KLK5 / 7+TH2 targeted antibody and its use

Abstract

Aspects of this application provide bispecific antibodies and methods of using them for treating conditions such as Netherton syndrome, eosinophilic esophagitis, and atopic dermatitis, by promoting barrier function and reducing inflammation. In some embodiments, the bispecific antibody includes at least one antigen-specific binding site that specifically binds to KLK5 and KLK7, and at least one antigen-specific binding site that specifically binds to a Th2 cytokine (e.g., IL-13) or its receptor.

Description

[Technical Field]

[0001] Related applications This application claims priority under § 119(e) of the United States Patent Act to U.S. Provisional Application No. 63 / 578,959 filed on 25 August 2023 and U.S. Provisional Application No. 63 / 549,274 filed on 2 February 2024, the entire contents of which are incorporated herein by reference.

[0002] Reference to electronic sequence listings The contents of the electronic sequence listing (A140770003WO00-SEQ-LJG.xml, size: 744,871 bytes, and creation date: August 22, 2024) are incorporated herein by reference in their entirety. [Background technology]

[0003] The skin, comprising tissue structures and cells such as epithelial cells and immune cells, together provides a functional and physical barrier that plays a crucial role in preventing the penetration of allergens into the body and responding to pathogens. Kallikrein (KLK) enzymes support skin homeostasis and wound healing by regulating desquamation and innate immunity. In healthy skin, the outermost layer of the epidermis is regularly shed through a KLK-driven proteolytic cascade, resulting in the degradation of corneodesmosomes and desquamation. KLK5 is understood to be the major activator of this proteolytic cascade. Autoactivating KLK5 enzymatically converts pro-KLK7 and pro-KLK14 into their active forms, stimulating a positive feedback loop that leads to the production of more pro-KLK5 via KLK14. These KLK enzymes are inhibited by endogenous serine protease inhibitors, such as lymphoepithelial Cazal-type-associated inhibitors. Dysregulation of KLK, including KLK5 and KLK7, is associated with skin disorders, inflammatory diseases, and cancer. For example, hyperactive kallikrein 5 and 7 are responsible for both hereditary and spontaneous epidermal barrier disorders (e.g., Netherton syndrome, eosinophilic esophagitis, atopic dermatitis). [Overview of the project] [Means for solving the problem]

[0004] Certain aspects of this disclosure relate to the recognition that a loss of balance between endogenous KLK proteases and associated protease inhibitors can lead to barrier dysfunction, induce inflammation (as shown in Figure 1), and result in inflammatory conditions such as Netherton syndrome, eosinophilic esophagitis, and atopic dermatitis. Furthermore, increased activity of T helper 2 (Th2) cytokines (e.g., IL-13 and IL-4) may further drive inflammation and contribute to barrier dysfunction and related conditions (as shown in Figure 2). In some embodiments, compositions and methods provided herein are useful for improving barrier function, reducing inflammation, and improving disease severity by inhibiting KLK5 / KLK7 and Th2 cytokine (e.g., IL-13, IL-4, IL-5, IL-6, IL-9, IL-31, IL-17E (IL-25), OX40L, TSLP, etc.) signaling.

[0005] Furthermore, aspects of the present disclosure provide multispecific antibodies comprising at least one antigen-specific binding site that specifically binds to KLK5 and KLK7, and at least one antigen-specific binding site that specifically binds to a Th2 cytokine (e.g., IL-13, IL-4, IL-5, IL-6, IL-9, IL-31, IL-17E (IL-25), OX40L, TSLP, etc.) or its receptor. In certain embodiments, such multispecific antibodies are configured to include arms that bind to the active sites of KLK5 and KLK7, as well as arms that bind to a Th2 cytokine or its receptor. In some embodiments, such multispecific antibodies (e.g., bispecific antibodies) are advantageous because they inhibit both KLK5 / 7 activity and Th2 cytokine activity in a single molecule. In some embodiments, with respect to the KLK5 / 7 binding site within a multispecific antibody (e.g., bispecific antibody), such antibodies specifically bind to the active form of the enzyme, rather than to the proform of the enzyme.

[0006] In some embodiments, methods and related compositions, as well as antibodies for use in the methods, are provided that are useful for inhibiting KLK5 and KLK7 along with Th2 cytokine activity, for the purpose of improving barrier function, reducing inflammation, and thereby improving disease severity. In particular, aspects of the present disclosure provide a bispecific antibody in which one arm comprises an antigen-specific binding site of a dual inhibitory antibody targeting KLK5 and KLK7 (referred to as an anti-KLK5 / KLK7 antibody) having high binding affinity and specificity to the active sites of both KLK5 and KLK7, and the other arm specifically binds to a Th2 cytokine (e.g., IL-13, IL-4, IL-5, IL-6, IL-9, IL-31, IL-17E (IL-25), OX40L, TSLP, etc.) or its receptor (referred to as an anti-KLK5 / KLK7 + Th2 targeted bispecific antibody) and inhibits its activity. Accordingly, in some embodiments, the present disclosure provides methods and related antibody compositions for treating conditions associated with KLK5 and KLK7 dysregulation and / or abnormal Th2 cytokine activity, such as Netherton syndrome, atopic dermatitis (with and without filaggrin mutations), eosinophilic esophagitis, prurigo nodularis, chronic pruritus of unknown cause (CPUO), asthma (e.g., KLK5-associated asthma), and ichthyosis vulgaris.

[0007] In certain embodiments, the Disclosure provides a bispecific antibody comprising at least one antigen-specific binding site of a dual inhibitory antibody targeting KLK5 and KLK7, and at least one antigen-specific binding site that specifically binds to a Th2 cytokine (e.g., IL-13, IL-4, IL-5, IL-6, IL-9, IL-31, IL-17E (IL-25), OX40L, TSLP, etc.) or its receptor and inhibits Th2 cytokine signaling. In some embodiments, the Disclosure provides a bispecific antibody comprising at least one antigen-specific binding site of a dual inhibitory antibody targeting KLK5 and KLK7, and at least one antigen-specific binding site that specifically binds to and inhibits IL-13 (referred to as anti-KLK5 / KLK7+IL-13 targeting the bispecific antibody). In some embodiments, the Disclosure provides a bispecific antibody comprising at least one antigen-specific binding site of a dual inhibitory antibody targeting KLK5 and KLK7, and at least one antigen-specific binding site that specifically binds to and inhibits IL-4 (referred to as anti-KLK5 / KLK7+IL-4 targeting the bispecific antibody). Accordingly, in some embodiments, the Disclosure provides methods and related antibody compositions for treating conditions associated with KLK5 and KLK7 dysregulation, in which Th2 cytokines such as IL-13, IL-4, and others also play a role in the pathogenesis of conditions such as Netherton syndrome, atopic dermatitis (with and without filaggrin mutations), eosinophilic esophagitis, prurigo nodularis, chronic pruritus of unknown cause (CPUO), asthma (e.g., KLK5-associated asthma), and ichthyosis vulgaris.

[0008] In some embodiments, the disclosure provides a bispecific antibody comprising an antigen-specific binding site that specifically binds to KLK5 and KLK7, and an antigen-specific binding site that specifically binds to a Th2 cytokine or its receptor.

[0009] In some embodiments, antigen-specific binding sites that specifically bind to KLK5 and KLK7 bind to the active sites of KLK5 and KLK7, inhibiting enzyme activity. In some embodiments, antigen-specific binding sites that specifically bind to KLK5 and KLK7 include HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 of any one of the antibodies listed in Tables 1a and 1b. In some embodiments, antigen-specific binding sites that specifically bind to KLK5 and KLK7 include HC CDR1, HC CDR2, HC CDR3 of the heavy chain variable domain having the amino acid sequence of SEQ ID NO: 7, and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain having the amino acid sequence of SEQ ID NO: 8. In some embodiments, the antigen-specific binding sites that specifically bind to KLK5 and KLK7 include HC CDR1, HC CDR2, and HC CDR3, which are heavy chain variable domains having the amino acid sequence of SEQ ID NO: 13, and LC CDR1, LC CDR2, and LC CDR3, which are light chain variable domains having the amino acid sequence of SEQ ID NO: 14. In some embodiments, the antigen-specific binding sites that specifically bind to KLK5 and KLK7 include HC CDR1, HC CDR2, and HC CDR3, which are heavy chain variable domains having the amino acid sequence of SEQ ID NO: 17, and LC CDR1, LC CDR2, and LC CDR3, which are light chain variable domains having the amino acid sequence of SEQ ID NO: 14. In some embodiments, the antigen-specific binding sites that specifically bind to KLK5 and KLK7 include HC CDR1, HC CDR2, and HC CDR3, which are heavy chain variable domains having the amino acid sequence of SEQ ID NO: 21, and LC CDR1, LC CDR2, and LC CDR3, which are light chain variable domains having the amino acid sequence of SEQ ID NO: 14. In some embodiments, the antigen-specific binding sites that specifically bind to KLK5 and KLK7 include HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, HC CDR3 having the amino acid sequence of SEQ ID NO: 3, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 6.In some embodiments, the antigen-specific binding sites that specifically bind to KLK5 and KLK7 include HC CDR1 having the amino acid sequence of SEQ ID NO: 9, HC CDR2 having the amino acid sequence of SEQ ID NO: 10, HC CDR3 having the amino acid sequence of SEQ ID NO: 11, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, the antigen-specific binding sites that specifically bind to KLK5 and KLK7 include HC CDR1 having the amino acid sequence of SEQ ID NO: 9, HC CDR2 having the amino acid sequence of SEQ ID NO: 15, HC CDR3 having the amino acid sequence of SEQ ID NO: 16, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, the antigen-specific binding sites that specifically bind to KLK5 and KLK7 include HC CDR1 having the amino acid sequence of SEQ ID NO: 18, HC CDR2 having the amino acid sequence of SEQ ID NO: 19, HC CDR3 having the amino acid sequence of SEQ ID NO: 20, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, the bispecific antibody includes an antigen-specific binding site that specifically binds to KLK5, and KLK7 is the VH and / or VL of any one of the antibodies listed in Table 1a. In some embodiments, the antigen-specific binding sites that specifically bind to KLK5 and KLK7 include a VH containing the amino acid sequence of SEQ ID NO: 7 and a VL containing the amino acid sequence of SEQ ID NO: 8. In some embodiments, the antigen-specific binding sites that specifically bind to KLK5 and KLK7 include a VH containing the amino acid sequence of SEQ ID NO: 13 and a VL containing the amino acid sequence of SEQ ID NO: 14. In some embodiments, the antigen-specific binding site that specifically binds to KLK5 and KLK7 includes VH, which contains the amino acid sequence of SEQ ID NO: 17, and VL, which contains the amino acid sequence of SEQ ID NO: 14. In some embodiments, the antigen-specific binding site that specifically binds to KLK5 and KLK7 includes VH, which contains the amino acid sequence of SEQ ID NO: 21, and VL, which contains the amino acid sequence of SEQ ID NO: 14.

[0010] In some embodiments, the bispecific antibody includes an antigen-specific binding site that specifically binds to a Th2 cytokine or its receptor, comprising any one of the antibodies listed in Table 2: HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3.

