Multispecific antibodies and uses thereof

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 specifically bind to one of IL-4, IL-13, IL-33, or TSLP. The present invention further relates to multispecific antibodies that specifically bind to IL-4 and IL-13, and at least one other target. The present invention relates to multispecific antibodies that specifically bind to one of IL-4, IL-13, and IL-33, TSLP, or p40. The present invention also relates to related molecules, such as nucleic acids encoding such antibodies or multispecific antibodies, compositions, and related methods, such as methods for producing and purifying such antibodies and multispecific antibodies, and their use in diagnostic and therapeutic methods. [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, for treating and preventing one or more symptoms associated with the respective diseases or conditions, including atopic dermatitis, asthma, cancer, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, and the like. and the use of an antibody of the present disclosure to treat one or more diseases or conditions selected from the group consisting of systemic sclerosis, diabetic kidney disease, Behcet's disease, gout, Alzheimer's disease, atherosclerosis, fungal keratitis, non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus (SLE), primary biliary cirrhosis, and hidradenitis suppurativa.

[0003] IL-4 and IL-13 are key drivers of immune activation, resulting in inflammation, edema, fibrosis, and pruritus in atopic disorders (48, 49). IL-4 and IL-13 interact with cells through a common receptor consisting of IL-4Rα and IL-13Rα1 (type II receptor), expressed on monocytes, fibroblasts, keratinocytes, epithelial cells, smooth muscle cells, and other nonlymphoid cell types (29). IL-4 can also activate cells through the IL-4Rα / IL-2Rγ common (type I receptor) expressed on T cells, B cells, and monocytes. Engagement of IL-4Rα through either receptor activates STAT6 and induces atopy-related genes (29). Although IL-4 and IL-13 may engage common receptors and signaling pathways, differences in cytokine availability, localization, and receptor binding affinity result in distinct response profiles (49, 50). Further differentiation can arise from the type I receptor (IL-4Rα / γc), which drives Th2 differentiation via IL-4 but not IL-13 ( 51 ), and the cell surface “decoy” IL-13Rα2, which mediates neutralization and depletion of IL-13 but not IL-4 ( 52 , 53 ).

[0004] The role of IL-4 and IL-13 in atopic disease is supported by genetic associations, extensive validation in preclinical models, and clinical efficacy of IL-4 and IL-13 neutralization in a range of atopic indications (48). The anti-IL-4Rα Dupixent® (dupilumab, Sanofi / Regeneron) blocks responses to both cytokines and has been approved for the treatment of moderate to severe atopic dermatitis (AD), asthma, and chronic rhinosinusitis with nasal polyps, demonstrating 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 key role for IL-13 neutralization in the efficacy of Dupixent®. Nevertheless, available meta-analyses (62, 63) suggest that Dupixent® has superior activity to lebrikizumab and tralokinumab, consistent with the additional benefit of IL-4 blockade.

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

[0006] Thymic stromal lymphopoietin (TSLP) is an epithelial cytokine important in the initiation and maintenance of inflammation. Tezspire® (tezepelumab, 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 T helper 1 (Th1) cell differentiation and interferon-γ (IFN-γ) production, while IL-23 promotes the maintenance of Th17 cells that produce IL-17 and other type 3 cytokines. Type 1 and type 3 responses are involved in a range of human inflammatory and autoimmune diseases. A causal role for IL-12p40-containing cytokines has been established by the approval of a number of drugs (75) (IL-12p40 will be referred to simply as p40 hereafter). The p40 neutralizer Stelara® (ustekinumab, Janssen) neutralizes both IL-12 and IL-23 and is approved for the treatment of plaque psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis. The IL-23 selective anti-IL-23p19 blockers Tremfya® (guselkumab, Janssen), Skyrizi® (risankizumab, Boehringer Ingelheim / AbbVie), and Ilumya® (tildrakizumab, Sun Pharmaceutical) are approved for a range of psoriatic disorders. Summary of the Invention [Problem to be solved by the invention]

[0008] Despite the efficacy of dupilumab, tezepelumab, guselkumab, risankizumab and tildrakizumab, there remains an unmet need for safe and effective therapies for the numerous diseases characterized by immune responses that address a broad range of pathogenic mechanisms. [Means for solving the problem]

[0009] overview Provided herein are antibodies (including antigen-binding fragments thereof) that specifically bind to one or more of IL-4, IL-13, IL-33, TSLP, and p40, as well as monomeric and multimeric antibodies thereof, related nucleic acids, uses, and related methods. The disclosure also provides methods for making, preparing, and producing antibodies that bind to one or more of IL-4, IL-13, IL-33, TSLP, and p40. The antibodies of the present disclosure may be used to treat a variety of conditions, including, but not limited to, atopic dermatitis, asthma, cancer, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, and systemic sclerosis, diabetic kidney disease, Behcet's disease, gout, Alzheimer's disease, atherosclerosis, fungal keratitis, non-alcoholic steatohepatitis (NASH). The antibodies are useful for one or more of the diagnosis, prevention, or treatment of disorders or conditions mediated by or associated with one or more of the activities of IL-4, IL-13, IL-33, TSLP, and p40, including 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 present disclosure further encompasses the expression of the antibodies, as well as compositions comprising the antibodies of the present disclosure, for example, the preparation and manufacture of pharmaceuticals for the use of the antibodies.

[0010] Polynucleotides encoding the antibodies that bind to one or more of IL-4, IL-13, IL-33, TSLP, and p40 are also provided. Polynucleotides encoding the heavy or light chains, or both, of the antibodies are also provided. Host cells expressing the antibodies are also provided. Methods of treatment using the antibodies are also provided. Such methods include, but are not limited to, the treatment of diseases associated with or mediated by one or more of IL-4, IL-13, IL-33, TSLP, and p40 expression, and / or one or more of IL-4, IL-13, IL-33, TSLP, and p40 binding, including atopic dermatitis, asthma, cancer, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, waterlogged skin, and the like. The present invention relates to a method for treating or preventing one or more of bullous pemphigoid, chronic urticaria, IPF, scleroderma, and systemic sclerosis, diabetic kidney disease, Behcet's disease, gout, Alzheimer's disease, atherosclerosis, fungal keratitis, non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus (SLE), primary biliary cirrhosis, and hidradenitis suppurativa.

[0011] The present invention may be more readily understood by reference to the following detailed description of the embodiments and examples of the present invention contained herein. It should be understood that the present invention is not limited to a specific method of making, which may of course be changed. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only, and is not intended to be limiting. Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, many equivalents to the specific embodiments of the present invention described herein. Such equivalents are intended to be encompassed by the following embodiment (E).

[0012] E1. An isolated antibody that specifically binds to IL-33, (i) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 73, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 78; (ii) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 63 and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 71, or (iii) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 80, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 81; An antibody comprising a heavy chain variable region (IL33-VH) and a light chain variable region (IL33-VL).

[0013] E2. An isolated antibody that specifically binds to IL-33, comprising a heavy chain variable region (IL33-VH) and a light chain variable region (IL33-VL) comprising the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO:73, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO:78.

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

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

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

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

[0019] E8. The antibody of any one of E1 to E7, comprising 98%, 99%, or 100% of the sequence of the IL33-VL and IL33-VH framework sequences, wherein one or both of the IL33-VL and IL33-VH framework sequences are at least 66%, 76%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% identical to the human germline sequence from which it is derived.

[0020] E9. The antibody of any one of 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 it is derived.

[0021] E10. The antibody of any one of E1 to E9, comprising an IL33-VH sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 73.

[0022] E11. The antibody of any one of E1 to E10, comprising an IL33-VL sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:78.

[0023] E12.(i) an IL33-VH sequence of SEQ ID NO: 73, and an IL33-VL sequence of SEQ ID NO: 78, or (ii) an IL33-VH sequence of SEQ ID NO: 63 and an IL33-VL sequence of SEQ ID NO: 71; or (iii) the IL33-VH sequence of SEQ ID NO: 80, and the IL33-VL sequence of SEQ ID NO: 81 The antibody of any one of E1 to E11, comprising:

[0024] E13. The antibody of any one of E1 to E12, comprising an IL33-VH sequence identical to SEQ ID NO: 73, and an IL33-VL sequence identical to SEQ ID NO: 78.

[0025] E14. The antibody of any one of E1 to E13, comprising an IL33-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 202.

[0026] E15. The antibody of any one of E1 to E14, comprising an IL33-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 203.

[0027] E16. The antibody of any one of E1 to E15, comprising an IL33-VH sequence encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127210.

[0028] E17. The antibody of any one of E1 to E16, comprising an IL33-VL sequence encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127209.

[0029] E18. An antibody comprising an IL33-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127210, and an IL33-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127209.

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

[0031] E20. K value of about 15 pM or less D The antibody described in E1 to E19, which binds to human IL-33 at

[0032] E21. K value of about 1 pM or less D The antibody described in E1 to E20, which binds to human IL-33 at

[0033] E22. K at or below a value of about 250 fM D The antibody described in E1 to E21, which binds to human IL-33 at

[0034] E23.K D The antibody of any one of E19 to E22, wherein the value is measured by equilibrium exclusion assay.

[0035] E24.K D The antibody of any one of E19 to E22, wherein the value is measured by surface plasmon resonance (SPR).

[0036] E25.IL-33 IC 50 is less than 20 pM in a HEK Blue® IL-33 neutralization SEAP assay.

[0037] E26.IL-33 IC 50 is less than 15 pM in the HEK Blue® IL-33 neutralization SEAP assay.

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

[0039] E28.IL-33 IC 50 is less than 15 pM, as calculated by ELISA measurement of IFNγ in a human whole blood assay treated with IL-33 and IL-12.

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

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

[0042] E31. Binding of antibodies to cynomolgus monkey IL-33 D The binding K of the antibody to human IL-33 D The antibody of any one of E1 to E30, wherein the antibody is within 3 orders of magnitude of

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

[0044] The antibody of 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] The antibody of E32 to E33, wherein IL33-CH1 comprises the sequence set forth in SEQ ID NO:6.

[0046] The antibody of E32 to E34, wherein IL33-CL comprises a sequence selected from the group consisting of SEQ ID NO: 16, SEQ ID NO: 108, and SEQ ID NO: 113.

[0047] The antibody of E32 to E35, wherein IL33-CL comprises the sequence set forth in SEQ ID NO: 16.

[0048] E37. The antibody of E32 to E36, wherein IL33-CH1 is connected to IL33-VL and IL33-CL is connected to IL33-VH to form a IL-33-binding domain-swapped Fab domain (IL33-xFab).

[0049] E38. The antibody of E32 to E37, wherein IL33-CH1 is connected to IL33-VH and IL33-CL is connected to IL33-VL to form an IL-33 binding Fab domain (IL33-Fab).

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

[0051] E40. The Fc domain is an IgA (e.g., IgA 1 or IgA 2 ), IgD, IgE, IgM, or IgG (e.g., IgG 1 , IgG 2 , IgG 3 , or IgG 4 The antibody described in E39, which is an Fc domain of

[0052] The E41.Fc domain is 1 The antibody of E40, which is an Fc domain of

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

[0054] E43. The antibody of E41 to E42, wherein the first and second Fc chains each comprise, from N-terminus to C-terminus, a hinge region, a CH2 region, and a CH3 region.

[0055] E44. The antibody of E43, wherein the hinge region comprises a sequence selected from the group consisting of SEQ ID NO:7, SEQ ID NO:102, SEQ ID NO:123, SEQ ID NO:126, SEQ ID NO:129, and SEQ ID NO:131.

[0056] E45. The antibody of E44, wherein the hinge region comprises the sequence set forth in SEQ ID NO:7.

[0057] E46. The antibody of E44, wherein the hinge region in the first Fc chain and the hinge region in the second Fc chain comprise the pair of sequences set forth in SEQ ID NO: 129 and SEQ ID NO: 131.

[0058] E47. The antibody of E43 to E46, wherein the CH2 region comprises the sequence set forth in SEQ ID NO:8.

[0059] E48. The CH3 region of the first Fc chain and the CH3 region of the second Fc chain (i) SEQ ID NO: 9 and SEQ ID NO: 9, (ii) SEQ ID NO: 111 and SEQ ID NO: 106, (iii) SEQ ID NO: 111 and SEQ ID NO: 114, (iv) SEQ ID NO: 114 and SEQ ID NO: 117, (v) SEQ ID NO: 124 and SEQ ID NO: 127, (vi) SEQ ID NO: 139 and SEQ ID NO: 141, and (vii) SEQ ID NO: 147 and SEQ ID NO: 148 The antibody described in E43 to E47, comprising a pair of sequences selected from the group consisting of:

[0060] E49. The antibody of E48, wherein the CH3 region of the first Fc chain and the CH region of the second Fc chain each comprise the sequence set forth in SEQ ID NO:9.

[0061] E50. The antibody of E48, wherein the CH3 region of the first Fc chain and the CH3 region of the second Fc chain comprise the pair of sequences set forth in SEQ ID NO: 124 and SEQ ID NO: 127.

[0062] E51. The antibody of any one of E1 to E50, comprising a polypeptide having an IL33-VH comprising 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] E52. The antibody of 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] The antibody of any one of E52 to E53, wherein the polypeptide having E53.IL33-VH comprises the sequence set forth in SEQ ID NO:74.

[0065] The antibody of any one of E52 to E52, wherein the polypeptide having E54.IL33-VH comprises the sequence set forth in SEQ ID NO: 132.

[0066] The antibody of E32 to E54, wherein E55.IL33-CL comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 16, SEQ ID NO: 108, SEQ ID NO: 113.

[0067] The antibody of E32 to E55, wherein E56.IL33-CL comprises the amino acid sequence of SEQ ID NO: 16.

[0068] E57. The antibody of any one of E1 to 56, comprising a polypeptide having an IL33-VL comprising 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:79, SEQ ID NO:107, SEQ ID NO:115, SEQ ID NO:121, and SEQ ID NO:138, SEQ ID NO:144, and SEQ ID NO:145.

[0069] E58. The antibody of any one of E1 to E57, comprising a polypeptide having an IL33-VL comprising the amino acid sequence of SEQ ID NO:79.

[0070] E59. The antibody 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] E60. The antibody of E1 to E59, comprising a polypeptide having an IL33-VH of SEQ ID NO: 132 and a polypeptide having an IL33-VL of SEQ ID NO: 79.

[0072] E61. The antibody of any one of E1 to E60, comprising a polypeptide sequence having an IL33-VH encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127208.

[0073] E62. The antibody of any one of E1 to E61, comprising a polypeptide sequence having an IL33-VL encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127207.

[0074] E63. An antibody comprising a polypeptide sequence having IL33-VH encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127208, and a polypeptide having IL33-VL encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127207.

[0075] E64. An isolated antibody that specifically binds to IL-33, the antibody comprising the CDRs of an antibody selected from one or more of Tables 82, 85, and 87.

[0076] E65. An isolated antibody that specifically binds IL-33, the antibody comprising a VH and VL of an antibody selected from one or more of Tables 82, 84, and 87.

[0077] E66. An isolated antibody that specifically binds to IL-33, wherein the antibody is selected from one or more of Tables 82, 84, and 87.

[0078] E67. The antibody of any one of E1 to 65 for use as a medicament.

[0079] E68. The antibody of E67, wherein the use is for the treatment of one or more selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, diabetic kidney disease, Behcet's disease, gout, Alzheimer's disease, and atherosclerosis.

[0080] E69. The antibody of any one of E67 to E68, wherein the use is for the treatment of one or more selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, and non-alcoholic steatohepatitis (NASH).

[0081] E70. The antibody of any one of E67 to E69, wherein the use is for atopic dermatitis.

[0082] E71. The antibody of any one of E67 to E69, wherein the use is for non-alcoholic steatohepatitis (NASH).

[0083] E72. A pharmaceutical composition comprising a therapeutically effective amount of an antibody of E1 to E71, and a pharma- ceutically acceptable carrier.

[0084] E73. A method of 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 of E73, wherein the condition is selected from atopic dermatitis, asthma, cancer, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, diabetic kidney disease, Behcet's disease, gout, Alzheimer's disease, and atherosclerosis.

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

[0087] E76. The method of any one of E73 to E75, wherein the antibody, or pharmaceutical composition thereof is administered about twice per week, once per week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, twice per month, once per month, once every 2 months, once every 3 months, or once every 4 months.

[0088] E77. An isolated antibody that specifically binds to TSLP, (i) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 92, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 94; (ii) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 92, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 93; (iii) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 92 and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 213; (iv) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 92 and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 214; (v) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 221, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 213; (vi) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 221 and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 94, or (vii) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 221, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 223. An antibody comprising a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL).

[0089] E78. An isolated antibody that specifically binds TSLP, comprising a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL) comprising the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO:92, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO:94.

[0090] E79. An isolated antibody that specifically binds to TSLP, (i) a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), wherein CDR-H1 comprises the amino acid sequence of SEQ ID NO: 82, CDR-H2 comprises the amino acid sequence of SEQ ID NO: 83, CDR-H3 comprises the amino acid sequence of SEQ ID NO: 85, CDR-L1 comprises the amino acid sequence of SEQ ID NO: 86, CDR-L2 comprises the amino acid sequence of SEQ ID NO: 88, and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 90; (ii) a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), wherein CDR-H1 comprises the amino acid sequence of SEQ ID NO: 82, CDR-H2 comprises the amino acid sequence of SEQ ID NO: 83, CDR-H3 comprises the amino acid sequence of SEQ ID NO: 85, CDR-L1 comprises the amino acid sequence of SEQ ID NO: 86, CDR-L2 comprises the amino acid sequence of SEQ ID NO: 88, and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 211; (iii) a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), wherein CDR-H1 comprises the amino acid sequence of SEQ ID NO: 82, CDR-H2 comprises the amino acid sequence of SEQ ID NO: 83, CDR-H3 comprises the amino acid sequence of SEQ ID NO: 85, CDR-L1 comprises the amino acid sequence of SEQ ID NO: 86, CDR-L2 comprises the amino acid sequence of SEQ ID NO: 88, and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 212; (iv) a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), wherein CDR-H1 comprises the amino acid sequence of SEQ ID NO: 82, CDR-H2 comprises the amino acid sequence of SEQ ID NO: 83, CDR-H3 comprises the amino acid sequence of SEQ ID NO: 85, CDR-L1 comprises the amino acid sequence of SEQ ID NO: 86, CDR-L2 comprises the amino acid sequence of SEQ ID NO: 87, and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 211; (v) a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), wherein CDR-H1 comprises the amino acid sequence of SEQ ID NO: 82, CDR-H2 comprises the amino acid sequence of SEQ ID NO: 83, CDR-H3 comprises the amino acid sequence of SEQ ID NO: 85, CDR-L1 comprises the amino acid sequence of SEQ ID NO: 86, CDR-L2 comprises the amino acid sequence of SEQ ID NO: 88, and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 90; or (vi) A heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), wherein CDR-H1 comprises the amino acid sequence of SEQ ID NO: 82, CDR-H2 comprises the amino acid sequence of SEQ ID NO: 83, CDR-H3 comprises the amino acid sequence of SEQ ID NO: 85, CDR-L1 comprises the amino acid sequence of SEQ ID NO: 86, CDR-L2 comprises the amino acid sequence of SEQ ID NO: 87, and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 212. An antibody comprising:

[0091] E80. The antibody of any one of E77 to E79, comprising a TSLP-VH framework sequence derived from a human germline VH sequence selected from the group consisting of DP47, DP49, DP50, DP54, and DP53.

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

[0093] E82. The antibody of any one of E77 to E81, comprising a TSLP-VL framework sequence derived from a human germline VL sequence selected from the group consisting of DPL16, DPL23, V2-6, V2-8, V2-14, and V2-17.

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

[0095] E84. The antibody of any one of E77 to E84, comprising a TSLP-VL framework sequence and a TSLP-VH framework sequence, wherein one or both of the TSLP-VL framework sequence or the TSLP-VH framework sequence 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] E85. The antibody of any one of E77 to E84, comprising a TSLP-VL framework sequence and a TSLP-VH framework sequence, wherein one or both of the TSLP-VL framework sequence or the TSLP-VH framework sequence are identical to the human germline sequence from which it is derived.

[0097] E86. The antibody of any one of E77 to E85, comprising a TSLP-VH sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 92.

[0098] E87. The antibody of any one of E77 to E86, comprising a TSLP-VL sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 94.

[0099] E88.(i) a TSLP-VH sequence of SEQ ID NO: 92, and a TSLP-VL sequence of SEQ ID NO: 94; (ii) a TSLP-VH sequence of SEQ ID NO: 92, and a TSLP-VL sequence of SEQ ID NO: 93; (iii) a TSLP-VH sequence of SEQ ID NO: 92, and a TSLP-VL sequence of SEQ ID NO: 213; (iv) a TSLP-VH sequence of SEQ ID NO: 92, and a TSLP-VL sequence of SEQ ID NO: 214; (v) a TSLP-VH sequence of SEQ ID NO: 221, and a TSLP-VL sequence of SEQ ID NO: 215; (vi) a TSLP-VH sequence of SEQ ID NO: 221, and a TSLP-VL sequence of SEQ ID NO: 99; or (vii) the TSLP-VH sequence of SEQ ID NO: 221, and the TSLP-VL sequence of SEQ ID NO: 224 The antibody of any one of E77 to E86, comprising:

[0100] E89. The antibody of any one of E77 to E88, comprising a TSLP-VH sequence identical to SEQ ID NO: 92, and a TSLP-VL sequence identical to SEQ ID NO: 94.

[0101] E90. The antibody of any one of E77 to E88, comprising a TSLP-VH sequence identical to SEQ ID NO: 92, and a TSLP-VL sequence identical to SEQ ID NO: 93.

[0102] E91. The antibody of any one of E77 to E88, comprising a TSLP-VH sequence identical to SEQ ID NO: 92, and a TSLP-VL sequence identical to SEQ ID NO: 213.

[0103] E92. The antibody of any one of E77 to E88, comprising a TSLP-VH sequence identical to SEQ ID NO: 92, and a TSLP-VL sequence identical to SEQ ID NO: 214.

[0104] E93. The antibody of any one of E77 to E89, comprising a TSLP-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 205.

[0105] E94. The antibody of E91, comprising a TSLP-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 217.

[0106] E95. The antibody of E92, comprising a TSLP-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 218.

[0107] E96. The antibody of any one of E77 to E95, comprising a TSLP-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 204.

[0108] E97. The antibody of any one of E77 to E96, comprising a TSLP-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127200.

[0109] E98. The antibody of any one of E77 to E89, comprising a TSLP-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127199.

[0110] E99. An antibody comprising the TSLP-VH sequence encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127200, and comprising the TSLP-VL sequence encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127199.

[0111] E100. The antibody of any one of E77 to E88, comprising a TSLP-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-______.

[0112] E101. An antibody comprising a TSLP-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127200, and comprising a TSLP-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-______.

[0113] E102. The antibody of any one of E77 to E88, comprising a TSLP-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-______.

[0114] E103. An antibody comprising a TSLP-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127200, and comprising a TSLP-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-______.

[0115] E104. IC of less than 10 pM in the TARC production bioassay in human peripheral blood monocytes 50 The antibody according to E77 to E102, characterized by:

[0116] E105. IC of less than 7 pM in the TARC production bioassay in human peripheral blood monocytes 50 The antibody according to any one of E77 to E104, characterized by:

[0117] E106. IC of less than 6 pM in the TARC production bioassay in human peripheral blood monocytes 50 The antibody according to any one of E77 to E105, characterized by:

[0118] E107. The antibody according to E77 to E106, having a melting temperature of 68°C.

[0119] E108. The antibody according to E77 to E107, wherein the pH3.4 hold ΔHMMS%, as defined as the difference between the percentage of high molecular weight species attributable to degradation after 5 hours of incubation of the antibody at pH 3.4 at room temperature and the percentage of high molecular weight species attributable to degradation after 5 hours of incubation of the antibody at pH 7.2 at room temperature, is less than 5.

[0120] The antibody of E77 to E108 having a lower pH 3.4 hold ΔHMMS% than E109.1.

[0121] The antibody of E77 to E109 having a low pH 3.4 hold ΔHMMS% of less than E110.0.1.

[0122] E111. The antibody of E77 to E110, further comprising a constant heavy domain (TSLP-CH1) and a constant light domain (TSLP-CL).

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

[0124] E113. The antibody of E111 to E112, wherein TSLP-CH1 comprises the sequence set forth in SEQ ID NO:6.

