according to any one of E1 to E71.

[0350] E338. The antibody according to any one of E336 to E337, wherein the specific binding to IL-4 is mediated by the antibody according to any one of E199 to E259.

[0351] E339. The antibody according to any one of E336 to E338, wherein the specific binding to IL-13 is mediated by the antibody according to any one of E265 to E330.

[0352] E340. (i) The IL-33 binding domain comprises a heavy chain variable region (IL33-VH) and a light chain variable region (IL33-VL), the CDR-H1 of the IL-33 binding domain comprises the amino acid sequence of SEQ ID NO: 60, the CDR-H2 of the IL-33 binding domain comprises the amino acid sequence of SEQ ID NO: 61, the CDR-H3 of the IL-33 binding domain comprises the amino acid sequence of SEQ ID NO: 72, the CDR-L1 of the IL-33 binding domain comprises the amino acid sequence of SEQ ID NO: 75, the CDR-L2 of the IL-33 binding domain comprises the amino acid sequence of SEQ ID NO: 76, and the CDR-L3 of the IL-33 binding domain comprises the amino acid sequence of SEQ ID NO: 77. (ii) The IL-4 binding domain comprises a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL), the CDR-H1 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 18, the CDR-H2 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 2, the CDR-H3 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 3, the CDR-L1 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 24, the CDR-L2 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 12, and the CDR-L3 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 25. (iii) The IL-13 binding domain comprises a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL), the CDR-H1 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 41, the CDR-H2 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 42, the CDR-H3 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 50, the CDR-L1 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 53, the CDR-L2 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 37, and the CDR-L3 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 38. The antibody according to any one of E336 to E339.

[0353] E341. (i) The IL-33 binding domain comprises IL33-VH of SEQ ID NO: 73 and IL33-VL of SEQ ID NO: 78. (i) The IL-4 binding domain comprises IL4-VH of SEQ ID NO: 22 and IL4-VL of SEQ ID NO: 26, (ii) The IL-13 binding domain comprises IL13-VH of SEQ ID NO: 51 and IL13-VL of SEQ ID NO: 54, The antibody described in E336 to E340.

[0354] E342. (i) The IL-33 binding domain comprises the IL33-VH sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127210, and the IL33-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127209, (ii) The IL-4 binding domain comprises the IL4-VH sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127198, and the IL4-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127197, (iii) The IL-13 binding domain comprises the IL13-VH sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127196, and the IL13-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127195, The antibody described in E336 to 341.

[0355] E343. The antibody described in E336 to E342, wherein the IL-33 binding domain is fused to the IL-13 binding domain with or without a linker.

[0356] E344. The antibody described in E336 to E342, wherein the IL-33 binding domain is fused to the IL-4 binding domain with or without a linker.

[0357] The antibody according to any one of E336 to E342, wherein the IL-13 binding domain is fused to the IL-4 binding domain, with or without a linker.

[0358] E346. The antibody according to any one of E343 to E345, wherein the fusion is with a linker.

[0359] E347. The antibody according to any one of E336 to E346, wherein the IL-13 binding domain is fused to the IL-4 binding domain with a linker.

[0360] E348. The antibody according to any one of E343 to E347, wherein the linker comprises SEQ ID NO: 104.

[0361] E349. (i) The second and fifth polypeptide chains together form a first Fab domain containing a first antigen-binding site, (ii) The second and fourth polypeptide chains together form a second Fab domain containing a second antigen-binding site, (iii) The first and third polypeptide chains together form a third Fab domain containing a third antigen-binding site The antibody according to any one of E336 to E348, comprising first, second, third, fourth, and fifth polypeptide chains such that

[0362] E350. The antibody according to E349, wherein the first and second polypeptide chains associate together to form an antibody comprising two arms, a dual Fab arm containing the first Fab domain and the second Fab domain, and a single Fab arm containing the third Fab domain.

[0363] E351. The antibody according to any one of E349 to E350, wherein the fifth polypeptide chain comprises the sequence EPKSC (SEQ ID NO: 122) at the C-terminus.

[0364] The antibody according to E349 to E351, wherein the first antigen-binding site specifically binds to IL-13, the second antibody-binding site specifically binds to IL-4, and the third antigen-binding site specifically binds to IL-33.

[0365] E353. The first Fab domain, the second Fab domain, and the third Fab domain are as follows: (i) The IL33-Fab described in E38, (ii) The IL4-Fab described in E234, and (iii) The IL13-Fab described in E302 The antibody according to E349 to E352, each containing different options selected from (i), (ii), and (iii) above.

[0366] E354. The first Fab domain is the IL13-Fab described in E302, the second Fab domain is the IL4-Fab described in E234, and the third Fab domain is the IL33-Fab described in E38. The antibody according to E349 to E353.

[0367] E355. The first polypeptide contains the first Fc chain, and the second polypeptide contains the second Fc chain. The antibody according to E349 to E354.

[0368] E356. The first Fc chain and the second Fc chain each contain one or more amino acid modifications that promote the association of the first Fc chain with the second Fc chain. The antibody according to E355.

[0369] E357. The first Fc chain contains the first CH3 domain, the second Fc chain contains the second CH3 domain, the first CH3 domain and the second CH3 domain each contain different complementary sequences, and the different complementary sequences are the following pairs of different complementary sequences: (i) SEQ ID NO: 111 and SEQ ID NO: 106, (ii) SEQ ID NO: 111 and SEQ ID NO: 114, (iii) SEQ ID NO: 114 and SEQ ID NO: 117, (iv) selected from one of SEQ ID NO: 124 and SEQ ID NO: 127, (v) SEQ ID NO: 139 and SEQ ID NO: 141, and (vi) SEQ ID NO: 147 and SEQ ID NO: 148 The antibody described in E349 to E356, which is selected from one of them.

[0370] E358. The antibody described in E357, wherein the first CH3 domain and the second CH3 domain comprise SEQ ID NO: 124 and SEQ ID NO: 127.

[0371] E359. The identities of the first, second, third, fourth, and fifth polypeptide chains are (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 contains SEQ ID NO: 209, the second polypeptide chain contains SEQ ID NO: 121, the third polypeptide chain contains SEQ ID NO: 196, the fourth polypeptide chain contains SEQ ID NO: 109, and the fifth polypeptide chain contains SEQ ID NO: 103; (vii) The first polypeptide chain contains SEQ ID NO: 128, the second polypeptide chain contains SEQ ID NO: 125, the third polypeptide chain contains SEQ ID NO: 79, the fourth polypeptide chain contains SEQ ID NO: 208, and the fifth polypeptide chain contains SEQ ID NO: 122; (viii) The first polypeptide chain contains SEQ ID NO: 134, the second polypeptide chain contains SEQ ID NO: 133, the third polypeptide chain contains SEQ ID NO: 79, the fourth polypeptide chain contains SEQ ID NO: 27, and the fifth polypeptide chain contains SEQ ID NO: 122; (ix) The first polypeptide chain contains SEQ ID NO: 121, the second polypeptide chain contains SEQ ID NO: 144, the third polypeptide chain contains SEQ ID NO: 196, the fourth polypeptide chain contains SEQ ID NO: 136, and the fifth polypeptide chain contains SEQ ID NO: 143; (x) The first polypeptide chain contains SEQ ID NO: 137, the second polypeptide chain contains SEQ ID NO: 135, the third polypeptide chain contains SEQ ID NO: 138, the fourth polypeptide chain contains SEQ ID NO: 136, and the fifth polypeptide chain contains SEQ ID NO: 122; (xi) The first polypeptide chain contains SEQ ID NO: 142, the second polypeptide chain contains SEQ ID NO: 140, the third polypeptide chain contains SEQ ID NO: 79, the fourth polypeptide chain contains SEQ ID NO: 27, and the fifth polypeptide chain contains SEQ ID NO: 122 The antibody according to any one of E349 to E358, selected from the group consisting of

[0372] The antibody according to 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.

[0373] E361. An isolated antibody that specifically binds to IL-33, specifically binds to IL-4, and specifically binds to IL-13, and comprises first, second, third, fourth, and fifth polypeptide chains, (i) the second and fifth polypeptide chains together form a first Fab domain comprising an IL-13 binding site, (ii) the second and fourth polypeptide chains together form a second Fab domain comprising an IL-4 binding site, (iii) the first and third polypeptide chains together form a third Fab domain comprising an IL-33 binding site, 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, antibody.

[0374] E362. An isolated antibody that specifically binds to IL-33, specifically binds to IL-4, and specifically binds to IL-13, and comprises first, second, third, fourth, and fifth polypeptide chains, (i) the second and fifth polypeptide chains together form a first Fab domain comprising an IL-13 binding site, (ii) the second and fourth polypeptide chains together form a second Fab domain comprising an IL-4 binding site, (iii) the first and third polypeptide chains together form a third Fab domain comprising an IL-33 binding site, The first polypeptide chain comprises an array encoded by a plasmid deposited with the ATCC and having the ATCC accession number PTA-127208, the second polypeptide chain comprises an array encoded by a plasmid deposited with the ATCC and having the ATCC accession number PTA-127192, the third polypeptide chain comprises an array encoded by a plasmid deposited with the ATCC and having the ATCC accession number PTA-127207, the fourth polypeptide chain comprises an array encoded by a plasmid deposited with the ATCC and having the ATCC accession number PTA-127194, and the fifth polypeptide chain comprises an array encoded by a plasmid deposited with the ATCC and having the ATCC accession number PTA-127193. Antibody.

[0375] The antibody according to E336 to E362, having 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.

[0376] The antibody according to E336 to E363, having a viscosity of 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.

[0377] The antibody according to E336 to E364, having a terminal phase half-life of at least 12 days in cynomolgus monkeys.

[0378] The antibody according to E330 to E365, having a terminal phase half-life of at least 16 days in TG32 mice.

[0379] The antibody according to E330 to E366, binding to human IL-4 with a binding affinity of less than 220 nM as measured by SPR.

[0380] The antibody described in E330 to E367, which binds to human IL-13 with a binding affinity of less than 220 nM as measured by E368.SPR.

[0381] The antibody described in E336 to E368, which binds to human IL-4 with a binding affinity of less than 1 pM as measured by KinExA in a fixed antigen assay in PBS.

[0382] The antibody described in E336 to E369, which binds to cynomolgus IL-4 with a binding affinity of less than 5 pM as measured by KinExA in a fixed antigen assay in PBS.

[0383] The antibody described in E336 to E370, which binds to human IL-13 with a binding affinity of less than 1 pM as measured by KinExA in a fixed antigen assay in PBS.

[0384] The antibody described in E336 to E371, which binds to cynomolgus IL-13 with a binding affinity of less than 1 pM as measured by KinExA in a fixed antigen assay in PBS.

[0385] E373. An IC less than 20 nM in a human monocyte assay for neutralization of IL-4 induction of CD23 50 characterized by, the antibody described in E336 to E372.

[0386] E374. An IC less than 20 nM in a human monocyte assay for neutralization of IL-13 induction of CD23 50 characterized by, the antibody described in E336 to E373.

[0387] E375. An IC less than 30 nM in a wild-type IL-33 neutralization HEK-Blue SEAP assay 50 characterized by, the antibody described in E336 to E374.

[0388] E376. An antibody according to any one of E336 to E375, characterized by an IC of less than 15 pM in a recombinant constitutively active IL-33 neutralizing HEK-Blue SEAP assay. 50 An antibody according to any one of E336 to E375, characterized by 50 .

[0389] E377. An antibody according to any one of E336 to E376 for use as a medicament.

[0390] E378. An antibody according to E377, wherein the use is for one or more treatments selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloid, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, diabetic kidney disease, Behcet's disease, gout, Alzheimer's disease, and atherosclerosis.

[0391] E379. An antibody according to any one of E377 to E378, wherein the use is for one or more treatments selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, and non-alcoholic steatohepatitis (NASH).

[0392] E380. An antibody according to any one of E377 to E379, wherein the use is for atopic dermatitis.

[0393] E381. An antibody according to any one of E377 to E379, wherein the use is for non-alcoholic steatohepatitis (NASH).

[0394] E382. A pharmaceutical composition comprising a therapeutically effective amount of an antibody according to any one of E336 to E381 and a pharmaceutically acceptable carrier.

[0395] A method of treating a medical condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of an antibody according to any one of E336 to E381, or a pharmaceutical composition according to E382.

[0396] E384. The method according to E383, wherein the condition is selected from atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloid, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, diabetic nephropathy, Behcet's disease, gout, Alzheimer's disease, and atherosclerosis.

[0397] E385. The method according to any one of E383 to E384, comprising subcutaneous administration of the antibody or pharmaceutical composition.

[0398] E386. The method according to any one of E383 to E385, wherein the antibody or pharmaceutical composition is administered 2 times a week, once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, 2 times a month, once a month, once every 2 months, once every 3 months, or once every 4 months.

[0399] E387. An isolated antibody that specifically binds to TSLP, specifically binds to IL-4, and specifically binds to IL-13, the antibody comprising a TSLP binding domain, an IL-4 binding domain, and an IL-13 binding domain.

[0400] E388. The antibody according to E387, wherein the specific binding to TSLP is mediated by an antibody according to any one of E77 to E143.

[0401] E389. The antibody according to E387 to E388, wherein the specific binding to IL-4 is mediated by an antibody according to any one of E199 to E259.

[0402] An antibody according to any one of E387 to E389, wherein the specific binding to IL-13 is mediated by an antibody according to any one of E265 to E330.

[0403] E391. (i) The TSLP binding domain comprises a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), 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, CDR-L3 comprises the amino acid sequence of SEQ ID NO: 90, (ii) The IL-4 binding domain comprises a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL), CDR-H1 comprises the amino acid sequence of SEQ ID NO: 18, CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2, CDR-H3 comprises the amino acid sequence of SEQ ID NO: 3, CDR-L1 comprises the amino acid sequence of SEQ ID NO: 24, CDR-L2 comprises the amino acid sequence of SEQ ID NO: 12, CDR-L3 comprises the amino acid sequence of SEQ ID NO: 25, (iii) The IL-13 binding domain comprises a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL), CDR-H1 comprises the amino acid sequence of SEQ ID NO: 41, CDR-H2 comprises the amino acid sequence of SEQ ID NO: 42, CDR-H3 comprises the amino acid sequence of SEQ ID NO: 50, CDR-L1 comprises the amino acid sequence of SEQ ID NO: 53, CDR-L2 comprises the amino acid sequence of SEQ ID NO: 37, CDR-L3 comprises the amino acid sequence of SEQ ID NO: 38. An antibody according to any one of E381 to E384.

[0404] E392. (i) The TSLP binding portion comprises TSLP-VH of SEQ ID NO: 92 and TSLP-VL of SEQ ID NO: 94. (ii) The IL-4 binding portion comprises IL4-VH of SEQ ID NO: 22 and IL4-VL of SEQ ID NO: 26. (iii) The IL-13 binding portion comprises IL13-VH of SEQ ID NO: 51 and IL13-VL of SEQ ID NO: 54, the antibody described in E387 to E391.

[0405] E393. (i) The TSLP binding domain comprises a TSLP-VH sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127200, and a TSLP-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA0-127199, (ii) The IL-4 binding domain comprises an IL4-VH sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127198, and an IL4-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127197, (iii) The IL-13 binding domain comprises an IL13-VH sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127196, and an IL13-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127195, the antibody described in E387 to E392.

[0406] E394. The antibody described in E387 to E393, wherein the TSLP binding domain is fused to the IL-13 binding domain with or without a linker.

[0407] E395. The antibody described in E387 to E393, wherein the TSLP binding domain is fused to the IL-4 binding domain with or without a linker.

[0408] E396. The antibody described in E387 to E393, wherein the IL-13 binding domain is fused to the IL-4 binding domain with or without a linker.

[0409] E397. An antibody according to any one of E394 to E396, wherein the fusion involves a linker.

[0410] E398. An antibody according to any one of E394 to E397, wherein the IL-13 binding domain is fused to the IL-4 binding domain with a linker.

[0411] E399. An antibody according to E394 to E398, wherein the linker comprises SEQ ID NO: 104.

[0412] E400. (i) The second and fifth polypeptide chains together form a first Fab domain containing a first antigen-binding site, (ii) The second and fourth polypeptide chains together form a second Fab domain containing a second antigen-binding site, (iii) The first and third polypeptide chains together form a third Fab domain containing a third antigen-binding site An antibody according to any one of E387 to E399, comprising first, second, third, fourth, and fifth polypeptide chains as described above.

[0413] E401. An antibody according to E400, wherein the first and second polypeptide chains associate together to form an antibody comprising two arms: a dual Fab arm containing a first Fab domain and a second Fab domain, and a single Fab arm containing a third Fab domain.

[0414] E402. An antibody according to E400 to E401, wherein the fifth polypeptide chain contains the sequence EPKSC (SEQ ID NO: 122) at the C-terminus.