[0011] In some embodiments, the Th2 cytokine is IL-13. In some embodiments, the bispecific antibody includes an antigen-specific binding site that specifically binds to IL-13 or IL-13R. In some embodiments, the antigen-specific binding site that specifically binds to IL-13 or IL-13R includes heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 53, and light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 54. In some embodiments, the antigen-specific binding site that specifically binds to IL-13 or IL-13R includes heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 32, and light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 33. In some embodiments, the antigen-specific binding site that specifically binds to IL-13 or IL-13R includes HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain having the amino acid sequence of SEQ ID NO: 74, and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain having the amino acid sequence of SEQ ID NO: 75. In some embodiments, the antigen-specific binding site that specifically binds to IL-13 or IL-13R includes HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain having the amino acid sequence of SEQ ID NO: 94, and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain having the amino acid sequence of SEQ ID NO: 95. In some embodiments, the antigen-specific binding site that specifically binds to IL-13 or IL-13R includes HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain having the amino acid sequence of SEQ ID NO: 114, and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain having the amino acid sequence of SEQ ID NO: 115.In some embodiments, the antigen-specific binding site that specifically binds to IL-13 or IL-13R includes HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain having the amino acid sequence of SEQ ID NO: 134, and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain having the amino acid sequence of SEQ ID NO: 135. In some embodiments, the antigen-specific binding site that specifically binds to IL-13 or IL-13R includes HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain having the amino acid sequence of SEQ ID NO: 657, and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain having the amino acid sequence of SEQ ID NO: 658. In some embodiments, the antigen-specific binding site that specifically binds to IL-13 or IL-13R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 55, HC CDR2 having the amino acid sequence of SEQ ID NO: 56, HC CDR3 having the amino acid sequence of SEQ ID NO: 57, LC CDR1 having the amino acid sequence of SEQ ID NO: 58, LC CDR2 having the amino acid sequence of SEQ ID NO: 59, and LC CDR3 having the amino acid sequence of SEQ ID NO: 60. In some embodiments, the antigen-specific binding site that specifically binds to IL-13 or IL-13R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 61, HC CDR2 having the amino acid sequence of SEQ ID NO: 62, HC CDR3 having the amino acid sequence of SEQ ID NO: 63, LC CDR1 having the amino acid sequence of SEQ ID NO: 64, LC CDR2 having the amino acid sequence of SEQ ID NO: 65, and LC CDR3 having the amino acid sequence of SEQ ID NO: 66. In some embodiments, the antigen-specific binding sites that specifically bind to IL-13 or IL-13R include HC CDR1 having the amino acid sequence of SEQ ID NO: 67, HC CDR2 having the amino acid sequence of SEQ ID NO: 68, HC CDR3 having the amino acid sequence of SEQ ID NO: 69, LC CDR1 having the amino acid sequence of SEQ ID NO: 70, LC CDR2 having the amino acid sequence of SEQ ID NO: 71, and LC CDR3 having the amino acid sequence of SEQ ID NO: 72.In some embodiments, the antigen-specific binding site that specifically binds to IL-13 or IL-13R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 34, HC CDR2 having the amino acid sequence of SEQ ID NO: 35, HC CDR3 having the amino acid sequence of SEQ ID NO: 36, LC CDR1 having the amino acid sequence of SEQ ID NO: 37, LC CDR2 having the amino acid sequence of SEQ ID NO: 38, and LC CDR3 having the amino acid sequence of SEQ ID NO: 39. In some embodiments, the antigen-specific binding site that specifically binds to IL-13 or IL-13R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 40, HC CDR2 having the amino acid sequence of SEQ ID NO: 41, HC CDR3 having the amino acid sequence of SEQ ID NO: 42, LC CDR1 having the amino acid sequence of SEQ ID NO: 43, LC CDR2 having the amino acid sequence of SEQ ID NO: 44, and LC CDR3 having the amino acid sequence of SEQ ID NO: 45. In some embodiments, the antigen-specific binding site that specifically binds to IL-13 or IL-13R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 46, HC CDR2 having the amino acid sequence of SEQ ID NO: 47, HC CDR3 having the amino acid sequence of SEQ ID NO: 48, LC CDR1 having the amino acid sequence of SEQ ID NO: 49, LC CDR2 having the amino acid sequence of SEQ ID NO: 50, and LC CDR3 having the amino acid sequence of SEQ ID NO: 51. In some embodiments, the antigen-specific binding site that specifically binds to IL-13 or IL-13R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 76, HC CDR2 having the amino acid sequence of SEQ ID NO: 77, HC CDR3 having the amino acid sequence of SEQ ID NO: 78, LC CDR1 having the amino acid sequence of SEQ ID NO: 79, LC CDR2 having the amino acid sequence of SEQ ID NO: 80, and LC CDR3 having the amino acid sequence of SEQ ID NO: 81. In some embodiments, the antigen-specific binding sites that specifically bind to IL-13 or IL-13R include HC CDR1 having the amino acid sequence of SEQ ID NO: 82, HC CDR2 having the amino acid sequence of SEQ ID NO: 83, HC CDR3 having the amino acid sequence of SEQ ID NO: 84, LC CDR1 having the amino acid sequence of SEQ ID NO: 85, LC CDR2 having the amino acid sequence of SEQ ID NO: 86, and LC CDR3 having the amino acid sequence of SEQ ID NO: 87.In some embodiments, the antigen-specific binding site that specifically binds to IL-13 or IL-13R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 88, HC CDR2 having the amino acid sequence of SEQ ID NO: 89, HC CDR3 having the amino acid sequence of SEQ ID NO: 90, LC CDR1 having the amino acid sequence of SEQ ID NO: 91, LC CDR2 having the amino acid sequence of SEQ ID NO: 92, and LC CDR3 having the amino acid sequence of SEQ ID NO: 93. In some embodiments, the antigen-specific binding site that specifically binds to IL-13 or IL-13R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 96, HC CDR2 having the amino acid sequence of SEQ ID NO: 97, HC CDR3 having the amino acid sequence of SEQ ID NO: 98, LC CDR1 having the amino acid sequence of SEQ ID NO: 99, LC CDR2 having the amino acid sequence of SEQ ID NO: 100, and LC CDR3 having the amino acid sequence of SEQ ID NO: 101. In some embodiments, the antigen-specific binding site that specifically binds to IL-13 or IL-13R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 102, HC CDR2 having the amino acid sequence of SEQ ID NO: 103, HC CDR3 having the amino acid sequence of SEQ ID NO: 104, LC CDR1 having the amino acid sequence of SEQ ID NO: 105, LC CDR2 having the amino acid sequence of SEQ ID NO: 106, and LC CDR3 having the amino acid sequence of SEQ ID NO: 107. In some embodiments, the antigen-specific binding site that specifically binds to IL-13 or IL-13R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 108, HC CDR2 having the amino acid sequence of SEQ ID NO: 109, HC CDR3 having the amino acid sequence of SEQ ID NO: 110, LC CDR1 having the amino acid sequence of SEQ ID NO: 111, LC CDR2 having the amino acid sequence of SEQ ID NO: 112, and LC CDR3 having the amino acid sequence of SEQ ID NO: 113.In some embodiments, the antigen-specific binding site that specifically binds to IL-13 or IL-13R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 116, HC CDR2 having the amino acid sequence of SEQ ID NO: 117, HC CDR3 having the amino acid sequence of SEQ ID NO: 118, LC CDR1 having the amino acid sequence of SEQ ID NO: 119, LC CDR2 having the amino acid sequence of SEQ ID NO: 120, and LC CDR3 having the amino acid sequence of SEQ ID NO: 121. In some embodiments, the antigen-specific binding site that specifically binds to IL-13 or IL-13R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 122, HC CDR2 having the amino acid sequence of SEQ ID NO: 123, HC CDR3 having the amino acid sequence of SEQ ID NO: 124, LC CDR1 having the amino acid sequence of SEQ ID NO: 125, LC CDR2 having the amino acid sequence of SEQ ID NO: 126, and LC CDR3 having the amino acid sequence of SEQ ID NO: 127. In some embodiments, the antigen-specific binding site that specifically binds to IL-13 or IL-13R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 128, HC CDR2 having the amino acid sequence of SEQ ID NO: 129, HC CDR3 having the amino acid sequence of SEQ ID NO: 130, LC CDR1 having the amino acid sequence of SEQ ID NO: 131, LC CDR2 having the amino acid sequence of SEQ ID NO: 132, and LC CDR3 having the amino acid sequence of SEQ ID NO: 133. In some embodiments, the antigen-specific binding site that specifically binds to IL-13 or IL-13R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 136, HC CDR2 having the amino acid sequence of SEQ ID NO: 137, HC CDR3 having the amino acid sequence of SEQ ID NO: 138, LC CDR1 having the amino acid sequence of SEQ ID NO: 139, LC CDR2 having the amino acid sequence of SEQ ID NO: 140, and LC CDR3 having the amino acid sequence of SEQ ID NO: 141.In some embodiments, the antigen-specific binding site that specifically binds to IL-13 or IL-13R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 142, HC CDR2 having the amino acid sequence of SEQ ID NO: 143, HC CDR3 having the amino acid sequence of SEQ ID NO: 144, LC CDR1 having the amino acid sequence of SEQ ID NO: 145, LC CDR2 having the amino acid sequence of SEQ ID NO: 146, and LC CDR3 having the amino acid sequence of SEQ ID NO: 147. In some embodiments, the antigen-specific binding site that specifically binds to IL-13 or IL-13R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 148, HC CDR2 having the amino acid sequence of SEQ ID NO: 149, HC CDR3 having the amino acid sequence of SEQ ID NO: 150, LC CDR1 having the amino acid sequence of SEQ ID NO: 151, LC CDR2 having the amino acid sequence of SEQ ID NO: 152, and LC CDR3 having the amino acid sequence of SEQ ID NO: 153. In some embodiments, the antigen-specific binding sites that specifically bind to IL-13 or IL-13R include HC CDR1 having the amino acid sequence of SEQ ID NO: 655, HC CDR2 having the amino acid sequence of SEQ ID NO: 41, HC CDR3 having the amino acid sequence of SEQ ID NO: 42, LC CDR1 having the amino acid sequence of SEQ ID NO: 43, LC CDR2 having the amino acid sequence of SEQ ID NO: 44, and LC CDR3 having the amino acid sequence of SEQ ID NO: 45. In some embodiments, the antigen-specific binding sites that specifically bind to IL-13 or IL-13R include HC CDR1 having the amino acid sequence of SEQ ID NO: 656, HC CDR2 having the amino acid sequence of SEQ ID NO: 47, HC CDR3 having the amino acid sequence of SEQ ID NO: 48, and SEQ ID NO: 49. The antigen-specific binding sites include LC CDR1 having an amino acid sequence, LC CDR2 having the amino acid sequence of SEQ ID NO: 50, and LC CDR3 having the amino acid sequence of SEQ ID NO: 51. In some embodiments, the antigen-specific binding sites that specifically bind to IL-13 or IL-13R include VH containing the amino acid sequence of SEQ ID NO: 53, and VL containing the amino acid sequence of SEQ ID NO: 54. In some embodiments, the antigen-specific binding sites that specifically bind to IL-13 or IL-13R include VH containing the amino acid sequence of SEQ ID NO: 32, and VL containing the amino acid sequence of SEQ ID NO: 33. In some embodiments, the antigen-specific binding sites that specifically bind to IL-13 or IL-13R include VH containing the amino acid sequence of SEQ ID NO: 74, and VL containing the amino acid sequence of SEQ ID NO: 75. In some embodiments, the antigen-specific binding sites that specifically bind to IL-13 or IL-13R include VH containing the amino acid sequence of SEQ ID NO: 94, and VL containing the amino acid sequence of SEQ ID NO: 95. In some embodiments, the antigen-specific binding site that specifically binds to IL-13 or IL-13R includes VH containing the amino acid sequence of SEQ ID NO: 114 and VL containing the amino acid sequence of SEQ ID NO: 115. In some embodiments, the antigen-specific binding site that specifically binds to IL-13 or IL-13R includes VH containing the amino acid sequence of SEQ ID NO: 134 and VL containing the amino acid sequence of SEQ ID NO: 135. In some embodiments, the antigen-specific binding site that specifically binds to IL-13 or IL-13R includes VH containing the amino acid sequence of SEQ ID NO: 657 and VL containing the amino acid sequence of SEQ ID NO: 658.

