Multispecific antibodies that bind to IL-4, IL-13 and / or TSLP and uses thereof

Abstract

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

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

[0002] References to sequence listings

[0003] “This application contains a Sequence Listing, which has been submitted electronically in .xml format and is incorporated herein by reference in its entirety. The .xml file was created on February 9, 2023, is named PC072799SequenceListing.xml, and is 252KB in size. Background Art

[0004] The present invention relates to antibodies that specifically bind to one or more of IL-4, IL-13, IL-33, TSLP, and p40, as well as compositions, methods, and uses thereof, including the use of the disclosed antibodies to treat one or more diseases or conditions selected from the group consisting of atopic dermatitis, atopic dermatitis, asthma, cancer, chronic obstructive pulmonary disease (COPD), food allergies, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, Rash, idiopathic pulmonary fibrosis (IPF), scleroderma, and systemic sclerosis, diabetic nephropathy, Behcet's disease, gout, Alzheimer's disease, atherosclerosis, fungal keratitis, non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus (SLE), primary biliary cirrhosis and hidradenitis suppurativa, the uses including the treatment and prevention of one or more symptoms associated with various diseases or conditions.

[0005] IL-4 and IL-13 are key drivers of immune activation, leading to inflammation, edema, fibrosis, and pruritus in atopic diseases (48, 49). IL-4 and IL-13 interact with cells through a common receptor composed of IL-4Rα and IL-13Rα1 (type II receptors) expressed on monocytes, fibroblasts, keratinocytes, epithelial cells, smooth muscle cells, and other non-lymphoid cell types (29). IL-4 can also activate cells through the IL-4Rα / IL-2Rγ common receptor (type I receptor) expressed on T cells, B cells, and monocytes. IL-4Rα activates STAT6 to induce atopy-related genes through engagement of either receptor (29). Although IL-4 and IL-13 can engage common receptors and signaling pathways, differences in cytokine availability, localization, and receptor binding affinity lead to different response profiles (49, 50). Further differentiation can be driven by the type I receptor (IL-4Rα / γc), which drives Th2 differentiation through IL-4 rather than IL-13 (51), and the cell surface “decoy” IL-13Rα2, which mediates the neutralization and depletion of IL-13 but not IL-4 (52, 53).

[0006] The role of IL-4 and IL-13 in atopic diseases is supported by genetic associations, extensive validation in preclinical models, and the clinical efficacy of IL-4 and IL-13 neutralization in several atopic indications (48). Dupilumab (Sanofi / Regeneron) blocks responses to both cytokines and is approved for the treatment of moderate-to-severe atopic dermatitis (AD), asthma, and chronic rhinosinusitis with nasal polyposis, demonstrating the activity of IL-4 and IL-13 in these indications (54-56). The anti-IL-13 mAbs lebrikizumab (Lilly) (57) and tralokinumab (Adbry TM ; Leo Pharma) (58, 59) have also been shown to be effective in AD, with more limited activity in asthma (60, 61). The effectiveness of anti-IL-13 mAbs in AD suggests that IL-13 neutralization is However, available meta-analyses (62, 63) suggest that The activity of levofloxacin was superior to that of nerolizumab and troloxetine, consistent with the additive benefit of IL-4 blockade.

[0007] IL-33 is passively released upon cell necrosis or tissue damage, suggesting that it may function as an alarm, alerting the immune system following endothelial or epithelial cell damage during infection, physical stress, or trauma. IL-33 activates eosinophils, basophils, mast cells, macrophages, and type 2 innate lymphoid cells (ILC2) associated with allergic inflammation through its receptor ST2, playing an important role in type 2 innate immunity (96).

[0008] Thymic stromal lymphoprotein (TSLP) is an epithelial cell factor that plays a key role in the initiation and maintenance of inflammation. Tezepelumab (Amgen) is a TSLP antibody approved for the treatment of asthma.

[0009] IL-4 and IL-13 are primarily associated with type 2 effector responses. In contrast, IL-12 and IL-23 are associated with type 1 and type 3 (Th17) responses, respectively (77). IL-12 drives the differentiation of helper T cells 1 (Th1) and the production of interferon gamma (IFN-γ), 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 associated with several human inflammatory and autoimmune diseases. The causal role of cytokines containing IL-12p40 has been demonstrated by a large number of drug approvals (75) (IL-12p40 is hereafter referred to as p40). p40 neutralizers Ustekinumab (ustekinumab; Janssen) neutralizes both IL-12 and IL-23 and is approved for the treatment of plaque psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis. IL-23 selective anti-IL-23p19 blocker (guselkumab; Janssen), (risankizumab; Boehringer Ingelheim / AbbVie) and (tildrakizumab; Sun Pharmaceutical) is approved for some psoriatic conditions.

[0010] Despite the efficacy of dupilumab, tezelumab, guselkumab, risankizumab, and tirazumab, there remains an unmet need for safe and effective treatments that address a broad range of pathogenic mechanisms for the many diseases characterized by inflammatory responses. Summary of the Invention

[0011] Provided herein are antibodies (including antigen-binding fragments thereof) that specifically bind to one or more of IL-4, IL-13, IL-33, TSLP, and p40, as well as monomeric and multimeric antibodies, related nucleic acids, uses, and methods thereof. The present disclosure also provides 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 disclosed herein can be used for one or more of the diagnosis, prevention, or treatment of diseases or conditions mediated by or associated with one or more of IL-4, IL-13, IL-33, TSLP, and p40 activity, including but not limited to atopic dermatitis, asthma, cancer, chronic obstructive pulmonary disease (COPD), food allergies, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous dermatitis, eczema, dermatitis ... Herpes, chronic urticaria, idiopathic pulmonary fibrosis (IPF), scleroderma, and systemic sclerosis, diabetic nephropathy, Behcet's disease, gout, Alzheimer's disease, atherosclerosis, fungal keratitis, non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus (SLE), primary biliary cirrhosis, and hidradenitis suppurativa. The present disclosure also includes the expression of antibodies, and the preparation and manufacture of compositions comprising the antibodies of the present disclosure, such as for the preparation and manufacture of medicaments using the antibodies.

[0012] Also provided are polynucleotides encoding antibodies that bind to one or more of IL-4, IL-13, IL-33, TSLP, and p40. Also provided are polynucleotides encoding antibody heavy chains or light chains or both. Host cells expressing the antibodies are provided. Methods of treatment using the antibodies are provided. Such methods include, but are not limited to, one or more methods of treating or preventing 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, chronic obstructive pulmonary disease (COPD), food allergies, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, nodules Prurigo, keloids, bullous pemphigoid, chronic urticaria, idiopathic pulmonary fibrosis (IPF), scleroderma, and systemic sclerosis, diabetic nephropathy, Behçet's disease, gout, Alzheimer's disease, atherosclerosis, fungal keratitis, nonalcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus (SLE), primary biliary cirrhosis, and hidradenitis suppurativa.

[0013] By referring to the following detailed description of the embodiments of the present invention and the examples included herein, the present invention can be more easily understood. It should be understood that the present invention is not limited only to specific preparation methods, and the preparation methods can certainly change. It should also be understood that the terms used herein are only used to describe the purpose of specific embodiments, rather than being intended to limit. Those skilled in the art will recognize or be able to determine many equivalent forms of the specific embodiments of the present invention described herein without exceeding routine experiments. Such equivalent forms are intended to be covered by the following embodiments (E).

[0014] E1. An isolated antibody that specifically binds to IL-33, comprising a heavy chain variable region (IL33-VH) and a light chain variable region (IL33-VL), comprising:

[0015] (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;

[0016] (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

[0017] (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.

[0018] 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: CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO: 73, and CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO: 78.

[0019] 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.

[0020] E4. The antibody according to any one of E1 to E3, which comprises an IL33-VH framework sequence derived from a human germline VH sequence selected from the group consisting of DP47, DP48, DP50, DP51, DP54 and DP77.

[0021] E5. The antibody according to any one of E1 to E4, comprising an IL33-VH framework sequence derived from the human DP54 germline sequence.

[0022] E6. The antibody according to any one of E1 to E5, which comprises an IL33-VL framework sequence derived from a human germline VL sequence selected from the group consisting of DPK1, DPK3, DPK4, DPK5, DPK7, DPK8 and DPK9.

[0023] E7. The antibody according to any one of E1 to E6, comprising an IL33-VL framework sequence derived from the human germline DPK9 sequence.

[0024] E8. An antibody according to any one of E1 to E7, comprising 98%, 99% or 100% sequence of an IL33-VL framework sequence and an IL33-VH framework sequence, and wherein one or both of the IL33-VL framework sequence and the IL33-VH framework sequence are at least 66%, 76%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% identical to the human germline sequence from which they are derived.

[0025] E9. The antibody according to any one of E1 to E8, comprising an IL33-VL framework sequence and an IL33-VH framework sequence, and wherein one or both of the IL33-VL framework sequence or the IL33-VH framework sequence are identical to the human germline sequence from which they are derived.

[0026] E10. The antibody according to any one of E1-E9, comprising an IL33-VH sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 73.

[0027] E11. The antibody according to any one of E1-E10, which comprises an IL33-VL sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 78.

[0028] E12. The antibody according to any one of E1 to E11, comprising:

[0029] (i) the IL33-VH sequence of SEQ ID NO: 73, and the IL33-VL sequence of SEQ ID NO: 78; or

[0030] (ii) the IL33-VH sequence of SEQ ID NO: 63, and the IL33-VL sequence of SEQ ID NO: 71; or

[0031] (iii) the IL33-VH sequence of SEQ ID NO: 80, and the IL33-VL sequence of SEQ ID NO: 81.

[0032] E13. The antibody according to any one of E1 to E12, comprising an IL33-VH sequence identical to SEQ ID NO: 73 and an IL33-VL sequence identical to SEQ ID NO: 78.

[0033] E14. The antibody according to any one of E1 to E13, comprising an IL33-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 202.

[0034] E15. The antibody according to any one of E1 to E14, comprising an IL33-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 203.

[0035] E16. The antibody according to any one of E1 to E15, comprising an IL33-VH sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-127210.

[0036] E17. The antibody according to any one of E1 to E16, comprising an IL33-VL sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-127209.

[0037] E18. An antibody comprising an IL33-VH sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-127210 and an IL33-VL sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-127209.

[0038] E19. The antibody according to E1-E18, wherein the antibody binds to the K of human IL-33 D 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.

[0039] E20. The antibody according to E1-E19, wherein the antibody binds to the K of human IL-33 D A value of about 15 pM or less.

[0040] E21. The antibody according to E1-E20, wherein the antibody binds to the K of human IL-33 D It is a value of about 1 pM or less.

[0041] E22. The antibody according to E1-E21, wherein the antibody binds to the K of human IL-33 D A value of about 250 fM or less.

[0042] E23. The antibody according to any one of E19-E22, wherein K D The values ​​were measured by kinetic exclusion assay.

[0043] E24. The antibody according to any one of E19-E22, wherein K D The values ​​were measured by surface plasmon resonance (SPR).

[0044] E25. The antibody according to E1-E24, wherein the IL-33 neutralization and IL-33IC in SEAP assay 50 Less than 20pM.

[0045] E26. The antibody according to E1-E25, wherein the IL-33 neutralization and IL-33IC in SEAP assay 50 Less than 15pM.

[0046] E27. The antibody according to E25-E26, wherein HEK IL-33 neutralization SEAP assay was performed at 37°C for 20 hours.

[0047] E28. The antibody according to E1-E27, wherein IL-33 IC 50 Less than 15 pM and calculated by ELISA measurement of IFNγ in human whole blood assays treated with IL-33 and IL-12.

[0048] E29. The antibody according to E28, wherein the human whole blood assay is performed at 37°C for 22 hours.

[0049] E30. The antibody according to E1-E29, wherein the antibody binds to cynomolgus monkey IL-33.

[0050] E31. The antibody according to E1-E30, wherein the antibody binds to cynomolgus monkey IL-33 D The binding K of the antibody to human IL-33 D within 3 orders of magnitude.

[0051] E32. The antibody according to E1-E31, further comprising a constant heavy chain domain (IL33-CH1) and a constant light chain domain (IL33-CL).

[0052] E33. The antibody according to E32, wherein the IL33-CH1 comprises a sequence selected from the group consisting of SEQ ID NO: 6, SEQ ID NO: 105 and SEQ ID NO: 110.

[0053] E34. The antibody according to E32-E33, wherein the IL33-CH1 comprises the sequence shown in SEQ ID NO: 6.

[0054] E35. The antibody according to E32-E34, wherein the IL33-CL comprises a sequence selected from the group consisting of SEQ ID NO: 16, SEQ ID NO: 108 and SEQ ID NO: 113.

[0055] E36. The antibody according to E32-E35, wherein the IL33-CL comprises the sequence shown in SEQ ID NO: 16.

[0056] E37. The antibody according to E32-E36, wherein IL33-CH1 is linked to IL33-VL, and IL33-CL is linked to IL33-VH to form an IL-33 binding domain-exchange Fab domain (IL33-xFab).

[0057] E38. The antibody according to E32-E37, wherein IL33-CH1 is linked to IL33-VH, and IL33-CL is linked to IL33-VL to form an IL-33 binding Fab domain (IL33-Fab).

[0058] E39. The antibody according to any one of E1-E38, which comprises an antibody Fc domain comprising a first Fc chain and a second Fc chain.

[0059] E40. The antibody according to E39, wherein the Fc domain is an Fc domain of IgA (eg, IgA1 or IgA2), IgD, IgE, IgM, or IgG (eg, IgG1, IgG2, IgG3, or IgG4).

[0060] E41. The antibody according to E40, wherein the Fc domain is the Fc domain of IgG1.

[0061] E42. The antibody according to E40, wherein the N-terminus of the first Fc chain or the second Fc chain is linked to the C-terminus of the IL33-CH1 domain.

[0062] E43. The antibody according to E41-E42, wherein the first Fc chain and the second Fc chain each comprise, from N-terminus to C-terminus: a hinge region, a CH2 region and a CH3 region.

[0063] E44. The antibody according to 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.

[0064] E45. The antibody according to E44, wherein the hinge region comprises the sequence shown in SEQ ID NO: 7.

[0065] E46. The antibody according to E44, wherein the hinge region on the first Fc chain and the hinge region on the second Fc chain comprise a pair of sequences shown in SEQ ID NO: 129 and SEQ ID NO: 131.

[0066] E47. The antibody according to E43-E46, wherein the CH2 region comprises the sequence shown in SEQ ID NO:8.

[0067] E48. The antibody of E43-E47, wherein the CH3 region on the first Fc chain and the CH3 region on the second Fc chain comprise a pair of sequences selected from the group consisting of:

[0068] (i) SEQ ID NO: 9 and SEQ ID NO: 9;

[0069] (ii) SEQ ID NO: 111 and SEQ ID NO: 106;

[0070] (iii) SEQ ID NO: 111 and SEQ ID NO: 114;

[0071] (iv) SEQ ID NO: 114 and SEQ ID NO: 117;

[0072] (v) SEQ ID NO: 124 and SEQ ID NO: 127;

[0073] (vi) SEQ ID NO: 139 and SEQ ID NO: 141; and

[0074] (vii) SEQ ID NO: 147 and SEQ ID NO: 148.

[0075] E49. The antibody according to E48, wherein the CH3 region on the first Fc chain and the CH region on the second Fc chain each comprise the sequence shown in SEQ ID NO: 9.

[0076] E50. The antibody according to E48, wherein the CH3 region on the first Fc chain and the CH3 region on the second Fc chain comprise a pair of sequences shown in SEQ ID NO: 124 and SEQ ID NO: 127.

[0077] E51. An antibody according to any one of E1 to E50, comprising a polypeptide carrying IL33-VH, said polypeptide comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98%, 99% or 100% identical to a sequence selected from 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.

[0078] E52. The antibody according to any one of E1 to E51, comprising a polypeptide carrying IL33-VH, said polypeptide 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.

[0079] E53. The antibody according to any one of E52-E53, wherein the polypeptide carrying IL33-VH comprises the sequence shown in SEQ ID NO: 74.

[0080] E54. The antibody according to any one of E52-E52, wherein the polypeptide carrying IL33-VH comprises the sequence shown in SEQ ID NO: 132.

[0081] E55. The antibody according to E32-E54, wherein IL33-CL comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 16, SEQ ID NO: 108, and SEQ ID NO: 113.

[0082] E56. The antibody according to E32-E55, wherein IL33-CL comprises the amino acid sequence shown in SEQ ID NO: 16.

[0083] E57. An antibody according to any one of E1 to E56, comprising a polypeptide carrying IL33-VL, said polypeptide comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to a sequence selected from the group consisting of SEQ ID NO: 79, SEQ ID NO: 107, SEQ ID NO: 115, SEQ ID NO: 121 and SEQ ID NO: 138, SEQ ID NO: 144 and SEQ ID NO: 145.

[0084] E58. The antibody according to any one of E1 to E57, comprising a polypeptide carrying IL33-VL, said polypeptide comprising the amino acid sequence of SEQ ID NO: 79.

[0085] E59. The antibody according to E1-E58, comprising the polypeptide carrying IL33-VH of SEQ ID NO: 74 and the polypeptide carrying IL33-VL of SEQ ID NO: 79.

[0086] E60. The antibody according to E1-E59, comprising the polypeptide carrying IL33-VH of SEQ ID NO: 132 and the polypeptide carrying IL33-VL of SEQ ID NO: 79.

[0087] E61. The antibody according to any one of E1 to E60, which comprises the polypeptide sequence carrying IL33-VH encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127208.

[0088] E62. The antibody according to any one of E1 to E61, which comprises a polypeptide sequence carrying IL33-VL encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127207.

[0089] E63. An antibody comprising the polypeptide sequence carrying IL33-VH encoded by the plasmid deposited with ATCC and having ATCC Accession No. PTA-127208 and the polypeptide sequence carrying IL33-VL encoded by the plasmid deposited with ATCC and having ATCC Accession No. PTA-127207.

[0090] E64. An isolated antibody that specifically binds IL-33, comprising the CDRs of an antibody selected from one or more of Tables 82, 85 and 87.

[0091] E65. An isolated antibody that specifically binds to IL-33, comprising the VH and VL of an antibody selected from one or more of Tables 82, 84 and 87.

[0092] E66. An isolated antibody that specifically binds IL-33 selected from one or more of Tables 82, 84 and 87.

[0093] E67. The antibody according to any one of E1 to E65 for use as a medicament.

[0094] E68. The antibody according to E67, wherein the use is for treating one or more selected from the group consisting of: atopic dermatitis, asthma, cancer, chronic obstructive pulmonary disease (COPD), food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, idiopathic pulmonary fibrosis (IPF), scleroderma, systemic sclerosis, diabetic nephropathy, Behçet's disease, gout, Alzheimer's disease and atherosclerosis.

[0095] E69. The antibody according to any one of E67-E68, wherein the use is for treating one or more selected from the group consisting of: atopic dermatitis, asthma, cancer, chronic obstructive pulmonary disease (COPD), food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata and non-alcoholic steatohepatitis (NASH).

[0096] E70. The antibody according to any one of E67-E69, wherein the use is for atopic dermatitis.

[0097] E71. The antibody according to any one of E67-E69, wherein the use is for non-alcoholic steatohepatitis (NASH).

[0098] E72. A pharmaceutical composition comprising a therapeutically effective amount of the antibody according to E1-E71 and a pharmaceutically acceptable carrier.

[0099] E73. A method of treating a medical condition, comprising administering to a subject in need thereof a therapeutically effective amount of an antibody according to any one of E1-E71, or a pharmaceutical composition according to E72.

[0100] E74. The method according to E73, wherein the condition is selected from the group consisting of: atopic dermatitis, asthma, cancer, chronic obstructive pulmonary disease (COPD), food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, idiopathic pulmonary fibrosis (IPF), scleroderma, systemic sclerosis, diabetic nephropathy, Behçet's disease, gout, Alzheimer's disease and atherosclerosis.

[0101] E75. The method according to any one of E73-E74, comprising administering the antibody or pharmaceutical composition subcutaneously.

[0102] E76. The method of any one of E73-E75, wherein the antibody or pharmaceutical composition is administered approximately twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, twice a month, once a month, once every two months, once every three months, or once every four months.

[0103] E77. An isolated antibody that specifically binds to TSLP, comprising a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), comprising:

[0104] (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;

[0105] (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;

[0106] (iii) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 92, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 213; or

[0107] (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;

[0108] (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;

[0109] (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

[0110] (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.

[0111] E78. An isolated antibody that specifically binds to TSLP, comprising a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), comprising: the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO: 92, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO: 94.

[0112] E79. An isolated antibody that specifically binds to TSLP, comprising:

[0113] (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;

[0114] (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;

[0115] (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.

[0116] (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;

[0117] (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

[0118] (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.

[0119] E80. The antibody according to any one of E77 to E79, which comprises a TSLP-VH framework sequence derived from a human germline VH sequence selected from the group consisting of DP47, DP49, DP50, DP54 and DP53.

[0120] E81. The antibody according to any one of E77-E80, comprising a TSLP-VH framework sequence derived from a human DP50 germline sequence.

[0121] E82. The antibody of any one of E77-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.

[0122] E83. The antibody of any one of E77-E82, comprising a TSLP-VL framework sequence derived from a human germline V2-14 sequence.

[0123] E84. An antibody according to any one of E77-E84, comprising a TSLP-VL framework sequence and a TSLP-VH framework sequence, and wherein one or both of the TSLP-VL framework sequence or the TSLP-VH framework sequence is at least 66%, 76%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the human germline sequence from which they are derived.

[0124] E85. The antibody according to any one of E77 to E84, comprising a TSLP-VL framework sequence and a TSLP-VH framework sequence, and wherein one or both of the TSLP-VL framework sequence or the TSLP-VH framework sequence are identical to the human germline sequence from which they are derived.

[0125] E86. The antibody according to any one of E77-E85, comprising a TSLP-VH sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 92.

[0126] E87. The antibody according to any one of E77-E86, comprising a TSLP-VL sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 94.

[0127] E88. The antibody according to any one of E77 to E86, comprising:

[0128] (i) TSLP-VH sequence of SEQ ID NO: 92, and TSLP-VL of SEQ ID NO: 94;

[0129] (ii) the TSLP-VH sequence of SEQ ID NO: 92, and the TSLP-VL sequence of SEQ ID NO: 93;

[0130] (iii) TSLP-VH sequence of SEQ ID NO: 92, and TSLP-VL of SEQ ID NO: 213;

[0131] (iv) TSLP-VH sequence of SEQ ID NO: 92, and TSLP-VL of SEQ ID NO: 214;

[0132] (v) TSLP-VH sequence of SEQ ID NO: 221, and TSLP-VL of SEQ ID NO: 215;

[0133] (vi) the TSLP-VH sequence of SEQ ID NO: 221, and the TSLP-VL sequence of SEQ ID NO: 99; or

[0134] (vii) TSLP-VH sequence of SEQ ID NO: 221, and TSLP-VL of SEQ ID NO: 224.

[0135] E89. The antibody according to any one of E77-E88, comprising a TSLP-VH sequence identical to SEQ ID NO: 92 and a TSLP-VL identical to SEQ ID NO: 94.

[0136] E90. The antibody according to any one of E77-E88, comprising the same TSLP-VH sequence as SEQ ID NO: 92 and the same TSLP-VL as SEQ ID NO: 93.

[0137] E91. The antibody according to any one of E77-E88, comprising a TSLP-VH sequence identical to SEQ ID NO: 92 and a TSLP-VL identical to SEQ ID NO: 213.

[0138] E92. The antibody according to any one of E77-E88, comprising the same TSLP-VH sequence as SEQ ID NO: 92 and the same TSLP-VL as SEQ ID NO: 214.

[0139] E93. The antibody according to any one of E77-E89, comprising a TSLP-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 205.

[0140] E94. The antibody according to E91, comprising a TSLP-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 217.

[0141] E95. The antibody according to any one of E92, comprising a TSLP-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 218.

[0142] E96. The antibody according to any one of E77-E95, comprising a TSLP-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 204.

[0143] E97. The antibody according to any one of E77 to E96, comprising a TSLP-VH sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-127200.

[0144] E98. The antibody according to any one of E77 to E89, comprising a TSLP-VL sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-127199.

[0145] E99. An antibody comprising a TSLP-VH sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-127200, and comprising a TSLP-VL sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-127199.

[0146] E100. The antibody according to any one of E77 to E88, comprising a TSLP-VL sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-______.

[0147] E101. An antibody comprising a TSLP-VH sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-127200, and comprising a TSLP-VL sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-______.

[0148] E102. The antibody according to any one of E77-E88, comprising a TSLP-VL sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-______.

[0149] E103. An antibody comprising a TSLP-VH sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-127200, and comprising a TSLP-VL sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-______.

[0150] E104. The antibody of E77-E102, wherein the antibody is characterized by an IC of 0.05 in a TARC production bioassay in human peripheral blood mononuclear cells. 50 Less than 10pM.

[0151] E105. The antibody of E77-E104, wherein the antibody is characterized by an IC of 0.05 in a TARC production bioassay in human peripheral blood mononuclear cells. 50 Less than 7pM.

[0152] E106. The antibody of E77-E105, wherein the antibody is characterized by an IC of 0.05 in a TARC production bioassay in human peripheral blood mononuclear cells. 50 Less than 6pM.

[0153] E107. The antibody according to E77-E106, wherein the melting temperature of the antibody is 68°C.

[0154] E108. The antibody according to E77-E107, wherein the pH 3.4 retention Δ% HMMS is less than 5, such that the pH 3.4 retention Δ% HMMS is defined as the difference between the percentage of high molecular weight species due to degradation of the antibody after incubation at pH 3.4 for 5 hours at room temperature and the percentage of high molecular weight species due to degradation of the antibody after incubation at pH 7.2 for 5 hours at room temperature.

[0155] E109. The antibody according to E77-E108, wherein the antibody has a low pH 3.4 retention Δ% HMMS of less than 1.

[0156] E110. The antibody of E77-E109, wherein the antibody has a low pH 3.4 retention Δ% HMMS of less than 0.1.

[0157] E111. The antibody according to E77-E110, further comprising a constant heavy chain domain (TSLP-CH1) and a constant light chain domain (TSLP-CL).

[0158] E112. The antibody according to E111, wherein TSLP-CH1 comprises a sequence selected from the group consisting of SEQ ID NO: 6, SEQ ID NO: 105 and SEQ ID NO: 110.

[0159] E113. The antibody according to E111-E112, wherein TSLP-CH1 comprises the sequence shown in SEQ ID NO: 6.

[0160] E114. The antibody according to E111-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.

[0161] E115. The antibody according to E111-E114, wherein TSLP-CL comprises the sequence shown in SEQ ID NO:95.

[0162] E116. The antibody according to E111-E115, wherein TSLP-CH1 is linked to TSLP-VL, and TSLP-CL is linked to TSLP-VH to form a TSLP binding domain exchanged Fab domain (TSLP-xFab).

[0163] E117. The antibody according to E111-E115, wherein TSLP-CH1 is linked to TSLP-VH, and TSLP-CL is linked to TSLP-VL to form a TSLP binding Fab domain (TSLP-Fab).

[0164] E118. The antibody according to any one of E77-E117, comprising an Fc domain comprising a first Fc chain and a second Fc chain.

[0165] E119. The antibody according to E118, wherein the Fc domain is an Fc domain of IgA (eg, IgA1 or IgA2), IgD, IgE, IgM, or IgG (eg, IgG1, IgG2, IgG3, or IgG4).

[0166] E120. The antibody according to any one of E118-E119, wherein the Fc domain is the Fc domain of IgG1.

[0167] E121. The antibody according to E118-E120, wherein the N-terminus of the first Fc chain or the second Fc chain is linked to the C-terminus of the TSLP-CH1 domain.

[0168] E122. The antibody according to E118-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.

[0169] E123. The antibody according to E122, wherein the hinge region comprises a sequence selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 102, SEQ ID NO: 123, SEQ ID NO: 126, SEQ ID NO: 129 and SEQ ID NO: 131.

[0170] E124. The antibody according to E122-E123, wherein the hinge region comprises the sequence shown in SEQ ID NO: 7.

[0171] E125. The antibody according to E122-E123, wherein the hinge region on the first Fc chain and the hinge region on the second Fc chain comprise a pair of sequences shown as SEQ ID NO: 129 and SEQ ID NO: 131.

[0172] E126. The antibody according to E122-E123, wherein the CH2 region comprises the sequence shown in SEQ ID NO:8.

[0173] E127. The antibody according to E122-E126, wherein the CH3 region on the first Fc chain and the CH3 region on the second Fc chain comprise a pair of sequences selected from the group consisting of:

[0174] (i) SEQ ID NO: 124 and SEQ ID NO: 127;

[0175] (ii) SEQ ID NO: 9 and SEQ ID NO: 9;

[0176] (iii) SEQ ID NO: 111 and SEQ ID NO: 106;

[0177] (iv) SEQ ID NO: 111 and SEQ ID NO: 114;

[0178] (v) SEQ ID NO: 114 and SEQ ID NO: 117;

[0179] (vi) SEQ ID NO: 139 and SEQ ID NO: 141; and

[0180] (vii) SEQ ID NO: 147 and SEQ ID NO: 148.

[0181] E128. The antibody according to E127, wherein the CH3 region on the first Fc chain and the CH region on the second Fc chain each comprise the sequence shown in SEQ ID NO: 9.

[0182] E129. The antibody according to E128, wherein the CH3 region on the first Fc chain and the CH region on the second Fc chain consist of a pair of sequences represented by SEQ ID NO: 124 and SEQ ID NO: 127.

[0183] E130. An antibody according to any one of E77-E129, comprising a polypeptide carrying TSLP-VH, said polypeptide comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to a sequence selected from the group consisting of SEQ ID NO: 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.

[0184] E131. An antibody according to any one of E77-E130, comprising a polypeptide carrying TSLP-VH, wherein the polypeptide comprises 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.

[0185] E132. The antibody according to any one of E77-E131, wherein the polypeptide carrying TSLP-VH comprises the sequence shown in SEQ ID NO: 97.