[0415] E403. An antibody according to E400 to E402, wherein the first antigen-binding site specifically binds to IL-13, the second antibody-binding site specifically binds to IL-4, and the third antigen-binding site specifically binds to TSLP.

[0416] E404. The first Fab domain, the second Fab domain, and the third Fab domain are as follows: (i) the TSLP-Fab described in E117, (ii) the IL4-Fab described in E234, and (iii) the IL13-Fab described in E302 The antibodies described in E400 to E403, each containing a different option selected from (i), (ii), and (iii) above.

[0417] E405. The antibodies described in E400 to E406, wherein the first Fab domain is the IL13-Fab described in E302, the second Fab domain is the IL4-Fab described in E234, and the third Fab domain is the TSLP-Fab described in E117.

[0418] E406. The antibodies described in E400 to E405, wherein the first polypeptide contains a first Fc chain and the second polypeptide contains a second Fc chain.

[0419] E407. The antibodies described in E406, wherein the first Fc chain and the second Fc chain each contain one or more amino acid modifications that promote the association of the first Fc chain with the second Fc chain.

[0420] E408. The first Fc chain contains a first CH3 domain, the second Fc chain contains a second CH3 domain, the first CH3 domain and the second CH3 domain each contain different complementary sequences, and the different complementary sequences are the following pairs of different complementary sequences: (i) SEQ ID NO: 111 and SEQ ID NO: 106, (ii) SEQ ID NO: 111 and SEQ ID NO: 114, (iii) SEQ ID NO: 114 and SEQ ID NO: 117, (iv) SEQ ID NO: 124 and SEQ ID NO: 127, (v) SEQ ID NO: 139 and SEQ ID NO: 141, and (vi) SEQ ID NO: 147 and SEQ ID NO: 148 The antibodies described in E400 to E407, selected from one of the above.

[0421] The antibody according to E408, wherein the first CH3 domain and the second CH3 domain comprise SEQ ID NO: 124 and SEQ ID NO: 127.

[0422] E410. The identity of the first, second, third, fourth, and fifth polypeptide chains is (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; (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; (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; (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; (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; (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; (vii) The first polypeptide chain contains SEQ ID NO: 112, the second polypeptide chain contains SEQ ID NO: 156, the third polypeptide chain contains SEQ ID NO: 196, the fourth polypeptide chain contains SEQ ID NO: 109, and the fifth polypeptide chain contains SEQ ID NO: 155, (viii) The first polypeptide chain contains SEQ ID NO: 146, the second polypeptide chain contains SEQ ID NO: 152, the third polypeptide chain contains SEQ ID NO: 109, the fourth polypeptide chain contains SEQ ID NO: 196, and the fifth polypeptide chain contains SEQ ID NO: 98, (ix) The first polypeptide chain contains SEQ ID NO: 112, the second polypeptide chain contains SEQ ID NO: 153, the third polypeptide chain contains SEQ ID NO: 196, the fourth polypeptide chain contains SEQ ID NO: 109, and the fifth polypeptide chain contains SEQ ID NO: 98, (x) The first polypeptide chain contains SEQ ID NO: 112, the second polypeptide chain contains SEQ ID NO: 157, the third polypeptide chain contains SEQ ID NO: 196, the fourth polypeptide chain contains SEQ ID NO: 109, and the fifth polypeptide chain contains SEQ ID NO: 158, (xi) The first polypeptide chain contains SEQ ID NO: 146, the second polypeptide chain contains SEQ ID NO: 160, the third polypeptide chain contains SEQ ID NO: 109, the fourth polypeptide chain contains SEQ ID NO: 196, and the fifth polypeptide chain contains SEQ ID NO: 158, (xii) The first polypeptide chain contains SEQ ID NO: 161, the second polypeptide chain contains SEQ ID NO: 164, the third polypeptide chain contains SEQ ID NO: 98, the fourth polypeptide chain contains SEQ ID NO: 197, and the fifth polypeptide chain contains SEQ ID NO: 122, (xiii) The first polypeptide chain contains SEQ ID NO: 165, the second polypeptide chain contains SEQ ID NO: 130, the third polypeptide chain contains SEQ ID NO: 215, the fourth polypeptide chain contains SEQ ID NO: 27, and the fifth polypeptide chain contains SEQ ID NO: 122, and (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. An antibody according to any one of E400 to E409, selected from the group consisting of.

[0423] E411. An antibody according to 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.

[0424] E412. An isolated antibody that specifically binds to TSLP, specifically binds to IL-4, and specifically binds to IL-13, and comprises first, second, third, fourth, and fifth polypeptide chains. (i) The second and fifth polypeptide chains together form a first Fab domain containing an IL-13 binding site. (ii) The second and fourth polypeptide chains together form a second Fab domain containing an IL-4 binding site. (iii) The first and third polypeptide chains together form a third Fab domain containing a TSLP binding site. 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. Antibody.

[0425] E413. An isolated antibody that specifically binds to TSLP, specifically binds to IL-4, and specifically binds to IL-13, and comprises first, second, third, fourth, and fifth polypeptide chains. (i) The second and fifth polypeptide chains together form a first Fab domain containing an IL-13 binding site. (ii) The second and fourth polypeptide chains together form a second Fab domain containing an IL-4 binding site, (iii) The first and third polypeptide chains together form a third Fab domain containing a TSLP binding site, The first polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127202, the second polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127192, the third polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127201, the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127194, and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127193, Antibody.

[0426] E414. The antibody according to any one of E387 to E413, having a terminal phase half-life of at least 14 days in cynomolgus monkeys.

[0427] E415. The antibody according to any one of E387 to E414, having a terminal phase half-life of at least 18 days in TG32 mice.

[0428] E416. The antibody according to any one of E387 to E415, characterized by an anti-TSLP biological activity with an IC 50 of less than 10 pM as measured in a TARC production bioassay in human primary PBMCs.

[0429] E417. The antibody according to 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.

[0430] An antibody according to any one of E387 to E417, characterized by a score of less than 2% of high molecular weight species when determined by analytical size exclusion chromatography (aSEC).

[0431] An antibody according to any one of E387 to E418, characterized by a score of less than 12 in an affinity capture self-interaction nanoparticle spectroscopy (AC SINS) assay.

[0432] An antibody according to any one of E387 to E419, which binds to human IL-4 with a binding affinity of less than 1 pM as measured by KinExA in a fixed antigen assay in PBS.

[0433] An antibody according to any one of E387 to E420, which binds to cynomolgus IL-4 with a binding affinity of less than 1 pM as measured by KinExA in a fixed antigen assay in PBS.

[0434] An antibody according to any one of E387 to E421, which binds to human IL-13 with a binding affinity of less than 1 pM as measured by KinExA in a fixed antigen assay in PBS.

[0435] An antibody according to any one of E387 to E422, which binds to cynomolgus IL-13 with a binding affinity of less than 1 pM as measured by KinExA in a fixed antigen assay in PBS.

[0436] An antibody according to any one of E387 to E423, which binds to human TSLP with a binding affinity of less than 5 pM as measured by KinExA in a fixed antigen assay in PBS.

[0437] An antibody according to any one of E387 to E424, which binds to cynomolgus IL-13 with a binding affinity of less than 20 pM as measured by KinExA in a solid antigen assay in E425.PBS.

[0438] E426. An antibody according to any one of E387 to E425, characterized by an IC of less than 25 pM in a human monocyte assay for neutralization of IL-4 induction of CD23 50 thereof.

[0439] E427. An antibody according to any one of E387 to E426, characterized by an IC of less than 15 pM in a human monocyte assay for neutralization of IL-4 induction of CD23 50 thereof.

[0440] E428. An antibody according to any one of E387 to E427, characterized by an IC of less than 60 pM in a human monocyte assay for neutralization of cynomolgus IL-4 induction of CD23 50 thereof.

[0441] E429. An antibody according to any one of E387 to E428, characterized by an IC of less than 15 pM in human TSLP neutralization in a TARC production bioassay in human primary PBMC 50 thereof.

[0442] E430. An antibody according to any one of E387 to E429, characterized by an IC of less than 35 pM in a cynomolgus TSLP neutralization assay 50 thereof.

[0443] E431. An antibody according to any one of E387 to 430 for use as a medicament.

[0444] The antibody according to E431, wherein the use is for one or more treatments selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloid, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, and fungal keratitis.

[0445] The antibody according to any one of E431 to E432, wherein the use is for one or more treatments selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, and non-alcoholic steatohepatitis (NASH).

[0446] The antibody according to any one of E431 to E433, wherein the use is for atopic dermatitis.

[0447] The antibody according to any one of E431 to E433, wherein the use is for non-alcoholic steatohepatitis (NASH).

[0448] A pharmaceutical composition comprising a therapeutically effective amount of the antibody according to E387 to E435 and a pharmaceutically acceptable carrier.

[0449] A method of treating a medical condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of the antibody according to any one of E387 to E435 or the pharmaceutical composition according to E436.

[0450] The method according to E437, wherein the condition is selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloid, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, and fungal keratitis.

[0451] The method according to any one of E437 to E438, comprising subcutaneous administration of the antibody or pharmaceutical composition.

[0452] E440. The method according to any one of E437 to E439, wherein the antibody or pharmaceutical composition is administered 2 times per week, 1 time per week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, 2 times per month, 1 time per month, once every 2 months, once every 3 months, or once every 4 months.

[0453] E445. An isolated antibody that specifically binds to p40, specifically binds to IL-4, and specifically binds to IL-13, the antibody comprising a p40 binding domain, an IL-4 binding domain, and an IL-13 binding domain.

[0454] E446. The antibody according to E445, wherein the specific binding to p40 is mediated by the antibody according to any one of E144 to E193.

[0455] E447. The antibody according to any one of E445 to E446, wherein the specific binding to IL-4 is mediated by the antibody according to any one of E199 to E259.

[0456] E448. The antibody according to any one of E445 to E447, wherein the specific binding to IL-13 is mediated by the antibody according to any one of E265 to E330.

[0457] The p40 binding domain contains a heavy chain variable region (p40-VH) and a light chain variable region (p40-VL). The CDR-H1 of the p40 binding domain contains the amino acid sequence of SEQ ID NO: 166. The CDR-H2 of the p40 binding domain contains the amino acid sequence of SEQ ID NO: 167. The CDR-H3 of the p40 binding domain contains the amino acid sequence of SEQ ID NO: 168. The CDR-L1 of the p40 binding domain contains the amino acid sequence of SEQ ID NO: 171. The CDR-L2 of the p40 binding domain contains the amino acid sequence of SEQ ID NO: 172. The CDR-L3 of the p40 binding domain contains the amino acid sequence of SEQ ID NO: 173. (ii) The IL-4 binding domain contains a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL). The CDR-H1 of the IL-4 binding domain contains the amino acid sequence of SEQ ID NO: 18. The CDR-H2 of the IL-4 binding domain contains the amino acid sequence of SEQ ID NO: 2. The CDR-H3 of the IL-4 binding domain contains the amino acid sequence of SEQ ID NO: 3. The CDR-L1 of the IL-4 binding domain contains the amino acid sequence of SEQ ID NO: 24. The CDR-L2 of the IL-4 binding domain contains the amino acid sequence of SEQ ID NO: 12. The CDR-L3 of the IL-4 binding domain contains the amino acid sequence of SEQ ID NO: 25. (iii) The IL-13 binding domain contains a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL). The CDR-H1 of the IL-13 binding domain contains the amino acid sequence of SEQ ID NO: 41. The CDR-H2 of the IL-13 binding domain contains the amino acid sequence of SEQ ID NO: 42. The CDR-H3 of the IL-13 binding domain contains the amino acid sequence of SEQ ID NO: 50. The CDR-L1 of the IL-13 binding domain contains the amino acid sequence of SEQ ID NO: 53. The CDR-L2 of the IL-13 binding domain contains the amino acid sequence of SEQ ID NO: 37. The CDR-L3 of the IL-13 binding domain contains the amino acid sequence of SEQ ID NO: 38. The antibody according to any one of E445 to E448.

[0458] E450. (i) The p40 binding domain contains p40-VH of SEQ ID NO: 169 and p40-VL of SEQ ID NO: 175. (ii) The IL-4 binding domain comprises IL4-VH of SEQ ID NO: 22 and IL4-VL of SEQ ID NO: 26, (iii) The IL-13 binding domain comprises IL13-VH of SEQ ID NO: 51 and IL13-VL of SEQ ID NO: 54, The antibody described in E445 to 449.

[0459] E451. (i) The p40 binding domain comprises the p40-VH sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127206, and the p40-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127205, (ii) The IL-4 binding domain comprises the IL4-VH sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127198, and the IL4-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127197, (iii) The IL-13 binding domain comprises the IL13-VH sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127196, and the IL13-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127195, The antibody described in E445 to 450.

[0460] E452. The antibody described in E445 to E451, wherein the p40 binding domain is fused to the IL-13 binding domain with or without a linker.

[0461] E453. The antibody described in E445 to E451, wherein the p40 binding domain is fused to the IL-4 binding domain with or without a linker.

[0462] E454. The antibody described in E445 to E451, wherein the IL-13 binding domain is fused to the IL-4 binding domain with or without a linker.

[0463] E455. An antibody according to any one of E452 to E454, wherein the fusion involves a linker.

[0464] E456. An antibody according to any one of E452 to E455, wherein the IL-13 binding domain is fused to the IL-4 binding domain with a linker.

[0465] E457. An antibody according to E456, wherein the linker comprises SEQ ID NO: 104.

[0466] E458. (i) The second and fifth polypeptide chains together form a first Fab domain containing a first antigen-binding site, (ii) The second and fourth polypeptide chains together form a second Fab domain containing a second antigen-binding site, (iii) The first and third polypeptide chains together form a third Fab domain containing a third antigen-binding site An antibody according to any one of E445 to E457, comprising first, second, third, fourth, and fifth polypeptide chains such that.

[0467] E459. An antibody according to E458, wherein the first and second polypeptide chains associate together to form an antibody comprising two arms: a dual Fab arm containing the first and second Fab domains, and a single Fab arm containing the third Fab domain.

[0468] E460. An antibody according to E458 to E459, wherein the fifth polypeptide chain contains, at its C-terminus, the sequence EPKSC (SEQ ID NO: 122).

[0469] E461. An antibody according to E458 to E460, wherein the first antigen-binding site specifically binds to IL-13, the second antibody-binding site specifically binds to IL-4, and the third antigen-binding site specifically binds to p40.

[0470] The first Fab domain, the second Fab domain, and the third Fab domain are as follows: (i) the p40-Fab described in E166, (ii) the IL4-Fab described in E234, and (iii) the IL13-Fab described in E302 The antibody described in E458 to E461, each containing a different option selected from (i), (ii), and (iii) above.

[0471] The antibody described in E458 to E462, wherein the first Fab domain is the IL13-Fab described in E302, the second Fab domain is the IL4-Fab described in E234, and the third Fab domain is the p40-Fab described in E166.

[0472] The antibody described in E458 to E463, wherein the first polypeptide contains a first Fc chain and the second polypeptide contains a second Fc chain.

[0473] The antibody described in E464, wherein the first Fc chain and the second Fc chain each contain one or more amino acid modifications that promote the association of the first Fc chain with the second Fc chain.

[0474] The antibody described in E464 to E465, wherein the first Fc chain contains a first CH3 domain, the second Fc chain contains a second CH3 domain, the first CH3 domain and the second CH3 domain each contain different complementary sequences, and the different complementary sequences are pairs of the following different complementary sequences: (i) SEQ ID NO: 106 and SEQ ID NO: 111, (ii) SEQ ID NO: 147 and SEQ ID NO: 148, and (iii) SEQ ID NO: 124 and SEQ ID NO: 127 The antibody described in E464 to E465, selected from one of the above.

[0475] The antibody according to E466, wherein the first CH3 domain and the second CH3 domain comprise SEQ ID NO: 124 and SEQ ID NO: 127.

[0476] E468. The identities of the first, second, third, fourth, and fifth polypeptide chains are (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, (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, (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, (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, (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, (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 (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. An antibody according to any one of E458 to E467, selected from the group consisting of.

[0477] E469. An antibody according to 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.

[0478] E470. An isolated antibody that specifically binds to p40, specifically binds to IL-4, and specifically binds to IL-13, and comprises first, second, third, fourth, and fifth polypeptide chains. (i) The second and fifth polypeptide chains together form a first Fab domain containing an IL-13 binding site. (ii) The second and fourth polypeptide chains together form a second Fab domain containing an IL-4 binding site. (iii) The first and third polypeptide chains together form a third Fab domain containing a p40 binding site. 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. Antibody.

[0479] E471. An isolated antibody that specifically binds to p40, specifically binds to IL-4, and specifically binds to IL-13, and comprises first, second, third, fourth, and fifth polypeptide chains. (i) The second and fifth polypeptide chains together form a first Fab domain containing an IL-13 binding site. (ii) The second and fourth polypeptide chains together form a second Fab domain containing an IL-4 binding site, (iii) The first and third polypeptide chains together form a third Fab domain containing a p40 binding site, The first polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127204, the second polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127192, the third polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127203, the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127194, and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127193, antibody.