[0012] In some embodiments, the bispecific antibody targets IL-4 or IL-4R. In some embodiments, the antigen-specific binding site that specifically binds to IL-4 or IL-4R includes heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 154, and light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 155. In some embodiments, the antigen-specific binding site that specifically binds to IL-4 or IL-4R includes heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 174, and light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 175. In some embodiments, the antigen-specific binding site that specifically binds to IL-4 or IL-4R includes HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain having the amino acid sequence of SEQ ID NO: 194, and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain having the amino acid sequence of SEQ ID NO: 195. In some embodiments, the antigen-specific binding site that specifically binds to IL-4 or IL-4R includes HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain having the amino acid sequence of SEQ ID NO: 214, and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain having the amino acid sequence of SEQ ID NO: 215. In some embodiments, the antigen-specific binding site that specifically binds to IL-4 or IL-4R includes HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain having the amino acid sequence of SEQ ID NO: 234, and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain having the amino acid sequence of SEQ ID NO: 235. In some embodiments, the antigen-specific binding site that specifically binds to IL-4 or IL-4R includes heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 254, and light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 255.In some embodiments, the antigen-specific binding site that specifically binds to IL-4 or IL-4R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 156, HC CDR2 having the amino acid sequence of SEQ ID NO: 157, HC CDR3 having the amino acid sequence of SEQ ID NO: 158, LC CDR1 having the amino acid sequence of SEQ ID NO: 159, LC CDR2 having the amino acid sequence of SEQ ID NO: 160, and LC CDR3 having the amino acid sequence of SEQ ID NO: 161. In some embodiments, the antigen-specific binding site that specifically binds to IL-4 or IL-4R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 162, HC CDR2 having the amino acid sequence of SEQ ID NO: 163, HC CDR3 having the amino acid sequence of SEQ ID NO: 164, LC CDR1 having the amino acid sequence of SEQ ID NO: 165, LC CDR2 having the amino acid sequence of LGS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 167. In some embodiments, the antigen-specific binding site that specifically binds to IL-4 or IL-4R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 168, HC CDR2 having the amino acid sequence of SEQ ID NO: 169, HC CDR3 having the amino acid sequence of SEQ ID NO: 170, LC CDR1 having the amino acid sequence of SEQ ID NO: 171, LC CDR2 having the amino acid sequence of SEQ ID NO: 172, and LC CDR3 having the amino acid sequence of SEQ ID NO: 173. In some embodiments, the antigen-specific binding site that specifically binds to IL-4 or IL-4R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 176, HC CDR2 having the amino acid sequence of SEQ ID NO: 177, HC CDR3 having the amino acid sequence of SEQ ID NO: 178, LC CDR1 having the amino acid sequence of SEQ ID NO: 179, LC CDR2 having the amino acid sequence of SEQ ID NO: 180, and LC CDR3 having the amino acid sequence of SEQ ID NO: 181.In some embodiments, the antigen-specific binding site that specifically binds to IL-4 or IL-4R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 182, HC CDR2 having the amino acid sequence of SEQ ID NO: 183, HC CDR3 having the amino acid sequence of SEQ ID NO: 184, LC CDR1 having the amino acid sequence of SEQ ID NO: 185, LC CDR2 having the amino acid sequence of AAS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 187. In some embodiments, the antigen-specific binding site that specifically binds to IL-4 or IL-4R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 188, HC CDR2 having the amino acid sequence of SEQ ID NO: 189, HC CDR3 having the amino acid sequence of SEQ ID NO: 190, LC CDR1 having the amino acid sequence of SEQ ID NO: 191, LC CDR2 having the amino acid sequence of SEQ ID NO: 192, and LC CDR3 having the amino acid sequence of SEQ ID NO: 193. In some embodiments, the antigen-specific binding site that specifically binds to IL-4 or IL-4R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 196, HC CDR2 having the amino acid sequence of SEQ ID NO: 197, HC CDR3 having the amino acid sequence of SEQ ID NO: 198, LC CDR1 having the amino acid sequence of SEQ ID NO: 199, LC CDR2 having the amino acid sequence of SEQ ID NO: 200, and LC CDR3 having the amino acid sequence of SEQ ID NO: 201. In some embodiments, the antigen-specific binding site that specifically binds to IL-4 or IL-4R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 202, HC CDR2 having the amino acid sequence of SEQ ID NO: 203, HC CDR3 having the amino acid sequence of SEQ ID NO: 204, LC CDR1 having the amino acid sequence of SEQ ID NO: 205, LC CDR2 having the amino acid sequence of SEQ ID NO: 206, and LC CDR3 having the amino acid sequence of SEQ ID NO: 207.In some embodiments, the antigen-specific binding sites that specifically bind to IL-4 or IL-4R include HC CDR1 having the amino acid sequence of SEQ ID NO: 208, HC CDR2 having the amino acid sequence of SEQ ID NO: 209, HC CDR3 having the amino acid sequence of SEQ ID NO: 210, LC CDR1 having the amino acid sequence of SEQ ID NO: 211, LC CDR2 having the amino acid sequence of GAS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 213. In some embodiments, the antigen-specific binding sites that specifically bind to IL-4 or IL-4R include HC CDR1 having the amino acid sequence of SEQ ID NO: 216, HC CDR2 having the amino acid sequence of SEQ ID NO: 217, HC CDR3 having the amino acid sequence of SEQ ID NO: 218, LC CDR1 having the amino acid sequence of SEQ ID NO: 219, LC CDR2 having the amino acid sequence of SEQ ID NO: 220, and LC CDR3 having the amino acid sequence of SEQ ID NO: 221. In some embodiments, the antigen-specific binding sites that specifically bind to IL-4 or IL-4R include HC CDR1 having the amino acid sequence of SEQ ID NO: 222, HC CDR2 having the amino acid sequence of SEQ ID NO: 223, HC CDR3 having the amino acid sequence of SEQ ID NO: 224, LC CDR1 having the amino acid sequence of SEQ ID NO: 225, LC CDR2 having the amino acid sequence of YTS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 227. In some embodiments, the antigen-specific binding sites that specifically bind to IL-4 or IL-4R include HC CDR1 having the amino acid sequence of SEQ ID NO: 228, HC CDR2 having the amino acid sequence of SEQ ID NO: 229, HC CDR3 having the amino acid sequence of SEQ ID NO: 230, LC CDR1 having the amino acid sequence of SEQ ID NO: 231, LC CDR2 having the amino acid sequence of SEQ ID NO: 232, and LC CDR3 having the amino acid sequence of SEQ ID NO: 233.In some embodiments, the antigen-specific binding site that specifically binds to IL-4 or IL-4R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 236, HC CDR2 having the amino acid sequence of SEQ ID NO: 237, HC CDR3 having the amino acid sequence of SEQ ID NO: 238, LC CDR1 having the amino acid sequence of SEQ ID NO: 239, LC CDR2 having the amino acid sequence of SEQ ID NO: 240, and LC CDR3 having the amino acid sequence of SEQ ID NO: 241. In some embodiments, the antigen-specific binding site that specifically binds to IL-4 or IL-4R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 242, HC CDR2 having the amino acid sequence of SEQ ID NO: 243, HC CDR3 having the amino acid sequence of SEQ ID NO: 244, LC CDR1 having the amino acid sequence of SEQ ID NO: 245, LC CDR2 having the amino acid sequence of SEQ ID NO: 246, and LC CDR3 having the amino acid sequence of SEQ ID NO: 247. In some embodiments, the antigen-specific binding site that specifically binds to IL-4 or IL-4R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 248, HC CDR2 having the amino acid sequence of SEQ ID NO: 249, HC CDR3 having the amino acid sequence of SEQ ID NO: 250, LC CDR1 having the amino acid sequence of SEQ ID NO: 251, LC CDR2 having the amino acid sequence of SEQ ID NO: 252, and LC CDR3 having the amino acid sequence of SEQ ID NO: 253. In some embodiments, the antigen-specific binding site that specifically binds to IL-4 or IL-4R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 256, HC CDR2 having the amino acid sequence of SEQ ID NO: 257, HC CDR3 having the amino acid sequence of SEQ ID NO: 258, LC CDR1 having the amino acid sequence of SEQ ID NO: 259, LC CDR2 having the amino acid sequence of SEQ ID NO: 260, and LC CDR3 having the amino acid sequence of SEQ ID NO: 261.In some embodiments, the antigen-specific binding site that specifically binds to IL-4 or IL-4R comprises HC CDR1 having the amino acid sequence of SEQ ID NO: 262, HC CDR2 having the amino acid sequence of SEQ ID NO: 263, HC CDR3 having the amino acid sequence of SEQ ID NO: 264, LC CDR1 having the amino acid sequence of SEQ ID NO: 265, LC CDR2 having the amino acid sequence of SEQ ID NO: 267, and LC CDR3 having the amino acid sequence of SEQ ID NO: 268. In some embodiments, the antigen-specific binding site that specifically binds to IL-4 or IL-4R comprises HC CDR1 having the amino acid sequence of SEQ ID NO: 269, HC CDR2 having the amino acid sequence of SEQ ID NO: 270, HC CDR3 having the amino acid sequence of SEQ ID NO: 271, LC CDR1 having the amino acid sequence of SEQ ID NO: 272, LC CDR2 having the amino acid sequence of SAS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 274. In some embodiments, the antigen-specific binding site that specifically binds to IL-4 or IL-4R comprises VH comprising the amino acid sequence of SEQ ID NO: 154 and VL comprising the amino acid sequence of SEQ ID NO: 155. In some embodiments, the antigen-specific binding site that specifically binds to IL-4 or IL-4R comprises VH comprising the amino acid sequence of SEQ ID NO: 174 and VL comprising the amino acid sequence of SEQ ID NO: 175. In some embodiments, the antigen-specific binding site that specifically binds to IL-4 or IL-4R comprises VH comprising the amino acid sequence of SEQ ID NO: 194 and VL comprising the amino acid sequence of SEQ ID NO: 195. In some embodiments, the antigen-specific binding site that specifically binds to IL-4 or IL-4R comprises VH comprising the amino acid sequence of SEQ ID NO: 214 and VL comprising the amino acid sequence of SEQ ID NO: 215. In some embodiments, the antigen-specific binding site that specifically binds to IL-4 or IL-4R comprises VH comprising the amino acid sequence of SEQ ID NO: 234 and VL comprising the amino acid sequence of SEQ ID NO: 235. In some embodiments, the antigen-specific binding site that specifically binds to IL-4 or IL-4R comprises VH comprising the amino acid sequence of SEQ ID NO: 254 and VL comprising the amino acid sequence of SEQ ID NO: 255.

