Multispecific antibodies and their use

Abstract

To provide safe and effective therapeutic compositions for numerous diseases characterized by inflammatory responses, which address a broad range of pathogenic mechanisms.SOLUTION: The present invention provides pharmaceutical compositions comprising either: antibodies that specifically bind to one or more of IL-4, IL-13, IL-33, TSLP and p40; antibodies that bind to one of IL-4, IL-13, IL-33 and TSLP; multispecific antibodies that specifically bind to IL-4 and IL-13 and to at least one other target; or multispecific antibodies that bind to IL-4, IL-13, and one of IL-33, TSLP and p40.SELECTED DRAWING: None

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, as well as 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, e.g., nucleic acids encoding such antibodies or multispecific antibodies, compositions, and related methods, e.g., methods for producing and purifying such antibodies and multispecific antibodies, as well as their use in diagnostic and therapeutic methods. [Background technology]

[0002] background The present invention relates to antibodies that specifically bind to one or more of IL-4, IL-13, IL-33, TSLP, and p40, as well as 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 allergies, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, nodular prurigo, keloids, bullous pemphigoid, chronic urticaria, IPF, and scleroderma. This includes the use of the antibodies of this disclosure to treat one or more diseases or conditions selected from the group consisting of 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, allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus (SLE), primary biliary cirrhosis, and hidradenitis suppurativa.

[0003] IL-4 and IL-13 are key drivers of immune activation, leading to inflammation, edema, fibrosis, and pruritus 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 common IL-4Rα / IL-2Rγ (type I receptor), expressed in T cells, B cells, and monocytes. Association of IL-4Rα via either receptor activates STAT6, inducing atopic-related genes (29). Although IL-4 and IL-13 may be involved in common receptors and signaling pathways, differences in cytokine availability, localization, and receptor binding affinity result in distinct response profiles (49, 50). Further differentiation may arise from type I receptors (IL-4Rα / γc) (51) that drive Th2 differentiation via IL-4 rather than IL-13, and from cell surface "decoy" IL-13Rα2 (52, 53) that mediate the neutralization and depletion of IL-13 rather than IL-4.

[0004] The roles of IL-4 and IL-13 in atopic diseases are supported by genetic associations, extensive validation in preclinical models, and the clinical efficacy of IL-4 and IL-13 neutralization in a range of atopic indications (48). The anti-IL-4Rα Dupixent® (dupilumab, Sanofi / Regeneron) blocks responses to both cytokines and is approved for the treatment of moderate to severe atopic dermatitis (AD), asthma, and chronic rhinosinusitis with nasal polyps, demonstrating 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) have also demonstrated efficacy in AD, with more limited activity in asthma (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 leburikizumab and tralokinumab, in line with the additional benefit of IL-4 blockade.

[0005] IL-33 is passively released during cell necrosis or when tissue is damaged, suggesting that it may function as an alarmin that modifies the immune system after damage to endothelial or epithelial cells during infection, physical stress, or trauma. IL-33 plays a crucial role in type 2 innate immunity through the activation of eosinophils, basophils, mast cells, macrophages, and group 2 innate lymphoid cells (ILC2s) associated with allergic inflammation via its receptor ST2 (96).

[0006] Thymic interstitial lymphocyte neogenesis factor (TSLP) is an important epithelial cytokine in the initiation and persistence of inflammation. Tezspire® (tezeperumab, Amgen) is a TSLP antibody approved for the treatment of asthma.

[0007] IL-4 and IL-13 are primarily 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 roles of IL-12p40-containing cytokines have been established by the approval of numerous drugs (75) (IL-12p40 will be simply referred to as p40 hereafter). The p40 antagonist Stellara® (ustekinumab, Janssen) neutralizes both IL-12 and IL-23 and is approved for the treatment of psoriasis vulgaris, psoriatic arthritis, Crohn's disease, and ulcerative colitis. The IL-23 selective anti-IL-23p19 blockers Tremfya® (guselkumab, Janssen), Skyrizi® (risankizumab, Boehringer Ingelheim / AbbVie), and Ilumya® (tildrakizumab, Sun Pharmaceutical) are approved for a range of psoriatic disorders. [Overview of the project] [Problems that the invention aims to solve]

[0008] Despite the efficacy of dupilumab, tezeperumab, guselkumab, risankizumab, and tildrakizumab, an unmet need remains for safe and effective treatments for numerous diseases characterized by immune responses that address a wide range of pathogenesis mechanisms. [Means for solving the problem]

[0009] overview Antibodies (including their antigen-binding fragments) 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, their associated nucleic acids, uses, and related methods are provided herein. The disclosure also provides methods for constructing, preparing, and producing antibodies that bind to one or more of IL-4, IL-13, IL-33, TSLP, and p40. The antibodies disclosed herein, but are not limited to, are used to treat atopic dermatitis, asthma, cancer, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, nodular prurigo, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, and systemic sclerosis, diabetic nephropathy, Behçet's disease, gout, Alzheimer's disease, atherosclerosis, fungal keratitis, and non-alcoholic steatohepatitis (NASH). This disclosure is useful for the diagnosis, prevention, or treatment of one or more disorders or conditions mediated by or associated with the activity of one or more of IL-4, IL-13, IL-33, TSLP, and p40, including psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus (SLE), primary biliary cirrhosis, and hidradenitis suppurativa. The disclosure further encompasses the expression of antibodies, as well as compositions comprising the antibodies of the disclosure, for example, the preparation and manufacture of pharmaceuticals for the use of antibodies.

[0010] Polynucleotides encoding antibodies that bind to one or more of IL-4, IL-13, IL-33, TSLP, and p40 are also provided. Polynucleotides encoding the heavy chain or light chain, or both, of an antibody are also provided. Host cells expressing antibodies are also provided. Methods of treatment using antibodies are also provided. Such methods, but are not limited to, diseases associated with or mediated by the expression of one or more of IL-4, IL-13, IL-33, TSLP, and p40, and / or the binding of one or more of IL-4, IL-13, IL-33, TSLP, and p40, including atopic dermatitis, asthma, cancer, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, nodular prurigo, keloids, and water The invention includes one or more methods for treating or preventing 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, allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus (SLE), primary biliary cirrhosis, and hidradenitis suppurativa.

[0011] The present invention may be more readily understood by referring to the following detailed description of the embodiments and examples of the invention included herein. It should be understood that the present invention is not limited to specific methods of production, which may, of course, be modified. It should also be understood that the technical terms used herein are for the purpose of describing specific embodiments only and are not intended to limit them. Those skilled in the art will be able to recognize or confirm many equivalents to the specific embodiments of the invention described herein by means of experiments that are merely customary. Such equivalents are intended to be encompassed by the following embodiment (E).

[0012] An isolated antibody that specifically binds to E1.IL-33, (i) The CDR-H1, CDR-H2, and CDR-H3 sequences of sequence number 73, and the CDR-L1, CDR-L2, and CDR-L3 sequences of sequence number 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 containing a heavy chain variable region (IL33-VH) and a light chain variable region (IL33-VL).

[0013] 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) including 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.

[0014] E3. An isolated antibody that specifically binds to IL-33, comprising a heavy chain variable region (IL33-VH) and a light chain variable region (IL33-VL), wherein 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.

[0015] An antibody according to any one of items E1 to E3, comprising an IL33-VH framework sequence derived from a human germline VH sequence selected from the group consisting of E4.DP47, DP48, DP50, DP51, DP54, and DP77.

[0016] E5. An antibody according to any one of items E1 to E4, comprising an IL33-VH framework sequence derived from a human DP54 germline sequence.

[0017] E6. An antibody according to any one of items E1 to E5, comprising an IL33-VL framework sequence derived from a human germline VL sequence selected from the group consisting of DPK1, DPK3, DPK4, DPK5, DPK7, DPK8, and DPK9.

[0018] E7. An antibody according to any one of items E1 to E6, comprising an IL33-VL framework sequence derived from a human germline DPK9 sequence.

[0019] An antibody according to any one of the E1 to E7, comprising 98%, 99%, or 100% 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 are at least 66%, 76%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, or 97% identical to the human germline sequence from which it is derived.

[0020] E9. An antibody according to any one of items E1 to E8, comprising an IL33-VL framework sequence and an IL33-VH framework sequence, wherein one or both of the IL33-VL framework sequence or the IL33-VH framework sequence are identical to the human germline sequence from which they are derived.

[0021] E10. An antibody according to any one of items 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 sequence number 73.

[0022] E11. An antibody according to any one of items 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 sequence number 78.

[0023] E12.(i) IL33-VH sequence of sequence number 73, and IL33-VL sequence of sequence number 78, or (ii) the IL33-VH sequence of sequence number 63 and the IL33-VL sequence of sequence number 71, or (iii) IL33-VH sequence of sequence number 80, and IL33-VL sequence of sequence number 81 An antibody, including any one of the items E1 to E11.

[0024] E13. An antibody according to any one of items E1 to E12, containing the same IL33-VH sequence as SEQ ID NO: 73 and the same IL33-VL sequence as SEQ ID NO: 78.

[0025] E14. An antibody according to any one of items E1 to E13, comprising an IL33-VH sequence encoded by the nucleic acid sequence of Sequence ID No. 202.

[0026] E15. An antibody according to any one of items E1 to E14, comprising the IL33-VL sequence encoded by the nucleic acid sequence of Sequence ID No. 203.

[0027] E16. An antibody described in any one of items E1 to E15, comprising an IL33-VH sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127210.

[0028] E17. An antibody according to any one of items E1 to E16, comprising an IL33-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127209.

[0029] E18.An antibody containing an IL33-VH sequence encoded by a plasmid deposited in ATCC with ATCC accession number PTA-127210, and an IL33-VL sequence encoded by a plasmid deposited in ATCC with ATCC accession number PTA-127209.

[0030] E19. K less than a value selected from the group consisting of 100pM, 50pM, 40pM, 30pM, 25pM, 20pM, 15pM, and 10pM, 5pM, 2pM, 1pM, 750fM, 500fM, and 250fM. D Antibodies listed in E1 to E18 that bind to human IL-33.

[0031] E20. K values ​​of approximately 15 pM or less. D Antibodies that bind to human IL-33, as described in E1 to E19.

[0032] E21. K values ​​of approximately 1 pM or less D Antibodies that bind to human IL-33, as described in E1 to E20.

[0033] E22. K values ​​of approximately 250 fM or less. D Antibodies described in E1 to E21 that bind to human IL-33.

[0034] E23.K D The antibody described in any one of items E19 to E22, whose value is measured by the binding equilibrium exclusion method.

[0035] E24.K D An antibody listed in any one of the items E19 to E22, whose value is measured by surface plasmon resonance (SPR).

[0036] IC for E25.IL-33 50 However, the antibodies listed in E1 to E24 are less than 20 pM in the HEK Blue® IL-33 neutralizing SEAP assay.

[0037] IC of E26.IL-33 50 However, the antibodies listed in E1 to E25 are less than 15 pM in the HEK Blue® IL-33 neutralizing SEAP assay.

[0038] E27. The HEK Blue® IL-33 neutralizing SEAP assay is performed at 37°C for 20 hours using the antibodies described in E25 to E26.

[0039] 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.

[0040] E29. The antibody according to E28, wherein the human whole blood assay is performed at 37°C for 22 hours.

[0041] E30. The antibody according to E1 to E29, which binds to cynomolgus monkey IL-33.

[0042] 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.

[0043] E32. The antibody according to E1 to E31, further comprising a constant heavy domain (IL33-CH1) and a constant light domain (IL33-CL).

[0044] 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.

[0045] E34. The antibody according to E32 to E33, wherein IL33-CH1 comprises the sequence described in SEQ ID NO: 6.

[0046] 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.

[0047] E36. The antibody according to E32 to E35, wherein IL33-CL comprises the sequence described in SEQ ID NO: 16.

[0048] The antibodies described in E32 to E36, wherein E37.IL33-CH1 is bound to IL33-VL and IL33-CL is bound to IL33-VH, forming an IL-33-binding domain-swap Fab domain (IL33-xFab).

[0049] The antibodies described in E32 to E37, wherein E38.IL33-CH1 is linked to IL33-VH and IL33-CL is linked to IL33-VL, forming an IL-33 binding Fab domain (IL33-Fab).

[0050] E39. An antibody according to any one of items E1 to E38, comprising an antibody Fc domain including a first Fc chain and a second Fc chain.

[0051] The antibody described in E39, wherein the E40.Fc domain is the Fc domain of IgA (e.g., IgA1 or IgA2), IgD, IgE, IgM, or IgG (e.g., IgG1, IgG2, IgG3, or IgG4).

[0052] The antibody described in E40, in which the E41.Fc domain is the Fc domain of IgG1.

[0053] E42. The antibody described in E40, wherein the N-terminus of the first or second Fc chain is connected to the C-terminus of the IL33-CH1 domain.

[0054] E43. The antibody described in E41 to E42, 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, respectively.

[0055] E44. The antibody according to E43, 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.

[0056] E45. The antibody described in E44, wherein the hinge region contains the sequence described in Sequence ID No. 7.

[0057] E46. The antibody according to E44, wherein the hinge region of the first Fc chain and the hinge region of the second Fc chain contain the sequence pairs described in SEQ ID NO: 129 and SEQ ID NO: 131.

[0058] The antibodies described in E43 to E46, wherein the E47.CH2 region contains the sequence described in Sequence ID No. 8.

[0059] E48. The CH3 region in the first Fc chain and the CH3 region in the second Fc chain (i) Sequence ID 9 and Sequence ID 9, (ii) Sequence IDs 111 and 106, (iii) Sequence IDs 111 and 114, (iv) Sequence IDs 114 and 117, (v) Sequence IDs 124 and 127, (vi) Sequence IDs 139 and 141, and (vii) Sequence IDs 147 and 148 An antibody as described in E43 to E47, comprising a pair of sequences selected from the group consisting of the following.

[0060] E49. The antibody described in E48, wherein the CH3 region of the first Fc chain and the CH region of the second Fc chain each contain the sequence described in Sequence ID No. 9.

[0061] E50. The antibody according to E48, wherein the CH3 region in the first Fc chain and the CH3 region in the second Fc chain contain the sequence pairs described in SEQ ID NO: 124 and SEQ ID NO: 127.

[0062] E51. An antibody according to any one of the claims E1 to E50, comprising a polypeptide having IL33-VH which contains an amino acid sequence 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.

[0063] An 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.

[0064] An 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.

[0065] An 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.

[0066] An 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.

[0067] An antibody according to E32 to E55, wherein the IL33-CL comprises the amino acid sequence of SEQ ID NO: 16.

[0068] An antibody according to any one of E1 to E56, comprising a polypeptide having an IL33-VL comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a sequence selected from 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.

[0069] An 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.

[0070] An 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] An isolated antibody that specifically binds to IL-33, which is an antibody selected from one or more of Tables 82, 84, and 87.

[0078] An antibody according to any one of E1 to 65 for use as a medicament.

[0079] E68. The antibody described in E67, which is 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, nodular prurigo, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, diabetic nephropathy, Behçet's disease, gout, Alzheimer's disease, and atherosclerosis.

[0080] E69. An antibody according to any one of the items E67 to E68, 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, and non-alcoholic steatohepatitis (NASH).

[0081] E70. An antibody described in any one of items E67 to E69, whose use is for atopic dermatitis.

[0082] E71. An antibody described in any one of items E67 to E69, whose use is for non-alcoholic steatohepatitis (NASH).

[0083] E72. A pharmaceutical composition comprising a therapeutically effective amount of the antibodies described in E1 to E71 and a pharmaceutically acceptable carrier.

[0084] E73. A method for treating a medical condition, comprising administering a therapeutically effective amount of an antibody described in any one of E1 to E71, or a pharmaceutical composition described in E72, to a subject in need thereof.

[0085] E74. 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, nodular prurigo, keloid, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, diabetic nephropathy, Behçet's disease, gout, Alzheimer's disease, and atherosclerosis.

[0086] E75. The method according to any one of E73 to E74, comprising subcutaneously administering the antibody or pharmaceutical composition.

[0087] E76. The method according to any one of E73 to E75, wherein the antibody or pharmaceutical composition is administered approximately 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.

[0088] An isolated antibody that specifically binds to E77.TSLP, (i) The CDR-H1, CDR-H2, and CDR-H3 sequences of sequence number 92, and the CDR-L1, CDR-L2, and CDR-L3 sequences of sequence number 94, (ii) The CDR-H1, CDR-H2, and CDR-H3 sequences of sequence number 92, and the CDR-L1, CDR-L2, and CDR-L3 sequences of sequence number 93, (iii) The CDR-H1, CDR-H2, and CDR-H3 sequences of sequence number 92, and the CDR-L1, CDR-L2, and CDR-L3 sequences of sequence number 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 sequence number 221, and the CDR-L1, CDR-L2, and CDR-L3 sequences of sequence number 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) that include the same.

[0089] 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) that include 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.

[0090] An isolated antibody that specifically binds to E79.TSLP, (i) A heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL) wherein CDR-H1 includes the amino acid sequence of SEQ ID NO: 82, CDR-H2 includes the amino acid sequence of SEQ ID NO: 83, CDR-H3 includes the amino acid sequence of SEQ ID NO: 85, CDR-L1 includes the amino acid sequence of SEQ ID NO: 86, CDR-L2 includes the amino acid sequence of SEQ ID NO: 88, and CDR-L3 includes 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 includes the amino acid sequence of SEQ ID NO: 82, CDR-H2 includes the amino acid sequence of SEQ ID NO: 83, CDR-H3 includes the amino acid sequence of SEQ ID NO: 85, CDR-L1 includes the amino acid sequence of SEQ ID NO: 86, CDR-L2 includes the amino acid sequence of SEQ ID NO: 88, and CDR-L3 includes the amino acid sequence of SEQ ID NO: 211 [[ID=!15]] (iii) A heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL) wherein CDR-H1 includes the amino acid sequence of SEQ ID NO: 82, CDR-H2 includes the amino acid sequence of SEQ ID NO: 83, CDR-H3 includes the amino acid sequence of SEQ ID NO: 85, CDR-L1 includes the amino acid sequence of SEQ ID NO: 86, CDR-L2 includes the amino acid sequence of SEQ ID NO: 88, and CDR-L3 includes the amino acid sequence of SEQ ID NO: 212 (iv) 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, a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), (v) Heavy chain variable region (TSLP-VH) and light chain variable region (TSLP-VL) where 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) Heavy chain variable region (TSLP-VH) and light chain variable region (TSLP-VL) where 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. Antibodies containing this substance.

[0091] An antibody according to any one of items 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.

[0092] E81. An antibody according to any one of items E77 to E80, comprising a TSLP-VH framework sequence derived from a human DP50 germline sequence.

[0093] An antibody according to any one of items 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.

[0094] E83. An antibody according to any one of items E77 to E82, comprising a TSLP-VL framework sequence derived from a human germline V2-14 sequence.

[0095] An antibody according to any one of the items 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 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.

[0096] An antibody according to any one of items 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 are identical to the human germline sequence from which they are derived.

[0097] E86. An antibody according to any one of items 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 sequence number 92.

[0098] E87. An antibody according to any one of items 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 sequence number 94.

[0099] E88.(i) The TSLP-VH sequence of sequence number 92, and the TSLP-VL sequence of sequence number 94, (ii) The TSLP-VH sequence of sequence number 92, and the TSLP-VL sequence of sequence number 93, (iii) The TSLP-VH sequence of sequence number 92, and the TSLP-VL sequence of sequence number 213, (iv) The TSLP-VH sequence of sequence number 92 and the TSLP-VL sequence of sequence number 214, (v) The TSLP-VH sequence of sequence number 221, and the TSLP-VL sequence of sequence number 215, (vi) the TSLP-VH sequence of sequence number 221 and the TSLP-VL sequence of sequence number 99, or (vii) The TSLP-VH sequence of sequence number 221 and the TSLP-VL sequence of sequence number 224 An antibody, including any one of the items from E77 to E86.

[0100] E89. An antibody according to any one of items E77 to E88, comprising the same TSLP-VH sequence as SEQ ID NO: 92 and the same TSLP-VL sequence as SEQ ID NO: 94.

[0101] E90. An antibody according to any one of items E77 to E88, comprising the same TSLP-VH sequence as SEQ ID NO: 92 and the same TSLP-VL sequence as SEQ ID NO: 93.

[0102] E91. An antibody according to any one of items E77 to E88, comprising the same TSLP-VH sequence as SEQ ID NO: 92 and the same TSLP-VL sequence as SEQ ID NO: 213.

[0103] E92. An antibody according to any one of items E77 to E88, comprising the same TSLP-VH sequence as SEQ ID NO: 92 and the same TSLP-VL sequence as SEQ ID NO: 214.

[0104] E93. An antibody according to any one of the items E77 to E89, comprising a TSLP-VL sequence encoded by the nucleic acid sequence of Sequence ID No. 205.

[0105] E94. The antibody described in E91, comprising the TSLP-VL sequence encoded by the nucleic acid sequence of Sequence ID No. 217.

[0106] E95. The antibody described in E92, comprising the TSLP-VL sequence encoded by the nucleic acid sequence of Sequence ID No. 218.

[0107] E96. An antibody according to any one of the items E77 to E95, comprising a TSLP-VH sequence encoded by the nucleic acid sequence of sequence number 204.

[0108] An antibody as described in any one of items E77 to E96, comprising a TSLP-VH sequence encoded by a plasmid deposited in ATCC and having ATCC accession number PTA-127200.

[0109] An antibody as described in any one of items E77 to E89, comprising a TSLP-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127199.

[0110] An antibody containing a TSLP-VH sequence encoded by a plasmid deposited in ATCC with ATCC accession number PTA-127200, and a TSLP-VL sequence encoded by a plasmid deposited in ATCC with ATCC accession number PTA-127199.

[0111] An antibody as described in any one of items E77 to E88, comprising a TSLP-VL sequence encoded by a plasmid deposited in E100.ATCC and having ATCC accession number PTA-______.

[0112] An antibody containing a TSLP-VH sequence encoded by a plasmid deposited in E101.ATCC with ATCC accession number PTA-127200, and a TSLP-VL sequence encoded by a plasmid deposited in ATCC with ATCC accession number PTA-______.

[0113] An antibody as described in any one of items E77 to E88, comprising a TSLP-VL sequence encoded by a plasmid deposited in E102.ATCC and having ATCC accession number PTA-______.

[0114] An antibody containing a TSLP-VH sequence encoded by a plasmid deposited in ATCC with ATCC accession number PTA-127200, and a TSLP-VL sequence encoded by a plasmid deposited in ATCC with ATCC accession number PTA-______.

[0115] E104. IC <10 pM in TARC production bioassays in human peripheral blood monocytes 50 Antibodies described in E77 to E102, characterized by the above.

[0116] E105. IC <7 pM in TARC production bioassay in human peripheral blood monocytes 50 Antibodies described in E77 to E104, characterized by the above.

[0117] E106. IC <6 pM in TARC production bioassay in human peripheral blood monocytes 50 Antibodies described in E77 to E105, characterized by the above.

[0118] An antibody as described in E77 to E106, having a melting temperature of E107.68℃.

[0119] E108. The antibodies described in E77 to E107, wherein the pH 3.4 hold ΔHMMS% is less than 5, such that the pH 3.4 hold ΔHMMS% is defined as the difference between the percentage of high molecular weight species resulting from the degradation of the antibody at pH 3.4 at room temperature after 5 hours of incubation and the percentage of high molecular weight species resulting from the degradation of the antibody at pH 7.2 at room temperature after 5 hours of incubation.

[0120] Antibodies described in E77 to E108 that have a low pH 3.4 hold ΔHMMS% of less than E109.1.

[0121] Antibodies described in E77 to E109 that have a low pH 3.4 hold ΔHMMS% of less than E110.0.1.

[0122] E111. Antibodies as described in E77 to E110, further comprising a constant heavy domain (TSLP-CH1) and a constant light domain (TSLP-CL).

[0123] The antibody according to E111, wherein E112.TSLP-CH1 contains a sequence selected from the group consisting of SEQ ID NO: 6, SEQ ID NO: 105, and SEQ ID NO: 110.

[0124] E113.TSLP-CH1 is an antibody described in E111 to E112, containing the sequence described in SEQ ID NO: 6.

[0125] The antibodies described in E111 to E113, wherein E114.TSLP-CL contains 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.

[0126] E115.TSLP-CL is an antibody described in E111 to E114, containing the sequence described in SEQ ID NO: 95.

[0127] The antibodies described in E111 to E115, wherein E116.TSLP-CH1 is bound to TSLP-VL and TSLP-CL is bound to TSLP-VH, forming a TSLP-binding domain-swap Fab domain (TSLP-xFab).

[0128] The antibodies described in E111 to E115, wherein E117.TSLP-CH1 is connected to TSLP-VH, and TSLP-CL is connected to TSLP-VL, forming a TSLP-binding Fab domain (TSLP-Fab).

[0129] E118. An antibody according to any one of items E77 to E117, comprising an Fc domain including a first Fc chain and a second Fc chain.

[0130] E119. The antibody described in E118, wherein the Fc domain is the Fc domain of IgA (e.g., IgA1 or IgA2), IgD, IgE, IgM, or IgG (e.g., IgG1, IgG2, IgG3, or IgG4).

[0131] An antibody described in any one of items E118 to E119, wherein the E120.Fc domain is the Fc domain of IgG1.

[0132] E121. The antibodies described in E118 to E120, wherein the N-terminus of the first or second Fc chain is connected to the C-terminus of the TSLP-CH1 domain.

[0133] E122. The antibody described in E118 to E121, wherein the first Fc chain and the second Fc chain each contain a hinge region, a CH2 region, and a CH3 region from the N-terminus to the C-terminus, respectively.

[0134] E123. The antibody according to E122, 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.

[0135] E124. The antibodies described in E122 to E123, wherein the hinge region contains the sequence described in Sequence ID No. 7.

[0136] E125. The antibodies according to E122 to E123, wherein the hinge region in the first Fc chain and the hinge region in the second Fc chain contain the sequence pair described in SEQ ID NO: 129 and SEQ ID NO: 131.

[0137] The antibodies described in E122 to E123, wherein the E126.CH2 region contains the sequence described in Sequence ID No. 8.

[0138] E127. The CH3 region in the first Fc chain and the CH3 region in the second Fc chain are (i) Sequence IDs 124 and 127, (ii) Sequence ID 9 and Sequence ID 9, (iii) Sequence IDs 111 and 106, (iv) Sequence IDs 111 and 114, (v) Sequence IDs 114 and 117, (vi) Sequence IDs 139 and 141, and (vii) Sequence IDs 147 and 148 The antibodies described in E122 to E126, comprising a pair of sequences selected from the group consisting of the following.

[0139] E128. The antibody described in E127, wherein the CH3 region of the first Fc chain and the CH region of the second Fc chain each contain the sequence described in Sequence ID No. 9.