[0480] The antibody according to E445 to E471, having a viscosity of 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.

[0481] The antibody according to E445 to E472, having 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.

[0482] E474. The antibody according to E445 to E473, having a terminal phase half-life of at least 12 days in cynomolgus monkeys.

[0483] E475. The antibody according to E445 to E474, having a terminal phase half-life of at least 18 days in TG-32 mice.

[0484] An antibody as described from E445 to E475, which binds to human IL-4 with an affinity constant of less than 220 pM, as measured by E476.SPR.

[0485] An antibody as described from E445 to E476, which binds to human IL-13 with an affinity constant of less than 220 pM, as measured by E477.SPR.

[0486] An antibody as described from E445 to E477, which binds to human IL-12 with an affinity constant of less than 130 pM, as measured by E478.SPR.

[0487] An antibody as described from E445 to E478, which binds to human IL-23 with an affinity constant of less than 100 pM, as measured by E479.SPR.

[0488] An antibody as described from E445 to E479, which binds to human IL-4 with a binding affinity of less than 1 pM, as measured by KinExA in a fixed antigen assay in PBS.

[0489] An antibody as described from E445 to E480, which binds to cynomolgus IL-13 with a binding affinity of less than 2 pM, as measured by KinExA in a fixed antigen assay in PBS.

[0490] E482. An IC of less than 12 pM, as measured in a human monocyte assay for neutralization of IL-4 induction of CD23, 50 characterized by, an antibody as described from E445 to E481.

[0491] E483. An IC of less than 12 pM, as measured in a human monocyte assay for neutralization of cynomolgus IL-4 induction of CD23, 50 characterized by, an antibody as described from E445 to E482.

[0492] E484. An IC of less than 12 pM, as measured in a human monocyte assay for neutralization of cynomolgus IL-13 induction of CD23, 50An antibody according to E445 to E483, characterized by

[0493] An IC of less than 45 pM, measured in a human monocyte assay for the neutralization of IL-13 induction of E485.CD23 50 An antibody according to E445 to E484, characterized by

[0494] An IC of less than 600 pM in the human IL-12 neutralization Kit-225 assay in human peripheral blood monocytes for E486. 50 An antibody according to E445 to E485, characterized by

[0495] An IC of less than 2100 pM in the cynomolgus IL-23 Kit-225 neutralization assay in human peripheral blood monocytes for E487. 50 An antibody according to E445 to E486, characterized by

[0496] An IC of less than 400 pM in the human IL-12 neutralization assay in human whole blood for E488. 50 An antibody according to E445 to E487, characterized by

[0497] An IC of less than 10,000 pM in the cynomolgus IL-23 neutralization assay in human whole blood for E489. 50 An antibody according to E445 to E488, characterized by

[0498] An antibody according to any one of E445 to 489 for use as a medicament.

[0499] The antibody according to E490, wherein the use is for one or more treatments selected from the group consisting of non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, atopic dermatitis, Crohn's disease, ulcerative colitis, asthma (severe), allergy, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloid, systemic lupus erythematosus, primary biliary cirrhosis, and hidradenitis suppurativa.

[0500] The antibody according to any one of E490 to E491, wherein the use is for one or more treatments selected from the group consisting of non-alcoholic steatohepatitis (NASH), atopic dermatitis, asthma (severe), alopecia, idiopathic pulmonary fibrosis, and systemic sclerosis.

[0501] The antibody according to any one of E490 to E482, wherein the use is for atopic dermatitis.

[0502] The antibody according to any one of E490 to E483, wherein the use is for non-alcoholic steatohepatitis (NASH).

[0503] A pharmaceutical composition comprising a therapeutically effective amount of the antibody according to E445 to E484 and a pharmaceutically acceptable carrier.

[0504] A method of treating a medical condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of the antibody according to any one of E445 to E494 or the pharmaceutical composition according to E495.

[0505] The method according to E496, wherein the condition is selected from the group consisting of non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, atopic dermatitis, Crohn's disease, ulcerative colitis, asthma (severe), allergy, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloid, systemic lupus erythematosus, primary biliary cirrhosis, and hidradenitis suppurativa.

[0506] The method according to any one of E496 to E497, comprising subcutaneous administration of the antibody or the pharmaceutical composition.

[0507] The method according to any one of E496 to E498, wherein the antibody or pharmaceutical composition is administered 2 times a week, once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, 2 times a month, once a month, once every 2 months, once every 3 months, or once every 4 months.

[0508] E500. (i) The second and fifth polypeptide chains together form a first Fab domain containing a first antigen-binding site, (ii) The second and fourth polypeptide chains together form a second Fab domain containing a second antigen-binding site, (iii) The first and third polypeptide chains together form a third Fab domain containing a third antigen-binding site An antibody comprising first, second, third, fourth, and fifth polypeptide chains such that.

[0509] E501. The antibody according to E500, wherein the first and second polypeptide chains associate together to form an antibody comprising two arms, a dual Fab arm comprising a first Fab domain and a second Fab domain, and a single Fab arm comprising a third Fab domain.

[0510] E502. The antibody according to E501, wherein the first Fab comprises a first antigen-binding VH (VH-1), a first antigen-binding VL (VL-1), a first antigen-binding CL (CL-1), and a first antigen-binding CH1 (CH1-1).

[0511] E503. The antibody according to E504, wherein the C-terminus of VH-1 is covalently fused to the N-terminus of CH1-1 by a peptide bond.

[0512] E504. The antibody according to E502 to E503, wherein the C-terminus of VL-1 is covalently fused to the N-terminus of CL-1 by a peptide bond.

[0513] The antibody according to any one of E501 to E504, wherein the second Fab comprises a second antigen-binding VH (VH-2), a second antigen-binding VL (VL-2), a second antigen-binding CL (CL-2), and a second antigen-binding CH1 (CH1-2).

[0514] The antibody according to E505, wherein the C-terminus of VH-2 is covalently fused to the N-terminus of CH1-2 by a peptide bond.

[0515] The antibody according to any one of E505 to E506, wherein the C-terminus of VL-2 is covalently fused to the N-terminus of CL-2 by a peptide bond.

[0516] The antibody according to any one of E501 to E507, wherein the third Fab comprises a third antigen-binding VH (VH-3), a first antigen-binding VL (VL-3), a first antigen-binding CL (CL-3), and a first antigen-binding CH1 (CH1-3).

[0517] The antibody according to E508, wherein the C-terminus of VH-3 is covalently fused to the N-terminus of CH1-3 by a peptide bond.

[0518] The antibody according to any one of E508 to E509, wherein the C-terminus of VL-3 is covalently fused to the N-terminus of CL-3 by a peptide bond.

[0519] The antibody according to any one of E500 to 510, wherein the second polypeptide comprises, from the N-terminus to the C-terminus, (VL-1)-(CL-1)-(linker)-(VH-2)-(CH1-2)-(second hinge)-(second CH2)-(second CH3), the fifth polypeptide comprises, from the N-terminus to the C-terminus, (VH1)-(CL-1), and the fourth polypeptide comprises (VL-2)-(CL-2).

[0520] The antibody according to any one of E500 to E511, wherein the first polypeptide comprises, from the N-terminus to the C-terminus, (VH-3)-(CH1-3)-(the first hinge)-(the first CH2)-(the first CH3), and the third polypeptide may comprise (VL-3)-(CL-3).

[0521] The antibody according to any one 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 the group consisting of SEQ ID NO: 6, SEQ ID NO: 105, and SEQ ID NO: 110.

[0522] The antibody according to any one of E508 to E513, wherein one or more of the CL-1 domain, the CL-2 domain, and the CL-3 domain comprise 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.

[0523] The antibody according to any one of E512 to E514, wherein the first hinge region and the second hinge region comprise a pair of sequences set forth in SEQ ID NO: 129 and SEQ ID NO: 131.

[0524] The antibody according to any one of E512 to E515, wherein one or both of the first CH2 domain and the second CH2 domain comprise the sequence set forth in SEQ ID NO: 8.

[0525] E517. The first CH3 domain and the second CH3 domain each comprise different complementary sequences, and the different complementary sequences are the following pairs of different complementary sequences: (i) SEQ ID NO: 111 and SEQ ID NO: 106, (ii) SEQ ID NO: 111 and SEQ ID NO: 114, (iii) SEQ ID NO: 114 and SEQ ID NO: 117, (iv) SEQ ID NO: 124 and SEQ ID NO: 127, (v) SEQ ID NO: 139 and SEQ ID NO: 141, and (vi) SEQ ID NO: 147 and SEQ ID NO: 148 An antibody as described in E512 to E516, selected from one of them.

[0526] E518. (i) CL-1 contains the sequence described in SEQ ID NO: 16, the linker contains the sequence described in SEQ ID NO: 104, CH1-2 contains the sequence described in SEQ ID NO: 6, the second hinge contains the sequence described in SEQ ID NO: 129, the second CH2 contains the sequence described in SEQ ID NO: 8, and the second CH3 contains the sequence described in SEQ ID NO: 124. (ii) CH1-1 contains the sequence described in SEQ ID NO: 6. (iii) CL-2 contains the sequence described in SEQ ID NO: 16. An antibody as described in E512 to E517.

[0527] E519. An antibody as described in E508 to 518, wherein CL-3 contains the sequence described in 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.

[0528] E520. An antibody as described in E508 to E519, wherein CL-3 contains the sequence described in SEQ ID NO: 95.

[0529] E521. An antibody as described in E508 to E519, wherein CL-3 contains the sequence described in SEQ ID NO: 16.

[0530] E522. An antibody as described in E508 to E521, wherein CH1-3 contains the sequence described in SEQ ID NO: 6.

[0531] E523. An antibody as described in E512 to E522, wherein the first hinge contains the sequence described in SEQ ID NO: 131.

[0532] E524. An antibody as described in E512 to E523, wherein the first CH2 contains the sequence described in SEQ ID NO: 8.

[0533] E525. An antibody as described in E512 to E524, wherein the first CH3 contains the sequence described in SEQ ID NO: 127.

[0534] An isolated antibody according to any one of E500 to E525, which specifically binds to IL-4 and specifically binds to IL-13, and comprises an IL-4 binding domain and an IL-13 binding domain.

[0535] An isolated antibody according to any one of E1 to E525, which specifically binds to IL-4 and specifically binds to IL-13, and comprises an IL-4 binding domain and an IL-13 binding domain.

[0536] An isolated antibody that specifically binds to IL-4 and specifically binds to IL-13, and is an antibody comprising an IL-4 binding domain and an IL-13 binding domain.

[0537] The antibody according to E526 to E528, wherein the specific binding to IL-4 is mediated by the antibody according to any one of E199 to E259.

[0538] The antibody according to any one of E526 to E529, wherein the specific binding to IL-13 is mediated by the antibody according to any one of E265 to E330.

[0539] The antibody according to any one of E526 to E530, which comprises at least one additional antigen-binding domain that binds to at least one different target for both IL-4 and IL-13.

[0540] The antibody according to E531, wherein at least one different target is selected from the group consisting of IL-33, TSLP, and p40, and when the target is IL-33, the antibody according to E1 to E71 may further optionally be included, when the target is TSLP, the antibody according to E77 to E143 may further optionally be included, and when the target is p40, the antibody according to E144 to E193 may further optionally be included.

[0541] The antibody according to E531, wherein at least one different target is not IL-33.

[0542] E534. An antibody according to E531, wherein at least one different target is not TSLP.

[0543] E535. An antibody according to E531, wherein at least one different target is not p40.

[0544] E536. (i) The IL-4 binding domain comprises a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL), the CDR-H1 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 18, the CDR-H2 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 2, the CDR-H3 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 3, the CDR-L1 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 24, the CDR-L2 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 12, and the CDR-L3 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 25. (ii) The IL-13 binding domain comprises a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL), the CDR-H1 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 41, the CDR-H2 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 42, the CDR-H3 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 50, the CDR-L1 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 53, the CDR-L2 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 37, and the CDR-L3 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 38. An antibody according to any one of E526 to E535.

[0545] E537. (i) The IL-4 binding domain comprises IL4-VH of SEQ ID NO: 22 and IL4-VL of SEQ ID NO: 26. (ii) The IL-13 binding domain comprises IL13-VH of SEQ ID NO: 51 and IL13-VL of SEQ ID NO: 54. An antibody according to E526 to E536.

[0546] Antibodies according to any one of E531 to E537, wherein an additional antigen-binding domain is fused to the IL-13 binding domain, with or without a linker.

[0547] Antibodies according to any one of E531 to E537, wherein an additional antigen-binding domain is fused to the IL-4 binding domain, with or without a linker.

[0548] Antibodies according to any one of E531 to E537, wherein the IL-13 binding domain is fused to the IL-4 binding domain, with or without a linker.

[0549] Antibodies according to any one of E538 to E540, wherein the fusion is with a linker.

[0550] Antibodies according to any one of E540 to E541, wherein the IL-13 binding domain is fused to the IL-4 binding domain with a linker.

[0551] Antibodies according to E542, wherein the linker comprises SEQ ID NO: 104.

[0552] Antibodies according to any one of E526 to E543, comprising first, second, third, fourth, and fifth polypeptide chains such that: (i) the second and fifth polypeptide chains together form a first Fab domain comprising a first antigen-binding site; (ii) the second and fourth polypeptide chains together form a second Fab domain comprising a second antigen-binding site; (iii) the first and third polypeptide chains together form a third Fab domain comprising a third antigen-binding site.

[0553] The antibody according to E544, wherein the first and second polypeptide chains associate together to form an antibody comprising two arms, a dual Fab arm comprising a first Fab domain and a second Fab domain, and a single Fab arm comprising a third Fab domain.

[0554] E546. (i) The first antigen-binding site specifically binds to IL-13, the second antibody-binding site specifically binds to IL-4, and the third antigen-binding site specifically binds to at least one additional target, or (ii) The first antigen-binding site specifically binds to IL-4, the second antibody-binding site specifically binds to IL-13, and the third antigen-binding site specifically binds to at least one additional target, or (iii) The first antigen-binding site specifically binds to IL-4, the second antibody-binding site specifically binds to at least one additional target, and the third antigen-binding site specifically binds to IL-13, or (iv) The first antigen-binding site specifically binds to IL-13, the second antibody-binding site specifically binds to at least one additional target, and the third antigen-binding site specifically binds to IL-4, or (v) The first antigen-binding site specifically binds to 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 (vi) The first antigen-binding site specifically binds to 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. The antibody according to any one of E526 to E545.

[0555] The antibody according to any one of E544 to E546, wherein the first Fab domain is the IL13-Fab described in E302, the second Fab domain is the IL4-Fab described in E234, and the third Fab domain is an additional target Fab.

[0556] The antibody according to E44 to E547, wherein the fifth polypeptide chain contains the sequence EPKSC (SEQ ID NO: 122) at the C-terminus.

[0557] The antibody according to E544 to E548, wherein the first polypeptide contains the first Fc chain and the second polypeptide contains the second Fc chain.

[0558] The antibody according to E549, wherein the first Fc chain and the second Fc chain each contain one or more amino acid modifications that promote the association of the first Fc chain with the second Fc chain.

[0559] The first Fc chain contains the first CH3 domain, the second Fc chain contains the second CH3 domain, the first CH3 domain and the second CH3 domain each contain different complementary sequences, and the different complementary sequences are the following pairs of different complementary sequences: (i) SEQ ID NO: 111 and SEQ ID NO: 106, (ii) SEQ ID NO: 111 and SEQ ID NO: 114, (iii) SEQ ID NO: 114 and SEQ ID NO: 117, (iv) SEQ ID NO: 124 and SEQ ID NO: 127, (v) SEQ ID NO: 139 and SEQ ID NO: 141, and (vi) SEQ ID NO: 147 and SEQ ID NO: 148 The antibody according to E544 to E550, which is selected from one of the above.

[0560] The antibody according to E551, wherein the first CH3 domain and the second CH3 domain contain SEQ ID NO: 124 and SEQ ID NO: 127.