[0186] E133. The antibody according to any one of E77-E131, wherein the polypeptide carrying TSLP-VH comprises the sequence shown in SEQ ID NO: 165.

[0187] E134. An antibody according to any one of E77-E133, comprising a polypeptide carrying TSLP-VL, said polypeptide comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to a sequence selected from the group consisting of SEQ ID NO: 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.

[0188] E135. An antibody according to any one of E77-E134, comprising a polypeptide carrying TSLP-VL, wherein the polypeptide comprises 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.

[0189] E136. The antibody according to any one of E77 to E135, comprising a polypeptide carrying TSLP-VL, said polypeptide comprising the sequence shown in SEQ ID NO: 99.

[0190] E137. The antibody according to any one of E77 to E135, which comprises a TSLP-VL-carrying polypeptide sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127201.

[0191] E138. The antibody according to any one of E77 to E135, comprising a polypeptide sequence carrying TSLP-VL encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-______.

[0192] E139. The antibody according to any one of E77 to E135, comprising a polypeptide sequence carrying TSLP-VL encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-______.

[0193] E140. The antibody according to any one of E77 to E139, which comprises a polypeptide sequence carrying TSLP-VH encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127202.

[0194] E141. An antibody comprising a polypeptide sequence carrying TSLP-VH encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127202 and a polypeptide sequence carrying TSLP-VL encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127201.

[0195] E142. An antibody comprising a polypeptide sequence carrying TSLP-VH encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127202 and a polypeptide sequence carrying TSLP-VL encoded by a plasmid deposited with ATCC and having ATCC accession number PTA______.

[0196] E143. An antibody comprising a polypeptide sequence carrying TSLP-VH encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127202 and a polypeptide sequence carrying TSLP-VL encoded by a plasmid deposited with ATCC and having ATCC accession number PTA______.

[0197] E144. An isolated antibody that specifically binds p40 through a p40 binding domain, and wherein the antibody comprises at least one additional antigen binding domain that specifically binds an antigen selected from 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.

[0198] E145. An isolated antibody that specifically binds p40 through a p40 binding domain, and wherein the antibody comprises at least one additional antigen binding domain that specifically binds an antigen selected from the group consisting of IL-4, IL-13, IL-33, and TSLP, and wherein the p40 binding domain comprises a heavy chain variable region (p40-VH) and a light chain variable region (p40-VL), wherein CDR-H1 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 166; CDR-H2 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 167; CDR-H3 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 168; CDR-L1 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 171; CDR-L2 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 172, and CDR-L3 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 173. The amino acid sequence of NO:173.

[0199] E146. The antibody according to any one of E144-E145, wherein the antibody further comprises one or both of an IL-4 binding domain that specifically binds to IL-4 and an IL-13 binding domain that specifically binds to IL-13.

[0200] E147. The antibody according to any one of E144 to E146, wherein the p40 binding domain comprises a p40-VH framework sequence derived from a human germline VH sequence selected from the group consisting of DP3, DP7, DP73, DP75 and DP88.

[0201] E148. The antibody according to any one of E144 to E147, wherein the p40 binding domain comprises a p40-VH framework sequence derived from a human DP73 germline sequence.

[0202] E149. The antibody according to any one of E144 to E148, wherein the p40 binding domain comprises a p40-VL framework sequence derived from a human germline VL sequence selected from the group consisting of DPK4, DPK5, DPK7, DPK8 and DPK9.

[0203] E150. The antibody according to any one of E144 to E149, wherein the p40 binding domain comprises a p40-VL framework sequence derived from a human germline DPK7 sequence.

[0204] E151. The antibody according to any one of E144 to E150, wherein the p40 binding domain comprises a p40-VL framework sequence and a p40-VH framework sequence, and wherein 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 they are derived.

[0205] E152. The antibody according to any one of E144 to E151, wherein the p40 binding domain comprises a p40-VL framework sequence and a p40-VH framework sequence, and wherein one or both of the p40-VL framework sequence or the p40-VH framework sequence are identical to the human germline sequence from which they are derived.

[0206] E153. The antibody according to any one of E144-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.

[0207] E154. The antibody according to any one of E144-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.

[0208] E155. The antibody according to any one of E144-E154, wherein the p40 binding domain comprises p40-VH of SEQ ID NO: 169 and p40-VL of SEQ ID NO: 175.

[0209] E156. The antibody according to any one of E144-E155, wherein the p40 binding domain comprises a p40-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 206.

[0210] E157. The antibody according to any one of E145-E156, wherein the p40 binding domain comprises a p40-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 207.

[0211] E158. The antibody according to any one of E144 to E157, wherein said p40 binding domain comprises a p40-VH sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-127206.

[0212] E159. The antibody according to any one of E144 to E158, wherein said p40 binding domain comprises a p40-VL sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-127205.

[0213] E160. The antibody according to E144-E159, further comprising a constant heavy chain domain (p40-CH1) and a constant light chain domain (p40-CL).

[0214] E161. The antibody according to 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.

[0215] E162. The antibody according to E160-E161, wherein p40-CH1 comprises the sequence shown in SEQ ID NO:6.

[0216] E163. The antibody according to E160-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.

[0217] E164. The antibody according to E160-E163, wherein p40-CL comprises the sequence shown in SEQ ID NO:16.

[0218] E165. The antibody according to E160-E164, wherein p40-CH1 is connected to p40-VL, and p40-CL is connected to p40-VH to form a p40 binding domain exchange Fab domain (p40-xFab).

[0219] E166. The antibody according to E160-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).

[0220] E167. The antibody according to any one of E144-E166, comprising an antibody Fc domain comprising a first Fc chain and a second Fc chain.

[0221] E168. The antibody according to E167, wherein the Fc domain is an Fc domain of IgA (eg, IgA1 or IgA2), IgD, IgE, IgM, or IgG (eg, IgG1, IgG2, IgG3, or IgG4).

[0222] E169. The antibody according to E168, wherein the Fc domain is the Fc domain of IgG1.

[0223] E170. The antibody according to any one of E167-E169, wherein the N-terminus of the first Fc chain or the second Fc chain is linked to the C-terminus of the p40-CH1 domain.

[0224] E171. The antibody according to E167-E170, wherein the first Fc chain and the second Fc chain each comprise, from N-terminus to C-terminus: a hinge region, a CH2 region and a CH3 region.

[0225] E172. The antibody according to 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.

[0226] E173. The antibody according to E171-E172, wherein the hinge region on the first Fc chain and the hinge region on the second Fc chain comprise a pair of sequences shown as SEQ ID NO: 129 and SEQ ID NO: 131.

[0227] E174. The antibody according to E171-E172, wherein the CH2 region comprises the sequence shown in SEQ ID NO:8.

[0228] E175. The antibody according to E171-E174, wherein the CH3 region on the first Fc chain and the CH3 region on the second Fc chain comprise a pair of sequences selected from the group consisting of:

[0229] (i) SEQ ID NO: 9 and SEQ ID NO: 9;

[0230] (ii) SEQ ID NO: 111 and SEQ ID NO: 106;

[0231] (iii) SEQ ID NO: 111 and SEQ ID NO: 114;

[0232] (iv) SEQ ID NO: 114 and SEQ ID NO: 117;

[0233] (v) SEQ ID NO: 124 and SEQ ID NO: 127;

[0234] (vi) SEQ ID NO: 139 and SEQ ID NO: 141; and

[0235] (vii) SEQ ID NO: 147 and SEQ ID NO: 148.

[0236] E176. The antibody according to E171-E175, wherein the CH3 region on the first Fc chain and the CH region on the second Fc chain each comprise the sequence shown in SEQ ID NO: 9.

[0237] E177. The antibody according to E171-E176, wherein the CH3 region on the first Fc chain and the CH region on the second Fc chain comprise a pair of sequences shown as SEQ ID NO: 124 and SEQ ID NO: 127.

[0238] E178. An antibody according to any one of E144-E177, comprising a polypeptide carrying p40-VH, said polypeptide comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to a sequence selected from the group consisting of SEQ ID NO: 170, SEQ ID NO: 177, SEQ ID NO: 181, SEQ ID NO: 185 and SEQ ID NO: 186.

[0239] E179. The antibody according to any one of E144-E178, comprising a polypeptide carrying p40-VH comprising an amino acid 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.

[0240] E180. The antibody according to any one of E144 to E179, comprising a polypeptide carrying p40-VH comprising the amino acid sequence of SEQ ID NO: 186.

[0241] E181. An antibody according to any one of E144 to E180, comprising a polypeptide carrying p40-VL, said polypeptide comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to a sequence selected from the group consisting of SEQ ID NO: 176, SEQ ID NO: 178, SEQ ID NO: 179, SEQ ID NO: 182 and SEQ ID NO: 183.

[0242] E182. The antibody according to any one of E144-E181, comprising a polypeptide carrying p40-VL, said polypeptide comprising the amino acid sequence of SEQ ID NO: 176.

[0243] E183. The antibody according to any one of E144 to E182, comprising a polypeptide sequence carrying p40-VH encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127204.

[0244] E184. The antibody according to any one of E144 to E183, which comprises a polypeptide sequence carrying p40-VL encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127203.

[0245] E185. An antibody comprising a polypeptide sequence carrying p40-VH encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127204, and a polypeptide sequence carrying p40-VL encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127203.

[0246] E186. An isolated antibody that binds to p40 and to one or both of IL-4, IL-13, comprising the CDRs of an antibody selected from one or more of Tables 86 and 87.

[0247] E187. An isolated antibody that binds to p40 and to one or both of IL-4, IL-13, comprising the VH and VL of an antibody selected from one or more of Tables 86 and 87.

[0248] E188. An isolated antibody that binds to p40 and to one or both of IL-4, IL-13, selected from one or more of Tables 86 and 87.

[0249] E189. The antibody according to any one of E144-E188 for use as a medicament.

[0250] E190. The antibody according to E189, wherein the use is for treating one or more selected from the group consisting of: non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, atopic dermatitis, Crohn's disease, ulcerative colitis, asthma (severe), allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus, primary biliary cirrhosis and hidradenitis suppurativa.

[0251] E191. The antibody according to any one of E189-E190, wherein the use is for treating one or more selected from the group consisting of: non-alcoholic steatohepatitis (NASH), atopic dermatitis, asthma (severe), alopecia, idiopathic pulmonary fibrosis and systemic sclerosis.

[0252] E192. The antibody according to any one of E189-E191, wherein the use is for atopic dermatitis.

[0253] E193. The antibody according to any one of E189-E191, wherein the use is for non-alcoholic steatohepatitis (NASH).

[0254] E194. A pharmaceutical composition comprising a therapeutically effective amount of the antibody according to E144-E193 and a pharmaceutically acceptable carrier.

[0255] E195. A method of treating a medical condition, comprising administering to a subject in need thereof a therapeutically effective amount of the antibody according to any one of E144-E193, or the pharmaceutical composition according to E194.

[0256] E196. The method according to E195, wherein the condition is selected from the group consisting of non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, atopic dermatitis, Crohn's disease, ulcerative colitis, asthma (severe), allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus, primary biliary cirrhosis and hidradenitis suppurativa.

[0257] E197. The method according to any one of E195-E196, comprising administering the antibody or pharmaceutical composition subcutaneously.

[0258] E198. The method according to any one of E195-E196, wherein the antibody or pharmaceutical composition is administered approximately twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, twice a month, once a month, once every two months, once every three months, or once every four months.

[0259] E199. An isolated antibody that specifically binds to IL-4, comprising a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL), comprising:

[0260] (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;

[0261] (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;

[0262] (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; or

[0263] (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

[0264] (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.

[0265] 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: CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO: 22, and CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO: 26.

[0266] 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.

[0267] E202. The antibody according to any one of E199 to E201, comprising an IL4-VH framework sequence derived from a human germline VH sequence selected from the group consisting of DP26, DP27, DP28 and DP76.

[0268] E203. The antibody according to any one of E199-E202, comprising an IL4-VH framework sequence derived from a human DP76 germline sequence.

[0269] E204. The antibody according to any one of E199 to E203, comprising an IL4-VL framework sequence derived from a human germline VL sequence selected from the group consisting of DPK1, DPK3, DPK4, DPK5, DPK7, DPK8, DPK9 and DPK24.

[0270] E205. The antibody according to any one of E199-E204, comprising an IL4-VL framework sequence derived from a human germline DPK9 sequence.

[0271] E206. An antibody according to any one of E199 to E205, comprising an IL4-VL framework sequence and an IL4-VH framework sequence, and wherein one or both of the IL4-VL framework sequence or the IL4-VH framework sequence are at least 66%, 76%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the human germline sequence from which they are derived.

[0272] E207. The antibody according to any one of E199 to E206, comprising an IL4-VL framework sequence and an IL4-VH framework sequence, and wherein one or both of the IL4-VL framework sequence or the IL4-VH framework sequence are identical to the human germline sequence from which they are derived.

[0273] E208. The antibody according to any one of E199-E207, comprising an IL4-VH sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 22.

[0274] E209. The antibody according to any one of E199-E208, comprising an IL4-VL sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 20.

[0275] E210. The antibody according to any one of E199 to E209, comprising:

[0276] (i) the IL4-VH sequence of SEQ ID NO: 22, and the IL4-VL sequence of SEQ ID NO: 26;

[0277] (ii) the IL4-VH sequence of SEQ ID NO: 19, and the IL4-VL sequence of SEQ ID NO: 20;

[0278] (iii) the IL4-VH sequence of SEQ ID NO: 22, and the IL4-VL sequence of SEQ ID NO: 20;

[0279] (iv) the IL4-VH sequence of SEQ ID NO: 28, and the IL4-VL sequence of SEQ ID NO: 29; or

[0280] (v) IL4-VH sequence of SEQ ID NO: 22, and IL4-VL sequence of SEQ ID NO: 30.

[0281] E211. The antibody according to any one of E199-E210, comprising the same IL4-VH sequence as SEQ ID NO: 26 and the same IL4-VL sequence as SEQ ID NO: 26.

[0282] E212. The antibody according to any one of E199-E211, comprising an IL4-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 200.

[0283] E213. The antibody according to any one of E199-E212, comprising an IL4-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 201.

[0284] E214. The antibody according to any one of E199 to E213, comprising an IL4-VH sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-127198.

[0285] E215. The antibody according to any one of E199 to E214, comprising an IL4-VL sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-127197.

[0286] E216. An antibody comprising an IL4-VH sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127198 and an IL4-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127197.

[0287] E217. The antibody according to E199-E216, wherein the antibody binds to the K of human IL-4 D Less than a value selected from the group consisting of about 10 pM, 5 pM, 1 pM, and 800 fM.

[0288] E218. The antibody according to E199-E217, wherein the antibody binds to the K of human IL-4 D A value of less than about 1 pM.

[0289] E219. The antibody according to any one of E199-E218, wherein K D The values ​​were measured by kinetic exclusion assay.

[0290] E220. The antibody according to E199-E219, wherein the antibody binds to cynomolgus monkey IL-4.

[0291] E221. The antibody according to E199-E220, wherein the antibody does not bind to IL-4 from one or more selected from the group consisting of dog, sheep, rabbit, rat and mouse.

[0292] E222. The antibody according to E199-E221, wherein the binding K of the antibody to cynomolgus monkey IL-4 is D The binding K of the antibody to human IL-4 D within one order of magnitude.

[0293] E223. The antibody according to E199-E222, wherein the antibody binds to cynomolgus monkey IL-4 D The binding K of the antibody to human IL-4 D within 2 times of the difference.

[0294] E224. The antibody according to E199-E223, wherein the antibody is characterized by an IC of 0.05 for neutralization of IL-4 induction of CD23 in a human monocyte assay. 50 Less than 10pM.

[0295] E225. The antibody according to E199-E224, wherein the antibody is characterized by an IC of cynomolgus monkey IL-4 induced for neutralization of CD23 in a human monocyte assay. 50 Less than 20pM.

[0296] E226. The antibody according to E199-E225, wherein the viscosity of the antibody at a concentration of 80 mg / mL in histidine-sucrose pH 5.8 buffer at 25°C is 20 cP or less.

[0297] E227. The antibody according to E199-E226, wherein the viscosity of the antibody at a concentration of 100 mg / mL in histidine-sucrose pH 5.8 buffer at 25°C is 20 cP or less.

[0298] E228. The antibody according to E199-E227, wherein the viscosity of the antibody at 25°C is 20 cP or less at a concentration of 120 mg / mL in histidine-sucrose pH 5.8 buffer.

[0299] E229. The antibody of E199-E228, wherein the antibody comprises a lysine at residue 93 in the light chain.

[0300] E230. The antibody according to E199-E229, further comprising a constant heavy chain domain (IL4-CH1) and a constant light chain domain (IL4-CL).

[0301] E231. The antibody according to E230, wherein the IL4-CH1 comprises the sequence shown in SEQ ID NO: 6.

[0302] E232. The antibody according to E230-E231, wherein the IL4-CL comprises the sequence shown in SEQ ID NO: 16.

[0303] E233. The antibody according to E230-E232, wherein IL4-CH1 is linked to IL4-VL, and IL4-CL is linked to IL-4-VH to form an IL-4 binding domain-exchange Fab domain (IL4-xFab).

[0304] E234. The antibody according to E230-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).

[0305] E235. The antibody according to any one of E199-E234, comprising: an Fc domain comprising a first Fc chain and a second Fc chain.

[0306] E236. The antibody according to E235, wherein the Fc domain is an Fc domain of IgA (eg, IgA1 or IgA2), IgD, IgE, IgM, or IgG (eg, IgG1, IgG2, IgG3, or IgG4).

[0307] E237. The antibody according to E235-E236, wherein the Fc domain is the Fc domain of IgG1.

[0308] E238. The antibody or antigen-binding fragment thereof according to E235-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.

[0309] E239. The antibody or antigen-binding fragment thereof according to E235-E238, wherein the first Fc chain and the second Fc chain each comprise, from N-terminus to C-terminus: a hinge region, a CH2 region and a CH3 region.

[0310] E240. The antibody or antigen-binding fragment thereof according to 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.

[0311] E241. The antibody or antigen-binding fragment thereof according to E240, wherein the hinge region comprises the sequence shown in SEQ ID NO: 7.

[0312] E242. The antibody or antigen-binding fragment thereof according to E240, wherein the hinge region on the first Fc chain and the hinge region on the second Fc chain comprise a pair of sequences shown in SEQ ID NO: 129 and SEQ ID NO: 131.

[0313] E243. The antibody or antigen-binding fragment thereof according to E239-E242, wherein the CH2 region comprises the sequence shown in SEQ ID NO: 8.

[0314] E244. The antibody or antigen-binding fragment thereof according to E239-E243, wherein the CH3 region on the first Fc chain and the CH3 region on the second Fc chain comprise a pair of sequences selected from the group consisting of:

[0315] (i) SEQ ID NO: 9 and SEQ ID NO: 9;

[0316] (ii) SEQ ID NO: 111 and SEQ ID NO: 106;

[0317] (iii) SEQ ID NO: 111 and SEQ ID NO: 114;

[0318] (iv) SEQ ID NO: 114 and SEQ ID NO: 117;

[0319] (v) SEQ ID NO: 124 and SEQ ID NO: 127;

[0320] (vi) SEQ ID NO: 139 and SEQ ID NO: 141; and

[0321] (vii) SEQ ID NO: 147 and SEQ ID NO: 148.

[0322] E245. The antibody or antigen-binding fragment thereof according to E244, wherein the CH3 region on the first Fc chain and the CH region on the second Fc chain each comprise the sequence shown in SEQ ID NO: 9.

[0323] E246. The antibody or antigen-binding fragment thereof according to E244, wherein the CH3 region on the first Fc chain and the CH3 region on the second Fc chain comprise a pair of sequences shown in SEQ ID NO: 124 and SEQ ID NO: 127.

[0324] E247. The antibody according to any one of E199 to E246, comprising a polypeptide carrying IL4-VH, said polypeptide comprising a polypeptide selected from the group consisting of SEQ ID NO: 23, SEQ ID NO: 107, SEQ ID NO: 115, SEQ ID NO: 121, SEQ ID NO: 125, SEQ ID NO: 130, SEQ ID NO: 133, SEQ ID NO: 135, SEQ ID NO: 140, SEQ ID NO: 144, SEQ ID NO: 146, SEQ ID NO: 151, SEQ ID NO: 153, SEQ ID NO: 153, SEQ ID NO: 156, SEQ ID NO: 157, SEQ ID NO: 159, SEQ ID NO: 162, SEQ ID NO: 164, SEQ ID NO: 179, SEQ ID NO: 180, and SEQ ID NO: 181. The sequences of the group consisting of NO: 183 are at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98%, 99% or 100% identical amino acid sequences.

[0325] E248. The antibody according to any one of E199-E247, comprising a polypeptide carrying IL4-VH, said polypeptide comprising the amino acid sequence of SEQ ID NO: 23.

[0326] E249. The antibody according to any one of E199-E241, which comprises a polypeptide carrying IL4-VH, said polypeptide comprising the amino acid sequence of SEQ ID NO 8:130.

[0327] E250. An antibody according to any one of E199 to E249, comprising a polypeptide carrying IL4-VL, said polypeptide comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to a sequence selected from the group consisting of SEQ ID NO: 27, SEQ ID NO: 109 and SEQ ID NO: 116, SEQ ID NO: 136, SEQ ID NO: 197 and SEQ ID NO: 208.

[0328] E251. The antibody according to any one of E199-E250, which comprises a polypeptide carrying IL4-VL, said polypeptide comprising the amino acid sequence of SEQ ID NO: 27.

[0329] E252. The antibody according to any one of E199 to E251, which comprises the polypeptide sequence carrying IL4-VH encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127192.

[0330] E253. The antibody according to any one of E199 to E252, which comprises the polypeptide sequence carrying IL4-VL encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127194.

[0331] E254. An antibody comprising a polypeptide sequence carrying IL4-VH encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127192 and a polypeptide sequence carrying IL4-VL encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127194.

[0332] E255. The antibody according to any one of E199-E254, for use as a medicament.

[0333] E256. The antibody according to any one of E199 to E255, wherein the use is for treating one or more selected from the group consisting of: atopic dermatitis, asthma, cancer, chronic obstructive pulmonary disease (COPD), food allergies, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, idiopathic pulmonary fibrosis (IPF), scleroderma, and systemic sclerosis, diabetic nephropathy, Behcet's disease, gout, Alzheimer's disease, atherosclerosis, fungal keratitis, non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus (SLE), primary biliary cirrhosis and hidradenitis suppurativa.

[0334] E257. An antibody according to any one of E199-E256, wherein the use is for treating one or more selected from the group consisting of: atopic dermatitis, asthma, cancer, chronic obstructive pulmonary disease (COPD), food allergies, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, non-alcoholic steatohepatitis (NASH), alopecia, idiopathic pulmonary fibrosis and systemic sclerosis.

[0335] E258. The antibody according to any one of E199-E257, wherein the use is for atopic dermatitis.

[0336] E259. The antibody according to any one of E199-E257, wherein the use is for non-alcoholic steatohepatitis (NASH).

[0337] E260. A pharmaceutical composition comprising a therapeutically effective amount of the antibody according to E199-E259 and a pharmaceutically acceptable carrier.

[0338] E261. A method of treating a medical condition, comprising administering to a subject in need thereof a therapeutically effective amount of the antibody according to any one of E199-E259, or the pharmaceutical composition according to E260.

[0339] E262. The method according to E261, wherein the condition is selected from the group consisting of: atopic dermatitis, asthma, cancer, chronic obstructive pulmonary disease (COPD), food allergies, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, idiopathic pulmonary fibrosis (IPF), scleroderma, systemic sclerosis, diabetic nephropathy, Behçet's disease, gout, Alzheimer's disease and atherosclerosis.

[0340] E263. The method according to any one of E261-E262, comprising administering the antibody or pharmaceutical composition subcutaneously.

[0341] E264. The method according to any one of E261-E263, wherein the antibody or pharmaceutical composition is administered approximately twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, twice a month, once a month, once every two months, once every three months, or once every four months.

[0342] E265. An isolated antibody that specifically binds to IL-13, comprising a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL), comprising:

[0343] (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;

[0344] (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;

[0345] (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;

[0346] (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

[0347] (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;

[0348] 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.

[0349] 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.

[0350] E268. The antibody according to any one of E265-E267, comprising an IL13-VH framework sequence derived from a human germline VH sequence selected from the group consisting of DP7, DP10, DP35, DP47, DP50, DP51, DP54 and DP77.

[0351] E269. The antibody according to any one of E265-E268, comprising an IL13-VH framework sequence derived from a human DP54 germline sequence.

[0352] E270. The antibody according to any one of E265 to E269, comprising an IL13-VL framework sequence derived from a human germline VL sequence selected from the group consisting of DPK3, DPK4, DPK5, DPK8, DPK9, DPK10, DPK23.

[0353] E271. The antibody according to any one of E265-E270, comprising an IL13-VL framework sequence derived from a human germline DPK9 sequence.

[0354] E272. An antibody according to any one of E265-E271, comprising an IL13-VL framework sequence and an IL13-VH framework sequence, and wherein one or both of the IL13-VL framework sequence or the IL13-VH framework sequence are at least 66%, 76%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the human germline sequence from which they are derived.

[0355] E273. The antibody according to any one of E265 to E272, comprising an IL13-VL framework sequence and an IL13-VH framework sequence, and wherein one or both of the IL13-VL framework sequence or the IL13-VH framework sequence are identical to the human germline sequence from which they are derived.

[0356] E274. The antibody according to any one of E265-E273, comprising an IL13-VH sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 51.

[0357] E275. The antibody according to any one of E265-E274, comprising an IL13-VL sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 54.

[0358] E276. The antibody according to any one of E265-E275, comprising:

[0359] (i) the IL13-VH sequence of SEQ ID NO: 51, and the IL13-VL sequence of SEQ ID NO: 54;

[0360] (ii) the IL13-VH sequence of SEQ ID NO: 44, and the IL13-VL sequence of SEQ ID NO: 46;

[0361] (iii) the IL13-VH sequence of SEQ ID NO: 48, and the IL13-VL sequence of SEQ ID NO: 49;

[0362] (iv) the IL13-VH sequence of SEQ ID NO: 48, and the IL13-VL sequence of SEQ ID NO: 68; or

[0363] (v) IL13-VH sequence of SEQ ID NO: 57, and IL13-VL sequence of SEQ ID NO: 59.

[0364] E277. The antibody according to any one of E265-E276, which comprises the same IL13-VH as SEQ ID NO: 51 and the same IL13-VL as SEQ ID NO: 54.

[0365] E278. The antibody according to any one of E265-E277, comprising a VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 198.

[0366] E279. The antibody according to any one of E265-E278, comprising a VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 199.

[0367] E280. The antibody according to any one of E265 to E279, comprising an IL13-VH sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-127196.

[0368] E281. The antibody according to any one of E265 to E280, comprising an IL13-VL sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-127195.

[0369] E282. An antibody comprising an IL13-VH sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-127196 and an IL13-VL sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-127195.

[0370] E283. The antibody according to E265-E282, wherein the antibody binds to the K of human IL-13 D 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.

[0371] E284. The antibody according to E265-E276, wherein the antibody binds to the K of human IL-13 D Less than 60pM.

[0372] E285. The antibody according to any one of E283-E284, wherein K D The values ​​were measured by kinetic exclusion assay.

[0373] E286. The antibody according to any one of E283-E285, wherein K D The values ​​were measured by SPR.

[0374] E287. The antibody according to E265-E286, wherein the antibody binds to cynomolgus monkey IL-13.

[0375] E288. The antibody according to E265-E287, wherein the antibody does not bind to IL-13 from one or more selected from the group consisting of dog, rabbit and mouse.

[0376] E289. The antibody according to E265-E288, wherein the antibody binds to cynomolgus monkey IL-13 D The binding K of the antibody to human IL-13 D within one order of magnitude.

[0377] E290. The antibody according to E265-E289, wherein the antibody binds to cynomolgus monkey IL-13 D The binding K of the antibody to human IL-13 D within 5 times of the difference.

[0378] E291. The antibody according to E265-E290, wherein the antibody binds to cynomolgus monkey IL-13 D The binding K of the antibody to human IL-13 D within 2 times of the difference.

[0379] E292. The antibody according to E265-E291, wherein IL-13 IC is measured by neutralization of IL-13pSTAT6 phosphorylation in HT-29 cells 50 Less than 100pM.

[0380] E293. The antibody according to E265-E292, wherein the IL-13 IC for IL-13 induction for neutralization of CD23 is measured in a human monocyte assay. 50 Less than 20pM.

[0381] E294. The antibody according to E265-E293, wherein the IL-13 IC for neutralizing IL-13 induction of CD23 measured in a human monocyte assay 50 Less than 15pM.

[0382] E295. The antibody according to E265-E294, wherein the IL-13 IC for IL-13 induction for neutralization of CD23 is measured in a human monocyte assay. 50 Less than 12pM.

[0383] E296. The antibody according to E265-E295, further comprising a constant heavy chain domain (IL13-CH1) and a constant light chain domain (IL13-CL).

[0384] E297. The antibody according to E296, wherein the IL13-CH1 comprises a sequence selected from the group consisting of SEQ ID NO: 6, SEQ ID NO: 105 and SEQ ID NO: 110.

[0385] E298. The antibody according to E296-E297, wherein the IL13-CH1 comprises the sequence shown in SEQ ID NO: 6.

[0386] E299. The antibody according to E296-E298, wherein the IL13-CL comprises a sequence selected from the group consisting of SEQ ID NO: 16, SEQ ID NO: 108 and SEQ ID NO: 113.

[0387] E300. The antibody according to E296-E299, wherein the IL13-CL comprises the sequence shown in SEQ ID NO: 16.

[0388] E301. The antibody according to E296-E300, wherein IL13-CH1 is linked to IL13-VL, and IL13-CL is linked to IL13-VH to form an IL-13 binding domain-exchange Fab domain (IL13-xFab).

[0389] E302. The antibody according to E296-E301, wherein IL13-CH1 is connected to IL13-VH, and IL13-CL is connected to IL33-VL to form an IL-13 binding Fab domain (IL13-Fab).