[0140] 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 the sequence pairs described in SEQ ID NO: 124 and SEQ ID NO: 127.

[0141] An antibody according to any one of the claims E77 to E129, comprising a polypeptide having TSLP-VH containing 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 NOs: 97, 152, 153, 155, 158, 161, 165, and 222.

[0142] E131. An antibody according to any one of items E77 to E130, comprising a polypeptide having 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.

[0143] An antibody according to any one of the items E77 to E131, wherein the polypeptide having E132.TSLP-VH contains the sequence described in SEQ ID NO: 97.

[0144] An antibody according to any one of items E77 to E131, wherein the polypeptide having E133.TSLP-VH contains the sequence described in SEQ ID NO: 165.

[0145] E134. An antibody according to any one of items E77 to E133, comprising a polypeptide having a TSLP-VL that contains an amino acid sequence 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 NOs. 98, 99, 150, 154, 156, 157, 160, 215, 216, and 224.

[0146] E135. An antibody according to any one of items E77 to E134, comprising a polypeptide having a TSLP-VL containing a sequence selected from the group consisting of SEQ ID NOs: 98, 99, 150, 154, 156, 157, 160, 215, 216, and 224.

[0147] E136. An antibody according to any one of items E77 to E135, comprising a polypeptide having a TSLP-VL containing the sequence described in Sequence ID No. 99.

[0148] An antibody as described in any one of items E77 to E135, comprising a polypeptide sequence having TSLP-VL encoded by a plasmid deposited in ATCC and having ATCC accession number PTA-127201.

[0149] An antibody as described in any one of items E77 to E135, comprising a polypeptide sequence having TSLP-VL encoded by a plasmid deposited in ATCC and having ATCC accession number PTA-_____.

[0150] An antibody as described in any one of items E77 to E135, comprising a polypeptide sequence having TSLP-VL encoded by a plasmid deposited in ATCC and having ATCC accession number PTA-_____.

[0151] An antibody as described in any one of items E77 to E139, comprising a polypeptide sequence having TSLP-VH encoded by a plasmid deposited in E140.ATCC and having ATCC accession number PTA-127202.

[0152] An antibody containing a polypeptide sequence having TSLP-VH encoded by a plasmid deposited in E141.ATCC with ATCC accession number PTA-127202, and a polypeptide sequence having TSLP-VL encoded by a plasmid deposited in ATCC with ATCC accession number PTA-127201.

[0153] An antibody containing a polypeptide sequence having TSLP-VH encoded by a plasmid deposited in E142.ATCC with ATCC accession number PTA-127202, and a polypeptide sequence having TSLP-VL encoded by a plasmid deposited in ATCC with ATCC accession number PTA-_____.

[0154] An antibody containing a polypeptide sequence having TSLP-VH encoded by a plasmid deposited in E143.ATCC with ATCC accession number PTA-127202, and a polypeptide sequence having TSLP-VL encoded by a plasmid deposited in ATCC with ATCC accession number PTA-_____.

[0155] E144. An isolated antibody that specifically binds to p40 via a p40 binding domain, comprising 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) containing 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.

[0156] E145. An isolated antibody that specifically binds to p40 via a p40 binding domain, comprising 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.

[0157] An antibody according to any one of items 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.

[0158] An antibody according to any one of items E144 to E146, wherein the E147.p40 binding domain contains a p40-VH framework sequence derived from a human germline VH sequence selected from the group consisting of DP3, DP7, DP73, DP75, and DP88.

[0159] An antibody according to any one of items E144 to E147, wherein the E148.p40 binding domain contains a p40-VH framework sequence derived from a human DP73 germline sequence.

[0160] An antibody according to any one of items E144 to E148, wherein the E149.p40 binding domain contains a p40-VL framework sequence derived from a human germline VL sequence selected from the group consisting of DPK4, DPK5, DPK7, DPK8, and DPK9.

[0161] An antibody according to any one of items E144 to E149, wherein the E150.p40 binding domain contains a p40-VL framework sequence derived from a human germline DPK7 sequence.

[0162] E151. The antibody according to any one of the items 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.

[0163] An antibody according to any one of items 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.

[0164] An antibody according to any one of items E144 to E152, wherein the E153.p40 binding domain contains a p40-VH that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to that of SEQ ID NO: 169.

[0165] An antibody according to any one of items E144 to E153, wherein the E154.p40 binding domain contains a p40-VL that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to that of SEQ ID NO: 175.

[0166] An antibody according to any one of items E144 to E154, wherein the E155.p40 binding domain includes p40-VH of SEQ ID NO: 169 and p40-VL of SEQ ID NO: 175.

[0167] An antibody according to any one of items E144 to E155, wherein the E156.p40 binding domain contains a p40-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 206.

[0168] An antibody according to any one of items E145 to E156, wherein the E157.p40 binding domain contains a p40-VL sequence encoded by the nucleic acid sequence of Sequence ID No. 207.

[0169] An antibody as described in any one of items E144 to E157, wherein the E158.p40 binding domain contains a p40-VH sequence encoded by a plasmid deposited in ATCC and having ATCC accession number PTA-127206.

[0170] An antibody according to any one of items E144 to E158, wherein the E159.p40 binding domain contains a p40-VL sequence encoded by a plasmid deposited in ATCC and having ATCC accession number PTA-127205.

[0171] E160. Antibodies as described in E144 to E159, further comprising a constant heavy domain (p40-CH1) and a constant light domain (p40-CL).

[0172] The antibody described in E160, wherein E161.p40-CH1 contains a sequence selected from the group consisting of SEQ ID NO: 6, SEQ ID NO: 105, and SEQ ID NO: 110.

[0173] E162.p40-CH1 is an antibody described in E160 to E161, containing the sequence described in SEQ ID NO: 6.

[0174] The antibodies 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.

[0175] E164.p40-CL is an antibody described in E160 to E163, containing the sequence described in SEQ ID NO: 16.

[0176] The antibodies described in E160 to E164, wherein E165.p40-CH1 is attached to p40-VL and p40-CL is attached to p40-VH, forming a p40-binding domain-swap Fab domain (p40-xFab).

[0177] The antibodies described in E160 to E164, wherein E166.p40-CH1 is linked to p40-VH and p40-CL is linked to p40-VL, forming a p40-binding Fab domain (p40-Fab).

[0178] E167. An antibody according to any one of items E144 to E166, comprising an antibody Fc domain including a first Fc chain and a second Fc chain.

[0179] The antibody described in E167, wherein the E168.Fc domain is the Fc domain of IgA (e.g., IgA1 or IgA2), IgD, IgE, IgM, or IgG (e.g., IgG1, IgG2, IgG3, or IgG4).

[0180] The antibody described in E168, in which the E169.Fc domain is the Fc domain of IgG1.

[0181] E170. An antibody as described in any one of items E167 to E169, wherein the N-terminus of the first or second Fc chain is connected to the C-terminus of the p40-CH1 domain.

[0182] E171. The antibodies described in 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, respectively.

[0183] 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.

[0184] E173. The antibodies according to E171 to E172, wherein the hinge region in the first Fc chain and the hinge region in the second Fc chain contain the sequence pair described in SEQ ID NO: 129 and SEQ ID NO: 131.

[0185] The antibodies described in E171 to E172, wherein the E174.CH2 region contains the sequence described in SEQ ID NO: 8.

[0186] E175. The CH3 region in the first Fc chain and the CH3 region in the second Fc chain (i) Sequence ID 9 and Sequence ID 9, (ii) Sequence IDs 111 and 106, (iii) Sequence IDs 111 and 114, (iv) Sequence IDs 114 and 117, (v) Sequence IDs 124 and 127, (vi) Sequence IDs 139 and 141, and (vii) Sequence IDs 147 and 148 An antibody according to E171 to E174, comprising a pair of sequences selected from the group consisting of the following.

[0187] E176. The antibodies described in E171 to E175, wherein the CH3 region of the first Fc chain and the CH region of the second Fc chain each contain the sequence described in Sequence ID No. 9.

[0188] E177. The antibodies according to E171 to E176, wherein the CH3 region in the first Fc chain and the CH region in the second Fc chain contain the sequence pair described in SEQ ID NO: 124 and SEQ ID NO: 127.

[0189] An antibody according to any one of the items E144 to E177, comprising a polypeptide having p40-VH which has an amino acid sequence 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.

[0190] E179. An antibody according to any one of items E144 to E178, comprising a polypeptide having p40-VH containing an amino acid selected from the group consisting of SEQ ID NOs: 170, 177, 181, 185, and 186.

[0191] An antibody according to any one of items E144 to E179, comprising a polypeptide having p40-VH containing the amino acid sequence of E180.

[0192] An antibody according to any one of the items E144 to E180, comprising a polypeptide having a p40-VL that has an amino acid sequence 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.

[0193] E182. An antibody according to any one of items E144 to E181, comprising a polypeptide having p40-VL containing the amino acid sequence of SEQ ID NO: 176.

[0194] An antibody as described in any one of items E144 to E182, comprising a polypeptide sequence having p40-VH encoded by a plasmid deposited in ATCC and having ATCC accession number PTA-127204.

[0195] An antibody as described in any one of items E144 to E183, comprising a polypeptide sequence having p40-VL encoded by a plasmid deposited in E184.ATCC and having ATCC accession number PTA-127203.

[0196] An antibody containing a polypeptide sequence having p40-VH encoded by a plasmid deposited in E185.ATCC with ATCC accession number PTA-127204, and a polypeptide sequence having p40-VL encoded by a plasmid deposited in ATCC with ATCC accession number PTA-127203.

[0197] An isolated antibody that binds to E186.p40 and one or both of IL-4 and IL-13, comprising a CDR of an antibody selected from one or more of Tables 86 and 87.

[0198] An isolated antibody that binds to E187.p40 and one or both of IL-4 and IL-13, comprising VH and VL of an antibody selected from one or more of Tables 86 and 87.

[0199] An isolated antibody that binds to E188.p40 and one or both of IL-4 and IL-13, selected from one or more of Tables 86 and 87.

[0200] E189. An antibody described in any one of items E144 to E188 for use as a pharmaceutical.

[0201] E190. The antibody described in E189, for use in 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, keloids, systemic lupus erythematosus, primary biliary cirrhosis, and hidradenitis suppurativa.

[0202] E191. An antibody according to any one of items E189 to E190, for use in 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.

[0203] E192. An antibody described in any one of items E189 to E191, whose use is for atopic dermatitis.

[0204] E193. An antibody described in any one of items E189 to E191, whose use is for non-alcoholic steatohepatitis (NASH).

[0205] E194. A pharmaceutical composition comprising a therapeutically effective amount of an antibody described in E144 to E193 and a pharmaceutically acceptable carrier.

[0206] E195. A method for treating a medical condition, comprising administering a therapeutically effective amount of an antibody described in any one of E144 to E193, or a pharmaceutical composition described in E194, to a subject in need thereof.

[0207] E196. 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, keloids, systemic lupus erythematosus, primary biliary cirrhosis, and hidradenitis suppurativa.

[0208] E197. The method according to any one of E195 to E196, comprising subcutaneously administering the antibody or pharmaceutical composition.

[0209] E198. The method according to any one of E195 to E196, wherein the antibody or pharmaceutical composition is administered approximately 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.

[0210] An isolated antibody that specifically binds to E199.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) CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 22, and CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 30 An antibody containing a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL).

[0211] An isolated antibody that specifically binds to E200.IL-4, comprising a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL) including 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.

[0212] E201. An isolated antibody that specifically binds to IL-4, comprising a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL), wherein 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.

[0213] An antibody according to any one of items E199 to E201, comprising an IL4-VH framework sequence derived from a human germline VH sequence selected from the group consisting of E202.DP26, DP27, DP28, and DP76.

[0214] E203. An antibody according to any one of items E199 to E202, comprising an IL4-VH framework sequence derived from a human DP76 germline sequence.

[0215] An antibody according to any one of items E199 to E203, comprising an IL4-VL framework sequence derived from a human germline VL sequence selected from the group consisting of E204.DPK1, DPK3, DPK4, DPK5, DPK7, DPK8, DPK9, and DPK24.

[0216] E205. An antibody according to any one of items E199 to E204, comprising an IL4-VL framework sequence derived from a human germline DPK9 sequence.

[0217] An antibody according to any one of the claims from 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 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.

[0218] An antibody according to any one of the items from 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 are identical to the human germline sequence from which they are derived.

[0219] E208. An antibody according to any one of the items from E199 to E207, containing 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.

[0220] E209. An antibody according to any one of the items from E199 to E208, containing 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.

[0221] E210.(i) IL4-VH sequence of sequence number 22, and IL4-VL sequence of sequence number 26, (ii) The IL4-VH sequence of sequence number 19 and the IL4-VL sequence of sequence number 20, (iii) IL4-VH sequence of sequence number 22, and IL4-VL sequence of sequence number 20, (iv) the IL4-VH sequence of sequence number 28 and the IL4-VL sequence of sequence number 29, or (v) IL4-VH sequence of sequence number 22, and IL4-VL sequence of sequence number 30 An antibody, including any one of the items from E199 to E209.

[0222] E211. An antibody according to any one of items E199 to E210, containing the same IL4-VH sequence as SEQ ID NO: 22 and the same IL4-VL sequence as SEQ ID NO: 26.

[0223] E212. An antibody according to any one of items E199 to E211, comprising an IL4-VH sequence encoded by the nucleic acid sequence of sequence number 200.

[0224] E213. An antibody according to any one of items E199 to E212, comprising an IL4-VL sequence encoded by the nucleic acid sequence of Sequence ID No. 201.

[0225] An antibody described in any one of items E199 to E213, comprising an IL4-VH sequence encoded by a plasmid deposited in E214.ATCC and having ATCC accession number PTA-127198.

[0226] An antibody as described in any one of items E199 to E214, comprising an IL4-VL sequence encoded by a plasmid deposited in E215.ATCC and having ATCC accession number PTA-127197.

[0227] An antibody containing the IL4-VH sequence encoded by a plasmid deposited in E216.ATCC with ATCC accession number PTA-127198, and the IL4-VL sequence encoded by a plasmid deposited in ATCC with ATCC accession number PTA-127197.

[0228] E217. K less than a value selected from the group consisting of approximately 10 pM, 5 pM, 1 pM, and 800 fM. D Antibodies listed in E199 to E216 that bind to human IL-4.

[0229] E218. K values ​​less than approximately 1 pM D Antibodies listed in E199 to E217 that bind to human IL-4.

[0230] E219.K D The antibody whose value is measured by the binding equilibrium exclusion method, as described in any one of the items from E199 to E218.

[0231] E220. Antibodies that bind to IL-4 in cynomolgus monkeys, as described in E199 to E219.

[0232] E221. Antibodies described in E199 to E220 that do not bind to IL-4, derived from one or more species selected from the group consisting of dogs, sheep, rabbits, rats, and mice.

[0233] E222. Antibody binding to IL-4 in cynomolgus monkeys K D However, the binding of the antibody to human IL-4 K D one digit difference Antibodies listed in E199 to E221 that are within the specified range.

[0234] E223. Antibody binding to IL-4 in cynomolgus monkeys K D However, the binding of the antibody to human IL-4 K D Antibodies listed in E199 to E222 that are within a twofold difference.

[0235] <10 pM IC20 in a human monocyte assay for IL-4 induction neutralization of E224.CD23 50 Antibodies described in E199 to E223, characterized by the above.

[0236] Neutralization of E225.CD23 by IL-4 induction in cynomolgus monkeys in a human monocyte assay with IC20 <20 pM 50 Antibodies described in E199 to E224, characterized by the above.

[0237] E226. The antibody described in E199 to E225, having a viscosity of 20 cP or less at 25°C at a concentration of 80 mg / mL in histidine-sucrose buffer at pH 5.8.

[0238] E227. The antibody described in E199 to E226, having a viscosity of 20 cP or less at 25°C at a concentration of 100 mg / mL in histidine-sucrose buffer at pH 5.8.

[0239] E228. The antibody described in E199 to E227, having a viscosity of 20 cP or less at 25°C at a concentration of 120 mg / mL in histidine-sucrose buffer at pH 5.8.

[0240] E229. Antibodies described in E199 to E228, which contain lysine at residue 93 in the light chain.

[0241] E230. Antibodies as described in E199 to E229, further comprising a constant heavy domain (IL4-CH1) and a constant light domain (IL4-CL).

[0242] E231.IL4-CH1 is the antibody described in E230, which contains the sequence described in SEQ ID NO: 6.

[0243] E232.IL4-CL is an antibody described in E230 to E231, containing the sequence described in SEQ ID NO: 16.

[0244] The antibodies described in E230 to E232, wherein E233.IL4-CH1 is attached to IL4-VL and IL4-CL is attached to IL-4-VH, forming an IL-4-binding domain-swap Fab domain (IL4-xFab).

[0245] The antibodies described in E230 to E232, wherein E234.IL4-CH1 is connected to IL4-VH and IL4-CL is connected to IL4-VL, forming an IL-4 binding Fab domain (IL4-Fab).

[0246] E235. An antibody according to any one of items E199 to E234, comprising an Fc domain including a first Fc chain and a second Fc chain.

[0247] The antibody described in E235, wherein the E236.Fc domain is the Fc domain of IgA (e.g., IgA1 or IgA2), IgD, IgE, IgM, or IgG (e.g., IgG1, IgG2, IgG3, or IgG4).

[0248] The antibodies described in E235 to E236, in which the E237.Fc domain is the Fc domain of IgG1.

[0249] E238. The antibody or antigen-binding fragment described in E235 to E237, wherein the N-terminus of the first or second Fc chain is connected to the C-terminus of the IL33-CH1 domain.

[0250] E239. The antibody or antigen-binding fragment 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, respectively.

[0251] E240. The antibody or antigen-binding fragment 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.

[0252] E241. The antibody or antigen-binding fragment according to E240, wherein the hinge region contains the sequence described in Sequence ID No. 7.

[0253] E242. The antibody or antigen-binding fragment according to E240, wherein the hinge region in the first Fc chain and the hinge region in the second Fc chain contain the sequence pair described in SEQ ID NO: 129 and SEQ ID NO: 131.

[0254] The antibody or antigen-binding fragment described in E239 to E242, wherein the E243.CH2 region contains the sequence described in Sequence ID No. 8.

[0255] E244. The CH3 region in the first Fc chain and the CH3 region in the second Fc chain (i) Sequence ID 9 and Sequence ID 9, (ii) Sequence IDs 111 and 106, (iii) Sequence IDs 111 and 114, (iv) Sequence IDs 114 and 117, (v) Sequence IDs 124 and 127, (vi) Sequence IDs 139 and 141, and (vii) Sequence IDs 147 and 148 An antibody or antigen-binding fragment according to E239 to E243, comprising a pair of sequences selected from the group consisting of the following.

[0256] E245. The antibody or antigen-binding fragment according to E244, wherein the CH3 region of the first Fc chain and the CH region of the second Fc chain each contain the sequence described in Sequence ID No. 9.

[0257] E246. The antibody or antigen-binding fragment according to E244, wherein the CH3 region in the first Fc chain and the CH3 region in the second Fc chain contain the sequence pair described in SEQ ID NO: 124 and SEQ ID NO: 127.

[0258] E247. An antibody according to any one of claims E199 to E246, comprising a polypeptide having IL4-VH containing 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 NOs. 23, SEQ ID NOs. 107, SEQ ID NOs. 115, SEQ ID NOs. 121, SEQ ID NOs. 125, SEQ ID NOs. 130, SEQ ID NOs. 133, SEQ ID NOs. 140, SEQ ID NOs. 144, SEQ ID NOs. 146, SEQ ID NOs. 151, SEQ ID NOs. 153, SEQ ID NOs. 156, SEQ ID NOs. 157, SEQ ID NOs. 159, SEQ ID NOs. 162, and SEQ ID NOs. 164, SEQ ID NOs. 179, SEQ ID NOs. 180, and SEQ ID NOs. 183.

[0259] E248. An antibody according to any one of items E199 to E247, comprising a polypeptide having IL4-VH containing the amino acid sequence of Sequence ID No. 23.

[0260] An antibody according to any one of items E199 to E241, comprising a polypeptide having IL4-VH containing the amino acid sequence E249.Sequence ID 8:130.

[0261] An antibody according to any one of the claims from E199 to E249, comprising a polypeptide having an IL4-VL that has an amino acid sequence 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.

[0262] E251. An antibody according to any one of items E199 to E250, comprising a polypeptide having IL4-VL containing the amino acid sequence of SEQ ID NO: 27.

[0263] An antibody as described in any one of items E199 to E251, comprising a polypeptide sequence having IL4-VH, which is deposited in E252.ATCC and encoded by a plasmid having ATCC accession number PTA-127192.

[0264] An antibody according to any one of items E199 to E252, comprising a polypeptide sequence having IL4-VL, which is deposited in E253.ATCC and encoded by a plasmid having ATCC accession number PTA-127194.

[0265] An antibody containing a polypeptide sequence having IL4-VH encoded by a plasmid deposited in E254.ATCC with ATCC accession number PTA-127192, and a polypeptide sequence having IL4-VL encoded by a plasmid deposited in ATCC with ATCC accession number PTA-127194.

[0266] E255. An antibody as described in any one of items E199 to E254 for use as a pharmaceutical.

[0267] E256. An antibody described in any one of items 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, nodular prurigo, keloids, 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, keloids, systemic lupus erythematosus (SLE), primary biliary cirrhosis, and hidradenitis suppurativa.

[0268] E257. An antibody as described in any one of items 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.

[0269] E258. An antibody described in any one of items E199 to E257, whose use is for atopic dermatitis.

[0270] E259. An antibody described in any one of items E199-257, whose use is for non-alcoholic steatohepatitis (NASH).

[0271] E260. A pharmaceutical composition comprising a therapeutically effective amount of an antibody described in E199 to E259 and a pharmaceutically acceptable carrier.

[0272] E261. A method for treating a medical condition, comprising administering a therapeutically effective amount of an antibody described in any one of the items E199 to E259, or a pharmaceutical composition described in E260, to a subject in need thereof.

[0273] E262. 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, nodular prurigo, keloid, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, diabetic nephropathy, Behçet's disease, gout, Alzheimer's disease, and atherosclerosis.

[0274] E263. The method according to any one of E261 to E262, comprising subcutaneously administering the antibody or pharmaceutical composition.

[0275] E264. The method according to any one of E261 to E263, wherein the antibody or pharmaceutical composition is administered approximately 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.

[0276] An isolated antibody that specifically binds to E265.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 sequence number 44, and the CDR-L1, CDR-L2, and CDR-L3 sequences of sequence number 46, (iii) The CDR-H1, CDR-H2, and CDR-H3 sequences of sequence number 48, and the CDR-L1, CDR-L2, and CDR-L3 sequences of sequence number 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) CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 57, and CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 59 An antibody containing a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL).

[0277] 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) including 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.

[0278] E267. An isolated antibody that specifically binds to IL-13, comprising a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL), wherein 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.

[0279] An antibody according to any one of items 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.

[0280] E269. An antibody according to any one of items E265 to E268, comprising an IL13-VH framework sequence derived from a human DP54 germline sequence.

[0281] An antibody according to any one of items 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.

[0282] E271. An antibody according to any one of items E265 to E270, comprising an IL13-VL framework sequence derived from a human germline DPK9 sequence.

[0283] An antibody according to any one of the items 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 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.

[0284] An antibody according to any one of items 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 are identical to the human germline sequence from which they are derived.

[0285] E274. An antibody according to any one of items E265 to E273, containing IL13-VH that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 51.

[0286] E275. An antibody according to any one of items E265 to E274, containing IL13-VL that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 54.

[0287] E276.(i) IL13-VH of sequence number 51 and IL13-VL of sequence number 54 (ii) IL13-VH of sequence number 44, and IL13-VL of sequence number 46, (iii) IL13-VH of sequence number 48, and IL13-VL of sequence number 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 An antibody, including any one of the items from E265 to E275.

[0288] E277. An antibody according to any one of items E265 to E276, containing the same IL13-VH as SEQ ID NO: 51 and the same IL13-VL as SEQ ID NO: 54.

[0289] E278. An antibody according to any one of the items E265 to E277, comprising a VH sequence encoded by the nucleic acid sequence of sequence number 198.

[0290] E279. An antibody according to any one of the items E265 to E278, comprising a VL sequence encoded by the nucleic acid sequence of sequence number 199.

[0291] An antibody as described in any one of items E265 to E279, comprising an IL13-VH sequence encoded by a plasmid deposited in E280.ATCC and having ATCC accession number PTA-127196.

[0292] An antibody as described in any one of items E265 to E280, comprising an IL13-VL sequence encoded by a plasmid deposited in ATCC and having ATCC accession number PTA-127195.

[0293] An antibody containing the IL13-VH sequence encoded by a plasmid deposited in E282.ATCC with ATCC accession number PTA-127196, and the IL13-VL sequence encoded by a plasmid deposited in ATCC with ATCC accession number PTA-127195.

[0294] E283. K is less than a value selected from the group consisting of 10nM, 5nM, 2nM, 1nM, 900pM, 800pM, 700pM, 600pM, 500pM, 400pM, 300pM, 250pM, 200pM, 150pM, 100pM, and 60pM. D Antibodies listed in E265 to E282 that bind to human IL-13.

[0295] K below E284.60 pM D Antibodies described in E265 to E276 that bind to human IL-13.

[0296] E285.K D The antibody described in any one of items E283 to E284, whose value is measured by the binding equilibrium exclusion method.

[0297] E286.K D The antibody whose value is measured by SPR, as described in any one of the items E283 to E285.

[0298] E287. Antibodies described in E265 to E286 that bind to IL-13 in cynomolgus monkeys.

[0299] E288. Antibodies described in E265 to E287 that do not bind to IL-13, derived from one or more species selected from the group consisting of dogs, rabbits, and mice.

[0300] E289. Antibody binding to IL-13 in cynomolgus monkeys K D However, the binding of the antibody to human IL-13 K D one digit difference Antibodies listed in E265 to E288 that are within the specified range.

[0301] E290. Antibody binding to IL-13 in cynomolgus monkeys K D However, the binding K of that antibody to human IL-13 D Antibodies listed in E265 to E289 that are within a 5-fold difference.

[0302] E291. Antibody binding to IL-13 in cynomolgus monkeys K DHowever, the binding K of that antibody to human IL-13 D Antibodies listed in E265 to E290 that are within a twofold difference.

[0303] IC E292.IL-13 50 However, the antibodies listed in E265 to E291, as measured by neutralization of IL-13 pSTAT6 phosphorylation in HT-29 cells, are less than 100 pM.

[0304] IC of E293.IL-13 50 However, the antibodies listed in E265 to E292, measured in a human monocyte assay for IL-13 induction of CD23, are less than 20 pM.

[0305] IC of E294.IL-13 50 However, the antibodies listed in E265 to E293, measured in a human monocyte assay for IL-13 induction of CD23, are less than 15 pM.