[0013] In some embodiments, the bispecific antibody targets IL-5 or IL-5R. In some embodiments, the antigen-specific binding site that specifically binds to IL-5 or IL-5R includes heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 275, and light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the antigen-specific binding site that specifically binds to IL-5 or IL-5R includes heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 295, and light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 296. In some embodiments, the antigen-specific binding site that specifically binds to IL-5 or IL-5R includes HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain having the amino acid sequence of SEQ ID NO: 315, and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain having the amino acid sequence of SEQ ID NO: 316. In some embodiments, the antigen-specific binding site that specifically binds to IL-5 or IL-5R includes HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain having the amino acid sequence of SEQ ID NO: 335, and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain having the amino acid sequence of SEQ ID NO: 336. In some embodiments, the antigen-specific binding site that specifically binds to IL-5 or IL-5R includes HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain having the amino acid sequence of SEQ ID NO: 355, and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain having the amino acid sequence of SEQ ID NO: 356. In some embodiments, the antigen-specific binding site that specifically binds to IL-5 or IL-5R includes heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 375, and light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 376.In some embodiments, the antigen-specific binding site that specifically binds to IL-5 or IL-5R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 277, HC CDR2 having the amino acid sequence of SEQ ID NO: 278, HC CDR3 having the amino acid sequence of SEQ ID NO: 279, LC CDR1 having the amino acid sequence of SEQ ID NO: 280, LC CDR2 having the amino acid sequence of SEQ ID NO: 281, and LC CDR3 having the amino acid sequence of SEQ ID NO: 282. In some embodiments, the antigen-specific binding site that specifically binds to IL-5 or IL-5R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 283, HC CDR2 having the amino acid sequence of SEQ ID NO: 284, HC CDR3 having the amino acid sequence of SEQ ID NO: 285, LC CDR1 having the amino acid sequence of SEQ ID NO: 286, LC CDR2 having the amino acid sequence of SEQ ID NO: 287, and LC CDR3 having the amino acid sequence of SEQ ID NO: 288. In some embodiments, the antigen-specific binding site that specifically binds to IL-5 or IL-5R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 289, HC CDR2 having the amino acid sequence of SEQ ID NO: 290, HC CDR3 having the amino acid sequence of SEQ ID NO: 291, LC CDR1 having the amino acid sequence of SEQ ID NO: 292, LC CDR2 having the amino acid sequence of SEQ ID NO: 293, and LC CDR3 having the amino acid sequence of SEQ ID NO: 294. In some embodiments, the antigen-specific binding site that specifically binds to IL-5 or IL-5R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 297, HC CDR2 having the amino acid sequence of SEQ ID NO: 298, HC CDR3 having the amino acid sequence of SEQ ID NO: 299, LC CDR1 having the amino acid sequence of SEQ ID NO: 300, LC CDR2 having the amino acid sequence of SEQ ID NO: 301, and LC CDR3 having the amino acid sequence of SEQ ID NO: 302.In some embodiments, the antigen-specific binding sites that specifically bind to IL-5 or IL-5R include HC CDR1 having the amino acid sequence of SEQ ID NO: 303, HC CDR2 having the amino acid sequence of SEQ ID NO: 304, HC CDR3 having the amino acid sequence of SEQ ID NO: 305, LC CDR1 having the amino acid sequence of SEQ ID NO: 306, LC CDR2 having the amino acid sequence of GAS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 308. In some embodiments, the antigen-specific binding sites that specifically bind to IL-5 or IL-5R include HC CDR1 having the amino acid sequence of SEQ ID NO: 309, HC CDR2 having the amino acid sequence of SEQ ID NO: 310, HC CDR3 having the amino acid sequence of SEQ ID NO: 311, LC CDR1 having the amino acid sequence of SEQ ID NO: 312, LC CDR2 having the amino acid sequence of SEQ ID NO: 313, and LC CDR3 having the amino acid sequence of SEQ ID NO: 314. In some embodiments, antigen-specific binding sites that specifically bind to IL-5 or IL-5R include HC CDR1 having the amino acid sequence of SEQ ID NO: 317, HC CDR2 having the amino acid sequence of SEQ ID NO: 318, HC CDR3 having the amino acid sequence of SEQ ID NO: 319, LC CDR1 having the amino acid sequence of SEQ ID NO: 320, LC CDR2 having the amino acid sequence of SEQ ID NO: 321, and LC CDR3 having the amino acid sequence of SEQ ID NO: 322. In some embodiments, antigen-specific binding sites that specifically bind to IL-5 or IL-5R include HC CDR1 having the amino acid sequence of SEQ ID NO: 323, HC CDR2 having the amino acid sequence of SEQ ID NO: 324, HC CDR3 having the amino acid sequence of SEQ ID NO: 325, LC CDR1 having the amino acid sequence of SEQ ID NO: 326, LC CDR2 having the amino acid sequence of GAN, and LC CDR3 having the amino acid sequence of SEQ ID NO: 328.In some embodiments, the antigen-specific binding site that specifically binds to IL-5 or IL-5R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 329, HC CDR2 having the amino acid sequence of SEQ ID NO: 330, HC CDR3 having the amino acid sequence of SEQ ID NO: 331, LC CDR1 having the amino acid sequence of SEQ ID NO: 332, LC CDR2 having the amino acid sequence of SEQ ID NO: 333, and LC CDR3 having the amino acid sequence of SEQ ID NO: 334. In some embodiments, the antigen-specific binding site that specifically binds to IL-5 or IL-5R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 337, HC CDR2 having the amino acid sequence of SEQ ID NO: 338, HC CDR3 having the amino acid sequence of SEQ ID NO: 339, LC CDR1 having the amino acid sequence of SEQ ID NO: 340, LC CDR2 having the amino acid sequence of SEQ ID NO: 341, and LC CDR3 having the amino acid sequence of SEQ ID NO: 342. In some embodiments, the antigen-specific binding sites that specifically bind to IL-5 or IL-5R include HC CDR1 having the amino acid sequence of SEQ ID NO: 343, HC CDR2 having the amino acid sequence of SEQ ID NO: 344, HC CDR3 having the amino acid sequence of SEQ ID NO: 345, LC CDR1 having the amino acid sequence of SEQ ID NO: 346, LC CDR2 having the amino acid sequence of G, and LC CDR3 having the amino acid sequence of SEQ ID NO: 348. In some embodiments, the antigen-specific binding sites that specifically bind to IL-5 or IL-5R include HC CDR1 having the amino acid sequence of SEQ ID NO: 349, HC CDR2 having the amino acid sequence of SEQ ID NO: 350, HC CDR3 having the amino acid sequence of SEQ ID NO: 351, LC CDR1 having the amino acid sequence of SEQ ID NO: 352, LC CDR2 having the amino acid sequence of SEQ ID NO: 353, and LC CDR3 having the amino acid sequence of SEQ ID NO: 354.In some embodiments, the antigen-specific binding sites that specifically bind to IL-5 or IL-5R include HC CDR1 having the amino acid sequence of SEQ ID NO: 357, HC CDR2 having the amino acid sequence of SEQ ID NO: 358, HC CDR3 having the amino acid sequence of SEQ ID NO: 359, LC CDR1 having the amino acid sequence of SEQ ID NO: 360, LC CDR2 having the amino acid sequence of SEQ ID NO: 361, and LC CDR3 having the amino acid sequence of SEQ ID NO: 362. In some embodiments, the antigen-specific binding sites that specifically bind to IL-5 or IL-5R include HC CDR1 having the amino acid sequence of SEQ ID NO: 363, HC CDR2 having the amino acid sequence of SEQ ID NO: 364, HC CDR3 having the amino acid sequence of SEQ ID NO: 365, LC CDR1 having the amino acid sequence of SEQ ID NO: 366, LC CDR2 having the amino acid sequence of RAD, and LC CDR3 having the amino acid sequence of SEQ ID NO: 368. In some embodiments, the antigen-specific binding site that specifically binds to IL-5 or IL-5R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 369, HC CDR2 having the amino acid sequence of SEQ ID NO: 370, HC CDR3 having the amino acid sequence of SEQ ID NO: 371, LC CDR1 having the amino acid sequence of SEQ ID NO: 372, LC CDR2 having the amino acid sequence of SEQ ID NO: 373, and LC CDR3 having the amino acid sequence of SEQ ID NO: 374. In some embodiments, the antigen-specific binding site that specifically binds to IL-5 or IL-5R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 377, HC CDR2 having the amino acid sequence of SEQ ID NO: 378, HC CDR3 having the amino acid sequence of SEQ ID NO: 379, LC CDR1 having the amino acid sequence of SEQ ID NO: 380, LC CDR2 having the amino acid sequence of SEQ ID NO: 381, and LC CDR3 having the amino acid sequence of SEQ ID NO: 382.In some embodiments, antigen-specific binding sites that specifically bind to IL-5 or IL-5R include HC CDR1 having the amino acid sequence of SEQ ID NO: 383, HC CDR2 having the amino acid sequence of SEQ ID NO: 384, HC CDR3 having the amino acid sequence of SEQ ID NO: 385, LC CDR1 having the amino acid sequence of SEQ ID NO: 386, LC CDR2 having the amino acid sequence of AAS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 388. In some embodiments, antigen-specific binding sites that specifically bind to IL-5 or IL-5R include HC CDR1 having the amino acid sequence of SEQ ID NO: 389, HC CDR2 having the amino acid sequence of SEQ ID NO: 390, HC CDR3 having the amino acid sequence of SEQ ID NO: 391, LC CDR1 having the amino acid sequence of SEQ ID NO: 392, LC CDR2 having the amino acid sequence of SEQ ID NO: 393, and LC CDR3 having the amino acid sequence of SEQ ID NO: 394. In some embodiments, antigen-specific binding sites that specifically bind to IL-5 or IL-5R include VH having the amino acid sequence of SEQ ID NO: 275, and VL having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the antigen-specific binding site that specifically binds to IL-5 or IL-5R includes VH containing the amino acid sequence of SEQ ID NO: 295 and VL containing the amino acid sequence of SEQ ID NO: 296. In some embodiments, the antigen-specific binding site that specifically binds to IL-5 or IL-5R includes VH containing the amino acid sequence of SEQ ID NO: 315 and VL containing the amino acid sequence of SEQ ID NO: 316. In some embodiments, the antigen-specific binding site that specifically binds to IL-5 or IL-5R includes VH containing the amino acid sequence of SEQ ID NO: 335 and VL containing the amino acid sequence of SEQ ID NO: 336. In some embodiments, the antigen-specific binding site that specifically binds to IL-5 or IL-5R includes VH containing the amino acid sequence of SEQ ID NO: 355 and VL containing the amino acid sequence of SEQ ID NO: 356. In some embodiments, the antigen-specific binding site that specifically binds to IL-5 or IL-5R includes VH containing the amino acid sequence of SEQ ID NO: 375 and VL containing the amino acid sequence of SEQ ID NO: 376.