[0390] E303. The antibody according to any one of E265-E302, comprising an Fc domain comprising a first Fc chain and a second Fc chain.

[0391] E304. The antibody according to E303, wherein the Fc domain is an Fc domain of IgA (eg, IgA1 or IgA2), IgD, IgE, IgM, or IgG (eg, IgG1, IgG2, IgG3, or IgG4).

[0392] E305. The antibody according to E303-E304, wherein the Fc domain is the Fc domain of IgG1.

[0393] E306. The antibody according to E303-E305, wherein the N-terminus of the first Fc chain or the second Fc chain is linked to the C-terminus of the IL13-CH1 domain.

[0394] E307. The antibody according to E303-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.

[0395] E308. The antibody according to E307, wherein the hinge region comprises a sequence selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 102, SEQ ID NO: 123, SEQ ID NO: 126, SEQ ID NO: 129 and SEQ ID NO: 131.

[0396] E309. The antibody according to E307-E308, wherein the hinge region comprises the sequence shown in SEQ ID NO: 7.

[0397] E310. The antibody according to E307-E309, wherein the hinge region comprises the sequence shown in SEQ ID NO: 102.

[0398] E311. The antibody according to E307-E310, wherein the CH2 region comprises the sequence shown in SEQ ID NO:8.

[0399] E312. The antibody of E307-E311, wherein the CH3 region on the first Fc chain and the CH3 region on the second Fc chain comprise a pair of sequences selected from the group consisting of:

[0400] (i) SEQ ID NO: 124 and SEQ ID NO: 127;

[0401] (ii) SEQ ID NO: 9 and SEQ ID NO: 9;

[0402] (iii) SEQ ID NO: 111 and SEQ ID NO: 106;

[0403] (iv) SEQ ID NO: 111 and SEQ ID NO: 114;

[0404] (v) SEQ ID NO: 114 and SEQ ID NO: 117;

[0405] (vi) SEQ ID NO: 139 and SEQ ID NO: 141; and

[0406] (vii) SEQ ID NO: 147 and SEQ ID NO: 148.

[0407] E313. The antibody according to E307-E312, wherein the CH3 region on the first Fc chain and the CH region on the second Fc chain each comprise the sequence shown in SEQ ID NO: 9.

[0408] E314. The antibody according to E307-E312, wherein the CH3 region on the first Fc chain and the CH3 region on the second Fc chain comprise a pair of sequences shown in SEQ ID NO: 124 and SEQ ID NO: 127.

[0409] E315. The antibody according to any one of E265-E314, comprising a polypeptide carrying IL13-VH, said polypeptide comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98%, 99% or 100% identical to a sequence selected from the group consisting of SEQ ID NO: 52, SEQ ID NO: 66, SEQ ID NO: 112, SEQ ID NO: 118, SEQ ID NO: 121, SEQ ID NO: 122, SEQ ID NO: 130, SEQ ID NO: 145, SEQ ID NO: 149, SEQ ID NO: 152, SEQ ID NO: 154, SEQ ID NO: 160, SEQ ID NO: 162, SEQ ID NO: 164 and SEQ ID NO: 209.

[0410] E316. The antibody according to any one of E265-E315, comprising a polypeptide carrying IL13-VH consisting of SEQ ID NO: 52, SEQ ID NO: 66, SEQ ID NO: 112, SEQ ID NO: 118, SEQ ID NO: 121, SEQ ID NO: 122, SEQ ID NO: 130, SEQ ID NO: 145, SEQ ID NO: 149, SEQ ID NO: 152, SEQ ID NO: 154, SEQ ID NO: 160, SEQ ID NO: 162, SEQ ID NO: 164 and SEQ ID NO: 209.

[0411] E317. The antibody according to any one of E264-E316, comprising a polypeptide carrying IL13-VH, said polypeptide comprising the amino acid sequence of SEQ ID NO: 52.

[0412] E318. The antibody according to any one of E265-E316, comprising a polypeptide carrying IL13-VH, said polypeptide comprising the amino acid sequence of SEQ ID NO: 122.

[0413] E319. An antibody according to any one of E265-E318, comprising a polypeptide carrying IL13-VL, said polypeptide comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to a sequence selected from the group consisting of SEQ ID NO: 55, SEQ ID NO: 163 and SEQ ID NO: 196.

[0414] E320. The antibody according to any one of E265-E319, comprising a polypeptide carrying IL13-VL, said polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 55, SEQ ID NO: 119, SEQ ID NO: 120, SEQ ID NO: 125, SEQ ID NO: 130, SEQ ID NO: 133, SEQ ID NO: 135, SEQ ID NO: 140, SEQ ID NO: 163, SEQ ID NO: 164 and SEQ ID NO: 196.

[0415] E321. The antibody according to any one of E265-E320, comprising a polypeptide carrying IL13-VL, said polypeptide comprising the amino acid sequence of SEQ ID NO: 55.

[0416] E322. The antibody according to any one of E265-E321, comprising a polypeptide carrying IL13-VL, said polypeptide comprising the amino acid sequence of SEQ ID NO: 130.

[0417] E323. The antibody according to any one of E265 to E322, comprising a polypeptide sequence carrying IL13-VH encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127193.

[0418] E324. The antibody according to any one of E265 to E323, which comprises a polypeptide sequence carrying IL13-VL encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127192.

[0419] E325. An antibody comprising a polypeptide sequence carrying IL13-VH encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127193 and a polypeptide sequence carrying IL13-VL encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127192.

[0420] E326. The antibody according to any one of E265-E325, for use as a medicament.

[0421] E327. The antibody according to E326, wherein the use is for the treatment of one or more selected from the group consisting of: atopic dermatitis, asthma, cancer, chronic obstructive pulmonary disease (COPD), food allergies, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, idiopathic pulmonary fibrosis (IPF), scleroderma, and systemic sclerosis, diabetic nephropathy, Behçet's disease, gout, Alzheimer's disease, atherosclerosis, fungal keratitis, non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus (SLE), primary biliary cirrhosis and hidradenitis suppurativa.

[0422] E328. The antibody according to any one of E326-E327, wherein the use is for treating one or more selected from the group consisting of: atopic dermatitis, asthma, cancer, chronic obstructive pulmonary disease (COPD), food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, non-alcoholic steatohepatitis (NASH), alopecia, idiopathic pulmonary fibrosis and systemic sclerosis.

[0423] E329. The antibody according to any one of E326-E328, wherein the use is for atopic dermatitis.

[0424] E330. The antibody according to any one of E326-E329, wherein the use is for non-alcoholic steatohepatitis (NASH).

[0425] E331. A pharmaceutical composition comprising a therapeutically effective amount of the antibody according to E265-E330 and a pharmaceutically acceptable carrier.

[0426] E332. A method of treating a medical condition, comprising administering to a subject in need thereof a therapeutically effective amount of the antibody according to any one of E265-E330, or the pharmaceutical composition according to E331.

[0427] E333. The method according to E332, wherein the condition is selected from the group consisting of non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, atopic dermatitis, Crohn's disease, ulcerative colitis, asthma (severe), allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus, primary biliary cirrhosis and hidradenitis suppurativa.

[0428] E334. The method according to any one of E332-E333, comprising administering the antibody or pharmaceutical composition subcutaneously.

[0429] E335. The method of any one of E332-E334, wherein the antibody or pharmaceutical composition is administered approximately twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, twice a month, once a month, once every two months, once every three months, or once every four months.

[0430] E336. An isolated antibody that specifically binds to IL-33, specifically binds to IL-4 and specifically binds to IL-13, comprising an IL-33 binding domain, an IL-4 binding domain and an IL-13 binding domain.

[0431] E337. The antibody according to E336, wherein specific binding to IL-33 is achieved by the antibody according to any one of E1-E71.

[0432] E338. The antibody according to E336-E337, wherein specific binding to IL-4 is achieved by the antibody according to any one of E199-E259.

[0433] E339. The antibody according to E336-E338, wherein specific binding to IL-13 is achieved by the antibody according to any one of E265-E330.

[0434] E340. The antibody according to any one of E336-E339, wherein

[0435] (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; and

[0436] (ii) 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; and

[0437] (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.

[0438] E341. The antibody according to E336-E340, wherein:

[0439] (i) the IL-33 binding domain comprises IL33-VH of SEQ ID NO: 73 and IL33-VL of SEQ ID NO: 78;

[0440] (ii) the IL-4 binding domain comprises IL4-VH of SEQ ID NO: 22 and IL4-VL of SEQ ID NO: 26; and

[0441] (iii) The IL-13 binding domain comprises IL13-VH of SEQ ID NO: 51 and IL13-VL of SEQ ID NO: 54.

[0442] E342. The antibody according to E336-341, wherein:

[0443] (i) the IL-33 binding domain comprises the IL33-VH sequence encoded by the plasmid deposited with ATCC and having ATCC Accession No. PTA-127210, and the IL33-VL sequence encoded by the plasmid deposited with ATCC and having ATCC Accession No. PTA-127209;

[0444] (ii) the IL-4 binding domain comprises 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

[0445] (iii) The IL-13 binding domain comprises the IL13-VH sequence encoded by the plasmid deposited with ATCC and having ATCC Accession No. PTA-127196, and the IL13-VL sequence encoded by the plasmid deposited with ATCC and having ATCC Accession No. PTA-127195.

[0446] E343. The antibody according to E336-E342, wherein the IL-33 binding domain is fused to the IL-13 binding domain with or without a linker.

[0447] E344. The antibody according to E336-E342, wherein the IL-33 binding domain is fused to the IL-4 binding domain with or without a linker.

[0448] E345. The antibody according to E336-E342, wherein the IL-13 binding domain is fused to the IL-4 binding domain with or without a linker.

[0449] E346. The antibody according to any one of E343-E345, wherein the fusion is performed via a linker.

[0450] E347. The antibody according to any one of E336-E346, wherein the IL-13 binding domain is fused to the IL-4 binding domain via a linker.

[0451] E348. The antibody according to E343-E347, wherein the linker comprises SEQ ID NO: 104.

[0452] E349. The antibody according to any one of E336-E348, wherein the antibody comprises a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain and a fifth polypeptide chain, such that

[0453] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising a first antigen binding site;

[0454] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising a second antigen binding site;

[0455] (iii) The first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a third antigen binding site.

[0456] E350. The antibody according to E349, wherein the first polypeptide chain and the second polypeptide chain associate together to form an antibody comprising two arms: a dual Fab arm comprising the first and second Fab domains, and a single Fab arm comprising the third Fab domain.

[0457] E351. The antibody according to E349-E350, wherein the fifth polypeptide chain comprises the sequence EPKSC (SEQ ID NO: 122) at the C-terminus.

[0458] E352. The antibody according to E349-E351, wherein the first antigen binding site specifically binds IL-13, the second antibody binding site specifically binds IL-4, and the third antigen binding site specifically binds IL-33.

[0459] E353. The antibody according to E349-E352, wherein the first Fab domain, the second Fab domain and the third Fab domain each comprise a different option selected from the following (i), (ii) and (iii):

[0460] (i) IL33-Fab of E38;

[0461] (ii) IL4-Fab of E234; and

[0462] (iii) IL13-Fab of E302.

[0463] E354. The antibody according to E349-E353, wherein the first Fab domain is the IL13-Fab of E302, the second Fab domain is the IL4-Fab of E234, and the third Fab domain is the IL33-Fab of E38.

[0464] E355. The antibody according to E349-E354, wherein the first polypeptide comprises a first Fc chain and the second polypeptide comprises a second Fc chain.

[0465] E356. The antibody according to E355, wherein the first Fc chain and the second Fc chain each comprise one or more amino acid modifications that promote association of the first Fc chain with the second Fc chain.

[0466] E357. The antibody according to E349-E356, wherein the first Fc chain comprises a first CH3 domain, the second Fc chain comprises a second CH3 domain, and the first CH3 domain and the second CH3 domain each comprise different but complementary sequences, the different but complementary sequences being selected from one of the following different but complementary sequence pairs:

[0467] (i) SEQ ID NO: 111 and SEQ ID NO: 106;

[0468] (ii) SEQ ID NO: 111 and SEQ ID NO: 114;

[0469] (iii) SEQ ID NO: 114 and SEQ ID NO: 117;

[0470] (iv) SEQ ID NO: 124 and SEQ ID NO: 127;

[0471] (v) SEQ ID NO: 139 and SEQ ID NO: 141; and

[0472] (vi) SEQ ID NO: 147 and SEQ ID NO: 148.

[0473] E358. The antibody according to E357, wherein the first CH3 domain and the second CH3 domain comprise SEQ ID NO: 124 and SEQ ID NO: 127.

[0474] E359. The antibody according to E349-E358, wherein the identity of the first polypeptide chain, the second polypeptide chain, the third polypeptide chain, the fourth polypeptide chain and the fifth polypeptide chain is selected from the group consisting of:

[0475] (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;

[0476] (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;

[0477] (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;

[0478] (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;

[0479] (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;

[0480] (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;

[0481] (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;

[0482] (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;

[0483] (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;

[0484] (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;

[0485] (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.

[0486] E360. The antibody according to any one of E349-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.

[0487] E361. An isolated antibody that specifically binds to IL-33, specifically binds to IL-4, and specifically binds to IL-13, comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein

[0488] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site;

[0489] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site;

[0490] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising an IL-33 binding site, and

[0491] 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.

[0492] E362. An isolated antibody that specifically binds to IL-33, specifically binds to IL-4, and specifically binds to IL-13, comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein

[0493] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site;

[0494] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site;

[0495] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising an IL-33 binding site, and

[0496] wherein the first polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127208; the second polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127192; the third polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127207; the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127194; and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127193.

[0497] E363. The antibody according to E336-E362, wherein the viscosity of the antibody is less than 20 cP in a buffer of 20 mM histidine, 8.5% sucrose, 0.05 mg / mL EDTA pH 6.0 at a concentration of at least 50 mg / mL.

[0498] E364. The antibody according to E336-E363, wherein the viscosity of the antibody is less than 15 cP at a concentration of at least 90 mg / mL in a buffer of 20 mM histidine, 8.5% sucrose, 0.05 mg / mL EDTA pH 6.0.

[0499] E365. The antibody according to E336-E364, wherein the terminal half-life of the antibody in cynomolgus monkeys is at least 12 days.

[0500] E366. The antibody according to E330-E365, wherein the terminal half-life of the antibody in TG32 mice is at least 16 days.

[0501] E367. The antibody according to E330-E366, wherein the binding affinity of the antibody to human IL-4 is less than 220 nM as measured by SPR.

[0502] E368. The antibody according to E330-E367, wherein the antibody binds to human IL-13 with a binding affinity of less than 220 nM as measured by SPR.

[0503] E369. The antibody according to E336-E368, wherein the antibody binds human IL-4 with a binding affinity of less than 1 pM as measured by KinExA in an immobilized antigen assay in PBS.

[0504] E370. The antibody according to E336-E369, wherein the antibody binds cynomolgus monkey IL-4 with a binding affinity of less than 5 pM as measured by KinExA in an immobilized antigen assay in PBS.

[0505] E371. The antibody according to E336-E370, wherein the antibody binds human IL-13 with a binding affinity of less than 1 pM as measured by KinExA in an immobilized antigen assay in PBS.

[0506] E372. The antibody according to E336-E371, wherein the antibody binds cynomolgus monkey IL-13 with a binding affinity of less than 1 pM as measured by KinExA in an immobilized antigen assay in PBS.

[0507] E373. The antibody according to E336-E372, wherein the antibody is characterized by an IC of 0.05 for neutralization of IL-4-induced CD23 in a human monocyte assay. 50 Less than 20nM.

[0508] E374. The antibody according to E336-E373, wherein the antibody is characterized by an IC of 0.05 for neutralization of IL-13 induction of CD23 in a human monocyte assay. 50 Less than 20nM.

[0509] E375. The antibody according to E336-E374, wherein the antibody is characterized by neutralization of wild-type IL-33 and IC in a HEK-Blue SEAP assay 50 Less than 30nM.

[0510] E376. The antibody according to E336-E375, wherein the antibody is characterized by neutralization of recombinant constitutively active IL-33 and IC in a HEK-Blue SEAP assay 50 Less than 15pM.

[0511] E377. The antibody according to any one of E336-E376, for use as a medicament.

[0512] E378. The antibody according to E377, wherein the use is for treating one or more selected from the group consisting of: atopic dermatitis, asthma, cancer, chronic obstructive pulmonary disease (COPD), food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, idiopathic pulmonary fibrosis (IPF), scleroderma, systemic sclerosis, diabetic nephropathy, Behçet's disease, gout, Alzheimer's disease and atherosclerosis.

[0513] E379. The antibody according to any one of E377-378, wherein the use is for treating one or more selected from the group consisting of: atopic dermatitis, asthma, cancer, chronic obstructive pulmonary disease (COPD), food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, and non-alcoholic steatohepatitis (NASH).

[0514] E380. The antibody according to any one of E377-E379, wherein the use is for atopic dermatitis.

[0515] E381. The antibody according to any one of E377-E379, wherein the use is for non-alcoholic steatohepatitis (NASH).

[0516] E382. A pharmaceutical composition comprising a therapeutically effective amount of the antibody according to E336-E381 and a pharmaceutically acceptable carrier.

[0517] E383. A method of treating a medical condition, comprising administering to a subject in need thereof a therapeutically effective amount of an antibody according to any one of E336-E381, or a pharmaceutical composition according to E382.

[0518] E384. The method according to E383, wherein the condition is selected from the group consisting of: atopic dermatitis, asthma, cancer, chronic obstructive pulmonary disease (COPD), food allergies, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, idiopathic pulmonary fibrosis (IPF), scleroderma, systemic sclerosis, diabetic nephropathy, Behçet's disease, gout, Alzheimer's disease and atherosclerosis.

[0519] E385. The method according to any one of E383-E384, comprising administering the antibody or pharmaceutical composition subcutaneously.

[0520] E386. The method according to any one of E383-E385, wherein the antibody or pharmaceutical composition is administered approximately twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, twice a month, once a month, once every two months, once every three months, or once every four months.

[0521] E387. An isolated antibody that specifically binds to TSLP, specifically binds to IL-4 and specifically binds to IL-13, comprising a TSLP binding domain, an IL-4 binding domain and an IL-13 binding domain.

[0522] E388. The antibody according to E387, wherein specific binding to TSLP is achieved by the antibody according to any one of E77-E143.

[0523] E389. The antibody according to E387-E388, wherein specific binding to IL-4 is achieved by the antibody according to any one of E199-E259.

[0524] E390. The antibody according to E387-E389, wherein specific binding to IL-13 is achieved by the antibody according to any one of E265-E330.

[0525] E391. The antibody according to any one of E381-E384, wherein

[0526] (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: 88, and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 90; and

[0527] (ii) an IL-4 binding domain 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; and

[0528] (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.

[0529] E392. The antibody according to E387-E391, wherein

[0530] (i) the TSLP binding domain comprises TSLP-VH of SEQ ID NO: 92 and TSLP-VL of SEQ ID NO: 94;

[0531] (ii) the IL-4 binding domain comprises IL4-VH of SEQ ID NO: 22 and IL4-VL of SEQ ID NO: 26; and

[0532] (iii) The IL-13 binding domain comprises IL13-VH of SEQ ID NO: 51 and IL13-VL of SEQ ID NO: 54.

[0533] E393. The antibody according to E387-E392, wherein

[0534] (i) the TSLP binding domain comprises a TSLP-VH sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-127200, and a TSLP-VL sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA0-127199;

[0535] (ii) the IL-4 binding domain comprises 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

[0536] (iii) The IL-13 binding domain comprises the IL13-VH sequence encoded by the plasmid deposited with ATCC and having ATCC Accession No. PTA-127196, and the IL13-VL sequence encoded by the plasmid deposited with ATCC and having ATCC Accession No. PTA-127195.

[0537] E394. The antibody according to E387-E393, wherein the TSLP binding domain is fused to the IL-13 binding domain with or without a linker.

[0538] E395. The antibody according to E387-E393, wherein the TSLP binding domain is fused to the IL-4 binding domain with or without a linker.

[0539] E396. The antibody according to E387-E393, wherein the IL-13 binding domain is fused to the IL-4 binding domain with or without a linker.

[0540] E397. The antibody according to any one of E394-E396, wherein the fusion is performed via a linker.

[0541] E398. The antibody according to any one of E394-E397, wherein the IL-13 binding domain is fused to the IL-4 binding domain via a linker.

[0542] E399. The antibody according to E394-E398, wherein the linker comprises SEQ ID NO: 104.

[0543] E400. The antibody according to any one of 387-E399, wherein the antibody comprises a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain and a fifth polypeptide chain, such that

[0544] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising a first antigen binding site;

[0545] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising a second antigen binding site;

[0546] (iii) The first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a third antigen binding site.

[0547] E401. The antibody according to E400, wherein the first polypeptide chain and the second polypeptide chain associate together to form an antibody comprising two arms: a dual Fab arm comprising the first and second Fab domains, and a single Fab arm comprising the third Fab domain.

[0548] E402. The antibody according to E400-E401, wherein the fifth polypeptide chain comprises the sequence EPKSC (SEQ ID NO: 122) at the C-terminus.

[0549] E403. The antibody according to E400-E402, wherein the first antigen binding site specifically binds IL-13, the second antibody binding site specifically binds IL-4, and the third antigen binding site specifically binds TSLP.

[0550] E404. The antibody according to E400-E403, wherein the first Fab domain, the second Fab domain and the third Fab domain each comprise a different option selected from the following (i), (ii) and (iii):

[0551] (i) TSLP-Fab of E117;

[0552] (ii) IL4-Fab of E234; and

[0553] (iii) IL13-Fab of E302.

[0554] E405. The antibody according to E400-E406, wherein the first Fab domain is IL13-Fab of E302, the second Fab domain is IL4-Fab of E234, and the third Fab domain is TSLP-Fab of E117.

[0555] E406. The antibody according to E400-E405, wherein the first polypeptide comprises a first Fc chain and the second polypeptide comprises a second Fc chain.

[0556] E407. The antibody according to E406, wherein the first Fc chain and the second Fc chain each comprise one or more amino acid modifications that promote association of the first Fc chain with the second Fc chain.

[0557] E408. The antibody according to E400-E407, wherein the first Fc chain comprises a first CH3 domain, the second Fc chain comprises a second CH3 domain, and the first CH3 domain and the second CH3 domain each comprise different but complementary sequences selected from one of the following different but complementary sequence pairs:

[0558] (i) SEQ ID NO: 111 and SEQ ID NO: 106;

[0559] (ii) SEQ ID NO: 111 and SEQ ID NO: 114;

[0560] (iii) SEQ ID NO: 114 and SEQ ID NO: 117;

[0561] (iv) SEQ ID NO: 124 and SEQ ID NO: 127;

[0562] (v) SEQ ID NO: 139 and SEQ ID NO: 141; and

[0563] (vi) SEQ ID NO: 147 and SEQ ID NO: 148.

[0564] E409. The antibody according to E408, wherein the first CH3 domain and the second CH3 domain comprise SEQ ID NO: 124 and SEQ ID NO: 127.

[0565] E410. The antibody according to E400-E409, wherein the identity of the first polypeptide chain, the second polypeptide chain, the third polypeptide chain, the fourth polypeptide chain and the fifth polypeptide chain is selected from the group consisting of:

[0566] (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;

[0567] (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;

[0568] (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;

[0569] (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;

[0570] (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;

[0571] (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;

[0572] (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;

[0573] (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;

[0574] (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;

[0575] (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;

[0576] (xi) the first polypeptide chain comprises SEQ ID NO: 146, the second polypeptide chain comprises SEQ ID NO: 160, the third polypeptide chain comprises SEQ ID NO: 109, the fourth polypeptide chain comprises SEQ ID NO: 196, and the fifth polypeptide chain comprises SEQ ID NO: 158; and

[0577] (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;

[0578] (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

[0579] (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.

[0580] E411. The antibody according to E411-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.

[0581] E412. An isolated antibody that specifically binds to TSLP, specifically binds to IL-4, and specifically binds to IL-13, comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein

[0582] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site;

[0583] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site;

[0584] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a TSLP binding site, and

[0585] 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.

[0586] E413. An isolated antibody that specifically binds to TSLP, specifically binds to IL-4, and specifically binds to IL-13, comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein

[0587] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site;

[0588] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site;

[0589] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a TSLP binding site, and

[0590] wherein the first polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127202; the second polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127192; the third polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127201; the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127194; and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127193.

[0591] E414. The antibody according to any one of E387-E413, wherein the terminal half-life of the antibody in cynomolgus monkeys is at least 14 days.

[0592] E415. The antibody according to any one of E387-E414, wherein the terminal half-life of the antibody in TG32 mice is at least 18 days.

[0593] E416. The antibody according to any one of E387-E415, characterized by an IC of 0.05 as measured in a TARC production bioassay in human primary PBMCs. 50Less than 10 pM of anti-TSLP bioactivity.

[0594] E417. The antibody according to any one of E387-E416, characterized in that it has a viscosity of 20 cP at a concentration of at least 100 mg / mL in 20 mM histidine, 8.5% sucrose, 0.05 mg / mL EDTA pH 6.0 buffer.

[0595] E418. The antibody according to any one of E387-E417, characterized by a score of less than 2% high molecular weight species as determined by analytical size exclusion chromatography (aSEC).

[0596] E419. The antibody according to any one of E387-E418, characterized in that it has a score of less than 12 in an affinity capture self-interaction nanoparticle spectroscopy (AC SINS) assay.

[0597] E420. The antibody according to any one of E387-E419, wherein the antibody binds human IL-4 with a binding affinity of less than 1 pM as measured by KinExA in an immobilized antigen assay in PBS.

[0598] E421. The antibody according to any one of E387-E420, wherein the antibody binds cynomolgus monkey IL-4 with a binding affinity of less than 1 pM as measured by KinExA in an immobilized antigen assay in PBS.

[0599] E422. The antibody according to any one of E387-E421, wherein the antibody binds human IL-13 with a binding affinity of less than 1 pM as measured by KinExA in an immobilized antigen assay in PBS.

[0600] E423. The antibody according to any one of E387-E422, wherein the antibody binds cynomolgus monkey IL-13 with a binding affinity of less than 1 pM as measured by KinExA in an immobilized antigen assay in PBS.

[0601] E424. The antibody according to any one of E387-E423, wherein the antibody binds to human TSLP with a binding affinity of less than 5 pM as measured by KinExA in an immobilized antigen assay in PBS.

[0602] E425. The antibody according to any one of E387-E424, wherein the antibody binds cynomolgus monkey IL-13 with a binding affinity of less than 20 pM as measured by KinExA in an immobilized antigen assay in PBS.

[0603] E426. The antibody according to any one of E387-E425, wherein the antibody is characterized by an IC of 0.05 for neutralization of IL-4 induction of CD23 in a human monocyte assay. 50 Less than 25pM.

[0604] E427. The antibody according to any one of E387-E426, wherein the antibody is characterized by an IC of 0.05 for neutralization of IL-4 induction of CD23 in a human monocyte assay. 50 Less than 15pM.

[0605] E428. The antibody according to any one of E387-E427, wherein the antibody is characterized by an IC of 0.05 for cynomolgus IL-4-induced neutralization of CD23 in a human monocyte assay. 50 Less than 60pM.

[0606] E429. The antibody according to any one of E387-E428, wherein the antibody is characterized by an IC of 0.05 for neutralization of human TSLP in a TARC production bioassay of human primary PBMCs. 50 Less than 15pM.

[0607] E430. The antibody according to any one of E387-E429, wherein the antibody is characterized by an IC in a cynomolgus monkey TSLP neutralization assay. 50 Less than 35pM.

[0608] E431. The antibody according to any one of E387-430, for use as a medicament.

[0609] E432. The antibody according to E431, wherein the use is for treating one or more selected from the group consisting of: atopic dermatitis, asthma, cancer, chronic obstructive pulmonary disease (COPD), food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, idiopathic pulmonary fibrosis (IPF), scleroderma, systemic sclerosis, and fungal keratitis.

[0610] E433. The antibody according to any one of E431-E432, wherein the use is for treating one or more selected from the group consisting of: atopic dermatitis, asthma, cancer, chronic obstructive pulmonary disease (COPD), food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, and non-alcoholic steatohepatitis (NASH).

[0611] E434. The antibody according to any one of E431-433, wherein the use is for atopic dermatitis.

[0612] E435. The antibody according to any one of E431-433, wherein the use is for non-alcoholic steatohepatitis (NASH).

[0613] E436. A pharmaceutical composition comprising a therapeutically effective amount of the antibody according to E387-E435 and a pharmaceutically acceptable carrier.

[0614] E437. A method of treating a medical condition, comprising administering to a subject in need thereof a therapeutically effective amount of the antibody according to any one of E387-E435, or the pharmaceutical composition according to E436.

[0615] E438. The method according to E437, wherein the condition is selected from the group consisting of: atopic dermatitis, asthma, cancer, chronic obstructive pulmonary disease (COPD), food allergies, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, idiopathic pulmonary fibrosis (IPF), scleroderma, systemic sclerosis, and fungal keratitis.

[0616] E439. The method according to any one of E437-E438, comprising administering the antibody or pharmaceutical composition subcutaneously.

[0617] E440. The method according to any one of E437-E439, wherein the antibody or pharmaceutical composition is administered approximately twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, twice a month, once a month, once every two months, once every three months, or once every four months.

[0618] E445. An isolated antibody that specifically binds to p40, specifically binds to IL-4 and specifically binds to IL-13, comprising a p40 binding domain, an IL-4 binding domain and an IL-13 binding domain.

[0619] E446. The antibody according to E445, wherein specific binding to p40 is achieved by the antibody according to any one of E144-E193.

[0620] E447. The antibody according to E445-E446, wherein specific binding to IL-4 is achieved by the antibody according to any one of E199-E259.

[0621] E448. The antibody according to any one of E445-E447, wherein specific binding to IL-13 is achieved by the antibody according to any one of E265-E330.

[0622] E449. The antibody according to any one of E445-E448, wherein

[0623] (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; and

[0624] (ii) 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; and

[0625] (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.