[0306] IC E295.IL-13 50 However, the antibodies listed in E265 to E294, measured in a human monocyte assay for IL-13 induction of CD23, are less than 12 pM.

[0307] E296. Antibodies according to E265 to E295, further comprising a constant heavy domain (IL13-CH1) and a constant light domain (IL13-CL).

[0308] The antibody according to E296, wherein E297.IL13-CH1 contains a sequence selected from the group consisting of SEQ ID NO: 6, SEQ ID NO: 105, and SEQ ID NO: 110.

[0309] E298.IL13-CH1 is an antibody described in E296 to E297, containing the sequence described in SEQ ID NO: 6.

[0310] The antibodies described in E296 to E298, wherein E299.IL13-CL contains a sequence selected from the group consisting of SEQ ID NO: 16, SEQ ID NO: 108, and SEQ ID NO: 113.

[0311] E300.IL13-CL is an antibody described in E296 to E299, containing the sequence described in SEQ ID NO: 16.

[0312] The antibodies described in E296 to E300, wherein E301.IL13-CH1 is bound to IL13-VL and IL13-CL is bound to IL13-VH, forming an IL-13-binding domain-swap Fab domain (IL13-xFab).

[0313] The antibodies described in E296 to E301, in which E302.IL13-CH1 is linked to IL13-VH and IL13-CL is linked to IL33-VL, forming an IL-13 binding Fab domain (IL13-Fab).

[0314] E303. An antibody according to any one of items E265 to E302, comprising an Fc domain including a first Fc chain and a second Fc chain.

[0315] The antibody described in E303, wherein the E304.Fc domain is the Fc domain of IgA (e.g., IgA1 or IgA2), IgD, IgE, IgM, or IgG (e.g., IgG1, IgG2, IgG3, or IgG4).

[0316] The antibodies described in E303 to E304, in which the E305.Fc domain is the Fc domain of IgG1.

[0317] E306. The antibodies described in E303 to E305, wherein the N-terminus of the first or second Fc chain is connected to the C-terminus of the IL13-CH1 domain.

[0318] E307. The antibody described in E303 to E306, wherein the first Fc chain and the second Fc chain each contain a hinge region, a CH2 region, and a CH3 region from the N-terminus to the C-terminus, respectively.

[0319] E308. The antibody according to E307, 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.

[0320] E309. Antibodies according to E307 to E308, wherein the hinge region contains the sequence described in Sequence ID No. 7.

[0321] E310. Antibodies according to E307 to E309, wherein the hinge region contains the sequence described in SEQ ID NO: 102.

[0322] The antibodies described in E307 to E310, wherein the E311.CH2 region contains the sequence described in SEQ ID NO: 8.

[0323] E312. The CH3 region in the first Fc chain and the CH3 region in the second Fc chain are (i) Sequence IDs 124 and 127, (ii) Sequence ID 9 and Sequence ID 9, (iii) Sequence IDs 111 and 106, (iv) Sequence IDs 111 and 114, (v) Sequence IDs 114 and 117, (vi) Sequence IDs 139 and 141, and (vii) Sequence IDs 147 and 148 An antibody according to E307 to E311, comprising a pair of sequences selected from the group consisting of the following.

[0324] E313. The antibodies described in E307 to E312, wherein the CH3 region of the first Fc chain and the CH region of the second Fc chain each contain the sequence described in SEQ ID NO: 9.

[0325] E314. The antibodies according to E307 to E312, wherein the CH3 region in the first Fc chain and the CH region in the second Fc chain contain the sequence pair described in SEQ ID NO: 124 and SEQ ID NO: 127.

[0326] E315. An antibody according to any one of items E265 to E314, comprising a polypeptide having IL13-VH which contains an amino acid sequence 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 NOs. 52, 66, 112, 118, 121, 122, 130, 145, 149, 152, 154, 160, 162, and 164, and SEQ ID NOs. 209.

[0327] E316. An antibody according to any one of items E265 to E315, comprising a polypeptide having IL13-VH, consisting of SEQ ID NOs. 52, 66, 112, 118, 121, 122, 130, 145, 149, 152, 154, 160, 162, and 164, and SEQ ID NOs.

[0328] E317. An antibody according to any one of items E264 to E316, comprising a polypeptide having IL13-VH containing the amino acid sequence of SEQ ID NO: 52.

[0329] E318. An antibody according to any one of items E265 to E316, comprising a polypeptide having IL13-VH containing the amino acid sequence of SEQ ID NO: 122.

[0330] An antibody according to any one of the claims E265 to E318, comprising a polypeptide having IL13-VL which contains an amino acid sequence 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.

[0331] An antibody according to any one of items E265 to E319, comprising a polypeptide having IL13-VL containing 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.

[0332] E321. An antibody according to any one of items E265 to E320, comprising a polypeptide having IL13-VL containing the amino acid sequence of SEQ ID NO: 55.

[0333] E322. An antibody according to any one of items E265 to E321, comprising a polypeptide having IL13-VL containing the amino acid sequence of SEQ ID NO: 130.

[0334] An antibody as described in any one of items E265 to E322, comprising a polypeptide sequence having IL13-VH, which is encoded by a plasmid deposited in ATCC and having ATCC accession number PTA-127193.

[0335] An antibody as described in any one of items E265 to E323, comprising a polypeptide sequence having IL13-VL, which is deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127192.

[0336] An antibody containing an IL13-VH polypeptide sequence encoded by a plasmid deposited in ATCC with ATCC accession number PTA-127193, and an IL13-VL polypeptide sequence encoded by a plasmid deposited in ATCC with ATCC accession number PTA-127192.

[0337] E326. An antibody as described in any one of the items E265 to E325 for use as a pharmaceutical.

[0338] E327. The antibody described in E326, for use in one or more treatments selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, nodular prurigo, keloids, 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, allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus (SLE), primary biliary cirrhosis, and hidradenitis suppurativa.

[0339] E328. An antibody according to any one of paragraphs 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.

[0340] E329. An antibody described in any one of items E326 to E328, whose use is for atopic dermatitis.

[0341] E330. An antibody described in any one of items E326 to E329, for use in non-alcoholic steatohepatitis (NASH).

[0342] E331. A pharmaceutical composition comprising a therapeutically effective amount of an antibody described in E265 to E330 and a pharmaceutically acceptable carrier.

[0343] E332. A method for treating a medical condition, comprising administering a therapeutically effective amount of an antibody described in any one of E265 to E330, or a pharmaceutical composition described in E331, to a subject in need thereof.

[0344] E333. 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, keloids, systemic lupus erythematosus, primary biliary cirrhosis, and hidradenitis suppurativa.

[0345] E334. The method according to any one of E332 to E333, comprising subcutaneously administering the antibody or pharmaceutical composition.

[0346] E335. The method according to any one of E332 to E334, wherein the antibody or pharmaceutical composition is administered approximately 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.

[0347] E336. An isolated antibody that specifically binds to IL-33, specifically binds to IL-4, and specifically binds to IL-13, comprising an IL-33 binding domain, an IL-4 binding domain, and an IL-13 binding domain.

[0348] E337. The antibody according to E336, wherein specific binding to IL-33 is mediated by any one of the antibodies described in E1 to E71.

[0349] E338. An antibody according to E336 to E337, wherein specific binding to IL-4 is mediated by an antibody described in any one of the items E199 to E259.

[0350] E339. An antibody according to any one of items E336 to E338, wherein specific binding to IL-13 is mediated by an antibody according to any one of items E265 to E330.

[0351] E340.(i) The IL-33 binding domain comprises a heavy chain variable region (IL33-VH) and a light chain variable region (IL33-VL), CDR-H1 of the IL-33 binding domain comprises the amino acid sequence of SEQ ID NO: 60, CDR-H2 of the IL-33 binding domain comprises the amino acid sequence of SEQ ID NO: 61, CDR-H3 of the IL-33 binding domain comprises the amino acid sequence of SEQ ID NO: 72, CDR-L1 of the IL-33 binding domain comprises the amino acid sequence of SEQ ID NO: 75, CDR-L2 of the IL-33 binding domain comprises the amino acid sequence of SEQ ID NO: 76, and CDR-L3 of the IL-33 binding domain comprises the amino acid sequence of SEQ ID NO: 77. (ii) The IL-4 binding domain comprises a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL), where CDR-H1 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 18, CDR-H2 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 2, CDR-H3 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 3, CDR-L1 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 24, CDR-L2 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 12, and CDR-L3 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 25. (iii) The IL-13 binding domain comprises a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL), where CDR-H1 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 41, CDR-H2 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 42, CDR-H3 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 50, CDR-L1 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 53, CDR-L2 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 37, and CDR-L3 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 38. An antibody described in any one of the items E336 to E339.

[0352] E341.(i) The IL-33 binding domain includes IL33-VH of SEQ ID NO: 73 and IL33-VL of SEQ ID NO: 78, (i) The IL-4 binding domain includes IL4-VH of SEQ ID NO: 22 and IL4-VL of SEQ ID NO: 26, (ii) The IL-13 binding domain includes IL13-VH of SEQ ID NO: 51 and IL13-VL of SEQ ID NO: 54 Antibodies listed in E336 to E340.

[0353] E342.(i) The IL-33 binding domain includes an IL33-VH sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127210, and an IL33-VL sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127209, (ii) The IL-4 binding domain comprises an IL4-VH sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127198, and an IL4-VL sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127197, (iii) The IL-13 binding domain includes an IL13-VH sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127196, and an IL13-VL sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127195, Antibodies described in E336 to E341.

[0354] E343.Antibodies according to E336 to E342, wherein the IL-33 binding domain is fused to the IL-13 binding domain with or without a linker.

[0355] E344.Antibodies as described in E336 to E342, wherein the IL-33 binding domain is fused to the IL-4 binding domain with or without a linker.

[0356] E345. The antibodies described in E336 to E342, wherein the IL-13 binding domain is fused to the IL-4 binding domain with or without a linker.

[0357] E346. An antibody described in any one of items E343 to E345, which is fused with a linker.

[0358] E347. An antibody according to any one of items E336 to E346, wherein the IL-13 binding domain is fused to the IL-4 binding domain with a linker.

[0359] E348. The linker is an antibody as described in E343 to E347, including SEQ ID NO: 104.

[0360] E349.(i) The second and fifth polypeptide chains together form a first Fab domain containing the first antigen-binding site, (ii) The second and fourth polypeptide chains together form a second Fab domain containing the 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 items E336 to E348, comprising a first, second, third, fourth, and fifth polypeptide chain.

[0361] 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 a first Fab domain and a second Fab domain, and a single Fab arm containing a third Fab domain.

[0362] E351. The antibody described in E349 to E350, wherein the fifth polypeptide chain contains the sequence EPKSC (SEQ ID NO: 122) at its C-terminus.

[0363] E352. The antibody described in 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.

[0364] E353. The first Fab domain, the second Fab domain, and the third Fab domain are as follows: (i) IL33-Fab as described in E38, (ii) IL4-Fab as described in E234, and (iii) IL13-Fab described in E302 The antibodies described in E349 to E352, each comprising a different option selected from (i), (ii), and (iii).

[0365] E354. The antibodies described in E349 to E353, wherein the first Fab domain is IL13-Fab as described in E302, the second Fab domain is IL4-Fab as described in E234, and the third Fab domain is IL33-Fab as described in E38.

[0366] E355. The antibody according to E349 to E354, wherein the first polypeptide comprises a first Fc chain and the second polypeptide comprises a second Fc chain.

[0367] E356. The antibody according to E355, wherein the first Fc chain and the second Fc chain each contain one or more amino acid modifications that promote association of the first Fc chain with the second Fc chain.

[0368] E357. The first Fc chain contains a first CH3 domain, the second Fc chain contains a second CH3 domain, and 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) Sequence IDs 111 and 106, (ii) Sequence IDs 111 and 114, (iii) Sequence IDs 114 and 117, (iv) Sequence IDs 124 and 127, (v) Sequence IDs 139 and 141, and (vi) Sequence IDs 147 and 148 An antibody selected from one of the following, as described in E349 to E356.

[0369] E358. The antibody described in E357, wherein the first and second CH3 domains contain the sequence numbers 124 and 127.

[0370] E359. The identities of the first, second, third, fourth, and fifth polypeptide chains are, (i) The first polypeptide chain includes SEQ ID NO: 132, the second polypeptide chain includes SEQ ID NO: 130, the third polypeptide chain includes SEQ ID NO: 79, the fourth polypeptide chain includes SEQ ID NO: 27, and the fifth polypeptide chain includes SEQ ID NO: 122. (ii) The first polypeptide chain contains SEQ ID NO: 146, the second polypeptide chain contains SEQ ID NO: 145, 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: 103. (iii) The first polypeptide chain contains SEQ ID NO: 112, the second polypeptide chain contains SEQ ID NO: 107, 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. (iv) The first polypeptide chain contains SEQ ID NO: 118, the second polypeptide chain contains SEQ ID NO: 115, the third polypeptide chain contains SEQ ID NO: 119, the fourth polypeptide chain contains SEQ ID NO: 116, and the fifth polypeptide chain contains SEQ ID NO: 103. (v) The first polypeptide chain contains SEQ ID NO: 118, the second polypeptide chain contains SEQ ID NO: 115, the third polypeptide chain contains SEQ ID NO: 120, the fourth polypeptide chain contains SEQ ID NO: 116, and the fifth polypeptide chain contains 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. Antibodies selected from the group consisting of E349 to E358.

[0371] E360. An antibody according to any one of items 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.

[0372] E361. An isolated antibody that specifically binds to IL-33, specifically to IL-4, and specifically 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 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 an IL-33 binding site, The first polypeptide chain contains SEQ ID NO: 132, the second polypeptide chain contains SEQ ID NO: 130, 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. antibody.

[0373] E362. An isolated antibody that specifically binds to IL-33, specifically to IL-4, and specifically 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 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 an IL-33 binding site, The first polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127208; the second polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127192; the third polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127207; the fourth polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127194; and the fifth polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127193. antibody.

[0374] E363: An antibody described in 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, and 0.05 mg / mL of EDTA at pH 6.0.

[0375] E364. Antibodies described in 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, and 0.05 mg / mL EDTA pH 6.0.

[0376] E365. Antibodies described in E336 to E364, having a terminal phase half-life of at least 12 days in cynomolgus monkeys.

[0377] The antibodies described in E330 to E365, having a terminal phase half-life of at least 16 days in E366.TG32 mice.

[0378] E367. Antibodies described in E330 to E366 that bind to human IL-4 with a binding affinity of less than 220 nM, as measured by SPR.

[0379] E368. Antibodies described in E330 to E367 that bind to human IL-13 with a binding affinity of less than 220 nM, as measured by SPR.

[0380] E369. Antibodies described in E336 to E368 that bind to human IL-4 with a binding affinity of less than 1 pM, as measured by KinExA in a fixed antigen assay in PBS.

[0381] E370. Antibodies described in E336 to E369 that bind to cynomolgus monkey IL-4 with a binding affinity of less than 5 pM, as measured by KinExA in a fixed antigen assay in PBS.

[0382] E371. Antibodies described in E336 to E370 that bind to human IL-13 with a binding affinity of less than 1 pM, as measured by KinExA in a fixed antigen assay in PBS.

[0383] E372. Antibodies described in E336 to E371 that bind to cynomolgus monkey IL-13 with a binding affinity of less than 1 pM, as measured by KinExA in a fixed antigen assay in PBS.

[0384] E373.CD23 neutralization by IL-4 induction in a human monocyte assay with IC20 nM less than 20 nM 50 Antibodies described in E336 to E372, characterized by the above.

[0385] E374. Neutralization of CD23 by IL-13 induction in a human monocyte assay with IC20 <20 nM 50 Antibodies described in E336 to E373, characterized by the above.

[0386] E375. IC20 <30 nM in wild-type IL-33 neutralizing HEK-Blue SEAP assay 50 Antibodies described in E336 to E374, characterized by the above.

[0387] E376. IC <15 pM in recombinant constitutively active IL-33 neutralizing HEK-Blue SEAP assay 50 Antibodies described in E336 to E375, characterized by the above.

[0388] E377. An antibody as described in any one of the items E336 to E376 for use as a pharmaceutical.

[0389] E378. The antibody described in E377, for use in one or more treatments selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, nodular prurigo, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, diabetic nephropathy, Behçet's disease, gout, Alzheimer's disease, and atherosclerosis.

[0390] E379. An antibody according to any one of paragraphs E377 to 378, 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, and non-alcoholic steatohepatitis (NASH).

[0391] E380. An antibody described in any one of items E377 to E379, whose use is for atopic dermatitis.

[0392] E381. An antibody described in any one of items E377 to E379, whose use is for non-alcoholic steatohepatitis (NASH).

[0393] E382. A pharmaceutical composition comprising a therapeutically effective amount of an antibody described in E336 to E381 and a pharmaceutically acceptable carrier.

[0394] E383. A method for treating a medical condition, comprising administering a therapeutically effective amount of an antibody described in any one of E336 to E381, or a pharmaceutical composition described in E382, to a subject in need thereof.

[0395] 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, nodular prurigo, keloid, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, diabetic nephropathy, Behçet's disease, gout, Alzheimer's disease, and atherosclerosis.

[0396] E385. The method according to any one of E383 to E384, comprising subcutaneously administering the antibody or pharmaceutical composition.

[0397] E386. The method according to any one of E383 to E385, wherein the antibody or pharmaceutical composition is administered approximately 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.

[0398] E387. An isolated antibody that specifically binds to TSLP, specifically binds to IL-4, and specifically binds to IL-13, comprising a TSLP-binding domain, an IL-4-binding domain, and an IL-13-binding domain.

[0399] The antibody described in E387, wherein specific binding to E388.TSLP is mediated by an antibody described in any one of the items E77 to E143.

[0400] E389.Antibodies according to E387 to E388, wherein specific binding to IL-4 is mediated by any one of the antibodies described in E199 to E259.

[0401] E390. An antibody according to any one of items E387 to E389, wherein specific binding to IL-13 is mediated by an antibody according to any one of items E265 to E330.

[0402] E391.(i) The TSLP-binding domain comprises a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), where 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. (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. An antibody described in any one of the items E381 to E384.

[0403] E392.(i) The TSLP join includes TSLP-VH of SEQ ID NO: 92 and TSLP-VL of SEQ ID NO: 94 (ii) The IL-4 binding moiety includes IL4-VH of SEQ ID NO: 22 and IL4-VL of SEQ ID NO: 26, (iii) The IL-13 binding moiety includes IL13-VH of SEQ ID NO: 51 and IL13-VL of SEQ ID NO: 54 Antibodies listed in E387 to E391.

[0404] E393.(i) The TSLP-binding domain includes a TSLP-VH sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127200, and a TSLP-VL sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA0-127199, (ii) The IL-4 binding domain comprises an IL4-VH sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127198, and an IL4-VL sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127197, (iii) The IL-13 binding domain includes an IL13-VH sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127196, and an IL13-VL sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127195, Antibodies listed in E387 to E392.

[0405] E394.Antibodies as described in E387 to E393, wherein the TSLP-binding domain is fused to the IL-13-binding domain with or without a linker.

[0406] E395. The antibodies described in E387 to E393, wherein the TSLP-binding domain is fused to the IL-4-binding domain with or without a linker.

[0407] E396. Antibodies as described in E387 to E393, wherein the IL-13 binding domain is fused to the IL-4 binding domain with or without a linker.

[0408] E397. An antibody described in any one of items E394 to E396, wherein the fusion is accompanied by a linker.

[0409] E398. An antibody according to any one of items E394 to E397, wherein the IL-13 binding domain is fused to the IL-4 binding domain with a linker.

[0410] E399. The linker is one of the antibodies listed in E394 to E398, including SEQ ID NO: 104.

[0411] E400.(i) The second and fifth polypeptide chains together form a first Fab domain containing the first antigen-binding site, (ii) The second and fourth polypeptide chains together form a second Fab domain containing the 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 the items E387 to E399, comprising a first, second, third, fourth, and fifth polypeptide chain.

[0412] E401. The 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.

[0413] E402. The antibody described in E400 to E401, wherein the fifth polypeptide chain contains the sequence EPKSC (SEQ ID NO: 122) at its C-terminus.

[0414] E403. The antibody described in 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.

[0415] E404. The first Fab domain, the second Fab domain, and the third Fab domain are as follows: (i) TSLP-Fab as described in E117, (ii) IL4-Fab as described in E234, and (iii) IL13-Fab described in E302 The antibodies described in E400 to E403, each containing different options selected from (i), (ii), and (iii).

[0416] E405. Antibodies described in E400 to E406, wherein the first Fab domain is IL13-Fab as described in E302, the second Fab domain is IL4-Fab as described in E234, and the third Fab domain is TSLP-Fab as described in E117.

[0417] E406. The antibody according to E400 to E405, wherein the first polypeptide comprises a first Fc chain and the second polypeptide comprises a second Fc chain.

[0418] E407. The antibody according to E406, wherein the first Fc chain and the second Fc chain each contain one or more amino acid modifications that promote association of the first Fc chain with the second Fc chain.

[0419] E408. The first Fc chain contains the first CH3 domain, the second Fc chain contains the second CH3 domain, and 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) Sequence IDs 111 and 106, (ii) Sequence IDs 111 and 114, (iii) Sequence IDs 114 and 117, (iv) Sequence IDs 124 and 127, (v) Sequence IDs 139 and 141, and (vi) Sequence IDs 147 and 148 An antibody selected from one of the following, as described in E400 to E407.

[0420] E409. The antibody described in E408, wherein the first and second CH3 domains contain the sequence numbers 124 and 127.

[0421] E410. The identities of the first, second, third, fourth, and fifth polypeptide chains are, (i) 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: 99, the fourth polypeptide chain contains SEQ ID NO: 27, and the fifth polypeptide chain contains SEQ ID NO: 122. (ii) The first polypeptide chain contains SEQ ID NO: 146, the second polypeptide chain contains SEQ ID NO: 149, 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: 150. (iii) The first polypeptide chain includes SEQ ID NO: 112, the second polypeptide chain includes SEQ ID NO: 151, the third polypeptide chain includes SEQ ID NO: 196, the fourth polypeptide chain includes SEQ ID NO: 109, and the fifth polypeptide chain includes SEQ ID NO: 150. (iv) The first polypeptide chain contains SEQ ID NO: 112, the second polypeptide chain contains SEQ ID NO: 159, 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: 150. (v) The first polypeptide chain contains SEQ ID NO: 161, the second polypeptide chain contains SEQ ID NO: 162, 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: 163. (vi) The first polypeptide chain contains SEQ ID NO: 146, the second polypeptide chain contains SEQ ID NO: 154, 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: 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 includes SEQ ID NO: 165, the second polypeptide chain includes SEQ ID NO: 130, the third polypeptide chain includes SEQ ID NO: 215, the fourth polypeptide chain includes SEQ ID NO: 27, and the fifth polypeptide chain includes SEQ ID NO: 122. (xiv) 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: 216, the fourth polypeptide chain contains SEQ ID NO: 27, and the fifth polypeptide chain contains SEQ ID NO: 122. Antibodies selected from the group consisting of E400 to E409.

[0422] E411. An antibody according to any one of items 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.

[0423] An isolated antibody that specifically binds to E412.TSLP, specifically to IL-4, and specifically 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 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 contains SEQ ID NO: 165, the second polypeptide chain contains SEQ ID NO: 130, the third polypeptide chain contains SEQ ID NO: 99, the fourth polypeptide chain contains SEQ ID NO: 27, and the fifth polypeptide chain contains SEQ ID NO: 122. antibody.

[0424] An isolated antibody that specifically binds to E413.TSLP, specifically to IL-4, and specifically 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 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 contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127202; the second polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127192; the third polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127201; the fourth polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127194; and the fifth polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127193. antibody.

[0425] E414. An antibody described in any one of items E387 to E413, having a terminal phase half-life of at least 14 days in cynomolgus monkeys.

[0426] An antibody described in any one of items E387 to E414, having a terminal phase half-life of at least 18 days in E415.TG32 mice.

[0427] E416. IC25 <10 pM, as measured by TARC production bioassay in primary human PBMCs. 50 An antibody characterized by anti-TSLP biological activity, as described in any one of items E387 to E415.

[0428] An antibody as described in any one of items 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, and 0.05 mg / mL EDTA pH 6.0.

[0429] E418. An antibody as described in any one of items E387 to E417, characterized by a score of less than 2% of high molecular weight species, as determined by analytical size exclusion chromatography (aSEC).

[0430] E419. An antibody described in any one of items E387 to E418, characterized by a score of less than 12 in an affinity capture self-interacting nanoparticle spectroscopy (AC SINS) assay.

[0431] E420. An antibody described in any one of items 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.

[0432] E421. An antibody described in any one of items E387 to E420, which binds to cynomolgus monkey IL-4 with a binding affinity of less than 1 pM, as measured by KinExA in a fixed antigen assay in PBS.

[0433] E422. An antibody described in any one of items 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.

[0434] E423. An antibody described in any one of items E387 to E422, which binds to cynomolgus monkey IL-13 with a binding affinity of less than 1 pM, as measured by KinExA in a fixed antigen assay in PBS.

[0435] E424. An antibody described in any one of items 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.

[0436] E425. An antibody described in any one of items E387 to E424, which binds to cynomolgus monkey IL-13 with a binding affinity of less than 20 pM, as measured by KinExA in a fixed antigen assay in PBS.

[0437] E426.CD23 neutralization by IL-4 induction in a human monocyte assay with IC <25 pM 50 An antibody characterized by any one of the items E387 to E425.

[0438] E427.CD23 neutralization by IL-4 induction in a human monocyte assay with IC15 pM. 50 An antibody characterized by any one of the items E387 to E426.

[0439] Neutralization of E428.CD23 by IL-4 induction in cynomolgus monkeys in a human monocyte assay with an IC of less than 60 pM 50 An antibody characterized by any one of the items E387 to E427.

[0440] E429. IC25 <15 pM in human TSLP neutralization of TARC-producing bioassay in human primary PBMCs. 50 An antibody characterized by any one of the items E387 to E428.

[0441] E430. IC <35 pM in cynomolgus monkey TSLP neutralization assay 50 An antibody characterized by any one of the items E387 to E429.

[0442] E431. An antibody as described in any one of the items E387 to E430 for use as a pharmaceutical.

[0443] E432. The antibody described in E431, 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, nodular prurigo, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, and fungal keratitis.

[0444] E433. An antibody according to any one of items E431 to E432, 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, and non-alcoholic steatohepatitis (NASH).

[0445] E434. An antibody described in any one of items E431 to E433, whose use is for atopic dermatitis.

[0446] E435. An antibody described in any one of items E431 to E433, for use in non-alcoholic steatohepatitis (NASH).