[0561] The identity of the second, fourth, and fifth polypeptide chains is (i) the second polypeptide chain contains SEQ ID NO: 145, the fourth polypeptide chain contains SEQ ID NO: 196, and the fifth polypeptide chain contains SEQ ID NO: 103, (ii) The second polypeptide chain contains SEQ ID NO: 107, the fourth polypeptide chain contains SEQ ID NO: 109, and the fifth polypeptide chain contains SEQ ID NO: 103, (iii) The second polypeptide chain contains SEQ ID NO: 115, the fourth polypeptide chain contains SEQ ID NO: 116, and the fifth polypeptide chain contains SEQ ID NO: 103, (iv) The second polypeptide chain contains SEQ ID NO: 121, the fourth polypeptide chain contains SEQ ID NO: 109, and the fifth polypeptide chain contains SEQ ID NO: 103, (v) The second polypeptide chain contains SEQ ID NO: 125, the fourth polypeptide chain contains SEQ ID NO: 208, and the fifth polypeptide chain contains SEQ ID NO: 122, (vi) The second polypeptide chain contains SEQ ID NO: 130, the fourth polypeptide chain contains SEQ ID NO: 27, and the fifth polypeptide chain contains SEQ ID NO: 122, (vii) The second polypeptide chain contains SEQ ID NO: 133, the fourth polypeptide chain contains SEQ ID NO: 27, and the fifth polypeptide chain contains SEQ ID NO: 122, (viii) The second polypeptide chain contains SEQ ID NO: 144, the fourth polypeptide chain contains SEQ ID NO: 136, and the fifth polypeptide chain contains SEQ ID NO: 143, (ix) The second polypeptide chain contains SEQ ID NO: 135, the fourth polypeptide chain contains SEQ ID NO: 136, and the fifth polypeptide chain contains SEQ ID NO: 122, (x) The second polypeptide chain contains SEQ ID NO: 140, the fourth polypeptide chain contains SEQ ID NO: 27, and the fifth polypeptide chain contains SEQ ID NO: 122, (xi) The second polypeptide chain contains SEQ ID NO: 149, the fourth polypeptide chain contains SEQ ID NO: 196, and the fifth polypeptide chain contains SEQ ID NO: 150, (xii) The second polypeptide chain contains SEQ ID NO: 151, the fourth polypeptide chain contains SEQ ID NO: 109, and the fifth polypeptide chain contains SEQ ID NO: 150, (xiii) The second polypeptide chain contains SEQ ID NO: 159, the fourth polypeptide chain contains SEQ ID NO: 109, and the fifth polypeptide chain contains SEQ ID NO: 150, (xiv) The second polypeptide chain contains SEQ ID NO: 162, the fourth polypeptide chain contains SEQ ID NO: 197, and the fifth polypeptide chain contains SEQ ID NO: 163, (xv) The second polypeptide chain contains SEQ ID NO: 154, the fourth polypeptide chain contains SEQ ID NO: 196, and the fifth polypeptide chain contains SEQ ID NO: 155, (xvi) The second polypeptide chain contains SEQ ID NO: 156, the fourth polypeptide chain contains SEQ ID NO: 109, and the fifth polypeptide chain contains SEQ ID NO: 155, (xvii) The second polypeptide chain contains SEQ ID NO: 152, the fourth polypeptide chain contains SEQ ID NO: 196, and the fifth polypeptide chain contains SEQ ID NO: 98, (xviii) The second polypeptide chain contains SEQ ID NO: 153, the fourth polypeptide chain contains SEQ ID NO: 109, and the fifth polypeptide chain contains SEQ ID NO: 98, (xix) The second polypeptide chain contains SEQ ID NO: 157, the fourth polypeptide chain contains SEQ ID NO: 109, and the fifth polypeptide chain contains SEQ ID NO: 158, (xx) The second polypeptide chain contains SEQ ID NO: 160, the fourth polypeptide chain contains SEQ ID NO: 196, and the fifth polypeptide chain contains SEQ ID NO: 158, (xxi) The second polypeptide chain contains SEQ ID NO: 164, the fourth polypeptide chain contains SEQ ID NO: 197, and the fifth polypeptide chain contains SEQ ID NO: 122, and (xxii) The second polypeptide chain contains SEQ ID NO: 178, the fourth polypeptide chain contains SEQ ID NO: 196, and the fifth polypeptide chain contains SEQ ID NO: 177, (xxiii) The second polypeptide chain contains SEQ ID NO: 179, the fourth polypeptide chain contains SEQ ID NO: 109, and the fifth polypeptide chain contains SEQ ID NO: 177, (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, (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, (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, (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 selected from the group consisting of The antibody according to any one of E544 to E552.

[0562] E554. The antibody according to 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.

[0563] E555. An isolated antibody that specifically binds to IL-4 and specifically binds to IL-13 and at least one additional target, comprising first, second, third, fourth, and fifth polypeptide chains, (i) The second and fifth polypeptide chains together form a first Fab domain comprising an IL-13 binding site, (ii) The second and fourth polypeptide chains together form a second Fab domain comprising an IL-4 binding site, (iii) The first and third polypeptide chains together form a third Fab domain comprising at least one additional target binding site, 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, antibody.

[0564] An antibody comprising an antibody Fc domain comprising a first Fc chain and a second Fc chain, wherein the first Fc chain and the second Fc chain each comprise two amino acid modifications that promote the association of the first Fc chain with the second Fc chain, (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 (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 An antibody characterized by the above.

[0565] E557. The first Fc chain comprises a first hinge region connected to a first CH2 region connected to a first CH3 region in order from the N-terminus to the C-terminus, where the second Fc chain comprises a second hinge region connected to a second CH2 region connected to a second CH3 region in order from the N-terminus to the C-terminus, and the first hinge region and the second hinge region comprise a pair of sequences set forth in SEQ ID NO: 129 and SEQ ID NO: 131, and the first CH3 region and the second CH3 region comprise one of the following two pairs of sequence pairs: SEQ ID NO: 124 and SEQ ID NO: 127, or SEQ ID NO: 147 and SEQ ID NO: 148. The antibody according to E556.

[0566] E558. The antibody according to any one of E556 to E557, further comprising an antibody according to 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.

[0567] E559. An isolated antibody comprising CDRs of an antibody selected from one or more of Tables 80, 81, 82, 83, 84, 85, 86, and 87.

[0568] E560. An isolated antibody comprising VH and VL of an antibody selected from one or more of Tables 80, 81, 82, 83, 84, 85, 86, and 87.

[0569] An isolated antibody selected from one or more of Tables 80, 81, 82, 83, 84, 85, 86, and 87.

[0570] E562. An isolated polynucleotide comprising one or more nucleotide sequences encoding an antibody according to any one of items E1 to E71, E77 to E143, E144 to 193, E199 to 259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, and E500 to E561.

[0571] E563. The polynucleotide according to E562, which is RNA.

[0572] E564. The polynucleotide according to E562 to E563, comprising at least one chemical modification.

[0573] E565. The polynucleotide according to E564, wherein the chemical modification is selected from pseudouridine, 1-methylpseudouridine, N1-methylpseudouridine, N1-ethylpseudouridine, 2-thiouridine, 4'-thiouridine, 5-methylcytosine, 2-thio-1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio-dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio-pseudouridine, 4-methoxy-pseudouridine, 4-thio-1-methyl-pseudouridine, 4-thio-pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methyluridine, 5-methoxyuridine, and 2'-O-methyluridine.

[0574] E566. The polynucleotide according to E562 to E563, which does not contain a chemical modification.

[0575] An isolated polynucleotide encoding a 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.

[0576] An isolated polynucleotide encoding a polypeptide having a VH of an antibody that binds to IL-33 and a polypeptide having a VL, or both, 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.

[0577] An isolated polynucleotide encoding a VH, VL, or both of an antibody that binds to IL-33, wherein the nucleic acid comprises the nucleic acid sequence of the insert of the plasmid deposited with ATCC and having accession number PTA-127209, the nucleic acid sequence of the insert of the plasmid deposited with ATCC and having accession number PTA-127210, or both.

[0578] An isolated polynucleotide encoding a polypeptide having a VH of an antibody that binds to IL-33 and a polypeptide having a VL, or both, wherein the nucleic acid comprises the nucleic acid sequence of the insert of the plasmid deposited with ATCC and having accession number PTA-127207, the nucleic acid sequence of the insert of the plasmid deposited with ATCC and having accession number PTA-127208, or both.

[0579] An isolated polynucleotide encoding a 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.

[0580] An isolated polynucleotide encoding a polypeptide having VH of an antibody that binds to E572.TSLP and / or a polypeptide having VL, wherein said nucleic acid comprises the nucleic acid sequence of SEQ ID NO: 192, the nucleic acid sequence of SEQ ID NO: 193, or both.

[0581] An isolated polynucleotide encoding VH, VL, or both of an antibody that binds to E573.TSLP, wherein said nucleic acid comprises the nucleic acid sequence of the insert of the plasmid deposited with ATCC and having accession number PTA-127200, the nucleic acid sequence of the insert of the plasmid deposited with ATCC and having accession number PTA-127199, or both.

[0582] An isolated polynucleotide encoding a polypeptide having VH of an antibody that binds to E574.TSLP and / or a polypeptide having VL, wherein said nucleic acid comprises the nucleic acid sequence of the insert of the plasmid deposited with ATCC and having accession number PTA-127202, the nucleic acid sequence of the insert of the plasmid deposited with ATCC and having accession number PTA-127201, or both.

[0583] An isolated polynucleotide encoding a polypeptide having VH of an antibody that binds to E575.p40 and / or a polypeptide having VL, wherein said nucleic acid comprises the nucleic acid sequence of SEQ ID NO: 194, the nucleic acid sequence of SEQ ID NO: 195, or both.

[0584] An isolated polynucleotide encoding a polypeptide having VH of an antibody that binds to E576.p40 and / or a polypeptide having VL, wherein said nucleic acid comprises the nucleic acid sequence of the insert of the plasmid deposited with ATCC and having accession number PTA-127204, the nucleic acid sequence of the insert of the plasmid deposited with ATCC and having accession number PTA-127203, or both.

[0585] 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.

[0586] An isolated polynucleotide encoding a polypeptide having the VH of an antibody that binds to IL-4 and a polypeptide having the VL, or both, 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.

[0587] 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 the insert of the plasmid deposited with the ATCC and having accession number PTA-127198, the nucleic acid sequence of the insert of the plasmid deposited with the ATCC and having accession number PTA-127197, or both.

[0588] An isolated polynucleotide encoding a polypeptide having the VH of an antibody that binds to IL-4 and a polypeptide having the VL, or both, wherein the nucleic acid comprises the nucleic acid sequence of the insert of the plasmid deposited with the ATCC and having accession number PTA-127192, the nucleic acid sequence of the insert of the plasmid deposited with the ATCC and having accession number PTA-127194, or both.

[0589] 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.

[0590] An isolated polynucleotide encoding a polypeptide having VH of an antibody that binds to IL-13 and / or a polypeptide having VL, wherein said nucleic acid comprises the nucleic acid sequence of SEQ ID NO: 187, the nucleic acid sequence of SEQ ID NO: 188, or both.

[0591] An isolated polynucleotide encoding VH, VL, or both of an antibody that binds to IL-13, wherein said nucleic acid comprises the nucleic acid sequence of the insert of the plasmid deposited with ATCC and having accession number PTA-127196, the nucleic acid sequence of the insert of the plasmid deposited with ATCC and having accession number PTA-127195, or both.

[0592] An isolated polynucleotide encoding a polypeptide having VH of an antibody that binds to IL-13 and / or a polypeptide having VL, wherein said nucleic acid comprises the nucleic acid sequence of the insert of the plasmid deposited with ATCC and having accession number PTA-127193, the nucleic acid sequence of the insert of the plasmid deposited with ATCC and having accession number PTA-127192, or both.

[0593] E585. An isolated polynucleotide encoding one or more of the first, second, third, fourth, or fifth polypeptides of an anti-IL-4 / IL-13 / IL-33 antibody, (i) the IL33-VH sequence encoded by the plasmid deposited with ATCC and having ATCC accession number PTA-127210, and the IL33-VL sequence encoded by the plasmid deposited with ATCC and having ATCC accession number PTA-127209, (ii) the IL4-VH sequence encoded by the plasmid deposited with ATCC and having ATCC accession number PTA-127198, and the IL4-VL sequence encoded by the plasmid deposited with ATCC and having ATCC accession number PTA-127197, and (iii) The IL13-VH sequence encoded by a plasmid deposited with the ATCC and having the ATCC accession number PTA-127196, and the IL13-VL sequence encoded by a plasmid deposited with the ATCC and having the ATCC accession number PTA-127195 A polynucleotide comprising the same.

[0594] E586. An isolated polynucleotide encoding one or more of the first, second, third, fourth, or fifth polypeptides 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, and comprises first, second, third, fourth, and fifth polypeptide chains, (i) The second and fifth polypeptide chains together form a first Fab domain comprising an IL-13 binding site, (ii) The second and fourth polypeptide chains together form a second Fab domain comprising an IL-4 binding site, (iii) The first and third polypeptide chains together form a third Fab domain comprising an IL-33 binding site, The first polypeptide chain comprises the sequence encoded by a plasmid deposited with the ATCC and having the ATCC accession number PTA-127208, the second polypeptide chain comprises the sequence encoded by a plasmid deposited with the ATCC and having the ATCC accession number PTA-127192, the third polypeptide chain comprises the sequence encoded by a plasmid deposited with the ATCC and having the ATCC accession number PTA-127207, the fourth polypeptide chain comprises the sequence encoded by a plasmid deposited with the ATCC and having the ATCC accession number PTA-127194, and the fifth polypeptide chain comprises the sequence encoded by a plasmid deposited with the ATCC and having the ATCC accession number PTA-127193, A polynucleotide.

[0595] An isolated polynucleotide encoding one or more of the first, second, third, fourth, or fifth polypeptides of an anti-IL-4 / IL-13 / TSLP antibody, wherein the antibody is (i) a TSLP-VH sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127200, and a TSLP-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA0-127199, (ii) an IL4-VH sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127198, and an IL4-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127197, and (iii) an IL13-VH sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127196, and an IL13-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127195 comprising a polynucleotide.

[0596] An isolated polynucleotide encoding one or more of the first, second, third, fourth, or fifth polypeptides of an anti-IL-4 / IL-13 / TSLP antibody, wherein the antibody comprises first, second, third, fourth, and fifth polypeptide chains, (i) the second and fifth polypeptide chains together form a first Fab domain comprising an IL-13 binding site, (ii) the second and fourth polypeptide chains together form a second Fab domain comprising an IL-4 binding site, (iii) the first and third polypeptide chains together form a third Fab domain comprising a TSLP binding site, The first polypeptide chain comprises an array encoded by a plasmid deposited with the ATCC and having the ATCC accession number PTA-127202, the second polypeptide chain comprises an array encoded by a plasmid deposited with the ATCC and having the ATCC accession number PTA-127192, the third polypeptide chain comprises an array encoded by a plasmid deposited with the ATCC and having the ATCC accession number PTA-127201, the fourth polypeptide chain comprises an array encoded by a plasmid deposited with the ATCC and having the ATCC accession number PTA-127194, and the fifth polypeptide chain comprises an array encoded by a plasmid deposited with the ATCC and having the ATCC accession number PTA-127193. Polynucleotide.

[0597] E589. An isolated polynucleotide encoding one or more of the first, second, third, fourth, or fifth polypeptides of an anti-IL-4 / IL-13 / p40 antibody, wherein the antibody (i) a p40-VH sequence encoded by a plasmid deposited with the ATCC and having the ATCC accession number PTA-127206, and a p40-VL sequence encoded by a plasmid deposited with the ATCC and having the ATCC accession number PTA-127205, (ii) an IL4-VH sequence encoded by a plasmid deposited with the ATCC and having the ATCC accession number PTA-127198, and an IL4-VL sequence encoded by a plasmid deposited with the ATCC and having the ATCC accession number PTA-127197, and (iii) an IL13-VH sequence encoded by a plasmid deposited with the ATCC and having the ATCC accession number PTA-127196, and an IL13-VL sequence encoded by a plasmid deposited with the ATCC and having the ATCC accession number PTA-127195 comprising a polynucleotide.

[0598] An isolated polynucleotide encoding one or more of the first, second, third, fourth, or fifth polypeptides of an anti-IL-4 / IL-13 / p40 antibody, wherein the antibody comprises first, second, third, fourth, and fifth polypeptide chains, (i) the second and fifth polypeptide chains together form a first Fab domain comprising an IL-13 binding site, (ii) the second and fourth polypeptide chains together form a second Fab domain comprising an IL-4 binding site, (iii) the first and third polypeptide chains together form a third Fab domain comprising a p40 binding site, the first polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127204, the second polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127192, the third polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127203, the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127194, and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127193, polynucleotide.

[0599] E591. A vector comprising the polynucleotide according to E562 to E590.

[0600] E592. An isolated host cell comprising the polynucleotide according to E562 to E590, or the vector according to E591.

[0601] E593. A method for producing an isolated antibody, comprising culturing the host cell according to E592 under conditions that result in the production of the antibody, and recovering the antibody.

[0602] E594. A pharmaceutical composition comprising an antibody according to any one of E1 to E71, E77 to E143, E144 to 193, E199 to 259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, and E500 to E557 in a therapeutically effective amount, and a pharmaceutically acceptable carrier.