[0014] In some embodiments, the bispecific antibody targets IL-9 or IL-9R. In some embodiments, the antigen-specific binding site that specifically binds to IL-9 or IL-9R includes heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 395, and light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 396. In some embodiments, the antigen-specific binding site that specifically binds to IL-9 or IL-9R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 397, HC CDR2 having the amino acid sequence of SEQ ID NO: 398, HC CDR3 having the amino acid sequence of SEQ ID NO: 399, LC CDR1 having the amino acid sequence of SEQ ID NO: 400, LC CDR2 having the amino acid sequence of SEQ ID NO: 401, and LC CDR3 having the amino acid sequence of SEQ ID NO: 402. In some embodiments, antigen-specific binding sites that specifically bind to IL-9 or IL-9R include HC CDR1 having the amino acid sequence of SEQ ID NO: 403, HC CDR2 having the amino acid sequence of SEQ ID NO: 404, HC CDR3 having the amino acid sequence of SEQ ID NO: 405, LC CDR1 having the amino acid sequence of SEQ ID NO: 406, LC CDR2 having the amino acid sequence of GTS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 408. In some embodiments, antigen-specific binding sites that specifically bind to IL-9 or IL-9R include HC CDR1 having the amino acid sequence of SEQ ID NO: 409, HC CDR2 having the amino acid sequence of SEQ ID NO: 410, HC CDR3 having the amino acid sequence of SEQ ID NO: 411, LC CDR1 having the amino acid sequence of SEQ ID NO: 412, LC CDR2 having the amino acid sequence of SEQ ID NO: 413, and LC CDR3 having the amino acid sequence of SEQ ID NO: 414. In some embodiments, antigen-specific binding sites that specifically bind to IL-9 or IL-9R include VH having the amino acid sequence of SEQ ID NO: 395, and VL having the amino acid sequence of SEQ ID NO: 396. In some embodiments, the bispecific antibody targets either OX40L or OX40.In some embodiments, the antigen-specific binding site that specifically binds to OX40L or OX40 includes HC CDR1, HC CDR2, and HC CDR3, which are heavy chain variable domains having the amino acid sequence of SEQ ID NO: 415, and LC CDR1, LC CDR2, and LC CDR3, which are light chain variable domains having the amino acid sequence of SEQ ID NO: 416. In some embodiments, the antigen-specific binding site that specifically binds to OX40L or OX40 includes HC CDR1, HC CDR2, and HC CDR3, which are heavy chain variable domains having the amino acid sequence of SEQ ID NO: 435, and LC CDR1, LC CDR2, and LC CDR3, which are light chain variable domains having the amino acid sequence of SEQ ID NO: 436. In some embodiments, the antigen-specific binding site that specifically binds to OX40L or OX40 includes HC CDR1, HC CDR2, and HC CDR3, which are heavy chain variable domains having the amino acid sequence of SEQ ID NO: 819, and LC CDR1, LC CDR2, and LC CDR3, which are light chain variable domains having the amino acid sequence of SEQ ID NO: 820. In some embodiments, the antigen-specific binding site that specifically binds to OX40L or OX40 includes HC CDR1, HC CDR2, and HC CDR3, which are heavy chain variable domains having the amino acid sequence of SEQ ID NO: 839, and LC CDR1, LC CDR2, and LC CDR3, which are light chain variable domains having the amino acid sequence of SEQ ID NO: 840. In some embodiments, the antigen-specific binding site that specifically binds to OX40L or OX40 includes HC CDR1, HC CDR2, and HC CDR3, which are heavy chain variable domains having the amino acid sequence of SEQ ID NO: 859, and LC CDR1, LC CDR2, and LC CDR3, which are light chain variable domains having the amino acid sequence of SEQ ID NO: 860. In some embodiments, the antigen-specific binding sites that specifically bind to OX40L or OX40 include HC CDR1 having the amino acid sequence of SEQ ID NO: 417, HC CDR2 having the amino acid sequence of SEQ ID NO: 418, HC CDR3 having the amino acid sequence of SEQ ID NO: 419, LC CDR1 having the amino acid sequence of SEQ ID NO: 420, LC CDR2 having the amino acid sequence of SEQ ID NO: 421, and LC CDR3 having the amino acid sequence of SEQ ID NO: 422.In some embodiments, antigen-specific binding sites that specifically bind to OX40L or OX40 include HC CDR1 having the amino acid sequence of SEQ ID NO: 423, HC CDR2 having the amino acid sequence of SEQ ID NO: 424, HC CDR3 having the amino acid sequence of SEQ ID NO: 425, LC CDR1 having the amino acid sequence of SEQ ID NO: 426, LC CDR2 having the amino acid sequence of GAS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 428. In some embodiments, antigen-specific binding sites that specifically bind to OX40L or OX40 include HC CDR1 having the amino acid sequence of SEQ ID NO: 429, HC CDR2 having the amino acid sequence of SEQ ID NO: 430, HC CDR3 having the amino acid sequence of SEQ ID NO: 431, LC CDR1 having the amino acid sequence of SEQ ID NO: 432, LC CDR2 having the amino acid sequence of SEQ ID NO: 433, and LC CDR3 having the amino acid sequence of SEQ ID NO: 434. In some embodiments, the antigen-specific binding sites that specifically bind to OX40L or OX40 include HC CDR1 having the amino acid sequence of SEQ ID NO: 437, HC CDR2 having the amino acid sequence of SEQ ID NO: 438, HC CDR3 having the amino acid sequence of SEQ ID NO: 439, LC CDR1 having the amino acid sequence of SEQ ID NO: 440, LC CDR2 having the amino acid sequence of SEQ ID NO: 441, and LC CDR3 having the amino acid sequence of SEQ ID NO: 442. In some embodiments, the antigen-specific binding sites that specifically bind to OX40L or OX40 include HC CDR1 having the amino acid sequence of SEQ ID NO: 443, HC CDR2 having the amino acid sequence of SEQ ID NO: 444, HC CDR3 having the amino acid sequence of SEQ ID NO: 445, LC CDR1 having the amino acid sequence of SEQ ID NO: 446, LC CDR2 having the amino acid sequence of AAS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 448.In some embodiments, the antigen-specific binding sites that specifically bind to OX40L or OX40 include HC CDR1 having the amino acid sequence of SEQ ID NO: 449, HC CDR2 having the amino acid sequence of SEQ ID NO: 450, HC CDR3 having the amino acid sequence of SEQ ID NO: 451, LC CDR1 having the amino acid sequence of SEQ ID NO: 452, LC CDR2 having the amino acid sequence of SEQ ID NO: 453, and LC CDR3 having the amino acid sequence of SEQ ID NO: 454. In some embodiments, the antigen-specific binding sites that specifically bind to OX40L or OX40 include HC CDR1 having the amino acid sequence of SEQ ID NO: 821, HC CDR2 having the amino acid sequence of SEQ ID NO: 822, HC CDR3 having the amino acid sequence of SEQ ID NO: 823, LC CDR1 having the amino acid sequence of SEQ ID NO: 824, LC CDR2 having the amino acid sequence of SEQ ID NO: 825, and LC CDR3 having the amino acid sequence of SEQ ID NO: 826. In some embodiments, antigen-specific binding sites that specifically bind to OX40L or OX40 include HC CDR1 having the amino acid sequence of SEQ ID NO: 827, HC CDR2 having the amino acid sequence of SEQ ID NO: 828, HC CDR3 having the amino acid sequence of SEQ ID NO: 829, LC CDR1 having the amino acid sequence of SEQ ID NO: 830, LC CDR2 having the amino acid sequence of ATS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 832. In some embodiments, antigen-specific binding sites that specifically bind to OX40L or OX40 include HC CDR1 having the amino acid sequence of SEQ ID NO: 833, HC CDR2 having the amino acid sequence of SEQ ID NO: 834, HC CDR3 having the amino acid sequence of SEQ ID NO: 835, LC CDR1 having the amino acid sequence of SEQ ID NO: 836, LC CDR2 having the amino acid sequence of SEQ ID NO: 837, and LC CDR3 having the amino acid sequence of SEQ ID NO: 838.In some embodiments, the antigen-specific binding sites that specifically bind to OX40L or OX40 include HC CDR1 having the amino acid sequence of SEQ ID NO: 841, HC CDR2 having the amino acid sequence of SEQ ID NO: 842, HC CDR3 having the amino acid sequence of SEQ ID NO: 843, LC CDR1 having the amino acid sequence of SEQ ID NO: 844, LC CDR2 having the amino acid sequence of SEQ ID NO: 845, and LC CDR3 having the amino acid sequence of SEQ ID NO: 846. In some embodiments, the antigen-specific binding sites that specifically bind to OX40L or OX40 include HC CDR1 having the amino acid sequence of SEQ ID NO: 847, HC CDR2 having the amino acid sequence of SEQ ID NO: 848, HC CDR3 having the amino acid sequence of SEQ ID NO: 849, LC CDR1 having the amino acid sequence of SEQ ID NO: 850, LC CDR2 having the amino acid sequence of AAS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 852. In some embodiments, the antigen-specific binding sites that specifically bind to OX40L or OX40 include HC CDR1 having the amino acid sequence of SEQ ID NO: 853, HC CDR2 having the amino acid sequence of SEQ ID NO: 854, HC CDR3 having the amino acid sequence of SEQ ID NO: 855, LC CDR1 having the amino acid sequence of SEQ ID NO: 856, LC CDR2 having the amino acid sequence of SEQ ID NO: 857, and LC CDR3 having the amino acid sequence of SEQ ID NO: 858. In some embodiments, the antigen-specific binding sites that specifically bind to OX40L or OX40 include HC CDR1 having the amino acid sequence of SEQ ID NO: 861, HC CDR2 having the amino acid sequence of SEQ ID NO: 862, HC CDR3 having the amino acid sequence of SEQ ID NO: 863, LC CDR1 having the amino acid sequence of SEQ ID NO: 864, LC CDR2 having the amino acid sequence of SEQ ID NO: 865, and LC CDR3 having the amino acid sequence of SEQ ID NO: 866.In some embodiments, the antigen-specific binding site that specifically binds to OX40L or OX40 comprises HC CDR1 having the amino acid sequence of SEQ ID NO: 867, HC CDR2 having the amino acid sequence of SEQ ID NO: 868, HC CDR3 having the amino acid sequence of SEQ ID NO: 869, LC CDR1 having the amino acid sequence of SEQ ID NO: 870, LC CDR2 having the amino acid sequence of RAS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 872. In some embodiments, the antigen-specific binding site that specifically binds to OX40L or OX40 comprises HC CDR1 having the amino acid sequence of SEQ ID NO: 873, HC CDR2 having the amino acid sequence of SEQ ID NO: 874, HC CDR3 having the amino acid sequence of SEQ ID NO: 875, LC CDR1 having the amino acid sequence of SEQ ID NO: 876, LC CDR2 having the amino acid sequence of SEQ ID NO: 878, and LC CDR3 having the amino acid sequence of SEQ ID NO: 872. In some embodiments, the antigen-specific binding site that specifically binds to OX40L or OX40 comprises VH comprising the amino acid sequence of SEQ ID NO: 415 and VL comprising the amino acid sequence of SEQ ID NO: 416. In some embodiments, the antigen-specific binding site that specifically binds to OX40L or OX40 comprises VH comprising the amino acid sequence of SEQ ID NO: 435 and VL comprising the amino acid sequence of SEQ ID NO: 436. In some embodiments, the antigen-specific binding site that specifically binds to OX40L or OX40 comprises VH comprising the amino acid sequence of SEQ ID NO: 819 and VL comprising the amino acid sequence of SEQ ID NO: 820. In some embodiments, the antigen-specific binding site that specifically binds to OX40L or OX40 comprises VH comprising the amino acid sequence of SEQ ID NO: 839 and VL comprising the amino acid sequence of SEQ ID NO: 840. In some embodiments, the antigen-specific binding site that specifically binds to OX40L or OX40 comprises VH comprising the amino acid sequence of SEQ ID NO: 859, and. and VL comprising the amino acid sequence of SEQ ID NO: 860.