[0447] E436. A pharmaceutical composition comprising a therapeutically effective amount of an antibody described in E387 to E435 and a pharmaceutically acceptable carrier.

[0448] E437. A method for treating a medical condition, comprising administering a therapeutically effective amount of an antibody described in any one of E387 to E435, or a pharmaceutical composition described in E436, to a subject in need thereof.

[0449] E438. 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, nodular prurigo, keloid, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, and fungal keratitis.

[0450] E439. The method according to any one of E437 to E438, comprising subcutaneously administering the antibody or pharmaceutical composition.

[0451] E440. The method according to any one of E437 to E439, wherein the antibody or pharmaceutical composition is administered approximately 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.

[0452] An isolated antibody that specifically binds to E445.p40, specifically to IL-4, and specifically to IL-13, comprising a p40-binding domain, an IL-4-binding domain, and an IL-13-binding domain.

[0453] The antibody described in E445, wherein specific binding to E446.p40 is mediated by the antibody described in any one of the items E144 to E193.

[0454] E447. Antibodies according to E445 to E446, wherein specific binding to IL-4 is mediated by any one of the antibodies described in E199 to E259.

[0455] E448. An antibody according to any one of items E445 to E447, wherein specific binding to IL-13 is mediated by an antibody according to any one of items E265 to E330.

[0456] E449.(i) The p40 binding domain comprises a heavy chain variable region (p40-VH) and a light chain variable region (p40-VL), where CDR-H1 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 166, CDR-H2 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 167, CDR-H3 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 168, CDR-L1 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 171, CDR-L2 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 172, and CDR-L3 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 173. (ii) The IL-4 binding domain comprises a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL), where CDR-H1 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 18, CDR-H2 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 2, CDR-H3 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 3, CDR-L1 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 24, CDR-L2 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 12, and CDR-L3 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 25. (iii) The IL-13 binding domain comprises a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL), where CDR-H1 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 41, CDR-H2 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 42, CDR-H3 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 50, CDR-L1 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 53, CDR-L2 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 37, and CDR-L3 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 38. The antibody described in any one of the items E445 to E448.

[0457] E450.(i) The p40 binding domain includes p40-VH of SEQ ID NO: 169 and p40-VL of SEQ ID NO: 175. (ii) The IL-4 binding domain includes IL4-VH of SEQ ID NO: 22 and IL4-VL of SEQ ID NO: 26, (iii) The IL-13 binding domain includes IL13-VH of SEQ ID NO: 51 and IL13-VL of SEQ ID NO: 54 Antibodies listed in E445 to E449.

[0458] E451.(i) The p40 binding domain includes a p40-VH sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127206, and a p40-VL sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127205. (ii) An IL-4 binding domain is an IL4-VH sequence encoded by a plasmid deposited in ATCC and having ATCC accession number PTA-127198, and an IL4-VL sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127197. (iii) The IL-13 binding domain includes an IL13-VH sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127196, and an IL13-VL sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127195, Antibodies described in E445 to E450.

[0459] The antibodies described in E445 to E451, wherein the E452.p40 binding domain is fused to the IL-13 binding domain with or without a linker.

[0460] The antibodies described in E445 to E451, wherein the E453.p40 binding domain is fused to the IL-4 binding domain with or without a linker.

[0461] E454.Antibodies as described in E445 to E451, wherein the IL-13 binding domain is fused to the IL-4 binding domain with or without a linker.

[0462] E455. An antibody described in any one of items E452 to E454, wherein the fusion is accompanied by a linker.

[0463] An antibody as described in any one of items E452 to E455, wherein the IL-13 binding domain is fused to the IL-4 binding domain with a linker.

[0464] E457. The linker is the antibody described in E456, containing SEQ ID NO: 104.

[0465] E458.(i) The second and fifth polypeptide chains together form a first Fab domain containing the first antigen-binding site, (ii) The second and fourth polypeptide chains together form a second Fab domain containing the 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 the items E445 to E457, comprising a first, second, third, fourth, and fifth polypeptide chain.

[0466] E459. The 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 a first Fab domain and a second Fab domain, and a single Fab arm containing a third Fab domain.

[0467] E460. The antibody described in E458 to E459, wherein the fifth polypeptide chain contains the sequence EPKSC (SEQ ID NO: 122) at its C-terminus.

[0468] E461. The antibody described in 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.

[0469] E462. The first Fab domain, the second Fab domain, and the third Fab domain are as follows: (i) p40-Fab as described in E166, (ii) IL4-Fab as described in E234, and (iii) IL13-Fab described in E302 The antibodies described in E458 to E461, each containing different options selected from (i), (ii), and (iii).

[0470] E463. Antibodies described in E458 to E462, wherein the first Fab domain is IL13-Fab as described in E302, the second Fab domain is IL4-Fab as described in E234, and the third Fab domain is p40-Fab as described in E166.

[0471] E464. The antibody according to E458 to E463, wherein the first polypeptide comprises a first Fc chain and the second polypeptide comprises a second Fc chain.

[0472] E465. The antibody according to E464, wherein the first Fc chain and the second Fc chain each contain one or more amino acid modifications that promote association of the first Fc chain with the second Fc chain.

[0473] E466. The first Fc chain contains the first CH3 domain, the second Fc chain contains the second CH3 domain, and 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) Sequence IDs 106 and 111, (ii) Sequence IDs 147 and 148, and (iii) Sequence ID 124 and Sequence ID 127 An antibody selected from one of the following, as described in E464 to E465.

[0474] E467. The antibody described in E466, wherein the first and second CH3 domains contain the sequences 124 and 127.

[0475] E468. The identities of the first, second, third, fourth, and fifth polypeptide chains are, (i) The first polypeptide chain contains SEQ ID NO: 186, the second polypeptide chain contains SEQ ID NO: 130, the third polypeptide chain contains SEQ ID NO: 176, the fourth polypeptide chain contains SEQ ID NO: 27, and the fifth polypeptide chain contains SEQ ID NO: 122. (ii) The first polypeptide chain contains SEQ ID NO: 146, the second polypeptide chain contains SEQ ID NO: 178, 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: 177. (iii) The first polypeptide chain contains SEQ ID NO: 112, the second polypeptide chain contains SEQ ID NO: 179, 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: 177. (iv) The first polypeptide chain contains SEQ ID NO: 181, the second polypeptide chain contains SEQ ID NO: 180, the third polypeptide chain contains SEQ ID NO: 182, the fourth polypeptide chain contains SEQ ID NO: 109, and the fifth polypeptide chain contains SEQ ID NO: 122. (v) The first polypeptide chain contains SEQ ID NO: 118, the second polypeptide chain contains SEQ ID NO: 183, the third polypeptide chain contains SEQ ID NO: 120, the fourth polypeptide chain contains SEQ ID NO: 116, and the fifth polypeptide chain contains SEQ ID NO: 177. (vi) The first polypeptide chain includes SEQ ID NO: 185, the second polypeptide chain includes SEQ ID NO: 125, the third polypeptide chain includes SEQ ID NO: 176, the fourth polypeptide chain includes SEQ ID NO: 207, and the fifth polypeptide chain includes SEQ ID NO: 122. (vii) The first polypeptide chain contains SEQ ID NO: 185, the second polypeptide chain contains SEQ ID NO: 125, the third polypeptide chain contains SEQ ID NO: 176, the fourth polypeptide chain contains SEQ ID NO: 27, and the fifth polypeptide chain contains SEQ ID NO: 122. Antibodies selected from the group consisting of E458 to E467.

[0476] E469. An antibody according to any one of items 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.

[0477] An isolated antibody that specifically binds to E470.p40, specifically to IL-4, and specifically 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 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 contains SEQ ID NO: 186, the second polypeptide chain contains SEQ ID NO: 130, the third polypeptide chain contains SEQ ID NO: 176, the fourth polypeptide chain contains SEQ ID NO: 27, and the fifth polypeptide chain contains SEQ ID NO: 122. antibody.

[0478] An isolated antibody that specifically binds to E471.p40, specifically to IL-4, and specifically 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 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 contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127204; the second polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127192; the third polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127203; the fourth polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127194; and the fifth polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127193. antibody.

[0479] The antibodies described in 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, and 0.05 mg / mL EDTA pH 6.0.

[0480] E473: An antibody described in 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, and 0.05 mg / mL of EDTA at pH 6.0.

[0481] E474. Antibodies described in E445 to E473, having a terminal phase half-life of at least 12 days in cynomolgus monkeys.

[0482] Antibodies described in E445 to E474, having a terminal phase half-life of at least 18 days in E475.TG-32 mice.

[0483] E476. Antibodies listed in E445 to E475 that bind to human IL-4 with an affinity constant of less than 220 pM, as measured by SPR.

[0484] E477. Antibodies described in E445 to E476 that bind to human IL-13 with an affinity constant of less than 220 pM, as measured by SPR.

[0485] E478. Antibodies described in E445 to E477 that bind to human IL-12 with an affinity constant of less than 130 pM, as measured by SPR.

[0486] E479. Antibodies described in E445 to E478 that bind to human IL-23 with an affinity constant of less than 100 pM, as measured by SPR.

[0487] E480. Antibodies described in E445 to E479 that bind to human IL-4 with a binding affinity of less than 1 pM, as measured by KinExA in a fixed antigen assay in PBS.

[0488] E481. Antibodies described in E445 to E480 that bind to cynomolgus monkey IL-13 with a binding affinity of less than 2 pM, as measured by KinExA in a fixed antigen assay in PBS.

[0489] IC50 <12 pM, as measured in a human monocyte assay for IL-4 induction neutralization of E482.CD23. 50 Antibodies described in E445 to E481, characterized by the above.

[0490] IC50 <12 pM, as measured in a human monocyte assay for IL-4 induction of E483 CD23 in cynomolgus monkeys. 50 Antibodies described in E445 to E482, characterized by the above.

[0491] IC50 <12 pM, as measured in a human monocyte assay for IL-13 induction of E484.CD23 in cynomolgus monkeys. 50Antibodies described in E445 to E483, characterized by the above.

[0492] IC5M <45 pM, as measured in a human monocyte assay for IL-13 induction neutralization of E485.CD23. 50 Antibodies described in E445 to E484, characterized by the above.

[0493] E486. IC <600 pM in the human IL-12 neutralization Kit-225 assay in human peripheral blood monocytes. 50 Antibodies described in E445 to E485, characterized by the above.

[0494] E487. IC <2100 pM in cynomolgus monkey IL-23 Kit-225 neutralization assay in human peripheral blood monocytes 50 Antibodies described in E445 to E486, characterized by the above.

[0495] E488. IC <400 pM in human IL-12 neutralization assay in human whole blood 50 Antibodies described in E445 to E487, characterized by the above.

[0496] E489. IC <10,000 pM in cynomolgus monkey IL-23 neutralization assay using human whole blood. 50 Antibodies described in E445 to E488, characterized by the above.

[0497] E490. An antibody as described in any one of the items E445 to E489 for use as a pharmaceutical.

[0498] E491. The antibody described in E490, for use in 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, keloids, systemic lupus erythematosus, primary biliary cirrhosis, and hidradenitis suppurativa.

[0499] E492. An antibody according to any one of items E490 to E491, for use in 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.

[0500] E483. An antibody described in any one of items E490 to E482, whose use is for atopic dermatitis.

[0501] E484. An antibody described in any one of items E490 to E483, whose use is for non-alcoholic steatohepatitis (NASH).

[0502] E495. A pharmaceutical composition comprising a therapeutically effective amount of an antibody described in E445 to E484 and a pharmaceutically acceptable carrier.

[0503] E496. A method for treating a medical condition, comprising administering a therapeutically effective amount of an antibody described in any one of E445 to E494, or a pharmaceutical composition described in E495, to a subject in need thereof.

[0504] E497. 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, keloids, systemic lupus erythematosus, primary biliary cirrhosis, and hidradenitis suppurativa.

[0505] E498. The method according to any one of E496 to E497, comprising subcutaneously administering the antibody or pharmaceutical composition.

[0506] E499. The method according to any one of E496 to E498, wherein the antibody or pharmaceutical composition is administered approximately 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.

[0507] E500.(i) The second and fifth polypeptide chains together form a first Fab domain containing the first antigen-binding site, (ii) The second and fourth polypeptide chains together form a second Fab domain containing the second antigen-binding site, (iii) The first and third polypeptide chains together form a third Fab domain containing a third antigen-binding site. Antibodies containing the first, second, third, fourth, and fifth polypeptide chains, such as those described above.

[0508] 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 containing a first Fab domain and a second Fab domain, and a single Fab arm containing a third Fab domain.

[0509] E502. The antibody according to E501, wherein the first Fab comprises the first antigen-associated VH (VH-1), the first antigen-associated VL (VL-1), the first antigen-associated CL (CL-1), and the first antigen-associated CH1 (CH1-1).

[0510] The antibody described in E504, wherein the C-terminus of E503.VH-1 is covalently fused to the N-terminus of CH1-1 by a peptide bond.

[0511] The antibodies described in E502 to E503, wherein the C-terminus of E504.VL-1 is covalently fused to the N-terminus of CL-1 by a peptide bond.

[0512] E505. The antibodies described in E501 to E504, wherein the second Fab comprises the second antigen-associated VH (VH-2), the second antigen-associated VL (VL-2), the second antigen-associated CL (CL-2), and the second antigen-associated CH1 (CH1-2).

[0513] The antibody described in E505, wherein the C-terminus of E506.VH-2 is covalently fused to the N-terminus of CH1-2 by a peptide bond.

[0514] The antibodies described in E505 to E506, wherein the C-terminus of E507.VL-2 is covalently fused to the N-terminus of CL-2 by a peptide bond.

[0515] E508. The antibodies described in E501 to E507, wherein the third Fab comprises the third antigen-associated VH (VH-3), the first antigen-associated VL (VL-3), the first antigen-associated CL (CL-3), and the first antigen-associated CH1 (CH1-3).

[0516] The antibody described in E508, wherein the C-terminus of E509.VH-3 is covalently fused to the N-terminus of CH1-3 by a peptide bond.

[0517] The antibodies described in E508 to E509, wherein the C-terminus of E510.VL-3 is covalently fused to the N-terminus of CL-3 by a peptide bond.

[0518] E511. The antibody described in E500 to E510, wherein the second polypeptide comprises (VL-1)-(CL-1)-(linker)-(VH-2)-(CH1-2)-(second hinge)-(second CH2)-(second CH3) from the N-terminus to the C-terminus, the fifth polypeptide comprises (VH1)-(CL-1) from the N-terminus to the C-terminus, and the fourth polypeptide comprises (VL-2)-(CL-2).

[0519] E512. The antibody according to E500 to E511, wherein the first polypeptide comprises (VH-3)-(CH1-3)-(first hinge)-(first CH2)-(first CH3) from the N-terminus to the C-terminus, and the third polypeptide may contain (VL-3)-(CL-3).

[0520] E513. The antibodies according to E508 to E512, wherein one or more of the CH1-1 domain, CH1-2 domain, and CH1-3 domain may contain a sequence selected from the group consisting of SEQ ID NO: 6, SEQ ID NO: 105, and SEQ ID NO: 110.

[0521] E514.Antibodies according to E508 to E513, wherein one or more of the CL-1 domain, CL-2 domain, and CL-3 domain contain 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.

[0522] E515. The antibodies according to E512 to E514, wherein the first hinge region and the second hinge region contain the sequence pair described in SEQ ID NO: 129 and SEQ ID NO: 131.

[0523] E516. The antibodies described in E512 to E515, wherein one or both of the first and second CH2 domains contain the sequence described in Sequence ID No. 8.

[0524] E517. The first CH3 domain and the second CH3 domain each contain different complementary sequences, and these different complementary sequences are paired with the following different complementary sequences: (i) Sequence IDs 111 and 106, (ii) Sequence IDs 111 and 114, (iii) Sequence IDs 114 and 117, (iv) Sequence IDs 124 and 127, (v) Sequence IDs 139 and 141, and (vi) Sequence IDs 147 and 148 An antibody selected from one of the following, as described in E512 to E516.

[0525] E518.(i)CL-1 includes the sequence described in Sequence ID 16, the linker includes the sequence described in Sequence ID 104, CH1-2 includes the sequence described in Sequence ID 6, the second hinge includes the sequence described in Sequence ID 129, the second CH2 includes the sequence described in Sequence ID 8, and the second CH3 includes the sequence described in Sequence ID 124. (ii) CH1-1 contains the sequence described in Sequence ID No. 6, (iii) CL-2 contains the sequence described in Sequence ID No. 16, Antibodies listed in E512 to E517.

[0526] The antibodies described in E508 to E518, wherein E519.CL-3 contains 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.

[0527] E520.CL-3 is an antibody described in E508 to E519, containing the sequence described in SEQ ID NO: 95.

[0528] E521.CL-3 is an antibody described in E508 to E519, containing the sequence described in SEQ ID NO: 16.

[0529] E522.CH1-3 is an antibody described in E508 to E521, containing the sequence described in Sequence ID No. 6.

[0530] E523. The antibodies described in E512 to E522, wherein the first hinge contains the sequence described in SEQ ID NO: 131.

[0531] E524. The antibodies described in E512 to E523, wherein the first CH2 contains the sequence described in Sequence ID No. 8.

[0532] E525. Antibodies described in E512 to E524, wherein the first CH3 contains the sequence described in SEQ ID NO: 127.

[0533] E526. An isolated antibody according to any one of items 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.

[0534] E527. An isolated antibody according to any one of items 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.

[0535] E528. An isolated antibody that specifically binds to IL-4 and specifically binds to IL-13, comprising an IL-4 binding domain and an IL-13 binding domain.

[0536] E529.Antibodies according to E526 to E528, wherein specific binding to IL-4 is mediated by any one of the antibodies described in E199 to E259.

[0537] E530. An antibody according to any one of items E526 to E529, wherein specific binding to IL-13 is mediated by an antibody according to any one of items E265 to E330.

[0538] E531. An antibody according to any one of items E526 to E530, comprising at least one additional antigen-binding domain that binds to at least one different target for both IL-4 and IL-13.

[0539] E532. The antibody according to E531, wherein at least one different target is selected from the group consisting of IL-33, TSLP, and p40, and if the target is IL-33, it may further optionally include the antibodies described in E1 to E71; if the target is TSLP, it may further optionally include the antibodies described in E77 to E143; and if the target is p40, it may further optionally include the antibodies described in E144 to E193.

[0540] E533. The antibody described in E531, wherein at least one different target is not IL-33.

[0541] E534. An antibody described in E531, which has at least one different target, and is not TSLP.

[0542] E535. The antibody described in E531, which has at least one different target, not p40.

[0543] E536.(i) The IL-4 binding domain comprises a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL), CDR-H1 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 18, CDR-H2 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 2, CDR-H3 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 3, CDR-L1 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 24, CDR-L2 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 12, and CDR-L3 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 25. (ii) The IL-13 binding domain comprises a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL), where CDR-H1 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 41, CDR-H2 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 42, CDR-H3 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 50, CDR-L1 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 53, CDR-L2 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 37, and CDR-L3 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO: 38. An antibody described in any one of the items E526 to E535.

[0544] E537.(i) The IL-4 binding domain includes IL4-VH of SEQ ID NO: 22 and IL4-VL of SEQ ID NO: 26, (ii) The IL-13 binding domain includes IL13-VH of SEQ ID NO: 51 and IL13-VL of SEQ ID NO: 54 Antibodies described in E526 to E536.

[0545] E538. The antibodies described in E531 to E537, wherein an additional antigen-binding domain is fused to the IL-13 binding domain, with or without a linker.

[0546] E539. The antibodies described in E531 to E537, wherein an additional antigen-binding domain is fused to the IL-4 binding domain, with or without a linker.

[0547] E540. Antibodies as described in E531 to E537, wherein the IL-13 binding domain is fused to the IL-4 binding domain with or without a linker.

[0548] E541. An antibody described in any one of the items E538 to E540, which is fused with a linker.

[0549] An antibody as described in any one of items E540 to E541, wherein the IL-13 binding domain is fused to the IL-4 binding domain with a linker.

[0550] E543. The linker is the antibody described in E542, containing SEQ ID NO: 104.

[0551] E544.(i) The second and fifth polypeptide chains together form a first Fab domain containing the first antigen-binding site, (ii) The second and fourth polypeptide chains together form a second Fab domain containing the 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 items E526 to E543, comprising a first, second, third, fourth, and fifth polypeptide chain.

[0552] E545. 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 containing a first Fab domain and a second Fab domain, and a single Fab arm containing a third Fab domain.

[0553] 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, (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, (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, (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, (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. Antibodies listed in E526 to E545.

[0554] E547. The antibodies described in E544 to E546, wherein the first Fab domain is IL13-Fab as described in E302, the second Fab domain is IL4-Fab as described in E234, and the third Fab domain is an additional target Fab.

[0555] E548. The antibodies described in E44 to E547, wherein the fifth polypeptide chain contains the sequence EPKSC (SEQ ID NO: 122) at its C-terminus.

[0556] E549. The antibody according to E544 to E548, wherein the first polypeptide comprises a first Fc chain and the second polypeptide comprises a second Fc chain.

[0557] E550. 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 association of the first Fc chain with the second Fc chain.

[0558] E551. The first Fc chain contains the first CH3 domain, the second Fc chain contains the second CH3 domain, and 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) Sequence IDs 111 and 106, (ii) Sequence IDs 111 and 114, (iii) Sequence IDs 114 and 117, (iv) Sequence IDs 124 and 127, (v) Sequence IDs 139 and 141, and (vi) Sequence IDs 147 and 148 An antibody selected from one of the following, as described in E544 to E550.

[0559] E552. The antibody according to E551, wherein the first and second CH3 domains contain the sequence numbers 124 and 127.

[0560] E553. 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, (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 contains SEQ ID NO: 180, the fourth polypeptide chain contains SEQ ID NO: 109, and the fifth polypeptide chain contains SEQ ID NO: 122. (xxv) The second polypeptide chain contains SEQ ID NO: 183, the fourth polypeptide chain contains SEQ ID NO: 116, and the fifth polypeptide chain contains SEQ ID NO: 177. (xxvi) The second polypeptide chain contains SEQ ID NO: 125, the fourth polypeptide chain contains SEQ ID NO: 207, and the fifth polypeptide chain contains SEQ ID NO: 122. (xxvii) The second polypeptide chain contains SEQ ID NO: 125, the fourth polypeptide chain contains SEQ ID NO: 27, and the fifth polypeptide chain contains SEQ ID NO: 122. Selected from the group consisting of, Antibodies listed in E544 to E552.

[0561] E554. An antibody according to any one of items 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.

[0562] 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 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 at least one additional target binding site, 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. antibody.

[0563] E556. An antibody comprising an antibody Fc domain including a first Fc chain and a second Fc chain, wherein the first Fc chain and the second Fc chain each contain two amino acid modifications that promote association of the first Fc chain with the second Fc chain. (i) The first Fc chain contains D(H232)R and K(H440)R, and the second Fc chain contains D(H232)E and L(H391)E, or (ii) The first Fc chain contains D(H232)E and K(H440)R, and the second Fc chain contains L(H391)R and D(H232)E. An antibody characterized by the following features.

[0564] E557. The antibody according to E556, wherein 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, in order from the N-terminus to the C-terminus, the first hinge region and the second hinge region comprise the sequence pair described in SEQ ID NO: 129 and SEQ ID NO: 131, and the first CH3 region and the second CH3 region comprise either of the following two pairs of sequence pairs: SEQ ID NO: 124 and SEQ ID NO: 127, or SEQ ID NO: 147 and SEQ ID NO: 148.

[0565] An antibody according to any one of the items E556 to E557, further comprising one or more antibodies from items 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.

[0566] E559. Isolated antibodies containing CDRs of antibodies selected from one or more of Tables 80, 81, 82, 83, 84, 85, 86, and 87.

[0567] E560. Isolated antibodies containing VH and VL of antibodies selected from one or more of Tables 80, 81, 82, 83, 84, 85, 86, and 87.

[0568] E561. Isolated antibodies selected from one or more of Tables 80, 81, 82, 83, 84, 85, 86, and 87.

[0569] Isolated polynucleotides comprising one or more nucleotide sequences encoding an antibody described in any one of the following items: E562.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.

[0570] E563. RNA, a polynucleotide as described in E562.

[0571] E564. The polynucleotides described in E562 to E563, comprising at least one chemical modification.

[0572] E565. The polynucleotide described in E564, wherein the chemical modification is selected from pseudouridine, 1-methylpsoiduridine, N1-methylpsoiduridine, N1-ethylpsoiduridine, 2-thiouridine, 4'-thiouridine, 5-methylcytosine, 2-thio-1-methyl-1-deaza-psoiduridine, 2-thio-1-methylpsoiduridine, 2-thio-5-aza-uridine, 2-thio-dihydropsoiduridine, 2-thio-dihydrouridine, 2-thiopsoiduridine, 4-methoxy-2-thiopsoiduridine, 4-methoxypsoiduridine, 4-thio-1-methylpsoiduridine, 4-thiopsoiduridine, 5-aza-uridine, dihydropsoiduridine, 5-methyluridine, 5-methoxyuridine, and 2'-O-methyluridine.

[0573] E566. Polynucleotides as described in E562 to E563, excluding chemical modifications.

[0574] An isolated polynucleotide encoding VH, VL, or both of the antibodies that bind to E567.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.

[0575] An isolated polynucleotide encoding a polypeptide having VH and a polypeptide having VL of an antibody that binds to E568.IL-33, or both thereof, 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.

[0576] An isolated polynucleotide encoding VH, VL, or both of an antibody that binds to E569.IL-33, wherein the nucleic acid comprises the nucleic acid sequence of an insert in a plasmid deposited with ATCC and having accession number PTA-127209, the nucleic acid sequence of an insert in a plasmid deposited with ATCC and having accession number PTA-127210, or both.

[0577] An isolated polynucleotide encoding a polypeptide having VH and a polypeptide having VL of an antibody that binds to E570.IL-33, or both thereof, wherein the nucleic acid comprises the nucleic acid sequence of an insert in a plasmid deposited in ATCC and having accession number PTA-127207, the nucleic acid sequence of an insert in a plasmid deposited in ATCC and having accession number PTA-127208, or both.

[0578] An isolated polynucleotide encoding VH, VL, or both of the antibodies that bind to E571.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.

[0579] An isolated polynucleotide encoding a polypeptide having VH and a polypeptide having VL of an antibody that binds to E572.TSLP, or both thereof, wherein the nucleic acid comprises the nucleic acid sequence of SEQ ID NO: 192, the nucleic acid sequence of SEQ ID NO: 193, or both.

[0580] An isolated polynucleotide encoding VH, VL, or both of an antibody that binds to E573.TSLP, wherein the nucleic acid comprises the nucleic acid sequence of an insert in a plasmid deposited in ATCC having accession number PTA-127200, the nucleic acid sequence of an insert in a plasmid deposited in ATCC having accession number PTA-127199, or both.