[0125] E114. The antibody of E111 to E113, wherein TSLP-CL comprises a sequence selected from the group consisting of SEQ ID NO: 16, SEQ ID NO: 95, SEQ ID NO: 108, and SEQ ID NO: 113.

[0126] E115. The antibody of E111 to E114, wherein TSLP-CL comprises the sequence set forth in SEQ ID NO: 95.

[0127] E116. The antibody of E111 to E115, wherein TSLP-CH1 is connected to TSLP-VL and TSLP-CL is connected to TSLP-VH to form a TSLP-binding domain-swapped Fab domain (TSLP-xFab).

[0128] E117. The antibody of E111 to E115, wherein TSLP-CH1 is connected to TSLP-VH and TSLP-CL is connected to TSLP-VL to form a TSLP-binding Fab domain (TSLP-Fab).

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

[0130] E119. The Fc domain is an IgA (e.g., IgA 1 or IgA 2 ), IgD, IgE, IgM, or IgG (e.g., IgG 1 , IgG 2 , IgG 3 , or IgG 4 The antibody described in E118, which is an Fc domain of

[0131] E120.Fc domain is IgG 1 The antibody of any one of E118 to E119, which is an Fc domain of

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

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

[0134] E123. The antibody of E122, wherein the hinge region comprises a sequence selected from the group consisting of SEQ ID NO:7, SEQ ID NO:102, SEQ ID NO:123, SEQ ID NO:126, SEQ ID NO:129, and SEQ ID NO:131.

[0135] E124. The antibody of E122 to E123, wherein the hinge region comprises the sequence set forth in SEQ ID NO:7.

[0136] E125. The antibody of E122 to E123, wherein the hinge region in the first Fc chain and the hinge region in the second Fc chain comprise the pair of sequences set forth in SEQ ID NO: 129 and SEQ ID NO: 131.

[0137] E126. The antibody described in E122 to E123, wherein the CH2 region comprises the sequence set forth in SEQ ID NO:8.

[0138] E127. The CH3 region of the first Fc chain and the CH3 region of the second Fc chain are (i) SEQ ID NO: 124 and SEQ ID NO: 127, (ii) SEQ ID NO: 9 and SEQ ID NO: 9, (iii) SEQ ID NO: 111 and SEQ ID NO: 106, (iv) SEQ ID NO: 111 and SEQ ID NO: 114, (v) SEQ ID NO: 114 and SEQ ID NO: 117, (vi) SEQ ID NO: 139 and SEQ ID NO: 141, and (vii) SEQ ID NO: 147 and SEQ ID NO: 148 The antibody of E122 to E126, comprising a pair of sequences selected from the group consisting of:

[0139] E128. The antibody of E127, wherein the CH3 region in the first Fc chain and the CH region in the second Fc chain each comprise the sequence set forth in SEQ ID NO:9.

[0140] E129. The antibody of E128, wherein the CH3 region in the first Fc chain and the CH region in the second Fc chain comprise the pair of sequences set forth in SEQ ID NO: 124 and SEQ ID NO: 127.

[0141] E130. The antibody of any one of E77 to E129, comprising a polypeptide having a TSLP-VH comprising 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:97, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:155, SEQ ID NO:158, SEQ ID NO:161, SEQ ID NO:165, SEQ ID NO:222.

[0142] E131. The antibody of any one of E77 to E130, comprising a polypeptide having a TSLP-VH comprising 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] E132. The antibody of any one of E77 to E131, wherein the polypeptide having the TSLP-VH comprises the sequence set forth in SEQ ID NO:97.

[0144] E133. The antibody of any one of E77 to E131, wherein the polypeptide having the TSLP-VH comprises the sequence set forth in SEQ ID NO: 165.

[0145] E134. The antibody of any one of E77 to E133, comprising a polypeptide having a TSLP-VL comprising 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:98, SEQ ID NO:99, SEQ ID NO:150, SEQ ID NO:154, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:160, SEQ ID NO:215, SEQ ID NO:216, and SEQ ID NO:224.

[0146] E135. The antibody of any one of E77 to E134, comprising a polypeptide having a TSLP-VL comprising a sequence selected from the group consisting of SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:150, SEQ ID NO:154, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:160, SEQ ID NO:215, SEQ ID NO:216, and SEQ ID NO:224.

[0147] E136. The antibody of any one of E77 to E135, comprising a polypeptide having a TSLP-VL comprising the sequence set forth in SEQ ID NO:99.

[0148] E137. The antibody of any one of E77 to E135, comprising a polypeptide sequence having TSLP-VL encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127201.

[0149] E138. The antibody of any one of E77 to E135, comprising a polypeptide sequence having TSLP-VL encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-_____.

[0150] E139. The antibody of any one of E77 to E135, comprising a polypeptide sequence having TSLP-VL encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-_____.

[0151] E140. The antibody of any one of E77 to E139, comprising a polypeptide sequence having a TSLP-VH encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127202.

[0152] E141. An antibody comprising a polypeptide sequence having a TSLP-VH encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127202, and a polypeptide sequence having a TSLP-VL encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127201.

[0153] E142. An antibody comprising a polypeptide sequence having a TSLP-VH encoded by a plasmid deposited with the ATCC having ATCC Accession No. PTA-127202, and a polypeptide sequence having a TSLP-VL encoded by a plasmid deposited with the ATCC having ATCC Accession No. PTA-____.

[0154] E143. An antibody comprising a polypeptide sequence having a TSLP-VH encoded by a plasmid deposited with the ATCC having ATCC Accession No. PTA-127202, and a polypeptide sequence having a TSLP-VL encoded by a plasmid deposited with the ATCC having ATCC Accession No. 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) comprising the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 169, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 175.

[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), wherein CDR-H1 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 166, CDR-H2 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 167, CDR-H3 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 168, CDR-L1 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 171, CDR-L2 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 172, and CDR-L3 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 173.

[0157] E146. The antibody of any one of E144 to E145, further comprising one or both of an IL-4 binding domain that specifically binds IL-4, and an IL-13 binding domain that specifically binds IL-13.

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

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

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

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

[0162] E151. The antibody of any one of E144 to E150, wherein the p40 binding domain comprises a p40-VL framework sequence and a p40-VH framework sequence, and 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] E152. The antibody of any one of E144 to E151, wherein the p40 binding domain comprises a p40-VL framework sequence and a p40-VH framework sequence, and 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] E153. The antibody of any one of E144 to E152, wherein the p40 binding domain comprises a p40-VH that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:169.

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

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

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

[0168] E157. The antibody of any one of E145 to E156, wherein the p40-binding domain comprises a p40-VL sequence encoded by the nucleic acid sequence of SEQ ID NO:207.

[0169] E158. The antibody of any one of E144 to E157, wherein the p40 binding domain comprises a p40-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127206.

[0170] E159. The antibody of any one of E144 to E158, wherein the p40 binding domain comprises a p40-VL sequence encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127205.

[0171] E160. The antibody of E144 to E159, further comprising a constant heavy domain (p40-CH1) and a constant light domain (p40-CL).

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

[0173] E162. The antibody described in E160 to E161, wherein p40-CH1 comprises the sequence set forth in SEQ ID NO:6.

[0174] E163. The antibody of E160 to E162, wherein p40-CL comprises a sequence selected from the group consisting of SEQ ID NO: 16, SEQ ID NO: 108, and SEQ ID NO: 113.

[0175] E164. The antibody described in E160 to E163, wherein p40-CL comprises the sequence set forth in SEQ ID NO: 16.

[0176] E165. The antibody of E160 to E164, wherein p40-CH1 is connected to p40-VL and p40-CL is connected to p40-VH to form a p40-binding domain-swapped Fab domain (p40-xFab).

[0177] E166. The antibody of E160 to E164, wherein p40-CH1 is connected to p40-VH and p40-CL is connected to p40-VL to form a p40-binding Fab domain (p40-Fab).

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

[0179] E168. The Fc domain is an IgA (e.g., IgA 1 or IgA 2 ), IgD, IgE, IgM, or IgG (e.g., IgG 1 , IgG 2 , IgG 3 , or IgG 4 The antibody described in E167, which is an Fc domain of

[0180] E169.Fc domain is IgG 1 The antibody of E168, which is an Fc domain of

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

[0182] E171. The antibody of E167 to E170, wherein the first and second Fc chains each comprise, from N-terminus to C-terminus, a hinge region, a CH2 region, and a CH3 region.

[0183] E172. The antibody of E171, wherein the hinge region comprises a sequence selected from the group consisting of SEQ ID NO:7, SEQ ID NO:102, SEQ ID NO:123, SEQ ID NO:126, SEQ ID NO:129, and SEQ ID NO:131.

[0184] E173. The antibody of E171 to E172, wherein the hinge region in the first Fc chain and the hinge region in the second Fc chain comprise the pair of sequences set forth in SEQ ID NO: 129 and SEQ ID NO: 131.

[0185] E174. The antibody of E171 to E172, wherein the CH2 region comprises the sequence set forth in SEQ ID NO:8.

[0186] E175. The CH3 region of the first Fc chain and the CH3 region of the second Fc chain (i) SEQ ID NO: 9 and SEQ ID NO: 9, (ii) SEQ ID NO: 111 and SEQ ID NO: 106, (iii) SEQ ID NO: 111 and SEQ ID NO: 114, (iv) SEQ ID NO: 114 and SEQ ID NO: 117, (v) SEQ ID NO: 124 and SEQ ID NO: 127, (vi) SEQ ID NO: 139 and SEQ ID NO: 141, and (vii) SEQ ID NO: 147 and SEQ ID NO: 148 The antibody described in E171 to E174, comprising a pair of sequences selected from the group consisting of:

[0187] E176. The antibody of E171 to E175, wherein the CH3 region of the first Fc chain and the CH region of the second Fc chain each comprise the sequence set forth in SEQ ID NO:9.

[0188] E177. The antibody of E171 to E176, wherein the CH3 region in the first Fc chain and the CH region in the second Fc chain comprise the pair of sequences set forth in SEQ ID NO: 124 and SEQ ID NO: 127.

[0189] E178. The antibody of any one of E144 to E177, comprising a polypeptide having a p40-VH comprising 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. The antibody of any one of E144 to E178, comprising a polypeptide having a p40-VH comprising an amino acid selected from the group consisting of SEQ ID NO:170, SEQ ID NO:177, SEQ ID NO:181, SEQ ID NO:185, and SEQ ID NO:186.

[0191] E180. The antibody of any one of E144 to E179, comprising a polypeptide having a p40-VH comprising the amino acid sequence of SEQ ID NO: 186.

[0192] E181. The antibody of any one of E144 to E180, comprising a polypeptide having a p40-VL comprising 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. The antibody of any one of E144 to E181, comprising a polypeptide having a p40-VL comprising the amino acid sequence of SEQ ID NO: 176.

[0194] E183. The antibody of any one of E144 to E182, comprising a polypeptide sequence having p40-VH encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127204.

[0195] E184. The antibody of any one of E144 to E183, comprising a polypeptide sequence having p40-VL encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127203.

[0196] E185. An antibody comprising a polypeptide sequence having p40-VH encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127204, and a polypeptide sequence having p40-VL encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127203.

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

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

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

[0200] E189. The antibody of any one of E144 to E188 for use as a medicament.

[0201] E190. The antibody of E189, wherein the use is for the treatment of one or more selected from the group consisting of non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, atopic dermatitis, Crohn's disease, ulcerative colitis, asthma (severe), allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus, primary biliary cirrhosis, and hidradenitis suppurativa.

[0202] E191. The antibody of any one of E189 to E190, wherein the use is for the treatment of one or more selected from the group consisting of non-alcoholic steatohepatitis (NASH), atopic dermatitis, asthma (severe), alopecia, idiopathic pulmonary fibrosis, and systemic sclerosis.

[0203] E192. The antibody of any one of E189 to E191, wherein the use is for atopic dermatitis.

[0204] E193. The antibody of any one of E189 to E191, wherein the use is for non-alcoholic steatohepatitis (NASH).

[0205] E194. A pharmaceutical composition comprising a therapeutically effective amount of the antibody of E144 to E193, and a pharma- ceutically acceptable carrier.

[0206] E195. A method of 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 of 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), allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus, primary biliary cirrhosis, and hidradenitis suppurativa.

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

[0209] E198. The method of any one of E195 to E196, wherein said antibody or pharmaceutical composition is administered about twice a week, once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, twice a month, once a month, once every 2 months, once every 3 months, or once every 4 months.

[0210] E199. An isolated antibody that specifically binds to IL-4, (i) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 22, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 26; (ii) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 19, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 20; (iii) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 22 and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 20; (iv) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 28 and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 29, or (v) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 22, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 30. An antibody comprising a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL) comprising:

[0211] E200. An isolated antibody that specifically binds to IL-4, comprising a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL) comprising the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO:22, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO:26.

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

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

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

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

[0217] E206. The antibody of any one of E199 to E205, comprising an IL4-VL framework sequence and an IL4-VH framework sequence, wherein one or both of the IL4-VL framework sequence or the IL4-VH framework sequence 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] E207. The antibody of any one of E199 to E206, comprising an IL4-VL framework sequence and an IL4-VH framework sequence, wherein one or both of the IL4-VL framework sequence or the IL4-VH framework sequence are identical to the human germline sequence from which it is derived.

[0219] E208. The antibody of any one of E199 to E207, comprising an IL4-VH sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:22.

[0220] E209. The antibody of any one of E199 to E208, comprising an IL4-VL sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:20.

[0221] E210.(i) an IL4-VH sequence according to SEQ ID NO: 22, and an IL4-VL sequence according to SEQ ID NO: 26; (ii) the IL4-VH sequence of SEQ ID NO: 19, and the IL4-VL sequence of SEQ ID NO: 20; (iii) the IL4-VH sequence of SEQ ID NO: 22, and the IL4-VL sequence of SEQ ID NO: 20; (iv) an IL4-VH sequence of SEQ ID NO: 28 and an IL4-VL sequence of SEQ ID NO: 29; or (v) the IL4-VH sequence of SEQ ID NO: 22, and the IL4-VL sequence of SEQ ID NO: 30 The antibody of any one of E199 to E209, comprising:

[0222] E211. The antibody of any one of E199 to E210, comprising an IL4-VH sequence identical to SEQ ID NO: 22, and an IL4-VL sequence identical to SEQ ID NO: 26.

[0223] E212. The antibody of any one of E199 to E211, comprising an IL4-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 200.

[0224] E213. The antibody of any one of E199 to E212, comprising an IL4-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 201.

[0225] E214. The antibody of any one of E199 to E213, comprising an IL4-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127198.

[0226] E215. The antibody of any one of E199 to E214, comprising an IL4-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127197.

[0227] E216. An antibody comprising an IL4-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127198, and an IL4-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127197.

[0228] E217. A K of less than a value selected from the group consisting of about 10 pM, 5 pM, 1 pM, and 800 fM. D The antibody of any one of E199 to E216, which binds to human IL-4 at

[0229] E218. K values ​​below approximately 1 pM D The antibody of any one of E199 to E217, which binds to human IL-4 at

[0230] E219.K D The antibody of any one of E199 to E218, wherein the value is measured by equilibrium binding exclusion method.

[0231] E220. The antibody of E199 to E219, which binds to cynomolgus IL-4.

[0232] E221. The antibody of E199 to E220, which does not bind to IL-4 from one or more selected from the group consisting of dog, sheep, rabbit, rat, and mouse.

[0233] E222. Binding of antibodies to cynomolgus monkey IL-4 D The binding K D The antibody according to any one of E199 to E221, wherein the antibody is within an order of magnitude of the amino acid sequence of E199 to E221.

[0234] E223. Binding of antibodies to cynomolgus monkey IL-4 D The binding K D The antibody according to any one of E199 to E222, wherein the antibody is within a 2-fold difference of

[0235] IC<10 pM in human monocyte assay for neutralization of IL-4 induction of E224.CD23 50 The antibody according to any one of E199 to E223, characterized by:

[0236] IC of less than 20 pM in the human monocyte assay for neutralization of cynomolgus IL-4 induction of E225.CD23 50 The antibody according to any one of E199 to E224, characterized by:

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

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

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

[0240] E229. The antibody of E199 to E228, comprising a lysine at residue 93 in the light chain.

[0241] E230. The antibody of E199 to E229, further comprising a constant heavy domain (IL4-CH1) and a constant light domain (IL4-CL).

[0242] The antibody of E230, wherein IL4-CH1 comprises the sequence set forth in SEQ ID NO:6.

[0243] The antibody of E230 to E231, wherein IL4-CL comprises the sequence set forth in SEQ ID NO: 16.

[0244] E233. The antibody of E230 to E232, wherein IL4-CH1 is connected to IL4-VL and IL4-CL is connected to IL-4-VH, forming an IL-4-binding domain-swapped Fab domain (IL4-xFab).

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

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

[0247] E236. The Fc domain is an IgA (e.g., IgA 1 or IgA 2 ), IgD, IgE, IgM, or IgG (e.g., IgG 1 , IgG 2 , IgG 3 , or IgG 4 The antibody described in E235, which is an Fc domain of

[0248] E237.Fc domain is IgG 1 The antibody described in E235 to E236, which is an Fc domain of.

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

[0250] E239. The antibody or antigen-binding fragment thereof of E235 to E238, wherein the first and second Fc chains each comprise, from N-terminus to C-terminus, a hinge region, a CH2 region, and a CH3 region.

[0251] E240. The antibody or antigen-binding fragment thereof of E239, wherein the hinge region comprises a sequence selected from the group consisting of SEQ ID NO:7, SEQ ID NO:102, SEQ ID NO:123, SEQ ID NO:126, SEQ ID NO:129, and SEQ ID NO:131.

[0252] E241. The antibody or antigen-binding fragment thereof of E240, wherein the hinge region comprises the sequence set forth in SEQ ID NO:7.

[0253] E242. The antibody or antigen-binding fragment thereof of E240, wherein the hinge region in the first Fc chain and the hinge region in the second Fc chain comprise the pair of sequences set forth in SEQ ID NO: 129 and SEQ ID NO: 131.

[0254] E243. The antibody or antigen-binding fragment thereof described in E239 to E242, wherein the CH2 region comprises the sequence set forth in SEQ ID NO:8.

[0255] E244. The CH3 region of the first Fc chain and the CH3 region of the second Fc chain (i) SEQ ID NO: 9 and SEQ ID NO: 9, (ii) SEQ ID NO: 111 and SEQ ID NO: 106, (iii) SEQ ID NO: 111 and SEQ ID NO: 114, (iv) SEQ ID NO: 114 and SEQ ID NO: 117, (v) SEQ ID NO: 124 and SEQ ID NO: 127, (vi) SEQ ID NO: 139 and SEQ ID NO: 141, and (vii) SEQ ID NO: 147 and SEQ ID NO: 148 The antibody or antigen-binding fragment thereof described in E239 to E243, comprising a pair of sequences selected from the group consisting of:

[0256] E245. The antibody or antigen-binding fragment thereof according to E244, wherein the CH3 region in the first Fc chain and the CH region in the second Fc chain each comprise the sequence set forth in SEQ ID NO:9.

[0257] E246. The antibody or antigen-binding fragment thereof according to E244, wherein the CH3 region in the first Fc chain and the CH3 region in the second Fc chain comprise the pair of sequences set forth in SEQ ID NO: 124 and SEQ ID NO: 127.

[0258] The antibody of any one of E199 to E246, comprising a polypeptide having an IL4-VH comprising 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:23, SEQ ID NO:107, SEQ ID NO:115, SEQ ID NO:121, SEQ ID NO:125, SEQ ID NO:130, SEQ ID NO:133, SEQ ID NO:135, SEQ ID NO:140, SEQ ID NO:144, SEQ ID NO:146, SEQ ID NO:151, SEQ ID NO:153, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:159, SEQ ID NO:162, and SEQ ID NO:164, SEQ ID NO:179, SEQ ID NO:180, and SEQ ID NO:183.

[0259] E248. The antibody of any one of E199 to E247, comprising a polypeptide having an IL4-VH comprising the amino acid sequence of SEQ ID NO:23.

[0260] E249. The antibody of any one of E199 to E241, comprising a polypeptide having an IL4-VH comprising the amino acid sequence of SEQ ID NO:8:130.

[0261] E250. The antibody of any one of E199 to E249, comprising a polypeptide having an IL4-VL comprising 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. The antibody of any one of E199 to E250, comprising a polypeptide having an IL4-VL comprising the amino acid sequence of SEQ ID NO:27.

[0263] E252. The antibody of any one of E199 to E251, comprising a polypeptide sequence having an IL4-VH encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127192.

[0264] E253. The antibody of any one of E199 to E252, comprising a polypeptide sequence having an IL4-VL encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127194.

[0265] E254. An antibody comprising a polypeptide sequence having an IL4-VH encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127192, and a polypeptide sequence having an IL4-VL encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127194.

[0266] E255. The antibody of any one of E199 to E254 for use as a medicament.

[0267] E256. The antibody of any one of E199 to E255, wherein the use is for the treatment of one or more selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, and systemic sclerosis, diabetic kidney disease, Behcet's disease, gout, Alzheimer's disease, atherosclerosis, fungal keratitis, non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus (SLE), primary biliary cirrhosis, and hidradenitis suppurativa.

[0268] E257. The antibody of any one of E199 to 256, wherein the use is for the treatment of one or more selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, non-alcoholic steatohepatitis (NASH), alopecia, idiopathic pulmonary fibrosis, and systemic sclerosis.

[0269] E258. The antibody of any one of E199 to 257, wherein the use is for atopic dermatitis.

[0270] E259. The antibody of any one of E199-257, wherein the use is for non-alcoholic steatohepatitis (NASH).

[0271] E260. A pharmaceutical composition comprising a therapeutically effective amount of the antibody of E199 to E259, and a pharma- ceutically acceptable carrier.

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

[0273] E262. The method of E261, wherein the condition is selected from atopic dermatitis, asthma, cancer, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, diabetic kidney disease, Behcet's disease, gout, Alzheimer's disease, and atherosclerosis.

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

[0275] E264. The method of any one of E261 to E263, wherein the antibody or pharmaceutical composition is administered about twice a week, once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, twice a month, once a month, once every 2 months, once every 3 months, or once every 4 months.

[0276] E265. An isolated antibody that specifically binds to IL-13, (i) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 51, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 54; (ii) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 44, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 46; (iii) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 48, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 49; (iv) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 48 and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 68, or (v) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 57, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 59. An antibody comprising a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL).

[0277] E266. An isolated antibody that specifically binds to IL-13, comprising a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL) comprising the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO:51, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO:54.

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

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

[0281] E270. The antibody of any one of E265 to E269, comprising an IL13-VL framework sequence derived from a human germline VL sequence selected from the group consisting of: DPK3, DPK4, DPK5, DPK8, DPK9, DPK10, DPK23.

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

[0283] E272. The antibody of any one of E265 to E271, comprising an IL13-VL framework sequence and an IL13-VH framework sequence, wherein one or both of the IL13-VL framework sequence or the IL13-VH framework sequence 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] E273. The antibody of any one of E265 to E272, comprising an IL13-VL framework sequence and an IL13-VH framework sequence, wherein one or both of the IL13-VL framework sequence or the IL13-VH framework sequence are identical to the human germline sequence from which it is derived.

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

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

[0287] E276.(i) IL13-VH of SEQ ID NO: 51, and IL13-VL of SEQ ID NO: 54 (ii) IL13-VH of SEQ ID NO: 44, and IL13-VL of SEQ ID NO: 46; (iii) IL13-VH of SEQ ID NO: 48, and IL13-VL of SEQ ID NO: 49; (iv) IL13-VH of SEQ ID NO: 48 and IL13-VL of SEQ ID NO: 68, or (v) IL13-VH of SEQ ID NO: 57, and IL13-VL of SEQ ID NO: 59 The antibody of any one of E265 to E275, comprising:

[0288] E277. The antibody of any one of E265 to E276, comprising an IL13-VH identical to SEQ ID NO: 51, and an IL13-VL identical to SEQ ID NO: 54.

[0289] E278. The antibody of any one of E265 to E277, comprising a VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 198.

[0290] E279. The antibody of any one of E265 to E278, comprising a VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 199.

[0291] E280. The antibody of any one of E265 to E279, comprising an IL13-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127196.

[0292] E281. The antibody of any one of E265 to E280, comprising an IL13-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127195.

[0293] E282. An antibody comprising an IL13-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127196, and an IL13-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127195.