[0626] E450. The antibody according to E445-449, wherein

[0627] (i) the p40 binding domain comprises p40-VH of SEQ ID NO: 169 and p40-VL of SEQ ID NO: 175;

[0628] (ii) the IL-4 binding domain comprises IL4-VH of SEQ ID NO: 22 and IL4-VL of SEQ ID NO: 26; and

[0629] (iii) The IL-13 binding domain comprises IL13-VH of SEQ ID NO: 51 and IL13-VL of SEQ ID NO: 54.

[0630] E451. The antibody according to E445-450, wherein

[0631] (i) the p40 binding domain comprises a p40-VH sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-127206, and a p40-VL sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-127205;

[0632] (ii) the IL-4 binding domain comprises 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

[0633] (iii) The IL-13 binding domain comprises the IL13-VH sequence encoded by the plasmid deposited with ATCC and having ATCC Accession No. PTA-127196, and the IL13-VL sequence encoded by the plasmid deposited with ATCC and having ATCC Accession No. PTA-127195.

[0634] E452. The antibody according to E445-E451, wherein the p40 binding domain is fused to the IL-13 binding domain with or without a linker.

[0635] E453. The antibody according to E445-E451, wherein the p40 binding domain is fused to the IL-4 binding domain with or without a linker.

[0636] E454. The antibody according to E445-E451, wherein the IL-13 binding domain is fused to the IL-4 binding domain with or without a linker.

[0637] E455. The antibody according to any one of E452-E454, wherein the fusion is via a linker.

[0638] E456. The antibody according to any one of E452-E455, wherein the IL-13 binding domain is fused to the IL-4 binding domain via a linker.

[0639] E457. The antibody according to E456, wherein the linker comprises SEQ ID NO: 104.

[0640] E458. The antibody according to any one of E445-E457, wherein the antibody comprises a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain and a fifth polypeptide chain, such that

[0641] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising a first antigen binding site;

[0642] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising a second antigen binding site;

[0643] (iii) The first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a third antigen binding site.

[0644] E459. The antibody according to E458, wherein the first polypeptide chain and the second polypeptide chain associate together to form an antibody comprising two arms: a dual Fab arm comprising the first and second Fab domains, and a single Fab arm comprising the third Fab domain.

[0645] E460. The antibody according to E458-E459, wherein the fifth polypeptide chain comprises the sequence EPKSC (SEQ ID NO: 122) at the C-terminus.

[0646] E461. The antibody according to E458-E460, wherein the first antigen binding site specifically binds IL-13, the second antibody binding site specifically binds IL-4, and the third antigen binding site specifically binds p40.

[0647] E462. The antibody according to E458-E461, wherein the first Fab domain, the second Fab domain and the third Fab domain each comprise a different option selected from the following (i), (ii) and (iii):

[0648] (i) p40-Fab of E166;

[0649] (ii) IL4-Fab of E234; and

[0650] (iii) IL13-Fab of E302.

[0651] E463. The antibody according to E458-E462, wherein the first Fab domain is the IL13-Fab of E302, the second Fab domain is the IL4-Fab of E234, and the third Fab domain is the p40-Fab of E166.

[0652] E464. The antibody according to E458-E463, wherein the first polypeptide comprises a first Fc chain and the second polypeptide comprises a second Fc chain.

[0653] E465. The antibody according to E464, wherein the first Fc chain and the second Fc chain each comprise one or more amino acid modifications that promote association of the first Fc chain with the second Fc chain.

[0654] E466. The antibody according to E464-E465, wherein the first Fc chain comprises a first CH3 domain, the second Fc chain comprises a second CH3 domain, and the first CH3 domain and the second CH3 domain each comprise different but complementary sequences, the different but complementary sequences being selected from one of the following different but complementary sequence pairs:

[0655] (i) SEQ ID NO: 106 and SEQ ID NO: 111;

[0656] (ii) SEQ ID NO: 147 and SEQ ID NO: 148; and

[0657] (iii) SEQ ID NO: 124 and SEQ ID NO: 127.

[0658] E467. The antibody according to E466, wherein the first CH3 domain and the second CH3 domain comprise SEQ ID NO: 124 and SEQ ID NO: 127.

[0659] E468. The antibody according to E458-E467, wherein the identity of the first polypeptide chain, the second polypeptide chain, the third polypeptide chain, the fourth polypeptide chain and the fifth polypeptide chain is selected from the group consisting of:

[0660] (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;

[0661] (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;

[0662] (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;

[0663] (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;

[0664] (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;

[0665] (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

[0666] (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.

[0667] E469. The antibody according to E458-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.

[0668] E470. An isolated antibody that specifically binds p40, specifically binds IL-4, and specifically binds IL-13, comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein

[0669] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site;

[0670] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site;

[0671] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a p40 binding site, and

[0672] 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.

[0673] E471. An isolated antibody that specifically binds p40, specifically binds IL-4, and specifically binds IL-13, comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein

[0674] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site;

[0675] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site;

[0676] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a p40 binding site, and

[0677] wherein the first polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127204; the second polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127192; the third polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127203; the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127194; and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127193.

[0678] E472. The antibody according to E445-E471, wherein the viscosity of the antibody in 20 mM histidine, 8.5% sucrose, 0.05 mg / mL EDTA pH 6.0 buffer at a concentration of at least 100 mg / mL is less than 20 cP.

[0679] E473. The antibody according to E445-E472, wherein the viscosity of the antibody in 20 mM histidine, 8.5% sucrose, 0.05 mg / mL EDTA pH 6.0 buffer at a concentration of at least 50 mg / mL is less than 12 cP.

[0680] E474. The antibody according to E445-E473, wherein the terminal half-life of the antibody in cynomolgus monkeys is at least 12 days.

[0681] E475. The antibody according to E445-E474, wherein the terminal half-life of the antibody in TG32 mice is at least 18 days.

[0682] E476. The antibody according to E445-E475, wherein the affinity constant of the antibody binding to human IL-4 is less than 220 pM as measured by SPR.

[0683] E477. The antibody according to E445-E476, wherein the affinity constant of the antibody binding to human IL-13 is less than 220 pM as measured by SPR.

[0684] E478. The antibody according to E445-E477, wherein the affinity constant of the antibody binding to human IL-12 is less than 130 pM as measured by SPR.

[0685] E479. The antibody according to E445-E478, wherein the affinity constant of the antibody binding to human IL-23 is less than 100 pM as measured by SPR.

[0686] E480. The antibody according to E445-E479, wherein the antibody binds human IL-4 with a binding affinity of less than 1 pM as measured by KinExA in an immobilized antigen assay in PBS.

[0687] E481. The antibody according to E445-E480, wherein the antibody binds cynomolgus monkey IL-13 with a binding affinity of less than 2 pM as measured by KinExA in an immobilized antigen assay in PBS.

[0688] E482. The antibody according to E445-E481, wherein the antibody is characterized by an IC of 0.05 for neutralization of IL-4 induced CD23 in a human monocyte assay. 50 Less than 12pM.

[0689] E483. The antibody according to E445-E482, wherein the antibody is characterized by an IC of cynomolgus monkey IL-4 induced for neutralization of CD23 in a human monocyte assay. 50 Less than 12pM.

[0690] E484. The antibody according to E445-E483, wherein the antibody is characterized by an IC of cynomolgus monkey IL-13 induced for neutralization of CD23 in a human monocyte assay. 50 Less than 12pM.

[0691] E485. The antibody according to E445-E484, wherein the antibody is characterized by an IC of 0.05 for neutralization of IL-13 induction of CD23 in a human monocyte assay. 50 Less than 45pM.

[0692] E486. The antibody according to E445-E485, wherein the antibody is characterized by an IC in human IL-12 and Kit-225 assays in human peripheral blood mononuclear cells. 50 Less than 600pM.

[0693] E487. The antibody according to E445-E486, wherein the antibody is characterized by an IC in cynomolgus IL-23 and Kit-225 assays in human peripheral blood mononuclear cells. 50Less than 2100pM.

[0694] E488. The antibody according to E445-E487, wherein the antibody is characterized by an IC in a human IL-12 neutralization assay in human whole blood. 50 Less than 400pM.

[0695] E489. The antibody according to E445-E488, wherein the antibody is characterized by an IC in a cynomolgus monkey IL-23 neutralization assay in human whole blood. 50 Less than 10,000pM.

[0696] E490. The antibody according to any one of E445-489, for use as a medicament.

[0697] E491. The antibody according to E490, wherein the use is for treating one or more selected from the group consisting of: non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, atopic dermatitis, Crohn's disease, ulcerative colitis, asthma (severe), allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus, primary biliary cirrhosis and hidradenitis suppurativa.

[0698] E492. The antibody according to any one of E490-E491, wherein the use is for treating one or more selected from the group consisting of: non-alcoholic steatohepatitis (NASH), atopic dermatitis, asthma (severe), alopecia, idiopathic pulmonary fibrosis and systemic sclerosis.

[0699] E483. The antibody according to any one of E490-E482, wherein the use is for atopic dermatitis.

[0700] E484. The antibody according to any one of E490-E483, wherein the use is for non-alcoholic steatohepatitis (NASH).

[0701] E495. A pharmaceutical composition comprising a therapeutically effective amount of the antibody according to E445-E484 and a pharmaceutically acceptable carrier.

[0702] E496. A method of treating a medical condition, comprising administering to a subject in need thereof a therapeutically effective amount of the antibody according to any one of E445-E494, or the pharmaceutical composition according to E495.

[0703] E497. The method according to E496, wherein the condition is selected from the group consisting of non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, atopic dermatitis, Crohn's disease, ulcerative colitis, asthma (severe), allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus, primary biliary cirrhosis and hidradenitis suppurativa.

[0704] E498. The method according to any one of E496-E497, comprising administering the antibody or pharmaceutical composition subcutaneously.

[0705] E499. The method according to any one of E496-E498, wherein the antibody or pharmaceutical composition is administered approximately twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, twice a month, once a month, once every two months, once every three months, or once every four months.

[0706] E500. An antibody comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain and a fifth polypeptide chain, such that

[0707] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising a first antigen binding site;

[0708] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising a second antigen binding site;

[0709] (iii) The first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a third antigen binding site.

[0710] E501. The antibody according to E500, wherein the first polypeptide chain and the second polypeptide chain associate together to form an antibody comprising two arms: a dual Fab arm comprising the first and second Fab domains, and a single Fab arm comprising the third Fab domain.

[0711] E502. The antibody according to E501, wherein the first Fab comprises a first antigen-related VH (VH-1), a first antigen-related VL (VL-1), a first antigen-related CL (CL-1) and a first antigen-related CH1 (CH1-1).

[0712] E503. The antibody according to E504, wherein the C-terminus of VH-1 is covalently fused to the N-terminus of CH1-1 via a peptide bond.

[0713] E504. The antibody according to E502-E503, wherein the C-terminus of VL-1 is covalently fused to the N-terminus of CL-1 via a peptide bond.

[0714] E505. The antibody according to E501-E504, wherein the second Fab comprises a second antigen-related VH (VH-2), a second antigen-related VL (VL-2), a second antigen-related CL (CL-2) and a second antigen-related CH1 (CH1-2).

[0715] E506. The antibody according to E505, wherein the C-terminus of VH-2 is covalently fused to the N-terminus of CH1-2 via a peptide bond.

[0716] E507. The antibody according to E505-E506, wherein the C-terminus of VL-2 is covalently fused to the N-terminus of CL-2 via a peptide bond.

[0717] E508. The antibody according to E501-E507, wherein the third Fab comprises a third antigen-related VH (VH-3), a first antigen-related VL (VL-3), a first antigen-related CL (CL-3) and a first antigen-related CH1 (CH1-3).

[0718] E509. The antibody according to E508, wherein the C-terminus of VH-3 is covalently fused to the N-terminus of CH1-3 via a peptide bond.

[0719] E510. The antibody according to E508-E509, wherein the C-terminus of VL-3 is covalently fused to the N-terminus of CL-3 via a peptide bond.

[0720] E511. The antibody according to E500-510, wherein the second polypeptide comprises (VL-1)-(CL-1)-(linker)-(VH-2)-(CH1-2)-(second hinge)-(second CH2)-(second CH3) from N-terminus to C-terminus; the fifth polypeptide comprises (VH1)-(CL-1) from N-terminus to C-terminus; and the fourth polypeptide comprises (VL-2)-(CL-2).

[0721] E512. The antibody according to E500-511, wherein the first polypeptide comprises (VH-3)-(CH1-3)-(first hinge)-(first CH2)-(first CH3) from N-terminus to C-terminus; and the third polypeptide may comprise (VL-3)-(CL-3).

[0722] E513. The antibody according to E508-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.

[0723] E514. The antibody according to E508-E513, wherein one or more of the CL-1 domain, the CL-2 domain and the CL-3 domain 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.

[0724] E515. The antibody according to E512-E514, wherein the first hinge region and the second hinge region comprise a pair of sequences shown as SEQ ID NO: 129 and SEQ ID NO: 131.

[0725] E516. The antibody according to E512-E515, wherein one or both of the first CH2 domain and the second CH2 domain comprise the sequence shown in SEQ ID NO:8.

[0726] E517. The antibody according to E512-E516, wherein the first CH3 domain and the second CH3 domain each comprise different but complementary sequences, and the different but complementary sequences are selected from one of the following different but complementary sequence pairs:

[0727] (i) SEQ ID NO: 111 and SEQ ID NO: 106;

[0728] (ii) SEQ ID NO: 111 and SEQ ID NO: 114;

[0729] (iii) SEQ ID NO: 114 and SEQ ID NO: 117;

[0730] (iv) SEQ ID NO: 124 and SEQ ID NO: 127;

[0731] (v) SEQ ID NO: 139 and SEQ ID NO: 141; and

[0732] (vi) SEQ ID NO: 147 and SEQ ID NO: 148.

[0733] E518. The antibody according to E512-E517, wherein

[0734] (i) the CL-1 comprises the sequence set forth in SEQ ID NO: 16, the linker comprises the sequence set forth in SEQ ID NO: 104, the 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;

[0735] (ii) CH1-1 comprises the sequence shown in SEQ ID NO: 6; and

[0736] (iii) The CL-2 comprises the sequence shown in SEQ ID NO: 16.

[0737] E519. The antibody according to E508-E518, wherein the CL-3 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.

[0738] E520. The antibody according to E508-E519, wherein the CL-3 comprises the sequence shown in SEQ ID NO: 95.

[0739] E521. The antibody according to E508-E519, wherein the CL-3 comprises the sequence shown in SEQ ID NO: 16.

[0740] E522. The antibody according to E508-E521, wherein CH1-3 comprises the sequence shown in SEQ ID NO: 6.

[0741] E523. The antibody according to E512-E522, wherein the first hinge comprises the sequence shown in SEQ ID NO: 131.

[0742] E524. The antibody according to E512-E523, wherein the first CH2 comprises the sequence shown in SEQ ID NO:8.

[0743] E525. The antibody according to E512-E524, wherein the first CH3 comprises the sequence shown in SEQ ID NO: 127.

[0744] E526. An isolated antibody that specifically binds IL-4 and specifically binds IL-13 according to any one of E500-E525, said antibody comprising an IL-4 binding domain and an IL-13 binding domain.

[0745] E527. An isolated antibody according to any one of E1 to E525 that specifically binds IL-4 and specifically binds IL-13, said antibody comprising an IL-4 binding domain and an IL-13 binding domain.

[0746] E528. An isolated antibody that specifically binds IL-4 and specifically binds IL-13, said antibody comprising an IL-4 binding domain and an IL-13 binding domain.

[0747] E529. The antibody according to E526-E528, wherein specific binding to IL-4 is carried out by the antibody of any one of E199-E259.

[0748] E530. The antibody according to any one of E526-E529, wherein specific binding to IL-13 is carried out by the antibody according to any one of E265-E330.

[0749] E531. The antibody according to any one of E526-E530, wherein the antibody comprises at least one additional antigen binding domain that binds to at least one target different from both IL-4 and IL-13.

[0750] E532. The antibody according to E531, wherein the at least one different target is selected from the group consisting of IL-33, TSLP and p40, and wherein when the target is IL-33, it can selectively further comprise the antibodies according to E1-E71, and wherein when the target is TSLP, it can selectively further comprise the antibodies according to E77-E143, and wherein when the target is p40, it can selectively further comprise the antibodies according to E144-E193.

[0751] E533. The antibody according to E531, wherein the at least one different target is not IL-33.

[0752] E534. The antibody according to E531, wherein the at least one different target is not TSLP.

[0753] E535. The antibody according to E531, wherein the at least one different target is not p40.

[0754] E536. The antibody according to any one of E526-E535, wherein

[0755] (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; and

[0756] (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.

[0757] E537. The antibody according to E526-E536, wherein

[0758] (i) the IL-4 binding domain comprises IL4-VH of SEQ ID NO: 22 and IL4-VL of SEQ ID NO: 26; and

[0759] (ii) The IL-13 binding domain comprises IL13-VH of SEQ ID NO: 51 and IL13-VL of SEQ ID NO: 54.

[0760] E538. The antibody according to E531-E537, wherein the additional antigen binding domain is fused to the IL-13 binding domain with or without a linker.

[0761] E539. The antibody according to E531-E537, wherein the additional antigen binding domain is fused to the IL-4 binding domain with or without a linker.

[0762] E540. The antibody according to E531-E537, wherein the IL-13 binding domain is fused to the IL-4 binding domain with or without a linker.

[0763] E541. The antibody according to any one of E538-E540, wherein the fusion is performed via a linker.

[0764] E542. The antibody according to any one of E540-E541, wherein the IL-13 binding domain is fused to the IL-4 binding domain via a linker.

[0765] E543. The antibody according to E542, wherein the linker comprises SEQ ID NO: 104.

[0766] E544. The antibody according to any one of E526-E543, wherein the antibody comprises a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain and a fifth polypeptide chain, such that

[0767] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising a first antigen binding site;

[0768] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising a second antigen binding site;

[0769] (iii) The first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a third antigen binding site.

[0770] E545. The antibody according to E544, wherein the first polypeptide chain and the second polypeptide chain associate together to form an antibody comprising two arms: a dual Fab arm comprising the first and second Fab domains, and a single Fab arm comprising the third Fab domain.

[0771] E546. The antibody according to E526-E545, wherein

[0772] (i) the first antigen binding site specifically binds IL-13, the second antibody binding site specifically binds IL-4, and the third antigen binding site specifically binds the at least one additional target;

[0773] (ii) the first antigen binding site specifically binds IL-4, the second antibody binding site specifically binds IL-13, and the third antigen binding site specifically binds the at least one additional target;

[0774] (iii) the first antigen binding site specifically binds to IL-4, the second antibody binding site specifically binds to the at least one additional target, and the third antigen binding site specifically binds to IL-13;

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

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

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

[0778] E547. The antibody according to E544-E546, wherein the first Fab domain is the IL13-Fab of E302, the second Fab domain is the IL4-Fab of E234, and the third Fab domain is an additional target-Fab.

[0779] E548. The antibody according to E44-E547, wherein the fifth polypeptide chain comprises the sequence EPKSC (SEQ ID NO: 122) at the C-terminus.

[0780] E549. The antibody according to E544-E548, wherein the first polypeptide comprises a first Fc chain and the second polypeptide comprises a second Fc chain.

[0781] E550. The antibody according to E549, wherein the first Fc chain and the second Fc chain each comprise one or more amino acid modifications that promote association of the first Fc chain with the second Fc chain.

[0782] E551. The antibody according to E544-E550, wherein the first Fc chain comprises a first CH3 domain, the second Fc chain comprises a second CH3 domain, and the first CH3 domain and the second CH3 domain each comprise different but complementary sequences, and the different but complementary sequences are selected from one of the following different but complementary sequence pairs:

[0783] (i) SEQ ID NO: 111 and SEQ ID NO: 106;

[0784] (ii) SEQ ID NO: 111 and SEQ ID NO: 114;

[0785] (iii) SEQ ID NO: 114 and SEQ ID NO: 117;

[0786] (iv) SEQ ID NO: 124 and SEQ ID NO: 127;

[0787] (v) SEQ ID NO: 139 and SEQ ID NO: 141; and

[0788] (vi) SEQ ID NO: 147 and SEQ ID NO: 148.

[0789] E552. The antibody according to E551, wherein the first CH3 domain and the second CH3 domain comprise SEQ ID NO: 124 and SEQ ID NO: 127.

[0790] E553. The antibody according to E544-E552, wherein the identity of the second polypeptide chain, the fourth polypeptide chain and the fifth polypeptide chain is selected from the group consisting of:

[0791] (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;

[0792] (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;

[0793] (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;

[0794] (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;

[0795] (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;

[0796] (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;

[0797] (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;

[0798] (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;

[0799] (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;

[0800] (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;

[0801] (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;

[0802] (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;

[0803] (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;

[0804] (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;

[0805] (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;

[0806] (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;

[0807] (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;

[0808] (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;

[0809] (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;

[0810] (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;

[0811] (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

[0812] (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;

[0813] (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;

[0814] (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;

[0815] (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;

[0816] (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;

[0817] (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.

[0818] E554. The antibody according to any one of E544-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.

[0819] E555. An isolated antibody that specifically binds IL-4, specifically binds IL-13, and specifically binds at least one additional target, comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein

[0820] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site;

[0821] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site;

[0822] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising at least one additional target binding site, and

[0823] 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.

[0824] E556. An antibody comprising an antibody Fc domain, the antibody Fc domain comprising a first Fc chain and a second Fc chain, wherein the first Fc chain and the second Fc chain each comprise two amino acid modifications, and the amino acid modifications promote association of the first Fc chain with the second Fc chain, characterized in that:

[0825] (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

[0826] (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.

[0827] E557. The antibody according to 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 herein, 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 wherein the first hinge region and the second hinge region comprise a pair of sequences shown in SEQ ID NO: 129 and SEQ ID NO: 131, and the first CH3 region and the second CH3 region comprise one of the following two pairs of sequences: SEQ ID NO: 124 and SEQ ID NO: 127; or SEQ ID NO: 147 and SEQ ID NO: 148.

[0828] E558. The antibody according to any one of E556-E557, further comprising an antibody according to one or more of E1-E71, E77-E143, E144-E193, E199-E259, E265-E330, E336-E381, E387-E435, E445-E484 and E500-E557.

[0829] 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.

[0830] E560. An isolated antibody comprising the VH and VL of an antibody selected from one or more of Tables 80, 81, 82, 83, 84, 85, 86 and 87.

[0831] E561. An isolated antibody which is an antibody selected from one or more of Tables 80, 81, 82, 83, 84, 85, 86 and 87.

[0832] E562. An isolated polynucleotide comprising one or more nucleotide sequences encoding an antibody according to any one of E1-E71, E77-E143, E144-193, E199-259, E265-E330, E336-E381, E387-E435, E445-E484 and E500-E561.

[0833] E563. The polynucleotide according to E562, wherein the polynucleotide is RNA.

[0834] E564. The polynucleotide according to E562-E563, wherein the polynucleotide comprises at least one chemical modification.

[0835] E565. A 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-thiol-1-methyl-1-deaza-pseudouridine, 2-thiol-1-methyl-pseudouridine, 2-thiol-5-aza-uridine, 2-thiol-dihydropseudouridine, 2-thiol-dihydrouridine, 2-thiol-pseudouridine, 4-methoxy-2-thiol-pseudouridine, 4-methoxy-pseudouridine, 4-thiol-1-methyl-pseudouridine, 4-thiol-pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methyluridine, 5-methoxyuridine and 2′-O-methyluridine.

[0836] E566. The polynucleotide according to E562-E563, wherein the polynucleotide does not comprise a chemical modification.

[0837] E567. An isolated polynucleotide encoding VH, VL, or both of an antibody that binds to IL-33, wherein the nucleic acid comprises: the nucleic acid sequence of SEQ ID NO: 202, the nucleic acid sequence of SEQ ID NO: 203, or both.

[0838] E568. An isolated polynucleotide encoding a VH-carrying polypeptide and a VL-carrying polypeptide, or both, of an antibody that binds to IL-33, wherein the nucleic acid comprises the nucleic acid sequence of SEQ ID NO: 190, the nucleic acid sequence of SEQ ID NO: 191, or both.

[0839] E569. An isolated polynucleotide encoding the VH, VL or both of an antibody that binds to IL-33, wherein the nucleic acid comprises: the nucleic acid sequence of the insert fragment of the plasmid deposited with ATCC and having accession number PTA-127209, the nucleic acid sequence of the insert fragment of the plasmid deposited with ATCC and having accession number PTA-127210, or both.

[0840] E570. An isolated polynucleotide encoding a VH-carrying polypeptide and a VL-carrying polypeptide, or both, of an antibody that binds to IL-33, wherein the nucleic acid comprises: the nucleic acid sequence of 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.

[0841] E571. An isolated polynucleotide encoding the VH, VL, or both of an antibody that binds to TSLP, wherein the nucleic acid comprises: the nucleic acid sequence of SEQ ID NO: 204, the nucleic acid sequence of SEQ ID NO: 205, or both.

[0842] E572. An isolated polynucleotide encoding a VH-carrying polypeptide and a VL-carrying polypeptide, or both, of an antibody that binds to TSLP, wherein the nucleic acid comprises: the nucleic acid sequence of SEQ ID NO: 192, the nucleic acid sequence of SEQ ID NO: 193, or both.

[0843] E573. An isolated polynucleotide encoding the VH, VL or both of an antibody that binds to TSLP, wherein the nucleic acid comprises: the nucleic acid sequence of an insert fragment of a plasmid deposited with ATCC and having accession number PTA-127200, the nucleic acid sequence of an insert fragment of a plasmid deposited with ATCC and having accession number PTA-127199, or both.

[0844] E574. An isolated polynucleotide encoding a VH-carrying polypeptide and a VL-carrying polypeptide or both of an antibody that binds to TSLP, wherein the nucleic acid comprises: the nucleic acid sequence of an insert fragment of a plasmid deposited with ATCC and having accession number PTA-127202, the nucleic acid sequence of an insert fragment of a plasmid deposited with ATCC and having accession number PTA-127201, or both.

[0845] E575. An isolated polynucleotide encoding a VH-carrying polypeptide and a VL-carrying polypeptide, or both, of an antibody that binds to p40, wherein the nucleic acid comprises: the nucleic acid sequence of SEQ ID NO: 194, the nucleic acid sequence of SEQ ID NO: 195, or both.

[0846] E576. An isolated polynucleotide encoding a VH-carrying polypeptide and a VL-carrying polypeptide or both of an antibody that binds to p40, wherein the nucleic acid comprises: the nucleic acid sequence of an insert fragment of a plasmid deposited with ATCC and having accession number PTA-127204, the nucleic acid sequence of an insert fragment of a plasmid deposited with ATCC and having accession number PTA-127203, or both.

[0847] E577. An isolated polynucleotide encoding VH, VL, or both of an antibody that binds to IL-4, wherein the nucleic acid comprises: the nucleic acid sequence of SEQ ID NO: 200, the nucleic acid sequence of SEQ ID NO: 201, or both.

[0848] E578. An isolated polynucleotide encoding a VH-carrying polypeptide and a VL-carrying polypeptide, or both, of an antibody that binds to IL-4, wherein the nucleic acid comprises: the nucleic acid sequence of SEQ ID NO: 188, the nucleic acid sequence of SEQ ID NO: 189, or both.

[0849] E579. An isolated polynucleotide encoding the VH, VL or both of an antibody that binds to IL-4, wherein the nucleic acid comprises: the nucleic acid sequence of an insert fragment of a plasmid deposited with the ATCC and having accession number PTA-127198, the nucleic acid sequence of an insert fragment of a plasmid deposited with the ATCC and having accession number PTA-127197, or both.

[0850] E580. An isolated polynucleotide encoding a VH-carrying polypeptide and a VL-carrying polypeptide or both of an antibody that binds to IL-4, wherein the nucleic acid comprises: the nucleic acid sequence of the insert fragment of the plasmid deposited with ATCC and with accession number PTA-127192, the nucleic acid sequence of the insert fragment of the plasmid deposited with ATCC and with accession number PTA-127194, or both.

[0851] E581. An isolated polynucleotide encoding VH, VL, or both of an antibody that binds to IL-13, wherein the nucleic acid comprises: the nucleic acid sequence of SEQ ID NO: 196, the nucleic acid sequence of SEQ ID NO: 195, or both.

[0852] E582. An isolated polynucleotide encoding a VH-carrying polypeptide and a VL-carrying polypeptide, 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.

[0853] E583. An isolated polynucleotide encoding the VH, VL or both of an antibody that binds to IL-13, wherein the nucleic acid comprises: the nucleic acid sequence of the insert fragment of the plasmid deposited with ATCC and with accession number PTA-127196, the nucleic acid sequence of the insert fragment of the plasmid deposited with ATCC and with accession number PTA-127195, or both.

[0854] E584. An isolated polynucleotide encoding a VH-carrying polypeptide and a VL-carrying polypeptide or both of an antibody that binds to IL-13, wherein the nucleic acid comprises: the nucleic acid sequence of the insert fragment of the plasmid deposited with ATCC and with accession number PTA-127193, the nucleic acid sequence of the insert fragment of the plasmid deposited with ATCC and with accession number PTA-127192, or both.

[0855] E585. An isolated polynucleotide encoding one or more of the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide, or the fifth polypeptide of an anti-IL-4 / IL-13 / IL-33 antibody, the antibody comprising:

[0856] (i) the IL33-VH sequence encoded by the plasmid deposited with ATCC and having ATCC Accession No. PTA-127210 and the IL33-VL sequence encoded by the plasmid deposited with ATCC and having ATCC Accession No. PTA-127209;

[0857] (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

[0858] (iii) the IL13-VH sequence encoded by the plasmid deposited with ATCC and having ATCC Accession No. PTA-127196 and the IL13-VL sequence encoded by the plasmid deposited with ATCC and having ATCC Accession No. PTA-127195.

[0859] E586. An isolated polynucleotide encoding one or more of a first polypeptide, a second polypeptide, a third polypeptide, a fourth polypeptide, or a fifth polypeptide of an anti-IL-4 / IL-13 / IL-33 antibody, wherein the isolated antibody specifically binds IL-33, specifically binds IL-4, and specifically binds IL-13, comprises a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein:

[0860] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site;

[0861] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site;

[0862] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising an IL-33 binding site, and

[0863] wherein the first polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127208; the second polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127192; the third polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127207; the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127194; and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127193.