[0603] 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, the single Fab arm comprises a third Fab domain connected to a second Fc domain, and the method (i) a first pre-assembly step, wherein the dual Fab arm is incubated at a temperature between 2 and 10 °C in a first pre-assembly conditioning buffer, and the pH of the first pre-assembly conditioning buffer is 1 to 3 units below the isoelectric point (pI) of the dual Fab arm, (ii) a second pre-assembly step, wherein the single Fab arm is incubated at a temperature between 2 and 10 °C in a second pre-assembly conditioning buffer, and the pH of the second pre-assembly conditioning buffer is 1 to 3 units below 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 an assembly buffer for 1 to 24 hours comprising the method.

[0604] E596. An isolated antibody that specifically binds to TSLP and comprises the CDRs of an antibody selected from one or more of Tables 83, 84, and 87.

[0605] E597. An isolated antibody that specifically binds to TSLP and comprises the VH and VL of an antibody selected from one or more of Tables 83, 84, and 87.

[0606] An isolated antibody that specifically binds to E598.TSLP, and is an antibody selected from one or more of Tables 83, 84, and 87.

[0607] E599. (i) The TSLP binding domain comprises a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), 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, (ii) The IL-4 binding domain comprises a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL), CDR-H1 comprises the amino acid sequence of SEQ ID NO: 18, CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2, CDR-H3 comprises the amino acid sequence of SEQ ID NO: 3, CDR-L1 comprises the amino acid sequence of SEQ ID NO: 24, CDR-L2 comprises the amino acid sequence of SEQ ID NO: 12, and CDR-L3 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), CDR-H1 comprises the amino acid sequence of SEQ ID NO: 41, CDR-H2 comprises the amino acid sequence of SEQ ID NO: 42, CDR-H3 comprises the amino acid sequence of SEQ ID NO: 50, CDR-L1 comprises the amino acid sequence of SEQ ID NO: 53, CDR-L2 comprises the amino acid sequence of SEQ ID NO: 37, and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 38, The antibody according to any one of E381 to E384.

[0608] E600. (i) The TSLP binding portion comprises the TSLP-VH of SEQ ID NO: 92 and the TSLP-VL of SEQ ID NO: 213, (ii) The IL-4 binding portion comprises the IL4-VH of SEQ ID NO: 22 and the IL4-VL of SEQ ID NO: 26, and (iii) The IL-13 binding portion comprises IL13-VH of SEQ ID NO: 51 and IL13-VL of SEQ ID NO: 54, the antibody described in E387 to E390, or E599.

[0609] E601. (i) The TSLP binding domain comprises a TSLP-VH sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127200, and a TSLP-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-_____, (ii) The IL-4 binding domain comprises an IL4-VH sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127198, and an IL4-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession 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 accession number PTA-127196, and an IL13-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127195, the antibody described in E387 to E390, or E599 to E600.

[0610] E602. An isolated antibody that specifically binds to TSLP, specifically binds to IL-4, and specifically binds to IL-13, and comprises first, second, third, fourth, and fifth polypeptide chains, (i) The second and fifth polypeptide chains together form a first Fab domain comprising an IL-13 binding site, (ii) The second and fourth polypeptide chains together form a second Fab domain comprising an IL-4 binding site, (iii) The first and third polypeptide chains together form a third Fab domain comprising a TSLP binding site, 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, Antibody.

[0611] An isolated antibody that specifically binds to E603.TSLP, specifically binds to IL-4, and specifically binds to IL-13, and comprises first, second, third, fourth, and fifth polypeptide chains, (iv) The second and fifth polypeptide chains together form a first Fab domain comprising an IL-13 binding site, (v) The second and fourth polypeptide chains together form a second Fab domain comprising an IL-4 binding site, (vi) The first and third polypeptide chains together form a third Fab domain comprising a TSLP binding site, The first polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127202, the second polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127192, the third polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-_____, the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127194, and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127193, Antibody.

[0612] E604. (i) The TSLP-binding domain comprises a heavy-chain variable region (TSLP-VH) and a light-chain variable region (TSLP-VL), 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, (ii) The IL-4-binding domain comprises a heavy-chain variable region (IL4-VH) and a light-chain variable region (IL4-VL), CDR-H1 comprises the amino acid sequence of SEQ ID NO: 18, CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2, CDR-H3 comprises the amino acid sequence of SEQ ID NO: 3, CDR-L1 comprises the amino acid sequence of SEQ ID NO: 24, CDR-L2 comprises the amino acid sequence of SEQ ID NO: 12, and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 25, (iii) The IL-13-binding domain comprises a heavy-chain variable region (IL13-VH) and a light-chain variable region (IL13-VL), CDR-H1 comprises the amino acid sequence of SEQ ID NO: 41, CDR-H2 comprises the amino acid sequence of SEQ ID NO: 42, CDR-H3 comprises the amino acid sequence of SEQ ID NO: 50, CDR-L1 comprises the amino acid sequence of SEQ ID NO: 53, CDR-L2 comprises the amino acid sequence of SEQ ID NO: 37, and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 38. The antibody according to any one of E381 to E390.

[0613] E605. (i) The TSLP-binding moiety comprises TSLP-VH of SEQ ID NO: 92 and TSLP-VL of SEQ ID NO: 214, (ii) The IL-4-binding moiety comprises IL4-VH of SEQ ID NO: 22 and IL4-VL of SEQ ID NO: 26, (iii) The IL-13-binding moiety comprises IL13-VH of SEQ ID NO: 51 and IL13-VL of SEQ ID NO: 54. The antibody according to E387 to E390 or E604.

[0614] The TSLP-binding domain comprises a TSLP-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127200, and a TSLP-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA0-_____, (ii) The IL-4-binding domain comprises an IL4-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127198, and an IL4-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127197, and (iii) The IL-13-binding domain comprises an IL13-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127196, and an IL13-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127195, The antibody according to E387 to E390, or E602 to E603.

[0615] An isolated antibody that specifically binds to TSLP, specifically binds to IL-4, and specifically binds to IL-13, and comprises first, second, third, fourth, and fifth polypeptide chains, (i) The second and fifth polypeptide chains together form a first Fab domain comprising an IL-13 binding site, (ii) The second and fourth polypeptide chains together form a second Fab domain comprising an IL-4 binding site, (iii) The first and third polypeptide chains together form a third Fab domain comprising a TSLP binding site, 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, Antibody.

[0616] An isolated antibody that specifically binds to E608.TSLP, specifically binds to IL-4, and specifically binds to IL-13, comprising first, second, third, fourth, and fifth polypeptide chains, (i) the second and fifth polypeptide chains together form a first Fab domain comprising an IL-13 binding site, (ii) the second and fourth polypeptide chains together form a second Fab domain comprising an IL-4 binding site, (iii) the first and third polypeptide chains together form a third Fab domain comprising a TSLP binding site, the first polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127202, the second polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127192, the third polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-_____, the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127194, and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127193, Antibody.

[0617] E609. An antibody according to any one of E77 to E143, or E596 to E608 for use as a medicament.

[0618] E610. The antibody according to E609, wherein the use is for one or more treatments selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloid, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, and fungal keratitis.

[0619] The antibody according to any one of E147 to E148, or E596 to E610, wherein the use is for one or more treatments selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, and non-alcoholic steatohepatitis (NASH).

[0620] The antibody according to any one of E147 to E149, or E596 to E611, wherein the use is for atopic dermatitis.

[0621] The antibody according to any one of E147 to E149, or E596 to E612, wherein the use is for non-alcoholic steatohepatitis (NASH).

[0622] A pharmaceutical composition comprising a therapeutically effective amount of the antibody according to E77 to E143 or E596 to E608, and a pharmaceutically acceptable carrier.

[0623] A method of treating a medical condition, comprising administering to a subject in need thereof a therapeutically effective amount of the antibody according to any one of E77 to E143, or E596 to E608, or the pharmaceutical composition according to E614.

[0624] The method according to E615, wherein the condition is selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloid, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, and fungal keratitis.

[0625] The method according to any one of E615 to E616, comprising subcutaneous administration of the antibody or the pharmaceutical composition.

[0626] E618. The method according to any one of E615 to E617, wherein the antibody or pharmaceutical composition is administered 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.

[0627] E619. An antibody according to any one of E1 to E71, E77 to E143, E144 to 193, E199 to 259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, E500 to E557, or E596 to E612 for use in the inhibition of tumor growth.

[0628] E620. An antibody according to any one of E1 to E71, E77 to E143, E144 to 193, E199 to 259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, E500 to E557, E596 to E612, or E619 for use in the inhibition of the progression of malignant cell growth in a patient.

[0629] E621. An antibody according to any one of E1 to E71, E77 to E143, E144 to 193, E199 to 259, 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 the inhibition of metastasis of malignant cells in a patient.

[0630] E622. An antibody according to any one of E1 to E71, E77 to E143, E144 to 193, E199 to 259, 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 the induction of tumor shrinkage in a patient.

[0631] An antibody according to any one of E1 to E71, E77 to E143, E144 to 193, E199 to 259, 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 the treatment of cancer presenting a solid tumor.

[0632] E624. An antibody according to any one of E1 to E71, E77 to E143, E144 to 193, E199 to 259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, E500 to E557, E596 to E612, or E619 to E623 for use in one or more treatments 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, small cell lung cancer (SCLC), triple-negative breast cancer, urothelial cancer, 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 lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), or small lymphocytic lymphoma (SLL).

[0633] The antibody according to any one of E1 to E71, E77 to E143, E144 to 193, E199 to 259, 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 one or more treatments selected from the group consisting of renal cell carcinoma (RCC), bladder cancer, breast cancer, clear cell renal carcinoma, head / neck squamous cell carcinoma (SCCHN), lung squamous cell carcinoma, melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, small cell lung cancer (SCLC), or triple negative breast cancer.

[0634] The antibody according to any one of E1 to E71, E77 to E143, E144 to 193, E199 to 259, 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 one or more treatments selected from the group consisting of hematological malignancies, and in some embodiments, the hematological malignancy is 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 lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), or small lymphocytic lymphoma (SLL).

[0635] A method for treating cancer in a subject, comprising administering to the subject a combination therapy comprising a first anti-cancer therapeutic agent and a second anti-cancer therapeutic agent, wherein the first anti-cancer therapeutic agent is an antibody against one or more of IL-4, IL-13, and TSLP, and the second anti-cancer therapeutic agent is selected from the group consisting of 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 TLR7 / 8 agonist, a TLR9 agonist, a bispecific anti-CD47 / anti-PD-L1 antibody, and a bispecific anti-P-cadherin / anti-CD3 antibody.

[0636] The method according to E627, wherein the first anti-cancer therapeutic agent comprises an anti-IL-4 antibody.

[0637] The method according to E627 to E628, wherein the first anti-cancer therapeutic agent comprises an anti-IL-4 antibody according to any one of E199 to E259.

[0638] The method according to E627 to E631, wherein the first anti-cancer therapeutic agent comprises an anti-IL-13 antibody.

[0639] The method according to E627 to E630, wherein the first anti-cancer therapeutic agent comprises an anti-IL-13 antibody according to any one of E265 to E330.

[0640] The method according to E627 to E631, wherein the first anti-cancer therapeutic agent comprises an anti-TSLP antibody.

[0641] The method according to E627 to E632, wherein the first anti-cancer therapeutic agent comprises an anti-TSLP antibody according to any one of E77 to E143, or E596 to E598.

[0642] The method according to E627 to E633, wherein the first anti-cancer therapeutic agent comprises an IL-4 / IL-13 antibody.

[0643] The method according to any one of E627 to E634, wherein the first anti-cancer therapeutic agent comprises an IL-4 / IL-13 antibody, and the IL-4 / IL-13 antibody comprises the IL-4 / IL-13 antibody according to any one of E526 to E558.

[0644] The method according to any one of E627 to E635, wherein the first anti-cancer therapeutic agent comprises an IL-4 / IL-13 / TSLP antibody.

[0645] The method according to any one of E627 to E636, wherein the first anti-cancer therapeutic agent comprises an IL-4 / IL-13 / TSLP antibody, and the IL-4 / IL-13 / TSLP antibody comprises the antibody according to any one of E387 to E435 or E599 to E613.

[0646] The method according to any one of E627 to E637, wherein the first anti-cancer therapeutic agent comprises an IL-4 / IL-13 / TSLP antibody, and the IL-4 / IL-13 / TSLP antibody comprises the antibody according to E412.

[0647] The method according to any one of E627 to E637, wherein the first anti-cancer therapeutic agent comprises an IL-4 / IL-13 / TSLP antibody, and the IL-4 / IL-13 / TSLP antibody comprises the antibody according to E603.

[0648] The method according to any one of E627 to E637, wherein the first anti-cancer therapeutic agent comprises an IL-4 / IL-13 / TSLP antibody, and the IL-4 / IL-13 / TSLP antibody comprises the antibody according to E607.

[0649] The method according to any one of E627 to E640, wherein the second anti-cancer therapeutic agent is a PD-1 pathway antagonist.

[0650] The method according to any one of E627 to E641, wherein the second anti-cancer therapeutic agent is a PD-1 antagonist.

[0651] E643. The method according to any one of E627 to E642, wherein the second anti-cancer therapeutic agent is a PD-1 antagonist, and the PD-1 antagonist is selected from the group consisting of sasunlimab, BCD-100, camrelizumab, semiprimab, genolimzumab, MEDI0680, nivolumab, pembrolizumab, sintilimab, spartalizumab, STI-A1110, tislelizumab, atezolizumab, durvalumab, BMS-936559 (MDX-1105), LY3300054, and TSR-042.

[0652] E644. The method according to any one 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 VH shown in SEQ ID NO: 4 and VL shown in SEQ ID NO: 8 of US 10155037.

[0653] E644. The method according to any one of E627 to E643, wherein the second anti-cancer therapeutic agent is a PD-1 antagonist, and the PD-1 antagonist is sasunlimab.

[0654] E645. The method according to any one of E627 to E646, wherein the second anti-cancer therapeutic agent is a PD-1 antagonist, and the PD-1 antagonist is sasunlimab, and the antibody comprises a heavy chain (HC) comprising the sequence set forth in SEQ ID NO: 225 and a light chain comprising the sequence set forth in SEQ ID NO: 226.

[0655] E646. A method for treating cancer in a subject, comprising administering to the subject a combination therapy comprising a first anti-cancer therapeutic agent and a second anti-cancer therapeutic agent, wherein the first anti-cancer therapeutic agent is the IL-4 / IL-13 / TSLP antibody according to E412, and the second anti-cancer therapeutic agent is a PD-1 antagonist antibody comprising a heavy chain (HC) comprising the sequence set forth in SEQ ID NO: 225 and a light chain comprising the sequence set forth in SEQ ID NO: 226.

[0656] A method for treating cancer in a subject, comprising administering to the subject a combination therapy comprising a first anti-cancer therapeutic agent and a second anti-cancer therapeutic agent, wherein the first anti-cancer therapeutic agent is an IL-4 / IL-13 / TSLP antibody as described in E603, and the second anti-cancer therapeutic agent is a PD-1 antagonist antibody comprising a heavy chain (HC) comprising the sequence described in SEQ ID NO: 225 and a light chain comprising the sequence described in SEQ ID NO: 226.

[0657] A method for treating cancer in a subject, comprising administering to the subject a combination therapy comprising a first anti-cancer therapeutic agent and a second anti-cancer therapeutic agent, wherein the first anti-cancer therapeutic agent is an IL-4 / IL-13 / TSLP antibody as described in E607, and the second anti-cancer therapeutic agent is a PD-1 antagonist antibody comprising a heavy chain (HC) comprising the sequence described in SEQ ID NO: 225 and a light chain comprising the sequence described in SEQ ID NO: 226.

[0658] A medicament comprising a first anti-cancer agent and a second anti-cancer agent, wherein the first anti-cancer therapeutic agent is an IL-4 / IL-13 / TSLP antibody as described in E412, and the second anti-cancer therapeutic agent is a PD-1 antagonist antibody comprising a heavy chain (HC) comprising the sequence described in SEQ ID NO: 225 and a light chain comprising the sequence described in SEQ ID NO: 226.

[0659] A medicament comprising a first anti-cancer agent and a second anti-cancer agent, wherein the first anti-cancer therapeutic agent is an IL-4 / IL-13 / TSLP antibody as described in E603, and the second anti-cancer therapeutic agent is a PD-1 antagonist antibody comprising a heavy chain (HC) comprising the sequence described in SEQ ID NO: 225 and a light chain comprising the sequence described in SEQ ID NO: 226.

[0660] A medicament comprising a first anti-cancer agent and a second anti-cancer agent, wherein the first anti-cancer therapeutic agent is an IL-4 / IL-13 / TSLP antibody as described in E607, and the second anti-cancer therapeutic agent is a PD-1 antagonist antibody comprising a heavy chain (HC) comprising the sequence described in SEQ ID NO: 225 and a light chain comprising the sequence described in SEQ ID NO: 226.

[0661] E650. A method or medicament according to any one of E627 to E649, wherein the cancer exhibits a solid tumor.