[0294] E283. A K of 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 The antibody according to any one of E265 to E282, which binds to human IL-13 at

[0295] E284.K below 60 pM D The antibody of any one of E265 to E276, which binds to human IL-13 at

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

[0297] E286.K D The antibody of any one of E283 to E285, wherein the value is measured by SPR.

[0298] E287. The antibody of E265 to E286, which binds to cynomolgus IL-13.

[0299] E288. The antibody of E265 to E287, which does not bind to IL-13 from one or more species selected from the group consisting of dog, rabbit, and mouse.

[0300] E289. Binding of antibodies to cynomolgus monkey IL-13 D The binding K D The antibody according to any one of E265 to E288, wherein the antibody is within an order of magnitude of the amino acid sequence of E265 to E288.

[0301] E290. Binding of antibodies to cynomolgus monkey IL-13 D The binding K of the antibody to human IL-13 D The antibody according to any one of E265 to E289, wherein the antibody is within a 5-fold difference of

[0302] E291. Binding of antibodies to cynomolgus monkey IL-13 DThe binding K of the antibody to human IL-13 D The antibody according to any one of E265 to E290, wherein the difference is within 2-fold.

[0303] E292.IL-13 IC 50 is less than 100 pM as measured by neutralization of IL-13 pSTAT6 phosphorylation in HT-29 cells.

[0304] E293.IL-13 IC 50 is less than 20 pM as measured in a human monocyte assay for neutralization of IL-13 induction of CD23.

[0305] E294.IL-13 IC 50 is less than 15 pM as measured in a human monocyte assay for neutralization of IL-13 induction of CD23.

[0306] E295.IL-13 IC 50 is less than 12 pM as measured in a human monocyte assay for neutralization of IL-13 induction of CD23.

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

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

[0309] The antibody of E296 to E297, wherein IL13-CH1 comprises the sequence set forth in SEQ ID NO:6.

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

[0311] The antibody of E296 to E299, wherein E300.IL13-CL comprises the sequence set forth in SEQ ID NO: 16.

[0312] E301. The antibody of E296 to E300, wherein IL13-CH1 is connected to IL13-VL and IL13-CL is connected to IL13-VH to form an IL-13-binding domain-swapped Fab domain (IL13-xFab).

[0313] E302. The antibody of E296 to E301, wherein IL13-CH1 is connected to IL13-VH and IL13-CL is connected to IL13-VL, forming an IL-13 binding Fab domain (IL13-Fab).

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

[0315] E304. The Fc domain is an IgA (e.g., IgA 1 or IgA 2 ), IgD, IgE, IgM, or IgG (e.g., IgG 1 , IgG 2 , IgG 3 , or IgG 4 The antibody described in E303, which is an Fc domain of

[0316] E305.Fc domain is IgG 1 The antibody described in E303 to E304, which is an Fc domain of.

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

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

[0319] E308. The antibody of E307, wherein the hinge region comprises a sequence selected from the group consisting of SEQ ID NO:7, SEQ ID NO:102, SEQ ID NO:123, SEQ ID NO:126, SEQ ID NO:129, and SEQ ID NO:131.

[0320] E309. The antibody of E307 to E308, wherein the hinge region comprises the sequence set forth in SEQ ID NO:7.

[0321] E310. The antibody of E307 to E309, wherein the hinge region comprises the sequence set forth in SEQ ID NO: 102.

[0322] E311. The antibody of E307 to E310, wherein the CH2 region comprises the sequence set forth in SEQ ID NO:8.

[0323] E312. The CH3 region of the first Fc chain and the CH3 region of the second Fc chain (i) SEQ ID NO: 124 and SEQ ID NO: 127, (ii) SEQ ID NO: 9 and SEQ ID NO: 9, (iii) SEQ ID NO: 111 and SEQ ID NO: 106, (iv) SEQ ID NO: 111 and SEQ ID NO: 114, (v) SEQ ID NO: 114 and SEQ ID NO: 117, (vi) SEQ ID NO: 139 and SEQ ID NO: 141, and (vii) SEQ ID NO: 147 and SEQ ID NO: 148 The antibody described in E307 to E311, comprising a pair of sequences selected from the group consisting of:

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

[0325] E314. The antibody of E307 to E312, wherein the CH3 region in the first Fc chain and the CH region in the second Fc chain comprise the pair of sequences set forth in SEQ ID NO: 124 and SEQ ID NO: 127.

[0326] E315. The antibody of any one of E265 to E314, comprising a polypeptide having an IL13-VH comprising 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:52, SEQ ID NO:66, SEQ ID NO:112, SEQ ID NO:118, SEQ ID NO:121, SEQ ID NO:122, SEQ ID NO:130, SEQ ID NO:145, SEQ ID NO:149, SEQ ID NO:152, SEQ ID NO:154, SEQ ID NO:160, SEQ ID NO:162, and SEQ ID NO:164, and SEQ ID NO:209.

[0327] E316. The antibody of any one of E265 to E315, comprising a polypeptide having an IL13-VH consisting of SEQ ID NO:52, SEQ ID NO:66, SEQ ID NO:112, SEQ ID NO:118, SEQ ID NO:121, SEQ ID NO:122, SEQ ID NO:130, SEQ ID NO:145, SEQ ID NO:149, SEQ ID NO:152, SEQ ID NO:154, SEQ ID NO:160, SEQ ID NO:162, and SEQ ID NO:164, and SEQ ID NO:209.

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

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

[0330] E319. The antibody of any one of E265 to E318, comprising a polypeptide having an IL13-VL comprising 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] E320. The antibody of any one of E265 to E319, comprising a polypeptide having an IL13-VL comprising an amino acid sequence selected from the group consisting of SEQ ID NO:55, SEQ ID NO:119, SEQ ID NO:120, SEQ ID NO:125, SEQ ID NO:130, SEQ ID NO:133, SEQ ID NO:135, SEQ ID NO:140, SEQ ID NO:163, SEQ ID NO:164, and SEQ ID NO:196.

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

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

[0334] E323. The antibody of any one of E265 to E322, comprising a polypeptide sequence having an IL13-VH encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127193.

[0335] E324. The antibody of any one of E265 to E323, comprising a polypeptide sequence having an IL13-VL encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127192.

[0336] E325. An antibody comprising an IL13-VH polypeptide sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127193, and an IL13-VL polypeptide sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127192.

[0337] E326. The antibody of any one of E265 to E325 for use as a medicament.

[0338] E327. The antibody of E326, wherein the use is for the treatment of one or more selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, and systemic sclerosis, diabetic kidney disease, Behcet's disease, gout, Alzheimer's disease, atherosclerosis, fungal keratitis, non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus (SLE), primary biliary cirrhosis, and hidradenitis suppurativa.

[0339] E328. The antibody of any one of E326 to E327, wherein the use is for the treatment of one or more selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, non-alcoholic steatohepatitis (NASH), alopecia, idiopathic pulmonary fibrosis, and systemic sclerosis.

[0340] E329. The antibody of any one of E326 to E328, wherein the use is for atopic dermatitis.

[0341] E330. The antibody of any one of E326 to E329, wherein the use is for non-alcoholic steatohepatitis (NASH).

[0342] E331. A pharmaceutical composition comprising a therapeutically effective amount of an antibody of E265 to E330, and a pharma- ceutically acceptable carrier.

[0343] E332. A method of 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 of 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), allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus, primary biliary cirrhosis, and hidradenitis suppurativa.

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

[0346] E335. The method of any one of E332 to E334, wherein the antibody or pharmaceutical composition is administered about twice per week, once per week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, twice per month, once per month, once every 2 months, once every 3 months, or once every 4 months.

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

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

[0349] E338. The antibody of E336 to E337, wherein the specific binding to IL-4 is mediated through the antibody of any one of E199 to E259.

[0350] E339. The antibody of any one of E336 to E338, wherein the specific binding to IL-13 is mediated through the antibody of any one of E265 to E330.

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

[0352] E341.(i) the IL-33 binding domain comprises an IL33-VH of SEQ ID NO: 73, and an IL33-VL of SEQ ID NO: 78; (i) the IL-4 binding domain comprises an IL4-VH of SEQ ID NO: 22 and an IL4-VL of SEQ ID NO: 26; (ii) the IL-13 binding domain comprises an IL13-VH of SEQ ID NO: 51, and an IL13-VL of SEQ ID NO: 54; An antibody according to E336 to E340.

[0353] E342.(i) the IL-33 binding domain comprises an IL33-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127210, and an IL33-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127209; (ii) the IL-4 binding domain comprises an IL4-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127198, and an IL4-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127197; (iii) the IL-13 binding domain comprises an IL13-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127196, and an IL13-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127195; An antibody according to E336 to 341.

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

[0355] E344. The antibody of E336 to E342, wherein the IL-33 binding domain is fused to the IL-4 binding domain, with or without a linker.

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

[0357] E346. The antibody of any one of E343 to E345, wherein the fusion is with a linker.

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

[0359] E348. The antibody of E343 to E347, wherein the linker comprises SEQ ID NO: 104.

[0360] E349.(i) the second and fifth polypeptide chains together form a first Fab domain comprising a first antigen-binding site; (ii) the second and fourth polypeptide chains together form a second Fab domain that comprises a second antigen-binding site; (iii) the first and third polypeptide chains together form a third Fab domain that comprises a third antigen-binding site. The antibody of any one of E336 to E348, comprising a first, second, third, fourth and fifth polypeptide chain such that

[0361] E350. The antibody of E349, wherein the first and second polypeptide chains associate together to form an antibody comprising two arms: a double Fab arm comprising a first Fab domain and a second Fab domain, and a single Fab arm comprising a third Fab domain.

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

[0363] E352. The antibody of E349 to E351, wherein a first antigen-binding site specifically binds IL-13, a second antigen-binding site specifically binds IL-4, and a third antigen-binding site specifically binds IL-33.

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

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

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

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

[0368] E357. The first Fc chain comprises a first CH3 domain and the second Fc chain comprises a second CH3 domain, wherein the first CH3 domain and the second CH3 domain each comprise a different complementary sequence, and the different complementary sequences are selected from the following pairs of different complementary sequences: (i) SEQ ID NO: 111 and SEQ ID NO: 106, (ii) SEQ ID NO: 111 and SEQ ID NO: 114, (iii) SEQ ID NO: 114 and SEQ ID NO: 117, (iv) SEQ ID NO: 124 and SEQ ID NO: 127, (v) SEQ ID NO: 139 and SEQ ID NO: 141, and (vi) SEQ ID NO: 147 and SEQ ID NO: 148 The antibody of E349 to E356, wherein the antibody is selected from one of the following:

[0369] E358. The antibody of E357, wherein the first CH3 domain and the second CH3 domain comprise SEQ ID NO: 124 and SEQ ID NO: 127.

[0370] E359. The identity of the first, second, third, fourth, and fifth polypeptide chains is (i) the first polypeptide chain comprises SEQ ID NO: 132, the second polypeptide chain comprises SEQ ID NO: 130, the third polypeptide chain comprises SEQ ID NO: 79, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122; (ii) the first polypeptide chain comprises SEQ ID NO: 146, the second polypeptide chain comprises SEQ ID NO: 145, the third polypeptide chain comprises SEQ ID NO: 109, the fourth polypeptide chain comprises SEQ ID NO: 196, and the fifth polypeptide chain comprises SEQ ID NO: 103; (iii) the first polypeptide chain comprises SEQ ID NO:112, the second polypeptide chain comprises SEQ ID NO:107, the third polypeptide chain comprises SEQ ID NO:196, the fourth polypeptide chain comprises SEQ ID NO:109, and the fifth polypeptide chain comprises SEQ ID NO:103; (iv) the first polypeptide chain comprises SEQ ID NO:118, the second polypeptide chain comprises SEQ ID NO:115, the third polypeptide chain comprises SEQ ID NO:119, the fourth polypeptide chain comprises SEQ ID NO:116, and the fifth polypeptide chain comprises SEQ ID NO:103; (v) the first polypeptide chain comprises SEQ ID NO:118, the second polypeptide chain comprises SEQ ID NO:115, the third polypeptide chain comprises SEQ ID NO:120, the fourth polypeptide chain comprises SEQ ID NO:116, and the fifth polypeptide chain comprises SEQ ID NO:103; (vi) the first polypeptide chain comprises SEQ ID NO:209, the second polypeptide chain comprises SEQ ID NO:121, the third polypeptide chain comprises SEQ ID NO:196, the fourth polypeptide chain comprises SEQ ID NO:109, and the fifth polypeptide chain comprises SEQ ID NO:103; (vii) the first polypeptide chain comprises SEQ ID NO: 128, the second polypeptide chain comprises SEQ ID NO: 125, the third polypeptide chain comprises SEQ ID NO: 79, the fourth polypeptide chain comprises SEQ ID NO: 208, and the fifth polypeptide chain comprises SEQ ID NO: 122; (viii) the first polypeptide chain comprises SEQ ID NO: 134, the second polypeptide chain comprises SEQ ID NO: 133, the third polypeptide chain comprises SEQ ID NO: 79, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122; (ix) the first polypeptide chain comprises SEQ ID NO: 121, the second polypeptide chain comprises SEQ ID NO: 144, the third polypeptide chain comprises SEQ ID NO: 196, the fourth polypeptide chain comprises SEQ ID NO: 136, and the fifth polypeptide chain comprises SEQ ID NO: 143; (x) the first polypeptide chain comprises SEQ ID NO: 137, the second polypeptide chain comprises SEQ ID NO: 135, the third polypeptide chain comprises SEQ ID NO: 138, the fourth polypeptide chain comprises SEQ ID NO: 136, and the fifth polypeptide chain comprises SEQ ID NO: 122; (xi) the first polypeptide chain comprises SEQ ID NO: 142, the second polypeptide chain comprises SEQ ID NO: 140, the third polypeptide chain comprises SEQ ID NO: 79, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122. The antibody of E349 to E358, selected from the group consisting of:

[0371] E360. The antibody of any one of E349 to E359, wherein the first polypeptide chain comprises SEQ ID NO: 132, the second polypeptide chain comprises SEQ ID NO: 130, the third polypeptide chain comprises SEQ ID NO: 79, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122.

[0372] E361. An isolated antibody that specifically binds IL-33, specifically binds IL-4, and specifically binds IL-13, comprising a first, a second, a third, a fourth, and a fifth polypeptide chain; (i) the second and fifth polypeptide chains together form a first Fab domain that contains an IL-13 binding site; (ii) the second and fourth polypeptide chains together form a second Fab domain that contains an IL-4 binding site; (iii) the first and third polypeptide chains together form a third Fab domain that contains an IL-33 binding site; the first polypeptide chain comprises SEQ ID NO: 132, the second polypeptide chain comprises SEQ ID NO: 130, the third polypeptide chain comprises SEQ ID NO: 79, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122; antibody.

[0373] E362. An isolated antibody that specifically binds to IL-33, specifically binds to IL-4, and specifically binds to IL-13, comprising a first, a second, a third, a fourth, and a fifth polypeptide chain; (i) the second and fifth polypeptide chains together form a first Fab domain that contains an IL-13 binding site; (ii) the second and fourth polypeptide chains together form a second Fab domain that contains an IL-4 binding site; (iii) the first and third polypeptide chains together form a third Fab domain that contains an IL-33 binding site; the first polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127208, the second polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127192, the third polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127207, the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127194, and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127193. antibody.

[0374] E363. The antibody of E336 to E362, having a viscosity of less than 20 cP at a concentration of at least 50 mg / mL in a buffer of 20 mM histidine, 8.5% sucrose, 0.05 mg / mL EDTA pH 6.0.

[0375] E364. The antibody of E336 to E363, having a viscosity of less than 15 cP at a concentration of at least 90 mg / mL in a buffer of 20 mM histidine, 8.5% sucrose, 0.05 mg / mL EDTA pH 6.0.

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

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

[0378] E367. The antibody of E330 to E366, which binds to human IL-4 with a binding affinity of less than 220 nM as measured by SPR.

[0379] E368. The antibody of E330 to E367, which binds to human IL-13 with a binding affinity of less than 220 nM as measured by SPR.

[0380] E369. The antibody of E336 to E368, which binds to human IL-4 with a binding affinity of less than 1 pM as measured by KinExA in a fixed antigen assay in PBS.

[0381] E370. The antibody of E336 to E369, which binds to cynomolgus IL-4 with a binding affinity of less than 5 pM as measured by KinExA in a fixed antigen assay in PBS.

[0382] E371. The antibody of E336 to E370, which binds to human IL-13 with a binding affinity of less than 1 pM as measured by KinExA in a fixed antigen assay in PBS.

[0383] E372. The antibody of E336 to E371, which binds to cyno IL-13 with a binding affinity of less than 1 pM as measured by KinExA in a fixed antigen assay in PBS.

[0384] IC<20nM in human monocyte assay for neutralization of IL-4 induction of E373.CD23 50 The antibody according to any one of E336 to E372, characterized by:

[0385] IC<20nM in human monocyte assay for neutralization of IL-13 induction of E374.CD23 50 The antibody according to any one of E336 to E373, characterized by:

[0386] E375. Wild-type IL-33 neutralization IC<30nM in HEK-Blue SEAP assay 50 The antibody according to any one of E336 to E374, characterized by:

[0387] E376. Recombinant constitutively active IL-33 neutralizing IC of less than 15 pM in the HEK-Blue SEAP assay 50 The antibody according to any one of E336 to E375, characterized by:

[0388] E377. The antibody of any one of E336 to E376 for use as a medicament.

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

[0390] E379. The antibody of any one of E377 to 378, wherein the use is for the treatment of one or more selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, and non-alcoholic steatohepatitis (NASH).

[0391] E380. The antibody of any one of E377 to E379, wherein the use is for atopic dermatitis.

[0392] E381. The antibody of any one of E377 to E379, wherein the use is for non-alcoholic steatohepatitis (NASH).

[0393] E382. A pharmaceutical composition comprising a therapeutically effective amount of an antibody of E336 to E381, and a pharma- ceutically acceptable carrier.

[0394] E383. A method of 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 of E383, wherein the condition is selected from atopic dermatitis, asthma, cancer, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, diabetic kidney disease, Behcet's disease, gout, Alzheimer's disease, and atherosclerosis.

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

[0397] E386. The method of any one of E383 to E385, wherein the antibody or pharmaceutical composition is administered about twice a week, once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, twice a month, once a month, once every 2 months, once every 3 months, or once every 4 months.

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

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

[0400] E389. The antibody of E387 to E388, wherein the specific binding to IL-4 is mediated through the antibody of any one of E199 to E259.

[0401] E390. The antibody of any one of E387 to E389, wherein the specific binding to IL-13 is mediated through the antibody of any one of E265 to E330.

[0402] E391.(i) a TSLP binding domain comprises a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), wherein CDR-H1 comprises the amino acid sequence of SEQ ID NO: 82, CDR-H2 comprises the amino acid sequence of SEQ ID NO: 83, CDR-H3 comprises the amino acid sequence of SEQ ID NO: 85, CDR-L1 comprises the amino acid sequence of SEQ ID NO: 86, CDR-L2 comprises the amino acid sequence of SEQ ID NO: 88, and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 90; (ii) the IL-4 binding domain comprises a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL), wherein CDR-H1 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), 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; An antibody described in any one of E381 to E384.

[0403] E392.(i) the TSLP-binding portion comprises a TSLP-VH of SEQ ID NO: 92, and a TSLP-VL of SEQ ID NO: 94; (ii) the IL-4 binding portion comprises an IL4-VH of SEQ ID NO: 22, and an IL4-VL of SEQ ID NO: 26; (iii) the IL-13 binding portion comprises an IL13-VH of SEQ ID NO: 51, and an IL13-VL of SEQ ID NO: 54; The antibody described in E387 to E391.

[0404] E393.(i) the TSLP binding domain comprises a TSLP-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127200, and a TSLP-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA0-127199; (ii) the IL-4 binding domain comprises an IL4-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127198, and an IL4-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127197; (iii) the IL-13 binding domain comprises an IL13-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127196, and an IL13-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127195; The antibody according to E387 to E392.

[0405] E394. The antibody of E387 to E393, wherein the TSLP-binding domain is fused to the IL-13-binding domain, with or without a linker.

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

[0407] E396. The antibody of E387 to E393, wherein the IL-13 binding domain is fused to the IL-4 binding domain, with or without a linker.

[0408] E397. The antibody of any one of E394 to E396, wherein the fusion is with a linker.

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

[0410] E399. The antibody of E394 to E398, wherein the linker comprises SEQ ID NO: 104.

[0411] E400.(i) the second and fifth polypeptide chains together form a first Fab domain comprising a first antigen-binding site; (ii) the second and fourth polypeptide chains together form a second Fab domain that comprises a second antigen-binding site; (iii) the first and third polypeptide chains together form a third Fab domain that comprises a third antigen-binding site. The antibody of any one of E387 to E399, comprising a first, second, third, fourth and fifth polypeptide chain such that

[0412] E401. The antibody of E400, wherein the first and second polypeptide chains associate together to form an antibody comprising two arms: a double Fab arm comprising a first Fab domain and a second Fab domain, and a single Fab arm comprising a third Fab domain.

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

[0414] E403. The antibody of E400 to E402, wherein the first antigen-binding site specifically binds IL-13, the second antigen-binding site specifically binds IL-4, and the third antigen-binding site specifically binds TSLP.

[0415] E404. The first Fab domain, the second Fab domain, and the third Fab domain are as follows: (i) TSLP-Fab described in E117; (ii) IL4-Fab as described in E234, and (iii) IL13-Fab described in E302 The antibody of E400 to E403, each of which comprises a different option selected from (i), (ii), and (iii).

[0416] E405. The antibody of E400 to E406, wherein the first Fab domain is an IL13-Fab described in E302, the second Fab domain is an IL4-Fab described in E234, and the third Fab domain is a TSLP-Fab described in E117.

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

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

[0419] E408. The first Fc chain comprises a first CH3 domain and the second Fc chain comprises a second CH3 domain, wherein the first CH3 domain and the second CH3 domain each comprise a different complementary sequence, and the different complementary sequences are a pair of the following different complementary sequences: (i) SEQ ID NO: 111 and SEQ ID NO: 106, (ii) SEQ ID NO: 111 and SEQ ID NO: 114, (iii) SEQ ID NO: 114 and SEQ ID NO: 117, (iv) SEQ ID NO: 124 and SEQ ID NO: 127, (v) SEQ ID NO: 139 and SEQ ID NO: 141, and (vi) SEQ ID NO: 147 and SEQ ID NO: 148 The antibody of E400 to E407, selected from one of the following:

[0420] E409. The antibody of E408, wherein the first CH3 domain and the second CH3 domain comprise SEQ ID NO: 124 and SEQ ID NO: 127.