[0864] E587. An isolated polynucleotide encoding one or more of the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide, or the fifth polypeptide of an anti-IL-4 / IL-13 / TSLP antibody, wherein the antibody comprises:

[0865] (i) the TSLP-VH sequence encoded by the plasmid deposited with ATCC and having ATCC Accession No. PTA-127200, and the TSLP-VL sequence encoded by the plasmid deposited with ATCC and having ATCC Accession No. PTA0-127199;

[0866] (ii) the IL4-VH sequence encoded by the plasmid deposited with ATCC and having ATCC Accession No. PTA-127198, and the IL4-VL sequence encoded by the plasmid deposited with ATCC and having ATCC Accession No. PTA-127197; and

[0867] (iii) the IL13-VH sequence encoded by the plasmid deposited with ATCC and having ATCC Accession No. PTA-127196, and the IL13-VL sequence encoded by the plasmid deposited with ATCC and having ATCC Accession No. PTA-127195.

[0868] E588. An isolated polynucleotide encoding one or more of a first polypeptide, a second polypeptide, a third polypeptide, a fourth polypeptide, or a fifth polypeptide of an anti-IL-4 / IL-13 / TSLP antibody, wherein the antibody comprises a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein:

[0869] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site;

[0870] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site;

[0871] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a TSLP binding site, and

[0872] wherein the first polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127202; the second polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127192; the third polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127201; the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127194; and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127193.

[0873] E589. An isolated polynucleotide encoding one or more of the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide, or the fifth polypeptide of an anti-IL-4 / IL-13 / p40 antibody, wherein the antibody comprises:

[0874] (i) the p40-VH sequence encoded by the plasmid deposited with ATCC and having ATCC Accession No. PTA-127206, and the p40-VL sequence encoded by the plasmid deposited with ATCC and having ATCC Accession No. PTA-127205;

[0875] (ii) the IL4-VH sequence encoded by the plasmid deposited with ATCC and having ATCC Accession No. PTA-127198, and the IL4-VL sequence encoded by the plasmid deposited with ATCC and having ATCC Accession No. PTA-127197; and

[0876] (iii) the IL13-VH sequence encoded by the plasmid deposited with ATCC and having ATCC Accession No. PTA-127196, and the IL13-VL sequence encoded by the plasmid deposited with ATCC and having ATCC Accession No. PTA-127195.

[0877] E590. An isolated polynucleotide encoding one or more of a first polypeptide, a second polypeptide, a third polypeptide, a fourth polypeptide, or a fifth polypeptide of an anti-IL-4 / IL-13 / p40 antibody, wherein the antibody comprises a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein:

[0878] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site;

[0879] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site;

[0880] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a p40 binding site, and

[0881] wherein the first polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127204; the second polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127192; the third polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127203; the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127194; and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC accession number PTA-127193.

[0882] E591. A vector comprising the polynucleotide according to E562-E590.

[0883] E592. An isolated host cell comprising the polynucleotide according to E562-E590, or the vector according to E591.

[0884] E593. A method of producing an isolated antibody, comprising culturing the host cell according to E592 under conditions that result in the production of said antibody, and recovering said antibody.

[0885] E594. A pharmaceutical composition comprising a therapeutically effective amount of an antibody according to any one of E1-E71, E77-E143, E144-193, E199-259, E265-E330, E336-E381, E387-E435, E445-E484 and E500-E557, and a pharmaceutically acceptable carrier.

[0886] E595. A method for producing a heterotrimeric antibody, said heterotrimeric antibody comprising a dual Fab arm and a single Fab arm, wherein the dual Fab arm comprises a first Fab domain connected to a second Fab domain, the second Fab domain is connected to a first Fc domain, and the single Fab arm comprises a third Fab domain connected to a second Fc domain, and the method comprises:

[0887] (i) a first preassembly step, wherein the dual-Fab arms are incubated in a first preassembly condition buffer at a temperature of 2-10° C., and wherein the pH of the first preassembly condition buffer is 1-3 units lower than the isoelectric point (pI) of the dual-Fab arms; and

[0888] (ii) a second preassembly step, wherein the single Fab arm is incubated in a second preassembly condition buffer at a temperature of 2-10° C., and wherein the pH of the second preassembly condition buffer is 1-3 units lower than the isoelectric point (pI) of the single Fab arm; and

[0889] (iii) A third assembly step, wherein the dual Fab arms and the single Fab arms from steps (i) and (ii) are mixed together in assembly buffer for 1-24 hours.

[0890] E596. An isolated antibody that specifically binds to TSLP, comprising the CDRs of an antibody selected from one or more of Tables 83, 84 and 87.

[0891] E597. An isolated antibody that specifically binds to TSLP, comprising the VH and VL of an antibody selected from one or more of Tables 83, 84 and 87.

[0892] E598. An isolated antibody that specifically binds to TSLP, which is one or more antibodies selected from Tables 83, 84 and 87.

[0893] E599. The antibody according to any one of E381-E384, wherein:

[0894] (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; and

[0895] (ii) an IL-4 binding domain 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; and

[0896] (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.

[0897] E600. The antibody according to E387-E390 or E599, wherein:

[0898] (i) the TSLP binding portion comprises TSLP-VH of SEQ ID NO: 92 and TSLP-VL of SEQ ID NO: 213;

[0899] (ii) the IL-4 binding portion comprises IL4-VH of SEQ ID NO: 22 and IL4-VL of SEQ ID NO: 26; and

[0900] (iii) the IL-13 binding portion comprises IL13-VH of SEQ ID NO: 51 and IL13-VL of SEQ ID NO: 54.

[0901] E601. The antibody according to E387-E390 or E599-E600, wherein:

[0902] (i) the TSLP binding domain comprises a TSLP-VH sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127200 and a TSLP-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-____;

[0903] (ii) the IL-4 binding domain comprises an IL4-VH sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-127198 and an IL4-VL sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-127197; and

[0904] (iii) the IL-13 binding domain comprises an IL13-VH sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127196 and an IL13-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127195.

[0905] E602. An isolated antibody that specifically binds TSLP, specifically binds IL-4, and specifically binds IL-13, comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein:

[0906] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site;

[0907] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site;

[0908] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a TSLP binding site, and

[0909] 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.

[0910] E603. An isolated antibody that specifically binds TSLP, specifically binds IL-4, and specifically binds IL-13, comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein:

[0911] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site;

[0912] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site;

[0913] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a TSLP binding site, and

[0914] The first polypeptide chain comprises a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127202; the second polypeptide chain comprises a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127192; the third polypeptide chain comprises a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-______; the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127194; and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127193.

[0915] E604. The antibody according to E381-E390, wherein:

[0916] (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; and

[0917] (ii) an IL-4 binding domain 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; and

[0918] (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.

[0919] E605. The antibody according to E387-E390 or E604, wherein:

[0920] (i) the TSLP binding portion comprises TSLP-VH of SEQ ID NO: 92 and TSLP-VL of SEQ ID NO: 214;

[0921] (ii) the IL-4 binding portion comprises IL4-VH of SEQ ID NO: 22 and IL4-VL of SEQ ID NO: 26; and

[0922] (iii) the IL-13 binding portion comprises IL13-VH of SEQ ID NO: 51 and IL13-VL of SEQ ID NO: 54.

[0923] E606. The antibody according to E387-E390 or E602-E603, wherein:

[0924] (i) the TSLP binding domain comprises a TSLP-VH sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127200 and a TSLP-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA0-______;

[0925] (ii) the IL-4 binding domain comprises an IL4-VH sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-127198 and an IL4-VL sequence encoded by a plasmid deposited with ATCC and having ATCC Accession No. PTA-127197; and

[0926] (iii) the IL-13 binding domain comprises an IL13-VH sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127196 and an IL13-VL sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127195.

[0927] E607. An isolated antibody that specifically binds TSLP, specifically binds IL-4, and specifically binds IL-13, comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein:

[0928] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site;

[0929] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site;

[0930] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a TSLP binding site; and

[0931] 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.

[0932] E608. An isolated antibody that specifically binds TSLP, specifically binds IL-4, and specifically binds IL-13, comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein:

[0933] (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site;

[0934] (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site;

[0935] (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a TSLP binding site, and

[0936] The first polypeptide chain comprises a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127202; the second polypeptide chain comprises a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127192; the third polypeptide chain comprises a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-______; the fourth polypeptide chain comprises a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127194; and the fifth polypeptide chain comprises a sequence encoded by a plasmid deposited with ATCC and having ATCC accession number PTA-127193.

[0937] E609. The antibody according to any one of E77-E143 or E596-E608 for use as a medicament.

[0938] E610. The antibody according to E609, wherein the use is for treating one or more selected from the group consisting of: atopic dermatitis, asthma, cancer, chronic obstructive pulmonary disease (COPD), food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, idiopathic pulmonary fibrosis (IPF), scleroderma, systemic sclerosis and fungal keratitis.

[0939] E611. The antibody according to any one of E147-E148 or E596-E610, wherein the use is for treating one or more selected from the group consisting of: atopic dermatitis, asthma, cancer, chronic obstructive pulmonary disease (COPD), food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, and non-alcoholic steatohepatitis (NASH).

[0940] E612. The antibody according to any one of E147-E149 or E596-E611, wherein the use is for atopic dermatitis.

[0941] E613. The antibody according to any one of E147-E149 or E596-E612, wherein the use is for non-alcoholic steatohepatitis (NASH).

[0942] E614. A pharmaceutical composition comprising a therapeutically effective amount of the antibody according to E77-E143 or E596-E608 and a pharmaceutically acceptable carrier.

[0943] E615. A method of treating a medical condition, comprising administering to a subject in need thereof a therapeutically effective amount of an antibody according to any one of E77-E143 or E596-E608, or a pharmaceutical composition according to E614.

[0944] E616. The method according to E615, wherein the condition is selected from the group consisting of: atopic dermatitis, asthma, cancer, chronic obstructive pulmonary disease (COPD), food allergies, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, idiopathic pulmonary fibrosis (IPF), scleroderma, systemic sclerosis and fungal keratitis.

[0945] E617. The method according to any one of E615-E616, comprising administering the antibody or pharmaceutical composition subcutaneously.

[0946] E618. The method according to any one of E615-E617, wherein the antibody or pharmaceutical composition is administered approximately twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, twice a month, once a month, once every two months, once every three months, or once every four months.

[0947] E619. An antibody according to any one of E1-E71, E77-E143, E144-E193, E199-E259, E265-E330, E336-E381, E387-E435, E445-E484, E500-E557 or E596-E612 for use in inhibiting tumor growth.

[0948] E620. An antibody according to any one of E1-E71, E77-E143, E144-E193, E199-E259, E265-E330, E336-E381, E387-E435, E445-E484, E500-E557, E596-E612 or E619 for use in inhibiting the progression of malignant cell growth in a patient.

[0949] E621. An antibody according to any one of E1-E71, E77-E143, E144-E193, E199-E259, E265-E330, E336-E381, E387-E435, E445-E484, E500-E557, E596-E612 or E619-E620 for use in inhibiting the metastasis of malignant cells in a patient.

[0950] E622. The antibody according to any one of E1-E71, E77-E143, E144-E193, E199-E259, E265-E330, E336-E381, E387-E435, E445-E484, E500-E557, E596-E612 or E619-E621 for use in inducing tumor regression in a patient.

[0951] E623. An antibody according to any one of E1-E71, E77-E143, E144-E193, E199-E259, E265-E330, E336-E381, E387-E435, E445-E484, E500-E557, E596-E612 or E619-E622 for use in the treatment of cancer manifesting as a solid tumor.

[0952] E624. An antibody according to any one of E1-E71, E77-E143, E144-E193, E199-E259, E265-E330, E336-E381, E387-E435, E445-E484, E500-E557, E596-E612 or E619-E623, wherein the use is for treating one or more selected from the group consisting of: bladder cancer, breast cancer, clear cell renal carcinoma, head / neck squamous cell carcinoma, lung squamous cell carcinoma, malignant melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, 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 leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), or small lymphocytic lymphoma (SLL).

[0953] E625. An antibody according to any one of E1-E71, E77-E143, E144-E193, E199-E259, E265-E330, E336-E381, E387-E435, E445-E484, E500-E557, E596-E612. or E619-E624, wherein the use is for treating one or more selected from the group consisting of: renal cell carcinoma (RCC), bladder cancer, breast cancer, clear cell renal carcinoma, squamous cell carcinoma of the head / neck (SCCHN), squamous cell carcinoma of the lung, malignant melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, small cell lung cancer (SCLC) or triple-negative breast cancer.

[0954] E626. The antibody according to any one of E1-E71, E77-E143, E144-E193, E199-E259, E265-E330, E336-E381, E387-E435, E445-E484, E500-E557, E596-E612 or E619-E625, wherein the use is for treating one or more selected from the group consisting of: a heme malignancy, and in some embodiments, the heme malignancy is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), or 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 leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), or small lymphocytic lymphoma (SLL).

[0955] E627. A method of treating cancer in a subject, comprising administering to the subject a combination therapy comprising a first anti-cancer therapeutic and a second anti-cancer therapeutic, wherein the first anti-cancer therapeutic is an antibody to one or more of IL-4, IL-13 and TSLP, and wherein the second anti-cancer therapeutic is selected from 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 TLR 7 / 8 agonist, a TLR9 agonist, a bispecific anti-CD47 / anti-PD-L1 antibody and a bispecific anti-P-cadherin / anti-CD3 antibody.

[0956] E628. The method according to E627, wherein the first anti-cancer therapeutic comprises an anti-IL-4 antibody.

[0957] E629. The method according to E627-E628, wherein the first anti-cancer therapeutic comprises an anti-IL-4 antibody according to any one of E199-E259.

[0958] E630. The method of E627-E631, wherein the first anti-cancer therapeutic comprises an anti-IL-13 antibody.

[0959] E631. The method according to E627-E630, wherein the first anti-cancer therapeutic comprises an anti-IL-13 antibody according to any one of E265-E330.

[0960] E632. The method of E627-E631, wherein the first anti-cancer therapeutic comprises an anti-TSLP antibody.

[0961] E633. The method according to E627-E632, wherein the first anti-cancer therapeutic comprises an anti-TSLP antibody according to any one of E77-E143 or E596-E598.

[0962] E634. The method of E627-E633, wherein the first anti-cancer therapeutic comprises an IL-4 / IL-13 antibody.

[0963] E635. The method according to E627-E634, wherein the first anti-cancer therapeutic agent comprises an IL-4 / IL-13 antibody, and wherein the IL-4 / IL-13 antibody comprises the IL-4 / IL-13 antibody according to any one of E526-E558.

[0964] E636. The method of E627-E635, wherein the first anti-cancer therapeutic comprises an IL-4 / IL-13 / TSLP antibody.

[0965] E637. The method according to E627-E636, wherein the first anti-cancer therapeutic comprises an IL-4 / IL-13 / TSLP antibody, and wherein the IL-4 / IL-13 / TSLP antibody comprises an antibody according to any one of E387-E435 or E599-E613.

[0966] E638. The method according to E627-E637, wherein the first anti-cancer therapeutic comprises an IL-4 / IL-13 / TSLP antibody, and wherein the IL-4 / IL-13 / TSLP antibody comprises an antibody according to any one of E412.

[0967] E639. The method according to E627-E637, wherein the first anti-cancer therapeutic comprises an IL-4 / IL-13 / TSLP antibody, and wherein the IL-4 / IL-13 / TSLP antibody comprises an antibody according to any one of E603.

[0968] E640. The method according to E627-E637, wherein the first anti-cancer therapeutic comprises an IL-4 / IL-13 / TSLP antibody, and wherein the IL-4 / IL-13 / TSLP antibody comprises an antibody according to any one of E607.

[0969] E641. The method of E627-E640, wherein the second anti-cancer therapeutic agent is a PD-1 pathway antagonist.

[0970] E642. The method of E627-E641, wherein the second anti-cancer therapeutic agent is a PD-1 antagonist.

[0971] E643. The method according to E627-E642, wherein the second anti-cancer therapeutic agent is a PD-1 antagonist, and the PD-1 antagonist is selected from the group consisting of sasanlimab, BCD-100, camrelizumab, cemiplimab, genolimzumab, MEDI0680, nivolumab, pembrolizumab, sintilimab, spartalizumab, STI-A1110, tislelizumab, atezolizumab, durvalumab, BMS-936559 (MDX-1105), LY3300054, and TSR-042.

[0972] E644. The method according to E627-E643, wherein the second anti-cancer therapeutic agent is a PD-1 antagonist, and the PD-1 antagonist is the antibody of US10155037 comprising VH as shown in SEQ ID NO: 4 and VL as shown in SEQ ID NO: 8.

[0973] E644. The method of E627-E643, wherein the second anti-cancer therapeutic is a PD-1 antagonist, and the PD-1 antagonist is sasanlimab.

[0974] E645. A method according to E627-E646, wherein the second anti-cancer therapeutic agent is a PD-1 antagonist, and the PD-1 antagonist is sasanlimab, and is an antibody comprising a HC comprising the sequence shown in SEQ ID NO: 225 and a light chain comprising the sequence shown in SEQ ID NO: 226.

[0975] E646. A method of treating cancer in a subject, comprising administering to the subject a combination therapy comprising a first anti-cancer therapeutic and a second anti-cancer therapeutic, wherein the first anti-cancer therapeutic is the IL-4 / IL-13 / TSLP antibody according to E412, and the second anti-cancer therapeutic is a PD-1 antagonist antibody comprising an HC comprising the sequence shown in SEQ ID NO: 225 and a light chain comprising the sequence shown in SEQ ID NO: 226.

[0976] E647. A method of treating cancer in a subject, comprising administering to the subject a combination therapy comprising a first anti-cancer therapeutic and a second anti-cancer therapeutic, wherein the first anti-cancer therapeutic is the IL-4 / IL-13 / TSLP antibody according to E603, and the second anti-cancer therapeutic is a PD-1 antagonist antibody comprising an HC comprising the sequence shown in SEQ ID NO: 225 and a light chain comprising the sequence shown in SEQ ID NO: 226.

[0977] E648. A method of treating cancer in a subject, comprising administering to the subject a combination therapy comprising a first anti-cancer therapeutic and a second anti-cancer therapeutic, wherein the first anti-cancer therapeutic is the IL-4 / IL-13 / TSLP antibody according to E607, and the second anti-cancer therapeutic is a PD-1 antagonist antibody comprising an HC comprising the sequence shown in SEQ ID NO: 225 and a light chain comprising the sequence shown in SEQ ID NO: 226.

[0978] E649. A medicament comprising a first anticancer agent and a second anticancer agent, wherein the first anticancer therapeutic agent is the IL-4 / IL-13 / TSLP antibody according to E412, and the second anticancer therapeutic agent is a PD-1 antagonist antibody comprising an HC comprising the sequence shown in SEQ ID NO: 225 and a light chain comprising the sequence shown in SEQ ID NO: 226.

[0979] E649. A medicament comprising a first anticancer agent and a second anticancer agent, wherein the first anticancer therapeutic agent is the IL-4 / IL-13 / TSLP antibody according to E603, and the second anticancer therapeutic agent is a PD-1 antagonist antibody, said PD-1 antagonist antibody comprising an HC comprising the sequence shown in SEQ ID NO: 225 and a light chain comprising the sequence shown in SEQ ID NO: 226.

[0980] E649. A medicament comprising a first anticancer agent and a second anticancer agent, wherein the first anticancer therapeutic agent is the IL-4 / IL-13 / TSLP antibody according to E607, and the second anticancer therapeutic agent is a PD-1 antagonist antibody, said PD-1 antagonist antibody comprising an HC comprising the sequence shown in SEQ ID NO: 225 and a light chain comprising the sequence shown in SEQ ID NO: 226.

[0981] E650. The method or medicament according to any one of E627-E649, wherein the cancer manifests as a solid tumor.

[0982] E651. The method or medicament according to any one of E627 to E650, wherein the cancer is one or more selected from the group consisting of: bladder cancer, breast cancer, clear cell renal carcinoma, head / neck squamous cell carcinoma, lung squamous cell carcinoma, malignant melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, small cell lung cancer (SCLC), triple-negative breast cancer, urothelial 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 leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL) or small lymphocytic lymphoma (SLL).

[0983] E652. A method or drug according to any one of E627-E651, wherein the cancer is one or more selected from the group consisting of: renal cell carcinoma (RCC), bladder cancer, breast cancer, clear cell renal carcinoma, head / neck squamous cell carcinoma (SCCHN), lung squamous cell carcinoma, malignant melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, small cell lung cancer (SCLC) or triple-negative breast cancer.

[0984] E653. The method or medicament according to any one of E627-E652, wherein the cancer is one or more selected from the group consisting of: a heme malignancy, and in some embodiments, the heme malignancy is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), EBV-positive DLBCL, primary mediastinal large B-cell lymphoma, T cell / histiocyte-rich large B-cell lymphoma, follicular lymphoma, Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL) or small lymphocytic lymphoma (SLL).

[0985] E654. The antibody use, method or medicament according to any one of E1 to E653, wherein at least one of the therapeutic agents is administered to the subject at an interval of once a day, once every two days, once every three days, once a week, once every two weeks, once every three weeks, once every four weeks, once every 30 days, once every five weeks, once every six weeks, once a month, once every two months, once every three months or once every four months.

[0986] E656. Use of an antibody according to any one of E1-E71, E77-E143, E144-E193, E199-E259, E265-E330, E336-E381, E387-E435, E445-E484, E500-E557, E596-E612 or E619-E625 in the manufacture of a medicament for treating one or more of the group consisting of atopic dermatitis, asthma, cancer, chronic obstructive pulmonary disease (COPD), food allergies, allergic rhinitis, eosinophilia Cellular esophagitis, chronic sinusitis with nasal polyps, alopecia areata, nonalcoholic steatohepatitis (NASH), prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, idiopathic pulmonary fibrosis (IPF), scleroderma, systemic sclerosis, fungal keratitis, bladder cancer, breast cancer, clear cell renal cell carcinoma, head / neck squamous cell carcinoma, 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), myeloid 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), These include 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 leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), and small lymphocytic lymphoma (SLL).

[0987] E657. A pharmaceutical composition for treating one or more selected from the group consisting of atopic dermatitis, asthma, cancer, chronic obstructive pulmonary disease (COPD), food allergy, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata and non-alcoholic steatohepatitis (NASH), prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, idiopathic pulmonary fibrosis (IPF), scleroderma, systemic sclerosis, fungal keratitis, bladder cancer, breast cancer, clear cell renal carcinoma, head / neck squamous cell carcinoma, lung squamous cell carcinoma , malignant melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, small cell lung cancer (SCLC), triple-negative breast cancer, urothelial carcinoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid 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 (MC L), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL) and small lymphocytic lymphoma (SLL), the pharmaceutical composition comprising the antibody according to any one of E1-E71, E77-E143, E144-E193, E199-E259, E265-E330, E336-E381, E387-E435, E445-E484, E500-E557, E596-E612 or E619-E625.

[0988] E658. An anti-disease agent comprising an antibody according to any one of E1-E71, E77-E143, E144-E193, E199-E259, E265-E330, E336-E381, E387-E435, E445-E484, E500-E557, E596-E612 or E619-E625, wherein the disease is one or more selected from the group consisting of atopic dermatitis, asthma, cancer, chronic obstructive pulmonary disease (COPD), food allergy, allergic rhinitis, eosinophilia Cellular esophagitis, chronic sinusitis with nasal polyps, alopecia areata, nonalcoholic steatohepatitis (NASH), prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, idiopathic pulmonary fibrosis (IPF), scleroderma, systemic sclerosis, fungal keratitis, bladder cancer, breast cancer, clear cell renal cell carcinoma, head / neck squamous cell carcinoma, 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), myeloid 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), These include 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 leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), and small lymphocytic lymphoma (SLL). BRIEF DESCRIPTION OF THE DRAWINGS

[0989] Figure 1AAn exemplary sequence is depicted illustrating the Pfabat numbering of the light chain portion of the anti-IL-13 and anti-IL-4 binding arms. Position names are displayed in a single column vertically, with dashes ("-") indicating gaps in the alignment. For example, residue L27D of the anti-IL-13 CDR-L1 is His, and the equivalent residue in the anti-IL-4 binding arm is Glu. Positions considered to be part of the CDR are shown in bold text, with the corresponding amino acids shown in bold and underlined.

[0990] Figure 1B An exemplary sequence is depicted illustrating the Pfabat numbering of the heavy chain portions of the anti-IL-13, anti-IL-4, and anti-IL-33 binding arms. Position names are shown in a single column vertically, with dashes ("-") indicating gaps in the alignment. For example, residue H100C of the anti-IL-4 CDR-L1 is Phe, while the anti-IL-13 binding arm with the shorter CDRH3 does not have a corresponding residue. Positions considered to be part of the CDR are shown in bold text, with the corresponding amino acids shown in bold and underlined. The anti-IL-13 heavy chain fragment used in most multispecific antibody sequences does not contain a complete hinge or Fc. The Pfabat algorithm numbers the sequence as an independent Fab domain and does not number the small upper hinge fragment ("EPKSC" (SEQ ID NO: 102)), although it is included here manually (lowercase, positions H226-H230) for reference.

[0991] Figure 2 A diagram summarizing the results of LC / MS analysis of the IL4-1285 antibody is depicted. The post-translational modification was revealed to be located on the light chain. Mass spectrometry analysis of Peak 1 (P1) relative to Peak 2 (P2) showed the presence of an 80 Dalton (Da) substance with a mass of 23755.0 Da in P2. P1 refers to the "main peak" substance isolated during analysis by the ion exchange purification method, which was also detected by using light chain LC / MS analysis (after LysC+TCEP). P2 refers to "Peak 2" isolated by the ion exchange purification method, which was also detected by using light chain LC / MS analysis (after LysC+TCEP). Peak 2 has additional sulfation on Tyr (L27a), so it has a migration of 80 Da in MS.

[0992] Figure 3 Depicted are graphs comparing LC / MS analysis of the light chains of IL4-1346 (hu3B9-VLv2.8) [lower two panels] and IL4-1285 (hu3B9-VLv2.0) antibodies [upper two panels]. The light chain CDR1 peptide (DRVTITCKASQSVD Y ) is O-linked and sulfated, YThe (L27d)F mutation eliminates heterogeneity. The top and bottom left panels are peptide level mapping data (AspN enzyme). The upper and lower right panels are subunits using the LysC method. Peptide mapping analysis (AspN digestion) is shown in the spectrum in the upper left corner, where the DFD light chain does not contain sulfation, while the DYD light chain does have some sulfation (+79.9568Da). Subunit analysis shows that the DFD light chain has no sulfated material (upper right spectrum), while the DYD light chain does have some sulfated Da material (lower right spectrum).

[0993] Figure 4 Depicted are changes incorporated into the IL4-1359 (VH1G07_VLv2.9) VH CDRH1 that contribute to higher affinity for IL-4.

[0994] Figure 5 Depicted are changes at Tyr(L27d)E that remove the O-sulfation post-translational modification and further stabilize the IL-4 / IL4-1285 (RA1-2 or hu3B9-VLv2.0) interface.

[0995] Figure 6 An alignment of IL-13 complexes is depicted, revealing contrasting binding orientations of IL13-1283 (IMA-638 or hu13.2) and IL13-1307 (hu13.4).

[0996] Figure 7 Depicted are CDRL1 differences in IL13-1307 (hu13.4) relative to IL13-1283 (IMA-638 or hu13.2) that result in higher affinity for human IL-13.

[0997] Figure 8 Depicted are CDRH3 amino acid differences between IL13-1307 (hu13.4) and IL13-1283 (IMA-638 or hu13.2) that result in higher affinity for IL-13.

[0998] Figure 9 Depicted is how the presence of serine at residue 30 in the CDRH1 of IL13-1307 (hu13.4) results in higher affinity for IL-13 relative to IL13-1283 (IMA-638 or hu13.2).

[0999] Figure 10 Depicted is how aspartic acid at position 55 in CDRH2 of IL13-1307 (hu13.4) rather than glycine at this site in IL13-1283 results in higher affinity for IL-13 relative to IL13-1283 (IMA-638 or hu13.2).

[1000] Figure 11 Depicted is how changes incorporated into the L13-0001 (1RVHC9-VLA4) VH CDRH3 result in higher affinity for IL-13.

[1001] Figure 12 Described is how changes incorporated into IL13-0001 (1RVHC9-VLA4) VL CDRL1 result in higher affinity for IL-13.

[1002] Figure 13 Depicted is a graph showing how increased IL-33 neutralization potency correlates with increased polyresponsiveness.

[1003] Figure 14 depicts a high throughput off-rate screen of anti-TSLP variants. Figure 14A Figure 2: Dissociation rate screening sensorgram. 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 : Spotfire plot of association index versus dissociation index. Variants within boxes are hits that met the selection criteria.

[1004] Figure 15 Depicted is the electrostatic surface map of the TSLP-0260 Fv region. The electrostatic surface map was determined using a Poisson Boltzmann calculator in Delphi. Positive charge potentials are shown in white, and negative charge potentials in black. The regions specifically targeted for viscosity reduction are the negatively charged patches outlined by black dashed circles. These three patches encompass portions of the CDRs L1-L2, L3-H2-H3, and H2, respectively.

[1005] Figure 16 Details of the antibody:TSLP interface are depicted. The VH-E99Y mutation may introduce a new hydrogen-bonding network at the TSLP-Ab interface. Selected interface residues are labeled and shown as sticks. N71 and R149 are from TSLP. Dashed lines represent salt bridges and hydrogen bonds. Light gray: TSLP with an α-helical structure. Dark gray: antibody. This also increases overall packing.

[1006] Figure 17 Depicted graphs show viscosity analysis of anti-TSLP variants. Viscosity was measured by a DLS bead-based method.