[0662] E651. A method or medicament according to any one of E627 to E650, wherein the cancer is 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, small cell lung cancer (SCLC), triple negative breast cancer, urothelial cancer, 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 lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), or small lymphocyte lymphoma (SLL).

[0663] E652. A method or medicament according to any one of E627 to E651, wherein the cancer is one or more selected from the group consisting of 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.

[0664] E653. The cancer is one or more selected from the group consisting of hematological malignancies, and in some embodiments, the hematological malignancy is 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 lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), or small lymphocytic lymphoma (SLL), the method or medicament according to any one of E627 to E652.

[0665] E654. At least one of the therapeutic agents is administered to the subject at intervals 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, the antibody, method or medicament for use according to any one of E1 to E653.

[0666] Use for the manufacture of a medicament for use (us) in one or more treatments selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, and non-alcoholic 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 cancer, 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 lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), or small lymphocytic lymphoma (SLL), hematological 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 lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), and small lymphocytic lymphoma (SLL) of an antibody according to any one of E1 to E71, E77 to E143, E144 to 193, E199 to 259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, E500 to E557, E596 to E612, or E619 to E625.

[0667] A pharmaceutical composition for one or more treatments selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, and non-alcoholic 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 cancer, 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 lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), or small lymphocytic lymphoma (SLL), hematological 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 lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), and small lymphocytic lymphoma (SLL), the pharmaceutical composition comprising an antibody according to any one of E1 to E71, E77 to E143, E144 to 193, E199 to 259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, E500 to E557, E596 to E612, or E619 to E625.

[0668] An anti-disease agent comprising an antibody according to any one of E658.E1 to E71, E77 to E143, E144 to 193, E199 to 259, 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 atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, and non-alcoholic 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 cancer, 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 lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), or small lymphocytic lymphoma (SLL), a hematological malignancy, 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 lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), and small lymphocytic lymphoma (SLL), which is one or more selected from the group consisting of.

Brief Description of the Drawings

[0669]

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[0670] **DETAILED DESCRIPTION** 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 together with one of IL-33, TSLP, and p40 are provided herein. Related nucleic acids, compositions, and methods of making and using the antibodies are also provided herein.

[0671] General Techniques All references cited herein, including patent applications, patent publications, UniProtKB accession numbers, are incorporated herein by reference as if each individual reference were specifically and individually indicated to be incorporated by reference in its entirety.

[0672] The techniques and procedures described or referenced in this specification are generally known to those skilled in the art from conventional methodologies such as Sambrook et al., Molecular Cloning: A Laboratory Manual, 3rd ed. (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; CURRENT PROTOCOLS IN MOLECULAR BIOLOGY (F.M. Ausubel et al., eds., (2003)); the series METHODS IN ENZYMOLOGY (Academic Press, Inc.): PCR 2: A PRACTICAL APPROACH (M.J. MacPherson, B.D. Hames, and G.R. Taylor, eds. (1995)), Harlow and Lane, eds. (1988) ANTIBODIES, A LABORATORY MANUAL, and ANIMAL CELL CULTURE (R.I. Freshney, ed. (1987)); Oligonucleotide Synthesis (M.J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J.E. Cellis, ed., 1998) Academic Press; Animal Cell Culture (R.I. Freshney) ed., 1987); Introduction to Cell and Tissue Culture (J.P. Mather and P.E. Roberts, 1998) Plenum Press; Cell and Tissue Culture Laboratory Procedures (A. Doyle, J.B. Griffiths, and D.G. Newell, eds., 1993 - 8) J.Wiley and Sons; Handbook of Experimental Immunology (D.M. Weir and C.C. Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (J.M. Miller and M.P.Calos, ed., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994); Current Protocols in Immunology (J.E. Coligan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C.A. 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 J.D. Capra, eds., Harwood Academic Publishers, 1995); and other widely used methodologies described in their revised editions, etc. are well understood and commonly used.

[0673] Definitions Unless otherwise defined, all technical terms, notations, and other scientific terms or terminology used herein are intended to have the meanings commonly understood by those of ordinary skill in the art to which the present invention pertains. For example, the term "and / or" used in phrases such as "A and / or B" herein is intended to include both 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 encompass 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, terms having commonly understood meanings are defined herein for clarity and / or immediate reference, and the inclusion of such definitions herein should not necessarily be construed as representing a substantial difference from what is generally understood in the art.

[0674] As used herein, the singular forms "a", "an", and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

[0675] As used herein, numerical ranges include the numbers defining the range.

[0676] References to "about" values or parameters herein include (and describe) embodiments that are directed to the value or parameter itself and values or parameters that may be either about 10% lower or higher than the numerical value described for that parameter. For example, a dosage of "about 5 mg / kg" includes 5 mg / kg and any value between 4.5 mg / kg and 5.5 mg / kg. When the term "about" is used in the context of a period (such as years, months, weeks, days, etc.), the term "about" means the period plus or minus an amount of the next lower period (e.g., about 1 year means 11 to 13 months, about 6 months means 6 months plus or minus 1 week, about 1 week means 6 to 8 days, etc.), or the longer of the two, within 10 percent of the indicated value.

[0677] "Antibody" refers to an immunoglobulin molecule that can specifically bind to a target, such as a polypeptide, carbohydrate, polynucleotide, lipid, etc., via 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), a portion of an intact antibody that retains the ability to bind to a given antigen (e.g., an "antigen-binding fragment"), and any other modified conformation of an immunoglobulin molecule that includes an antigen-binding site.

[0678] Antibodies include antibodies of any class, such as IgG, IgA, or IgM (or their subclasses), and the antibody does not need to be of any particular class. Depending on the antibody amino acid sequence of the constant region of its heavy chain (HC), immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and some of these can be further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant regions corresponding to different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional conformations of different classes of immunoglobulins are well known.

[0679] Examples of antigen-binding fragments and modified conformations of antibodies include: (i) Fab fragments (monovalent fragments consisting of the VL, VH, CL, and CH1 domains); (ii) F(ab’)2 fragments (bivalent fragments containing two Fab fragments linked by disulfide bridges in the hinge region), and (iii) Fv fragments consisting of the VL and VH domains of a single arm of an antibody. Furthermore, the two domains of the Fv fragment, VL and VH, are encoded by separate genes, but they can be joined using recombinant methods by a synthetic linker that allows the VL and VH regions to pair to form a single protein chain that forms a monovalent molecule (known as 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 included.

[0680] In addition, antibodies are further included in which the C-terminal lysine (K) amino acid residue is lost in the heavy chain polypeptide (e.g., human IgG1 heavy chain contains a terminal lysine). As is known in the art, the C-terminal lysine may be cleaved during antibody production, resulting in antibodies having a heavy chain lacking the C-terminal lysine. Alternatively, the antibody heavy chain may be produced using a nucleic acid that does not contain a C-terminal lysine.

[0681] The "variable region" of an antibody refers to either the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. As is known in the art, the variable regions of the heavy and light chains, also known as hypervariable regions, are each composed of four framework regions (FRs) connected by three complementarity-determining regions (CDRs) that contribute to the formation of the antigen-binding site of the antibody. When variants of the subject variable regions are desired, particularly those having substitutions in amino acid residues outside the CDR regions (i.e., in the framework regions), appropriate amino acid substitutions, preferably conservative amino acid substitutions, can be identified by comparing the subject variable region to the variable regions of other antibodies containing CDR1 and CDR2 sequences of the same canonical class as the subject variable region (Chothia and Lesk, J Mol Biol 196(4):901-917, 1987).

[0682] In certain embodiments, the final delineation of the CDRs and the identification of the residues that comprise the binding site of the antibody are achieved by elucidating the structure of the antibody or the structure of the antibody-ligand complex. In certain embodiments, this can be achieved by any of a variety of techniques known to those of skill in the art, such as X-ray crystallographic analysis. In certain embodiments, various methods of analysis can be used to identify or infer the CDR regions. Examples of such methods include, but are not limited to, the Kabat definition, the Chothia definition, the AbM definition, the contact definition, the conformation definition, and the Pfabat numbering method shown in Example 1.

[0683] The Kabat definition is a standard for numbering residues in an antibody and is often used to identify CDR regions. See, for example, Johnson and Wu, 2000, Nucleic Acids Res., 28:214-218. The Chothia definition is similar to the Kabat definition, but the Chothia definition takes into account the position of certain structural loop regions. See, for example, Chothia et al., 1986, J. Mol. Biol., 196:901-917, Chothia et al., 1989, Nature, 342:877-883. The AbM definition uses an integrated package of computer programs created by Oxford Molecular Group for modeling antibody structures. See, for example, Martin et al., 1989, Proc Natl Acad Sci (USA), 86:9268-9272, "AbM (trademark), A Computer Program for Modeling Variable Regions of Antibodies," Oxford, UK, Oxford Molecular, Ltd. The AbM definition uses a combination of knowledge databases and first methods, such as those described by Samudrala et al., 1999, "Ab Initio Protein Structure Prediction Using a Combined Hierarchical Approach," PROTEINS, Structure, Function and Genetics Supplement, 3:194-198, to model the tertiary structure of an antibody from its primary sequence. The contact definition is based on the analysis of available crystal structures of complexes. See, for example, MacCallum et al., 1996, J. Mol. Biol., 5:732-745. In another approach, herein referred to as the "conformational definition" of CDRs, the positions of CDRs can be identified as residues that make an enthalpic contribution to antigen binding. See, for example, Makabe et al., 2008, Journal of Biological Chemistry, 283:1156-1166.Still other CDR boundary definitions may not strictly follow one of the above methods, yet, while overlapping at least a portion of the Kabat CDRs, they may be shortened or lengthened in view of predictive or experimental findings that certain residues or groups of residues do not significantly affect antigen binding. The numbering system used in this application is the Pfabat numbering method shown in Example 1.

[0684] As used herein, CDR can refer to CDRs defined by any method known in the art, including combinations of methods. The methods used herein can utilize CDRs defined according to any of these methods. For any given embodiment containing two or more CDRs, the CDRs can be defined according to any one or more of the Kabat, Chothia, extended, AbM, contact, conformation definition, or Pfabat methods. The antibodies of this application are numbered according to a modified version of the Kabat numbering system, which is shown in more detail in Example 1.

[0685] The term "hinge region" as used herein includes the meaning known in the art, for example, as shown in 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.

[0686] The "constant region" of an antibody refers to either the constant region of the antibody light chain or the constant region of the antibody heavy chain, either alone or in combination. The IgG heavy chain constant region contains three contiguous immunoglobulin domains (CH1, CH2, and CH3) with a hinge region between the CH1 and CH2 domains. The IgG light chain constant region contains a single immunoglobulin domain (CL).

[0687] "Fc domain" refers to the portion of an Ig molecule that correlates with the crystallizable fragment obtained by papain digestion of the immunoglobulin (Ig) molecule. As used herein, this term relates to the constant regions of the two chains of an antibody, where each chain excludes the first constant region immunoglobulin domain. Within the Fc domain, there are two "Fc chains" (e.g., "the first Fc chain" and "the second Fc chain"). "Fc chain" generally refers to the C-terminal portion of the antibody heavy chain. Thus, the Fc chain refers to the last two constant region immunoglobulin domains (CH2 and CH3) of IgA, IgD, and IgG heavy chains, as well as the last three constant region immunoglobulin domains of IgE and IgM heavy chains, and optionally, the N-terminal flexible hinge to these domains.

[0688] The boundaries of the Fc chain can vary, but the human IgG heavy chain Fc chain is typically defined to include residues from C226 or P230 to its carboxyl terminus, where the numbering follows the EU index of Edelman et al., Proc. Natl. Acad. Sci. USA 1969; 63(1): 78-85, as described by Kabat et al., 1991. Typically, the Fc chain includes amino acid residues approximately 236 to approximately 447 of the human IgG1 heavy chain constant region. "Fc chain" can refer to this polypeptide in the context of being isolated or within a larger molecule (e.g., an antibody heavy chain or an Fc fusion protein).

[0689] A "functional" Fc domain refers to an Fc domain having 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. Such effector functions generally require combining the Fc domain with a binding domain (e.g., an antibody variable region), and can be assayed using various assays known in the art for evaluating such antibody effector functions.

[0690] A "native sequence" Fc chain or "wild-type Fc chain" refers to an Fc chain that contains an amino acid sequence identical to the amino acid sequence of an Fc chain found in nature. A "variant" Fc chain contains an amino acid sequence that differs from that of the native sequence Fc chain by at least one amino acid modification that still 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, e.g., from about 1 to about 10 amino acid substitutions in the wild-type Fc chain, preferably from about 1 to about 5 amino acid substitutions, compared to the wild-type Fc chain. Variant Fc chains herein preferably have at least about 80% sequence identity, most preferably at least about 90% sequence identity, more preferably at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity to the wild-type Fc chain. In some embodiments, the Fc chain includes a part or all of the wild-type hinge region (generally at its N-terminus). In some embodiments, the Fc polypeptide does not include a functional or wild-type hinge region.

[0691] Nomenclature The antibody domains disclosed herein may be prefixed with an indication of the individual target antigen to which the domain most closely associates. The prefix is added simply to provide clarity of the shorthand expression in identifying between the different domains recited throughout this disclosure and does not replace or oppose the actual function or structure of the various domains. For example, IL4-VH refers to the variable heavy domain of an antibody that includes CDRs capable of specifically binding to IL-4. IL4-CH1 refers to the CH1 domain that is C-terminally positioned relative to the IL-4 variable domain, regardless of whether its variable domain is a variable light domain (IL4-VL) or a variable heavy domain (IL4-VH). As described throughout this disclosure, the domains of the antibodies of the present disclosure may be combined with or fused to domains from other antibodies. Thus, for example, IL4-VH may be present on a polypeptide chain having IL13-VL, and each, independently or together, may be present in the same antibody, and the polypeptide may be referred to as both IL4-VH and IL13-VL (see, for example, FIG. 18). Again, by way of example, a polypeptide having IL4-VH is any polypeptide that includes the IL4-VH domain, i.e., a VH domain that includes CDRs specifically binding to IL-4. A polypeptide having IL4-VH may include a hinge region, CH1 domain, CH2 domain, and CH3 domain, as in the standard IgG format, or may include any of the various domains described herein, such as IL13-VL, together with CH1 and CL domains fused to either IL4-VH or IL13-VL (see FIG. 18 for examples of different combinations of antibody domains). For example, the DFab LC(1)-HC(2) arms of IL41333-1258, IL413TSLP-1024, and IL413P40-0705 (see FIG. 18I) each include, from N-terminus to C-terminus, IL13-VL, CL, linker, IL4-VH, CH1, CH2, and CH3, and may both be referred to as a polypeptide having IL4-VH and a polypeptide having IL13-VL.Furthermore, the framework regions may be referred to by the targets to which their CDRs are specific. For example, the framework regions of the IL-4 antibodies of the present disclosure may be referred to as the IL4-VL framework or the IL4-VH framework. One of ordinary skill in the art will understand that these designations do not impart and are not meant to imply any relationship between the framework region and the target to which the CDR specifically binds. Thus, the IL4-VL framework region may be derived from a human germline DPK9 sequence that is identical to a known human DPK9 germline sequence. This nomenclature is not limited to the specific antibodies exemplified in this paragraph and applies across all antibodies and combinations of antibodies possible within the present disclosure.

[0692] Antibodies IL13433-1258, IL134TSLP-1024, and IL134p40-0705 may each be described as including first, second, third, fourth, and fifth polypeptide chains, where the second polypeptide includes, from N-terminus to C-terminus, (VL-1)-(CL-1)-(linker)-(VH-2)-(CH1-2)-(second hinge)-(second CH2)-(second CH3), the fifth polypeptide includes, from N-terminus to C-terminus, (VH1)-(CL-1), the fourth polypeptide includes (VL-2)-(CL-2), the first polypeptide includes, from N-terminus to C-terminus, (VH-3)-(CH1-3)-(first hinge)-(first CH2)-(first CH3), and the third polypeptide includes (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.

[0693] A "monoclonal antibody" (mAb) refers to an antibody derived from a single copy or clone, including, for example, any eukaryotic clone, prokaryotic clone, or phage clone. Monoclonal antibodies are highly specific and are made against a single antigenic site. Furthermore, typically in contrast to polyclonal antibody preparations that include antibodies made against different determinants (epitopes), each monoclonal antibody is made against a single determinant on the antigen. The modifying phrase "monoclonal" indicates the characteristics of the antibody as being obtained from a substantially homogeneous population of antibodies, but should not be construed as requiring the production of the antibody by any particular method. For example, the monoclonal antibodies used in accordance with the present invention may be made by the hybridoma method first described by Kohler and Milstein, 1975, Nature 256:495, or by recombinant DNA methods such as those described in U.S. Patent No. 4,816,567. In another example, monoclonal antibodies may be isolated from phage libraries such as those made using the techniques described by McCafferty et al., 1990, Nature 348:552-554.