[0015] In some embodiments, the bispecific antibody targets IL-25 or IL-25R. In some embodiments, the antigen-specific binding site that specifically binds to IL-25 or IL-25R includes heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 455, and light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 456. In some embodiments, the antigen-specific binding site that specifically binds to IL-25 or IL-25R includes heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 719, and light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 720. In some embodiments, the antigen-specific binding site that specifically binds to IL-25 or IL-25R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 457, HC CDR2 having the amino acid sequence of SEQ ID NO: 458, HC CDR3 having the amino acid sequence of SEQ ID NO: 459, LC CDR1 having the amino acid sequence of SEQ ID NO: 460, LC CDR2 having the amino acid sequence of SEQ ID NO: 461, and LC CDR3 having the amino acid sequence of SEQ ID NO: 462. In some embodiments, the antigen-specific binding site that specifically binds to IL-25 or IL-25R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 463, HC CDR2 having the amino acid sequence of SEQ ID NO: 464, HC CDR3 having the amino acid sequence of SEQ ID NO: 465, LC CDR1 having the amino acid sequence of SEQ ID NO: 466, LC CDR2 having the amino acid sequence of DAS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 468. In some embodiments, the antigen-specific binding sites that specifically bind to IL-25 or IL-25R include HC CDR1 having the amino acid sequence of SEQ ID NO: 469, HC CDR2 having the amino acid sequence of SEQ ID NO: 470, HC CDR3 having the amino acid sequence of SEQ ID NO: 471, LC CDR1 having the amino acid sequence of SEQ ID NO: 472, LC CDR2 having the amino acid sequence of SEQ ID NO: 473, and LC CDR3 having the amino acid sequence of SEQ ID NO: 474.In some embodiments, the antigen-specific binding site that specifically binds to IL-25 or IL-25R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 721, HC CDR2 having the amino acid sequence of SEQ ID NO: 722, HC CDR3 having the amino acid sequence of SEQ ID NO: 723, LC CDR1 having the amino acid sequence of SEQ ID NO: 724, LC CDR2 having the amino acid sequence of SEQ ID NO: 725, and LC CDR3 having the amino acid sequence of SEQ ID NO: 726. In some embodiments, the antigen-specific binding site that specifically binds to IL-25 or IL-25R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 727, HC CDR2 having the amino acid sequence of SEQ ID NO: 728, HC CDR3 having the amino acid sequence of SEQ ID NO: 729, LC CDR1 having the amino acid sequence of SEQ ID NO: 730, LC CDR2 having the amino acid sequence of RTS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 732. In some embodiments, the antigen-specific binding site that specifically binds to IL-25 or IL-25R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 733, HC CDR2 having the amino acid sequence of SEQ ID NO: 734, HC CDR3 having the amino acid sequence of SEQ ID NO: 735, LC CDR1 having the amino acid sequence of SEQ ID NO: 736, LC CDR2 having the amino acid sequence of SEQ ID NO: 737, and LC CDR3 having the amino acid sequence of SEQ ID NO: 738. In some embodiments, the antigen-specific binding site that specifically binds to IL-25 or IL-25R includes VH having the amino acid sequence of SEQ ID NO: 455, and VL having the amino acid sequence of SEQ ID NO: 456. In some embodiments, the antigen-specific binding site that specifically binds to IL-25 or IL-25R includes VH having the amino acid sequence of SEQ ID NO: 719, and VL having the amino acid sequence of SEQ ID NO: 720.

[0016] In some embodiments, the bispecific antibody targets IL-31 or IL-31R. In some embodiments, the antigen-specific binding site that specifically binds to IL-31 or IL-31R includes heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 475, and light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 476. In some embodiments, the antigen-specific binding site that specifically binds to IL-31 or IL-31R includes heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 495, and light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 496. In some embodiments, the antigen-specific binding site that specifically binds to IL-31 or IL-31R includes HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain having the amino acid sequence of SEQ ID NO: 739, and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain having the amino acid sequence of SEQ ID NO: 740. In some embodiments, the antigen-specific binding site that specifically binds to IL-31 or IL-31R includes HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain having the amino acid sequence of SEQ ID NO: 759, and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain having the amino acid sequence of SEQ ID NO: 760. In some embodiments, the antigen-specific binding sites that specifically bind to IL-31 or IL-31R include HC CDR1 having the amino acid sequence of SEQ ID NO: 477, HC CDR2 having the amino acid sequence of SEQ ID NO: 478, HC CDR3 having the amino acid sequence of SEQ ID NO: 479, LC CDR1 having the amino acid sequence of SEQ ID NO: 480, LC CDR2 having the amino acid sequence of SEQ ID NO: 481, and LC CDR3 having the amino acid sequence of SEQ ID NO: 482.In some embodiments, the antigen-specific binding site that specifically binds to IL-31 or IL-31R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 483, HC CDR2 having the amino acid sequence of SEQ ID NO: 484, HC CDR3 having the amino acid sequence of SEQ ID NO: 485, LC CDR1 having the amino acid sequence of SEQ ID NO: 486, LC CDR2 having the amino acid sequence of SEQ ID NO: 487, and LC CDR3 having the amino acid sequence of SEQ ID NO: 488. In some embodiments, the antigen-specific binding site that specifically binds to IL-31 or IL-31R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 489, HC CDR2 having the amino acid sequence of SEQ ID NO: 490, HC CDR3 having the amino acid sequence of SEQ ID NO: 491, LC CDR1 having the amino acid sequence of SEQ ID NO: 492, LC CDR2 having the amino acid sequence of SEQ ID NO: 493, and LC CDR3 having the amino acid sequence of SEQ ID NO: 494. In some embodiments, the antigen-specific binding site that specifically binds to IL-31 or IL-31R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 497, HC CDR2 having the amino acid sequence of SEQ ID NO: 498, HC CDR3 having the amino acid sequence of SEQ ID NO: 499, LC CDR1 having the amino acid sequence of SEQ ID NO: 500, LC CDR2 having the amino acid sequence of SEQ ID NO: 501, and LC CDR3 having the amino acid sequence of SEQ ID NO: 502. In some embodiments, the antigen-specific binding site that specifically binds to IL-31 or IL-31R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 503, HC CDR2 having the amino acid sequence of SEQ ID NO: 504, HC CDR3 having the amino acid sequence of SEQ ID NO: 505, LC CDR1 having the amino acid sequence of SEQ ID NO: 506, LC CDR2 having the amino acid sequence of NIN, and LC CDR3 having the amino acid sequence of SEQ ID NO: 508.In some embodiments, the antigen-specific binding site that specifically binds to IL-33 or IL-33R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 509, HC CDR2 having the amino acid sequence of SEQ ID NO: 510, HC CDR3 having the amino acid sequence of SEQ ID NO: 511, LC CDR1 having the amino acid sequence of SEQ ID NO: 512, LC CDR2 having the amino acid sequence of SEQ ID NO: 513, and LC CDR3 having the amino acid sequence of SEQ ID NO: 514. In some embodiments, the antigen-specific binding site that specifically binds to IL-33 or IL-33R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 741, HC CDR2 having the amino acid sequence of SEQ ID NO: 742, HC CDR3 having the amino acid sequence of SEQ ID NO: 743, LC CDR1 having the amino acid sequence of SEQ ID NO: 744, LC CDR2 having the amino acid sequence of SEQ ID NO: 745, and LC CDR3 having the amino acid sequence of SEQ ID NO: 746. In some embodiments, the antigen-specific binding site that specifically binds to IL-31 or IL-31R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 747, HC CDR2 having the amino acid sequence of SEQ ID NO: 748, HC CDR3 having the amino acid sequence of SEQ ID NO: 749, LC CDR1 having the amino acid sequence of SEQ ID NO: 750, LC CDR2 having the amino acid sequence of QAS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 752. In some embodiments, the antigen-specific binding site that specifically binds to IL-31 or IL-31R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 753, HC CDR2 having the amino acid sequence of SEQ ID NO: 754, HC CDR3 having the amino acid sequence of SEQ ID NO: 755, LC CDR1 having the amino acid sequence of SEQ ID NO: 756, LC CDR2 having the amino acid sequence of SEQ ID NO: 757, and LC CDR3 having the amino acid sequence of SEQ ID NO: 758.In some embodiments, the antigen-specific binding site that specifically binds to IL-31 or IL-31R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 761, HC CDR2 having the amino acid sequence of SEQ ID NO: 762, HC CDR3 having the amino acid sequence of SEQ ID NO: 763, LC CDR1 having the amino acid sequence of SEQ ID NO: 764, LC CDR2 having the amino acid sequence of SEQ ID NO: 765, and LC CDR3 having the amino acid sequence of SEQ ID NO: 766. In some embodiments, the antigen-specific binding site that specifically binds to IL-31 or IL-31R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 767, HC CDR2 having the amino acid sequence of SEQ ID NO: 768, HC CDR3 having the amino acid sequence of SEQ ID NO: 770, LC CDR1 having the amino acid sequence of SEQ ID NO: 346, LC CDR2 having the amino acid sequence of NAK, and LC CDR3 having the amino acid sequence of SEQ ID NO: 772. In some embodiments, the antigen-specific binding site that specifically binds to IL-31 or IL-31R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 773, HC CDR2 having the amino acid sequence of SEQ ID NO: 774, HC CDR3 having the amino acid sequence of SEQ ID NO: 775, LC CDR1 having the amino acid sequence of SEQ ID NO: 776, LC CDR2 having the amino acid sequence of SEQ ID NO: 777, and LC CDR3 having the amino acid sequence of SEQ ID NO: 778. In some embodiments, the antigen-specific binding site that specifically binds to IL-31 or IL-31R includes VH having the amino acid sequence of SEQ ID NO: 475, and VL having the amino acid sequence of SEQ ID NO: 476. In some embodiments, the antigen-specific binding site that specifically binds to IL-31 or IL-31R includes VH having the amino acid sequence of SEQ ID NO: 495, and VL having the amino acid sequence of SEQ ID NO: 496. In some embodiments, the antigen-specific binding site that specifically binds to IL-31 or IL-31R includes VH having the amino acid sequence of SEQ ID NO: 739, and VL having the amino acid sequence of SEQ ID NO: 740. In some embodiments, the antigen-specific binding site that specifically binds to IL-31 or IL-31R includes VH, which contains the amino acid sequence of SEQ ID NO: 759, and VL, which contains the amino acid sequence of SEQ ID NO: 760.