[1007] Figure 18A 、 Figure 18B 、 Figure 18C 、 Figure 18D、 Figure 18E 、 Figure 18F 、 Figure 18G 、 Figure 18H and Figure 18I Depicted is a general schematic diagram and nomenclature of trispecific Tri-Fab-Fc and Fab domains. Figure 18A Depicted is a schematic diagram of Tri-Fab-Fc showing the domains Fab1, Fab2 and Fab3, and single Fab (SFab) and double Fab (DFab) arms expressed in separate cells. Figure 18: Depicted is a schematic diagram of a conventional Fab. Figure 18C A schematic diagram of the modified Fd is depicted. Figure 18D A schematic diagram of VH-VL swapping is depicted. Figure 18E A schematic diagram of S1 is depicted. Figure 18F A schematic diagram of S1Rev is depicted. Figure 18G A schematic diagram of CH-Ck exchange is depicted. Figure 18H A schematic diagram of the CH-Cl exchange is depicted. Figure 18 depicts an exploded view of Tri-Fab-Fc, showing the individual protein chains: the SFab HC (3) and SFab LC (3) chains, which together comprise the SFab arm; and the DFab LC (1)-HC (2), modified Fd (1), and DFab LC (2) chains, which together comprise the DFab arm. Note: VL denotes light chain variable domain; VH denotes heavy chain variable domain; Ck denotes kappa (κ) constant light chain domain, Cl denotes lambda (λ) constant light chain domain; CH1 denotes heavy chain constant domain 1. EPKSC (SEQ ID NO: 102): A stretch of amino acids from the upper hinge region of IgG1 is fused to the C-terminus of CH1, thereby forming a disulfide bond with CL (Fab1).

[1008] Figure 19 depicts the configuration and features of Tri-Fab-Fcs with native native chain pairing in the Fab1 position. Figure 19A and Figure 19B Depicted are the configurations of two native chain-paired Tri-Fab-Fc variants, in which all three Fabs have conventional chain pairing. S1: S1 mutation on CH1 / CK. S1rev: S1rev mutation on CH1 / CK. Positively charged (+) mutations are indicated by solid black circles. Negatively charged (-) mutations are indicated by dashed black circles. Figure 19C Depicted graphs show analytical SEC of IL413TSLP-0003 and IL413TSLP-0004 after Mab Select SuRe elution and after prepSEC superdex 200 purification. Figure 19D and Figure 19EThe figures depict LCMS analysis of IL413TSLP-0003 and IL413TSLP-0004, respectively. The tables list each chain of the trispecific antibody and the corresponding theoretical chain mass. Numbers 1-5 are placed in front of each chain to provide a shorthand description of the chain composition of the main peak in LCMS.

[1009] Figure 20A 、 Figure 20B 、 Figure 20C 、 Figure 20D 、 Figure 20E and Figure 20F The depicted diagram shows the configuration of CλS, CκS and VDS Tri-Fab-F variants, wherein the Fab1 domain (anti-TSLP) comprises the C1 domain fused to the C-terminus of the VH1 domain and the CH1 domain fused to the C-terminus of the VL1 domain. Figure 20A ) and IL413TSLP-0002( Figure 20B ) is a CλS configuration with a Fab1 light chain having structures VL-CH1 and VH-C1 located at the N-terminus of the double Fab arm. Figure 20C ) and IL413TSLP-0008( Figure 20D ) has the Fab1 Vl-CH1 and VH-Cl Fab1 light chains located at the N-terminus of the dual Fab chains. Figure 20E ) has Fab1 and Fab3 carrying S1 and S1rev mutations, respectively, Fab2 contains VL-CH1 structure, and VH-CL is fused to the N-terminus of Fc. Figure 20F ) has Fab1 and Fab3 carrying S1 and S1rev mutations, respectively, Fab2 comprises a VL-CH1 structure including an SS elbow between the VL and CH1 domains, and VH-CL is fused to the N-terminus of Fc.

[1010] Figure 21 Depicted is a graph showing the effect of domain geometry on Tri-Fab-Fc binding activity assessed by bridging ELISA. TPP-9662 is an IL-4 / IL-13 bispecific antibody with S1 / S1rev and KiH. mab8.8 is a negative control antibody.

[1011] FIG22 depicts improvement of Tri-Fab-Fc chain pairing by adjusting DNA ratios in transient transfection. Figure 22ADepicted is a NuPAGE Bis-tris gel analysis. R: reducing. NR: non-reducing. Figure 22B Depicted graphs show aSEC analysis.

[1012] Figure 23 depicts a diagram of Tri-Fab-Fc variants engineered with modified Fd formats and S1 / S1rev complementing mutations.

[1013] Figure 24 Depicted are non-reducing and reducing stain-free SDS-PAGE analysis of stable CHO-produced Tri-Fab-Fc.

[1014] Figure 25 depicts a diagram of representative tri-Fab-Fc trispecific antibody configurations using charge-based heterodimerization for Fab1 CκS or mFd pairing. RRR or EEE charge mutations: two RR / EE residues are located in the hinge region, and one R / E residue is located in CH3. The anti-IL-13 domain was designed as CκS (using IL413TSLP-0251 as an example) or mFd (using IL413TSLP-0252 as an example).

[1015] Figure 26 Depicted is a diagram of the anti-IL-13 / IL-4 dual Fab EEE arm design, where the anti-IL-13 domain is located as the mFd at the Fab1 position and the anti-IL-4 domain is located at the Fab2 position.

[1016] Figure 27 Depicted is a diagram of the anti-IL-13 / IL-4 dual Fab EEE CB arm design, where the anti-IL-4 domain is located as the mFd at the Fab1 position and the anti-IL-13 domain is located at the Fab2 position.

[1017] Figure 28 depicts a diagram of the anti-IL-13 / IL-4 dual Fab EEE arm design, with CKS located at the Fab1 position.

[1018] Figure 29 depicts a graph showing that Tri-Fab-Fc IL13433-0006 can simultaneously bind to human IL-4, IL-13, and IL-33.

[1019] Figure 30 Depicted are SPR sensorgrams of IL413p40-0705 with human IL-4, IL-13, and IL-23 in different injection orders.

[1020] Figure 31 depicts a dual-cell design Tri-Fab-Fc variant with mFd format and S1-S1rev complementing mutations.

[1021] Figure 32Depicted are Tri-Fab-Fc engineered with a modified Fd format and produced using a single-cell approach.

[1022] Figure 33 Depicted are the viscosities of IL413p40-0698 and IL413p40-0700 measured by differential light scattering (DLS).

[1023] Figure 34 The pharmacokinetics of anti-IL-4 / 13 / 33 Tri-Fab-Fc IV in Tg32 mice are described. Antibody names are abbreviated to four digits as follows: 1042 refers to IL13433-1042, 1258 refers to IL13433-1258, 1261 refers to IL13433-1261, 1270 refers to IL13433-1270, 1275 refers to IL13433-1275, and anti-IL-33 Ab LS refers to IL33-0232 VH and VL, wherein the Fc domain further comprises the LS mutations described herein.

[1024] Figure 35 depicts a graph showing binding of trispecific antibodies to human, cynomolgus monkey, mouse, and rat IL-4 as determined by surface plasmon resonance. Trispecific antibodies: (a) IL13433-1258, (b) IL413TSLP-1024, (c) IL413P40-0705 were immobilized on a CM5 sensor chip and binding to 200 nM human (hu), cynomolgus monkey (cy), mouse (mu), rabbit (rb), or rat (rb) IL-4 was determined by surface plasmon resonance.

[1025] Figure 36 depicts a graph showing binding of trispecific antibodies to human, cynomolgus monkey, mouse, and rat IL-13 as determined by surface plasmon resonance. Trispecific antibodies: (a) IL13433-1258, (b) IL413TSLP-1024, (c) IL413P40-0705 were immobilized on a CM5 sensor chip and binding to 200 nM human (hu), cynomolgus monkey (cy), mouse (mu), rabbit (rb), or rat (rb) IL-13 was determined by surface plasmon resonance.

[1026] Figure 37 is a diagram depicting the different Fab positions in a Tri-Fab-Fc construct with a modified Fd (mFd) design.

[1027] Figure 38 Depicted are 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.

[1028] Figure 39 Depicted is a graph showing species specificity of IL-33 binding to the trispecific antibody IL13433-1258 as determined by surface plasmon resonance.

[1029] Figure 40 Depicted are graphs showing the binding of short and long forms of TSLP to TSLP-0001, mAb TSLP-0875, and the trispecific antibody IL413TSLP-1024 as determined by surface plasmon resonance.

[1030] Figure 41 The graph depicts the biological activity of short and long forms of TSLP in inducing TARC production in monocytes. Monocytes isolated from human peripheral blood were incubated overnight at 37°C with 0.31 pg / mL-20 ng / ml recombinant human TSLP (Pfizer), short form TSLP (TSLPlf Avi V5 His 10 Biotin), or long form TSLP (TSLPlf Avi V5 His 10 Biotin). TARC production in cell supernatants was quantified by MSD. Data are presented as mean + / - SD. EC50 values ​​for hTSLP, sfISLP, and lfTSLP were 0.3680, N / A, and 7.472 ng / mL, respectively.

[1031] Figure 42 Depicted is the binding of human, cynomolgus monkey, mouse, and rat TSLP to the trispecific antibody IL413TSLP-1024 as determined by surface plasmon resonance. Biotinylated human (hu), cynomolgus monkey (cy), mouse (mu), or rat (mu) TSLP was captured onto a biotin CAP sensor chip, and binding of the IL413TSLP-1024 trispecific antibody was determined by surface plasmon resonance.

[1032] Figure 43 Depicted is a graph showing simultaneous binding of IL-4, IL-13 and TSLP to IL413TSLP-1024 as determined by surface plasmon resonance.

[1033] Figure 44 depicts a graph showing the mean volume of CT26 tumors over time and at the end of the study. Results of a study in which CT26 tumor-bearing Balb / c mice were administered the compounds listed in Table 88. (A) Mean volume (mm3) and standard error of the mean of implanted tumors for each treatment group starting on day 9 (first day of drug injection) over time. (B) Volume (mm3) of implanted tumors on day 22 post-implantation (last day of the study). Bars and whiskers represent the mean and standard deviation for each treatment group. Each point represents the final tumor volume for each mouse in that treatment group. Treatment with anti-PD-1 antibody, anti-IL-4 antibody plus mIL13Ra2-mFc, or anti-IL-4 antibody plus mIL13Ra2-mFc plus anti-PD-1 antibody did not significantly alter tumor growth characteristics compared to isotype-treated animals. In contrast, mice treated with anti-IL-4 plus anti-TSLP antibody plus mIL13Ra2-mFc (40% tumor growth inhibition, p = 0.043) or anti-IL-4 plus anti-TSLP plus anti-PD-1 antibody plus mIL13Ra2-mFc (54% tumor growth inhibition, p = 0.002) showed significant tumor growth inhibition compared to the isotype.

[1034] Figure 45 The graph depicts the change in CT26 tumor volume over time for each mouse in each treatment group. Starting from day 9 (the first day of drug injection), the volume (in mm3) of CT26 tumors implanted subcutaneously in individual mice in each treatment group changed over time.

[1035] Figure 46 depicts graphs showing that neutralization of IL-4 with mAb IL4-1040 or neutralization of TSLP with mAb TSLP-0875 prevents inhibition of interferon gamma secretion by primary human tumor-reactive T cells. Interferon gamma secretion from primary A375-reactive human T cells, polarized and restimulated using the treatments listed in Table 2 as described in Example 87. (A) shows interferon gamma secretion from six different donors tested over multiple days. T cells were polarized and restimulated with isotype antibody alone, isotype antibody and 0.8 ng / mL recombinant human IL-4, or mAb IL4-1040 and 0.8 ng / mL recombinant human IL-4. (B) shows interferon gamma secretion from the same six donors as in (A), polarized and restimulated with isotype antibody, isotype antibody and 0.8 ng / mL recombinant human TSLP, or mAb TSLP-0875 and 0.8 ng / mL recombinant human TSLP. Data in (A&B) are presented as means and standard deviations. Statistical tests in (A&B) were ANOVAs, with p values ​​from post hoc Multiple comparison tests for , shown above the bars.

[1036] Figure 47 depicts a graph showing that neutralization of IL-4 with mAb IL4-1040 and / or neutralization of TSLP with mAb TSLP-0875 improves T cell-mediated control of in vitro growth of human A375 cancer cells, which correlates with secretion of interferon gamma. Primary human T cells were polarized and restimulated as described in Example 87. Growth curves of A375 tumor cells were generated during T cell restimulation as described in Example 88. (A) Primary human T cells were polarized and restimulated with: (A) isotype antibody alone, isotype antibody and 0.8 ng / mL recombinant human IL-4, or mAb IL4-1040 and 0.8 ng / mL recombinant human IL-4; (B) isotype antibody alone, isotype antibody and 0.8 ng / mL recombinant human TSLP, or mAb TSLP-0875 and 0.8 ng / mL recombinant human TSLP; (C) isotype antibody alone, isotype antibody and 0.8 ng / mL each of recombinant human IL-4 and TSLP, or mAb 1040, mAb and 0.8 ng / mL each of recombinant human IL-4 and TSLP. (D) Interferon gamma was quantified in conditioned media collected on day 5 of restimulation as described in Example 87. Secreted interferon gamma levels were correlated with the normalized A375 AUC from the same well. (AC) are data from donor 1923, and (D) are data from donor 8385. The data in (AC) are presented as the mean and standard deviation of six technical replicates, and data from three different donors are shown as examples. The data in (D) are presented as the mean of six technical replicates, and data from four donors are shown as examples.

[1037] Figure 48 The graph depicts a decrease in the frequency of A375-polarized primary human CD8 T cells expressing perforin and granzyme B by recombinant human IL-4 or a combination of IL-4 and TSLP. The proportion of A375-polarized CD8 T cells expressing 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 different donors.

[1038] Figure 49 depicts a graph showing that the trispecific antibodies IL413TSLP-1028 and IL413TSLP-1037 neutralize IL-4 and IL-13-induced CCL17 secretion from the human clear cell renal cell carcinoma cell line 769-P. 769-P human clear cell renal cell carcinoma cells were incubated with recombinant human IL-4 (A) or IL-13 (B) and dilutions of the trispecific antibodies IL413TSLP-1028 or IL413TSLP-1037 for approximately 20 hours at 37°C. CCL17 secretion was quantified by Legendplex, and concentrations were extrapolated from the standard curve. DETAILED DESCRIPTION

[1039] 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 and to one of IL-33, TSLP, and p40. Also provided herein are related nucleic acids, compositions, and methods of making and using the antibodies.

[1040] General techniques

[1041] All references cited herein, including patent applications, patent publications, UniProtKB accession numbers, are hereby incorporated by reference to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference in its entirety.

[1042] The techniques and procedures described or referenced herein are generally well understood by those skilled in the art and are commonly employed using conventional methods, such as, for example, 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 (FM Ausubel et al., eds., (2003)); METHODS IN ENZYMOLOGY series (Academic Press, Inc.): PCR 2: A PRACTICAL APPROACH (MJ MacPherson, BD Hames and GR Taylor, eds. (1995)), Harlow and Lane, eds. (1988) ANTIBODIES, A LABORATORY MANUAL, and ANIMAL CELL CULTURE (RI Freshney, ed. (1987)); Oligonucleotide Synthesis (MJ Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (JECellis, editor, 1998) Academic Press; Animal Cell Culture (RIFreshney), editor, 1987); Introduction to Cell and Tissue Culture (JPMather and PERoberts, 1998) Plenum Press; Cell and Tissue Culture Laboratory Procedures (A.Doyle, JBGriffiths, and DG Newell, editors, 1993-8) J.Wiley and Sons; Handbook of Experimental Immunology (DMWeir and CC Blackwell, editors); Gene Transfer Vectors for Mammalian Cells (JMMiller and MP=The Polymerase Chain Reaction (Mullis et al., eds., 1994); Current Protocols in Immunology (J. E. Coligan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C. A. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: A Practical Approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999)); The Antibodies (M. Zanetti and JD Capra, eds., Harwood Academic Publishers, 1995); and its updated versions.

[1043] definition

[1044] Unless otherwise defined, all technical terms, symbols, and other scientific terms or terminology used herein are intended to have the meanings commonly understood by those skilled in the art to which the present invention relates. For example, the term "and / or" as used in phrases such as "A and / or B" herein is intended to include: A and B; A or B; A (alone); and B (alone). Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to cover each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone). In some cases, terms with commonly understood meanings are defined herein for clarity and / or ease of reference, and the inclusion of such definitions herein is not necessarily to be construed as representing a substantial difference from what is generally understood in the art.

[1045] As used herein, the singular forms "a," "an," and "the" include their plural referents unless the context clearly dictates otherwise.

[1046] As used herein, numerical ranges are inclusive of the numbers defining the range.

[1047] Reference herein to "about" a value or parameter includes (and describes) embodiments for the value or parameter itself, as well as values ​​or parameters that may be 10% lower or higher than the stated value of the parameter. For example, a dosage of "about 5 mg / kg" includes 5 mg / kg and any value between 4.5 mg / kg and 5.5 mg / kg. When the term "about" is used in the context of a time period (year, month, week, day, etc.), the term "about" refers to that time period plus or minus an amount of the next subordinate time period (e.g., about 1 year refers to 11-13 months; about 6 months refers to 6 months plus or minus 1 week; about 1 week refers to 6-8 days; etc.), or within 10% of the indicated value, whichever is greater.

[1048] "Antibody" refers to an immunoglobulin molecule that can specifically bind to a target (such as a polypeptide, carbohydrate, polynucleotide, lipid, etc.) through at least one antigen binding site located in the variable region of the immunoglobulin molecule. As used herein, the term "antibody" can include any type of antibody (e.g., monospecific, bispecific, trispecific, multispecific), and includes portions of intact antibodies that retain the ability to bind to a given antigen (e.g., "antigen-binding fragments"), as well as any other modified configurations of immunoglobulin molecules that contain an antigen-binding site.

[1049] Antibodies include antibodies of any class, such as IgG, IgA or IgM (or its subclass), and antibodies do not necessarily belong to any particular class. Immunoglobulins can be divided into different classes based on the antibody amino acid sequence of their heavy chain constant region (HC). There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG and IgM, some of which can be further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. The heavy chain constant regions corresponding to the different classes of immunoglobulins are called α, δ, ε, γ and μ, respectively. The subunit structures and three-dimensional configurations of the different classes of immunoglobulins are well known.

[1050] Examples of antibody antigen-binding fragments and modified configurations include: (i) Fab fragments (monovalent fragments composed of VL, VH, CL, and CH1 domains); (ii) F(ab')2 fragments (bivalent fragments composed of two Fab fragments linked by a disulfide bond in the hinge region); and (iii) Fv fragments composed of the VL and VH domains of a single antibody arm. In addition, although the two domains of the Fv fragment, VL and VH, are encoded by different genes, they can be linked together using recombinant methods through a synthetic linker, enabling them to be made into a single protein chain in which the VL and VH regions pair to form a monovalent molecule (called single-chain Fv (scFv)); see, for example, Bird et al., Science 1988; 242: 423-426 and Huston et al., Science 1988; 242: 423-426. Other forms of single-chain antibodies, such as diabodies, are also included.

[1051] Furthermore, antibodies are further included that lack a C-terminal lysine (K) amino acid residue on the heavy chain polypeptide (e.g., a human IgG1 heavy chain contains a terminal lysine). As is known in the art, during the antibody production process, the C-terminal lysine is sometimes cleaved, resulting in an antibody heavy chain lacking a C-terminal lysine. Alternatively, an antibody heavy chain can be produced using a nucleic acid that does not contain a C-terminal lysine.

[1052] The "variable region" of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, used alone or in combination. As is known in the art, the variable regions of the heavy and light chains are each composed of four framework regions (FRs) and three complementarity determining regions (FRs), which are connected by three complementarity determining regions (FRs), also known as hypervariable regions, and contribute to the formation of the antibody's antigen binding site. If a variant of the subject variable region is desired, particularly a variant having substitutions of amino acid residues outside the CDR regions (i.e., in the framework regions), appropriate amino acid substitutions, preferably conservative amino acid substitutions, can be identified by comparing the subject variable region with variable regions of other antibodies containing the same classical type of CDR1 and CDR2 sequences as the subject variable region (Chothia and Lesk, J Mol Biol 196(4):901-917, 1987).

[1053] In certain embodiments, the clear description of CDR and the identification of the residues comprising the antibody binding site are completed by resolving the structure of the antibody or the structure of the antibody-ligand complex. In certain embodiments, this can be completed by any of the various techniques well known to those skilled in the art, such as X-ray crystallography. In certain embodiments, various analytical methods can be adopted to identify or roughly estimate the CDR region. In certain embodiments, various analytical methods can be adopted to identify or approach the CDR region. The example of this type of method includes but is not limited to the Kabat definition shown in Example 1, Chothia definition, AbM definition, contact definition, conformational definition and the Pfabat numbering method.

[1054] The Kabat definition is a standard for numbering residues in antibodies and is commonly used to identify CDR regions. See, e.g., Johnson & Wu, 2000, Nucleic Acids Res., 28:214-8. The Chothia definition is similar to the Kabat definition, but the Chothia definition takes into account the positions of certain structural loop regions. See, e.g., Chothia et al., 1986, J. Mol. Biol., 196:901-17; Chothia et al., 1989, Nature. 342:877-83. The AbM definition uses an integrated suite of computer programs produced by the Oxford Molecular Group for modeling antibody structures. See, e.g., Martin et al., 1989, Proc Natl Acad Sci (USA), 86:9268-9272; "AbM TM, A Computer Program for Modeling Variable Regions of Antibodies," Oxford, UK; Oxford Molecular, Ltd. The AbM definition models the tertiary structure of an antibody from the original sequence using a combination of knowledge databases and ab initio computational methods, such as those described by Samudrala et al., 1999, "Ab Initio Protein Structure Prediction Using a Combined Hierarchical Approach," in PROTEINS, Structure, Function and Genetics Suppl., 3:194-198. Contact definitions are based on analysis of available complex crystal structures. See, e.g., MacCallum et al., 1996, J. Mol. Biol., 5:732-45. In another approach, referred to herein as "conformational definition" of the CDRs, the positions of the CDRs can be identified as residues that make enthalpic contributions to antigen binding. See, e.g., Makabe et al., 2008, Journal of Biological Chemistry, 283: 1156-1166. There are other CDR boundary definitions that may not strictly follow one of the above methods, but will still overlap with at least a portion of the Kabat CDRs, although they may be shortened or lengthened based on predictions or experimental results that a particular residue or residue group will not significantly affect antigen binding. The numbering system used in this application is the Kabat numbering method shown in Example 1.

[1055] As used herein, CDR can refer to the CDR defined by any means known in the art, including the combination of multiple modes. The method used herein can use the CDR defined according to any of these modes. For any given embodiment comprising a plurality of CDRs, CDR can be defined according to any one of Kabat, Chothia, expansion, AbM, contact, conformational definition or the Pfabat method. The antibody of the present application is numbered according to a modified version of the Kabat numbering system, and is listed in more detail in Example 1.

[1056] As used herein, the term "hinge region" includes meanings known in the art, for example, as described in Janeway et al., ImmunoBiology: the immune system in health and disease, Elsevier Science Ltd., NY (4th ed., 1999); Bloom et al., Protein Science, 6: 407-415, 1997; and Humphreys et al., J. Immunol. Methods, 209: 193-202, 1997.

[1057] 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, used alone or in combination. The IgG heavy chain constant region comprises three consecutive immunoglobulin domains (CH1, CH2, and CH3), with a hinge region between the CH1 and CH2 domains. The IgG light chain constant region comprises a single immunoglobulin domain (CL).

[1058] "Fc domain" refers to the portion of an immunoglobulin (Ig) molecule that is associated with the crystallizable fragment obtained by papain digestion of the Ig molecule. As used herein, the term relates to the 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., "the first Fc chain" and "the second Fc chain"). "Fc chain" generally refers to the C-terminal portion of an antibody heavy chain. Therefore, the Fc chain refers to the last two constant region immunoglobulin domains (CH2 and CH3) of IgA, IgD, and IgG heavy chains, and the last three constant region immunoglobulin domains of IgE and IgM heavy chains, and optionally the flexible hinge N-termini of these domains.

[1059] Although the boundaries of the Fc chain can vary, a human IgG heavy chain Fc chain is generally defined as comprising residues C226 or P230 at its carboxyl terminus, where numbering is according to the EU index of Edelman et al., Proc. Natl. Acad. Sci. USA 1969; 63(1): 78-85, and as described by Kabat et al., 1991. Typically, an Fc chain comprises from about amino acid residues 236 to about 447 of the human IgG1 heavy chain constant region. "Fc chain" can refer to such a polypeptide in isolation or in the context of a larger molecule (e.g., in an antibody heavy chain or Fc fusion protein).

[1060] A "functional" Fc domain refers to an Fc domain that has at least one effector function of a native sequence Fc domain. Exemplary "effector functions" include C1q binding; complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g., B cell receptors); and B cell activation, among others. Such effector functions generally require the Fc domain to be combined with a binding domain (e.g., an antibody variable region) and can be assessed using various assays known in the art for evaluating such antibody effector functions.

[1061] A "native sequence" Fc chain or "wild-type Fc chain" refers to an Fc chain comprising an amino acid sequence identical to the amino acid sequence of an Fc chain found in nature. A "variant" Fc chain comprises an amino acid sequence that differs from the amino acid sequence of a native sequence Fc chain because it has at least one amino acid modification, but retains at least one effector function of the wild-type Fc chain. In some embodiments, the variant Fc chain has at least one amino acid substitution compared to the wild-type Fc chain, for example, having from about 1 to about 10 amino acid substitutions in the wild-type Fc chain, and preferably from about 1 to about 5 amino acid substitutions. The variant Fc chain herein preferably has at least about 80% sequence identity to the wild-type Fc chain, and most preferably, has at least about 90% sequence identity, more preferably, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity. In some embodiments, the Fc chain comprises part or all of a wild-type hinge region (usually at its N-terminus). In some embodiments, the Fc polypeptide does not comprise a functional or wild-type hinge region.

[1062] Nomenclature

[1063] The antibody domains disclosed herein may be prefixed with the identifier of the corresponding target antigen most closely associated with the domain. The prefix is ​​added purely to provide a concise and clear distinction between the different domains referenced throughout the disclosure and does not replace or conflict with the actual function or structure of the individual domains. For example, IL4-VH refers to the variable heavy chain domain of an antibody, which comprises CDRs that can specifically bind to IL-4. IL4-CH1 refers to the CH1 domain located at the C-terminus of the IL-4 variable domain, regardless of whether the variable domain is a variable light chain domain (IL4-VL) or a variable heavy chain domain (IL4-VH). As described throughout the disclosure, the domains of the antibodies of the present disclosure can be combined or fused with domains from other antibodies. Thus, for example, IL4-VH can be present on a polypeptide chain together with IL13-VL, and can be present independently or together in the same antibody, and the polypeptides can be referred to as IL4-VH and IL13-VL at the same time (see, for example, Figure 18). Likewise, for example, a polypeptide carrying an IL4-VH is any polypeptide comprising an IL4-VH domain, i.e., a VH domain comprising CDRs that specifically bind to IL-4. A polypeptide carrying an IL4-VH polypeptide may comprise a hinge region, a CH1 domain, a CH2 domain, and a CH3 domain, as in a standard IgG format, or may comprise various domains described herein, such as an IL13-VL, and a CH1 and CL domain fused to an IL4-VH or IL13-VL (see Figure 18 for a diagram of different combinations of antibody domains). For example, the DFab LC(1)-HC(2) arms of IL41333-1258, IL413TSLP-1024, and IL413P40-0705 (see Figure 18I ) each comprise, from N-terminus to C-terminus, an IL13-VL, a CL, a linker, an IL4-VH, a CHI, a CH2, and a CH3, and may be referred to as an IL4-VH-carrying polypeptide and an IL13-VL-carrying polypeptide. Furthermore, framework regions may be referred to by the targets to which their CDRs are specific. For example, the framework regions of the IL-4 antibodies of the present disclosure may be referred to as the IL4-VL framework or the IL4-VH framework. It will be understood by those skilled in the art that these designations neither confer nor imply any relationship between the framework regions and the targets to which the CDRs specifically bind. Thus, the IL4-VL framework region may be derived from a human germline DPK9 sequence identical to a known human DPK9 germline sequence. This nomenclature is not limited to the specific antibodies exemplified in this paragraph but applies to all possible antibodies and antibody combinations disclosed herein.

[1064] Antibodies IL13433-1258, IL134TSLP-1024, and IL134p40-0705 can each be described as comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, wherein the second polypeptide comprises, from N-terminus to C-terminus, (VL-1)-(CL-1)-(linker)-(VH-2)-(CH1-2)-(second hinge)-(second CH2)-(second CH3), the fifth polypeptide comprises, from N-terminus to C-terminus, (VH1)-(CL-1); the fourth polypeptide comprises (VL-2)-(CL-2); the first polypeptide comprises, from N-terminus to C-terminus, (VH-3)-(CH1-3)-(first hinge)-(first CH2)-(first CH3); and the third polypeptide comprises (VL-3)-(CL-3). In each case, VL-1 and VH-1 are IL13-VL and IL13-VH; VL-2 and VH-2 are IL4-VL and IL4-VH, and VH-3 and VL-3 are IL33-VH and IL33-VL; or TSLP-VH and TSLP-VL; or p40-VH and p40-VL.

[1065] "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 directed against a single antigenic site and are highly specific. In addition, in contrast to polyclonal antibody preparations (which typically contain different antibodies directed against different determinants (epitopes)), each monoclonal antibody is directed against a single determinant on the antigen. The modifier "monoclonal" indicates that the characteristic of the antibody is obtained from a substantially homogeneous population of antibodies and should not be construed as requiring the antibody to be produced by any particular method. For example, the monoclonal antibodies used in accordance with the present invention can be made by the hybridoma method first described by Kohler and Milstein, 1975, Nature 256:495, or can be made by recombinant DNA methods, such as described in U.S. Patent No. 4,816,567. In another example, monoclonal antibodies can be isolated from phage libraries, such as phage libraries generated using the techniques described in McCafferty et al., 1990, Nature 348:552-554.