[0421] E410. The identity of the first, second, third, fourth, and fifth polypeptide chains is (i) the first polypeptide chain comprises SEQ ID NO: 165, the second polypeptide chain comprises SEQ ID NO: 130, the third polypeptide chain comprises SEQ ID NO: 99, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122; (ii) the first polypeptide chain comprises SEQ ID NO: 146, the second polypeptide chain comprises SEQ ID NO: 149, the third polypeptide chain comprises SEQ ID NO: 109, the fourth polypeptide chain comprises SEQ ID NO: 196, and the fifth polypeptide chain comprises SEQ ID NO: 150; (iii) the first polypeptide chain comprises SEQ ID NO: 112, the second polypeptide chain comprises SEQ ID NO: 151, the third polypeptide chain comprises SEQ ID NO: 196, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 150; (iv) the first polypeptide chain comprises SEQ ID NO: 112, the second polypeptide chain comprises SEQ ID NO: 159, the third polypeptide chain comprises SEQ ID NO: 196, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 150; (v) the first polypeptide chain comprises SEQ ID NO: 161, the second polypeptide chain comprises SEQ ID NO: 162, the third polypeptide chain comprises SEQ ID NO: 98, the fourth polypeptide chain comprises SEQ ID NO: 197, and the fifth polypeptide chain comprises SEQ ID NO: 163; (vi) the first polypeptide chain comprises SEQ ID NO: 146, the second polypeptide chain comprises SEQ ID NO: 154, the third polypeptide chain comprises SEQ ID NO: 109, the fourth polypeptide chain comprises SEQ ID NO: 196, and the fifth polypeptide chain comprises SEQ ID NO: 155; (vii) the first polypeptide chain comprises SEQ ID NO:112, the second polypeptide chain comprises SEQ ID NO:156, the third polypeptide chain comprises SEQ ID NO:196, the fourth polypeptide chain comprises SEQ ID NO:109, and the fifth polypeptide chain comprises SEQ ID NO:155; (viii) the first polypeptide chain comprises SEQ ID NO: 146, the second polypeptide chain comprises SEQ ID NO: 152, the third polypeptide chain comprises SEQ ID NO: 109, the fourth polypeptide chain comprises SEQ ID NO: 196, and the fifth polypeptide chain comprises SEQ ID NO: 98; (ix) the first polypeptide chain comprises SEQ ID NO: 112, the second polypeptide chain comprises SEQ ID NO: 153, the third polypeptide chain comprises SEQ ID NO: 196, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 98; (x) the first polypeptide chain comprises SEQ ID NO: 112, the second polypeptide chain comprises SEQ ID NO: 157, the third polypeptide chain comprises SEQ ID NO: 196, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 158; (xi) the first polypeptide chain comprises SEQ ID NO: 146, the second polypeptide chain comprises SEQ ID NO: 160, the third polypeptide chain comprises SEQ ID NO: 109, the fourth polypeptide chain comprises SEQ ID NO: 196, and the fifth polypeptide chain comprises SEQ ID NO: 158; (xii) the first polypeptide chain comprises SEQ ID NO: 161, the second polypeptide chain comprises SEQ ID NO: 164, the third polypeptide chain comprises SEQ ID NO: 98, the fourth polypeptide chain comprises SEQ ID NO: 197, and the fifth polypeptide chain comprises SEQ ID NO: 122; (xiii) the first polypeptide chain comprises SEQ ID NO: 165, the second polypeptide chain comprises SEQ ID NO: 130, the third polypeptide chain comprises SEQ ID NO: 215, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122; and (xiv) the first polypeptide chain comprises SEQ ID NO: 165, the second polypeptide chain comprises SEQ ID NO: 130, the third polypeptide chain comprises SEQ ID NO: 216, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122. The antibody of E400 to E409, selected from the group consisting of:

[0422] E411. The antibody of any one of E411 to E410, wherein the first polypeptide chain comprises SEQ ID NO: 165, the second polypeptide chain comprises SEQ ID NO: 130, the third polypeptide chain comprises SEQ ID NO: 99, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122.

[0423] E412. An isolated antibody that specifically binds TSLP, specifically binds IL-4, and specifically binds IL-13, comprising a first, a second, a third, a fourth, and a fifth polypeptide chain; (i) the second and fifth polypeptide chains together form a first Fab domain that contains an IL-13 binding site; (ii) the second and fourth polypeptide chains together form a second Fab domain that contains an IL-4 binding site; (iii) the first and third polypeptide chains together form a third Fab domain that contains a TSLP-binding site; the first polypeptide chain comprises SEQ ID NO: 165, the second polypeptide chain comprises SEQ ID NO: 130, the third polypeptide chain comprises SEQ ID NO: 99, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122; antibody.

[0424] E413. An isolated antibody that specifically binds TSLP, specifically binds IL-4, and specifically binds IL-13, comprising a first, a second, a third, a fourth, and a fifth polypeptide chain; (i) the second and fifth polypeptide chains together form a first Fab domain that contains an IL-13 binding site; (ii) the second and fourth polypeptide chains together form a second Fab domain that contains an IL-4 binding site; (iii) the first and third polypeptide chains together form a third Fab domain that contains a TSLP-binding site; the first polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127202, the second polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127192, the third polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127201, the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127194, and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127193. antibody.

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

[0426] E415.The antibody of any one of E387 to E414, which has a terminal half-life in TG32 mice of at least 18 days.

[0427] E416. IC of less than 10 pM as measured by TARC production bioassay in human primary PBMCs 50 The antibody of any one of E387 to E415, characterized by anti-TSLP biological activity of:

[0428] E417. The antibody of any one of E387 to E416, characterized by a viscosity of 20 cP at a concentration of at least 100 mg / mL in a buffer of 20 mM histidine, 8.5% sucrose, 0.05 mg / mL EDTA pH 6.0.

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

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

[0431] E420. The antibody of any one of E387 to E419, which binds to human IL-4 with a binding affinity of less than 1 pM as measured by KinExA in a fixed antigen assay in PBS.

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

[0433] E422. The antibody of any one of E387 to E421, which binds to human IL-13 with a binding affinity of less than 1 pM as measured by KinExA in a fixed antigen assay in PBS.

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

[0435] E424. The antibody of any one of E387 to E423, which binds to human TSLP with a binding affinity of less than 5 pM as measured by KinExA in a fixed antigen assay in PBS.

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

[0437] IC of less than 25 pM in the human monocyte assay for neutralization of IL-4 induction of E426.CD23 50 The antibody of any one of E387 to E425, characterized by:

[0438] IC of less than 15 pM in the human monocyte assay for neutralization of IL-4 induction of E427.CD23 50 The antibody of any one of E387 to E426, characterized by:

[0439] IC of less than 60 pM in the human monocyte assay for neutralization of cynomolgus IL-4 induction of E428.CD23 50 The antibody of any one of E387 to E427, characterized by:

[0440] E429. IC of less than 15 pM for neutralizing human TSLP in a TARC production bioassay in human primary PBMCs 50 The antibody of any one of E387 to E428, characterized by:

[0441] E430. IC<35 pM in Cynomolgus TSLP Neutralization Assay 50 The antibody of any one of E387 to E429, characterized by:

[0442] E431. The antibody of any one of E387 to 430 for use as a medicament.

[0443] E432. The antibody of E431, wherein the use is for the treatment of one or more selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloid, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, and fungal keratitis.

[0444] E433. The antibody of any one of E431 to E432, wherein the use is for the treatment of one or more selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, and non-alcoholic steatohepatitis (NASH).

[0445] E434. The antibody of any one of E431 to 433, wherein the use is for atopic dermatitis.

[0446] E435. The antibody of any one of E431 to 433, wherein the use is for non-alcoholic steatohepatitis (NASH).

[0447] E436. A pharmaceutical composition comprising a therapeutically effective amount of an antibody according to E387 to E435, and a pharma- ceutically acceptable carrier.

[0448] E437. A method of 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 of E437, wherein the condition is selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, and fungal keratitis.

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

[0451] E440. The method of any one of E437 to E439, wherein the antibody or pharmaceutical composition is administered about twice a week, once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, twice a month, once a month, once every 2 months, once every 3 months, or once every 4 months.

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

[0453] E446. The antibody according to E445, wherein the specific binding to p40 is mediated through an antibody according to any one of E144 to E193.

[0454] E447. The antibody of E445 to E446, wherein the specific binding to IL-4 is mediated through the antibody of any one of E199 to E259.

[0455] E448. The antibody of any one of E445 to E447, wherein the specific binding to IL-13 is mediated through the antibody of any one of E265 to E330.

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

[0457] E450.(i) the p40 binding domain comprises a p40-VH of SEQ ID NO: 169, and a p40-VL of SEQ ID NO: 175; (ii) the IL-4 binding domain comprises an IL4-VH of SEQ ID NO: 22 and an IL4-VL of SEQ ID NO: 26; (iii) the IL-13 binding domain comprises an IL13-VH of SEQ ID NO: 51, and an IL13-VL of SEQ ID NO: 54; An antibody according to E445 to 449.

[0458] E451.(i) the p40 binding domain comprises a p40-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127206, and a p40-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127205; (ii) an IL4-VH sequence, the IL-4 binding domain of which is encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127198, and an IL4-VL sequence, the IL-4 binding domain of which is encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127197; (iii) the IL-13 binding domain comprises an IL13-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127196, and an IL13-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127195; An antibody according to E445 to 450.

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

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

[0461] E454. The antibody of E445 to E451, wherein the IL-13 binding domain is fused to the IL-4 binding domain, with or without a linker.

[0462] E455. The antibody of any one of E452 to E454, wherein the fusion is with a linker.

[0463] E456. The antibody of any one of E452 to E455, wherein the IL-13 binding domain is fused to the IL-4 binding domain with a linker.

[0464] E457. The antibody of E456, wherein the linker comprises SEQ ID NO: 104.

[0465] E458.(i) the second and fifth polypeptide chains together form a first Fab domain comprising a first antigen-binding site; (ii) the second and fourth polypeptide chains together form a second Fab domain that comprises a second antigen-binding site; (iii) the first and third polypeptide chains together form a third Fab domain that comprises a third antigen-binding site. The antibody of any one of E445 to E457, comprising a first, second, third, fourth and fifth polypeptide chain such that

[0466] E459. The antibody of E458, wherein the first and second polypeptide chains associate together to form an antibody comprising two arms: a double Fab arm comprising a first Fab domain and a second Fab domain, and a single Fab arm comprising a third Fab domain.

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

[0468] E461. The antibody of E458 to E460, wherein a first antigen-binding site specifically binds IL-13, a second antigen-binding site specifically binds IL-4, and a third antigen-binding site specifically binds 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 antibody described in E458 to E461, each of which comprises a different option selected from (i), (ii), and (iii).

[0470] E463. The antibody of E458 to E462, wherein the first Fab domain is an IL13-Fab described in E302, the second Fab domain is an IL4-Fab described in E234, and the third Fab domain is a p40-Fab described in E166.

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

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

[0473] E466. The first Fc chain comprises a first CH3 domain and the second Fc chain comprises a second CH3 domain, wherein the first CH3 domain and the second CH3 domain each comprise a different complementary sequence, and the different complementary sequences are selected from the following pairs of different complementary sequences: (i) SEQ ID NO: 106 and SEQ ID NO: 111, (ii) SEQ ID NO: 147 and SEQ ID NO: 148, and (iii) SEQ ID NO: 124, and SEQ ID NO: 127 The antibody described in E464 to E465, which is selected from one of the following:

[0474] E467. The antibody of E466, wherein the first CH3 domain and the second CH3 domain comprise SEQ ID NO: 124 and SEQ ID NO: 127.

[0475] E468. The identity of the first, second, third, fourth, and fifth polypeptide chains is (i) the first polypeptide chain comprises SEQ ID NO: 186, the second polypeptide chain comprises SEQ ID NO: 130, the third polypeptide chain comprises SEQ ID NO: 176, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122; (ii) the first polypeptide chain comprises SEQ ID NO: 146, the second polypeptide chain comprises SEQ ID NO: 178, the third polypeptide chain comprises SEQ ID NO: 109, the fourth polypeptide chain comprises SEQ ID NO: 196, and the fifth polypeptide chain comprises SEQ ID NO: 177; (iii) the first polypeptide chain comprises SEQ ID NO: 112, the second polypeptide chain comprises SEQ ID NO: 179, the third polypeptide chain comprises SEQ ID NO: 196, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 177; (iv) the first polypeptide chain comprises SEQ ID NO: 181, the second polypeptide chain comprises SEQ ID NO: 180, the third polypeptide chain comprises SEQ ID NO: 182, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 122; (v) the first polypeptide chain comprises SEQ ID NO:118, the second polypeptide chain comprises SEQ ID NO:183, the third polypeptide chain comprises SEQ ID NO:120, the fourth polypeptide chain comprises SEQ ID NO:116, and the fifth polypeptide chain comprises SEQ ID NO:177; (vi) the first polypeptide chain comprises SEQ ID NO: 185, the second polypeptide chain comprises SEQ ID NO: 125, the third polypeptide chain comprises SEQ ID NO: 176, the fourth polypeptide chain comprises SEQ ID NO: 207, and the fifth polypeptide chain comprises SEQ ID NO: 122; and (vii) the first polypeptide chain comprises SEQ ID NO: 185, the second polypeptide chain comprises SEQ ID NO: 125, the third polypeptide chain comprises SEQ ID NO: 176, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122. The antibody described in E458 to E467, selected from the group consisting of:

[0476] E469. The antibody of any one of E458 to E468, wherein the first polypeptide chain comprises SEQ ID NO: 186, the second polypeptide chain comprises SEQ ID NO: 130, the third polypeptide chain comprises SEQ ID NO: 176, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122.

[0477] An isolated antibody that specifically binds p40, specifically binds IL-4, and specifically binds IL-13, comprising a first, a second, a third, a fourth, and a fifth polypeptide chain; (i) the second and fifth polypeptide chains together form a first Fab domain that contains an IL-13 binding site; (ii) the second and fourth polypeptide chains together form a second Fab domain that contains an IL-4 binding site; (iii) the first and third polypeptide chains together form a third Fab domain that contains a p40 binding site; the first polypeptide chain comprises SEQ ID NO: 186, the second polypeptide chain comprises SEQ ID NO: 130, the third polypeptide chain comprises SEQ ID NO: 176, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122; antibody.

[0478] An isolated antibody that specifically binds p40, specifically binds IL-4, and specifically binds IL-13, comprising a first, a second, a third, a fourth, and a fifth polypeptide chain; (i) the second and fifth polypeptide chains together form a first Fab domain that contains an IL-13 binding site; (ii) the second and fourth polypeptide chains together form a second Fab domain that contains an IL-4 binding site; (iii) the first and third polypeptide chains together form a third Fab domain that contains a p40 binding site; the first polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127204, the second polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127192, the third polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127203, the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127194, and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127193. antibody.

[0479] E472. The antibody of E445 to E471, having a viscosity of less than 20 cP at a concentration of at least 100 mg / mL in a buffer of 20 mM histidine, 8.5% sucrose, 0.05 mg / mL EDTA pH 6.0.

[0480] E473. The antibody of E445 to E472, having a viscosity of less than 12 cP at a concentration of at least 50 mg / mL in a buffer of 20 mM histidine, 8.5% sucrose, 0.05 mg / mL EDTA pH 6.0.

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

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

[0483] E476. The antibody of E445 to E475, which binds to human IL-4 with an affinity constant of less than 220 pM as measured by SPR.

[0484] E477. The antibody of E445 to E476, which binds to human IL-13 with an affinity constant of less than 220 pM as measured by SPR.

[0485] E478. The antibody of E445 to E477, which binds to human IL-12 with an affinity constant of less than 130 pM as measured by SPR.

[0486] E479. The antibody of E445 to E478, which binds to human IL-23 with an affinity constant of less than 100 pM as measured by SPR.

[0487] E480. The antibody of E445 to E479, which binds to human IL-4 with a binding affinity of less than 1 pM as measured by KinExA in a fixed antigen assay in PBS.

[0488] E481. The antibody of E445 to E480, which binds to cynomolgus IL-13 with a binding affinity of less than 2pM as measured by KinExA in a fixed antigen assay in PBS.

[0489] IC of less than 12 pM as measured in a human monocyte assay for neutralization of IL-4 induction of E482.CD23 50 The antibody according to any one of E445 to E481, characterized by:

[0490] IC of less than 12 pM as measured in a human monocyte assay for neutralization of cynomolgus IL-4 induction of E483.CD23 50 The antibody according to E445 to E482, characterized by:

[0491] IC of less than 12 pM as measured in a human monocyte assay for neutralization of cynomolgus IL-13 induction of E484.CD23 50The antibody according to E445 to E483, characterized by:

[0492] IC of less than 45 pM as measured in a human monocyte assay for neutralization of IL-13 induction of E485.CD23 50 The antibody according to any one of E445 to E484, characterized by:

[0493] E486. Human IL-12 neutralization in human peripheral blood monocytes Kit-225 assay IC of less than 600 pM 50 The antibody according to E445 to E485, characterized by:

[0494] E487. IC<2100pM in Cynomolgus IL-23 Kit-225 Neutralization Assay in Human Peripheral Blood Monocytes 50 The antibody according to any one of E445 to E486, characterized by:

[0495] E488. IC<400pM in human IL-12 neutralization assay in human whole blood 50 The antibody according to any one of E445 to E487, characterized by:

[0496] E489.IC<10,000pM in Cynomolgus IL-23 Neutralization Assay in Human Whole Blood 50 The antibody according to E445 to E488, characterized by:

[0497] E490. The antibody of any one of E445 to 489 for use as a medicament.

[0498] E491. The antibody of E490, wherein the use is for the treatment of one or more selected from the group consisting of non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, atopic dermatitis, Crohn's disease, ulcerative colitis, asthma (severe), allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus, primary biliary cirrhosis, and hidradenitis suppurativa.

[0499] E492. The antibody of any one of E490 to E491, wherein the use is for the treatment of one or more selected from the group consisting of non-alcoholic steatohepatitis (NASH), atopic dermatitis, asthma (severe), alopecia, idiopathic pulmonary fibrosis, and systemic sclerosis.

[0500] E483. The antibody of any one of E490 to E482, wherein the use is for atopic dermatitis.

[0501] E484. The antibody of any one of E490 to E483, wherein the use is for non-alcoholic steatohepatitis (NASH).

[0502] E495. A pharmaceutical composition comprising a therapeutically effective amount of an antibody according to E445 to E484, and a pharma- ceutically acceptable carrier.

[0503] E496. A method of 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 of 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), allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus, primary biliary cirrhosis, and hidradenitis suppurativa.

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

[0506] E499. The method of any one of E496 to E498, wherein said antibody or pharmaceutical composition is administered about twice per week, once per week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, twice per month, once per month, once every 2 months, once every 3 months, or once every 4 months.

[0507] E500.(i) the second and fifth polypeptide chains together form a first Fab domain comprising a first antigen-binding site; (ii) the second and fourth polypeptide chains together form a second Fab domain that comprises a second antigen-binding site; (iii) the first and third polypeptide chains together form a third Fab domain that comprises a third antigen-binding site. Such an antibody comprises a first, second, third, fourth, and fifth polypeptide chain.

[0508] E501. The antibody of E500, wherein the first and second polypeptide chains associate together to form an antibody comprising two arms: a double Fab arm comprising a first Fab domain and a second Fab domain, and a single Fab arm comprising a third Fab domain.

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

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

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

[0512] E505. The antibody of E501 to E504, wherein the second Fab comprises a second antigen-associating VH (VH-2), a second antigen-associating VL (VL-2), a second antigen-associating CL (CL-2), and a second antigen-associating CH1 (CH1-2).

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

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

[0515] E508. The antibody of E501 to E507, wherein the third Fab comprises a third antigen-associating VH (VH-3), a first antigen-associating VL (VL-3), a first antigen-associating CL (CL-3), and a first antigen-associating CH1 (CH1-3).

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

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

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

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

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

[0521] E514. The antibody of E508 to E513, wherein one or more of the CL-1 domain, the CL-2 domain, and the CL-3 domain comprise a sequence selected from the group consisting of SEQ ID NO: 16, SEQ ID NO: 95, SEQ ID NO: 108, and SEQ ID NO: 113.

[0522] E515. The antibody of E512 to E514, wherein the first hinge region and the second hinge region comprise the pair of sequences set forth in SEQ ID NO: 129 and SEQ ID NO: 131.

[0523] E516. The antibody of E512 to E515, wherein one or both of the first CH2 domain and the second CH2 domain comprise the sequence set forth in SEQ ID NO:8.

[0524] E517. The first CH3 domain and the second CH3 domain each comprise a different complementary sequence, and the different complementary sequences are selected from the following pairs of different complementary sequences: (i) SEQ ID NO: 111 and SEQ ID NO: 106, (ii) SEQ ID NO: 111 and SEQ ID NO: 114, (iii) SEQ ID NO: 114 and SEQ ID NO: 117, (iv) SEQ ID NO: 124 and SEQ ID NO: 127, (v) SEQ ID NO: 139 and SEQ ID NO: 141, and (vi) SEQ ID NO: 147 and SEQ ID NO: 148 The antibody of E512 to E516, selected from one of:

[0525] E518.(i) CL-1 comprises the sequence set forth in SEQ ID NO: 16, the linker comprises the sequence set forth in SEQ ID NO: 104, CH1-2 comprises the sequence set forth in SEQ ID NO: 6, the second hinge comprises the sequence set forth in SEQ ID NO: 129, the second CH2 comprises the sequence set forth in SEQ ID NO: 8, and the second CH3 comprises the sequence set forth in SEQ ID NO: 124; (ii) CH1-1 comprises the sequence set forth in SEQ ID NO:6; (iii) CL-2 comprises the sequence set forth in SEQ ID NO: 16; An antibody described in E512 to E517.

[0526] The antibody of E508 to E518, wherein E519.CL-3 comprises a sequence set forth in a sequence selected from the group consisting of SEQ ID NO: 16, SEQ ID NO: 95, SEQ ID NO: 108, SEQ ID NO: 113.

[0527] The antibody described in E508 to E519, wherein E520.CL-3 comprises the sequence set forth in SEQ ID NO:95.

[0528] The antibody described in E508 to E519, wherein E521.CL-3 comprises the sequence set forth in SEQ ID NO:16.

[0529] The antibody of E508 to E521, wherein E522.CH1-3 comprises the sequence set forth in SEQ ID NO:6.

[0530] E523. The antibody of E512 to E522, wherein the first hinge comprises the sequence set forth in SEQ ID NO: 131.

[0531] E524. The antibody of E512 to E523, wherein the first CH2 comprises the sequence set forth in SEQ ID NO:8.

[0532] E525. The antibody of E512 to E524, wherein the first CH3 comprises the sequence set forth in SEQ ID NO: 127.

[0533] E526. The isolated antibody of any one of E500 to E525, which specifically binds to IL-4 and specifically binds to IL-13, and comprises an IL-4 binding domain and an IL-13 binding domain.

[0534] E527. The isolated antibody of any one of E1 to E525, which specifically binds IL-4 and specifically binds 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, the antibody comprising an IL-4 binding domain and an IL-13 binding domain.

[0536] E529. The antibody of E526 to E528, wherein the specific binding to IL-4 is mediated through the antibody of any one of E199 to E259.

[0537] E530. The antibody of any one of E526 to E529, wherein the specific binding to IL-13 is mediated through the antibody of any one of E265 to E330.

[0538] E531. The antibody of any one of 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 of E531, wherein at least one distinct target is selected from the group consisting of IL-33, TSLP, and p40, and if the target is IL-33, may optionally further comprise an antibody as set forth in E1 to E71, if the target is TSLP, may optionally further comprise an antibody as set forth in E77 to E143, and if the target is p40, may optionally further comprise an antibody as set forth in E144 to E193.

[0540] E533. The antibody of E531, wherein at least one distinct target is not IL-33.

[0541] E534. The antibody of E531, wherein at least one distinct target is not TSLP.

[0542] E535. The antibody of E531, wherein at least one distinct target is not p40.

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

[0544] E537.(i) the IL-4 binding domain comprises an IL4-VH of SEQ ID NO: 22 and an IL4-VL of SEQ ID NO: 26; (ii) the IL-13 binding domain comprises an IL13-VH of SEQ ID NO: 51, and an IL13-VL of SEQ ID NO: 54; The antibody according to E526 to E536.

[0545] E538. The antibody of 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 antibody of E531 to E537, wherein an additional antigen binding domain is fused to the IL-4 binding domain, with or without a linker.

[0547] E540. The antibody of E531 to E537, wherein the IL-13 binding domain is fused to the IL-4 binding domain, with or without a linker.

[0548] E541. The antibody of any one of E538 to E540, wherein the fusion is with a linker.

[0549] E542. The antibody of any one of E540 to E541, wherein the IL-13 binding domain is fused to the IL-4 binding domain with a linker.

[0550] E543. The antibody of E542, wherein the linker comprises SEQ ID NO: 104.

[0551] E544.(i) the second and fifth polypeptide chains together form a first Fab domain comprising a first antigen-binding site; (ii) the second and fourth polypeptide chains together form a second Fab domain that comprises a second antigen-binding site; (iii) the first and third polypeptide chains together form a third Fab domain that comprises a third antigen-binding site. The antibody of any one of E526 to E543, comprising a first, second, third, fourth and fifth polypeptide chain such that

[0552] E545. The antibody of E544, wherein the first and second polypeptide chains associate together to form an antibody comprising two arms: a double Fab arm comprising a first Fab domain and a second Fab domain, and a single Fab arm comprising a third Fab domain.