[0017] In some embodiments, the bispecific antibody targets IL-36 or IL-36R. In some embodiments, the antigen-specific binding site that specifically binds to IL-36 or IL-36R includes heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 575, and light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 576. In some embodiments, the antigen-specific binding site that specifically binds to IL-36 or IL-36R includes heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 595, and light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 596. In some embodiments, the antigen-specific binding site that specifically binds to IL-36 or IL-36R includes heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 779, and light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 780. In some embodiments, the antigen-specific binding site that specifically binds to IL-36 or IL-36R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 577, HC CDR2 having the amino acid sequence of SEQ ID NO: 578, HC CDR3 having the amino acid sequence of SEQ ID NO: 579, LC CDR1 having the amino acid sequence of SEQ ID NO: 580, LC CDR2 having the amino acid sequence of SEQ ID NO: 581, and LC CDR3 having the amino acid sequence of SEQ ID NO: 582. In some embodiments, the antigen-specific binding sites that specifically bind to IL-36 or IL-36R include HC CDR1 having the amino acid sequence of SEQ ID NO: 583, HC CDR2 having the amino acid sequence of SEQ ID NO: 584, HC CDR3 having the amino acid sequence of SEQ ID NO: 585, LC CDR1 having the amino acid sequence of SEQ ID NO: 586, LC CDR2 having the amino acid sequence of RTS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 588.In some embodiments, the antigen-specific binding site that specifically binds to IL-36 or IL-36R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 589, HC CDR2 having the amino acid sequence of SEQ ID NO: 590, HC CDR3 having the amino acid sequence of SEQ ID NO: 591, LC CDR1 having the amino acid sequence of SEQ ID NO: 592, LC CDR2 having the amino acid sequence of SEQ ID NO: 593, and LC CDR3 having the amino acid sequence of SEQ ID NO: 594. In some embodiments, the antigen-specific binding site that specifically binds to IL-36 or IL-36R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 597, HC CDR2 having the amino acid sequence of SEQ ID NO: 598, HC CDR3 having the amino acid sequence of SEQ ID NO: 599, LC CDR1 having the amino acid sequence of SEQ ID NO: 600, LC CDR2 having the amino acid sequence of SEQ ID NO: 601, and LC CDR3 having the amino acid sequence of SEQ ID NO: 602. In some embodiments, the antigen-specific binding sites that specifically bind to IL-36 or IL-36R include HC CDR1 having the amino acid sequence of SEQ ID NO: 603, HC CDR2 having the amino acid sequence of SEQ ID NO: 604, HC CDR3 having the amino acid sequence of SEQ ID NO: 605, LC CDR1 having the amino acid sequence of SEQ ID NO: 606, LC CDR2 having the amino acid sequence of QMS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 608. In some embodiments, the antigen-specific binding sites that specifically bind to IL-36 or IL-36R include HC CDR1 having the amino acid sequence of SEQ ID NO: 609, HC CDR2 having the amino acid sequence of SEQ ID NO: 610, HC CDR3 having the amino acid sequence of SEQ ID NO: 611, LC CDR1 having the amino acid sequence of SEQ ID NO: 612, LC CDR2 having the amino acid sequence of SEQ ID NO: 613, and LC CDR3 having the amino acid sequence of SEQ ID NO: 614.In some embodiments, the antigen-specific binding site that specifically binds to IL-36 or IL-36R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 781, HC CDR2 having the amino acid sequence of SEQ ID NO: 782, HC CDR3 having the amino acid sequence of SEQ ID NO: 783, LC CDR1 having the amino acid sequence of SEQ ID NO: 784, LC CDR2 having the amino acid sequence of SEQ ID NO: 785, and LC CDR3 having the amino acid sequence of SEQ ID NO: 786. In some embodiments, the antigen-specific binding site that specifically binds to IL-36 or IL-36R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 787, HC CDR2 having the amino acid sequence of SEQ ID NO: 788, HC CDR3 having the amino acid sequence of SEQ ID NO: 789, LC CDR1 having the amino acid sequence of SEQ ID NO: 790, LC CDR2 having the amino acid sequence of STS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 792. In some embodiments, the antigen-specific binding site that specifically binds to IL-36 or IL-36R includes VH containing the amino acid sequence of SEQ ID NO: 575 and VL containing the amino acid sequence of SEQ ID NO: 576. In some embodiments, the antigen-specific binding site that specifically binds to IL-36 or IL-36R includes VH containing the amino acid sequence of SEQ ID NO: 595 and VL containing the amino acid sequence of SEQ ID NO: 596. In some embodiments, the antigen-specific binding site that specifically binds to IL-36 or IL-36R includes VH containing the amino acid sequence of SEQ ID NO: 779 and VL containing the amino acid sequence of SEQ ID NO: 780.

[0018] In some embodiments, the bispecific antibody targets TSLP or TSLPR. In some embodiments, the antigen-specific binding site that specifically binds to TSLP or TSLPR includes heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 615, and light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 616. In some embodiments, the antigen-specific binding site that specifically binds to TSLP or TSLPR includes heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 635, and light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 636. In some embodiments, the antigen-specific binding site that specifically binds to TSLP or TSLPR includes heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 879, and light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 880. In some embodiments, the antigen-specific binding site that specifically binds to TSLP or TSLPR includes heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 899, and light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 900. In some embodiments, the antigen-specific binding site that specifically binds to TSLP or TSLPR includes HC CDR1 having the amino acid sequence of SEQ ID NO: 617, HC CDR2 having the amino acid sequence of SEQ ID NO: 618, HC CDR3 having the amino acid sequence of SEQ ID NO: 619, LC CDR1 having the amino acid sequence of SEQ ID NO: 620, LC CDR2 having the amino acid sequence of SEQ ID NO: 621, and LC CDR3 having the amino acid sequence of SEQ ID NO: 622.In some embodiments, the antigen-specific binding sites that specifically bind to TSLP or TSLPR include HC CDR1 having the amino acid sequence of SEQ ID NO: 623, HC CDR2 having the amino acid sequence of SEQ ID NO: 624, HC CDR3 having the amino acid sequence of SEQ ID NO: 625, LC CDR1 having the amino acid sequence of SEQ ID NO: 626, LC CDR2 having the amino acid sequence of SEQ ID NO: DDS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 628. In some embodiments, the antigen-specific binding sites that specifically bind to TSLP or TSLPR include HC CDR1 having the amino acid sequence of SEQ ID NO: 629, HC CDR2 having the amino acid sequence of SEQ ID NO: 630, HC CDR3 having the amino acid sequence of SEQ ID NO: 631, LC CDR1 having the amino acid sequence of SEQ ID NO: 632, LC CDR2 having the amino acid sequence of SEQ ID NO: 633, and LC CDR3 having the amino acid sequence of SEQ ID NO: 634. In some embodiments, the antigen-specific binding site that specifically binds to TSLP or TSLPR includes HC CDR1 having the amino acid sequence of SEQ ID NO: 637, HC CDR2 having the amino acid sequence of SEQ ID NO: 638, HC CDR3 having the amino acid sequence of SEQ ID NO: 639, LC CDR1 having the amino acid sequence of SEQ ID NO: 640, LC CDR2 having the amino acid sequence of SEQ ID NO: 641, and LC CDR3 having the amino acid sequence of SEQ ID NO: 642. In some embodiments, the antigen-specific binding site that specifically binds to TSLP or TSLPR includes HC CDR1 having the amino acid sequence of SEQ ID NO: 643, HC CDR2 having the amino acid sequence of SEQ ID NO: 644, HC CDR3 having the amino acid sequence of SEQ ID NO: 645, LC CDR1 having the amino acid sequence of SEQ ID NO: 646, LC CDR2 having the amino acid sequence of GDN, and LC CDR3 having the amino acid sequence of SEQ ID NO: 648.In some embodiments, the antigen-specific binding sites that specifically bind to TSLP or TSLPR include HC CDR1 having the amino acid sequence of SEQ ID NO: 649, HC CDR2 having the amino acid sequence of SEQ ID NO: 650, HC CDR3 having the amino acid sequence of SEQ ID NO: 651, LC CDR1 having the amino acid sequence of SEQ ID NO: 652, LC CDR2 having the amino acid sequence of SEQ ID NO: 653, and LC CDR3 having the amino acid sequence of SEQ ID NO: 654. In some embodiments, the antigen-specific binding sites that specifically bind to TSLP or TSLPR include HC CDR1 having the amino acid sequence of SEQ ID NO: 881, HC CDR2 having the amino acid sequence of SEQ ID NO: 882, HC CDR3 having the amino acid sequence of SEQ ID NO: 883, LC CDR1 having the amino acid sequence of SEQ ID NO: 884, LC CDR2 having the amino acid sequence of SEQ ID NO: 885, and LC CDR3 having the amino acid sequence of SEQ ID NO: 886. In some embodiments, antigen-specific binding sites that specifically bind to TSLP or TSLPR include HC CDR1 having the amino acid sequence of SEQ ID NO: 887, HC CDR2 having the amino acid sequence of SEQ ID NO: 888, HC CDR3 having the amino acid sequence of SEQ ID NO: 889, LC CDR1 having the amino acid sequence of SEQ ID NO: 890, LC CDR2 having the amino acid sequence of FAR, and LC CDR3 having the amino acid sequence of SEQ ID NO: 892. In some embodiments, antigen-specific binding sites that specifically bind to TSLP or TSLPR include HC CDR1 having the amino acid sequence of SEQ ID NO: 893, HC CDR2 having the amino acid sequence of SEQ ID NO: 894, HC CDR3 having the amino acid sequence of SEQ ID NO: 895, LC CDR1 having the amino acid sequence of SEQ ID NO: 896, LC CDR2 having the amino acid sequence of SEQ ID NO: 897, and LC CDR3 having the amino acid sequence of SEQ ID NO: 898.In some embodiments, antigen-specific binding sites that specifically bind to TSLP or TSLPR include HC CDR1 having the amino acid sequence of SEQ ID NO: 901, HC CDR2 having the amino acid sequence of SEQ ID NO: 902, HC CDR3 having the amino acid sequence of SEQ ID NO: 903, LC CDR1 having the amino acid sequence of SEQ ID NO: 904, LC CDR2 having the amino acid sequence of SEQ ID NO: 905, and LC CDR3 having the amino acid sequence of SEQ ID NO: 906. In some embodiments, antigen-specific binding sites that specifically bind to TSLP or TSLPR include HC CDR1 having the amino acid sequence of SEQ ID NO: 907, HC CDR2 having the amino acid sequence of SEQ ID NO: 908, HC CDR3 having the amino acid sequence of SEQ ID NO: 909, LC CDR1 having the amino acid sequence of SEQ ID NO: 910, LC CDR2 having the amino acid sequence of FAK, and LC CDR3 having the amino acid sequence of SEQ ID NO: 912. In some embodiments, the antigen-specific binding site that specifically binds to TSLP or TSLPR includes HC CDR1 having the amino acid sequence of SEQ ID NO: 913, HC CDR2 having the amino acid sequence of SEQ ID NO: 914, HC CDR3 having the amino acid sequence of SEQ ID NO: 915, LC CDR1 having the amino acid sequence of SEQ ID NO: 916, LC CDR2 having the amino acid sequence of SEQ ID NO: 917, and LC CDR3 having the amino acid sequence of SEQ ID NO: 918. In some embodiments, the antigen-specific binding site that specifically binds to TSLP or TSLPR includes VH having the amino acid sequence of SEQ ID NO: 615 and VL having the amino acid sequence of SEQ ID NO: 616. In some embodiments, the antigen-specific binding site that specifically binds to TSLP or TSLPR includes VH having the amino acid sequence of SEQ ID NO: 635 and VL having the amino acid sequence of SEQ ID NO: 636. In some embodiments, the antigen-specific binding site that specifically binds to TSLP or TSLPR includes VH having the amino acid sequence of SEQ ID NO: 879 and VL having the amino acid sequence of SEQ ID NO: 880. In some embodiments, the antigen-specific binding site that specifically binds to TSLP or TSLPR includes VH, which contains the amino acid sequence of SEQ ID NO: 899, and VL, which contains the amino acid sequence of SEQ ID NO: 900.