[0581] An isolated polynucleotide encoding a polypeptide having VH and a polypeptide having VL of an antibody that binds to E574.TSLP, or both thereof, wherein the nucleic acid comprises the nucleic acid sequence of an insert in a plasmid deposited in ATCC and having accession number PTA-127202, the nucleic acid sequence of an insert in a plasmid deposited in ATCC and having accession number PTA-127201, or both.

[0582] An isolated polynucleotide encoding a polypeptide having VH and a polypeptide having VL, or both, of an antibody that binds to E575.p40, wherein the nucleic acid comprises the nucleic acid sequence of SEQ ID NO: 194, the nucleic acid sequence of SEQ ID NO: 195, or both.

[0583] An isolated polynucleotide encoding a polypeptide having VH and a polypeptide having VL, or both, of an antibody that binds to E576.p40, wherein the nucleic acid comprises the nucleic acid sequence of an insert in a plasmid deposited in ATCC and having accession number PTA-127204, the nucleic acid sequence of an insert in a plasmid deposited in ATCC and having accession number PTA-127203, or both.

[0584] E577. An isolated polynucleotide encoding 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.

[0585] An isolated polynucleotide encoding a polypeptide having VH and a polypeptide having VL of an antibody that binds to E578.IL-4, or both thereof, 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.

[0586] E579. An isolated polynucleotide encoding VH, VL, or both of an antibody that binds to IL-4, wherein the nucleic acid comprises the nucleic acid sequence of an insert in a plasmid deposited with ATCC and having accession number PTA-127198, the nucleic acid sequence of an insert in a plasmid deposited with ATCC and having accession number PTA-127197, or both.

[0587] An isolated polynucleotide encoding a polypeptide having VH and a polypeptide having VL of an antibody that binds to E580.IL-4, or both thereof, wherein the nucleic acid comprises the nucleic acid sequence of an insert in a plasmid deposited in ATCC and having accession number PTA-127192, the nucleic acid sequence of an insert in a plasmid deposited in ATCC and having accession number PTA-127194, or both.

[0588] E581. An isolated polynucleotide encoding 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.

[0589] An isolated polynucleotide encoding a polypeptide having VH and a polypeptide having VL of an antibody that binds to E582.IL-13, or both thereof, wherein the nucleic acid comprises the nucleic acid sequence of SEQ ID NO: 187, the nucleic acid sequence of SEQ ID NO: 188, or both.

[0590] E583. An isolated polynucleotide encoding VH, VL, or both of an antibody that binds to IL-13, wherein the nucleic acid comprises the nucleic acid sequence of an insert in a plasmid deposited in ATCC having accession number PTA-127196, the nucleic acid sequence of an insert in a plasmid deposited in ATCC having accession number PTA-127195, or both.

[0591] An isolated polynucleotide encoding a polypeptide having VH and a polypeptide having VL of an antibody that binds to E584.IL-13, or both thereof, wherein the nucleic acid comprises the nucleic acid sequence of an insert in a plasmid deposited in ATCC and having accession number PTA-127193, the nucleic acid sequence of an insert in a plasmid deposited in ATCC and having accession number PTA-127192, or both.

[0592] E585. Isolated polynucleotides encoding one or more of the first, second, third, fourth, or fifth polypeptides of an anti-IL-4 / IL-13 / IL-33 antibody, (i) an IL33-VH sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127210, and an IL33-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127209, (ii) an IL4-VH sequence deposited with ATCC and encoded by a plasmid having ATCC accession number PTA-127198, and an IL4-VL sequence deposited with ATCC and encoded by a plasmid having ATCC accession number PTA-127197, (iii) IL13-VH sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127196, and IL13-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127195 Polynucleotides, including [specifically, polynucleotides].

[0593] E586. Isolated polynucleotides 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 to IL-4, and specifically to IL-13, and comprises the 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 an IL-33 binding site, The first polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127208; the second polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127192; the third polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127207; the fourth polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127194; and the fifth polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127193. Polynucleotide.

[0594] E587. Isolated polynucleotides 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 (i) A TSLP-VH sequence deposited with ATCC and encoded by a plasmid having ATCC accession number PTA-127200, and a TSLP-VL sequence deposited with ATCC and encoded by a plasmid having ATCC accession number PTA0-127199, (ii) an IL4-VH sequence deposited with ATCC and encoded by a plasmid having ATCC accession number PTA-127198, and an IL4-VL sequence deposited with ATCC and encoded by a plasmid having ATCC accession number PTA-127197, (iii) IL13-VH sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127196, and IL13-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127195 Polynucleotides, including [specifically, polynucleotides].

[0595] E588. Isolated polynucleotides 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 the 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 contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127202; the second polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127192; the third polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127201; the fourth polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127194; and the fifth polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127193. Polynucleotide.

[0596] E589. Isolated polynucleotides 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 ATCC and having ATCC accession number PTA-127206, and a p40-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127205, (ii) an IL4-VH sequence deposited with ATCC and encoded by a plasmid having ATCC accession number PTA-127198, and an IL4-VL sequence deposited with ATCC and encoded by a plasmid having ATCC accession number PTA-127197, (iii) IL13-VH sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127196, and IL13-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127195 Polynucleotides, including [specifically, polynucleotides].

[0597] E590. Isolated polynucleotides 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 the 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 contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127204; the second polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127192; the third polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127203; the fourth polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127194; and the fifth polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127193. Polynucleotide.

[0598] A vector containing polynucleotides as described in E591.E562 to E590.

[0599] Isolated host cells containing polynucleotides described in E592.E562 to E590, or vectors described in E591.

[0600] E593. A method for producing an isolated antibody, comprising culturing host cells described in E592 under conditions that result in antibody production, and recovering the antibody.

[0601] E594. A pharmaceutical composition comprising a therapeutically effective amount of any one of the antibodies described in E1 to E71, E77 to E143, E144 to E193, E199 to E259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, and E500 to E557, and a pharmaceutically acceptable carrier.

[0602] E595. A method for producing a heterotrimeric antibody comprising a double Fab arm and a single Fab arm, wherein the double Fab arm comprises a first Fab domain connected to a second Fab domain connected to a first Fc domain, and the single Fab arm comprises a third Fab domain connected to a second Fc domain, and the method (i) A first pre-assembly step in which the dual Fab arms are incubated in a first pre-assembly conditioning buffer at a temperature between 2 and 10°C, and the pH of the first pre-assembly conditioning buffer is 1 to 3 units below the isoelectric point (pI) of the dual Fab arms. (ii) A second pre-assembly step in which a single Fab arm is incubated in a second pre-assembly conditioning buffer at a temperature between 2 and 10°C, wherein 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 in which the double Fab arm and the single Fab arm from steps (i) and (ii) are mixed together in an assembly buffer for 1 to 24 hours. Methods that include...

[0603] An isolated antibody that specifically binds to E596.TSLP, comprising a CDR of an antibody selected from one or more of Tables 83, 84, and 87.

[0604] An isolated antibody that specifically binds to E597.TSLP, comprising VH and VL of an antibody selected from one or more of Tables 83, 84, and 87.

[0605] An isolated antibody that specifically binds to E598.TSLP, selected from one or more of Tables 83, 84, and 87.

[0606] E599.(i) The TSLP-binding domain comprises a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), where 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. (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, 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. An antibody described in any one of the items E381 to E384.

[0607] E600.(i) The TSLP binding portion includes TSLP-VH of SEQ ID NO: 92 and TSLP-VL of SEQ ID NO: 213, (ii) The IL-4 binding moiety includes IL4-VH of SEQ ID NO: 22 and IL4-VL of SEQ ID NO: 26, and (iii) The IL-13 binding moiety includes IL13-VH of SEQ ID NO: 51 and IL13-VL of SEQ ID NO: 54 Antibodies listed in E387 to E390, or E599.

[0608] E601.(i) The TSLP-binding domain includes a TSLP-VH sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127200, and a TSLP-VL sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-_____, (ii) The IL-4 binding domain comprises an IL4-VH sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127198, and an IL4-VL sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127197, and (iii) The IL-13 binding domain includes an IL13-VH sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127196, and an IL13-VL sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127195, Antibodies listed in E387 to E390, or E599 to E600.

[0609] An isolated antibody that specifically binds to E602.TSLP, specifically to IL-4, and specifically 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 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 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. antibody.

[0610] An isolated antibody that specifically binds to E603.TSLP, specifically to IL-4, and specifically to IL-13, comprising first, second, third, fourth, and fifth polypeptide chains, (iv) The second and fifth polypeptide chains together form the first Fab domain containing the IL-13 binding site, (v) The second and fourth polypeptide chains together form a second Fab domain containing an IL-4 binding site, (vi) The first and third polypeptide chains together form a third Fab domain containing a TSLP binding site, The first polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127202; the second polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127192; the third polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-_____; the fourth polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127194; and the fifth polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127193. antibody.

[0611] E604.(i) The TSLP binding domain comprises a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), where 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. (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. An antibody described in any one of the items E381 to E390.

[0612] E605.(i) The TSLP join includes TSLP-VH of SEQ ID NO: 92 and TSLP-VL of SEQ ID NO: 214, (ii) The IL-4 binding moiety includes IL4-VH of SEQ ID NO: 22 and IL4-VL of SEQ ID NO: 26, (iii) The IL-13 binding moiety includes IL13-VH of SEQ ID NO: 51 and IL13-VL of SEQ ID NO: 54 Antibodies listed in E387 to E390 or E604.

[0613] E606.(i) The TSLP-binding domain comprises a TSLP-VH sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127200, and a TSLP-VL sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA0-_____, (ii) The IL-4 binding domain comprises an IL4-VH sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127198, and an IL4-VL sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127197, and (iii) The IL-13 binding domain includes an IL13-VH sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127196, and an IL13-VL sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127195, Antibodies listed in E387 to E390, or E602 to E603.

[0614] An isolated antibody that specifically binds to E607.TSLP, specifically to IL-4, and specifically 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 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 contains SEQ ID NO: 165, the second polypeptide chain contains SEQ ID NO: 130, the third polypeptide chain contains SEQ ID NO: 216, the fourth polypeptide chain contains SEQ ID NO: 27, and the fifth polypeptide chain contains SEQ ID NO: 122. antibody.

[0615] An isolated antibody that specifically binds to E608.TSLP, specifically to IL-4, and specifically 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 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 contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127202; the second polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127192; the third polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-_____; the fourth polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127194; and the fifth polypeptide chain contains a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127193. antibody.

[0616] E609. An antibody as described in any one of the following items, E77 to E143 or E596 to E608, for use as a pharmaceutical.

[0617] E610. The antibody described in E609, 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, nodular prurigo, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, and fungal keratitis.

[0618] E611. An antibody described in any one of the paragraphs E147 to E148 or E596 to E610, 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, and non-alcoholic steatohepatitis (NASH).

[0619] E612. An antibody described in any one of the items E147 to E149 or E596 to E611, whose use is for atopic dermatitis.

[0620] E613. An antibody described in any one of the following items, E147 to E149 or E596 to E612, for use in non-alcoholic steatohepatitis (NASH).

[0621] E614. A pharmaceutical composition comprising a therapeutically effective amount of an antibody described in E77 to E143 or E596 to E608, and a pharmaceutically acceptable carrier.

[0622] E615. A method for treating a medical condition, comprising administering a therapeutically effective amount of an antibody described in any one of the items E77 to E143 or E596 to E608, or a pharmaceutical composition described in E614, to a subject in need thereof.

[0623] E616. 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, nodular prurigo, keloid, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, and fungal keratitis.

[0624] E617. The method according to any one of E615 to E616, comprising subcutaneously administering the antibody or pharmaceutical composition.

[0625] E618. The method according to any one of E615 to E617, wherein the antibody or pharmaceutical composition is administered approximately 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.

[0626] E619. An antibody according to any one of the following items for use in inhibiting tumor growth: E1 to E71, E77 to E143, E144 to E193, E199 to E259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, E500 to E557, or E596 to E612.

[0627] E620. An antibody according to any one of the following 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, E500 to E557, E596 to E612, or E619, for use in inhibiting the progression of malignant cell growth in patients.

[0628] E621. An antibody according to any one of the following items for use in inhibiting the metastasis of malignant cells in patients: 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.

[0629] E622. An antibody according to any one of the following items for use in inducing tumor reduction in patients: 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.

[0630] E623. An antibody according to any one of the following items for use in the treatment of cancer presenting as a solid tumor: 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.

[0631] E624. Use is permitted for bladder cancer, breast cancer, clear cell kidney cancer, squamous cell carcinoma of the head / neck, squamous cell carcinoma of the lung, 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 lymphoma (HL), and mantle cell lymphoma (MCL). Antibodies as described in any one of the following clauses: 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 the treatment of one or more conditions selected from the group consisting of multiple myeloma (MM), myelocellular leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), or small lymphocytic lymphoma (SLL).

[0632] E625. An antibody described in any one of the following paragraphs, 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, for use in one or more treatments selected from the group consisting of renal cell carcinoma (RCC), bladder cancer, breast cancer, clear cell kidney cancer, squamous cell carcinoma of the head / neck (SCCHN), squamous cell carcinoma of the lung, malignant melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, small cell lung cancer (SCLC), or triple-negative breast cancer.

[0633] E626. Use is for one or more treatments selected from the group consisting of heme malignancies, and in some embodiments, heme malignancies include 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), and mantle cell lymphoma. An antibody described in any one of the following clauses: E1 to E71, E77 to E143, E144 to E193, E199 to E259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, E500 to E557, E596 to E612, or E619 to E625, which is a lymphoma (MCL), multiple myeloma (MM), myelocellular leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), or small lymphocytic lymphoma (SLL).

[0634] E627. A method for treating cancer in a subject, comprising administering a combination therapy comprising a first anticancer agent and a second anticancer agent to the subject, wherein the first anticancer agent is an antibody against one or more of IL-4, IL-13, and TSLP, and the second anticancer agent is selected from the group consisting of anti-OX40 antibody, anti-4-1BB antibody, anti-HER2 antibody, PD-1 pathway antagonist, anti-PD-1 antibody, anti-PD-L1 antibody, TLR3 agonist, TLR7 / 8 agonist, TLR9 agonist, bispecific anti-CD47 / anti-PD-L1 antibody, and bispecific anti-P-cadherin / anti-CD3 antibody.

[0635] E628. The method according to E627, wherein the first anticancer agent contains an anti-IL-4 antibody.

[0636] E629. The method according to E627 to E628, wherein the first anticancer agent comprises an anti-IL-4 antibody as described in any one of E199 to E259.

[0637] E630. The method according to E627 to E631, wherein the first anticancer agent contains an anti-IL-13 antibody.

[0638] E631. The method according to E627 to E630, wherein the first anticancer agent comprises an anti-IL-13 antibody as described in any one of E265 to E330.

[0639] E632. The method according to E627 to E631, wherein the first anticancer agent contains an anti-TSLP antibody.

[0640] E633. The method according to E627 to E632, wherein the first anticancer agent comprises an anti-TSLP antibody as described in any one of E77 to E143 or E596 to E598.

[0641] E634. The method described in E627 to E633, wherein the first anticancer agent contains an IL-4 / IL-13 antibody.

[0642] E635. The method according to E627 to E634, wherein the first anticancer agent comprises an IL-4 / IL-13 antibody, and the IL-4 / IL-13 antibody comprises an IL-4 / IL-13 antibody as described in any one of E526 to E558.

[0643] E636. The method according to E627 to E635, wherein the first anticancer agent contains an IL-4 / IL-13 / TSLP antibody.

[0644] E637. The method according to E627 to E636, wherein the first anticancer agent comprises an IL-4 / IL-13 / TSLP antibody, and the IL-4 / IL-13 / TSLP antibody comprises an antibody described in any one of the items E387 to E435 or E599 to E613.

[0645] E638. The method according to E627 to E637, wherein the first anticancer agent comprises an IL-4 / IL-13 / TSLP antibody, and the IL-4 / IL-13 / TSLP antibody comprises the antibody described in E412.

[0646] E639. The method according to E627 to E637, wherein the first anticancer agent comprises an IL-4 / IL-13 / TSLP antibody, and the IL-4 / IL-13 / TSLP antibody comprises the antibody described in E603.

[0647] E640. The method according to E627 to E637, wherein the first anticancer agent comprises an IL-4 / IL-13 / TSLP antibody, and the IL-4 / IL-13 / TSLP antibody comprises the antibody described in E607.

[0648] E641. The method described in E627 to E640, wherein the second anticancer agent is a PD-1 pathway antagonist.

[0649] E642. The method described in E627 to E641, wherein the second anticancer agent is a PD-1 antagonist.

[0650] E643. The method according to E627 to E642, wherein the second anticancer agent is a PD-1 antagonist, and the PD-1 antagonist is selected from the group consisting of sasamrimab, BCD-100, camrelizumab, semiprimab, genolimusumab, MEDI0680, nivolumab, pembrolizumab, cintilimab, spartalizumab, STI-A1110, tisrelizumab, atezolizumab, durvalumab, BMS-936559 (MDX-1105), LY3300054, and TSR-042.

[0651] E644. The method according to E627 to E643, wherein the second anticancer agent is a PD-1 antagonist, and the PD-1 antagonist is an antibody containing VH as shown in SEQ ID NO: 4 of US10155037 and VL as shown in SEQ ID NO: 8.

[0652] E644. The method described in E627 to E643, wherein the second anticancer agent is a PD-1 antagonist, and the PD-1 antagonist is sasamrimab.

[0653] E645. The method according to E627 to E646, wherein the second anticancer agent is a PD-1 antagonist, and the PD-1 antagonist is sasamrimab, an antibody comprising an HC containing the sequence described in SEQ ID NO: 225 and a light chain containing the sequence described in SEQ ID NO: 226.

[0654] E646. A method for treating cancer in a subject, comprising administering a combination therapy comprising a first anticancer agent and a second anticancer agent to the subject, wherein the first anticancer agent is the IL-4 / IL-13 / TSLP antibody described in E412, and the second anticancer agent is a PD-1 antagonist antibody comprising an HC containing the sequence described in SEQ ID NO: 225 and a light chain containing the sequence described in SEQ ID NO: 226.

[0655] E647. A method for treating cancer in a subject, comprising administering a combination therapy comprising a first anticancer agent and a second anticancer agent to the subject, wherein the first anticancer agent is the IL-4 / IL-13 / TSLP antibody described in E603, and the second anticancer agent is a PD-1 antagonist antibody comprising an HC containing the sequence described in SEQ ID NO: 225 and a light chain containing the sequence described in SEQ ID NO: 226.

[0656] E648. A method for treating cancer in a subject, comprising administering a combination therapy comprising a first anticancer agent and a second anticancer agent to the subject, wherein the first anticancer agent is the IL-4 / IL-13 / TSLP antibody described in E607, and the second anticancer agent is a PD-1 antagonist antibody comprising an HC containing the sequence described in SEQ ID NO: 225 and a light chain containing the sequence described in SEQ ID NO: 226.

[0657] E649. A pharmaceutical product comprising a first anticancer agent and a second anticancer agent, wherein the first anticancer agent is the IL-4 / IL-13 / TSLP antibody described in E412, and the second anticancer agent is a PD-1 antagonist antibody comprising an HC containing the sequence described in SEQ ID NO: 225 and a light chain containing the sequence described in SEQ ID NO: 226.

[0658] E649. A pharmaceutical product comprising a first anticancer agent and a second anticancer agent, wherein the first anticancer agent is the IL-4 / IL-13 / TSLP antibody described in E603, and the second anticancer agent is a PD-1 antagonist antibody comprising an HC containing the sequence described in SEQ ID NO: 225 and a light chain containing the sequence described in SEQ ID NO: 226.

[0659] E649. A pharmaceutical product comprising a first anticancer agent and a second anticancer agent, wherein the first anticancer agent is the IL-4 / IL-13 / TSLP antibody described in E607, and the second anticancer agent is a PD-1 antagonist antibody comprising an HC containing the sequence described in SEQ ID NO: 225 and a light chain containing the sequence described in SEQ ID NO: 226.

[0660] E650. Cancer, characterized by a solid tumor, as described in any one of the items E627 to E649, or the pharmacopoeia.

[0661] E651. Cancers include bladder cancer, breast cancer, clear cell kidney cancer, squamous cell carcinoma of the head / neck, squamous cell carcinoma of the lung, 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), and diffuse cancer. The method or pharmacopoeia described in any one of items E627 to E650, which is one or more selected from the group consisting of large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myelocellular leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), or small lymphocytic lymphoma (SLL).

[0662] E652. The method or pharmaceutical described in any one of items 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 kidney cancer, squamous cell carcinoma of the head / neck (SCCHN), squamous cell carcinoma of the lung, malignant melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, small cell lung cancer (SCLC), or triple-negative breast cancer.

[0663] E653. The method or pharmacopoeia described in any one of E627 to E652, wherein the cancer is one or more selected from the group consisting of heme malignancies, and in some embodiments, the heme 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), myelocellular leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), or small lymphocytic lymphoma (SLL).

[0664] E654. An antibody, method, or pharmaceutical product for use as described in any one of the items E1 to E653, wherein at least one of the therapeutic agents is administered to the subject at intervals of once daily, once every two days, once every three days, once 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.

[0665] E656. Atopic dermatitis, asthma, cancer, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, and non-alcoholic steatohepatitis (NASH), nodular prurigo, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, fungal keratitis, bladder cancer, breast cancer, clear cell kidney cancer, squamous cell carcinoma of the head / neck, squamous cell carcinoma of the lung, malignant melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, small Cellular 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 lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myelocellular leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), or small lymphocytic lymphoma Lymphoma (SLL), Heme 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), Myelocyte leukemia-1 protein (Mcl-1), Bone marrow Use of an antibody described in any one of the following paragraphs, E1 to E71, E77 to E143, E144 to E193, E199 to E259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, E500 to E557, E596 to E612, or E619 to E625, for the manufacture of a pharmaceutical product for use (us) in one or more treatments selected from the group consisting of dysplastic syndromes (MDS), non-Hodgkin lymphoma (NHL), and small lymphocytic lymphoma (SLL).

[0666] E657. Atopic dermatitis, asthma, cancer, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, and non-alcoholic steatohepatitis (NASH), nodular prurigo, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, fungal keratitis, bladder cancer, breast cancer, clear cell kidney cancer, squamous cell carcinoma of the head / neck, squamous cell carcinoma of the lung, 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 lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myelocellular leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), or small lymphocyte Lymphocyte lymphoma (SLL), heme 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), myelocyte leukemia-1 protein (Mcl-1) A pharmaceutical composition for one or more treatments selected from the group consisting of myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), and small lymphocytic lymphoma (SLL), comprising an antibody as described in any one of the following 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, E500 to E557, E596 to E612, or E619 to E625.

[0667] An antidisease agent comprising an antibody described in any one of the following paragraphs: E658.E1 to E71, E77 to E143, E144 to E193, E199 to E259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, E500 to E557, E596 to E612, or E619 to E625, wherein the disease is atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, and non- Alcoholic steatohepatitis (NASH), nodular prurigo, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, fungal keratitis, bladder cancer, breast cancer, clear cell kidney cancer, squamous cell carcinoma of the head / neck, squamous cell carcinoma of the lung, 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 (C) LL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myelocellular leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), or small lymphocytic lymphoma (SLL), heme malignancy, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia ( An anti-disease agent selected from the group consisting of 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), myelocellular leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), and small lymphocytic lymphoma (SLL). [Brief explanation of the drawing]