[0553] E546.(i) A first antigen-binding site specifically binds IL-13, a second antibody-binding site specifically binds IL-4, and a third antigen-binding site specifically binds at least one additional target; or (ii) a first antigen-binding site specifically binds IL-4, a second antibody-binding site specifically binds IL-13, and a third antigen-binding site specifically binds at least one additional target; or (iii) the first antigen-binding site specifically binds IL-4, the second antibody-binding site specifically binds at least one additional target, and the third antigen-binding site specifically binds IL-13; or (iv) the first antigen-binding site specifically binds IL-13, the second antibody-binding site specifically binds at least one additional target, and the third antigen-binding site specifically binds IL-4; or (v) the first antigen-binding site specifically binds to at least one additional target, the second antibody-binding site specifically binds to IL-13, and the third antigen-binding site specifically binds to IL-4; or (vi) the first antigen-binding site specifically binds to at least one additional target, the second antibody-binding site specifically binds to IL-4, and the third antigen-binding site specifically binds to IL-13; An antibody described in E526 to E545.

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

[0555] E548. The antibody of E44 to E547, wherein the fifth polypeptide chain comprises, at the C-terminus, the sequence EPKSC (SEQ ID NO: 122).

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

[0557] E550. The antibody of 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 comprises a first CH3 domain and the second Fc chain comprises a second CH3 domain, wherein the first CH3 domain and the second CH3 domain each comprise a different complementary sequence, and the different complementary sequences are selected from the following pairs of different complementary sequences: (i) SEQ ID NO: 111 and SEQ ID NO: 106, (ii) SEQ ID NO: 111 and SEQ ID NO: 114, (iii) SEQ ID NO: 114 and SEQ ID NO: 117, (iv) SEQ ID NO: 124 and SEQ ID NO: 127, (v) SEQ ID NO: 139 and SEQ ID NO: 141, and (vi) SEQ ID NO: 147 and SEQ ID NO: 148 The antibody of E544 to E550, selected from one of:

[0559] E552. The antibody of E551, wherein the first CH3 domain and the second CH3 domain comprise SEQ ID NO:124 and SEQ ID NO:127.

[0560] E553. The identity of the second, fourth, and fifth polypeptide chains is (i) the second polypeptide chain comprises SEQ ID NO: 145, the fourth polypeptide chain comprises SEQ ID NO: 196, and the fifth polypeptide chain comprises SEQ ID NO: 103; (ii) the second polypeptide chain comprises SEQ ID NO: 107, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 103; (iii) the second polypeptide chain comprises SEQ ID NO: 115, the fourth polypeptide chain comprises SEQ ID NO: 116, and the fifth polypeptide chain comprises SEQ ID NO: 103; (iv) the second polypeptide chain comprises SEQ ID NO: 121, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 103; (v) the second polypeptide chain comprises SEQ ID NO: 125, the fourth polypeptide chain comprises SEQ ID NO: 208, and the fifth polypeptide chain comprises SEQ ID NO: 122; (vi) the second polypeptide chain comprises SEQ ID NO: 130, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122; (vii) the second polypeptide chain comprises SEQ ID NO: 133, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122; (viii) the second polypeptide chain comprises SEQ ID NO: 144, the fourth polypeptide chain comprises SEQ ID NO: 136, and the fifth polypeptide chain comprises SEQ ID NO: 143; (ix) the second polypeptide chain comprises SEQ ID NO: 135, the fourth polypeptide chain comprises SEQ ID NO: 136, and the fifth polypeptide chain comprises SEQ ID NO: 122; (x) the second polypeptide chain comprises SEQ ID NO: 140, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122; (xi) the second polypeptide chain comprises SEQ ID NO: 149, the fourth polypeptide chain comprises SEQ ID NO: 196, and the fifth polypeptide chain comprises SEQ ID NO: 150; (xii) the second polypeptide chain comprises SEQ ID NO: 151, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 150; (xiii) the second polypeptide chain comprises SEQ ID NO: 159, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 150; (xiv) the second polypeptide chain comprises SEQ ID NO: 162, the fourth polypeptide chain comprises SEQ ID NO: 197, and the fifth polypeptide chain comprises SEQ ID NO: 163; (xv) the second polypeptide chain comprises SEQ ID NO: 154, the fourth polypeptide chain comprises SEQ ID NO: 196, and the fifth polypeptide chain comprises SEQ ID NO: 155; (xvi) the second polypeptide chain comprises SEQ ID NO: 156, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 155; (xvii) the second polypeptide chain comprises SEQ ID NO: 152, the fourth polypeptide chain comprises SEQ ID NO: 196, and the fifth polypeptide chain comprises SEQ ID NO: 98; (xviii) the second polypeptide chain comprises SEQ ID NO: 153, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 98; (xix) the second polypeptide chain comprises SEQ ID NO: 157, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 158; (xx) the second polypeptide chain comprises SEQ ID NO: 160, the fourth polypeptide chain comprises SEQ ID NO: 196, and the fifth polypeptide chain comprises SEQ ID NO: 158; (xxi) the second polypeptide chain comprises SEQ ID NO: 164, the fourth polypeptide chain comprises SEQ ID NO: 197, and the fifth polypeptide chain comprises SEQ ID NO: 122; and (xxii) the second polypeptide chain comprises SEQ ID NO: 178, the fourth polypeptide chain comprises SEQ ID NO: 196, and the fifth polypeptide chain comprises SEQ ID NO: 177; (xxiii) the second polypeptide chain comprises SEQ ID NO: 179, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 177; (xxiv) the second polypeptide chain comprises SEQ ID NO: 180, the fourth polypeptide chain comprises SEQ ID NO: 109, and the fifth polypeptide chain comprises SEQ ID NO: 122; (xxv) the second polypeptide chain comprises SEQ ID NO: 183, the fourth polypeptide chain comprises SEQ ID NO: 116, and the fifth polypeptide chain comprises SEQ ID NO: 177; (xxvi) the second polypeptide chain comprises SEQ ID NO: 125, the fourth polypeptide chain comprises SEQ ID NO: 207, and the fifth polypeptide chain comprises SEQ ID NO: 122; (xxvii) the second polypeptide chain comprises SEQ ID NO: 125, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122. Selected from the group consisting of: An antibody according to E544 to E552.

[0561] E554. The antibody of any one of E544 to E553, wherein the second polypeptide chain comprises SEQ ID NO: 130, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122.

[0562] E555. An isolated antibody that specifically binds IL-4 and specifically binds IL-13 and at least one additional target, comprising a first, a second, a third, a fourth, and a fifth polypeptide chain; (i) the second and fifth polypeptide chains together form a first Fab domain that contains an IL-13 binding site; (ii) the second and fourth polypeptide chains together form a second Fab domain that contains an IL-4 binding site; (iii) the first and third polypeptide chains together form a third Fab domain that contains at least one additional target binding site; the second polypeptide chain comprises SEQ ID NO: 130, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122; antibody.

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

[0564] E557. The antibody of E556, wherein the first Fc chain comprises, in N-terminal to C-terminal order, a first hinge region connected to a first CH2 region connected to a first CH3 region, and wherein the second Fc chain comprises, in N-terminal to C-terminal order, a second hinge region connected to a second CH2 region connected to a second CH3 region, and the first and second hinge regions comprise the pair of sequences set forth in SEQ ID NO: 129 and SEQ ID NO: 131, and the first and second CH3 regions 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] E558. The antibody of any one of E556 to E557, further comprising an antibody of one or more of E1 to E71, E77 to E143, E144 to E193, E199 to E259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, and E500 to E557.

[0566] E559. An isolated antibody comprising the CDRs of an antibody selected from one or more of Tables 80, 81, 82, 83, 84, 85, 86, and 87.

[0567] E560. An isolated antibody comprising a VH and a VL of an antibody selected from one or more of Tables 80, 81, 82, 83, 84, 85, 86, and 87.

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

[0569] E562.An isolated polynucleotide comprising one or more nucleotide sequences encoding an antibody of any one of E1 to E71, E77 to E143, E144 to 193, E199 to 259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, and E500 to E561.

[0570] E563. The polynucleotide according to E562, which is RNA.

[0571] E564. The polynucleotide of E562 to E563, comprising at least one chemical modification.

[0572] E565. The polynucleotide according to E564, wherein the chemical modification is selected from pseudouridine, 1-methylpseudouridine, N1-methylpseudouridine, N1-ethylpseudouridine, 2-thiouridine, 4'-thiouridine, 5-methylcytosine, 2-thio-1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio-dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio-pseudouridine, 4-methoxy-pseudouridine, 4-thio-1-methyl-pseudouridine, 4-thio-pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methyluridine, 5-methoxyuridine and 2'-O-methyluridine.

[0573] E566. The polynucleotide of E562 to E563, which does not comprise a chemical modification.

[0574] E567. An isolated polynucleotide encoding the VH, VL, or both, of an antibody that binds IL-33, wherein the nucleic acid comprises the nucleic acid sequence of SEQ ID NO: 202, the nucleic acid sequence of SEQ ID NO: 203, or both.

[0575] E568. An isolated polynucleotide encoding a polypeptide having a VH and a polypeptide having a VL, or both, of an antibody that binds to IL-33, wherein the nucleic acid comprises the nucleic acid sequence of SEQ ID NO: 190, the nucleic acid sequence of SEQ ID NO: 191, or both.

[0576] An isolated polynucleotide encoding the VH, VL, or both, of an antibody that binds E569.IL-33, wherein the nucleic acid comprises the nucleic acid sequence of an insert of a plasmid deposited with the ATCC and having Accession No. PTA-127209, the nucleic acid sequence of an insert of a plasmid deposited with the ATCC and having Accession No. PTA-127210, or both.

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

[0578] An isolated polynucleotide encoding the VH, VL, or both, of an antibody that binds 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 a VH and a polypeptide having a VL, or both, of an antibody that binds E572.TSLP, wherein the nucleic acid comprises the nucleic acid sequence of SEQ ID NO:192, the nucleic acid sequence of SEQ ID NO:193, or both.

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

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

[0582] An isolated polynucleotide encoding a polypeptide having a VH and a polypeptide having a 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 a VH and a polypeptide having a VL, or both, of an antibody that binds to E576.p40, wherein the nucleic acid comprises the nucleic acid sequence of an insert of a plasmid deposited with the ATCC and having accession number PTA-127204, the nucleic acid sequence of an insert of a plasmid deposited with the ATCC and having accession number PTA-127203, or both.

[0584] E577. An isolated polynucleotide encoding the VH, VL, or both, of an antibody that binds 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] E578. An isolated polynucleotide encoding a polypeptide having a VH and a polypeptide having a VL, or both, of an antibody that binds to IL-4, wherein the nucleic acid comprises the nucleic acid sequence of SEQ ID NO: 188, the nucleic acid sequence of SEQ ID NO: 189, or both.

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

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

[0588] E581. An isolated polynucleotide encoding the VH, VL, or both, of an antibody that binds IL-13, wherein the nucleic acid comprises the nucleic acid sequence of SEQ ID NO: 196, the nucleic acid sequence of SEQ ID NO: 195, or both.

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

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

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

[0592] E585. An isolated polynucleotide encoding one or more of the first, second, third, fourth, or fifth polypeptides of an anti-IL-4 / IL-13 / IL-33 antibody, (i) the IL33-VH sequence encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127210, and the IL33-VL sequence encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127209; (ii) the IL4-VH sequence encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127198, and the IL4-VL sequence encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127197; and (iii) the IL13-VH sequence encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127196, and the IL13-VL sequence encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127195. A polynucleotide comprising:

[0593] E586. An isolated polynucleotide encoding one or more of the first, second, third, fourth, or fifth polypeptides of an anti-IL-4 / IL-13 / IL-33 antibody, wherein the isolated antibody specifically binds IL-33, specifically binds IL-4, and specifically binds IL-13, and comprises a first, second, third, fourth, and fifth polypeptide chain; (i) the second and fifth polypeptide chains together form a first Fab domain that contains an IL-13 binding site; (ii) the second and fourth polypeptide chains together form a second Fab domain that contains an IL-4 binding site; (iii) the first and third polypeptide chains together form a third Fab domain that contains an IL-33 binding site; the first polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127208, the second polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127192, the third polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127207, the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127194, and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127193. Polynucleotide.

[0594] E587. An isolated polynucleotide encoding one or more of the first, second, third, fourth, or fifth polypeptides of an anti-IL-4 / IL-13 / TSLP antibody, wherein the antibody is (i) the TSLP-VH sequence encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127200, and the TSLP-VL sequence encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA0-127199; (ii) the IL4-VH sequence encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127198, and the IL4-VL sequence encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127197; and (iii) the IL13-VH sequence encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127196, and the IL13-VL sequence encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127195. A polynucleotide comprising:

[0595] E588. An isolated polynucleotide encoding one or more of the first, second, third, fourth, or fifth polypeptides of an anti-IL-4 / IL-13 / TSLP antibody, wherein the antibody comprises a first, second, third, fourth, and fifth polypeptide chain; (i) the second and fifth polypeptide chains together form a first Fab domain that contains an IL-13 binding site; (ii) the second and fourth polypeptide chains together form a second Fab domain that contains an IL-4 binding site; (iii) the first and third polypeptide chains together form a third Fab domain that contains a TSLP-binding site; the first polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127202, the second polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127192, the third polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127201, the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127194, and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127193. Polynucleotide.

[0596] E589. An isolated polynucleotide encoding one or more of the first, second, third, fourth, or fifth polypeptides of an anti-IL-4 / IL-13 / p40 antibody, wherein the antibody is (i) the p40-VH sequence encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127206, and the p40-VL sequence encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127205; (ii) the IL4-VH sequence encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127198, and the IL4-VL sequence encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127197; and (iii) the IL13-VH sequence encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127196, and the IL13-VL sequence encoded by the plasmid deposited with the ATCC and having ATCC Accession No. PTA-127195. A polynucleotide comprising:

[0597] E590. An isolated polynucleotide encoding one or more of the first, second, third, fourth, or fifth polypeptides of an anti-IL-4 / IL-13 / p40 antibody, wherein the antibody comprises a first, second, third, fourth, and fifth polypeptide chain; (i) the second and fifth polypeptide chains together form a first Fab domain that contains an IL-13 binding site; (ii) the second and fourth polypeptide chains together form a second Fab domain that contains an IL-4 binding site; (iii) the first and third polypeptide chains together form a third Fab domain that contains a p40 binding site; the first polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127204, the second polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127192, the third polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127203, the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127194, and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127193. Polynucleotide.

[0598] A vector comprising a polynucleotide according to any one of E591 to E562.

[0599] E592. An isolated host cell comprising a polynucleotide according to E562 to E590, or a vector according to E591.

[0600] E593. A method for producing an isolated antibody, comprising culturing a host cell according to E592 under conditions conducive to the production of the antibody, and recovering the antibody.

[0601] E594. A pharmaceutical composition comprising a therapeutically effective amount of an antibody of any one of E1 to E71, E77 to E143, E144 to 193, E199 to 259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, and E500 to E557, and a pharma- ceutically acceptable carrier.

[0602] E595. A method for making 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, the method comprising: (i) a first preassembly step in which the double Fab arms are incubated in a first preassembly conditioning buffer at a temperature between 2-10° C., the pH of the first preassembly conditioning buffer being 1-3 units below the isoelectric point (pI) of the double Fab arms; (ii) a second preassembly step in which the single Fab arm is incubated in a second preassembly conditioning buffer at a temperature between 2-10° C., the pH of the second preassembly conditioning buffer being 1-3 units below the isoelectric point (pI) of the single Fab arm; and (iii) a third assembly step, in which the double Fab arms and the single Fab arms from steps (i) and (ii) are mixed together in an assembly buffer for 1 to 24 hours. A method comprising:

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

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

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

[0606] E599.(i) a TSLP binding domain comprising a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), wherein CDR-H1 comprises the amino acid sequence of SEQ ID NO: 82, CDR-H2 comprises the amino acid sequence of SEQ ID NO: 83, CDR-H3 comprises the amino acid sequence of SEQ ID NO: 85, CDR-L1 comprises the amino acid sequence of SEQ ID NO: 86, CDR-L2 comprises the amino acid sequence of SEQ ID NO: 87, and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 211; (ii) the IL-4 binding domain comprises a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL), wherein CDR-H1 comprises the amino acid sequence of SEQ ID NO: 18, CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2, CDR-H3 comprises the amino acid sequence of SEQ ID NO: 3, CDR-L1 comprises the amino acid sequence of SEQ ID NO: 24, CDR-L2 comprises the amino acid sequence of SEQ ID NO: 12, and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 25; and (iii) the IL-13 binding domain comprises a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL), 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; An antibody described in any one of E381 to E384.

[0607] E600.(i) the TSLP binding portion comprises a TSLP-VH of SEQ ID NO: 92, and a TSLP-VL of SEQ ID NO: 213; (ii) the IL-4 binding portion comprises an IL4-VH of SEQ ID NO: 22 and an IL4-VL of SEQ ID NO: 26; and (iii) the IL-13 binding portion comprises an IL13-VH of SEQ ID NO: 51, and an IL13-VL of SEQ ID NO: 54; An antibody described in E387 to E390, or E599.

[0608] E601.(i) the TSLP binding domain comprises a TSLP-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127200, and a TSLP-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-____; (ii) the IL-4 binding domain comprises an IL4-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127198, and an IL4-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127197; and (iii) the IL-13 binding domain comprises an IL13-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127196, and an IL13-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127195; An antibody described in E387 to E390, or E599 to E600.

[0609] E602. An isolated antibody that specifically binds TSLP, specifically binds IL-4, and specifically binds IL-13, comprising a first, a second, a third, a fourth, and a fifth polypeptide chain; (i) the second and fifth polypeptide chains together form a first Fab domain that contains an IL-13 binding site; (ii) the second and fourth polypeptide chains together form a second Fab domain that contains an IL-4 binding site; (iii) the first and third polypeptide chains together form a third Fab domain that contains a TSLP-binding site; the first polypeptide chain comprises SEQ ID NO: 165, the second polypeptide chain comprises SEQ ID NO: 130, the third polypeptide chain comprises SEQ ID NO: 215, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122; antibody.

[0610] E603. An isolated antibody that specifically binds TSLP, specifically binds IL-4, and specifically binds IL-13, comprising a first, a second, a third, a fourth, and a fifth polypeptide chain; (iv) the second and fifth polypeptide chains together form a first Fab domain that contains an IL-13 binding site; (v) the second and fourth polypeptide chains together form a second Fab domain that contains an IL-4 binding site; (vi) the first and third polypeptide chains together form a third Fab domain that contains a TSLP-binding site; the first polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127202, the second polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127192, the third polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-_____, the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127194, and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127193. antibody.

[0611] E604.(i) a TSLP binding domain comprising a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), wherein CDR-H1 comprises the amino acid sequence of SEQ ID NO: 82, CDR-H2 comprises the amino acid sequence of SEQ ID NO: 83, CDR-H3 comprises the amino acid sequence of SEQ ID NO: 85, CDR-L1 comprises the amino acid sequence of SEQ ID NO: 86, CDR-L2 comprises the amino acid sequence of SEQ ID NO: 87, and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 212; (ii) the IL-4 binding domain comprises a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL), wherein CDR-H1 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), 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; An antibody described in any one of E381 to E390.

[0612] E605.(i) the TSLP binding portion comprises a TSLP-VH of SEQ ID NO: 92, and a TSLP-VL of SEQ ID NO: 214; (ii) the IL-4 binding portion comprises an IL4-VH of SEQ ID NO: 22, and an IL4-VL of SEQ ID NO: 26; (iii) the IL-13 binding portion comprises an IL13-VH of SEQ ID NO: 51, and an IL13-VL of SEQ ID NO: 54; An antibody described in E387 to E390 or E604.

[0613] E606.(i) the TSLP binding domain comprises a TSLP-VH sequence encoded by a plasmid deposited with the ATCC having ATCC Accession No. PTA-127200, and a TSLP-VL sequence encoded by a plasmid deposited with the ATCC having ATCC Accession No. PTA0-____; (ii) the IL-4 binding domain comprises an IL4-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127198, and an IL4-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127197; and (iii) the IL-13 binding domain comprises an IL13-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127196, and an IL13-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127195; An antibody described in E387 to E390, or E602 to E603.

[0614] E607. An isolated antibody that specifically binds TSLP, specifically binds IL-4, and specifically binds IL-13, comprising a first, a second, a third, a fourth, and a fifth polypeptide chain; (i) the second and fifth polypeptide chains together form a first Fab domain that contains an IL-13 binding site; (ii) the second and fourth polypeptide chains together form a second Fab domain that contains an IL-4 binding site; (iii) the first and third polypeptide chains together form a third Fab domain that contains a TSLP-binding site; the first polypeptide chain comprises SEQ ID NO: 165, the second polypeptide chain comprises SEQ ID NO: 130, the third polypeptide chain comprises SEQ ID NO: 216, the fourth polypeptide chain comprises SEQ ID NO: 27, and the fifth polypeptide chain comprises SEQ ID NO: 122; antibody.

[0615] E608. An isolated antibody that specifically binds TSLP, specifically binds IL-4, and specifically binds IL-13, comprising a first, a second, a third, a fourth, and a fifth polypeptide chain; (i) the second and fifth polypeptide chains together form a first Fab domain that contains an IL-13 binding site; (ii) the second and fourth polypeptide chains together form a second Fab domain that contains an IL-4 binding site; (iii) the first and third polypeptide chains together form a third Fab domain that contains a TSLP-binding site; the first polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127202, the second polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127192, the third polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-_____, the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127194, and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127193. antibody.

[0616] E609. The antibody of any one of E77 to E143, or E596 to E608 for use as a medicament.

[0617] E610. The antibody of E609, wherein the use is for the treatment of one or more selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloid, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, and fungal keratitis.

[0618] E611. The antibody of any one of E147 to E148, or E596 to E610, wherein the use is for the treatment of one or more selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, and non-alcoholic steatohepatitis (NASH).

[0619] E612. The antibody of any one of E147 to E149, or E596 to E611, wherein the use is for atopic dermatitis.

[0620] E613. The antibody of any one of E147 to E149, or E596 to E612, wherein the use is for non-alcoholic steatohepatitis (NASH).

[0621] E614. A pharmaceutical composition comprising a therapeutically effective amount of an antibody according to E77 to E143 or E596 to E608, and a pharma- ceutically acceptable carrier.

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

[0623] E616. The method of E615, wherein the condition is selected from the group consisting of atopic dermatitis, asthma, cancer, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, and fungal keratitis.

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

[0625] E618. The method of any one of E615 to E617, wherein the antibody or pharmaceutical composition is administered about twice a week, once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, twice a month, once a month, once every 2 months, once every 3 months, or once every 4 months.

[0626] E619. The antibody of any one of E1 to E71, E77 to E143, E144 to 193, E199 to 259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, E500 to E557, or E596 to E612 for use in inhibiting tumor growth.

[0627] E620. The antibody of any one of E1 to E71, E77 to E143, E144 to 193, E199 to 259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, E500 to E557, E596 to E612, or E619 for use in inhibiting the progression of malignant cell growth in a patient.

[0628] E621. The antibody of any one of E1 to E71, E77 to E143, E144 to 193, E199 to 259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, E500 to E557, E596 to E612, or E619 to E620 for use in inhibiting metastasis of malignant cells in a patient.

[0629] E622. The antibody of any one of E1 to E71, E77 to E143, E144 to 193, E199 to 259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, E500 to E557, E596 to E612, or E619 to E621 for use in inducing tumor shrinkage in a patient.

[0630] E623. The antibody of any one of E1 to E71, E77 to E143, E144 to 193, E199 to 259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, E500 to E557, E596 to E612, or E619 to E622 for use in treating cancer exhibiting solid tumors.

[0631] E624. Use in: Bladder cancer, Breast cancer, Clear cell renal cancer, Head / neck squamous cell carcinoma, Squamous cell lung cancer, 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) The antibody of any one of E1 to E71, E77 to E143, E144 to 193, E199 to 259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, E500 to E557, E596 to E612, or E619 to E623, which is for the treatment of one or more selected from the group consisting of: multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL), or small lymphocytic lymphoma (SLL).

[0632] E625. The antibody of any one of E1 to E71, E77 to E143, E144 to 193, E199 to 259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, E500 to E557, E596 to E612, or E619 to E624, wherein the use is for the treatment of one or more selected from the group consisting of renal cell carcinoma (RCC), bladder cancer, breast cancer, clear cell renal carcinoma, squamous cell carcinoma of the head / neck (SCCHN), squamous cell lung carcinoma, malignant melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, small cell lung cancer (SCLC) or triple negative breast cancer.