[0694] A "human antibody" refers to an antibody having an amino acid sequence corresponding to that of an antibody produced by a human, or an antibody made using any technique for making a fully human antibody. For example, fully human antibodies can be obtained by using commercially available mice engineered to express specific human immunoglobulin proteins, or by phage, yeast, or ribosome display techniques for preparing fully human antibodies. This definition of human antibody specifically excludes humanized antibodies that contain non-human antigen-binding residues.

[0695] 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.

[0696] A "humanized" antibody refers to a chimeric antibody containing minimal sequences derived from non-human immunoglobulins, which is a non-human (e.g., murine) antibody. Preferably, a humanized antibody is a human immunoglobulin (recipient antibody) in which residues derived from the recipient's CDRs are replaced by residues derived from the CDRs of a non-human species (donor antibody), such as mouse, rat, or rabbit, that have the desired specificity, affinity, and capacity. A humanized antibody may contain residues not found in the recipient antibody or in the incorporated CDR or framework sequences, but which are included to further improve and optimize the performance of the antibody.

[0697] "Antigen" refers to a molecular entity used for immunization of an immunocompetent vertebrate to produce antibodies that recognize the antigen or to screen an expression library (e.g., phage, yeast, or ribosome display library, among others) for antibody selection. As used herein, antigen is more broadly referred to and is generally intended to include target molecules specifically recognized by an antibody, and thus fragments or mimics of molecules used in the immunization process to generate an antibody or in library screening to select an antibody.

[0698] "Epitope" refers to an area or region of an antigen to which an antibody specifically binds, determined by any method well known in the art, e.g., an area or region containing residues that interact with the antibody. For example, as described in Chapter 11 of Harlow and Lane, Using Antibodies, a Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1999, there are many methods known in the art for mapping and characterizing the location of epitopes on proteins, including elucidation of the crystal structure of the antibody-antigen complex, competitive assays, gene fragment expression assays, epitope mapping, and assays based on synthetic peptides. In addition or alternatively, during the discovery process, the generation and characterization of antibodies can yield information regarding the desired epitope. From this information, it is then possible to competitively screen antibodies for binding to the same epitope.

[0699] As used herein, the term "binding affinity" refers to the overall strength of the 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 the members of a binding pair (e.g., an antibody and an antigen). The affinity of molecule X for its partner Y is generally the dissociation constant (K D) can be represented by. The affinity of molecule X for its partner Y can generally be represented by the dissociation constant (Kd). Affinity can be measured by general 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 more rapidly and tend to remain bound longer. Various methods for measuring binding affinity are known in the art, and any of these can be used for the purposes of the present invention. In particular, the term "binding affinity" is intended to refer to the dissociation rate of a particular antigen-antibody interaction. K D is the association rate of the rate of dissociation, also called the "off-rate (k off )", or the ratio to the "on-rate (k on )". Therefore, K D is, k off / k on equal to, and is expressed as molar concentration (M). As K D becomes smaller, the result is that the binding affinity becomes stronger. Thus, a K D of 1 μM exhibits a weaker binding affinity compared to a K D of 1 nM. The K D value of an antibody can be determined using methods well established in the art. One method for determining the K D of an antibody is by using surface plasmon resonance (SPR), typically by using a biosensor system such as a BIACORE system. BIACORE kinetic analysis involves analyzing the binding and dissociation of antigen from a chip having immobilized molecules (e.g., molecules containing an epitope-binding domain) on their surface. The k D and other ratios for determining, respectively, the association and dissociation rate constants of k on and k offThe determination may be made using a surface plasmon resonance-based biosensor to characterize the analyte / ligand interaction, for example, under conditions where the analyte is monovalent with respect to the binding of a ligand immobilized at low volume on the sensor surface via a capture reagent. The analysis may be performed using, for example, the kinetic titration methodology described by 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 provide stable capture of the ligand on the sensor surface, minimize non-specific binding of the analyte to the surface, and provide an analyte binding response appropriate for kinetic analysis, according to the recommendations of Myszka, J. Mol. Recognit 12, 279-284, 1999. The analyte binding response for each analyte / ligand interaction is double-referenced and fit to a 1:1 Langmuir "mass transport-limited model" using k a , k d and R max . The equilibrium dissociation constant K D is estimated from the ratio of the kinetic rate constants K D = k off / k on . Such determinations are preferably made at 25 °C or 37 °C. Typically, the rate constants (k on or k a and k off or k d ) and the equilibrium dissociation constant are measured using the whole antibody and monomer. Another method for determining the K D of an antibody is by using biolayer interferometry spectroscopy, typically by using the OCTET® technology (Octet QK e system, ForteBio). Alternatively, or in addition, the KinExA (binding equilibrium exclusion assay) assay available from Sapidyne Instruments (Boise, ID) can also be used.

[0700] As used herein, the terms "immunologically specifically bind," "immunologically specifically recognize," "specifically bind," "specifically recognize," and similar terms refer to a molecule, such as a binding domain, that specifically binds to an antigen (e.g., an epitope or an 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 a lower affinity, as determined by assays known in the art, such as immunoassays, BIACORE™, or other assays. Preferably, a molecule that specifically binds to an antigen does not cross-react with other proteins.

[0701] The term "specific binding" or "specifically binds," when used in reference to the interaction of an antibody and a protein or peptide, refers to an interaction that is dependent upon the presence of a particular structure (i.e., an antigenic determinant or epitope) on the protein, such that, in other words, the antibody recognizes and binds to a specific protein structure rather than to proteins generally. For example, if an 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.

[0702] In certain embodiments, "specifically binds" means, for example, that an antibody binds to a protein with a K D of about 0.1 nM or less, more generally, less than about 1 μM. In certain embodiments, "specifically binds" means that an antibody has a K DMeans binding to a target. Due to sequence identity between homologous proteins in different species, specific binding can include antibodies that recognize proteins in two or more species. Similarly, due to homology within a particular region of the polypeptide sequences of different proteins, specific binding can include antibodies that recognize two or more proteins. In certain embodiments, it is understood that an antibody or binding moiety that specifically binds to a first target may or may not specifically bind to a second target. Thus, "specific binding" does not necessarily require, but can include, exclusive binding, i.e., binding to a single target. Thus, in some embodiments, an antibody may specifically bind to two or more targets. In certain embodiments, multiple targets may bind to the same antigen-binding site on the antibody. For example, in certain instances, an antibody may contain 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 may be multispecific and may contain at least two antigen-binding sites with different specificities. As a non-limiting example, a bispecific antibody may contain one antigen-binding site that recognizes an epitope on one protein and may further contain 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.

[0703] An antibody that specifically binds to an antigen can bind to other peptides or polypeptides with lower affinity, as determined by assays known in the art, such as immunoassays, BIACORE™, or other assays. Preferably, an antibody that specifically binds to an antigen does not cross-react with other proteins.

[0704] The terms "non-specific binding" or "background binding", when used in reference to the interaction of an antibody with a protein or peptide, refer to an interaction that does not depend on the presence of a specific structure (i.e., the antibody binds to the protein generally without a specific structure such as an epitope).

[0705] A neutralizing antibody or "blocking" antibody refers to an antibody whose binding to one or more selected from the group consisting of IL-4, IL-13, IL-33, TSLP, and p40 is either (i) each preventing, restricting, or inhibiting the interaction between IL-4, IL-13, IL-33, TSLP, and p40 and their respective preferred ligands, or (ii) where appropriate, resulting in the inhibition of at least one biological function of IL-4, IL-13, IL-33, TSLP, or p40 binding. Assays for determining neutralization by the antibodies of the present disclosure are well known in the art.

[0706] As used herein, "antibodies that bind to a target", "antibodies that recognize a target", "antibodies that specifically bind to a target", "anti-target antibodies", "anti-target antibody molecules", "target antibodies", etc. include molecules containing at least one binding domain that specifically binds to the target.

[0707] "Monospecific antibody" refers to an antibody that contains one or more antigen-binding sites per molecule such that all of the antibody's binding sites specifically recognize the same epitope on an antigen. Thus, in instances where a monospecific antibody has two or more antigen-binding sites, the binding sites compete with each other for binding to one antigen molecule.

[0708] "Bispecific antibody" refers to a molecule having binding specificities for at least two different epitopes. In some embodiments, the bispecific antibody can bind to two different antigens simultaneously. In other embodiments, the two different epitopes may be present on the same antigen.

[0709] As used herein, "trispecific antibody" is an antibody having binding specificities for three different epitopes. In some embodiments, the trispecific antibody can bind simultaneously to three different antigens. In other embodiments, the three different epitopes may be present on the same antigen.

[0710] As used herein, "multispecific antibody" is an antibody having binding specificities for at least two different epitopes. In some embodiments, the multispecific antibody can bind simultaneously to at least two different antigens. In other embodiments, the at least two different epitopes may be present on the same antigen.

[0711] As used herein, the terms "IL-4 / IL-13 / IL-33 trispecific antibody" or "IL-4 / IL-13 / IL-33 multispecific antibody" refer to molecules designed to specifically bind to IL-4, IL-13, and IL-33. As used herein, the terms "IL-4 / IL-13 / TSLP trispecific antibody" or "IL-4 / IL-13 / TSLP multispecific antibody" refer to molecules designed to specifically bind to IL-4, IL-13, and TSLP. As used herein, the terms "IL-4 / IL-13 / p40 trispecific antibody" or "IL-4 / IL-13 / p40 multispecific antibody" refer to molecules designed to specifically bind to IL-4, IL-13, and p40.

[0712] The term "half maximal effective concentration (EC 50 )" refers to the concentration of a therapeutic agent that elicits a response that is half-way between the baseline and the maximum after a specified exposure time. The therapeutic agent may cause inhibition or stimulation. The EC 50 value is generally used and is used herein as a measure of potency.

[0713] The term "inhibitory concentration (IC 50) The term " ]]" refers to the concentration of an inhibitor at which 50% inhibition in its activity is achieved. A therapeutic agent may cause inhibition or stimulation. IC 50 values are generally used as a measure of potency and are used herein.

[0714] An "agonist" refers to a substance that promotes (i.e., induces, causes, enhances, or increases) the biological activity or effect of another molecule. The term agonist includes substances (such as antibodies) that bind to a molecule and promote its activity.

[0715] An "antagonist" refers to a substance that prevents, blocks, inhibits, neutralizes, or reduces the biological activity or effect of another molecule, such as a receptor. The term antagonist includes substances (such as antibodies) that bind to a molecule and prevent or reduce its activity.

[0716] As used herein with respect to antibodies, the term "competing" means that the binding of a first antibody to an epitope is sufficiently similar in manner to the binding of a second antibody such that the result of the binding of the second antibody to its cognate epitope is detectably decreased in the presence of the first antibody as compared to the binding of the second antibody in the absence of the first antibody. There may be an option that the binding of the first antibody to its epitope is also detectably decreased in the presence of the second antibody, but this is not necessary. That is, the first antibody can inhibit the binding of the second antibody to its epitope without the second antibody inhibiting the binding of the first antibody to its individual epitope. However, antibodies are said to "cross-compete" with each other for binding to their individual epitopes, whether to the same, higher, or lower extent, if each antibody detectably inhibits the binding of the other antibody to its cognate epitope or ligand. Both competing antibodies and cross-competing antibodies are encompassed by the present invention. Regardless of the mechanism by which such competition or cross-competition occurs (e.g., steric hindrance, conformational change, or binding to a common epitope or portion thereof), one of ordinary skill in the art will recognize, based on the teachings provided herein, that such competing or cross-competing antibodies are encompassed by and may be useful in the methods disclosed herein.

[0717] A "host cell" can refer to a recipient for a vector for the incorporation of a polynucleotide insert, or to an individual cell or cell culture that was such. Host cells include the progeny of a single host cell, which progeny need not be identical to the original parent cell, either in morphology or in genomic DNA complement, due to natural, accidental, or intentional mutation. Host cells include cells transfected with the polynucleotides of the present invention in vivo.

[0718] "Vector" refers to a construct that can deliver one or more genes or sequences of interest (e.g., antibody-encoding genes) in a host cell, preferably express them. Examples of vectors include, but are not limited to, plasmids and viral vectors, naked nucleic acids may be included, or nucleic acids associated with delivery support materials (e.g., cationic condensing agents, liposomes, etc.) may be included. Vectors can contain DNA or RNA. "Expression vector", as used herein, refers to a vector containing at least one polypeptide coding sequence and at least one regulatory element (e.g., promoter sequence, poly(A) sequence) related to the transcription or translation of a gene. Typically, the vectors used herein contain at least one antibody-encoding gene and one or more of regulatory elements or selectable markers. Vector components can include, for example, the following: signal sequences, origins of replication, one or more marker genes, one or more of suitable transcriptional control elements (such as promoters, enhancers and terminators). For translation, one or more translational control elements may also include, for example, ribosome binding sites, translation initiation sites, and stop codons.

[0719] An "isolated" molecule (e.g., an isolated antibody) is one that is not associated, by its origin or source of derivatization, (1) with the natural and associated components with which it is associated in its native state, (2) substantially free of other molecules from the same origin, e.g., species, cells in which it is expressed, library, etc., (3) expressed by cells from different species, or (4) not naturally occurring. Thus, a molecule synthesized chemically or expressed in a cell line different from its natural origin system is "isolated" from its natural associated components. Molecules may also be made substantially free of naturally associated components by isolation using purification techniques well known in the art.

[0720] 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 nonpolar amino acids. The linker can be, for example, 2 to 100 amino acids in length, such as between 2 and 50 amino acids in length, such as 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 or chemical cleavage. Cleavage sites in the amino acid sequence, as well as enzymes and chemicals that cleave at such sites, are well known in the art and are also described herein. In some embodiments, the linker comprises one or more repeat units of a sequence comprising glycine and serine residues. In some embodiments, the linker comprises one or more repeat units of G4S. In some embodiments, the linker comprises (G4S) 1~3 including. In some embodiments, the linker is GGGGS (SEQ ID NO: 10).

[0721] As used herein, the term "disulfide bond" or "cysteine-cysteine disulfide bond" refers to a covalent interaction between two cysteines, where the sulfur atoms of the cysteines are oxidized to form a disulfide bond. The average bond energy of a disulfide bond is about 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 within the framework region of a single-chain antibody and play a role in stabilizing the conformation of the antibody. Cysteine residues can be introduced, for example, by site-directed mutagenesis, so as to be able to create stabilizing disulfide bonds intramolecularly.

[0722] As used herein, the terms "linked", "fused", and "fusion" are used interchangeably and refer to joining two or more elements or components together by any means including chemical conjugation or recombinant means.

[0723] As used herein, the term "covalently linked" means that the specified moieties are directly covalently bonded to each other or are indirectly covalently joined to each other through one or more intervening moieties such as a peptide or moiety that links them.

[0724] As used herein, the term "connected" refers to a linear covalent linkage or attachment of two or more proteins, polypeptides, or fragments thereof through their respective peptide backbones. For example, one polypeptide may be connected to another polypeptide by the genetic expression of a single polynucleotide molecule that encodes these two polypeptides in-frame. Such gene fusions result in the expression of a single continuous protein containing both polypeptides.

[0725] As used herein, the term "modification" refers to an amino acid substitution, insertion, or deletion in a polypeptide sequence, a change to a moiety chemically linked to a protein, or a change in the function of a protein, such as an antibody. For example, the modification may be a change in the function of an antibody or a change in the 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" indicates a substitution of at least one existing amino acid residue with another different amino acid residue (e.g., replacing an amino acid residue). The term "amino acid deletion" indicates the removal of at least one amino acid residue at a given position in an amino acid sequence. For example, the mutation L234A indicates that the amino acid residue lysine at position 234 in the Fc region of the antibody has been replaced by the amino acid residue alanine (replacing lysine with alanine) (numbering follows the EU index numbering system).

[0726] The term "agent" is used herein to denote a biopolymer, an extract made from a biomaterial, a mixture of biopolymers, a chemical substance, a mixture of chemical substances, or a mixture of a chemical substance and a biopolymer. The term "therapeutic agent" refers to an agent having biological activity.

[0727] The term "polypeptide" or "protein" (used interchangeably herein) refers to a chain of amino acids of any length. The chain can be linear or branched. The chain may contain one or more modified amino acids. This term also encompasses amino acid chains that are natural or modified by intervention, such as disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. For example, polypeptides containing analogs of one or more amino acids (including, for example, non-natural amino acids) and other modifications known in the art are also included within this definition. It is understood that a polypeptide can exist as a single chain or as associated chains.

[0728] As used herein, a "first polypeptide" is any polypeptide that associates with a second polypeptide. The first polypeptide and the second polypeptide meet at an interface. In addition to the interface, the first polypeptide may include 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 a portion thereof) including CH2, CH1, and CL domains. Usually, the first polypeptide includes at least one domain derived from an antibody. This domain is preferably a constant domain, such as the CH3 domain of an antibody, which can form the interface of the first polypeptide. Exemplary first polypeptides include an antibody heavy chain polypeptide, a chimera in which an antibody constant domain is combined with a binding domain of a heterologous polypeptide, a receptor polypeptide, a ligand polypeptide, and an antibody variable domain polypeptide (e.g., a bispecific antibody).