[1066] A "human antibody" refers to an antibody having an amino acid sequence corresponding to an antibody produced by a human, or an antibody produced using any technique for producing fully human antibodies. For example, fully human antibodies can be obtained by using commercially available mice engineered to express specific human immunoglobulins, or by displaying libraries (e.g., phage, yeast, or ribosomes) for producing fully human antibodies. This definition of a human antibody explicitly excludes humanized antibodies that contain non-human antigen-binding residues.

[1067] A "chimeric antibody" refers to an antibody in which the variable region sequence is derived from one species and the constant region sequence is derived from another species, such as an antibody in which the variable region sequence is derived from a mouse antibody and the constant region sequence is derived from a human antibody.

[1068] "Humanized" antibody refers to a non-human (e.g., mouse) antibody, which is a chimeric antibody comprising minimal sequence from a non-human immunoglobulin. Preferably, a humanized antibody is a human immunoglobulin (recipient antibody) in which the residues from the CDRs of the receptor are replaced by residues from the CDRs of a non-human species (donor antibody), such as a mouse, rat, or rabbit with the desired specificity, affinity, and capacity. Humanized antibodies may include residues that are neither present in the receptor antibody nor in the imported CDR or framework sequences, but these residues are included to further improve and optimize antibody performance.

[1069] "Antigen" refers to a molecular entity used to immunize an immunocompetent vertebrate to produce antibodies that recognize the antigen or to screen expression libraries (e.g., phage, yeast, or ribosome display libraries) for antibody selection. In this article, antigen has a broader meaning and is generally intended to include target molecules that are specifically recognized by antibodies, and therefore includes molecular fragments or molecular mimetics used in the immunization process, for generating antibodies, or for selecting antibodies in library screening.

[1070] "Epitope" refers to the site or region of an antigen to which an antibody specifically binds, e.g., a site or region comprising residues that interact with the antibody, as determined by any method known in the art. There are many known methods in the art for locating and characterizing epitope positions on proteins, including crystal structure analysis of antibody-antigen complexes, competition assays, gene fragment expression assays, epitope mapping, and synthetic peptide-based assays, e.g., as described in Chapter 11 of Harlow and Lane, Using Antibodies, a Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1999. Additionally or alternatively, during the discovery process, the generation and characterization of antibodies can elucidate information about the desired epitope. Based on this information, it is possible to competitively screen for antibodies that bind to the same epitope.

[1071] As used herein, the term "binding affinity" refers to the total strength 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, "binding affinity" as used herein refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y can generally be expressed in terms of a dissociation constant (KD). The affinity of a molecule X for its partner Y can generally be expressed in terms of a dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein. Low-affinity antibodies generally bind to antigens more slowly and dissociate easily, while high-affinity antibodies generally bind to antigens faster and tend to remain bound longer. A variety of 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" refers to the dissociation rate of a specific antigen-antibody interaction. K D is the dissociation rate (also called the “off-rate” (k off )") and the association rate or "binding rate (k on )”. Therefore, K D Equal to k off / k on , expressed as molar concentration (M). Therefore, K D The smaller the value, the stronger the binding affinity. D Compared with 1 μM K D Indicates weak binding affinity. D The value can be determined using methods recognized in the art. D One method is to use surface plasmon resonance (SPR), typically using a biosensor system such as a BIACORE system. BIACORE kinetic analysis involves analyzing the binding and dissociation of an antigen from a chip having molecules (e.g., molecules comprising an epitope binding domain) immobilized on its surface. The association rate constant and dissociation rate constant k can be determined, respectively. on and k offTo determine KD and other ratios, for example, surface plasmon resonance-based biosensors are used to characterize analyte / ligand interactions under conditions in which the analyte is monovalent relative to the bound ligand, which is immobilized on the sensor surface at low capacity via a capture reagent. For example, the analysis can be performed using a kinetic titration method as described in Karlsson et al., Anal. Biochem 349, 136-147, 2006, or using multi-cycle kinetic analysis. The sensor chip, capture reagent, and assay buffer for a given assay are selected to stably capture the ligand on the sensor surface, minimize nonspecific binding of the analyte to the surface, and produce an analyte binding reaction suitable for kinetic analysis, as recommended in Myszka, J. Mol. Recognit 12, 279-284, 1999. The analyte binding reaction for each analyte / ligand interaction is double-referenced and fitted to a 1:1 Langmuir "mass transfer limiting model," where k a 、k d and R max As a global parameter, as described in Myszka & Morton et al., Biophys. Chem 64, 127-137 (1997). The equilibrium dissociation constant KD is calculated from the ratio of the kinetic rate constants K D =k off / k on Such determinations are preferably performed at 25°C or 37°C. Typically, the rate constant (k on or k a and k off or k d ) and equilibrium dissociation constants were measured using whole antibodies and monomers. Another method for determining antibody K D The method is to use Bio-Layer interferometry, usually using Technology (OctetQKe system, ForteBio). Alternatively or additionally, the KinExA (kinetic exclusion assay) assay available from Sapidyne Instruments (Boise, ID) may also be used.

[1072] As used herein, the terms "immunospecific binding," "immunospecific recognition," "specific binding," "specific recognition," 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 assays, and the like. TMPreferably, the molecule that specifically binds to the antigen does not cross-react with other proteins.

[1073] The term "specific binding" or "specifically binds" when referring to the interaction of an antibody with a protein or peptide refers to an interaction that is dependent on the presence of a specific structure (i.e., an antigenic determinant or epitope) on the protein; in other words, the antibody recognizes and binds to a specific protein structure, rather than proteins in general. For example, if an antibody is specific for epitope "A," then in the presence of a protein containing epitope A (or free, unlabeled A) in a reaction containing labeled "A," the antibody will reduce the amount of labeled A bound to the antibody.

[1074] In certain embodiments, "specific binding" means, for example, that an antibody binds to a protein with a K D In certain embodiments, "specific binding" refers to the K of an antibody that binds to a target. D At least about 0.1 μM or less, at other times at least about 0.01 μM or less, and at other times at least about 1 nM or less. Due to the sequence identity between homologous proteins in different species, specific binding can include antibodies that recognize proteins in multiple species. Similarly, due to homology in certain regions of the polypeptide sequences of different proteins, specific binding can include antibodies that recognize multiple proteins. It is understood that, in certain embodiments, an antibody or binding portion that specifically binds to a first target may or may not specifically bind to a second target. Therefore, "specific binding" does not necessarily require (although it can include) unique binding, that is, binding to a single target. Therefore, in some embodiments, an antibody can specifically bind to multiple targets. In certain embodiments, multiple targets can be bound by the same antigen binding site on the antibody. For example, in some cases, an antibody can include two identical antigen binding sites, each site specifically binding to the same epitope on two or more proteins. In certain alternative embodiments, an antibody can be multispecific and include at least two antigen binding sites with different specificities. By way of non-limiting example, a bispecific antibody may comprise one antigen binding site that recognizes an epitope on one protein and further comprise a second, different antigen binding site that recognizes a different epitope on a second protein. Reference to binding generally, but not necessarily, means specific binding.

[1075] An antibody that specifically binds to an antigen may bind to other peptides or polypeptides with lower affinity, as determined by assays known in the art, e.g., immunoassays, BIACORE assays, TM Preferably, the antibody that specifically binds to the antigen does not cross-react with other proteins.

[1076] The term "nonspecific binding" or "background binding" when referring to the interaction of an antibody with a protein or peptide refers to interactions that are not dependent on the presence of a specific structure (i.e., the antibody binds to the protein in general rather than to a specific structure such as an epitope).

[1077] Neutralizing or "blocking" antibodies refer to antibodies that bind to one or more of the group consisting of IL-4, IL-13, IL-33, TSLP, and p40, one or both of which (i) interfere with, limit, or inhibit the interaction between IL-4, IL-13, IL-33, TSLP, and p40, respectively, and an appropriate ligand; or (ii) inhibit at least one biological function to which IL-4, IL-13, IL-33, TSLP, or p40 binds, as appropriate. Assays for determining the neutralizing effect of the antibodies of the present disclosure are well known in the art.

[1078] As used herein, an antibody that "binds" to a target; an "antibody" that recognizes a target; an antibody that "specifically binds" to a target; an "anti-target antibody"; an "anti-target antibody molecule"; a "target antibody"; or similar terms, includes molecules that comprise at least one binding domain that specifically binds to a target.

[1079] A "monospecific antibody" is an antibody that contains one or more antigen-binding sites per molecule, such that any and all binding sites of the antibody specifically recognize the same epitope on the antigen. Therefore, when a monospecific antibody has multiple antigen-binding sites, the binding sites compete with each other for binding to a single antigen molecule.

[1080] "Bispecific antibodies" refer to molecules that have binding specificities for at least two different epitopes. In some embodiments, bispecific antibodies can bind to two different antigens simultaneously. In other embodiments, the two different epitopes can be located on the same antigen.

[1081] As used herein, a "trispecific antibody" is an antibody that has binding specificity for three different epitopes. In some embodiments, a trispecific antibody can bind to three different antigens simultaneously. In other embodiments, the three different epitopes can be located on the same antigen.

[1082] 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 bind to at least two different antigens simultaneously. In other embodiments, at least two different epitopes can be located on the same antigen.

[1083] 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.

[1084] The term "half maximal effective concentration (EC50)" refers to the concentration of a therapeutic agent that results in a response between baseline and maximum after a specified exposure time. A therapeutic agent can cause either inhibition or stimulation. EC50 50 The value is commonly used and is used herein as a measure of efficacy.

[1085] The term "inhibitory concentration" (IC 50 ) refers to the inhibitor concentration that achieves 50% inhibitory activity. Therapeutic agents can cause inhibition or stimulation. IC 50 The value is commonly used and is used herein as a measure of efficacy.

[1086] "Agonist" refers to a substance that promotes (ie, 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 to promote the activity of that molecule.

[1087] "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 to prevent or reduce the activity of that molecule.

[1088] As used herein, with respect to antibodies, the term "competition" means that the first antibody binds to the epitope in a manner sufficiently similar to that of the second antibody, such that, compared to the binding of the second antibody in the absence of the first antibody, in the presence of the first antibody, the binding results of the second antibody to its cognate epitope can be detected to be reduced. Alternatively, in the presence of the second antibody, the binding of the first antibody to its epitope can also be detected to be reduced, which may be the case but is not necessarily the case. In other words, the first antibody can inhibit the binding of the second antibody to its epitope, while the second antibody will not inhibit the binding of the first antibody to its respective epitope. However, if each antibody can be detected to inhibit the binding of another antibody to its cognate epitope or ligand, whether the same, greater or lesser degree, then these antibodies are said to "cross compete" with each other for the binding of their respective epitopes. The present invention includes competitive and cross-competitive antibodies. Regardless of the mechanism by which this competition or cross-competition occurs (e.g., steric hindrance, conformational change, or binding to a common epitope or part thereof), professionals and technicians will understand based on the teachings provided herein that this competition or cross-competitive antibody is included in the method disclosed herein and can be used for the method disclosed herein.

[1089] "Host cell" refers to a single cell or cell culture that can be or has been a recipient of a vector for incorporating a polynucleotide insert. Host cells include the progeny of a single host cell, which may not necessarily be completely identical (in morphology or genomic DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation. Host cells include cells transfected in vivo with a polynucleotide of the invention.

[1090] "Vector" refers to a construct that can deliver and preferably express one or more target genes or sequences (e.g., antibody encoding genes) in a host cell. Examples of vectors include, but are not limited to, plasmids and viral vectors, and may include naked nucleic acids, or may include nucleic acids associated with delivery auxiliary materials (e.g., cationic condensing agents, liposomes, etc.). A vector may include DNA or RNA. As used herein, "expression vector" refers to a vector that includes at least one polypeptide encoding gene, at least one regulatory element associated with gene transcription or translation (e.g., a promoter sequence, a poly (A) sequence). Typically, the vector used herein contains at least one antibody encoding gene, and one or more regulatory elements or selective markers. For example, the vector components may include one or more of the following: a signal sequence; a replication start point; one or more marker genes; suitable transcription control elements (such as promoters, enhancers, and terminators). For translation, one or more translation control elements may also be included, such as a ribosome binding site, a translation initiation site, and a stop codon.

[1091] An "isolated" molecule (e.g., an isolated antibody) is one that, by virtue of its source or derivation, (1) is not associated with naturally associated components with which it is naturally present, (2) is substantially free of other molecules from the same source (e.g., species, cell expressing it, 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 that from which it is naturally derived, will be "isolated" from its naturally associated components. A molecule can also be rendered substantially free of naturally associated components by isolation using purification techniques well known in the art.

[1092] As used herein, the term "linker" refers to an amino acid sequence that is two or more amino acids in length. A linker can be composed of neutral polar or non-polar amino acids. For example, a linker can be 2 to 100 amino acids in length, such as between 2 and 50 amino acids in length, for example, 3, 4, 5, 6, 8, 10, 12, 15, 20, 25, 30, 35, 40, 45, or 50 amino acids in length. A linker can be "cleavable," for example, by self-cleavage, enzymatic, or chemical cleavage. Cleavage sites in amino acid sequences and enzymes and chemicals that cleave at these sites are well known in the art and are also described herein. In some aspects, a linker comprises one or more repeating units of a sequence comprising glycine and serine residues. In some aspects, a linker comprises one or more repeating units of G4S. In some aspects, a linker comprises (G4S) 1-3 In certain aspects, the linker is GGGGS (SEQ ID NO: 10).

[1093] As used herein, the term "disulfide bond" or "cysteine-cysteine ​​disulfide bond" refers to a covalent interaction between two cysteines, wherein the sulfur atoms of the cysteines are oxidized to form a disulfide bond. The average bond energy of a disulfide bond is approximately 60 kcal / mol, while the average bond energy of a hydrogen bond is 1-2 kcal / mol. In the context of the present invention, the cysteines that form the disulfide bond are located within the framework region of the single-chain antibody and serve to stabilize the antibody conformation. Cysteine ​​residues can be introduced, for example, by site-directed mutagenesis, thereby forming a stable disulfide bond within the molecule.

[1094] As used herein, the terms "linked," "fused," and "fusion" are used interchangeably to refer to the joining together of two or more elements or components by any means including chemical conjugation or recombinant means.

[1095] As used herein, the term "covalently linked" means that the designated moieties are covalently bonded directly to one another, or indirectly to one another through one or more intervening moieties, such as a linker peptide or linking moiety.

[1096] As used herein, the term "linked to" refers to the colinearity, covalent linkage or attachment of two or more proteins, polypeptides, or fragments thereof through their respective peptide backbones. For example, one polypeptide can be linked to another polypeptide by genetic expression of a single polynucleotide molecule encoding both polypeptides in frame. Such a genetic fusion results in the expression of a single, continuous protein comprising both polypeptides.

[1097] As used herein, the term "modification" refers to amino acid replacements, insertions or deletions in a polypeptide sequence, changes to a portion chemically linked to a protein, or modifications to a protein (e.g., an antibody) function. For example, a modification can be a functional change of an antibody, or a change in the carbohydrate structure attached to a protein. As used herein, "amino acid modification" refers to a mutation (replacement), insertion (addition) or deletion of one or more amino acid residues in an antibody. The term "amino acid mutation" means that at least one existing amino acid residue is replaced by another different amino acid residue (e.g., a replacement amino acid residue). The term "amino acid deletion" means that at least one amino acid residue is removed at a predetermined position in an amino acid sequence. For example, the mutation L234A means that the amino acid residue lysine at position 234 of the Fc region of an antibody is replaced by the amino acid residue alanine (replacing lysine with alanine) (numbered according to the EU index numbering system).

[1098] The term "agent" is used herein to refer to a biomacromolecule, an extract made from biological material, a mixture of biomacromolecules, a chemical compound, a mixture of chemical compounds, or a mixture of chemical compounds and biomacromolecules. The term "therapeutic agent" refers to an agent with biological activity.

[1099] "Polypeptide" or "protein" (used interchangeably herein) refers to an amino acid chain of any length. The chain may be linear or branched. The chain may contain one or more modified amino acids. These terms also encompass amino acid chains modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. Also included in the definition are, for example, polypeptides containing one or more analogs of an amino acid (including, for example, unnatural amino acids, etc.), as well as other modifications known in the art. It is believed that a polypeptide may occur as a single chain or in an associated chain.

[1100] As used herein, a "first polypeptide" is any polypeptide that will associate with a second polypeptide. The first polypeptide and the second polypeptide meet at an interface. In addition to the interface, the first polypeptide may also include one or more additional domains, such as a "binding domain" (e.g., an antibody variable domain, a receptor binding domain, a ligand binding domain, or an enzyme domain) or an antibody constant domain (or portion thereof), including a CH2, CH1, and CL domain. Typically, the first polypeptide will include 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, antibody constant domains that combine binding domains with heterologous polypeptides, receptor polypeptides, ligand polypeptides, and chimeras (e.g., bispecific antibodies) of antibody variable domain polypeptides.

[1101] In addition to the interface, the second polypeptide may also include additional domains such as a "binding domain" (e.g., an antibody variable domain, a receptor binding domain, a ligand binding domain, or an enzyme domain) or an antibody constant domain (or portion thereof) comprising a CH2, CH1, and CL domain. Typically, the second polypeptide will comprise at least one domain derived from an antibody. This domain is conveniently a constant region, such as a CH3 domain of an antibody, and may form the interface of the second polypeptide. Exemplary second polypeptides include antibody heavy chain polypeptides, chimeras combining antibody constant domains with binding domains of heterologous polypeptides, and antibody variable domain polypeptides (e.g., bispecific antibodies).

[1102] "Polynucleotide" or "nucleic acid" (used interchangeably herein) refers to a chain of nucleotides of any length, including DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, or analogs thereof, or any substrate that can be incorporated into the chain by DNA or RNA polymerase. The polynucleotide can contain modified nucleotides, such as methylated nucleotides and their analogs. If present, the nucleotide structure can be modified before or after chain assembly. The nucleotide sequence can be interrupted by non-nucleotide components. The polynucleotide can be further modified after polymerization, such as by conjugation with a labeling component. Other types of modifications include, for example, "caps," substitution of one or more naturally occurring nucleotides with an analog, internucleotide modifications such as, for example, modifications with uncharged bonds (e.g., methylphosphonates, phosphotriesters, phosphamidates, carbamates, etc.) and modifications with charged bonds (e.g., phosphorothioates, phosphorodithioates, etc.), those containing overhanging moieties such as, for example, proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), those with intercalators (e.g., acridine, psoralen, etc.), those containing chelators (e.g., metals, radioactive metals, boron, oxidized metals, etc.), those containing alkylating agents, those with modified bonds (e.g., alpha anomeric nucleic acids, etc.), and unmodified forms of polynucleotides. In addition, any hydroxyl group normally present in the sugar can be substituted with a phosphonate group, a phosphate group, protected with standard protecting groups, or activated to prepare additional bonds to other nucleotides, or can be conjugated to a solid support. The 5' and 3' terminal OH groups can be phosphorylated or partially substituted with amine or organic end-capping groups of 1 to 20 carbon atoms. Other hydroxyl groups can also be derived into standard protecting groups. Polynucleotides can also include ribose or deoxyribose in the form of analogs generally known in the art, for example, including 2'-O-methyl-, 2'-O-allyl, 2'-fluoro- or 2'-azido-ribose, carbocyclic sugar analogs, α- or β-anomeric sugars, epimeric sugars such as arabinose, xylose or lyxose, pyranose, furanose, sedoheptulose, acyclic analogs and abasic nucleoside analogs such as methyl riboside.

[1103] As used herein, nucleic acids are written from left to right in a 5' to 3' direction; amino acid sequences are written from left to right in an amino to carboxyl direction, respectively. Practitioners are particularly directed to Sambrook et al., 1989 and Ausubel FM et al., 1993, for definitions and terminology in the art. It should be understood that the present invention is not limited to the specific methods, protocols, and reagents described, as these may vary.

[1104] Polynucleotides complementary to any such sequences are also encompassed within the present invention. Polynucleotides may be single-stranded (coding or antisense) or double-stranded, and may be DNA (genomic, cDNA or synthetic) or RNA molecules. RNA molecules include mature and immature mRNAs, such as precursor mRNA (pre-mRNA) or heterogeneous nuclear mRNA (hnRNA) and mature mRNA. Other coding or non-coding sequences may, but are not necessarily present in the polynucleotides of the present invention, and polynucleotides may, but are not necessarily connected to other molecules or support materials.

[1105] Those skilled in the art will appreciate that, due to the degeneracy of the genetic code, there are many nucleotide sequences encoding the amino acid sequences provided herein. Polynucleotides that vary due to differences in codon usage are specifically contemplated by the present invention.

[1106] "Conservative substitution" refers to replacing an amino acid with a biological, chemical or structurally similar residue. Biological similarity means that the substitution does not destroy biological activity. Structurally similar means that the amino acids have side chains of similar length (such as alanine, glycine and serine) or similar size. Chemical similarity means that the residues have the same charge or are both hydrophilic or hydrophobic. Specific examples include that a hydrophobic residue is replaced by another residue (such as isoleucine, valine, leucine or methionine), or a polar residue is replaced by another polar residue, such as lysine is replaced by arginine, aspartic acid is replaced by glutamic acid, or asparagine is replaced by glutamine, threonine is replaced by serine, etc. Specific examples of conservative substitutions include that hydrophobic residues such as isoleucine, valine, leucine or methionine are replaced with each other, and polar residues replace another polar residue, such as lysine is replaced by arginine, aspartic acid is replaced by glutamic acid, or asparagine is replaced by glutamine, etc. Conservative amino acid substitutions generally include, for example, substitutions within the following groups: glycine, alanine, valine, isoleucine, and leucine; aspartic acid and glutamic acid; asparagine and glutamine; serine and threonine; lysine and arginine; and phenylalanine and tyrosine.

[1107] The present invention also includes modifications of the antibodies provided herein, including functionally equivalent antibodies whose properties are not significantly affected, as well as variants with enhanced or reduced activity or affinity. For example, the amino acid sequence can be mutated to obtain an antibody with the desired binding affinity for IL-4, IL-13, IL-33, TSLP or p40. Examples of modified polypeptides include polypeptides with conservative substitutions of amino acid residues that do not significantly and adversely alter the functional activity, deletions or additions of one or more amino acids, or the affinity of mature (enhanced) polypeptides for their ligands, or the use of chemical analogs.

[1108] Amino acid sequence insertions include amino- or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing one hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include antibodies with an N-terminal methionyl residue or antibodies fused to an epitope tag. Other insertional variants of the antibody molecule include fusions to the N- or C-termini of enzymes or polypeptide antibodies to increase the half-life of the antibody in the blood circulation.

[1109] Substitution variants have at least removed an amino acid residue in the antibody molecule and have inserted different residues in its position. The most interesting sites of substitution mutagenesis include hypervariable regions, but FR changes are also considered. Conservative substitutions are shown below as residues in the same numbered groups (1-6). If this substitution causes a change in biological activity, more substantial changes can be introduced, referred to as "exemplary substitutions," as further described below about amino acid class, and the product is screened.

[1110] Substantial modification of the biological properties of the antibody is achieved by selecting substitutions that have significantly different effects on maintaining (a) the structure of the polypeptide backbone in the area of ​​the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain. Naturally occurring amino acid residues are divided into the following groups based on common side chain properties:

[1111] (1) Non-polar: norleucine, Met, Ala, Val, Leu, Ile;

[1112] (2) Polarity without charge: Cys, Ser, Thr, Asn, Gln;

[1113] (3) Acidic (negatively charged): Asp, Glu;

[1114] (4) Basic (positively charged): Lys, Arg;

[1115] (5) Residues that affect chain orientation: Gly, Pro; and

[1116] (6) Aromatic: Trp, Tyr, Phe, His.

[1117] Non-conservative substitutions are made by exchanging a member of one class for another.

[1118] Any cysteine ​​residue that is not involved in maintaining the proper conformation of the antibody may also be substituted, typically with serine, to improve the oxidative stability of the molecule and prevent abnormal cross-linking. Conversely, cysteine ​​bonds may be added to the antibody to improve its stability, particularly when the antibody is an antibody fragment (such as an Fv fragment).

[1119] Amino acid modifications can range from changing or modifying one or more amino acids to completely redesigning a region, such as a variable region. Changes in the variable region can alter binding affinity and / or specificity. In some embodiments, no more than 1 to 5 conservative amino acid substitutions are made within the CDR domain. In other embodiments, no more than 1 to 3 conservative amino acid substitutions are made within the CDR domain. In other embodiments, the CDR domain is one or both of the VH CDR3 or VL CDR3.

[1120] Modifications also include glycosylated and non-glycosylated polypeptides, as well as polypeptides with other post-translational modifications, such as, for example, glycosylation with different sugars, acetylation, and phosphorylation. Antibodies are glycosylated at conserved positions in their constant regions (Jefferis and Lund, Chem. Immunol. 65: 111-128, 1997; Wright and Morrison, TibTECH 15: 26-32, 1997). The oligosaccharide side chains of immunoglobulins influence protein function (Boyd et al., Mol. Immunol. 32:1311-1318, 1996; Wittwe and Howard, Biochem. 29:4175-4180, 1990) and intramolecular interactions between glycoprotein moieties, which can affect the conformation and three-dimensional surface presentation of the glycoprotein (Jefferis and Lund, supra; Wyss and Wagner, Current Opin. Biotech. 7:409-416, 1996). Oligosaccharides can also be used to target a given glycoprotein to certain molecules based on specific recognition structures. Glycosylation of antibodies has also been reported to affect antibody-dependent cellular cytotoxicity (ADCC). In particular, CHO cells with tetracycline-regulated expression of β(1,4)-N-acetylglucosaminyltransferase III (GnTIII), a glycosyltransferase that catalyzes the formation of bisecting GlcNAc, were reported to have improved ADCC activity (Umana et al., Mature Biotech. 17: 176-180, 1999).

[1121] Glycosylation of antibodies is typically either N-linked or O-linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine, asparagine-X-threonine, and asparagine-X-cysteine, where X is any amino acid except proline, are the recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Therefore, the presence of any of these tripeptide sequences in a polypeptide creat...

Claims

1. 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: (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.

2. The antibody according to claim 1, 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.

3. The antibody according to any one of claims 1 to 2, comprising: (i) the IL4-VH sequence of SEQ ID NO:22 and the IL4-VL sequence of SEQ ID NO:26; (ii) the IL4-VH sequence of SEQ ID NO: 19 and the IL4-VL sequence of SEQ ID NO: 20; (iii) the IL4-VH sequence of SEQ ID NO:22 and the IL4-VL sequence of SEQ ID NO:20; (iv) the IL4-VH sequence of SEQ ID NO:28 and the IL4-VL sequence of SEQ ID NO:29; or (v) the IL4-VH sequence of SEQ ID NO:22 and the IL4-VL sequence of SEQ ID NO:30; (vi) an IL4-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 200, and an IL4-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 201; (vii) a polypeptide sequence carrying IL4-VH encoded by the nucleic acid sequence of SEQ ID NO: 188, and a polypeptide sequence carrying IL4-VL encoded by the nucleic acid sequence of SEQ ID NO: 189; (viii) an IL4-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127198, and an IL4-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127197; or (ix) The polypeptide sequence carrying IL4-VH encoded by the plasmid deposited with ATCC and having ATCC accession number PTA-127192, and the polypeptide sequence carrying IL4-VL encoded by the plasmid deposited with ATCC and having ATCC accession number PTA-127194.

4. The antibody according to any one of claims 1 to 3, characterized in that One or more of the following: (i) The antibody binds to the K of human IL-4 D less than a value selected from the group consisting of about 10 pM, 5 pM, 1 pM, and 800 fM; (ii) the antibody binds to cynomolgus monkey IL-4; (iii) the antibody does not bind to IL-4 from one or more selected from the group consisting of dog, sheep, rabbit, rat and mouse; (iv) Binding K of the Antibody to Cynomolgus Monkey IL-4 D The binding K of the antibody to human IL-4 D within 1 order of magnitude; (v) The antibody is characterized by an IC of 0.04 for neutralization of IL-4-induced CD23 in a human monocyte assay. 50 Less than 10pM; (vi) the antibody has a viscosity of 20 cP or less at a concentration of 80 mg / mL in histidine-sucrose pH 5.8 buffer at 25°C; (vii) the antibody comprises a lysine at residue 93 in the light chain.

5. An isolated antibody that specifically binds to IL-3, comprising a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL), comprising: (i) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO:51, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO:54; (ii) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO:44, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO:46; (iii) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO:48, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO:49; (iv) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO:48, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO:68; or (v) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO:57, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO:

59.

6. An antibody that specifically binds to IL-13 according to any one of claims 1 to 5, comprising a heavy chain variable region (IL3-VH) and a light chain variable region (IL3-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.

7. The antibody according to any one of claims 1 to 6, comprising: (i) the IL13-VH sequence of SEQ ID NO:51, and the IL13-VL sequence of SEQ ID NO:54; (ii) the IL13-VH sequence of SEQ ID NO:44, and the IL13-VL of SEQ ID NO:46; (iii) the IL13-VH sequence of SEQ ID NO:48, and the IL13-VL sequence of SEQ ID NO:49; (iv) the IL13-VH sequence of SEQ ID NO:48, and the IL13-VL of SEQ ID NO:68; (v) the IL13-VH sequence of SEQ ID NO:57, and the IL13-VL sequence of SEQ ID NO:59; (vi) an IL13-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 198, and an IL13-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 199; (vii) a polypeptide sequence carrying IL13-VH encoded by the nucleic acid sequence of SEQ ID NO: 187, and a polypeptide sequence carrying IL13-VL encoded by the nucleic acid sequence of SEQ ID NO: 188; (viii) an IL13-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127196, and an IL13-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127195; or (ix) The polypeptide sequence carrying IL13-VH encoded by the plasmid deposited with ATCC and having ATCC accession number PTA-127193, and the polypeptide sequence carrying IL13-VL encoded by the plasmid deposited with ATCC and having ATCC accession number PTA-127192.