[0633] E626. Use is for the treatment of one or more selected from the group consisting of heme malignancies, and in some embodiments the heme malignancies are selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), EBV-positive DLBCL, primary mediastinal large B-cell lymphoma, T-cell / histiocyte-rich large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma (HL), mantle cell lymphoma, leukemia, myeloma, leukemia ... The antibody of any one of E1 to E71, E77 to E143, E144 to 193, E199 to 259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, E500 to E557, E596 to E612, or E619 to E625, which is a lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL), or small lymphocytic lymphoma (SLL).

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

[0635] E628. The method of E627, wherein the first anti-cancer therapeutic comprises an anti-IL-4 antibody.

[0636] E629. The method of E627 to E628, wherein the first anti-cancer therapy comprises an anti-IL-4 antibody of any one of E199 to E259.

[0637] E630. The method of E627 to E631, wherein the first anti-cancer therapeutic comprises an anti-IL-13 antibody.

[0638] E631. The method of E627 to E630, wherein the first anti-cancer therapy comprises an anti-IL-13 antibody of any one of E265 to E330.

[0639] E632. The method of E627 to E631, wherein the first anti-cancer therapeutic comprises an anti-TSLP antibody.

[0640] E633. The method of E627 to E632, wherein the first anti-cancer therapy comprises an anti-TSLP antibody of any one of E77 to E143, or E596 to E598.

[0641] E634. The method of E627 to E633, wherein the first anti-cancer therapeutic comprises an IL-4 / IL-13 antibody.

[0642] E635. The method of E627 to E634, wherein the first anti-cancer therapy comprises an IL-4 / IL-13 antibody, wherein the IL-4 / IL-13 antibody comprises an IL-4 / IL-13 antibody of any one of E526 to E558.

[0643] E636. The method of E627 to E635, wherein the first anti-cancer therapeutic comprises an IL-4 / IL-13 / TSLP antibody.

[0644] E637. The method of E627 to E636, wherein the first anti-cancer therapy comprises an IL-4 / IL-13 / TSLP antibody, wherein the IL-4 / IL-13 / TSLP antibody comprises an antibody of any one of E387 to E435, or E599 to E613.

[0645] E638. The method of E627 to E637, wherein the first anti-cancer therapy comprises an IL-4 / IL-13 / TSLP antibody, wherein the IL-4 / IL-13 / TSLP antibody comprises an antibody described in E412.

[0646] E639. The method of E627 to E637, wherein the first anti-cancer therapy comprises an IL-4 / IL-13 / TSLP antibody, wherein the IL-4 / IL-13 / TSLP antibody comprises an antibody described in E603.

[0647] E640. The method of E627 to E637, wherein the first anti-cancer therapy comprises an IL-4 / IL-13 / TSLP antibody, wherein the IL-4 / IL-13 / TSLP antibody comprises an antibody described in E607.

[0648] E641. The method of E627 to E640, wherein the second anti-cancer therapeutic agent is a PD-1 pathway antagonist.

[0649] E642. The method of E627 to E641, wherein the second anti-cancer therapeutic agent is a PD-1 antagonist.

[0650] E643. The method of E627 to E642, wherein the second anticancer therapeutic agent is a PD-1 antagonist, and the PD-1 antagonist is selected from the group consisting of: sasanlimab, BCD-100, camrelizumab, cemiplimab, genolimuzumab, MEDI0680, nivolumab, pembrolizumab, sintilimab, spartalizumab, STI-A1110, tislelizumab, atezolizumab, durvalumab, BMS-936559 (MDX-1105), LY3300054, TSR-042.

[0651] E644. The method of E627 to E643, wherein the second anti-cancer therapeutic agent is a PD-1 antagonist, and the PD-1 antagonist is an antibody comprising a VH set forth in SEQ ID NO: 4 and a VL set forth in SEQ ID NO: 8 of US10155037.

[0652] E644. The method of E627 to E643, wherein the second anti-cancer therapeutic agent is a PD-1 antagonist, and the PD-1 antagonist is sasanlimab.

[0653] E645. The method of E627 to E646, wherein the second anti-cancer therapeutic agent is a PD-1 antagonist, wherein the PD-1 antagonist is sasanlimab, an antibody comprising a HC comprising the sequence set forth in SEQ ID NO: 225, and a light chain comprising the sequence set forth in SEQ ID NO: 226.

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

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

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

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

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

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

[0660] E650. The method or medicament of any one of E627 to E649, wherein the cancer represents a solid tumor.

[0661] E651. Cancer is bladder cancer, breast cancer, clear cell renal cancer, head / neck squamous cell carcinoma, lung squamous cell carcinoma, 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 intestinal cancer (LDLC), diffuse large intestinal cancer (LV ... The method or medicament of any one of E627 to E650, wherein the lymphoma is one or more selected from the group consisting of large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin's lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL), or small lymphocytic lymphoma (SLL).

[0662] E652. The method or medicament of any one of E627 to E651, wherein the cancer is one or more selected from the group consisting of renal cell carcinoma (RCC), bladder cancer, breast cancer, clear cell renal carcinoma, squamous cell carcinoma of the head / neck (SCCHN), squamous cell lung carcinoma, malignant melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, small cell lung cancer (SCLC) or triple negative breast cancer.

[0663] E653. The method or medicament of 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 malignancies are acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), EBV-positive DLBCL, primary mediastinal large B-cell lymphoma, T-cell / histiocyte-rich large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL), or small lymphocytic lymphoma (SLL).

[0664] E654. The antibody, method or medicament for use of any one of E1 to E653, wherein at least one of the therapeutic agents is administered to the subject at intervals of once a day, once every 2 days, once every 3 days, once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 30 days, once every 5 weeks, once every 6 weeks, once a month, once every 2 months, once every 3 months, or once every 4 months.

[0665] E656. Atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, and nonalcoholic steatohepatitis (NASH), prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, fungal keratitis, bladder cancer, breast cancer, clear cell renal cancer, head / neck squamous cell carcinoma, lung squamous cell carcinoma, malignant melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, small cell lung cancer (SCLC), triple-negative breast cancer, urothelial carcinoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), or small lymphocytic Lymphoma (SLL), Heme malignancies, Acute lymphoblastic leukemia (ALL), Acute myeloid leukemia (AML), Chronic lymphocytic leukemia (CLL), Chronic myeloid leukemia (CML), Diffuse large B-cell lymphoma (DLBCL), EBV positive DLBCL, Primary mediastinal large B-cell lymphoma, T-cell / histiocyte-rich large B-cell lymphoma, Follicular lymphoma, Hodgkin lymphoma (HL), Mantle cell lymphoma (MCL), Multiple myeloma (MM), Myeloid cell leukemia-1 protein (Mcl-1), Myeloid Use of an antibody described in any one of E1 to E71, E77 to E143, E144 to 193, E199 to 259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, E500 to E557, E596 to E612, or E619 to E625 for the manufacture of a medicament for use in the treatment of one or more selected from the group consisting of dysplastic syndromes (MDS), non-Hodgkin's lymphoma (NHL), and small lymphocytic lymphoma (SLL).

[0666] E657. Atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, and nonalcoholic steatohepatitis (NASH), prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, fungal keratitis, bladder cancer, breast cancer, clear cell renal cancer, head / neck squamous cell carcinoma, lung squamous cell carcinoma, malignant melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, Small cell lung cancer (SCLC), triple-negative breast cancer, urothelial carcinoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), or small lymphoma Myeloid lymphoma (SLL), hemocytic malignancies, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), EBV-positive DLBCL, primary mediastinal large B-cell lymphoma, T-cell / histiocyte-rich large B-cell lymphoma, follicular lymphoma, Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1) , myelodysplastic syndromes (MDS), non-Hodgkin's lymphoma (NHL), and small lymphocytic lymphoma (SLL), comprising an antibody of any one of E1 to E71, E77 to E143, E144 to 193, E199 to 259, E265 to E330, E336 to E381, E387 to E435, E445 to E484, E500 to E557, E596 to E612, or E619 to E625.

[0667] An anti-disease agent comprising the antibody according to any one of 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, and 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-inflammatory diseases. Alcoholic steatohepatitis (NASH), prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, fungal keratitis, bladder cancer, breast cancer, clear cell renal cancer, head / neck squamous cell carcinoma, squamous cell lung carcinoma, 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), LL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), or small lymphocytic lymphoma (SLL), hemolytic malignancies, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CRL), chronic myelogenous leukemia (CRH ... CML), diffuse large B-cell lymphoma (DLBCL), EBV-positive DLBCL, primary mediastinal large B-cell lymphoma, T-cell / histiocyte-rich large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL), and small lymphocytic lymphoma (SLL). [Brief description of the drawings]

[0668] [Figure 1A]Figure 1A shows an exemplary sequence illustrating the Pfabat numbering of the light chain portion of the anti-IL-13 and anti-IL-4 binding arms. Position numbers are displayed vertically in a single column, with dashes ("-") indicating gaps in the 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 CDR positions considered are shown in bold, and the corresponding amino acids are bold and underlined. [Figure 1B] represents 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 displayed vertically in a single column, with dashes ("-") indicating gaps in the alignment. For example, residue H100C of anti-IL-4 CDR-L1 is Phe, and the anti-IL-13 binding arm with a shorter CDRH3 does not have a corresponding residue. The CDR positions considered are shown in bold, with the corresponding amino acids in bold and underlined. The anti-IL-13 heavy chain fragments used in most multispecific antibody sequences do not contain a complete hinge or Fc. The Pfabat algorithm numbers the sequences as independent Fab domains and does not number the small upper hinge fragment ("EPKSC" (SEQ ID NO: 102)), which is included manually for reference (lower case, positions H226-H230). [Diagram 2] FIG. 2 represents a graph summarizing the results of the LC / MS analysis of the IL4-1285 antibody. It reveals that the post-translational modification is located on the light chain. Mass analysis of peak 1 (P1) versus 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 as analyzed by ion exchange purification and also detected by using light chain LC / MS analysis (after LysC+TCEP). P2 refers to "peak 2" as isolated by ion exchange purification and also detected by using light chain LC / MS analysis (after LysC+TCEP). Peak 2 has an additional sulfation to Tyr (L27a), so it has a shift of 80 Da in MS. [Diagram 3] FIG. 3 represents a graph comparing LC / MS analysis 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 eliminated the heterogeneity. The left panels on both top and bottom are peptide level mapping data (AspN enzyme). The right panels on both top and bottom are subunits using the LysC method. Peptide mapping (AspN digestion) shows that in the top left spectrum, the DFD light chain contains no sulfation and the DYD light chain has some sulfation (one at +79.9568 Da). Subunit analysis shows that the DFD light chain has no sulfated species (upper right spectrum) and the DYD light chain has several sulfated Da species (lower right spectrum). [Figure 4] FIG. 4 depicts the changes engineered into IL4-1359 (VH1 G07_VLv2.9) VH CDRH1 that contribute to higher affinity for IL-4. [Diagram 5] FIG. 5 depicts changes at Tyr(L27d)E that can be made to remove the O-sulfation post-translational modification and further stabilize the IL-4 / IL4-1285 (RA1-2 or hu3B9-VLv2.0) interface. [Figure 6] FIG. 6 depicts an 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] FIG. 7 is an illustration depicting CDRL1 differences in IL13-1307 (hu13.4) versus IL13-1283 (IMA-638 or hu13.2) that contribute to higher affinity for human IL-13. [Figure 8] FIG. 8 depicts the amino acid differences in CDRH3 between IL13-1307 (hu13.4) and IL13-1283 (IMA-638 or hu13.2) that contribute to higher affinity for IL-13. [Figure 9] FIG. 9 depicts how the presence of a 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] FIG. 10 depicts how the aspartic acid at position 55 in IL13-1307 (hu13.4) CDRH2, instead of the glycine at this position in IL13-1283, contributes to the higher affinity for IL-13 compared to IL13-1283 (IMA-638 or hu13.2). [Figure 11] FIG. 11 depicts how the changes engineered into IL13-0001 (1RVHC9-VLA4) VH CDRH3 contribute to higher affinity for IL-13. [Figure 12] FIG. 12 depicts how the changes engineered into IL13-0001 (1RVHC9-VLA4) VL CDRL1 contribute to higher affinity for IL-13. [Figure 13] FIG. 13 depicts a graph showing how increasing potency of IL-33 neutralization correlates with increasing polyreactivity. [Figure 14A] Figure 14 shows high throughput off-rate screening of anti-TSLP variants. Figure 14A: Sensorgrams of off-rate screening. R represents 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 depicts high-throughput off-rate screening of anti-TSLP variants. Figure 14B: Spotfire plot of association index vs. dissociation index. Variants in 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 area focused on reducing viscosity was the negative charge patch circled with a black dashed line. These three patches contain parts of CDR L1-L2, L3-H2-H3 and H2, respectively. [Figure 16] Figure 16 is a diagram depicting details of the antibody:TSLP interface. The VH-E99Y mutation potentially introduces a new hydrogen bond network at the TSLP-Ab interface. Selected interface residues are labeled and shown as sticks. N71 and R149 are from TSLP. Dashed lines represent salt bridges and hydrogen bonds. Light grey: TSLP with a-helical structure. Dark grey: antibody. This also increases the overall packing. [Figure 17] 17 depicts a graph showing the viscosity analysis of anti-TSLP variants. Viscosity was measured by a DLS bead-based method. [Figure 18A] Figure 18A shows a general schematic and nomenclature of trispecific Tri-Fab-Fc and Fab domains. Figure 18A shows a schematic depicting Tri-Fab-Fc, showing domains Fab1, Fab2, and Fab3, and single Fab (SFab) and double Fab (DFab) arms expressed in separate cells. Note: VL indicates light chain variable domain, VH indicates heavy chain variable domain, Ck indicates kappa constant light domain, Cl indicates lambda constant light domain, and CH1 indicates heavy chain constant domain 1. EPKSC (SEQ ID NO: 102): A stretch of amino acids 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 depicts a general schematic and nomenclature of trispecific Tri-Fab-Fc and Fab domains. Figure 18B depicts a schematic of a conventional Fab. Note: VL denotes the light chain variable domain, VH denotes the heavy chain variable domain, Ck denotes the kappa constant light domain, Cl denotes the lambda constant light domain, and CH1 denotes the heavy chain constant domain 1. EPKSC (SEQ ID NO: 102): A stretch of amino acids from the IgG1 upper hinge region fused to the C-terminus of CH1 to form a disulfide bond with CL (Fab1). [Figure 18C] Figure 18C shows a general schematic and nomenclature of trispecific Tri-Fab-Fc and Fab domains. Figure 18C shows a schematic of modified Fd. Note: VL indicates light chain variable domain, VH indicates heavy chain variable domain, Ck indicates kappa constant light domain, Cl indicates lambda constant light domain, and CH1 indicates heavy chain constant domain 1. EPKSC (SEQ ID NO: 102): A stretch of amino acids from an IgG1 upper hinge region fused to the C-terminus of CH1 to form a disulfide bond with CL (Fab1). [Figure 18D] Figure 18D shows a general schematic and nomenclature of trispecific Tri-Fab-Fc and Fab domains. Figure 18D shows a schematic of VH-VL swap. Note: VL indicates light chain variable domain, VH indicates heavy chain variable domain, Ck indicates kappa constant light domain, Cl indicates lambda constant light domain, and CH1 indicates heavy chain constant domain 1. EPKSC (SEQ ID NO: 102): A stretch of amino acids from IgG1 upper hinge region fused to the C-terminus of CH1 to form a disulfide bond with CL (Fab1). [Figure 18E] Figure 18E depicts a general schematic and nomenclature of trispecific Tri-Fab-Fc and Fab domains. Figure 18E depicts a schematic of S1. Note: VL denotes light chain variable domain, VH denotes heavy chain variable domain, Ck denotes kappa constant light domain, Cl denotes lambda constant light domain, and CH1 denotes heavy chain constant domain 1. EPKSC (SEQ ID NO: 102): A stretch of amino acids from an IgG1 upper hinge region fused to the C-terminus of CH1 to form a disulfide bond with CL (Fab1). [Figure 18F] Figure 18F represents a general schematic and nomenclature of trispecific Tri-Fab-Fc and Fab domains. Figure 18F represents a schematic of S1Rev. Note: VL represents the light chain variable domain, VH represents the heavy chain variable domain, Ck represents the kappa constant light domain, Cl represents the lambda constant light domain, and CH1 represents the heavy chain constant domain 1. EPKSC (SEQ ID NO: 102): A stretch of amino acids 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 represents a general schematic and nomenclature of trispecific Tri-Fab-Fc and Fab domains. Figure 18G represents a schematic of CH-Ck swap. Note: VL represents the light chain variable domain, VH represents the heavy chain variable domain, Ck represents the kappa constant light domain, Cl represents the lambda constant light domain, and CH1 represents the heavy chain constant domain 1. EPKSC (SEQ ID NO: 102): A stretch of amino acids 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 represents a general schematic and nomenclature of trispecific Tri-Fab-Fc and Fab domains. Figure 18H represents a schematic of CH-Cl swap. Note: VL represents the light chain variable domain, VH represents the heavy chain variable domain, Ck represents the kappa constant light domain, Cl represents the lambda constant light domain, and CH1 represents the heavy chain constant domain 1. EPKSC (SEQ ID NO: 102): A stretch of amino acids from the IgG1 upper hinge region fused to the C-terminus of CH1 to form a disulfide bond with CL (Fab1). [Figure 18I]Figure 18I shows a general schematic and nomenclature of trispecific Tri-Fab-Fc and Fab domains. Figure 18I shows an exploded view of Tri-Fab-Fc, showing the individual protein chains: SFab HC(3) and SFab LC(3) chains that together make the SFab arm, and DFab LC(1)-HC(2), modified Fd(1), and DFab LC(2) chains that together make 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 stretch of amino acids 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 chain pairing at the Fab1 position. Figure 19A shows the configuration of two native chain pairing Tri-Fab-Fc variants, where all three Fabs have traditional chain pairing. S1: S1 mutation in CH1 / CK. S1rev: S1rev mutation in CH1 / CK. Positively charged (+) mutations are solid black circles. Negatively charged (-) mutations are dashed black circles. [Figure 19B] Figure 19B depicts the configuration and characterization of Tri-Fab-Fc with native chain pairing at the Fab1 position. Figure 19B depicts the configuration of two native chain pairing Tri-Fab-Fc variants, where all three Fabs have traditional chain pairing. S1: S1 mutation in CH1 / CK. S1rev: S1rev mutation in CH1 / CK. Positively charged (+) mutations are solid black circles. Negatively charged (-) mutations are dashed black circles. [Figure 19C] Figure 19C depicts the configuration and characterization of Tri-Fab-Fc with native chain pairing at the Fab1 position. Figure 19C depicts a graph showing analytical SEC of IL413TSLP-0003 and IL413TSLP-0004 after Mab Select SuRe elution and prepSEC superdex 200 purification. [Figure 19D]Figure 19D depicts the configuration and characterization of Tri-Fab-Fc with native chain pairing at the Fab1 position. Figure 19D depicts a graph showing the LCMS analysis of IL413TSLP-0003. The table lists each chain of the trispecific and the corresponding theoretical chain mass. The numbers 1-5 are placed in front of each chain to provide an abbreviated description of the chain composition for the major peak in LCMS. [Figure 19E] Figure 19E depicts the configuration and characterization of Tri-Fab-Fc with native chain pairing at the Fab1 position. Figure 19E depicts a graph showing the LCMS analysis of IL413TSLP-0004. The table lists each chain of the trispecific and the corresponding theoretical chain mass. The numbers 1-5 are placed in front of each chain to provide an abbreviated description of the chain composition for the major peak in LCMS. [Figure 20A] Figure 20A depicts a schematic diagram showing the configurations of 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 the structures VL-CH1 and VH-Cl at the N-terminus of the dual Fab arms. [Figure 20B] Figure 20B depicts a schematic diagram showing the configurations of 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 the structures VL-CH1 and VH-Cl at the N-terminus of the dual Fab arms. [Figure 20C]Figure 20C depicts a schematic diagram showing the configurations of 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 dual Fab chains and a VH-Cl Fab1 light chain. [Figure 20D] Figure 20D depicts a schematic diagram showing the configurations of 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 dual Fab chains and a VH-Cl Fab1 light chain. [Figure 20E] Figure 20E depicts a schematic showing the configurations of 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 represented by IL13433-0021 (Figure 20E) has Fab1 and Fab3 carrying the S1 and S1 rev mutations, respectively, with Fab2 containing the VL-CH1 structure and VH-CL fused to the N-terminus of the Fc. [Figure 20F] Figure 20F depicts a schematic showing the configurations of 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 represented by IL13433-0022 (Figure 20F) has Fab1 and Fab3 carrying S1 and S1 rev mutations, respectively, and Fab2 contains a VL-CH1 structure with a SS elbow between the VL and CH1 domains, and VH-CL is fused to the N-terminus of the Fc. [Figure 21] Figure 21 depicts a graph showing the effect of domain geometry on Tri-Fab-Fc binding activity assessed by bridging ELISA. TPP-9662 is an IL-4 / IL-13 bispecific antibody with S1 / S1rev and KiH. mab8.8 is a negative control antibody. [Figure 22A] Figure 22 shows the improvement of Tri-Fab-Fc chain pairing by adjusting the DNA ratio in transient transfection. Figure 22A shows NuPAGE Bis-tris gel analysis. R: reduced. NR: non-reduced. [Figure 22B] Figure 22 depicts the improvement of Tri-Fab-Fc chain pairing by adjusting the DNA ratio in transient transfections. Figure 22B depicts a graph showing aSEC analysis. [Figure 23A] FIG. 23A depicts a schematic of the Tri-Fab-Fc variants engineered with modified Fd format and S1 / S1rev complementary mutations. [Figure 23B] FIG. 23B depicts a schematic of the Tri-Fab-Fc variants engineered with modified Fd format and S1 / S1rev complementary mutations. [Figure 23C] FIG. 23C depicts a schematic of the Tri-Fab-Fc variants engineered with modified Fd format and S1 / S1rev complementary mutations. [Figure 23D] FIG. 23D depicts a schematic of the Tri-Fab-Fc variants engineered with modified Fd format and S1 / S1rev complementary mutations. [Figure 24] FIG. 24 depicts non-reduced and reduced unstained SDS-PAGE analysis of stable CHO-produced Tri-Fab-Fc. [Figure 25A]Figure 25A depicts schematics of representative Tri-Fab-Fc trispecific configurations with CkS or mFd pairing of Fab1 using charge-based heterodimerization. RRR or EEE charge mutations: two RR / EE in the hinge region and one R / E 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 depicts schematics of representative Tri-Fab-Fc trispecific configurations with CkS or mFd pairing of Fab1 using charge-based heterodimerization. RRR or EEE charge mutations: two RR / EE in the hinge region and one R / E 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] FIG. 26 depicts a schematic of the anti-IL-13 / IL-4 dual Fab EEE arm design with an anti-IL-13 domain as mFd in Fab position 1 and an anti-IL-4 domain in Fab position 2. [Figure 27] FIG. 27 depicts a schematic of the anti-IL-13 / IL-4 dual Fab EEE CB arm design with an anti-IL-4 binding domain as mFd in Fab position 1 and an anti-IL-13 domain in Fab position 2. [Figure 28A] FIG. 28A depicts a schematic of the anti-IL-13 / IL-4 dual Fab EEE arm design with CκS at Fab position 1. [Figure 28B] FIG. 28B depicts a schematic of the anti-IL-13 / IL-4 dual Fab EEE arm design with CκS at Fab position 1. [Figure 29A] FIG. 29A depicts a graph showing that Tri-Fab-Fc IL13433-0006 can simultaneously bind to human IL-4, IL-13, and IL-33. [Figure 29B]FIG. 29B depicts a graph showing that Tri-Fab-Fc IL13433-0006 can simultaneously bind to human IL-4, IL-13, and IL-33. [Figure 29C] FIG. 29C depicts a graph showing that Tri-Fab-Fc IL13433-0006 can simultaneously bind to human IL-4, IL-13, and IL-33. [Diagram 30] FIG. 30 depicts SPR sensorgrams of IL413p40-0705 with human IL-4, IL-13 and IL-23 in various injection orders. [Figure 31A] FIG. 31A depicts dual cell-designed Tri-Fab-Fc variants with mFd format and S1-S1rev complementary mutations. [Figure 31B] FIG. 31B depicts dual cell-designed Tri-Fab-Fc variants with mFd format and S1-S1rev complementary mutations. [Figure 31C] FIG. 31C depicts dual cell-designed Tri-Fab-Fc variants with mFd format and S1-S1rev complementary mutations. [Figure 31D] FIG. 31D depicts dual cell-designed Tri-Fab-Fc variants with mFd format and S1-S1rev complementary mutations. [Diagram 32] FIG. 32 depicts a Tri-Fab-Fc engineered with a modified Fd format and produced using a single-cell process. [Diagram 33] FIG. 33 depicts a graph showing the viscosity of IL413p40-0698 and IL413p40-0700 as measured by differential light scattering (DLS). [Diagram 34]Figure 34 is a graph depicting anti-IL-4 / 13 / 33 Tri-Fab-Fc IV pharmacokinetics in Tg32 mice. Antibody designs are abbreviated to their four numeric 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 with Fc domains further comprising the LS mutations described herein. [Figure 35A] Figure 35A depicts a graph showing trispecific binding to human, cynomolgus monkey, mouse, and rat IL-4 by surface plasmon resonance. Trispecific: (a) IL13433-1258 was immobilized on a CM5 sensor chip and binding of 200 nM human (hu), cynomolgus monkey (cy), mouse (mu), rabbit (rb) or rat (rt) IL-4 was determined by surface plasmon resonance. [Figure 35B] Figure 35B depicts a graph showing trispecific binding to human, cynomolgus monkey, mouse, and rat IL-4 by surface plasmon resonance. Trispecific: (b) IL413TSLP-1024 was immobilized on a CM5 sensor chip and binding of 200 nM human (hu), cynomolgus monkey (cy), mouse (mu), rabbit (rb) or rat (rt) IL-4 was determined by surface plasmon resonance. [Figure 35C] Figure 35C depicts a graph showing trispecific binding to human, cynomolgus monkey, mouse, and rat IL-4 by surface plasmon resonance. Trispecific: (c) IL413P40-0705 was immobilized on a CM5 sensor chip and binding of 200 nM human (hu), cynomolgus monkey (cy), mouse (mu), rabbit (rb) or rat (rt) IL-4 was determined by surface plasmon resonance. [Figure 36A]Figure 36A depicts a graph showing trispecific binding to human, cynomolgus monkey, mouse, and rat IL-13 by surface plasmon resonance. Trispecific: (a) IL13433-1258 was immobilized on a CM5 sensor chip and binding of 200 nM human (hu), cynomolgus monkey (cy), mouse (mu), rabbit (rb) or rat (rt) IL-13 was determined by surface plasmon resonance. [Figure 36B] Figure 36B depicts a graph showing trispecific binding to human, cynomolgus monkey, mouse, and rat IL-13 by surface plasmon resonance. Trispecific: (b) IL413TSLP-1024 was immobilized on a CM5 sensor chip and binding of 200 nM human (hu), cynomolgus monkey (cy), mouse (mu), rabbit (rb) or rat (rt) IL-13 was determined by surface plasmon resonance. [Figure 36C] Figure 36C depicts a graph showing trispecific binding to human, cynomolgus monkey, mouse, and rat IL-13 by surface plasmon resonance. Trispecific: (c) IL413P40-0705 was immobilized on a CM5 sensor chip and binding of 200 nM human (hu), cynomolgus monkey (cy), mouse (mu), rabbit (rb) or rat (rt) IL-13 was determined by surface plasmon resonance. [Figure 37] FIG. 37 is a schematic diagram depicting the location of different Fabs within a Tri-Fab-Fc construct with modified Fd (mFd) design. [Figure 38] FIG. 38 represents SPR sensorgrams of Tri-Fab-Fc IL413p40-0705 with human (hu), cynomolgus monkey (cy), mouse (mu), rat (rt) and rabbit (rb) IL-12, IL-23, IL-4, and IL-13. [Figure 39] FIG. 39 depicts a graph showing species specificity for IL-33 binding to trispecific IL13433-1258 by surface plasmon resonance. [Diagram 40]FIG. 40 depicts a graph showing binding of short and long form TSLP to TSLP-0001, mAb TSLP-0875, and trispecific IL413TSLP-1024 by surface plasmon resonance. [Diagram 41] Figure 41 depicts a graph showing the bioactivity of short- and long-form TSLP in inducing monocyte TARC production. Mononuclear cells isolated from human peripheral blood were incubated overnight at 37°C with 0.31 pg / mL to 20 ng / mL of recombinant human TSLP (Pfizer), short-form TSLP (TSLPlf Avi V5 His 10 Biotin), or long-form TSLP (TSLPlf Avi V5 His 10 Biotin). TARC production in cell supernatants was quantified by MSD. Data are expressed as mean + / - SD. EC50 values ​​for hTSLP, sfTSLP, and lfTSLP are 0.3680, N / A, and 7.472 ng / mL, respectively. [Diagram 42] 42 depicts a graph showing binding of human, cynomolgus monkey, mouse, and rat TSLP to the trispecific IL413TSLP-1024 by surface plasmon resonance. Biotinylated human (hu), cynomolgus monkey (cy), mouse (mu), or rat (rt) TSLP was captured on a biotin CAP sensor chip and binding of the IL413TSLP-1024 trispecific was determined by surface plasmon resonance. [Diagram 43] FIG. 43 depicts a graph showing simultaneous binding of IL-4, IL-13, and TSLP to IL413TSLP-1024 by surface plasmon resonance. [Figure 44A]FIG. 44A depicts a graph showing the mean CT26 tumor volume over time and at the end of the study. Results of a study in which CT26 tumor-bearing Balb / c mice were dosed with the compounds listed in Table 88. (A) Mean volume (mm3) of implanted tumors over time and standard error of the mean starting on 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 with mIL13Ra2-mFc, or anti-IL-4 antibody with mIL13Ra2-mFc and anti-PD-1 antibody did not significantly alter tumor growth characteristics compared to isotype-treated animals. In contrast, mice treated with anti-IL-4, anti-TSLP and mIL13Ra2-mFc (40% tumor growth inhibition, p=0.043) or anti-IL-4, anti-TSLP and anti-PD-1 and mIL13Ra2-mFc (54% tumor growth inhibition, p=0.002) showed significant tumor growth inhibition relative to the isotype. [Figure 44B] Figure 44B depicts a graph showing the mean CT26 tumor volume over time and at the end of the study. Results of a study in which CT26 tumor-bearing Balb / c mice were dosed with the compounds listed in Table 88. (B) Volume of implanted tumors (mm3) at day 22 post-implant (last day of 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, mIL13Ra2-mFc and anti-PD-1 antibody did not significantly alter tumor growth characteristics compared to isotype-treated animals. In contrast, mice treated with anti-IL-4, anti-TSLP and mIL13Ra2-mFc (40% tumor growth inhibition, p=0.043) or anti-IL-4, anti-TSLP and anti-PD-1 and mIL13Ra2-mFc (54% tumor growth inhibition, p=0.002) showed significant tumor growth inhibition relative to the isotype. [Diagram 45]Figure 45 depicts a graph showing CT26 tumor volume per mouse in each treatment group over time. Volume (mm3) of subcutaneously implanted CT26 tumors over time starting on day 9 (day 1 of drug injection) for individual mice in each treatment group. [Figure 46A] FIG. 46A depicts graphs showing that neutralization of IL-4 with mAb IL4-1040 or neutralization of TSLP with mAb TSLP-0875 prevents the 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 with treatments listed in Table 2. (A) shows interferon gamma secretion from six separate 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 presented as mean and standard deviation. Statistical tests in (A and B) are analysis of variance with p-values ​​from post-hoc Sidak multiple comparison tests shown above the bars. [Figure 46B] Figure 46B depicts a graph showing that neutralization of IL-4 with mAb IL4-1040 or neutralization of TSLP with mAb TSLP-0875 prevents the 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 with 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 presented as mean and standard deviation. Statistical tests in (A and B) are analysis of variance with p-values ​​from post-hoc Sidak multiple comparison tests shown above the bars. [Figure 47A]FIG. 47A depicts graphs showing that neutralization of IL-4 with mAb IL4-1040 and / or neutralization of TSLP with mAb TSLP-0875 improved T cell-mediated control of human A375 cancer cell growth in vitro, which 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 generated as described in Example 88. (A) Primary human T cells were polarized and restimulated with: (A) isotype antibody alone, isotype antibody and 0.8 ng / mL recombinant human IL-4, or mAb IL4-1040 and 0.8 ng / mL recombinant human IL-4. Secreted interferon gamma levels correlated with normalized A375 AUC from the same wells. (A-C) Data from donor 1923. Data in (A-C) are presented as the mean and standard deviation of six technical replicates and exemplary data from three different donors. [Figure 47B] FIG. 47B depicts graphs showing that neutralization of IL-4 with mAb IL4-1040 and / or neutralization of TSLP with mAb TSLP-0875 improved T cell-mediated control of human A375 cancer cell growth in vitro, which 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 generated as described in Example 88. (A) Primary human T cells were polarized and restimulated with: (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. Secreted interferon gamma levels correlated with normalized A375 AUC from the same wells. (A-C) Data from donor 1923. Data in (A-C) are presented as the mean and standard deviation of six technical replicates and exemplary data from three different donors. [Figure 47C]Figure 47C depicts a graph showing that neutralization of IL-4 with mAb IL4-1040 and / or neutralization of TSLP with mAb TSLP-0875 improved T cell-mediated control of human A375 cancer cell growth in vitro, which 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 generated as described in Example 88. (A) Primary human T cells were polarized and restimulated with: (C) isotype antibody alone, isotype antibody and 0.8 ng / mL of each recombinant human IL-4 and TSLP, or a combination of mAb1040, mAb and 0.8 ng / mL of each recombinant human IL-4 and TSLP. Levels of secreted interferon gamma were correlated with normalized A375 AUC from the same well. (A-C) Data from donor 1923. Data in (A-C) are represented as mean and standard deviation of six technical replicates and exemplary data from three different donors. [Figure 47D] FIG. 47D depicts a graph showing that neutralization of IL-4 with mAb IL4-1040 and / or neutralization of TSLP with mAb TSLP-0875 improved T cell-mediated control of human A375 cancer cell growth in vitro, which 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 generated as described in Example 88. (D) Interferon gamma was quantified in conditioned medium collected on day 5 of restimulation as described in Example 87. The level of secreted interferon gamma correlated with normalized A375 AUC from the same well. (D) Data from donor 8385. Data in (D) are presented as the average of six technical replicates and illustrative data from four donors. [Figure 48]Figure 48 depicts a graph showing 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 depicts a graph showing neutralization of IL-4- and IL-13-induced CCL17 secretion from human clear cell renal cell carcinoma cell line 769-P by trispecific IL413TSLP-1028 and IL413TSLP-1037. 769-P human clear cell renal cell carcinoma cells were incubated with recombinant human IL-4 (A) together with dilutions of trispecific IL413TSLP-1028 or IL413TSLP-1037 for approximately 20 hours at 37°C. CCL17 secretion was quantified by Legendplex and concentrations were extrapolated from a standard curve. [Figure 49B] Figure 49B depicts a graph showing neutralization of IL-4- and IL-13-induced CCL17 secretion from human clear cell renal cell carcinoma cell line 769-P by trispecific IL413TSLP-1028 and IL413TSLP-1037. 769-P human clear cell renal cell carcinoma cells were incubated with dilutions of trispecific IL413TSLP-1028 or IL413TSLP-1037 with IL-13 (B) for approximately 20 hours at 37°C. CCL17 secretion was quantified by Legendplex and concentrations were extrapolated from a standard curve. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0669] Detailed Description Provided herein are antibodies that specifically bind to IL-4, antibodies that specifically bind to IL-13, antibodies that specifically bind to IL-33, antibodies that specifically bind to TSLP, and multispecific antibodies that specifically bind to IL-4 and IL-13 together with one of IL-33, TSLP, and p40. Related nucleic acids, compositions, and methods of making and using the antibodies are also provided herein.