[0729] In addition to the interface, the second polypeptide may include 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 a portion thereof) including CH2, CH1 and CL domains. Usually, the second polypeptide includes at least one domain derived from an antibody. Conveniently, this domain is a constant region such as the CH3 domain of an antibody and can form the interface of the second polypeptide. Exemplary second polypeptides include antibody heavy chain polypeptides, chimeras in which an antibody constant domain is combined with a binding domain of a heterologous polypeptide, and antibody variable domain polypeptides (e.g., bispecific antibodies).

[0730] "Polynucleotide" or "nucleic acid" (used interchangeably herein) refers to a chain of nucleotides of any length and includes DNA and RNA. A nucleotide can be a deoxyribonucleotide, ribonucleotide, modified nucleotide or base, or an analog thereof, or any substance that can be incorporated into a chain by a DNA or RNA polymerase. A polynucleotide can include modified nucleotides, such as methylated nucleotides and their analogs. Where present, modifications to the nucleotide structure can be imparted either before or after assembly of the chain. The nucleotide sequence may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, for example, by conjugation with a labeling component. Other types of modifications include, for example, "caps", substitution by one or more analogs of naturally occurring nucleotides, internucleotide modifications, such as those having uncharged linkages (e.g., methylphosphonate, phosphotriester, phosphoramidate, carbamate, etc.) and charged linkages (e.g., phosphorothioate, phosphorodithioate, etc.), pendant moieties, such as those containing proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), those having intercalators (e.g., acridine, psoralen, etc.), those containing chelating agents (e.g., metals, radioactive metals, boron, oxidizing metals, etc.), those containing alkylating agents, those having modified linkages (e.g., alpha anomeric nucleic acids, etc.), as well as the unmodified form of the polynucleotide. Further, any of the hydroxyl groups normally present on the sugar can be replaced, for example, by a phosphonate group, a phosphate group, protected by a standard protecting group, or activated to prepare additional linkages to additional nucleotides, or conjugated to a solid support. The 5' and 3' terminal OHs can be phosphorylated or substituted with an amine or an organic capping group moiety of 1 to 20 carbon atoms. Other hydroxyls may also be derivatized with standard protecting groups.The polynucleotide can...

Claims

1. An isolated antibody that specifically binds to TSLP, (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; (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; or (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; An antibody comprising: (i) a TSLP-VH sequence of SEQ ID NO: 92, and a TSLP-VL sequence of SEQ ID NO: 94; (ii) the TSLP-VH sequence of SEQ ID NO: 92, and the TSLP-VL sequence of SEQ ID NO: 93; (iii) the TSLP-VH sequence of SEQ ID NO: 92, and the TSLP-VL sequence of SEQ ID NO: 213; (iv) a TSLP-VH sequence of SEQ ID NO: 92, and a TSLP-VL sequence of SEQ ID NO: 214; (v) a TSLP-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 204, and a TSLP-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 205; (vi) a TSLP-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 204, and a TSLP-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 217; (vii) a TSLP-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 204, and a TSLP-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 218; (viii) a polypeptide sequence having a TSLP-VH encoded by the nucleic acid sequence of SEQ ID NO: 192, and a polypeptide sequence having a TSLP-VL encoded by the nucleic acid sequence of SEQ ID NO: 193; (ix) a polypeptide sequence having a TSLP-VH encoded by the nucleic acid sequence of SEQ ID NO: 192, and a polypeptide sequence having a TSLP-VL encoded by the nucleic acid sequence of SEQ ID NO: 193; (x) a polypeptide sequence having a TSLP-VH encoded by the nucleic acid sequence of SEQ ID NO: 192, and a polypeptide sequence having a TSLP-VL encoded by the nucleic acid sequence of SEQ ID NO: 193; (xi) the TSLP-VH sequence encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127200, and the TSLP-VL sequence encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127199; or (xii) a polypeptide sequence having TSLP-VH encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127202, and a polypeptide sequence having TSLP-VL encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127201. The antibody of claim 1, comprising: (i) an IC50 of less than 10 pM in a TARC production bioassay in human peripheral blood monocytes; (ii) a melting temperature of 68°C; (iii) a pH 3.4 hold ΔHMMS% of less than 5, where ΔHMMS% is defined as the difference between the percentage of high molecular weight species attributable to degradation after 5 hours of incubation of the antibody at pH 3.4 at room temperature and the percentage of high molecular weight species attributable to degradation after 5 hours of incubation of the antibody at pH 7.2 at room temperature; (iv) anti-TSLP biological activity of less than 10 pM IC 50 as measured in a TARC production bioassay in human primary PBMCs; (v) 20 mM histidine, 8.5% sucrose, 0.05 mg / mL EDTA a viscosity of 20 cP at a concentration of at least 100 mg / mL in a buffer solution of pH 6.0; (vi) a score of less than 2% high molecular mass species as determined by analytical size exclusion chromatography (aSEC); (vii) Affinity Capture Self-Interacting Nanoparticle Spectroscopy (AC a score of less than 12 in the SINS assay; (viii) an IC 50 of less than 15 pM in neutralizing human TSLP in a TARC production bioassay in human primary PBMCs; (ix) an IC50 in the cynomolgus monkey TSLP neutralization assay of less than 35 pM 3. The antibody of claim 1 or 2, characterized by one or more of the following:

4. An antibody described in any one of claims 1 to 3, further comprising an antibody that specifically binds to IL-4.

5. The antibody described in claim 4, comprising a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL), wherein CDR-H1 comprises the amino acid sequence of SEQ ID NO: 18, CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2, CDR-H3 comprises the amino acid sequence of SEQ ID NO: 3, CDR-L1 comprises the amino acid sequence of SEQ ID NO: 24, CDR-L2 comprises the amino acid sequence of SEQ ID NO: 12, and CDR-L3 comprises the amino acid sequence of SEQ ID NO:

25. (i) an IL4-VH sequence of SEQ ID NO: 22, and an 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; (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 having an IL4-VH encoded by the nucleic acid sequence of SEQ ID NO: 188, and a polypeptide sequence having an IL4-VL encoded by the nucleic acid sequence of SEQ ID NO: 189; (viii) the IL4-VH sequence encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127198, and the IL4-VL sequence encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127197; or (ix) a polypeptide sequence comprising IL4-VH encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127192, and a polypeptide sequence comprising IL4-VL encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127194. The antibody of claim 4 or 5, comprising:

7. The following: (i) the antibody binds to human IL-4 with a K D of less than a value selected from the group consisting of about 10 pM, 5 pM, 1 pM, and 800 fM; (ii) the antibody binds to cynomolgus IL-4; (iii) the antibody does not bind to IL-4 from one or more selected from the group consisting of dog, sheep, rabbit, rat, and mouse; (iv) the binding K D of the antibody to cynomolgus monkey IL-4 is within one order of magnitude of the binding K D of the antibody to human IL-4; (v) the antibody is characterized by an IC 50 of less than 10 pM in a human monocyte assay for IL-4-induced neutralization of CD23; (vi) the antibody has 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) the antibody contains a lysine at residue 93 in the light chain.

7. The antibody of claim 4, characterized by one or more of the following:

8. The IL-4 binding domain comprises a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL), wherein CDR-H1 comprises the amino acid sequence of SEQ ID NO: 18, CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2, CDR-H3 comprises the amino acid sequence of SEQ ID NO: 3, CDR-L1 comprises the amino acid sequence of SEQ ID NO: 24, CDR-L2 comprises the amino acid sequence of SEQ ID NO: 12, and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 25, (i) the TSLP binding domain comprises 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 (ii) the TSLP binding domain comprises 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; or (iii) the TSLP binding domain comprises 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; The antibody described in claim 7. (i) the TSLP-binding portion comprises a TSLP-VH of SEQ ID NO: 92 and a TSLP-VL of SEQ ID NO: 94; and (ii) the IL-4 binding portion comprises an IL4-VH of SEQ ID NO: 22 and an IL4-VL of SEQ ID NO: 26; An antibody described in any one of claims 4 to 8. (i) 20 mM histidine, 8.5% sucrose, 0.05 mg / mL EDTA a viscosity of less than 20 cP at a concentration of at least 100 mg / mL in a buffer solution at pH 6.0; (ii) 20 mM histidine, 8.5% sucrose, 0.05 mg / mL EDTA a viscosity of less than 12 cP at a concentration of at least 50 mg / mL in a buffer solution at pH 6.0; (iii) a terminal half-life of at least 12 days in cynomolgus monkeys; (iv) a terminal half-life of at least 18 days in TG-32 mice; (v) binds to human IL-4 with an affinity constant of less than 220 pM as measured by SPR; (vi) binds to human IL-4 with an affinity constant of less than 1 pM as measured by KinExA in an immobilized antigen assay in PBS; (vii) an IC 50 of less than 12 pM as measured in a human monocyte assay for neutralization of IL-4 induction of CD23; and (viii) an IC 50 of less than 12 pM as measured in a human monocyte assay for neutralization of cynomolgus IL-4 induction of CD23; 10. The antibody of claim 9, characterized by one or more of: (i) the second and fifth polypeptide chains together form a first Fab domain comprising a first antigen-binding site; (ii) the second and fourth polypeptide chains together form a second Fab domain comprising a second antigen-binding site; (iii) the first and third polypeptide chains together form a third Fab domain that comprises a third antigen-binding site. and a fifth polypeptide chain comprising: the first and second polypeptide chains associate together to form an antibody comprising two arms: a double Fab arm comprising the first Fab domain and the second Fab domain, and a single Fab arm comprising the third Fab domain; the first Fab comprises a first antigen-engaging VH (VH-1), a first antigen-engaging VL (VL-1), a first antigen-engaging CL (CL-1), and a first antigen-engaging CH1 (CH1-1), wherein the C-terminus of VH-1 is covalently fused to the N-terminus of CH1-1 by a peptide bond and the C-terminus of VL-1 is covalently fused to the N-terminus of CL-1 by a peptide bond; the second Fab comprises a second antigen-engaging VH (VH-2), a second antigen-engaging VL (VL-2), a second antigen-engaging CL (CL-2), and a second antigen-engaging CH1 (CH1-2), wherein the C-terminus of VH-2 is covalently fused to the N-terminus of CH1-2 by a peptide bond and the C-terminus of VL-2 is covalently fused to the N-terminus of CL-2 by a peptide bond; the third Fab comprises a third antigen-engaging VH (VH-3), a first antigen-engaging VL (VL-3), a first antigen-engaging CL (CL-3), and a first antigen-engaging CH1 (CH1-3), wherein the C-terminus of VH-3 is covalently fused to the N-terminus of CH1-3 by a peptide bond and the C-terminus of VL-3 is covalently fused to the N-terminus of CL-3 by a peptide bond; the first polypeptide comprises, from N-terminus to C-terminus, (VH-3)-(CH1-3)-(first hinge)-(first CH2)-(first CH3); 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); the third polypeptide comprises (VL-3)-(CL-3); the fourth polypeptide comprises (VL-2)-(CL-2); and the fifth polypeptide comprises, from N-terminus to C-terminus, (VH1)-(CL-1). An antibody described in any one of claims 1 to 10.

12. An antibody described in any one of claims 1 to 11, comprising a first Fc chain and a second Fc chain, wherein the first Fc chain comprises, in N-terminal to C-terminal order, a first hinge region connected to a first CH2 region which is connected to a first CH3 region, and wherein the second Fc chain comprises, in N-terminal to C-terminal order, a second hinge region connected to a second CH2 region which is connected to a second CH3 region, the first hinge region and the second hinge region comprising the pair of sequences set forth in SEQ ID NO: 129 and SEQ ID NO: 131, and the first CH3 region and the second CH3 region comprising 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.

13. The method of claim 12, wherein the first CH3 domain and the second CH3 domain each comprise a different complementary sequence, and the different complementary sequences are a pair of the following different complementary sequences: (vii) SEQ ID NO: 111 and SEQ ID NO: 106; (viii) SEQ ID NO: 111 and SEQ ID NO: 114; (ix) SEQ ID NO: 114 and SEQ ID NO: 117; (x) SEQ ID NO: 124 and SEQ ID NO: 127; (xi) SEQ ID NO: 139 and SEQ ID NO: 141, and (xii) SEQ ID NO: 147 and SEQ ID NO: 148 The antibody of claim 12, wherein the antibody is selected from one of the following:

14. An antibody comprising an antibody Fc domain comprising a first Fc chain and a second Fc chain, wherein the first Fc chain and the second Fc chain each comprise two amino acid modifications that promote association of the first Fc chain with the second Fc chain; (iii) 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 (iv) 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. An antibody according to any one of claims 1 to 13, characterized in that

15. An antibody described in any one of claims 1 to 14, comprising one or more sequences encoded by nucleic acids set forth in sequences selected from the group consisting of SEQ ID NO: 187, SEQ ID NO: 188, SEQ ID NO: 189, SEQ ID NO: 192, SEQ ID NO: 193, SEQ ID NO: 198, SEQ ID NO: 199, SEQ ID NO: 200, SEQ ID NO: 201, SEQ ID NO: 204 and SEQ ID NO:

205.

16. The antibody of any one of claims 1 to 15, comprising one or more sequences encoded by a nucleic acid corresponding to an ATCC deposit selected from the group consisting of PTA-127192, PTA-127193, PTA-127194, PTA-127195, PTA-127196, PTA-127197, PTA-127198, PTA-127199, PTA-127200, PTA-127201 and PTA-127202.

17. An antibody described in any one of claims 1 to 16 for use as a pharmaceutical.

18. The antibody described in claim 17, wherein the use is for the treatment of one or more selected from the group consisting of atopic dermatitis, asthma, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloid, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, and fungal keratitis, and non-alcoholic steatohepatitis (NASH).

19. The use of the present invention in the treatment of cancer, bladder cancer, breast cancer, clear cell renal cancer, head / neck squamous cell carcinoma, squamous cell lung 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 syndromes (MDS), non-Hodgkin's lymphoma (NHL), or small lymphocytic lymphoma (SMLL).

18. The antibody of any one of claims 1 to 17, which is for the treatment of one or more selected from the group consisting of: myeloid leukemia (SLL), hemolytic 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 / histiocytocyte-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 syndromes (MDS), non-Hodgkin's lymphoma (NHL), and small lymphocytic lymphoma (SLL).

20. The method of claim 1, wherein the first anticancer therapeutic agent comprises the antibody of any one of claims 1 to 16, and 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 TLR7 / 8 agonist, a TLR9 agonist, a bispecific anti-CD47 / anti-PD-L1 antibody, and a bispecific anti-P-cadherin / anti-CD3 antibody, sasanlimab, B 20. The antibody of claim 19, wherein the second anticancer therapeutic agent is selected from the group consisting of CD-100, camrelizumab, cemiplimab, genolimuzumab, MEDI0680, nivolumab, pembrolizumab, sintilimab, spartalizumab, STI-A1110, tislelizumab, atezolizumab, durvalumab, BMS-936559 (MDX-1105), LY3300054, and TSR-042. (i) a nucleic acid encoding a TSLP-VH and a TSLP-VL of an antibody that binds to TSLP, the nucleic acid comprising the nucleic acid sequence of SEQ ID NO: 204 and the nucleic acid sequence of SEQ ID NO: 205; (ii) a nucleic acid encoding a polypeptide having a TSLP-VH and a polypeptide having a TSLP-VL of an antibody that binds to TSLP, the nucleic acid comprising the nucleic acid sequence of SEQ ID NO: 192 and the nucleic acid sequence of SEQ ID NO: 193; (iii) a nucleic acid encoding a TSLP-VH and a TSLP-VL of an antibody that binds to TSLP, the nucleic acid comprising the nucleic acid sequence of SEQ ID NO: 204 and the nucleic acid sequence of SEQ ID NO: 217; (iv) a nucleic acid encoding a TSLP-VH and a TSLP-VL of an antibody that binds to TSLP, the nucleic acid comprising the nucleic acid sequence of SEQ ID NO: 204 and the nucleic acid sequence of SEQ ID NO: 218; (v) a nucleic acid encoding a TSLP-VH and a TSLP-VL of an antibody that binds to TSLP, the nucleic acid comprising the nucleic acid sequence of the sequence encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127200 and the sequence encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127199; and (vi) a nucleic acid encoding a polypeptide having a TSLP-VH and a polypeptide having a TSLP-VL of an antibody that binds to TSLP, the nucleic acid comprising the nucleic acid sequence of a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127202, and a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127201; An isolated nucleic acid selected from the group consisting of:

22. A vector comprising the nucleic acid described in claim 21.

23. An isolated host cell comprising the nucleic acid of claim 21 or the vector of claim 22.

24. A method for producing an isolated antibody, comprising culturing a host cell according to claim 23 under conditions that result in the production of the antibody, and recovering the antibody.

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