[0668] [Figure 1A]Figure 1A shows an exemplary sequence illustrating the Pfabat numbering of the light chain portions of the anti-IL-13 and anti-IL-4 binding arms. Position numbers are shown vertically in a single column, and dashes ("-") indicate gaps in alignment. For example, residue L27D of anti-IL-13 CDR-L1 is His, and the equivalent residue in the anti-IL-4 binding arm is Glu. The portion considering the position of the CDR is shown in bold, and the corresponding amino acid is shown in bold and underlined. [Figure 1B] The image shows an exemplary sequence illustrating the Pfabat numbering of the heavy chain portions of the anti-IL-13, anti-IL-4, and anti-IL-33 binding arms. Position numbers are shown vertically in a single column, and dashes ("-") indicate gaps in alignment. For example, residue H100C of anti-IL-4 CDR-L1 is Phe, and the anti-IL-13 binding arm with the shorter CDRH3 does not have a corresponding residue. The portion considering the position of the CDR is shown in bold, and the corresponding amino acid is in bold and underlined. The anti-IL-13 heavy chain fragment used in most multispecific antibody sequences does not contain a complete hinge or Fc. The Pfabat algorithm numbers the sequence as an independent Fab domain and does not number the small upper hinge fragment ("EPKSC" (SEQ ID NO: 102)), which is manually included for reference (lower case, positions H226-H230). [Figure 2] Figure 2 shows a graph summarizing the results of LC / MS analysis of the IL4-1285 antibody. It reveals that the post-translational modification is located on the light chain. Mass spectrometry of peak 1 (P1) relative to peak 2 (P2) shows an 80 Dalton (Da) species with a mass of 23755.0 Da present in P2. P1 refers to the isolated "main peak" species when analyzed by ion exchange purification and detected using light chain LC / MS analysis (after LysC+TCEP). P2 refers to "peak 2" when isolated by ion exchange purification and detected using light chain LC / MS analysis (after LysC+TCEP). Peak 2 has additional sulfation relative to Tyr(L27a), and therefore has an 80 Da shift in MS. [Figure 3] Figure 3 shows a graph comparing LC / MS analyses for IL4-1346 (hu3B9-VLv2.8) [lower two panels] and IL4-1285 (hu3B9-VLv2.0) antibody light chains [upper two panels]. O-linked sulfation of the light chain CDR1 peptide (DRVTITCKASQSVDY) was identified by LC / MS analysis, and the Y(L27d)F mutation removed heterogeneity. The left panels in both the upper and lower sections are peptide-level mapping data (AspN enzyme). The right panels in both the upper and lower sections are subunits using the LysC method. Peptide mapping (AspN digestion) shows in the upper left spectrum that the DFD light chain does not contain sulfation, while the DYD light chain has some sulfation (+79.9568 Da). Subunit analysis shows that the DFD light chain does not contain sulfated species (upper right spectrum), while the DYD light chain contains several sulfated Da species (lower right spectrum). [Figure 4] Figure 4 shows the changes incorporated into IL4-1359(VH1 G07_VLv2.9)VH CDRH1 that contribute to a higher affinity for IL-4. [Figure 5] Figure 5 shows the changes in Tyr(L27d)E that can be made to remove the O-sulfate post-translational modification and further stabilize the IL-4 / IL4-1285(RA1-2 or hu3B9-VLv2.0) interface. [Figure 6] Figure 6 shows the alignment of the IL-13 complex, revealing the binding orientation of IL13-1283 (IMA-638 or hu13.2) versus IL13-1307 (hu13.4). [Figure 7] Figure 7 illustrates the differences in CDRL1 between IL13-1307 (hu13.4) and IL13-1283 (IMA-638 or hu13.2), which contribute to a higher affinity for human IL-13. [Figure 8] Figure 8 illustrates the amino acid differences in CDRH3 between IL13-1307 (hu13.4) and IL13-1283 (IMA-638 or hu13.2), which contribute to a higher affinity for IL-13. [Figure 9] Figure 9 illustrates how the presence of serine at residue 30 in IL13-1307(hu13.4)CDRH1 contributes to a higher affinity for IL-13 compared to IL13-1283(IMA-638 or hu13.2). [Figure 10] Figure 10 illustrates how the aspartic acid at position 55 in IL13-1307(hu13.4)CDRH2 contributes to a higher affinity for IL-13 compared to IL13-1283(IMA-638 or hu13.2), instead of glycine at the same position in IL13-1283. [Figure 11] Figure 11 illustrates how the changes incorporated into IL13-0001(1RVHC9-VLA4)VH CDRH3 contribute to a higher affinity for IL-13. [Figure 12] Figure 12 illustrates how the changes incorporated into IL13-0001(1RVHC9-VLA4)VL CDRL1 contribute to a higher affinity for IL-13. [Figure 13] Figure 13 shows a graph illustrating how increased IL-33 neutralization potency correlates with increased polyreactivity. [Figure 14A] Figure 14 shows high-throughput off-rate screening of anti-TSLP variants. Figure 14A: Sensorgram of off-rate screening. R represents the response (nM). t0, t240, and t640 represent time points. Association index = sample (Rt240-Rt0) / TSLP-0001(Rt240-Rt0). Dissociation index = sample (Rt640-Rt240) / TSLP-0001(Rt640-Rt240). [Figure 14B] Figure 14 shows high-throughput off-rate screening of anti-TSLP variants. Figure 14B: Spotfire plot of association index vs. dissociation index. Variants in the square boxes are hits that meet the selection criteria. [Figure 15]Figure 15 shows the electrostatic surface plot of the TSLP-0260 Fv region. The electrostatic surface plot was determined using the Poisson-Boltzmann computer Delphi. Here, positive charge potentials are shown in white and negative charge potentials are shown in black. The regions focused on reducing viscosity were the negative charge patches circled with black dashed lines. These three patches contain portions of CDR L1-L2, L3-H2-H3, and H2, respectively. [Figure 16] Figure 16 is a diagram illustrating the details of the antibody:TSLP interface. The VH-E99Y mutation potentially introduces a novel hydrogen bonding network at the TSLP-Ab interface. Selected interface residues are labeled and shown as sticks. N71 and R149 are derived from TSLP. Dashed lines represent salt crosslinking and hydrogen bonding. Light gray with α-helix structure: TSLP. Dark gray: antibody. This also increases overall packing. [Figure 17] Figure 17 shows a graph illustrating the viscosity analysis of the anti-TSLP variant. Viscosity was measured using a DLS bead-based method. [Figure 18A] Figure 18A shows a general schematic diagram and nomenclature of the triple-specific Tri-Fab-Fc and Fab domains. Figure 18A shows a schematic diagram of Tri-Fab-Fc, showing domains Fab1, Fab2, and Fab3, as well as single Fab (SFab) and double Fab (DFab) arms expressed in separate cells. Note: VL indicates the light chain variable domain, VH indicates the heavy chain variable domain, Ck indicates the kappa constant light chain domain, Cl indicates the lambda constant light chain domain, and CH1 indicates the heavy chain constant domain 1. EPKSC (SEQ ID NO: 102): A segment of amino acids derived from the IgG1 upper hinge region fused to the C-terminus of CH1 to form a disulfide bond with CL (Fab1). [Figure 18B]Figure 18B shows a general schematic diagram and nomenclature of the triple-specific Tri-Fab-Fc and Fab domains. Figure 18B shows a schematic diagram of a conventional Fab. Note: VL indicates the light chain variable domain, VH indicates the heavy chain variable domain, Ck indicates the kappa constant light chain domain, Cl indicates the lambda constant light chain domain, and CH1 indicates the heavy chain constant domain 1. EPKSC (SEQ ID NO: 102): The amino acid segment derived from the IgG1 upper hinge region fused to the C-terminus of CH1 for forming a disulfide bond with CL (Fab1). [Figure 18C] Figure 18C shows a general schematic and nomenclature of the triple-specific Tri-Fab-Fc and Fab domains. Figure 18C shows a schematic diagram of modified Fd. Note: VL indicates the light chain variable domain, VH indicates the heavy chain variable domain, Ck indicates the kappa constant light chain domain, Cl indicates the lambda constant light chain domain, and CH1 indicates the heavy chain constant domain 1. EPKSC (SEQ ID NO: 102): The amino acid segment derived from the IgG1 upper hinge region fused to the C-terminus of CH1 for forming a disulfide bond with CL (Fab1). [Figure 18D] Figure 18D shows a general schematic and nomenclature of the triple-specific Tri-Fab-Fc and Fab domains. Figure 18D shows a schematic diagram of the VH-VL swap. Note: VL represents the light chain variable domain, VH represents the heavy chain variable domain, Ck represents the kappa constant light chain domain, Cl represents the lambda constant light chain domain, and CH1 represents the heavy chain constant domain 1. EPKSC (SEQ ID NO: 102): The amino acid segment derived from the IgG1 upper hinge region fused to the C-terminus of CH1 to form a disulfide bond with CL (Fab1). [Figure 18E] Figure 18E shows a general schematic diagram and nomenclature of the triple-specific Tri-Fab-Fc and Fab domains. Figure 18E shows a schematic diagram of S1. Note: VL indicates the light chain variable domain, VH indicates the heavy chain variable domain, Ck indicates the kappa constant light chain domain, Cl indicates the lambda constant light chain domain, and CH1 indicates the heavy chain constant domain 1. EPKSC (SEQ ID NO: 102): The amino acid segment derived from the IgG1 upper hinge region fused to the C-terminus of CH1 for forming a disulfide bond with CL (Fab1). [Figure 18F] Figure 18F shows a general schematic and nomenclature of the triple-specific Tri-Fab-Fc and Fab domains. Figure 18F shows a schematic diagram of S1Rev. Note: VL indicates the light chain variable domain, VH indicates the heavy chain variable domain, Ck indicates the kappa constant light chain domain, Cl indicates the lambda constant light chain domain, and CH1 indicates the heavy chain constant domain 1. EPKSC (SEQ ID NO: 102): The amino acid segment derived from the IgG1 upper hinge region fused to the C-terminus of CH1 to form a disulfide bond with CL (Fab1). [Figure 18G] Figure 18G shows a general schematic and nomenclature of the triple-specific Tri-Fab-Fc and Fab domains. Figure 18G shows a schematic diagram of the CH-Ck swap. Note: VL represents the light chain variable domain, VH represents the heavy chain variable domain, Ck represents the kappa constant light chain domain, Cl represents the lambda constant light chain domain, and CH1 represents the heavy chain constant domain 1. EPKSC (SEQ ID NO: 102): The amino acid segment derived from the IgG1 upper hinge region fused to the C-terminus of CH1 to form a disulfide bond with CL (Fab1). [Figure 18H] Figure 18H shows a general schematic and nomenclature of the triple-specific Tri-Fab-Fc and Fab domains. Figure 18H shows a schematic diagram of the CH-Cl swap. Note: VL represents the light chain variable domain, VH represents the heavy chain variable domain, Ck represents the kappa constant light chain domain, Cl represents the lambda constant light chain domain, and CH1 represents the heavy chain constant domain 1. EPKSC (SEQ ID NO: 102): The amino acid segment derived from the IgG1 upper hinge region fused to the C-terminus of CH1 for forming a disulfide bond with CL (Fab1). [Figure 18I]Figure 18I shows a general schematic and nomenclature of the triple-specific Tri-Fab-Fc and Fab domains. Figure 18I shows a decomposed diagram of Tri-Fab-Fc, showing the individual protein chains: SFab HC(3) and SFab LC(3) chains that together form the SFab arm, and DFab LC(1)-HC(2), modified Fd(1), and DFab LC(2) chains that together form the DFab arm. Note: VL indicates the light chain variable domain, VH indicates the heavy chain variable domain, Ck indicates the kappa constant light chain domain, Cl indicates the lambda constant light chain domain, and CH1 indicates the heavy chain constant domain 1. EPKSC (SEQ ID NO: 102): A segment of amino acids derived from the IgG1 upper hinge region fused to the C-terminus of CH1 to form a disulfide bond with CL(Fab1). [Figure 19A] Figure 19A shows the configuration and characterization of Tri-Fab-Fc with native strand pairing at the Fab1 position. Figure 19A shows the configurations of two native strand-paired Tri-Fab-Fc variants, where all three Fabs have conventional strand pairing. S1: S1 mutation in CH1 / CK. S1rev: S1rev mutation in CH1 / CK. Positively charged (+) mutations are represented by solid black circles. Negatively charged (-) mutations are represented by dashed black circles. [Figure 19B] Figure 19B shows the configuration and characterization of Tri-Fab-Fc with native strand pairing at the Fab1 position. Figure 19B shows the configurations of two native strand-paired Tri-Fab-Fc variants, where all three Fabs have conventional strand pairing. S1: S1 mutation in CH1 / CK. S1rev: S1rev mutation in CH1 / CK. Positively charged (+) mutations are represented by solid black circles. Negatively charged (-) mutations are represented by dashed black circles. [Figure 19C] Figure 19C shows the configuration and characterization of Tri-Fab-Fc with native strand pairing at the Fab1 position. Figure 19C also shows a graph of the analytical SEC of IL413TSLP-0003 and IL413TSLP-0004 after Mab Select SuRe elution and prepSEC superdex 200 purification. [Figure 19D]Figure 19D shows the configuration and characterization of Tri-Fab-Fc with native strand pairing at the Fab1 position. Figure 19D shows a graph of the LCMS analysis of IL413TSLP-0003. The table lists the respective strands of the triple specificity and the corresponding theoretical strand masses. Numbers 1-5 are placed before each strand to provide a shortened description of the strand composition for the major peaks in LCMS. [Figure 19E] Figure 19E shows the configuration and characterization of Tri-Fab-Fc with native strand pairing at the Fab1 position. Figure 19E shows a graph illustrating the LCMS analysis of IL413TSLP-0004. The table lists the respective strands of the triple specificity and their corresponding theoretical strand masses. Numbers 1-5 are placed before each strand to provide a shortened description of the strand composition for the major peaks in LCMS. [Figure 20A] Figure 20A shows schematic diagrams of the configurations of the CλS, CκS, and VDS Tri-Fab-Fc variants, where the Fab1 domain (anti-TSLP) contains a Cl domain fused to the C-terminus of the VH1 domain and a CH1 domain fused to the C-terminus of the VL1 domain. The CλS configuration shown by IL413TLSP-0001 (Figure 20A) has a Fab1 light chain with structures VL-CH1 and VH-Cl at the N-terminus of the double Fab arms. [Figure 20B] Figure 20B shows schematic diagrams illustrating the configurations of the CλS, CκS, and VDS Tri-Fab-Fc variants, where the Fab1 domain (anti-TSLP) contains a Cl domain fused to the C-terminus of the VH1 domain and a CH1 domain fused to the C-terminus of the VL1 domain. The CλS configuration shown by IL413TSLP-0002 (Figure 20B) has a Fab1 light chain with structures VL-CH1 and VH-Cl at the N-terminus of a double Fab arm. [Figure 20C]Figure 20C shows schematic diagrams of the configurations of the CλS, CκS, and VDS Tri-Fab-Fc variants, where the Fab1 domain (anti-TSLP) contains a Cl domain fused to the C-terminus of the VH1 domain and a CH1 domain fused to the C-terminus of the VL1 domain. The VDS configuration shown by IL413TLSP-0007 (Figure 20C) has a Fab1 Vl-CH1 at the N-terminus of the double Fab chain and the VH-Cl Fab1 light chain. [Figure 20D] Figure 20D shows schematic diagrams of the configurations of the CλS, CκS, and VDS Tri-Fab-Fc variants, where the Fab1 domain (anti-TSLP) contains a Cl domain fused to the C-terminus of the VH1 domain and a CH1 domain fused to the C-terminus of the VL1 domain. The VDS configuration shown by IL413TSLP-0008 (Figure 20D) has a Fab1 Vl-CH1 at the N-terminus of the double Fab chain and the VH-Cl Fab1 light chain. [Figure 20E] Figure 20E shows schematic diagrams of the configurations of the CλS, CκS, and VDS Tri-Fab-Fc variants, where the Fab1 domain (anti-TSLP) contains a Cl domain fused to the C-terminus of the VH1 domain and a CH1 domain fused to the C-terminus of the VL1 domain. The CkS configuration shown by IL13433-0021 (Figure 20E) has Fab1 and Fab3, respectively, possessing S1 and S1 rev mutations, with Fab2 containing a VL-CH1 structure and VH-CL fused to the N-terminus of Fc. [Figure 20F] Figure 20F shows schematic diagrams of the configurations of the CλS, CκS, and VDS Tri-Fab-Fc variants, where the Fab1 domain (anti-TSLP) contains a Cl domain fused to the C-terminus of the VH1 domain and a CH1 domain fused to the C-terminus of the VL1 domain. The CkS configuration shown by IL13433-0022 (Figure 20F) has Fab1 and Fab3, respectively, possessing S1 and S1 rev mutations, while Fab2 contains a VL-CH1 structure with an SS elbow between the VL and CH1 domains, and VH-CL is fused to the N-terminus of Fc. [Figure 21] Figure 21 shows a graph evaluating the effect of domain shape on Tri-Fab-Fc binding activity by bridging ELISA. TPP-9662 is an IL-4 / IL-13 bispecific antibody with S1 / S1rev and KiH. mab8.8 is the negative control antibody. [Figure 22A] Figure 22 shows the improvement of Tri-Fab-Fc strand pairing by adjusting the DNA ratio in transient transfection. Figure 22A shows NuPAGE Bis-tris gel analysis. R: reduced. NR: unreduced. [Figure 22B] Figure 22 shows the improvement of Tri-Fab-Fc strand pairing by adjusting the DNA ratio in transient transfection. Figure 22B shows a graph of aSEC analysis. [Figure 23A] Figure 23A shows a schematic diagram of the Tri-Fab-Fc variant manipulated with a modified Fd format and S1 / S1rev complementary mutations. [Figure 23B] Figure 23B shows a schematic diagram of the Tri-Fab-Fc variant manipulated with a modified Fd format and S1 / S1rev complementary mutations. [Figure 23C] Figure 23C shows a schematic diagram of the Tri-Fab-Fc variant manipulated with a modified Fd format and S1 / S1rev complementary mutations. [Figure 23D] Figure 23D shows a schematic diagram of the Tri-Fab-Fc variant manipulated with a modified Fd format and S1 / S1rev complementary mutations. [Figure 24] Figure 24 shows unstained SDS-PAGE analysis of stable CHO-producing Tri-Fab-Fc in both unreduced and reduced states. [Figure 25A]Figure 25A shows a schematic diagram of a representative Tri-Fab-Fc triple-specific configuration with a CκS or mFd pairing in Fab1, using charge-based heterodimerization. RRR or EEE charge mutations: two RR / EE pairs are located in the hinge region, and one R / E pair is located in CH3. The anti-IL-13 domain is designed to be either CkS (exemplified by IL413TSLP-0251) or mFd (exemplified by IL413TSLP-0252). [Figure 25B] Figure 25B shows a schematic diagram of a representative Tri-Fab-Fc triple-specific configuration with a CκS or mFd pairing in Fab1, using charge-based heterodimerization. RRR or EEE charge variants: two RR / EE pairs are located in the hinge region, and one R / E pair is located in CH3. The anti-IL-13 domain is designed to be either CkS (exemplified by IL413TSLP-0251) or mFd (exemplified by IL413TSLP-0252). [Figure 26] Figure 26 shows a schematic diagram of an anti-IL-13 / IL-4 dual Fab EEE arm design, which has an anti-IL-13 domain as mFd at Fab1 and an anti-IL-4 domain at Fab2. [Figure 27] Figure 27 shows a schematic diagram of an anti-IL-13 / IL-4 dual Fab EEE CB arm design, which has an anti-IL-4 binding domain as mFd at Fab1 and an anti-IL-13 domain at Fab2. [Figure 28A] Figure 28A shows a schematic diagram of an anti-IL-13 / IL-4 dual Fab EEE arm design with CκS at Fab1. [Figure 28B] Figure 28B shows a schematic diagram of an anti-IL-13 / IL-4 dual Fab EEE arm design with CκS at Fab1. [Figure 29A] Figure 29A shows a graph demonstrating that Tri-Fab-Fc IL13433-0006 can simultaneously bind to human IL-4, IL-13, and IL-33. [Figure 29B]Figure 29B shows a graph demonstrating that Tri-Fab-Fc IL13433-0006 can simultaneously bind to human IL-4, IL-13, and IL-33. [Figure 29C] Figure 29C shows a graph demonstrating that Tri-Fab-Fc IL13433-0006 can simultaneously bind to human IL-4, IL-13, and IL-33. [Figure 30] Figure 30 shows SPR sensorgrams of IL413p40-0705 with human IL-4, IL-13, and IL-23 in various injection sequences. [Figure 31A] Figure 31A shows a dual-cell design Tri-Fab-Fc variant with mFd format and S1-S1rev complementary mutations. [Figure 31B] Figure 31B shows a dual-cell design Tri-Fab-Fc variant with mFd format and S1-S1rev complementary mutations. [Figure 31C] Figure 31C shows a dual-cell design Tri-Fab-Fc variant with mFd format and S1-S1rev complementary mutations. [Figure 31D] Figure 31D shows a dual-cell design Tri-Fab-Fc variant with mFd format and S1-S1rev complementary mutations. [Figure 32] Figure 32 shows Tri-Fab-Fc produced using a single-cell process and manipulated in a modified Fd format. [Figure 33] Figure 33 shows graphs illustrating the viscosity of IL413p40-0698 and IL413p40-0700 as measured by differential spectral scattering (DLS). [Figure 34]Figure 34 is a graph showing the pharmacokinetics of anti-IL-4 / 13 / 33 Tri-Fab-Fc IV in Tg32 mice. The antibody designs are abbreviated to their four numerical references as follows: 1042 refers to IL13433-1042, 1258 refers to IL13433-1258, 1261 refers to IL13433-1261, 1270 refers to IL13433-1270, 1275 refers to IL13433-1275, and anti-IL-33 Ab LS refers to IL33-0232 VH and VL having Fc domains further containing the LS mutations described herein. [Figure 35A] Figure 35A shows a graph illustrating the triplicate binding of IL-4 to human, cynomolgus monkey, mouse, and rat IL-4 by surface plasmon resonance. Triplicate binding: (a) IL13433-1258 was immobilized on a CM5 sensor chip, and binding to 200 nM human (hu), cynomolgus monkey (cy), mouse (mu), rabbit (rb), or rat (rt) IL-4 was determined by surface plasmon resonance. [Figure 35B] Figure 35B shows a graph illustrating the triplicate binding of IL-4 to human, cynomolgus monkey, mouse, and rat IL-4 by surface plasmon resonance. Triplicate binding: (b) IL413TSLP-1024 was immobilized on a CM5 sensor chip, and binding to 200 nM human (hu), cynomolgus monkey (cy), mouse (mu), rabbit (rb), or rat (rt) IL-4 was determined by surface plasmon resonance. [Figure 35C] Figure 35C shows a graph illustrating the triplicate binding of (c)IL413P40-0705 to human, cynomolgus monkey, mouse, and rat IL-4 by surface plasmon resonance. Triplicate binding: (c)IL413P40-0705 was immobilized on a CM5 sensor chip, and binding to 200 nM human (hu), cynomolgus monkey (cy), mouse (mu), rabbit (rb), or rat (rt) IL-4 was determined by surface plasmon resonance. [Figure 36A]Figure 36A shows a graph illustrating the triplicate binding of human, cynomolgus monkey, mouse, and rat IL-13 by surface plasmon resonance. Triplicate binding: (a) IL13433-1258 was immobilized on a CM5 sensor chip, and binding to 200 nM human (hu), cynomolgus monkey (cy), mouse (mu), rabbit (rb), or rat (rt) IL-13 was determined by surface plasmon resonance. [Figure 36B] Figure 36B shows a graph illustrating the triplicate binding of human, cynomolgus monkey, mouse, and rat IL-13 by surface plasmon resonance. Triplicate binding: (b) IL413TSLP-1024 was immobilized on a CM5 sensor chip, and binding to 200 nM human (hu), cynomolgus monkey (cy), mouse (mu), rabbit (rb), or rat (rt) IL-13 was determined by surface plasmon resonance. [Figure 36C] Figure 36C shows a graph illustrating the triplicate binding of (c) IL413P40-0705 to human, cynomolgus monkey, mouse, and rat IL-13 by surface plasmon resonance. Triplicate binding: (c) IL413P40-0705 was immobilized on a CM5 sensor chip, and binding to 200 nM human (hu), cynomolgus monkey (cy), mouse (mu), rabbit (rb), or rat (rt) IL-13 was determined by surface plasmon resonance. [Figure 37] Figure 37 is a schematic diagram showing the locations of different Fabs within a Tri-Fab-Fc structure with a modified Fd (mFd) design. [Figure 38] Figure 38 shows SPR sensorgrams of Tri-Fab-Fc IL413p40-0705 with IL-12, IL-23, IL-4, and IL-13 in humans (hu), cynomolgus monkeys (cy), mice (mu), rats (rt), and rabbits (rb). [Figure 39] Figure 39 shows a graph illustrating the species specificity of IL-33 binding to IL13433-1258, which exhibits triple specificity due to surface plasmon resonance. [Figure 40]Figure 40 shows a graph illustrating the binding of short-form and long-form TSLPs to TSLP-0001, mAb TSLP-0875, and triple-specific IL413TSLP-1024 via surface plasmon resonance. [Figure 41] Figure 41 shows a graph illustrating the biological activity of short-form and long-form TSLP in inducing monocyte TARC production. Mononuclear cells isolated from human peripheral blood were incubated overnight at 37°C with recombinant human TSLP (Pfizer), short-form TSLP (TSLPlf Avi V5 His 10 biotin), or long-form TSLP (TSLPlf Avi V5 His 10 biotin) at concentrations ranging from 0.31 pg / mL to 20 ng / mL. TARC production in the cell supernatant was quantified by MSD. Data are expressed as mean + / - SD. The EC50 values ​​for hTSLP, sfTSLP, and lfTSLP were 0.3680, N / A, and 7.472 ng / mL, respectively. [Figure 42] Figure 42 shows a graph illustrating the triplicate binding of human, cynomolgus monkey, mouse, and rat TSLP to IL413TSLP-1024 by surface plasmon resonance. Biotinylated human (hu), cynomolgus monkey (cy), mouse (mu), or rat (rt) TSLP were captured on a biotin CAP sensor chip, and the triplicate binding to IL413TSLP-1024 was determined by surface plasmon resonance. [Figure 43] Figure 43 shows a graph illustrating the simultaneous coupling of IL-4, IL-13, and TSLP to IL413TSLP-1024 via surface plasmon resonance. [Figure 44A]Figure 44A shows a graph illustrating the time-course and final mean CT26 tumor volume of the study. Results from a study in which CT26 tumor-bearing Balb / c mice were administered the compounds listed in Table 88. (A) Time-course mean volume (mm3) and mean standard error of the transplanted tumor, starting at day 9 (day 1 of drug injection) for each treatment group. Bars and whiskers represent the mean and standard deviation for each treatment group. Each dot represents the final tumor volume for each mouse in that treatment group. Treatment with anti-PD-1 antibody, anti-IL-4 antibody and mIL13Ra2-mFc, or anti-IL-4 antibody and mIL13Ra2-mFc and anti-PD-1 antibody did not significantly alter the characteristics of tumor growth compared to isotype-treated animals. In contrast, mice treated with anti-IL-4, anti-TSLP antibodies, and mIL13Ra2-mFc (40% tumor growth inhibition, p=0.043) or anti-IL-4, anti-TSLP, and anti-PD-1 antibodies, and mIL13Ra2-mFc (54% tumor growth inhibition, p=0.002) showed significant tumor growth inhibition for each isotype. [Figure 44B] Figure 44B shows a graph illustrating the time-course and final mean CT26 tumor volume of the study. Results from a study in which CT26 tumor-bearing Balb / c mice were administered the compounds listed in Table 88. (B) Volume of transplanted tumor (mm3) at 22 days post-transplant (final day of the study). Bars and whiskers represent the mean and standard deviation for each treatment group. Each dot represents the final tumor volume for each mouse in that treatment group. Treatment with anti-PD-1 antibody, anti-IL-4 antibody and mIL13Ra2-mFc, or anti-IL-4 antibody and mIL13Ra2-mFc and anti-PD-1 antibody did not significantly alter the characteristics of tumor growth compared to isotype-treated animals. In contrast, mice treated with anti-IL-4, anti-TSLP antibodies, and mIL13Ra2-mFc (40% tumor growth inhibition, p=0.043) or anti-IL-4, anti-TSLP, and anti-PD-1 antibodies, and mIL13Ra2-mFc (54% tumor growth inhibition, p=0.002) showed significant tumor growth inhibition for each isotype. [Figure 45]Figure 45 shows a graph illustrating the CT26 tumor volume for each mouse in each treatment group over time. The graph shows the volume (mm³) of subcutaneously transplanted CT26 tumors for individual mice in each treatment group, starting on day 9 (day 1 after drug injection). [Figure 46A] Figure 46A shows a graph demonstrating that neutralization of IL-4 with mAb IL4-1040 or TSLP with mAb TSLP-0875 prevents suppression of interferon-gamma secretion by primary human tumor-reactive T cells. Interferon-gamma secretion from primary A375-reactive human T cells polarized and restimulated as described in Example 87 by the treatments listed in Table 2. (A) shows interferon-gamma secretion from six distinct donors tested over multiple days. T cells were polarized and restimulated with either isotype antibody alone, isotype antibody and 0.8 ng / mL recombinant human IL-4, or mAb IL4-1040 and 0.8 ng / mL recombinant human IL-4. Data in (A and B) are expressed as mean and standard deviation. Statistical tests in (A and B) are ANOVA with p-values ​​from post-hoc Sidac multiple comparison tests, shown above the bars. [Figure 46B] Figure 46B shows a graph demonstrating that neutralization of IL-4 with mAb IL4-1040 or TSLP with mAb TSLP-0875 prevents suppression of interferon-gamma secretion by primary human tumor-reactive T cells. Interferon-gamma secretion from primary A375-reactive human T cells polarized and restimulated as described in Example 87 by the treatments listed in Table 2. (B) shows interferon-gamma secretion from the same six donors in (A) polarized and restimulated with either isotype antibody, isotype antibody and 0.8 ng / mL recombinant human TSLP, or mAb TSLP-0875 and 0.8 ng / mL recombinant human TSLP. Data in (A and B) are expressed as mean and standard deviation. Statistical tests in (A and B) are ANOVA with p-values ​​from post-hoc Sidac multiple comparison tests, shown above the bars. [Figure 47A]Figure 47A shows a graph demonstrating that neutralization of IL-4 with mAb IL4-1040 and / or TSLP with mAb TSLP-0875 improved T cell-mediated control of human A375 cancer cell growth in vitro, and that this correlated with interferon-gamma secretion. Primary human T cells were polarized and restimulated as described in Example 87. Growth curves of A375 tumor cells during T cell restimulation were prepared as described in Example 88. (A) Primary human T cells were polarized and restimulated using: (A) isotype antibody alone, isotype antibody and 0.8 ng / mL recombinant human IL-4, or mAb IL4-1040 and 0.8 ng / mL recombinant human IL-4. The levels of secreted interferon-gamma correlated with the normalized A375 AUC from the same well. (A-C) are data from donor 1923. The data in (A-C) are expressed as the mean and standard deviation of exemplary data from six technical iterations and three different donors. [Figure 47B] Figure 47B shows a graph demonstrating that neutralization of IL-4 with mAb IL4-1040 and / or TSLP with mAb TSLP-0875 improved T cell-mediated control of human A375 cancer cell growth in vitro, and this correlated with interferon-gamma secretion. Primary human T cells were polarized and restimulated as described in Example 87. Growth curves of A375 tumor cells during T cell restimulation were prepared as described in Example 88. (A) Primary human T cells were polarized and restimulated using: (B) isotype antibody alone, isotype antibody and 0.8 ng / mL recombinant human TSLP, or mAb TSLP-0875 and 0.8 ng / mL recombinant human TSLP. The levels of secreted interferon-gamma correlated with normalized A375 AUC from the same well. (A-C) are data from donor 1923. The data in (A-C) are expressed as the mean and standard deviation of exemplary data from six technical iterations and three different donors. [Figure 47C]Figure 47C shows a graph demonstrating that neutralization of IL-4 with the mAb IL4-1040 and / or TSLP with the mAb TSLP-0875 improved T cell-mediated regulation of human A375 cancer cell growth in vitro, and that this correlated with interferon-gamma secretion. Primary human T cells were polarized and restimulated as described in Example 87. Growth curves of A375 tumor cells during T cell restimulation were prepared as described in Example 88. (A) Primary human T cells were polarized and restimulated using: (C) isotype antibody alone, isotype antibody and 0.8 ng / mL of recombinant human IL-4 and TSLP respectively, or combination of mAb1040, mAb and 0.8 ng / mL of recombinant human IL-4 and TSLP respectively. The level of secreted interferon-gamma correlated with the normalized A375 AUC from the same well. (A-C) are data from donor 1923. Data in (A-C) are expressed as the mean and standard deviation of exemplary data from 6 technical replicates and 3 different donors. [Figure 47D] Figure 47D shows a graph demonstrating that neutralization of IL-4 with the mAb IL4-1040 and / or TSLP with the mAb TSLP-0875 improved T cell-mediated control of human A375 cancer cell growth in vitro, and that this correlated with interferon-gamma secretion. Primary human T cells were polarized and restimulated as described in Example 87. Growth curves of A375 tumor cells during T cell restimulation were prepared as described in Example 88. (D) Interferon-gamma in conditioned medium collected on day 5 of restimulation was quantified as described in Example 87. The level of secreted interferon-gamma correlated with the normalized A375 AUC from the same well. (D) is data from donor 8385. Data in (D) are represented as the mean of six technical replicates and exemplary data from four donors. [Figure 48]Figure 48 shows a graph demonstrating that recombinant human IL-4 or a combination of IL-4 and TSLP reduced the frequency of A375-polarized primary human CD8 T cells expressing both perforin and granzyme B. The percentage of A375-polarized CD8 T cells expressing both perforin and granzyme B was determined by flow cytometry as described in Example 89. Data are presented as the mean and standard deviation of three technical replicates and are representative of data from two separate donors. [Figure 49A] Figure 49A shows a graph illustrating the neutralization of IL-4- and IL-13-induced CCL17 secretion from human clear cell renal cell carcinoma cell line 769-P by triplicate specific IL413TSLP-1028 and IL413TSLP-1037. Human clear cell renal cell carcinoma cells 769-P were incubated with recombinant human IL-4(A) at 37°C for approximately 20 hours, along with dilutions of triplicate specific IL413TSLP-1028 or IL413TSLP-1037. CCL17 secretion was quantified using Legendplex, and concentrations were extrapolated from the standard curve. [Figure 49B] Figure 49B shows a graph illustrating the neutralization of IL-4- and IL-13-induced CCL17 secretion from the human clear cell renal cell carcinoma cell line 769-P by the triplicate specificity IL413TSLP-1028 and IL413TSLP-1037. 769-P human clear cell renal cell carcinoma cells were incubated with IL-13(B) at 37°C for approximately 20 hours with dilutions of triplicate specificity IL413TSLP-1028 or IL413TSLP-1037. CCL17 secretion was quantified using Legendplex, and concentrations were extrapolated from the standard curve. [Modes for carrying out the invention]