[0670] general technique All references cited herein, including patent applications, patent publications, and UniProtKB accession numbers, are hereby incorporated by reference as if each individual reference was specifically and individually indicated to be incorporated by reference in its entirety.

[0671] The techniques and procedures described or referenced herein will generally be understood by those of skill in the art to be readily understood using conventional methodology, e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual 3rd ed. (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY CURRENT PROTOCOLS IN MOLECULAR BIOLOGY (FMA Usubel et al., eds. (2003)); the series METHODS IN ENZYMOLOGY (Academic Press, Inc.): PCR 2: A PRACTICAL APPROACH (MJ MacPherson, B.D. Hames, and G.R. Taylor, eds. (1995)), Harlow and Lane, eds. (1988) ANTIBODIES, A LABORATORY MANUAL, and ANIMAL CELL CULTURE (R.I. Freshney, ed. (1987)); Oligonucleotide Synthesis (MJ Gait, ed. 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (ed. J. E. Elis, 1998) Academic Press; Animal Cell Culture (ed. R. I. Freshney, 1987); Introduction to Cell and Tissue Culture (J. P. Mather and P. E. Oberts, 1998) Plenum Press; Cell and Tissue Culture Laboratory Procedures (eds. A. Doyle, J. B. Griffiths, and D. G. Newell, 1993-8) J. Wiley and Sons; Handbook of Experimental Immunology (eds. D. M. Weir and C. C. Blackwell); Gene Transfer Vectors for Mammalian Cells (J. M. Miller and M. P.Calos, 1987; PCR: The Polymerase Chain Reaction, (Mullis et al., 1994); Current Protocols in Immunology (JE Coligan et al., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C.A. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: A Practical Approach (D. Catty, ed., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999)); The Antibodies (M. Zanetti and JD Capra, eds., Harwood Academic Press, 1999) Publishers, 1995); and revised editions thereof, using widely used methodologies that are well understood and commonly used.

[0672] definition Unless otherwise defined, all technical terms, notations, and other scientific terms or terminology used herein are intended to have the meanings that are commonly understood by those skilled in the art to which the present invention belongs. 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 (single), and B (single). 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 (single), B (single), and C (single). In some cases, terms with commonly understood meanings are defined herein for clarity and / or ready reference, and the inclusion of such definitions herein should not necessarily be interpreted as representing a substantial difference to what is commonly understood in the art.

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

[0674] As used herein, numerical ranges are inclusive of the numbers defining the range.

[0675] Reference herein to "about" a value or parameter includes (and describes) embodiments directed to the value or parameter itself, as well as values ​​or parameters that may be less than or greater than the stated numerical value for that parameter by about 10%. For example, a dose of "about 5 mg / kg" includes 5 mg / kg, and any value between 4.5 mg / kg and 5.5 mg / kg. When the term "about" is used within the context of a period (years, months, weeks, days, etc.), it means that period plus or minus some amount of the next subperiod (e.g., about 1 year means 11-13 months, about 6 months means 6 months plus or minus 1 week, about 1 week means 6-8 days, etc.), or within 10 percent of the stated value, whichever is greater.

[0676] "Antibody" refers to an immunoglobulin molecule capable of specifically binding to a target, e.g., a polypeptide, carbohydrate, polynucleotide, lipid, etc., via at least one antigen-binding site located in the variable region of the immunoglobulin molecule. As used herein, the term "antibody" can encompass any type of antibody (e.g., monospecific, bispecific, trispecific, multispecific), including portions of intact antibodies that retain the ability to bind to a given antigen (e.g., "antigen-binding fragments"), and any other modified configuration of an immunoglobulin molecule that contains an antigen-binding site.

[0677] Antibodies include antibodies of any class, e.g., IgG, IgA, or IgM (or subclasses thereof), and do not require that an antibody be of any particular class. Depending on the antibody amino acid sequence of the constant region of its heavy chain (HC), immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these are further subdivided into subclasses (isotypes), e.g., IgG 1 , IgG 2 , IgG 3 , IgG 4 , IgA 1 and IgA 2The heavy chain constant regions that correspond to the 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 antigen-binding fragments of antibodies and modified configurations 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 bridges at the hinge region), and (iii) Fv fragments consisting of the VL and VH domains of a single arm of an antibody. Furthermore, the two domains VL and VH of Fv fragments are coded by separate genes, but they can be joined using recombinant methods by a synthetic linker that allows the VL and VH domains to be made into a single protein chain that pairs to form a monovalent molecule (known as single-chain Fv (scFv)), see, for example, Bird et al., Science 1988, 242:423-426 and Huston et al., Proc.Natl.Acad.Sci.1988 USA 85:5879-5883. Other forms of single chain antibodies, such as diabodies, are also encompassed.

[0679] Additionally, further encompassed are antibodies in which the C-terminal lysine (K) amino acid residue is missing in the heavy chain polypeptide (e.g., human IgG1 heavy chains contain a terminal lysine). As is known in the art, the C-terminal lysine may be trimmed off during antibody production, resulting in an antibody having a heavy chain lacking a C-terminal lysine. Alternatively, the antibody heavy chain may be produced using a nucleic acid that does not contain a C-terminal lysine.

[0680] The "variable region" of an antibody refers to the variable region of an antibody light chain or the variable region of an antibody heavy chain, either alone or in combination. As known in the art, the variable regions of heavy and light chains are each composed of four framework regions (FRs) connected by three complementarity determining regions (CDRs), also known as hypervariable regions, which contribute to the formation of the antigen-binding site of the antibody. When a variant of a subject variable region is desired, particularly one having a substitution at an amino acid residue outside the CDR region (i.e., in the framework region), the appropriate amino acid substitution, preferably a conservative amino acid substitution, can be identified by comparing the subject variable region with the variable regions of other antibodies that contain the same standard class CDR1 and CDR2 sequences as the subject variable region (Chothia and Lesk, J Mol Biol 196(4):901-917, 1987).

[0681] In certain embodiments, the final delineation of the CDRs and the identification of the residues that comprise the antibody binding site are achieved by solving the structure of the antibody or the structure of the antibody-ligand complex. In certain embodiments, this can be achieved by any of a variety of techniques known to those skilled in the art, such as X-ray crystallography. In certain embodiments, various methods of analysis can be used to identify or predict the CDR regions. In certain embodiments, various methods of analysis can be used to identify or predict the CDR regions. Examples of such methods include, but are not limited to, the Kabat definition, the Chothia definition, the AbM definition, the contact definition, the conformational definition, and the Pfabat numbering system 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, e.g., Johnson and Wu, 2000, Nucleic Acids Res., 28:214-8. The Chothia definition is similar to the Kabat definition, but it takes into account the location of certain structural loop regions. See, e.g., Chothia et al., 1986, J. Mol. Biol., 196:901-17; Chothia et al., 1989, Nature, 342:877-83. The AbM definition uses an integrated suite of computer programs created by the Oxford Molecular Group to model antibody structures. See, e.g., Martin et al., 1989, Proc Natl Acad Sci (USA), 86:9268-9272, "AbM™, A Computer Program for Modeling Variable Regions of Antibodies," Oxford, UK, Oxford Molecular, Ltd. The AbM definition models the tertiary structure of antibodies from the primary sequence using a knowledge database and a combination of original methods, such as those described by Samudrala et al., 1999, "Ab Initio Protein Structure Prediction Using a Combined Hierarchical Approach," PROTEINS, Structure, Function and Genetics Supplement, 3:194-198. The contact definition is based on an analysis of available crystal structures of the complex. See, e.g., MacCallum et al., 1996, J. Mol. Biol., 5:732-45. In another approach, referred to herein as "conformational definition" of CDRs, the positions of the CDRs can be identified as residues that make enthalpic contributions to antigen binding. See, e.g., Makabe et al., 2008, Journal of Biological Chemistry, 283:1156-1166.Still other CDR boundary definitions may not strictly follow one of the above approaches, but nevertheless overlap with at least a portion of the Kabat CDRs, while they may be shortened or extended in light of predicted 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 system shown in Example 1.

[0683] As used herein, CDR can refer to the CDR defined by any method known in the art, including a combination of methods. The method used herein can utilize the CDR defined according to any of these methods. For any given embodiment that contains two or more CDRs, the CDR can be defined according to any one or more of Kabat, Chothia, extended, AbM, contact, conformational definition, or Pfabat method. The antibody of the present application is numbered according to a modified version of the Kabat numbering system, which is shown in more detail in Example 1.

[0684] The term "hinge region" as used herein includes its meaning known in the art, as set forth in, for example, Janeway et al., ImmunoBiology: the immune system in health and disease, Elsevier Science Ltd., NY (4th ed., 1999), Bloom et al., Protein Science, 6:407-415, 1997, and Humphreys et al., J. Immunol. Methods, 209:193-202, 1997.

[0685] The "constant region" of an antibody refers to the constant region of the antibody light chain or the constant region of the antibody heavy chain, 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] "Fc domain" refers to the portion of an immunoglobulin (Ig) molecule that correlates with the crystallizable fragment obtained by papain digestion of the Ig molecule. As used herein, the term refers to the constant regions of the 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., "first Fc chain" and "second Fc chain"). "Fc chain" generally refers to the C-terminal portion of an antibody heavy chain. Thus, Fc chain refers to the last two constant region immunoglobulin domains (CH2 and CH3) of IgA, IgD, and IgG heavy chains, and the last three constant region immunoglobulin domains of IgE and IgM heavy chains, and optionally a flexible hinge N-terminal to these domains.

[0687] Although the boundaries of an Fc chain can vary, the human IgG heavy chain Fc chain is usually defined to include residues C226 or P230 to the carboxyl terminus, where numbering is according to the EU index in Edelman et al., Proc. Natl. Acad. Sci. USA 1969;63(1):78-85 and as described in Kabat et al., 1991. Typically, an Fc chain includes amino acid residues from about 236 to about 447 of the human IgG1 heavy chain constant region. "Fc chain" can refer to this polypeptide in isolation or in the context of a larger molecule, such as an antibody heavy chain or an Fc fusion protein.

[0688] A "functional" Fc domain refers to an Fc domain that has at least one effector function of a native sequence Fc domain. Exemplary "effector functions" include C1q binding, complement dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis, down-regulation of cell surface receptors (e.g., B cell receptors), and B cell activation. Such effector functions generally require combining the Fc domain with a binding domain (e.g., an antibody variable region) and can be assessed using a variety of 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 that comprises an amino acid sequence identical to that of an Fc chain found in nature. A "variant" Fc chain comprises an amino acid sequence that differs from that of a native sequence Fc chain by at least one amino acid modification that still retains at least one effector function of the wild-type Fc chain. In some embodiments, a variant Fc chain has at least one amino acid substitution compared to a wild-type Fc chain, e.g., about 1 to about 10 amino acid substitutions, preferably about 1 to about 5 amino acid substitutions in the wild-type Fc chain. A variant Fc chain herein preferably has at least about 80% sequence identity with a wild-type Fc chain, most preferably at least about 90% sequence identity therewith, more preferably at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity therewith. In some embodiments, the Fc chain comprises part or all of a wild-type hinge region (generally at its N-terminus). In some embodiments, the Fc polypeptide does not comprise a functional or wild-type hinge region.

[0690] nomenclature The antibody domains disclosed herein may be prefixed with an indication of the individual target antigen with which the domain is most closely associated. The prefixes are added simply to provide clarity of shorthand in distinguishing between the different domains listed throughout this disclosure, and do not replace or conflict with the actual function or structure of the various domains. For example, IL4-VH refers to the variable heavy domain of an antibody that contains a CDR capable of specifically binding to IL-4. IL4-CH1 refers to the CH1 domain located C-terminal to the IL-4 variable domain, whether that variable domain is the variable light domain (IL4-VL) or the variable heavy domain (IL4-VH). As described throughout this disclosure, the domains of the antibodies of this disclosure may be combined or fused with domains from other antibodies. Thus, for example, IL4-VH may be present on a polypeptide chain with IL13-VL, each independently or together, in the same antibody, and the polypeptides may both be referred to as IL4-VH and IL13-VL (see, for example, FIG. 18). Again, by way of example, a polypeptide with IL4-VH is any polypeptide that includes an IL4-VH domain, i.e., a VH domain that includes a CDR that specifically binds IL-4. A polypeptide with IL4-VH may include a hinge region, a CH1 domain, a CH2 domain, and a CH3 domain, as in a standard IgG format, or may include various domains described herein, e.g., IL13-VL, together with a CH1 and CL domain fused to either IL4-VH or IL13-VL (see FIG. 18 for examples of different combinations of antibody domains). For example, the DFab LC(1)-HC(2) arms of IL41333-1258, IL413TSLP-1024, and IL413P40-0705 (see Figure 18I) comprise, from N-terminus to C-terminus, IL13-VL, CL, linker, IL4-VH, CH1, CH2, and CH3, respectively, and can both be referred to as a polypeptide having an IL4-VH and a polypeptide having an IL13-VL.Furthermore, framework regions may be referred to by the target to which their CDRs are specific. For example, the framework region of the IL-4 antibody of the present disclosure may be referred to as IL4-VL framework or IL4-VH framework. Those skilled in the art will understand that these designations do not confer or imply any relationship between the framework region and the target to which the CDRs specifically bind. 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 across all possible antibodies and antibody combinations within the present disclosure.