8. The antibody according to any one of claims 1 to 7, characterized in that One or more of the following: (i) The antibody binds to human IL-13 D 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; (ii) the antibody binds to cynomolgus monkey IL-13, optionally K D The binding K of antibody to human IL-13 D within 1 order of magnitude; (iii) IL-13 IC was measured by neutralization of IL-13pSTAT6 phosphorylation in HT-29 cells 50 Less than 100 pM; (iv) IL-13 IC induced by IL-13 for CD23 neutralization measured in human monocyte assay 50 Less than 20pM; (v) the terminal half-life of the antibody in cynomolgus monkeys is at least 14 days; (vi) the terminal half-life of the antibody in TG32 mice is at least 18 days; (vii) the antibody does not bind to IL-13 from one or more species selected from the group consisting of dog, rabbit and mouse.

9. The antibody according to any one of claims 1 to 8, 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, wherein: (i) the IL-4 binding domain as described in any one of claims 1 to 3, or (ii) the IL-13 binding domain is as described in any one of the claims, or (iii) the IL-4 binding domain is as described in any one of claims 1 to 3, and the IL-13 binding domain is as described in any one of claims 4 to 6.

10. The antibody according to claim 9, wherein the antibody comprises a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain and a fifth polypeptide chain, such that (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising a first antigen binding site; (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising a second antigen binding site; (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a third antigen binding site; and The first polypeptide chain and the second polypeptide chain associate together to form an antibody comprising two arms: a double Fab arm comprising the first Fab domain and the second Fab domain, and a single Fab arm comprising the third Fab domain.

11. The antibody according to claim 10, wherein: (i) the first antigen binding site specifically binds IL-13, the second antibody binding site specifically binds IL-4, and the third antigen binding site specifically binds at least one additional target; (ii) the first antigen binding site specifically binds IL-4, the second antibody binding site specifically binds IL-13, and the third antigen binding site specifically binds at least one additional target; (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; (iv) wherein 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; (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.

12. An isolated antibody that specifically binds IL-4, specifically binds IL-13, and specifically binds at least one additional target, comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein the identities of the second polypeptide chain, the fourth polypeptide chain, and the fifth polypeptide chain are selected from the group consisting of: (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.

13. An isolated antibody that specifically binds IL-4, specifically binds IL-13, and specifically binds at least one additional target, comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein: (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site; (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site; (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising at least one additional target binding site, and The second polypeptide chain comprises: from the N-terminus, SEQ ID NO:54, SEQ ID NO:16, an optional linker comprising SEQ ID NO:10, SEQ ID NO:22, SEQ ID NO:6, a CH2 domain and a CH3 domain; the fourth polypeptide chain comprises SEQ ID NO:27; and the fifth polypeptide chain comprises SEQ ID NO:

122.

14. An isolated antibody that specifically binds to TSLP, comprising a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), comprising: (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.

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

212.

16. The antibody according to any one of claims 14-15, comprising: (i) the TSLP-VH sequence of SEQ ID NO:92, and the TSLP-VL of SEQ ID NO:94; (ii) the TSLP-VH sequence of SEQ ID NO:92, and the TSLP-VL of SEQ ID NO:93; (iii) the TSLP-VH sequence of SEQ ID NO:92, and the TSLP-VL of SEQ ID NO:213; (iv) the TSLP-VH sequence of SEQ ID NO:92, and the TSLP-VL of SEQ ID NO:214; (v) a TSLP-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 204; and a TSLP-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 205; (vi) a TSLP-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 204; and a TSLP-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 217; (vii) a TSLP-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 204; and a TSLP-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 218; (viii) a polypeptide sequence carrying TSLP-VH encoded by the nucleic acid sequence of SEQ ID NO: 192; and a polypeptide sequence carrying TSLP-VL encoded by the nucleic acid sequence of SEQ ID NO: 193; (ix) a polypeptide sequence carrying TSLP-VH encoded by the nucleic acid sequence of SEQ ID NO: 192; and a polypeptide sequence carrying TSLP-VL encoded by the nucleic acid sequence of SEQ ID NO: 193; (x) a polypeptide sequence carrying TSLP-VH encoded by the nucleic acid sequence of SEQ ID NO: 192; and a polypeptide sequence carrying TSLP-VL encoded by the nucleic acid sequence of SEQ ID NO: 193; (xi) 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-127199; or (xii) The polypeptide sequence carrying TSLP-VH encoded by the plasmid deposited with ATCC and having ATCC Accession No. PTA-127202, and the polypeptide sequence carrying TSLP-VL encoded by the plasmid deposited with ATCC and having ATCC Accession No. PTA-127201.

17. The antibody of any one of claims 1-16, wherein the antibody is characterized by one or more of the following: (i) IC in TARC production bioassay in human peripheral blood mononuclear cells 50 Less than 10pM; (ii) melting temperature is 68°C; (iii) wherein the pH 3.4 retention Δ% HMMS is less than 5, such that the pH 3.4 retention Δ% HMMS is defined as the difference between the percentage of high molecular weight species produced by degradation of the antibody after incubation at room temperature at pH 3.4 for 5 hours and the percentage of high molecular weight species produced by degradation of the antibody after incubation at room temperature at pH 7.2 for 5 hours; (iv) IC measured in TARC production bioassay in human primary PBMCs 50 Less than 10 pM of anti-TSLP bioactivity; (v) a viscosity of 20 cP at a concentration of at least 100 mg / mL in 20 mM histidine, 8.5% sucrose, 0.05 mg / mL EDTA pH 6.0 buffer; (vi) a score of less than 2% high molecular weight material as determined by analytical size exclusion chromatography (aSEC); (vii) a score of less than 12 in the affinity capture self-interacting nanoparticle spectroscopy (AC SINS) assay; (viii) IC of human TSLP neutralization in TARC production bioassay in human primary PBMCs 50 Less than 15pM; (ix) IC in cynomolgus monkey TSLP neutralization assay 50 Less than 35pM.

18. An isolated antibody that specifically binds IL-4 and specifically binds IL-13, comprising the antibody of any one of claims 1-13, and wherein the antibody further specifically binds TSLP, and wherein the antibody optionally comprises the antibody of any one of claims 14-17.

19. The antibody according to claim 18, wherein: (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 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 (ii) an 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; and in: (iii) the TSLP binding domain comprises a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), wherein CDR-H1 comprises the amino acid sequence of SEQ ID NO: 82; CDR-H2 comprises the amino acid sequence of SEQ ID NO: 83; CDR-H3 comprises the amino acid sequence of SEQ ID NO: 85; CDR-L1 comprises the amino acid sequence of SEQ ID NO: 86; CDR-L2 comprises the amino acid sequence of SEQ ID NO: 88; and 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), wherein CDR-H1 comprises the amino acid sequence of SEQ ID NO: 82; CDR-H2 comprises the amino acid sequence of SEQ ID NO: 83; CDR-H3 comprises the amino acid sequence of SEQ ID NO: 85; CDR-L1 comprises the amino acid sequence of SEQ ID NO: 86; CDR-L2 comprises the amino acid sequence of SEQ ID NO: 87; and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 211; or (v) The TSLP binding domain comprises a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), wherein CDR-H1 comprises the amino acid sequence of SEQ ID NO:82; CDR-H2 comprises the amino acid sequence of SEQ ID NO:83; CDR-H3 comprises the amino acid sequence of SEQ ID NO:85; CDR-L1 comprises the amino acid sequence of SEQ ID NO:86; CDR-L2 comprises the amino acid sequence of SEQ ID NO:87; and CDR-L3 comprises the amino acid sequence of SEQ ID NO:

212.

20. The antibody of any one of claims 18-19, wherein the antibody comprises a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, such that the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising a first antigen binding site; the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising a second antigen binding site; and the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a third antigen binding site, and wherein the identities of the first polypeptide chain, the second polypeptide chain, the third polypeptide chain, the fourth polypeptide chain, and the fifth polypeptide chain are selected from the group consisting of: (i) the first polypeptide chain comprises SEQ ID NO: 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; and (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; (xv) the first polypeptide chain comprises a sequence encoded by the nucleic acid shown in SEQ ID NO: 192, the second polypeptide chain comprises a sequence encoded by the nucleic acid shown in SEQ ID NO: 188, the third polypeptide chain comprises a sequence encoded by the nucleic acid shown in SEQ ID NO: 193, the fourth polypeptide chain comprises a sequence encoded by the nucleic acid shown in SEQ ID NO: 187, and the fifth polypeptide chain comprises a sequence encoded by the nucleic acid shown in SEQ ID NO: 122; and (xvi) the first polypeptide chain comprises a sequence encoded by a nucleic acid corresponding to ATCC deposit PTA-127202, the second polypeptide chain comprises a sequence encoded by a nucleic acid corresponding to ATCC deposit PTA-127192, the third polypeptide chain comprises a sequence encoded by a nucleic acid corresponding to ATCC deposit PTA-127201, the fourth polypeptide chain comprises a sequence encoded by a nucleic acid corresponding to ATCC deposit PTA-127194, and the fifth polypeptide chain comprises a sequence encoded by a nucleic acid corresponding to ATCC deposit PTA-127193.

21. The antibody according to claims 18-20, wherein: (i) the TSLP binding portion comprises TSLP-VH of SEQ ID NO: 92 and TSLP-VL of SEQ ID NO: 94; (ii) the IL-4 binding portion comprises the IL4-VH of SEQ ID NO:22 and the IL4-VL of SEQ ID NO:26; and (iii) the IL-13 binding portion comprises IL13-VH of SEQ ID NO:51 and IL13-VL of SEQ ID NO:

54.

22. An isolated antibody that specifically binds TSLP, specifically binds IL-4, and specifically binds IL-13, comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, and wherein: (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising an IL-13 binding site; (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising an IL-4 binding site; (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a TSLP binding site; and 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.

23. An isolated antibody that specifically binds p40 via a p40 binding domain, and wherein the antibody comprises at least one additional antigen binding domain that specifically binds an antigen selected from the group consisting of IL-4, IL-13, IL-33, and TSLP, and wherein the p40 binding domain comprises: (i) 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; (ii) 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; (iii) p40-VH comprising the sequence shown in SEQ ID NO: 169, and p40-VL shown in SEQ ID NO: 175; (iv) a polypeptide carrying p40-VH comprising the sequence shown in SEQ ID NO: 186, and a polypeptide carrying p40-VL comprising the sequence shown in SEQ ID NO: 176; (v) p40-VH shown in SEQ ID NO:206, and p40-VL shown in SEQ ID NO:207; (vi) a polypeptide carrying p40-VH as shown in SEQ ID NO: 194, and a polypeptide carrying p40-VL as shown in SEQ ID NO: 195; (vii) p40-VH comprising the sequence encoded by the nucleic acid corresponding to ATCC deposit PTA-127206, and p40-VL comprising the sequence encoded by the nucleic acid corresponding to ATCC deposit PTA-127205; or (viii) a polypeptide carrying p40-VH comprising a sequence encoded by a nucleic acid corresponding to ATCC deposit PTA-127204, and a polypeptide carrying p40-VL comprising a sequence encoded by a nucleic acid corresponding to ATCC deposit PTA-127203.

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

173.

25. The antibody of any one of claims 23-24, wherein the p40 binding domain comprises p40-VH of SEQ ID NO: 169 and p40-VL of SEQ ID NO:

175.

26. The antibody of any one of claims 23-25, wherein the antibody comprises an IL-4 binding domain that specifically binds to IL-4 and an IL-13 binding domain that specifically binds to IL-13, and wherein the antibody further comprises the antibody of any one of claims 1-8.

27. The antibody according to any one of claims 23-26, wherein: (i) the p40 binding domain comprises a heavy chain variable region (p40-VH) and a light chain variable region (p40-VL), wherein CDR-H1 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 166; CDR-H2 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 167; CDR-H3 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 168; CDR-L1 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 171; CDR-L2 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 172; and CDR-L3 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 173; and (ii) the IL-4 binding domain comprises a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL), wherein CDR-H1 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 18; CDR-H2 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 2; CDR-H3 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 3; CDR-L1 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 24; CDR-L2 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 12; and CDR-L3 of the IL-4 binding domain comprises the amino acid sequence of SEQ ID NO: 25, and (iii) the IL-13 binding domain comprises a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL), wherein the CDR-H1 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO:41; the CDR-H2 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO:42; the CDR-H3 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO:50; the CDR-L1 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO:53; the CDR-L2 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO:37; and the CDR-L3 of the IL-13 binding domain comprises the amino acid sequence of SEQ ID NO:

38.

28. The antibody according to any one of claims 23-27, wherein: (i) the p40 binding domain comprises p40-VH of SEQ ID NO: 169 and p40-VL of SEQ ID NO: 175; (ii) the IL-4 binding domain comprises IL4-VH of SEQ ID NO: 22 and IL4-VL of SEQ ID NO: 26; (iii) the IL-13 binding domain comprises IL13-VH of SEQ ID NO:51 and IL13-VL of SEQ ID NO:

54.

29. The antibody of any one of claims 23-28, wherein the antibody comprises a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain, and a fifth polypeptide chain, such that the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising a first antigen binding site; the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising a second antigen binding site; the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a third antigen binding site, and wherein the identities of the first polypeptide chain, the second polypeptide chain, the third polypeptide chain, the fourth polypeptide chain, and the fifth polypeptide chain are selected from the group consisting of: (i) the first polypeptide chain comprises SEQ ID NO: 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; (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; (viii) the first polypeptide chain comprises a sequence encoded by the nucleic acid set forth in SEQ ID NO: 194, the second polypeptide chain comprises a sequence encoded by the nucleic acid set forth in SEQ ID NO: 188, the third polypeptide chain comprises a sequence encoded by the nucleic acid set forth in SEQ ID NO: 195, the fourth polypeptide chain comprises a sequence encoded by the nucleic acid set forth in SEQ ID NO: 187, and the fifth polypeptide chain comprises a sequence encoded by the nucleic acid set forth in SEQ ID NO: 122; and (ix) the first polypeptide chain comprises a sequence encoded by a nucleic acid corresponding to ATCC deposit PTA-127204, the second polypeptide chain comprises a sequence encoded by a nucleic acid corresponding to ATCC deposit PTA-127192, the third polypeptide chain comprises a sequence encoded by a nucleic acid corresponding to ATCC deposit PTA-127203, the fourth polypeptide chain comprises a sequence encoded by a nucleic acid corresponding to ATCC deposit PTA-127194, and the fifth polypeptide chain comprises a sequence encoded by a nucleic acid corresponding to ATCC deposit PTA-127193.

30. The antibody of claim 29, 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.

31. The antibody of any one of claims 1-30, wherein the antibody is characterized by one or more of the following: (i) a viscosity of less than 20 cP at a concentration of at least 100 mg / mL in 20 mM histidine, 8.5% sucrose, 0.05 mg / mL EDTA pH 6.0 buffer; (ii) a viscosity of less than 12 cP at a concentration of at least 50 mg / mL in 20 mM histidine, 8.5% sucrose, 0.05 mg / mL EDTA pH 6.0 buffer; (iii) a terminal half-life of at least 12 days in cynomolgus monkeys; (iv) a terminal half-life of at least 18 days in TG-32 mice; (v) the antibody binds to human IL-4 with an affinity constant of less than 220 pM, as measured by SPR; (vi) the antibody binds to human IL-13 with an affinity constant of less than 220 pM, as measured by SPR; (vii) the antibody binds to human IL-12 with an affinity constant of less than 130 pM, as measured by SPR; (viii) the antibody binds to human IL-23 with an affinity constant of less than 100 pM, as measured by SPR; (ix) the antibody binds human IL-4 with a binding affinity of less than 1 pM as measured by KinExA in an immobilized antigen assay in PBS; (x) the antibody binds cynomolgus monkey IL-13 with a binding affinity of less than 2 pM as measured by KinExA in an immobilized antigen assay in PBS; (xi) IC of IL-4-induced CD23 neutralization measured in human monocyte assay 50 Less than 12pM; (xii) IC of cynomolgus monkey IL-4 induced CD23 neutralization measured in human monocyte assay 50 Less than 12pM; (xiii) IC induced by cynomolgus monkey IL-13 for neutralization of CD23 measured in human monocyte assay 50 Less than 12pM; (xiv) IC of IL-13-induced CD23 neutralization measured in human monocyte assay 50 Less than 45pM; (xv) IC in human IL-12 and Kit-225 assays in human peripheral blood mononuclear cells 50 Less than 600pM; (xvi) IC in cynomolgus monkey IL-23Kit-225 neutralization assay in human peripheral blood mononuclear cells 50 Less than 2100pM; (xvii) IC in human IL-12 neutralization assay in human whole blood 50 Less than 400pM; (xviii) IC in cynomolgus monkey IL-23 neutralization assay in human whole blood 50 Less than 10000pM.

32. An antibody comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, a fourth polypeptide chain and a fifth polypeptide chain, such that (i) the second polypeptide chain and the fifth polypeptide chain together form a first Fab domain comprising a first antigen binding site; (ii) the second polypeptide chain and the fourth polypeptide chain together form a second Fab domain comprising a second antigen binding site; (iii) the first polypeptide chain and the third polypeptide chain together form a third Fab domain comprising a third antigen binding site; wherein the first polypeptide chain and the second polypeptide chain associate together to form an antibody comprising two arms: a double Fab arm comprising the first Fab domain and the second Fab domain, and a single Fab arm comprising the third Fab domain; and wherein: The first Fab comprises a first antigen-related VH (VH-1), a first antigen-related VL (VL-1), a first antigen-related CL (CL-1) and a first antigen-related CH1 (CH1-1), and wherein the C-terminus of VH-1 is covalently fused to the N-terminus of CH1-1 via a peptide bond, and wherein the C-terminus of VL-1 is covalently fused to the N-terminus of CL-1 via a peptide bond, and wherein the second Fab comprises a second antigen-related VH (VH-2), a second antigen-related VL (VL-2), a second antigen-related CL (CL-2), and a second antigen-related CH1 (CH1-2), and wherein the C-terminus of VH-2 is covalently fused to the N-terminus of CH1-2 via a peptide bond, and wherein the C-terminus of VL-2 is covalently fused to the N-terminus of CL-2 via a peptide bond, and wherein the third Fab comprises a third antigen-related VH (VH-3), a first antigen-related VL (VL-3), a first antigen-related CL (CL-3) and a first antigen-related CH1 (CH1-3), and wherein the C-terminus of VH-3 is covalently fused to the N-terminus of CH1-3 via a peptide bond, and wherein the C-terminus of VL-3 is covalently fused to the N-terminus of CL-3 via a peptide bond, and wherein the first polypeptide comprises (VH-3)-(CH1-3)-(first hinge)-(first CH2)-(first CH3) from N-terminus to C-terminus; the second polypeptide comprises (VL-1)-(CL-1)-(linker)-(VH-2)-(CH1-2)-(second hinge)-(second CH2)-(second CH3) from N-terminus to C-terminus; the third polypeptide comprises (VL-3)-(CL-3); the fourth polypeptide comprises (VL-2)-(CL-2); and the fifth polypeptide comprises (VH1)-(CL-1) from N-terminus to C-terminus.

33. The antibody according to any one of claims 1 to 32, comprising a first Fc chain and a second Fc chain, wherein the first Fc chain comprises, in order from N-terminus to C-terminus: a first hinge region, the first hinge region is connected to a first CH2 region, the first CH2 region is connected to a first CH3 region, and hereby, the second Fc chain comprises, in order from N-terminus to C-terminus: a second hinge region, the second hinge region is connected to a second CH2 region, the second CH2 region is connected to a second CH3 region, and wherein, The first hinge region and the second hinge region comprise a pair of sequences shown as SEQ ID NO:129 and SEQ ID NO:131, and the first CH3 region and the second CH3 region comprise one of the following two pairs of sequences: SEQ ID NO:124 and SEQ ID NO:127; or SEQ ID NO:147 and SEQ ID NO:

148.

34. The antibody of claim 33, wherein the first CH3 domain and the second CH3 domain each comprise different but complementary sequences, and the different but complementary sequences are selected from one of the following different but complementary sequence pairs: (vii) SEQ ID NO:111 and SEQ ID NO:106; (viii) SEQ ID NO:111 and SEQ ID NO:114; (ix) SEQ ID NO:114 and SEQ ID NO:117; (x) SEQ ID NO:124 and SEQ ID NO:127; (xi) SEQ ID NO: 139 and SEQ ID NO: 141; and (xii) SEQ ID NO:147 and SEQ ID NO:

148.

35. An antibody comprising an antibody Fc domain, wherein the antibody Fc domain comprises 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, and the amino acid modifications promote the association of the first Fc chain with the second Fc chain, characterized in that: (iii) the first Fc chain comprises D(H232)R and K(H440)R, and the second Fc chain comprises D(H232)E and L(H391)E; or (iv) the first Fc chain comprises D(H232)E and K(H440)R, and the second Fc chain comprises L(H391)R and D(H232)E.

36. An antibody according to any one of claims 1-35, comprising one or more sequences encoded by a nucleic acid as shown in a sequence selected from the group consisting of: SEQ ID NO: 187, SEQ ID NO: 188, SEQ ID NO: 189, SEQ ID NO: 190, SEQ ID NO: 191, SEQ ID NO: 192, SEQ ID NO: 103, SEQ ID NO: 194, SEQ ID NO: 195, SEQ ID NO: 198, SEQ ID NO: 199, SEQ ID NO: 200, SEQ ID NO: 210, SEQ ID NO: 202, SEQ ID NO: 203, SEQ ID NO: 204, SEQ ID NO: 205, SEQ ID NO: 206, SEQ ID NO: 207, SEQ ID NO: 217, SEQ ID NO: 218, SEQ ID NO: 219 and SEQ ID NO:

220.

37. The antibody of any one of claims 1-36, comprising one or more sequences encoded by a nucleic acid corresponding to an ATCC deposit selected from the group consisting of PTA-127192, PTA-127193, PTA-127194, PTA-127195, PTA-127196, PTA-127197, PTA-127198, PTA-127199, PTA-127200, PTA-127201, PTA-127202, PTA-127203, PTA-127204, PTA-127205, PTA-127206, PTA-127207, PTA-127208, PTA-127209, and PTA-127210.

38. The antibody according to any one of claims 1 to 37 for use as a medicament.

39. The antibody according to claim 38, wherein the use is for treating one or more selected from the group consisting of atopic dermatitis, asthma, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloid, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis and fungal keratitis, and non-alcoholic steatohepatitis (NASH).

40. The antibody according to any one of claims 1-39, wherein the use is for treating one or more selected from the group consisting of: cancer, bladder cancer, breast cancer, clear cell renal carcinoma, head / neck squamous cell carcinoma, lung squamous cell carcinoma, malignant melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, small cell lung cancer (SCLC), triple negative breast cancer, urothelial carcinoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid 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 leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), and small lymphocytic lymphoma (SLL).

41. The antibody of claim 40, wherein the use comprises a first anti-cancer therapeutic comprising an antibody according to any one of claims 1-34, and a second anti-cancer therapeutic 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 TLR 7 / 8 agonists, TLR9 agonists, bispecific anti-CD47 / anti-PD-L1 antibodies, and bispecific anti-P-cadherin / anti-CD3 antibodies, sasanlimab, BCD-100, camrelizumab, cemiplimab, genolimzumab, MEDI0680, nivolumab, pembrolizumab, sintilimab, spartalizumab, STI-A1110, tislelizumab, atezolizumab, durvalumab, BMS-936559 (MDX-1105), LY3300054, and TSR-042.

42. A pharmaceutical composition comprising a therapeutically effective amount of the antibody according to any one of claims 1-41 and a pharmaceutically acceptable carrier.

43. A method of treating one or more conditions selected from the group consisting of atopic dermatitis, asthma, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis and fungal keratitis, and nonalcoholic steatohepatitis (NASH), cancer, bladder cancer, breast cancer, clear cell renal carcinoma, head / neck squamous cell carcinoma, lung squamous cell cancer, 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 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 tumor, T cell / histiocyte-rich large B cell lymphoma, follicular lymphoma, Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL) and small lymphocytic lymphoma (SLL); the method comprises administering to the subject a therapeutically effective amount of the antibody according to any one of claims 1 to 41 or the pharmaceutical composition according to claim 42.

44. A medicament for treating one or more conditions selected from the group consisting of atopic dermatitis, asthma, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic sinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloid, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis and fungal keratitis, and non-alcoholic steatohepatitis (NASH), cancer, bladder cancer, breast cancer, clear cell renal carcinoma, head / neck squamous cell carcinoma, lung squamous cell carcinoma Malignant 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 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 ... B cell lymphoma, T cell / histiocyte-rich large B cell lymphoma, follicular lymphoma, Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL) and small lymphocytic lymphoma (SLL); the medicament comprises a therapeutically effective amount of the antibody according to any one of claims 1 to 41 or the pharmaceutical composition according to claim 42.

45. The antibody for use according to any one of claims 38-41, or the pharmaceutical composition according to claim 42, or the method of treatment according to claim 43, or the medicament according to claim 44, wherein the antibody, pharmaceutical composition or medicament is administered subcutaneously.

46. ​​An antibody for use according to any one of claims 38-41 or claim 45, or a pharmaceutical composition according to claim 42 or claim 45, or a method of treatment according to claim 43 or claim 45, or a medicament according to claim 44 or claim 45, wherein the antibody, pharmaceutical composition or medicament is administered approximately twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, twice a month, once a month, once every two months, once every three months or once every four months.

47. An isolated nucleic acid selected from the group consisting of: (i) encoding IL4-VH, IL4-VL, or both of an antibody that binds to IL-4, and 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; (ii) encoding a polypeptide carrying IL4-VH, a polypeptide carrying IL4-VL, or both, of an antibody that binds to IL-4, and 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; (iii) encoding IL4-VH, IL4-VL, or both of an antibody that binds to IL-4, and wherein the nucleic acid comprises: a nucleic acid sequence of a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127198, and a nucleic acid sequence of a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127197, or both; (iv) a polypeptide carrying IL4-VH, a polypeptide carrying IL4-VL, or both, encoding an antibody that binds to IL-4, and wherein the nucleic acid comprises: the nucleic acid sequence of a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127192, and the nucleic acid sequence of a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127194, or both; (v) IL13-VH, IL13-VL, or both encoding an antibody that binds to IL-13, and wherein the nucleic acid comprises: the nucleic acid sequence of SEQ ID NO: 198, the nucleic acid sequence of SEQ ID NO: 199, or both; (vi) encoding a polypeptide carrying IL13-VH, a polypeptide carrying IL13-VL, or both, of an antibody that binds to IL-13, and 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; (vii) IL13-VH, IL13-VL, or both encoding an antibody that binds to IL-13, and wherein the nucleic acid comprises: a nucleic acid sequence of a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127196, and a nucleic acid sequence of a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127195, or both; (viii) a polypeptide carrying IL13-VH, a polypeptide carrying IL13-VL, or both encoding an antibody that binds to IL-13, and wherein the nucleic acid comprises: the nucleic acid sequence of a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127193, and the nucleic acid sequence of a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127192, or both; (ix) TSLP-VH, TSLP-VL, or both encoding an antibody that binds to TSLP, and 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; (x) a polypeptide carrying TSLP-VH, a polypeptide carrying TSLP-VL, or both, encoding an antibody that binds to TSLP, and 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; (xi) TSLP-VH, TSLP-VL, or both encoding an antibody that binds to TSLP, and wherein the nucleic acid comprises: the nucleic acid sequence of SEQ ID NO: 204, the nucleic acid sequence of SEQ ID NO: 217, or both; (xii) a TSLP-VH, a TSLP-VL, or both encoding an antibody that binds to TSLP, and wherein the nucleic acid comprises: the nucleic acid sequence of SEQ ID NO: 204, the nucleic acid sequence of SEQ ID NO: 218, or both; (xiii) TSLP-VH, TSLP-VL, or both encoding an antibody that binds to TSLP, and wherein the nucleic acid comprises: a nucleic acid sequence of a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127200, and a nucleic acid sequence of a sequence encoded by a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127199, or both; (xiv) a TSLP-VH-carrying polypeptide, a TSLP-VL-carrying polypeptide, or both, encoding an antibody that binds to TSLP, and wherein the nucleic acid comprises: the nucleic acid sequence of a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127202, and the nucleic acid sequence of a plasmid deposited with the ATCC and having ATCC Accession No. PTA-127201, or both; (xv) a polypeptide carrying p40-VH, a polypeptide carrying p40-VL, or both, encoding an antibody that binds to p40, and wherein the nucleic acid comprises: the nucleic acid sequence of SEQ ID NO: 195, the nucleic acid sequence of SEQ ID NO: 194, or both; and (xvi) a polypeptide carrying p40-VH, a polypeptide carrying p40-VL, or both, encoding an antibody that binds to p40, and wherein the nucleic acid comprises: the nucleic acid sequence of a plasmid deposited with ATCC and having ATCC Accession No. PTA-127206, and the nucleic acid sequence of a plasmid deposited with ATCC and having ATCC Accession No. PTA-127205, or both.

48. A vector comprising the polynucleotide according to claim 47.

49. An isolated host cell comprising the polynucleotide of claim 47 or the vector of claim 48.

50. A method of producing an isolated antibody comprising culturing the host cell of claim 49 under conditions resulting in production of the antibody, and recovering the antibody.

51. The method of claim 50, wherein the isolated antibody is a heterotrimeric antibody comprising a dual Fab arm and a single Fab arm, wherein the dual Fab arm comprises a first Fab domain connected to a second Fab domain, the second Fab domain is connected to a first Fc domain, and the single Fab arm comprises a third Fab domain connected to a second Fc domain, and the method comprises: (i) a first preassembly step, wherein the dual-Fab arm is incubated in a first preassembly condition buffer at a temperature of 2-10° C., and wherein the pH of the first preassembly condition buffer is 1-3 units lower than the isoelectric point (pI) of the dual-Fab arm; as well as (ii) a second preassembly step, wherein the single Fab arm is incubated in a second preassembly condition buffer at a temperature of 2-10° C., and wherein the pH of the second preassembly condition buffer is 1-3 units lower than the isoelectric point (pI) of the single Fab arm; as well as (iii) A third assembly step, wherein the dual-Fab arms and the single-Fab arms from steps (i) and (ii) are mixed together in assembly buffer for 1-24 hours.

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