[0669] Detailed explanation 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 for preparing and using antibodies are also provided herein.

[0670] general technique All references cited herein, including patent applications, patent publications, and UniProtKB accession numbers, are incorporated herein by reference in such a way that each individual reference is specifically and individually indicated as being incorporated by reference in its entirety.

[0671] The techniques and procedures described or referenced herein are generally based on conventional methodologies by those skilled in the art, e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual, 3rd Edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NYCURRENT PROTOCOLS IN MOLECULAR BIOLOGY (FMAusubel et al., eds., (2003)); the series METHODS IN ENZYMOLOGY (Academic Press, Inc.): PCR 2: A PRACTICAL APPROACH (MJ MacPherson, BD Hames and GR Taylor, eds. (1995)), Harlow and Lane, eds. (1988); ANTIBODIES, A LABORATORY MANUAL, and ANIMAL CELL CULTURE (RIFreshney, ed. (1987)); Oligonucleotide Synthesis (MJ Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (JECellis, ed., 1998) Academic Press; Animal Cell Culture (RIFreshney, ed., 1987); Introduction to Cell and Tissue Culture (JPMather and PERoberts, 1998) Plenum Press; Cell and Tissue Culture Laboratory Procedures (A. Doyle, J.B. Griffiths, and D.G. Newell, eds., 1993-98) J. Wiley and Sons; Handbook of Experimental Immunology (DMWeir and C.C. Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (J.M. Miller and MPCalos (ed.), 1987); PCR: The Polymerase Chain Reaction (Mullis et al., eds.), 1994; Current Protocols in Immunology (JEColigan et al., eds.), 1991; Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (CA Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: A Practical Approach (D. Catty, ed., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999)); The Antibodies (M. Zanetti and JDCapra, eds., Harwood Academic The widely used methodologies described in Publishers, 1995, and its revised editions, are well understood and commonly employed.

[0672] definition Unless otherwise defined, all technical terms, notations, and other scientific terms or vocabulary used herein are intended to have meanings that are ordinarily understood by those skilled in the art to which the invention pertains. For example, the term "and / or" used herein in phrases such as "A and / or B" 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 that have meanings that are ordinarily understood 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 those generally understood in the art.

[0673] As used herein, the singular forms "a," "an," and "the" include their corresponding plural referents unless the context explicitly indicates otherwise.

[0674] As used herein, a numerical range includes the number that defines the range.

[0675] References to “approximately” values ​​or parameters in this specification include (and describe) embodiments relating to the value or parameter itself, and to values ​​or parameters that may be approximately 10% lower or higher than the numerical value stated for that parameter. For example, a dose of “approximately 5 mg / kg” includes 5 mg / kg and any value between 4.5 mg / kg and 5.5 mg / kg. When the term “approximately” is used in the context of a period (year, month, week, day, etc.), the term “approximately” means that period plus or minus some amount of the next subperiod (for example, approximately one year means 11 to 13 months, approximately six months means six months plus or minus one week, approximately one week means six to eight days, etc.), or within 10 percent of the indicated value, whichever is longer.

[0676] "Antibody" refers to an immunoglobulin molecule that can specifically bind to a target, such as polypeptides, carbohydrates, polynucleotides, lipids, 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, tripspecific, multispecific) and includes 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 the immunoglobulin molecule containing the antigen-binding site.

[0677] Antibodies can be any class of antibody, e.g., IgG, IgA, or IgM (or their subclasses), and an antibody does not need to be of any particular class. Depending on the 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, some of which can be further divided into subclasses (isotypes), e.g., 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 configurations of different classes of immunoglobulins are well known.

[0678] Examples of antibody antigen-binding fragments and modified conformations include (i) Fab fragments (monovalent fragments consisting of VL, VH, CL, and CH1 domains); (ii) F(ab')2 fragments (bivalent fragments containing two Fab fragments linked by disulfide crosslinks at the hinge region); and (iii) Fv fragments consisting of the VL and VH domains of a single arm of the antibody. Furthermore, although the VL and VH domains of the two domains of the Fv fragment are encoded by separate genes, they can be joined using recombination by a synthetic linker that allows the VL and VH regions to pair up and be constructed as a single protein chain forming a monovalent molecule (known as single-stranded 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.

[0679] In addition, antibodies in which the C-terminal lysine (K) amino acid residue is lost in the heavy chain polypeptide are further included (for example, the human IgG1 heavy chain contains terminal lysine). As is well known in the art, the C-terminal lysine may be cleaved during antibody production, resulting in antibodies with heavy chains lacking C-terminal lysine. Alternatively, the antibody heavy chain may be produced using nucleic acids that do not contain C-terminal lysine.

[0680] The “variable region” of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. As is known in the art, the variable regions of the heavy and light chains are also known as hypervariable regions and each consists of four framework regions (FRs) connected by three complementarity-determining regions (CDRs) that contribute to the formation of the antibody's antigen-binding site. When a variant of the target variable region is desired, particularly one having substitutions in amino acid residues outside the CDR region (i.e., within the framework regions), suitable amino acid substitutions, preferably conservative amino acid substitutions, can be identified by comparing the target variable region with the variable region of another antibody containing the same standard class of CDR1 and CDR2 sequences as the target variable region (Chothia and Lesk, J Mol Biol 196(4):901~917, 1987).

[0681] In certain embodiments, the final depiction of the CDR and the identification of residues containing the antibody binding site are achieved by elucidating the structure of the antibody or the antibody-ligand complex. In certain embodiments, this can be achieved by any of the various techniques known to those skilled in the art, such as X-ray crystallography. In certain embodiments, the CDR region can be identified or estimated using various analytical methods. Examples of such methods, but not limited to, include the Kabat definition, Chothia definition, AbM definition, contact definition, conformation definition, and the Pfabat numbering method shown in Example 1.

[0682] The Kabat definition is a standard for numbering residues in antibodies and is often used to identify CDR regions. See, for example, Johnson and Wu, 2000, Nucleic Acids Res., 28:214-8. The Chothia definition is similar to the Kabat definition, but takes into account the location of certain structural loop regions. See, for example, Chothia et al., 1986, J.Mol.Biol., 196:901-17, and Chothia et al., 1989, Nature, 342:877-83. The AbM definition uses an integrated software package of computer programs created by the Oxford Molecular Group to model antibody structures. For example, see 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 models the tertiary structure of an antibody from its primary sequence using a combination of knowledge databases and first methods, e.g., Samudrala et al., 1999, "Ab Initio Protein Structure Prediction Using a Combined Hierarchical Approach," PROTEINS, Structure, Function and Genetics Supplement, 3:194-198. The contact definition is based on the analysis of the crystal structure of the available complexes. For example, see MacCallum et al., 1996, J.Mol.Biol., 5:732-745. In another method referred to herein as the “conformational definition” of CDRs, the location of a CDR can be identified as a residue that contributes enthalpy to antigen binding. See, for example, Makabe et al., 2008, Journal of Biological Chemistry, 283:1156-1166.Furthermore, other CDR boundary definitions may not strictly adhere to one of the above methods, but nevertheless overlap with at least a portion of the Kabat CDR, while they may be shortened or extended to take into account 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.

[0683] As used herein, CDR may refer to a CDR defined by any method known in the art, including combinations of methods. Methods used herein may utilize a CDR defined according to any of these methods. For any given embodiment containing two or more CDRs, a CDR may be defined according to one or more of the following methods: Kabat, Chothia, Extended, AbM, Contact, Conformation Definition, or Pfabat. 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.

[0684] When used herein, the term “hinge region” 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 edition, 1999), Bloom et al., Protein Science, 6:407-415, 1997, and Humphreys et al., J.Immunol.Methods, 209:193-202, 1997.

[0685] The "constant region" of an antibody refers to the constant region of either the antibody light chain or the antibody heavy chain, either alone or in combination. The IgG heavy chain constant region contains three consecutive 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).

[0686] The “Fc domain” refers to the portion of an immunoglobulin (Ig) molecule that correlates with a crystallizable fragment obtained by papain digestion of the Ig molecule. As used herein, this term refers to the constant regions of two chains of an antibody, each chain excluding 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”). The “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 the IgA, IgD, and IgG heavy chains, as well as the last three constant region immunoglobulin domains of the IgE and IgM heavy chains, and optionally, the N-terminal flexible hinge to these domains.

[0687] While the boundaries of the Fc chain can vary, the human IgG heavy chain Fc chain is typically defined as containing residues C226 or P230 to its carboxyl terminus, where the numbering follows the EU index in Edelman et al., Proc. Natl. Acad. Sci. USA 1969; 63(1): 78-85, as described in Kabat et al., 1991. Typically, the Fc chain contains approximately 236-447 amino acid residues from the constant region of the human IgG1 heavy chain. The term "Fc chain" can refer to this polypeptide in isolation or in the context of a large molecule (e.g., an antibody heavy chain or Fc fusion protein).

[0688] A “functional” Fc domain refers to an Fc domain that possesses at least one effector function of the 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 the combination of an Fc domain with a binding domain (e.g., an antibody variable region) and can be assessed using various assays known in the art for evaluating such antibody effector functions.

[0689] A “native sequence” Fc chain or “wild-type Fc chain” refers to an Fc chain containing the same amino acid sequence as an Fc chain found in nature. A “variant” Fc chain contains an amino acid sequence different from that of the native sequence Fc chain by at least one amino acid modification, while still retaining 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 compared to the wild-type Fc chain, for example, about 1 to about 10 amino acid substitutions, preferably about 1 to about 5 amino acid substitutions, in the wild-type Fc chain. Variant Fc chains as used herein preferably have at least about 80% sequence identity with the wild-type Fc chain, most preferably at least about 90% sequence identity, and more preferably at least about 95%, at least about 96%, at least about 97%, at least about 98%, and at least about 99% sequence identity. In some embodiments, the Fc chain includes part or all of the wild-type hinge region (generally at its N-terminus). In some embodiments, the Fc polypeptide does not contain a functional or wild-type hinge region.

[0690] nomenclature The antibody domains disclosed herein may be prefixed with an indicator of the individual target antigen to which the domain most closely associates. The prefix is ​​added solely to provide clarity of abbreviation when identifying different domains listed throughout this disclosure and does not replace or contradict the actual function or structure of the different domains. For example, IL4-VH refers to the variable weight domain of an antibody containing a CDR that can specifically bind to IL-4. IL4-CH1 refers to the CH1 domain located at the C-terminus of the IL-4 variable domain, regardless of whether its variable domain is a variable light domain (IL4-VL) or a variable weight domain (IL4-VH). As described throughout this disclosure, the domains of the antibodies disclosed herein may be combined with or fused with domains derived from other antibodies. Therefore, for example, IL4-VH may be present on a polypeptide chain having IL13-VL, and they may be present independently or together in the same antibody, and both polypeptides may be referred to as IL4-VH and IL13-VL (see, for example, Figure 18). Again, for example, a polypeptide having IL4-VH is any polypeptide having an IL4-VH domain, i.e., a VH domain containing a CDR that specifically binds to IL-4. A polypeptide having IL4-VH may contain a hinge region, a CH1 domain, a CH2 domain, and a CH3 domain, as in the standard IgG format, or it may contain various domains described herein, such as IL13-VL, together with the CH1 and CL domains fused to either IL4-VH or IL13-VL (see Figure 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 Figure 18I) contain IL13-VL, CL, a linker, IL4-VH, CH1, CH2, and CH3 from the N-terminus to the C-terminus, respectively, and can be described as polypeptides having IL4-VH and polypeptides having IL13-VL.Furthermore, 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 this disclosure may be referred to as the IL4-VL framework or the IL4-VH framework. Those skilled in the art will understand that these designations do not confer any relationship between the framework region and the targets to which the CDRs specifically bind, nor do they imply any such relationship. 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, but applies to all possible antibodies and antibody combinations within this disclosure.

[0691] Antibodies IL13433-1258, IL134TSLP-1024, and IL134p40-0705 may be described as comprising the first, second, third, fourth, and fifth polypeptide chains, respectively, where the second polypeptide is (VL-1)-(CL-1)-(linker)-(VH-2)-(CH1-2)-(second hinge)-(second CH2)-( The fifth polypeptide contains (VH1)-(CL-1) from the N-terminus to the C-terminus, the fourth polypeptide contains (VL-2)-(CL-2), the first polypeptide contains (VH-3)-(CH1-3)-(first hinge)-(first CH2)-(first CH3) from the N-terminus to the C-terminus, and the third polypeptide contains (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.

[0692] 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 produced against a single antigenic site. Furthermore, in contrast to polyclonal antibody preparations, which typically contain different antibodies produced against different determinants (epitopes), each monoclonal antibody is produced against a single determinant on an antigen. The modifier “monoclonal” characterizes the antibody as being obtained from a substantially homogeneous population of antibodies, but should not be interpreted as requiring antibody production by any particular method. For example, monoclonal antibodies used in this invention may be produced 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 a phage library, such as one prepared using the technique described by McCafferty et al., 1990, Nature 348:552-554.

[0693] "Human antibodies" refer to antibodies that have an amino acid sequence corresponding to that of antibodies produced by humans, or antibodies produced using any technique for creating fully human antibodies. For example, fully human antibodies can be obtained by using commercially available mice engineered to express specific human immunoglobulin proteins, or by library (e.g., phage, yeast, or ribosome) display techniques for preparing fully human antibodies. This definition of human antibodies specifically excludes humanized antibodies that contain non-human antigen-binding residues.

[0694] A "chimeric antibody" refers to an antibody in which the variable region sequence originates from one species and the constant region sequence originates from another species. For example, an antibody in which the variable region sequence originates from a mouse antibody and the constant region sequence originates from a human antibody.

[0695] A "humanized" antibody refers to a non-human (e.g., mouse) antibody that is a chimeric antibody containing a minimal sequence derived from a non-human immunoglobulin. Preferably, the humanized antibody is a human immunoglobulin (recipient antibody) in which residues derived from the recipient's CDR are replaced by residues derived from a non-human species (donor antibody), e.g., mouse, rat, or rabbit CDR, which have the desired specificity, affinity, and capabilities. The humanized antibody may also contain residues that are not found in the recipient antibody or in the incorporated CDR or framework sequence, but are included to further improve and optimize the performance of the antibody.

[0696] "Antigen" refers to a molecular entity used for immunization of immunocompetent vertebrates to produce antibodies that recognize the antigen, or to screen expression libraries (e.g., phages, yeast, or ribosome display libraries, among others) for antibody selection. In this specification, antigen is more broadly intended to include target molecules specifically recognized by antibodies, and therefore fragments or mimics of molecules used in the immunization process to generate antibodies or in library screening for antibody selection.

[0697] An "epitope" refers to an area or region of an antigen to which an antibody specifically binds, determined by any method known in the art, such as an area or region containing residues that interact with the antibody. There are many methods known in the art for mapping and characterizing the location of epitopes on proteins, including elucidation of the crystalline structure of antibody-antigen complexes, competitive assays, gene fragment expression assays, epitope mapping, and assays based on synthetic peptides, 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. In addition to or alternatively, during the discovery process, antibody production and characterization may elucidate information about a desired epitope. From this information, it is then possible to competitively screen antibodies for binding to the same epitope.

[0698] As used herein, the term “binding affinity” refers to the sum 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 herein, “binding affinity” refers to the endogenous binding affinity, which reflects the 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 expressed by the dissociation constant (K). DThe affinity of molecule X to its partner Y can generally be expressed by the dissociation constant (Kd). Affinity can be measured by general methods known in the art, including those described herein. Low-affinity antibodies generally tend to bind slowly to antigens and dissociate easily, while high-affinity antibodies generally tend to bind more quickly to antigens and remain bound for longer. Various methods for measuring binding affinity are known in the art, and any of these can be used for the purposes of this invention. In particular, the term “binding affinity” is intended to refer to the dissociation rate of a particular antigen-antibody interaction. K D is, "off rate (k off The rate of dissociation, also called the association rate or "on rate (k)," is the rate of dissociation. on It is the ratio to )". Therefore, K D is, k off / k on It is equal to and expressed as molar concentration (M). K D As the value decreases, the affinity of the bond becomes stronger. Therefore, 1 μM K D This is 1nM K D Compared to that, it shows weaker binding affinity. Antibody K D The value can be determined using methods well established in the art. Antibody K D One method for determining this is by using surface plasmon resonance (SPR), typically by using a biosensor system such as the BIACORE system. BIACORE kinetic analysis involves analyzing the binding and dissociation of antigens from chips having immobilized molecules (e.g., molecules containing epitope-binding domains) on their surface. D And to determine the other ratios, the k of the association and dissociation rate constants, respectively. on and k offThe determination may be performed, for example, using a surface plasmon resonance-based biosensor to characterize the analyte / ligand interaction under conditions where the analyte is monovalent with respect to the binding of a ligand immobilized at low volumes on the sensor surface via a capture reagent. The analysis may be performed using, for example, the kinetic titration methodology described in Karlsson et al., Anal. Biochem 349, 136-147, 2006, or using multi-cycle kinetic analysis. The sensor tip, capture reagent, and assay buffer used for a given assay are selected to provide stable capture of the ligand on the sensor surface, minimize nonspecific binding of the analyte to the surface, and provide an analyte binding response suitable for kinetic analysis, in accordance with the recommendations of Myszka, J. Mol. Recognit 12, 279-284, 1999. The analyte binding response for each analyte / ligand interaction is double-referenced, as described in Myszka and Morton et al., Biophys. Chem 64, 127-137 (1997), and k is used as an inclusive parameter. a , k d and R max It is fitted to a 1:1 Langmuir "mass transport-only model" using the equilibrium dissociation constant K. D K is the ratio of the dynamic rate constants. D =k off / k on It is estimated from. Such a determination is preferably made at 25°C or 37°C. Typically, the rate constant (k on or k a and k off or k d The K of the antibody is measured using the whole antibody and monomers. D Another method for determining this is by using biolayer interference spectroscopy, typically employing the OCTET® technology (Octet QK). e This is done by using the ForteBio system. Alternatively, or in addition to that, the KinExA (binding equilibrium exclusion) assay available from Sapidyne Instruments (Boise, ID) can also be used.

[0699] As used herein, the terms “immunely binding,” “immunely recognizing,” “specifically binding,” “specifically recognizing,” and similar terms refer to a molecule, e.g., a binding domain, that specifically binds to an antigen (e.g., an epitope or immune complex) but does not specifically bind to another molecule. A molecule that specifically binds to an antigen may bind to other peptides or polypeptides with lower affinity, as determined by assays known in the art, e.g., immunoassays, BIACORE®, or other assays. Preferably, a molecule that specifically binds to an antigen does not cross-react with other proteins.

[0700] The terms "specific binding" or "specifically binding," when used in reference to interactions between antibodies and proteins or peptides, refer to interactions that depend on the presence of a specific structure on the protein (i.e., an antigenic determinant or epitope). In other words, antibodies recognize and bind to specific protein structures, rather than proteins in general. For example, if an antibody is specific to epitope "A," the presence of a protein containing epitope A (or free, unlabeled A) in a reaction involving labeled "A" and the antibody will reduce the amount of labeled A bound to the antibody.

[0701] In a particular embodiment, "specifically binding" means, for example, that the antibody has a K content of about 0.1 nM or less, and more generally, less than 1 μM. D This means that it binds to the protein. In a particular embodiment, "specifically binds" means that the antibody binds to the protein at a concentration of K, sometimes at least about 0.1 μM or less, sometimes at least about 0.01 μM or less, and sometimes at least about 1 nM or less. DThis means 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 specific region of the polypeptide sequence 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 site 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 may include) exclusive binding, i.e., binding to a single target. Therefore, 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 a particular example, 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 contain at least two antigen-binding sites having different specificities. As a non-limiting example, a bispecific antibody may contain one antigen-binding site that recognizes an epitope on one protein, and further contain a second distinct antigen-binding site that recognizes a different epitope on a second protein. Generally, though not necessarily, references to binding imply specific binding.

[0702] Antibodies that specifically bind to an antigen may bind to other peptides or polypeptides with lower affinity, as determined by assays known in the art, such as immunoassays, BIACORE®, or other assays. Preferably, antibodies that specifically bind to an antigen do not cross-react with other proteins.

[0703] The terms "non-specific binding" or "background binding," when used in reference to interactions between antibodies and proteins or peptides, refer to interactions that do not depend on the presence of a specific structure (i.e., antibodies generally bind to proteins rather than specific structures such as epitopes).

[0704] 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 results in either or both of the following: (i) interfering with, limiting, or inhibiting the interaction between IL-4, IL-13, IL-33, TSLP, and p40 and a suitable ligand, respectively, or (ii) where appropriate, inhibiting the biological function of at least one of the IL-4, IL-13, IL-33, TSLP, or p40 binding. Assays for determining neutralization by the antibodies of this disclosure are well known in the art.

[0705] As used herein, "antibody that binds to a target," "antibody that recognizes a target," "antibody that specifically binds to a target," "antitarget antibody," "antitarget antibody molecule," and "target antibody" include molecules that contain at least one binding domain that specifically binds to a target.

[0706] A "monospecific antibody" refers to an antibody that contains one or more antigen-binding sites on each molecule, such that all antibody binding sites specifically recognize the same epitope on an antigen. Therefore, in examples where a monospecific antibody has two or more antigen-binding sites, the binding sites compete with each other for binding to a single antigen molecule.

[0707] A "bispecific antibody" refers to a molecule that has binding specificity to at least two different epitopes. In some embodiments, a bispecific antibody can bind to two different antigens simultaneously. In other embodiments, the two different epitopes may be present on the same antigen.