[0691] Antibodies IL13433-1258, IL134TSLP-1024, and IL134p40-0705 can be described as comprising a first, second, third, fourth, and fifth polypeptide chain, respectively, where the second polypeptide comprises, from N-terminus to C-terminus, (VL-1)-(CL-1)-(linker)-(VH-2)-(CH1-2)-(second hinge)-(second CH2)-( the fifth polypeptide comprises, from N-terminus to C-terminus, (VH1)-(CL-1), the fourth polypeptide comprises, from N-terminus to C-terminus, (VL-2)-(CL-2), the first polypeptide comprises, from N-terminus to C-terminus, (VH-3)-(CH1-3)-(first hinge)-(first CH2)-(first CH3), and the third polypeptide comprises (VL-3)-(CL-3). In each case, VL-1 and VH-1 are IL13-VL and IL13-VH, VL-2 and VH-2 are IL4-VL and IL4-VH, and VH-3 and VL-3 are IL33-VH and IL33-VL, or TSLP-VH and TSLP-VL, or p40-VH and p40-VL.

[0692] "Monoclonal antibody" (mAb) refers to an antibody derived from a single copy or clone, including, for example, any eukaryotic, prokaryotic, or phage clone. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to polyclonal antibody preparations which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, but should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the present invention may be produced by the hybridoma method first described by Kohler and Milstein, 1975, Nature 256:495, or may be produced by recombinant DNA methods such as those described in U.S. Pat. No. 4,816,567. In another example, the monoclonal antibodies may be isolated from phage libraries, such as those generated using the techniques described in McCafferty et al., 1990, Nature 348:552-554.

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

[0694] A "chimeric antibody" refers to an antibody in which the variable region sequences are derived from one species and the constant region sequences are derived from another species, e.g., the variable region sequences are derived from a murine antibody and the constant region sequences are derived from a human antibody.

[0695] "Humanized" antibody refers to a non-human (e.g., murine) antibody that is a chimeric antibody containing minimal sequence derived from non-human immunoglobulin. Preferably, a humanized antibody is a human immunoglobulin (recipient antibody) in which residues from the recipient's CDRs are replaced by residues from the CDRs of a non-human species (donor antibody), e.g., mouse, rat, or rabbit, that has the desired specificity, affinity, and capacity. Humanized antibodies may contain residues that are found neither in the recipient antibody nor in the incorporated CDR or framework sequences, but are included to further improve and optimize antibody performance.

[0696] "Antigen" refers to a molecular entity used to immunize an immunocompetent vertebrate to produce antibodies that recognize the antigen, or to screen an expression library (e.g., phage, yeast or ribosome display libraries, among others) for antibody selection. As used herein, antigen is referred to more broadly and is generally intended to include the target molecule that is specifically recognized by an antibody, and thus to include fragments or mimetics of the molecule used in the immunization process to raise antibodies, or in library screening to select antibodies.

[0697] "Epitope" refers to the area or region of an antigen to which an antibody specifically binds, as determined by any method known in the art, for example, the area or region that contains the residue that interacts with an antibody.There are many methods known in the art for mapping and characterizing the location of epitopes on proteins, including elucidation of the crystal structure of antibody-antigen complexes, competitive assays, gene fragment expression assays, epitope mapping, and synthetic peptide-based assays, as described, for example, 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 or alternatively, during the discovery process, the generation and characterization of antibodies can reveal information about the 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 strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y is generally determined by the dissociation constant (K D) The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein. Low affinity antibodies generally bind antigens slowly and tend to dissociate easily, while high affinity antibodies generally bind antigens faster and tend to remain bound longer. Various methods for measuring binding affinity are known in the art, any of which can be used for the purposes of the present invention. In particular, the term "binding affinity" is intended to refer to the dissociation rate of a particular antigen-antibody interaction. K D is the "off rate (k off The rate of dissociation, also called the on-rate (k on )" Therefore, K D is k off / k on and is expressed as molar concentration (M). D A smaller K results in a stronger binding affinity. Thus, a K of 1 μM D has a K of 1 nM D The antibody shows weak binding affinity compared to the D Values ​​can be determined using methods well established in the art. D One method for determining K is by using surface plasmon resonance (SPR), typically using a biosensor system such as a BIACORE system. BIACORE kinetic analysis involves analyzing the binding and dissociation of antigens from chips that have immobilized molecules (e.g., molecules that contain epitope binding domains) on their surfaces. D and other ratios to determine the association and dissociation rate constants, respectively, k on and k offThe determination of 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 binding of the ligand that is immobilized at low volume on the sensor surface via the capture reagent. The analysis may be performed, for example, using the kinetic titration methodology described in Karlsson et al., Anal.Biochem 349, 136-147, 2006, or using multi-cycle kinetic analysis. The sensor chip, capture reagent, and assay buffer used for a given assay are selected to provide stable capture of the ligand on the sensor surface, minimize non-specific binding of the analyte to the surface, and provide an appropriate analyte binding response for kinetic analysis, following the recommendations of Myszka, J.Mol.Recognit 12, 279-284, 1999. The analyte binding response for each analyte / ligand interaction is double-referenced and expressed as a global parameter, k, as described by Myszka and Morton et al., Biophys. Chem 64, 127-137 (1997). a , k d and R max The equilibrium dissociation constant, K, is fitted to a 1:1 Langmuir "mass transport limited model" using D is the ratio of kinetic rate constants K D =k off / k on Such determinations are preferably made at 25° C. or 37° C. Typically, the rate constant (k on or k a and k off or k d ) and the equilibrium dissociation constant are measured using whole antibodies and monomers. D Another method for determining the concentration of β-aminobutyric acid is by using biolayer interferometry, typically using OCTET® technology (Octet QK e Alternatively, or in addition, one can use the KinExA (KinExA) assay available from Sapidyne Instruments (Boise, ID).

[0699] As used herein, the terms "immunospecifically bind", "immunospecifically recognize", "specifically bind", "specifically recognize", 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) and does not specifically bind to another molecule. A molecule that specifically binds to an antigen may bind to other peptides or polypeptides with lower affinity as determined by assays known in the art, e.g., immunoassays, BIACORE™, 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 binds", when used in reference to the interaction of an antibody and a protein or peptide, refer to an interaction that is dependent on the presence of a particular structure (i.e., an antigenic determinant or epitope) on the protein; in other words, the antibody recognizes and binds to a specific protein structure, rather than proteins in general. For example, if an antibody is specific for epitope "A", then the presence of a protein containing epitope A (or free unlabeled A) in a reaction containing labeled "A" and an antibody will reduce the amount of labeled A bound to the antibody.

[0701] In certain embodiments, "specifically binds" refers to, for example, an antibody that binds to a target molecule with a K of about 0.1 nM or less, more usually less than about 1 μM. D In certain embodiments, "specifically binds" means that the antibody binds to a protein with a K of at least about 0.1 μM or less in some cases, at least about 0.01 μM or less in other cases, and at least about 1 nM or less. DSpecific binding means binding to a target at a specific site. Because of sequence identity between homologous proteins in different species, specific binding can include antibodies that recognize proteins in more than one species. Similarly, because of homology within certain regions of the polypeptide sequences of different proteins, specific binding can include antibodies that recognize more than one protein. It is understood that in certain embodiments, an antibody or binding moiety that specifically binds to a first target may or may not specifically bind to a second target. Thus, "specific binding" does not necessarily require (but can include) exclusive binding, i.e., binding to a single target. Thus, in some embodiments, an antibody may specifically bind to more than one target. In certain embodiments, multiple targets may bind to the same antigen-binding site on the antibody. For example, in certain instances, an antibody may contain two identical antigen-binding sites, each of which specifically binds to the same epitope on more than one protein. In certain alternative embodiments, an antibody may be multispecific and contain at least two antigen-binding sites with different specificities. As a non-limiting example, a bispecific antibody may contain one antigen binding site that recognizes an epitope on one protein and may further contain a second, different antigen binding site that recognizes a different epitope on a second protein. Generally, but not necessarily, reference to binding refers to specific binding.

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

[0703] The terms "non-specific binding" or "background binding," when used in reference to the interaction of an antibody and a protein or peptide, refer to an interaction that is not dependent on the presence of a specific structure (i.e., the antibody is generally binding to the protein, not to a specific structure such as an epitope).

[0704] A neutralizing 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 either or both: (i) prevents, limits, or inhibits the interaction between IL-4, IL-13, IL-33, TSLP, and p40, respectively, and a suitable ligand, or (ii) results in inhibition of at least one biological function of IL-4, IL-13, IL-33, TSLP, or p40 binding, as appropriate. Assays for determining neutralization by the antibodies of the present disclosure are well known in the art.

[0705] As used herein, an "antibody that binds" to a target, an "antibody that recognizes" a target, an "antibody that specifically binds" to a target, "anti-target antibody," "anti-target antibody molecule," "targeting antibody," and the like, includes a molecule that contains 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 per molecule, such that every single antibody binding site specifically recognizes the same epitope on the antigen. Thus, in instances where a monospecific antibody has two or more antigen binding sites, the binding sites compete with each other for binding to a single antigen molecule.

[0707] "Bispecific antibodies" refer to molecules that have binding specificities for at least two different epitopes. In some embodiments, bispecific antibodies can bind to two different antigens simultaneously. In other embodiments, the two different epitopes may be present on the same antigen.

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

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

[0710] As used herein, the term "IL-4 / IL-13 / IL-33 trispecific antibody" or "IL-4 / IL-13 / IL-33 multispecific antibody" refers to a molecule designed to specifically bind to IL-4, IL-13, and IL-33. As used herein, the term "IL-4 / IL-13 / TSLP trispecific antibody" or "IL-4 / IL-13 / TSLP multispecific antibody" refers to a molecule designed to specifically bind to IL-4, IL-13, and TSLP. As used herein, the term "IL-4 / IL-13 / p40 trispecific antibody" or "IL-4 / IL-13 / p40 multispecific antibody" refers to a molecule designed to specifically bind to IL-4, IL-13, and p40.

[0711] "Half-maximal effective concentration (EC 50 The term "EC" refers to the concentration of a therapeutic agent that produces a response halfway between baseline and maximum after a specified exposure time. A therapeutic agent may produce inhibition or stimulation. 50 The value is commonly used as a measure of efficacy and is used herein.

[0712] Inhibitory concentration (IC 50The term "IC" refers to the concentration of an inhibitor at which 50% of the inhibition in its activity is achieved. A therapeutic agent may cause inhibition or stimulation. 50 The value is commonly used as a measure of efficacy and is used herein.

[0713] "Agonist" refers to a substance that promotes (i.e., induces, causes, enhances, or increases) the biological activity or effect of another molecule. The term agonist includes substances (such as antibodies) that bind to a molecule and promote the activity of that molecule.

[0714] "Antagonist" refers to a substance that prevents, blocks, inhibits, neutralizes, or reduces the biological activity or effect of another molecule, such as a receptor. The term antagonist includes substances (such as antibodies) that bind to a molecule and prevent or reduce the activity of that molecule.

[0715] The term "compete" as used herein with respect to antibodies means that a first antibody binds to an epitope in a manner sufficiently similar to that of a second antibody such that the result of binding of the second antibody to its cognate epitope is detectably decreased in the presence of the first antibody compared to the binding of the second antibody in the absence of the first antibody. Optionally, but not necessarily, the binding of the first antibody to its epitope is also detectably decreased in the presence of the second antibody. That is, a first antibody can inhibit the binding of a second antibody to its epitope without the second antibody inhibiting the binding of the first antibody to its respective epitope. However, if each antibody detectably inhibits the binding of the other antibody to its cognate epitope or ligand, whether to the same, higher, or lower degree, the antibodies are said to "cross-compete" with each other for binding of their respective epitopes. 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), one of skill in the art will recognize, based on the teachings provided herein, that such competing or cross-competing antibodies are encompassed by and may be useful in the methods disclosed herein.

[0716] "Host cell" refers to an individual cell or cell culture that can be or has been a recipient for a vector for incorporation of a polynucleotide insert. A host cell includes the progeny of a single host cell, which may not necessarily be completely identical (in morphology or in genomic DNA complement) to the original parent cell due to natural, accidental, or deliberate mutations. A host cell includes cells transfected in vivo with a polynucleotide of the invention.

[0717] "Vector" refers to a construct capable of delivering, and preferably expressing, one or more genes or sequences of interest (e.g., antibody-encoding genes) in a host cell. Examples of vectors include, but are not limited to, plasmids and viral vectors, and may include naked nucleic acids or may include nucleic acids associated with delivery-assisting materials (e.g., cationic condensing agents, liposomes, etc.). Vectors may include DNA or RNA. "Expression vector" as used herein refers to a vector that includes at least one polypeptide-encoding sequence, at least one regulatory element (e.g., promoter sequence, poly(A) sequence) associated with transcription or translation of the gene. Typically, vectors used herein contain at least one antibody-encoding gene, and one or more of the following regulatory elements or selection markers. Vector components may include, for example, one or more of the following: signal sequence, origin of replication, one or more marker genes, suitable transcription control elements (such as promoters, enhancers and terminators). For translation, the one or more translational control elements may also 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, depending on its source of origin or derivatization, (1) is not associated with naturally associated components with which it is natively associated, (2) is substantially free of other molecules from the same source, e.g., species, cell in which it is expressed, library, etc., (3) is expressed by cells from a different species, or (4) does not occur in nature. Thus, a chemically synthesized molecule or a molecule expressed in a cellular system different from the system in which it naturally originated is "isolated" from its naturally associated components. A molecule may also be rendered substantially free of 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 of two or more amino acids in length. The linker may be composed of neutral polar or non-polar amino acids. The linker may be, for example, 2-100 amino acids in length, for example, between 2-50 amino acids in length, for example, 3, 4, 5, 6, 8, 10, 12, 15, 20, 25, 30, 35, 40, 45, or 50 amino acids in length. The linker may be "cleavable", for example, by self-cleavage or enzymatic or chemical cleavage. Cleavage sites in the amino acid sequence, as well as enzymes and chemicals that cleave at such sites, are well known in the art and are also described herein. In some embodiments, the linker comprises one or more repeat units of a sequence that includes glycine and serine residues ... 4 In some embodiments, the linker comprises one or more repeat units of (G 4 S) 1~3 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 a disulfide bond. The average bond energy of a disulfide bond is about 60 kcal / mol, compared to 1-2 kcal / mol for a hydrogen bond. In the context of the present invention, the cysteines that form the disulfide bond are in the framework region of a single chain antibody and serve to stabilize the conformation of the antibody. Cysteine ​​residues can be introduced, for example, by site-directed mutagenesis, so that a stabilizing disulfide bond can be created within the molecule.

[0721] As used herein, the terms "linked," "fused," and "fusion" are used interchangeably and refer to the joining together of more than two elements or components by whatever means, including chemical conjugation or recombinant means.

[0722] As used herein, the term "covalently linked" means that the specified moieties are either directly covalently bonded to one another or indirectly covalently joined to one another through one or more intervening moieties, such as a linking peptide or moiety.

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

[0724] As used herein, the term "modification" refers to the substitution, insertion, or deletion of an amino acid in a polypeptide sequence, a change to a moiety chemically linked to a protein, or a modification of the function of a protein, for example, an antibody. For example, the modification may be a change in the function of an antibody, or a change in a 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 replacement 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, the mutation L234A indicates that the amino acid residue lysine at position 234 in the antibody Fc region is replaced by the amino acid residue alanine (replacing lysine with alanine) (numbering according to the EU index numbering system).

[0725] The term "agent" is used herein to refer to a biopolymer, an extract made from biological material, a mixture of biopolymers, a chemical, a mixture of chemicals, or a mixture of chemicals and biopolymers. The term "therapeutic agent" refers to an agent that has biological activity.

[0726] "Polypeptide" or "protein" (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 encompasses amino acid chains that are natural or modified by intervention, such as disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. For example, polypeptides containing one or more amino acid analogs (including, for example, unnatural amino acids, etc.), and other modifications known in the art, are also included within this definition. It is understood that polypeptides can exist as single chains or associated chains.

[0727] As used herein, a "first polypeptide" is any polypeptide that associates with a second polypeptide. The first and second polypeptides meet at an interface. In addition to the interface, the first polypeptide may contain one or more additional domains, such as a "binding domain" (e.g., an antibody variable domain, a receptor binding domain, a ligand binding domain or an enzyme domain), or an antibody constant domain (or a portion thereof) including the CH2, CH1 and CL domains. Usually, the first polypeptide contains at least one domain derived from an antibody. This domain is conveniently a constant domain, such as the CH3 domain of an antibody, and can form the interface of the first polypeptide. Exemplary first polypeptides include antibody heavy chain polypeptides, chimeras 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 contain additional domains such as a "binding domain" (e.g., an antibody variable domain, a receptor binding domain, a ligand binding domain or an enzymatic domain), or an antibody constant domain (or a portion thereof) including the CH2, CH1 and CL domains. Usually, the second polypeptide contains at least one domain derived from an antibody. This domain is conveniently a constant region, such as the CH3 domain of an antibody, which may 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" (used interchangeably herein) refers to a chain of nucleotides of any length, including DNA and RNA. Nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases or their analogs, or any substance that can be incorporated into a chain by DNA or RNA polymerase. Polynucleotides can include modified nucleotides, such as methylated nucleotides and their analogs. If present, modifications to the nucleotide structure can be imparted before or after assembly of the chain. The sequence of nucleotides can be interrupted by non-nucleotide components. Polynucleotides can be further modified after polymerization, for example, by conjugation with a labeling component. Other types of modifications include, for example, "caps", substitutions with one or more analogs of naturally occurring nucleotides, internucleotide modifications such as those with uncharged linkages (e.g., methylphosphonates, phosphotriesters, phosphoamidates, carbamates, etc.) and charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.), those containing pendant moieties, such as proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), those with intercalators (e.g., acridine, psoralen, etc.), those containing chelators (e.g., metals, radioactive metals, boron, oxidizing metals, etc.), those containing alkylators, those with modified linkages (e.g., alpha anomeric nucleic acids, etc.), as well as unmodified forms of polynucleotides. Additionally, any of the hydroxyl groups normally present on the sugar may be replaced, for example, by phosphonate groups, phosphate groups, protected by standard protecting groups, or activated to prepare additional linkages to additional nucleotides, or conjugated to solid supports. The 5' and 3' terminal OH can be phosphorylated or substituted with amines or organic capping group moieties of 1 to 20 carbon atoms. The other hydroxyls may also be derivatized to standard protecting groups.Polynucleotides can also contain analog forms of ribose or deoxyribose sugars commonly known in the art, including, for example, 2'-O-methyl-, 2'-O-allyl, 2'-fluoro- or 2'-azido-ribose, carbocyclic sugar analogs, alpha or beta-anomeric sugars, epimeric sugars, e.g., arabinose, xylose or lyxose, pyranose sugars, furanose sugars, sedoheptulose, acyclic analogs, and abasic nucleoside analogs such as methyl riboside.

[0730] As used herein, nucleic acids are written from left to right in 5' to 3' orientation, and amino acid sequences are written from left to right in amino to carboxy orientation, respectively. Practitioners are particularly directed to Sambrook et al., 1989, and Ausubel FM et al., 1993, for definitions and terms of the art. It should be understood that the invention is not limited to the specific methodology, protocols, and reagents described, as these may vary.

[0731] The polynucleotides complementary to any such sequences are also included in the present invention.Polynucleotides can be single-stranded (coding or antisense) or double-stranded, and can be DNA (genomic, cDNA or synthetic) or RNA molecules.RNA molecules include mature and non-mature mRNA, such as precursor mRNA (pre-mRNA) or heterogeneous nuclear mRNA (hnRNA) and mature mRNA.Additional coding or non-coding sequences can, but do not have to, be present in the polynucleotides of the present invention, and polynucleotides can, but do not have to, be linked to other molecules or supporting materials.

[0732] It will be appreciated by those of skill in the art that, as a result of the degeneracy of the genetic code, there are many nucleotide sequences that code for the amino acid sequences provided herein. Polynucleotides that vary due to differences in codon usage are specifically contemplated by the present invention.

[0733] "Conservative substitution" refers to the replacement of one amino acid with a biologically, chemically or structurally similar residue. Biologically similar means that the substitution does not destroy biological activity. Structurally similar means that the amino acids have similar length or similar size of side chains, for example, alanine, glycine and serine. Chemical similarity means that the residues have the same charge or are both hydrophilic or hydrophobic. Particular examples include the replacement of a hydrophobic residue, such as isoleucine, valine, leucine or methionine, with another, or the replacement of one polar residue with another, such as the replacement of arginine with lysine, the replacement of glutamic acid with aspartic acid, or the replacement of glutamine with asparagine, the replacement of serine with threonine, etc. Particular examples of conservative substitutions include the substitution of a hydrophobic residue such as isoleucine, valine, leucine or methionine for another, or a polar residue for another, such as, for example, the substitution of arginine with lysine, glutamic acid with aspartic acid, or glutamine with asparagine. Conservative amino acid substitutions typically include, for example, substitutions within the following groups: glycine, alanine, valine, isoleucine, and leucine; aspartic acid and glutamic acid; asparagine and glutamine; serine and threonine; lysine and arginine; and phenylalanine and tyrosine.

[0734] The present invention also encompasses modifications to the antibodies provided herein, including functionally equivalent antibodies that do not significantly affect their properties, and variants with enhanced or reduced activity or affinity. For example, amino acid sequences may be mutated to obtain antibodies with the desired binding affinity to IL-4, IL-13, IL-33, TSLP, or p40. Examples of modified polypeptides include polypeptides with conservative substitutions of amino acid residues, one or more deletions or additions of amino acids that do not significantly adversely alter functional activity or mature (enhance) the affinity of the polypeptide to its ligand, or the use of chemical analogs.

[0735] Amino acid sequence insertions include amino- or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing 100 or more residues, and intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include antibodies with an N-terminal methionyl residue or antibodies fused to an epitope tag. Other insertion variants of antibody molecules include the fusion to the N- or C-terminus of the antibody of an enzyme or a polypeptide that increases the half-life of the antibody in the blood circulation.

[0736] Substitutional variants have at least one amino acid residue in the antibody molecule removed and a different residue inserted in its place. Sites of greatest interest for substitutional mutagenesis include hypervariable regions, although FR changes are also contemplated. Conservative substitutions are shown below as residues within the same numbering group (1-6). If such substitutions result in changes in biological activity, more substantial changes may be introduced, designated "exemplary substitutions," further described below in reference to amino acid classes, and the products may be screened.

[0737] Substantial modification of the biological properties of the antibody is achieved by selecting substitutions that do not differ significantly in their effect on (a) the structure of the polypeptide backbone in the area of ​​the substitution, e.g., sheet or helix conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) maintaining side chain bulk. Naturally occurring amino acid residues are divided into groups based on common side chain properties: (1) Nonpolar: Norleucine, Met, Ala, Val, Leu, Ile; (2) uncharged polar: Cys, Ser, Thr, Asn, Gln; (3) Acidic (negatively charged): Asp, Glu; (4) Basic (positively charged): Lys, Arg; (5) Residues that influence chain orientation: Gly, Pro; and (6) Aromatic: Trp, Tyr, Phe, His.

[0738] Non-conservative substitutions are made by exchanging a member of one of these classes for another class.

[0739] Any cysteine ​​residue not involved in maintaining the proper conformation of the antibody may also be substituted, generally with serine, to improve the oxidative stability of the molecule and prevent aberrant crosslinking Conversely, cysteine ​​bond(s) may be added to the antibody to improve its stability, particularly where the antibody is an antibody fragment such as an Fv fragment.

[0740] Amino acid modifications can range from changing or modifying one or more amino acids to a complete redesign of a region such as a variable region. Changes in the variable region can alter binding affinity and / or specificity. In some embodiments, no more than 1-5 conservative amino acid substitutions are made in the CDR dom...

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 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 contains SEQ ID NO: 133, the fourth polypeptide chain contains SEQ ID NO: 27, and the fifth polypeptide chain contains 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) IC20 <10 pM as measured by a 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 <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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