[0708] As used herein, a "triply specific antibody" is an antibody that has binding specificity to three different epitopes. In some embodiments, a triply specific antibody can bind to three different antigens simultaneously. In other embodiments, the three different epitopes may be present on the same antigen.

[0709] As used herein, “multispecific antibody” is an antibody having binding specificity to at least two different epitopes. In some embodiments, a multispecific antibody can bind to at least two different antigens simultaneously. In other embodiments, at least two different epitopes may be present on the same antigen.

[0710] 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.

[0711] "Half-maximum effective concentration (EC)" 50 The term "maximum" refers to the concentration of the therapeutic agent that elicits half of the response between baseline and maximum after a specified exposure time. The therapeutic agent may cause inhibition or stimulation. EC 50 The value is commonly used as a measure of potency and is used herein.

[0712] "Inhibition concentrations (IC)" 50The term "(1)" refers to the concentration of the inhibitor at which 50% of its activity inhibition is achieved. The therapeutic agent may cause inhibition or stimulation. IC 50 The value is commonly used as a measure of potency and is used herein.

[0713] 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 encompasses substances (such as antibodies) that bind to a molecule and promote its activity.

[0714] 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 encompasses substances (such as antibodies) that bind to a molecule and prevent or reduce its activity.

[0715] When used herein in relation to antibodies, the term “competing” means that the first antibody binds to an epitope in a manner sufficiently similar to that of the second antibody, such that the result of the second antibody’s binding to its congener’s epitope is detectably reduced in the presence of the first antibody compared to the binding of the second antibody in the absence of the first antibody. While there may be an option, but it is not required, for the first antibody’s binding to its epitope to also be detectably reduced in the presence of the second antibody, this is not necessary. That is, the first antibody can inhibit the second antibody’s binding to its individual epitope without the second antibody inhibiting the first antibody’s binding to that individual epitope. However, if each antibody detectably inhibits the binding of the other antibody to its congener’s epitope or ligand, the antibodies are said to “cross-compete” with respect to the binding of their individual epitopes, whether to the same, higher, or lower degree. Both competing 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 changes, or binding to a common epitope or portion thereof), those skilled in the art will recognize, based on the teachings provided herein, that such competing or cross-competing antibodies may be included in and useful in the methods disclosed herein.

[0716] "Host cell" refers to an individual cell or cell culture that may or may have been a recipient of a vector for the incorporation of a polynucleotide insert. The host cell includes offspring of a single host cell, which may not necessarily be completely identical to the original parent cell (morphologically or in terms of genomic DNA complementation) due to natural, accidental, or intentional mutations. The host cell includes cells transfected with the polynucleotide of the present invention in vivo.

[0717] A “vector” refers to a construct capable of delivering, and preferably expressing, one or more genes or sequences of interest (e.g., antibody-coding genes) in a host cell. Examples of vectors, but not limited to, include plasmids and viral vectors, naked nucleic acids, or nucleic acids associated with delivery support materials (e.g., cationic condensers, liposomes, etc.). Vectors may include DNA or RNA. “Expression vector,” as used herein, refers to a vector comprising at least one polypeptide-coding sequence, at least one regulatory element (e.g., promoter sequence, poly(A) sequence) related to gene transcription or translation. Typically, vectors as used herein contain at least one antibody-coding gene and one or more regulatory elements or selection markers. Examples of vector components include: signal sequences, origins of replication, one or more marker genes, and one or more suitable transcriptional regulatory elements (e.g., promoters, enhancers, and terminators). For translation, one or more translation control elements may include, for example, a ribosome binding site, a translation initiation site, and a stop codon.

[0718] An “isolated” molecule (e.g., an isolated antibody) refers to a molecule that, by its origin or source of derivatization, (1) does not associate with the naturally associated components it has in its native state, (2) substantially does not contain other molecules from the same origin, e.g., species, cell in which it is expressed, library, etc., (3) is expressed by cells of a different species, or (4) does not exist in nature. Thus, a chemically synthesized molecule, or a molecule expressed in a cell system different from the system of its naturally occurring origin, is “isolated” from its naturally associated components. A molecule may also be made substantially free of its naturally associated components by isolation using purification techniques well known in the art.

[0719] As used herein, the term "linker" refers to an amino acid sequence that is two or more amino acids in length. The linker can be composed of neutral polar or non - polar 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 by enzymatic or chemical cleavage. Cleavage sites in the amino acid sequence, as well as the 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 repeating units of a sequence containing glycine and serine residues. In some embodiments, the linker comprises one or more repeating units of G4S. In some embodiments, the linker comprises (G4S) 1~3 including. In some embodiments, the linker is GGGGS (SEQ ID NO: 10).

[0720] 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 the 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 create stabilizing disulfide bonds intramolecularly.

[0721] 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.

[0722] As used herein, the term “covalently linked” means that the defined parts are directly covalently linked to one another, or are indirectly covalently linked to one another via one or more intervening parts, such as linking peptides or parts.

[0723] As used herein, the term “connected” refers to the identical linear covalent linkage or attachment of two or more proteins, polypeptides, or fragments thereof via their individual peptide backbones. For example, one polypeptide may be connected to another polypeptide by the genetic expression of a single polynucleotide molecule encoding these two polypeptides in frame. Such a gene fusion results in the expression of a single continuous protein containing both polypeptides.

[0724] As used herein, the term “modification” refers to the substitution, insertion, or deletion of amino acids in a polypeptide sequence, a change to a portion chemically linked to a protein, or a modification of the function of a protein, such as an antibody. For example, a 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 the mutation (substitution), insertion (addition), or deletion of one or more amino acid residues in an antibody. The term “amino acid mutation” refers to the 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” refers to the removal of at least one amino acid residue at a given position in an amino acid sequence. For example, mutation L234A indicates that the amino acid residue lysine at position 234 in the antibody Fc region is substituted with the amino acid residue alanine (lysine replaced with alanine) (numbering follows the EU index numbering system).

[0725] The term "pharmaceutical" is used herein to refer to biomolecules, extracts made from biomaterials, mixtures of biomolecules, chemical substances, mixtures of chemical substances, or mixtures of chemical substances and biomolecules. The term "therapeutic agent" refers to a pharmaceutical agent having biological activity.

[0726] A "polypeptide" or "protein" (as used interchangeably herein) refers to a chain of amino acids of any length. The chain may be linear or branched. The chain may contain one or more modified amino acids. The term also includes amino acid chains that are naturally occurring or modified by intervention, e.g., disulfide bond formation, glycosylation, lipidization, acetylation, phosphorylation, or any other operation or modification, e.g., conjugation with a labeling component. For example, polypeptides containing one or more amino acid analogs (e.g., non-natural amino acids) and other modifications known in the art are also included in this definition. It is understood that polypeptides may exist as single chains or as associated chains.

[0727] As used herein, “first polypeptide” is any polypeptide that associates with the 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) containing CH2, CH1, and CL domains. Typically, the first polypeptide includes at least one domain derived from the antibody. This domain is conveniently a constant domain, such as the CH3 domain of the antibody, and can form the interface of the first polypeptide. Exemplary first polypeptides include antibody heavy chain polypeptides, chimeras in which an antibody constant domain is combined with a binding domain of a heterologous polypeptide, receptor polypeptides, ligand polypeptides, and antibody variable domain polypeptides (e.g., bispecific antibodies).

[0728] In addition to the interface, the second polypeptide may include additional domains such as a "binding domain" (e.g., an antibody-variable domain, receptor-binding domain, ligand-binding domain, or enzyme domain), or an antibody-constant domain (or a portion thereof) containing CH2, CH1, and CL domains. Typically, the second polypeptide contains at least one domain derived from the antibody. This domain is conveniently a constant region of the antibody, such as the CH3 domain, 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).

[0729] "Polynucleotide" or "nucleic acid" (as used interchangeably herein) refers to a chain of nucleotides of any length, including DNA and RNA. Nucleotides may be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases or their analogues, or any substance that can be incorporated into the chain by DNA or RNA polymerase. Polynucleotides may include modified nucleotides, e.g., methylated nucleotides and their analogues. Modifications to the nucleotide structure, where present, may be conjugated before or after the chain assembly. The nucleotide sequence may be interrupted by non-nucleotide components. Polynucleotides may be further modified after polymerization, for example, by conjugation with labeled components. Other types of modifications include, for example, "caps," substitution with one or more naturally occurring analogues of nucleotides, internucleotide modifications, such as those having uncharged bonds (e.g., methylphosphonates, phosphotriesters, phosphoamidates, carbamates, etc.) and charged bonds (e.g., phosphorothioates, phosphorodithioates, etc.), pendant portions, such as those containing proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), those having intercalators (e.g., acridine, psoralens, 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.), and the unmodified form of the polynucleotide. Furthermore, any of the hydroxyl groups normally present in the sugar may be replaced by, for example, a phosphonate group or a phosphate group, protected by a standard protecting group, activated to prepare additional linkages to additional nucleotides, or conjugated to a solid support. The 5' and 3' terminal OH groups can be phosphorylated or substituted with amines or organic capping groups of 1 to 20 carbon atoms. Other hydroxyls may also be derivatized to standard protecting groups.Polynucleotides may also contain analog forms of ribose or deoxyribose sugars commonly known in the art, such as 2'-O-methyl-, 2'-O-allyl, 2'-fluoro- or 2'-azid-ribose, carbocyclic sugar analogs, alpha or beta-anomeric sugars, epimeric sugars, such as arabinose, xylose or lyxose, pyranose sugars, furanose sugars, sedoheptulose, acyclic analogs, and debasic nucleoside analogs such as methylriboside.

[0730] Where used herein, nucleic acids are written from left to right in the 5' to 3' direction, and amino acid sequences are written from left to right in the amino to carboxyl direction. Practitioners should refer in particular to Sambrook et al., 1989, and Ausubel FM et al., 1993, for definitions and terminology in the art. It should be understood that the present invention is not limited to the specific methodologies, protocols, and reagents described, as these may vary.

[0731] Polynucleotides complementary to any such sequence are also included in the present invention. Polynucleotides may be single-stranded (coding or antisense) or double-stranded, and may be DNA (genomic, cDNA, or synthetic) or RNA molecules. RNA molecules include mature and immature mRNA, e.g., precursor mRNA (pre-mRNA) or heteronuclear mRNA (hnRNA) and mature mRNA. Additional coding or non-coding sequences may be present in the polynucleotides of the present invention, although they are not required, and polynucleotides may be ligated to other molecules or supporting materials, although they are not required.

[0732] Those skilled in the art will recognize that, as a result of the degeneracy of the genetic code, there are many nucleotide sequences that encode the amino acid sequences provided herein. Polynucleotides that vary due to differences in codon usage frequency are specifically intended by the present invention.

[0733] A "conservative substitution" refers to the replacement of one amino acid with a biologically, chemically, or structurally similar residue. Biological similarity means that the substitution does not disrupt biological activity. Structural similarity means that the amino acids have side chains of similar length or size, such as alanine, glycine, and serine. Chemical similarity means that the residues have the same charge or are both hydrophilic and hydrophobic. Specific examples include...

Claims

1. A pharmaceutical composition comprising an isolated antibody that specifically binds to IL-4, The aforementioned antibody (i) the IL4-VH sequence of sequence number 22 and the IL4-VL sequence of sequence number 26, (ii) The IL4-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 200, and the IL4-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 201, (iii) A polypeptide sequence having IL4-VH encoded by the nucleic acid sequence of SEQ ID NO: 188, and a polypeptide sequence having IL4-VL encoded by the nucleic acid sequence of SEQ ID NO: 189, (iv) The IL4-VH sequence, which is deposited with ATCC and encoded by a plasmid having ATCC accession number PTA-127198, and the IL4-VL sequence, which is deposited with ATCC and encoded by a plasmid having ATCC accession number PTA-127197, or (v) A polypeptide sequence having IL4-VH, which is deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127192, and a polypeptide sequence having IL4-VL, which is deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127194. It shares at least 90% amino acid sequence identity, The aforementioned antibody is measured in a human monocyte assay for IL-4 induction neutralization of CD23 with an IC50 of less than 25 pM. ５０ It has, The antibody, in a buffer of 20 mM histidine, 8.5% sucrose, and 0.05 mg / mL EDTA pH 6.0, is at a concentration of at least 100 mg / mL and has a viscosity of less than 20 cP. The antibody comprises CDR-H1 containing the amino acid sequence of SEQ ID NO: 18, CDR-H2 containing the amino acid sequence of SEQ ID NO: 2, CDR-H3 containing the amino acid sequence of SEQ ID NO: 3, CDR-L1 containing the amino acid sequence of SEQ ID NO: 24, CDR-L2 containing the amino acid sequence of SEQ ID NO: 12, and CDR-L3 containing the amino acid sequence of SEQ ID NO:

25. Pharmaceutical composition.

2. below: (i) The antibody has a K value less than a value selected from the group consisting of approximately 10 pM, 5 pM, 1 pM, and 800 fM. Ｄ And it binds to human IL-4, (ii) The antibody binds to cynomolgus monkey IL-4. (iii) The antibody does not bind to IL-4 derived from one or more species selected from the group consisting of dogs, sheep, rabbits, rats, and mice. (iv) Antibody binding to IL-4 in cynomolgus monkeys K Ｄ However, the binding of antibodies to human IL-4 K Ｄ The difference must be within one digit. (v) Antibody with an IC of less than 10 pM in a human monocyte assay for IL-4 induction of CD23 ５０ To be characterized by, (vi) The antibody, at a concentration of 80 mg / mL in histidine-sucrose buffer at pH 5.8, has a viscosity of 20 cP or less at 25°C. (vii) The antibody contains lysine at residue 93 in its light chain. The pharmaceutical composition according to claim 1, characterized by one or more of the following.

3. The pharmaceutical composition according to claim 1, further comprising an isolated antibody that specifically binds to IL-4 and an antibody that specifically binds to IL-13.

4. The pharmaceutical composition according to claim 3, wherein the antibody 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.

5. below: (i) IL13-VH sequence of sequence number 51 and IL13-VL sequence of sequence number 54 (ii) The IL13-VH sequence of sequence number 44, and the IL13-VL sequence of sequence number 46, (iii) IL13-VH sequence of sequence number 48, and IL13-VL sequence of sequence number 49, (iv) IL13-VH sequence of sequence number 48, and IL13-VL sequence of sequence number 58, (v) The IL13-VH sequence of sequence number 57 and the IL13-VL sequence of sequence number 59, (vi) The IL13-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 198, and the IL13-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 199, (vii) A polypeptide sequence having IL13-VH encoded by the nucleic acid sequence of SEQ ID NO: 187, and a polypeptide sequence having IL13-VL encoded by the nucleic acid sequence of SEQ ID NO: 188, (viiii) An IL13-VH sequence deposited with ATCC and encoded by a plasmid having ATCC accession number PTA-127196, and an IL13-VL sequence deposited with ATCC and encoded by a plasmid having ATCC accession number PTA-127195, or (ix) A polypeptide sequence having IL13-VH, deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127193, and a polypeptide sequence having IL13-VL, deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127192. The pharmaceutical composition according to claim 3, comprising one or more of the above.

6. below: (i) The antibody has a K level less than a value selected from the group consisting of 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 It binds to human IL-13. (ii) The antibody binds to human IL-13 K Ｄ Within a difference of one order of magnitude, it will optionally bind to cynomolgus macaque IL-13. (iii) IL-13 IC ５０ However, IL-13 in HT-29 cells The concentration was measured by neutralization of pSTAT6 phosphorylation and was less than 100 pM. (iv) IC of IL-13 ５０ which is less than 20 pM when measured in a human monocyte assay for neutralization of IL-13 induction of CD23, (v) The antibody has a terminal phase half-life of at least 14 days in cynomolgus monkeys. (vi) The antibody has a terminal phase half-life of at least 18 days in TG32 mice. (vii) The antibody does not bind to IL-13 derived from one or more species selected from the group consisting of dogs, rabbits, and mice. The pharmaceutical composition according to claim 5, characterized by one or more of the above.

7. (i) The second and fifth polypeptide chains together form a first Fab domain containing the 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. It includes, for example, first, second, third, fourth, and fifth polypeptide chains, The first and second polypeptide chains associate together to form an antibody comprising two arms: a double Fab arm containing the first Fab domain and the second Fab domain, and a single Fab arm containing the third Fab domain. The antibody according to claim 3, (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, (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, (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, (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, (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. A pharmaceutical composition comprising the antibody described in claim 3.

8. The antibody according to claim 3, further comprising an antibody that specifically binds to at least one additional target, comprising first, second, third, fourth, and fifth polypeptide chains, wherein the identity of the second, fourth, and fifth polypeptide chains is (i) The second polypeptide chain includes SEQ ID NO: 130, the fourth polypeptide chain includes SEQ ID NO: 27, and the fifth polypeptide chain includes SEQ ID NO:

122. (ii) The second polypeptide chain includes SEQ ID NO: 133, the fourth polypeptide chain includes SEQ ID NO: 27, and the fifth polypeptide chain includes SEQ ID NO:

122. (iii) 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. (iv) 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. (v) 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. (vi) 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. (vii) 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. (viiii) The second polypeptide chain includes SEQ ID NO: 160, the fourth polypeptide chain includes SEQ ID NO: 196, and the fifth polypeptide chain includes SEQ ID NO: 158, (ix) The second polypeptide chain contains SEQ ID NO: 125, the fourth polypeptide chain contains SEQ ID NO: 27, and the fifth polypeptide chain contains SEQ ID NO:

122. A pharmaceutical composition containing an antibody, selected from the group consisting of the following.

9. It comprises the 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 at least one additional target binding site, The second polypeptide chain contains, in the direction from the N-terminus to the C-terminus, an optional linker including SEQ ID NO: 54, SEQ ID NO: 16, SEQ ID NO: 104, SEQ ID NO: 22, SEQ ID NO: 6, a CH2 domain, and a CH3 domain, the fourth polypeptide chain contains SEQ ID NO: 27, and the fifth polypeptide chain contains SEQ ID NO:

122. The pharmaceutical composition according to claim 8.

10. The pharmaceutical composition according to claim 3, further comprising an antibody in which the antibody described in claim 3 specifically binds to TSLP.

11. below: (i) A heavy chain variable region (TSLP-VH) and a 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. (ii) 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: 211, comprising a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), (iii) Heavy chain variable region (TSLP-VH) and light chain variable region (TSLP-VL) where 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:

212. The pharmaceutical composition according to claim 10, comprising one or more of the above.

12. below: (i) the TSLP-VH sequence of sequence number 92 and the TSLP-VL sequence of sequence number 94, (ii) The TSLP-VH sequence of sequence number 92 and the TSLP-VL sequence of sequence number 93, (iii) The TSLP-VH sequence of sequence number 92 and the TSLP-VL sequence of sequence number 213, (iv) The TSLP-VH sequence of sequence number 92 and the TSLP-VL sequence of sequence number 214, (v) The TSLP-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 204, and the TSLP-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 205, (vi) The TSLP-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 204, and the TSLP-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 217, (vii) The TSLP-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 204, and the TSLP-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 218, (viiii) A polypeptide sequence having TSLP-VH encoded by the nucleic acid sequence of SEQ ID NO: 192, and a polypeptide sequence having TSLP-VL encoded by the nucleic acid sequence of SEQ ID NO: 193, (ix) A polypeptide sequence having TSLP-VH encoded by the nucleic acid sequence of SEQ ID NO: 192, and a polypeptide sequence having TSLP-VL encoded by the nucleic acid sequence of SEQ ID NO: 193, (x) A polypeptide sequence having TSLP-VH encoded by the nucleic acid sequence of SEQ ID NO: 192, and a polypeptide sequence having TSLP-VL encoded by the nucleic acid sequence of SEQ ID NO: 193, (xi) A TSLP-VH sequence deposited with ATCC and encoded by a plasmid having ATCC accession number PTA-127200, and a TSLP-VL sequence deposited with ATCC and encoded by a plasmid having ATCC accession number PTA-127199, (xi) A polypeptide sequence having TSLP-VH, which is deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127202, and a polypeptide sequence having TSLP-VL, which is deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127201. The pharmaceutical composition according to claim 10, comprising one or more of the above.

13. (i) IC < 10 pM in a TARC production bioassay in human peripheral blood monocytes ５０ , (ii) Melting point of 68°C, (iii) The pH 3.4 hold ΔHMMS% is less than 5, such that the pH 3.4 hold ΔHMMS% is defined as the difference between the percentage of high molecular weight species resulting from the degradation of the antibody at pH 3.4 at room temperature after 5 hours of incubation and the percentage of high molecular weight species resulting from the degradation of the antibody at pH 7.2 at room temperature after 5 hours of incubation. (iv) IC25 <10 pM as measured by TARC production bioassay in primary human PBMCs ５０ Anti-TSLP biological activity, (v) A score of less than 2% of high molecular weight species, as determined by analytical size exclusion chromatography (aSEC), (vi) A score of less than 12 in the affinity capture self-interacting nanoparticle spectroscopy (AC SINS) assay, (vii) IC25 pM <15 pM in human TSLP neutralization of TARC-producing bioassays in human primary PBMCs ５０ , and (viiii) IC <35 pM in cynomolgus monkey TSLP neutralization assay ５０ The pharmaceutical composition according to claim 12, characterized by one or more of the above.

14. (i) 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. (ii) 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, and (iii) The TSLP-binding domain comprises a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), where 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, or (iv) The TSLP-binding domain comprises a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), where 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, CDR-L3 comprises the amino acid sequence of SEQ ID NO: 211, or (v) The TSLP-binding domain comprises a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), where 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 pharmaceutical composition according to claim 10.

15. The first, second, third, fourth, and fifth polypeptide chains are included such that the second and fifth polypeptide chains together form a first Fab domain containing a first antigen-binding site, the second and fourth polypeptide chains together form a second Fab domain containing a second antigen-binding site, and the first and third polypeptide chains together form a third Fab domain containing a third antigen-binding site, and the identity of the first, second, third, fourth, and fifth polypeptide chains is, (i) The first polypeptide chain includes SEQ ID NO: 165, the second polypeptide chain includes SEQ ID NO: 130, the third polypeptide chain includes SEQ ID NO: 99, the fourth polypeptide chain includes SEQ ID NO: 27, and the fifth polypeptide chain includes SEQ ID NO:

122. (ii) The first polypeptide chain includes SEQ ID NO: 165, the second polypeptide chain includes SEQ ID NO: 130, the third polypeptide chain includes SEQ ID NO: 215, the fourth polypeptide chain includes SEQ ID NO: 27, and the fifth polypeptide chain includes SEQ ID NO:

122. (iii) The first polypeptide chain includes SEQ ID NO: 165, the second polypeptide chain includes SEQ ID NO: 130, the third polypeptide chain includes SEQ ID NO: 216, the fourth polypeptide chain includes SEQ ID NO: 27, and the fifth polypeptide chain includes SEQ ID NO:

122. (iv) The first polypeptide chain includes a sequence encoded by the nucleic acid described in SEQ ID NO: 192, the second polypeptide chain includes a sequence encoded by the nucleic acid described in SEQ ID NO: 188, the third polypeptide chain includes a sequence encoded by the nucleic acid described in SEQ ID NO: 193, the fourth polypeptide chain includes a sequence encoded by the nucleic acid described in SEQ ID NO: 189, and the fifth polypeptide chain includes a sequence encoded by the nucleic acid described in SEQ ID NO: 187, and (v) The first polypeptide chain includes a sequence encoded by the nucleic acid corresponding to ATCC deposit PTA-127202, the second polypeptide chain includes a sequence encoded by the nucleic acid corresponding to ATCC deposit PTA-127192, the third polypeptide chain includes a sequence encoded by the nucleic acid corresponding to ATCC deposit PTA-127201, the fourth polypeptide chain includes a sequence encoded by the nucleic acid corresponding to ATCC deposit PTA-127194, and the fifth polypeptide chain includes a sequence encoded by the nucleic acid corresponding to ATCC deposit PTA-127193. A pharmaceutical composition according to claim 10, selected from the group consisting of the following.

16. (i) The TSLP junction includes TSLP-VH of SEQ ID NO: 92 and TSLP-VL of SEQ ID NO: 94 (ii) The IL-4 binding portion includes IL4-VH of SEQ ID NO: 22 and IL4-VL of SEQ ID NO: 26, (iii) The IL-13 binding portion includes IL13-VH of SEQ ID NO: 51 and IL13-VL of SEQ ID NO: 54 The pharmaceutical composition according to claim 10.

17. It comprises the 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 includes SEQ ID NO: 165, the second polypeptide chain includes SEQ ID NO: 130, the third polypeptide chain includes SEQ ID NO: 99, the fourth polypeptide chain includes SEQ ID NO: 27, and the fifth polypeptide chain includes SEQ ID NO:

122. The pharmaceutical composition according to claim 10.

18. (i) In a buffer solution of 20 mM histidine, 8.5% sucrose, and 0.05 mg / mL EDTA at pH 6.0, at a concentration of at least 100 mg / mL, with a viscosity of less than 20 cP. (ii) In a buffer solution of 20 mM histidine, 8.5% sucrose, and 0.05 mg / mL EDTA at pH 6.0, at a concentration of at least 50 mg / mL, with a viscosity of less than 12 cP. (iii) In cynomolgus monkeys, the terminal phase half-life is at least 12 days. (iv) In TG-32 mice, the terminal phase half-life is at least 18 days. (v) To bind to human IL-4 with an affinity constant of less than 220 pM, as measured by SPR. (vi) To bind to human IL-13 with an affinity constant of less than 220 pM, as measured by SPR. (vii) Binding to human IL-4 with an affinity constant of less than 1 pM, as measured by KinExA in a fixed antigen assay in PBS. (viiii) Binding to cynomolgus monkey IL-13 with an affinity constant of less than 2 pM, as measured by KinExA in a fixed antigen assay in PBS. IC23 <12 pM, as measured in a human monocyte assay for IL-4 induction of (ix)CD23 in cynomolgus monkeys. ５０ , (x) IC <12 pM as measured in a human monocyte assay for IL-13 induction of CD23 in cynomolgus monkeys. ５０ , The pharmaceutical composition according to claim 5, characterized by one or more of the above.

19. Atopic dermatitis, asthma, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, nodular prurigo, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, fungal keratitis, non-alcoholic steatohepatitis (NASH), cancer, bladder cancer, breast cancer, clear cell kidney cancer, squamous cell carcinoma of the head / neck, squamous cell carcinoma of the lung, 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 lymphoma (HL), mantle cell lymphoma (MCL), multiple Myeloma (MM), myelocellular leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), or small lymphocytic lymphoma (SLL), heme 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 longitudinal myeloma A pharmaceutical composition according to any one of claims 1 to 18 for use in one or more treatments selected from the group consisting of septate large cell B-cell lymphoma, T-cell / histiocyte-rich large B-cell lymphoma, follicular lymphoma, Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), and small lymphocytic lymphoma (SLL).

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