[0019] In some embodiments, the bispecific antibody targets IL-33 or IL-33R. In some embodiments, the antigen-specific binding site that specifically binds to IL-33 or IL-33R includes heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 677, and light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 678. In some embodiments, the antigen-specific binding site that specifically binds to IL-33 or IL-33R includes heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 697, and light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 698. In some embodiments, the antigen-specific binding site that specifically binds to IL-33 or IL-33R includes HC CDR1, HC CDR2, and HC CDR3, which are heavy chain variable domains having the amino acid sequence of SEQ ID NO: 717, and LC CDR1, LC CDR2, and LC CDR3, which are light chain variable domains having the amino acid sequence of SEQ ID NO: 718. In some embodiments, the antigen-specific binding site that specifically binds to IL-33 or IL-33R includes HC CDR1, HC CDR2, and HC CDR3, which are heavy chain variable domains having the amino acid sequence of SEQ ID NO: 799, and LC CDR1, LC CDR2, and LC CDR3, which are light chain variable domains having the amino acid sequence of SEQ ID NO: 800. In some embodiments, the antigen-specific binding sites that specifically bind to IL-33 or IL-33R include HC CDR1 having the amino acid sequence of SEQ ID NO: 659, HC CDR2 having the amino acid sequence of SEQ ID NO: 660, HC CDR3 having the amino acid sequence of SEQ ID NO: 661, LC CDR1 having the amino acid sequence of SEQ ID NO: 662, LC CDR2 having the amino acid sequence of SEQ ID NO: 663, and LC CDR3 having the amino acid sequence of SEQ ID NO: 664.In some embodiments, the antigen-specific binding sites that specifically bind to IL-33 or IL-33R include HC CDR1 having the amino acid sequence of SEQ ID NO: 665, HC CDR2 having the amino acid sequence of SEQ ID NO: 666, HC CDR3 having the amino acid sequence of SEQ ID NO: 667, LC CDR1 having the amino acid sequence of SEQ ID NO: 668, LC CDR2 having the amino acid sequence of RDT, and LC CDR3 having the amino acid sequence of SEQ ID NO: 670. In some embodiments, the antigen-specific binding sites that specifically bind to IL-33 or IL-33R include HC CDR1 having the amino acid sequence of SEQ ID NO: 671, HC CDR2 having the amino acid sequence of SEQ ID NO: 672, HC CDR3 having the amino acid sequence of SEQ ID NO: 673, LC CDR1 having the amino acid sequence of SEQ ID NO: 674, LC CDR2 having the amino acid sequence of SEQ ID NO: 675, and LC CDR3 having the amino acid sequence of SEQ ID NO: 676. In some embodiments, the antigen-specific binding site that specifically binds to IL-33 or IL-33R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 679, HC CDR2 having the amino acid sequence of SEQ ID NO: 680, HC CDR3 having the amino acid sequence of SEQ ID NO: 681, LC CDR1 having the amino acid sequence of SEQ ID NO: 682, LC CDR2 having the amino acid sequence of SEQ ID NO: 683, and LC CDR3 having the amino acid sequence of SEQ ID NO: 684. In some embodiments, the antigen-specific binding site that specifically binds to IL-33 or IL-33R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 685, HC CDR2 having the amino acid sequence of SEQ ID NO: 686, HC CDR3 having the amino acid sequence of SEQ ID NO: 687, LC CDR1 having the amino acid sequence of SEQ ID NO: 688, LC CDR2 having the amino acid sequence of AAS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 690.In some embodiments, the antigen-specific binding site that specifically binds to IL-33 or IL-33R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 691, HC CDR2 having the amino acid sequence of SEQ ID NO: 692, HC CDR3 having the amino acid sequence of SEQ ID NO: 693, LC CDR1 having the amino acid sequence of SEQ ID NO: 694, LC CDR2 having the amino acid sequence of SEQ ID NO: 695, and LC CDR3 having the amino acid sequence of SEQ ID NO: 696. In some embodiments, the antigen-specific binding site that specifically binds to IL-33 or IL-33R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 699, HC CDR2 having the amino acid sequence of SEQ ID NO: 700, HC CDR3 having the amino acid sequence of SEQ ID NO: 701, LC CDR1 having the amino acid sequence of SEQ ID NO: 702, LC CDR2 having the amino acid sequence of SEQ ID NO: 703, and LC CDR3 having the amino acid sequence of SEQ ID NO: 704. In some embodiments, the antigen-specific binding sites that specifically bind to IL-33 or IL-33R include HC CDR1 having the amino acid sequence of SEQ ID NO: 705, HC CDR2 having the amino acid sequence of SEQ ID NO: 706, HC CDR3 having the amino acid sequence of SEQ ID NO: 707, LC CDR1 having the amino acid sequence of SEQ ID NO: 708, LC CDR2 having the amino acid sequence of WAS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 710. In some embodiments, the antigen-specific binding sites that specifically bind to IL-33 or IL-33R include HC CDR1 having the amino acid sequence of SEQ ID NO: 711, HC CDR2 having the amino acid sequence of SEQ ID NO: 712, HC CDR3 having the amino acid sequence of SEQ ID NO: 713, LC CDR1 having the amino acid sequence of SEQ ID NO: 714, LC CDR2 having the amino acid sequence of SEQ ID NO: 715, and LC CDR3 having the amino acid sequence of SEQ ID NO: 716.In some embodiments, the antigen-specific binding sites that specifically bind to IL-33 or IL-33R include HC CDR1 having the amino acid sequence of SEQ ID NO: 801, HC CDR2 having the amino acid sequence of SEQ ID NO: 802, HC CDR3 having the amino acid sequence of SEQ ID NO: 803, LC CDR1 having the amino acid sequence of SEQ ID NO: 804, LC CDR2 having the amino acid sequence of SEQ ID NO: 805, and LC CDR3 having the amino acid sequence of SEQ ID NO: 806. In some embodiments, the antigen-specific binding sites that specifically bind to IL-33 or IL-33R include HC CDR1 having the amino acid sequence of SEQ ID NO: 807, HC CDR2 having the amino acid sequence of SEQ ID NO: 808, HC CDR3 having the amino acid sequence of SEQ ID NO: 809, LC CDR1 having the amino acid sequence of SEQ ID NO: 810, LC CDR2 having the amino acid sequence of FTN, and LC CDR3 having the amino acid sequence of SEQ ID NO: 812. In some embodiments, the antigen-specific binding site that specifically binds to IL-33 or IL-33R includes HC CDR1 having the amino acid sequence of SEQ ID NO: 813, HC CDR2 having the amino acid sequence of SEQ ID NO: 814, HC CDR3 having the amino acid sequence of SEQ ID NO: 815, LC CDR1 having the amino acid sequence of SEQ ID NO: 816, LC CDR2 having the amino acid sequence of SEQ ID NO: 817, and LC CDR3 having the amino acid sequence of SEQ ID NO: 818. In some embodiments, the antigen-specific binding site that specifically binds to IL-33 or IL-33R includes VH having the amino acid sequence of SEQ ID NO: 677, and VL having the amino acid sequence of SEQ ID NO: 678. In some embodiments, the antigen-specific binding site that specifically binds to IL-33 or IL-33R includes VH having the amino acid sequence of SEQ ID NO: 799, and VL having the amino acid sequence of SEQ ID NO: 800.

[0020] In some embodiments, the antigen-specific binding site that specifically binds to a Th2 cytokine or its receptor includes the VH and / or VL of any one of the antibodies in Table 2.

[0021] In some embodiments, the bispecific antibody retains binding affinity to KLK5 and KLK7 with a difference of 20% or less compared to an anti-KLK5 / KLK7 antibody containing the same CDR and / or VH / VL as the bispecific antibody. In some embodiments, the bispecific antibody retains binding affinity to Th2 targets with a difference of 20% or less compared to a Th2-targeted antibody containing the same CDR and / or VH / VL as the bispecific antibody. In some embodiments, the bispecific antibody retains at least 80% of the inhibitory activity against KLK5 and KLK7 compared to an anti-KLK5 / KLK7 antibody containing the same CDR and / or VH / VL as the bispecific antibody. In some embodiments, the bispecific antibody retains at least 80% of the inhibitory activity against Th2 signaling compared to a Th2-targeted antibody containing the same CDR and / or VH / VL as the bispecific antibody.

[0022] This disclosure provides compositions comprising a bispecific antibody as described herein and an acceptable carrier.

[0023] In some embodiments, the Disclosure provides a method comprising administering a bispecific antibody or composition described herein to a subject. In some embodiments, the subject has a skin barrier defect. In some embodiments, the Disclosure provides a method for treating a skin barrier defect, the method comprising administering an effective amount of a bispecific antibody or composition described herein to a subject. In some embodiments, the skin barrier defect is associated with Netherton syndrome, atopic dermatitis, eosinophilic esophagitis, prurigo nodosa, chronic pruritus of unknown cause (CPUO), dry skin, asthma (particularly KLK5), ichthyosis vulgaris, or itching or chronic itching. In some embodiments, the subject has atopic dermatitis.

[0024] In some embodiments, the administration reduces ear thickness by more than 30% compared to subjects administered with a Th2-targeted antibody containing the same CDR and / or VH / VL as the bispecific antibody. In some embodiments, the administration reduces ear thickness by more than 30% compared to subjects administered with a Th2-targeted antibody containing the same CDR and / or VH / VL as the bispecific antibody. In some embodiments, the administration reduces skin erythema / bleeding by more than 30% compared to subjects administered with a Th2-targeted antibody containing the same CDR and / or VH / VL as the bispecific antibody. In some embodiments, the administration reduces skin erythema / bleeding by more than 30% compared to subjects administered with a Th2-targeted antibody containing the same CDR and / or VH / VL as the bispecific antibody. In some embodiments, the administration reduces skin erythema / bleeding by more than 30% compared to subjects administered with a Th2-targeted antibody containing the same CDR and / or VH / VL as the bispecific antibody. In some embodiments, the administration reduces skin peeling / erosion by more than 30% compared to subjects administered with a Th2-targeted antibody containing the same CDR and / or VH / VL as the bispecific antibody. In some embodiments, the administration reduces skin scaling / dryness by more than 30% compared to subjects administered with a Th2-targeted antibody containing the same CDR and / or VH / VL as the bispecific antibody. In some embodiments, the administration reduces skin scaling / dryness by more than 30% compared to subjects administered with a Th2-targeted antibody containing the same CDR and / or VH / VL as the bispecific antibody. In some embodiments, the administration reduces skin edema by more than 30% compared to subjects administered with a Th2-targeted antibody containing the same CDR and / or VH / VL as the bispecific antibody. In some embodiments, the administration reduces skin edema by more than 30% compared to subjects administered with a Th2-targeted antibody containing the same CDR and / or VH / VL as the bispecific antibody.

[0025] The preceding and other aspects, embodiments, actions, functions, features, and embodiments of this instruction can be better understood from the following description in conjunction with the accompanying drawings.

[0026] The accompanying drawings are incorporated herein and constitute part of this specification, illustrating certain embodiments and, together with the written description, are useful in providing non-limiting examples of certain aspects of the compositions and methods disclosed herein. [Brief explanation of the drawing]

[0027] [Figure 1] This chart shows abnormal protease activation (e.g., abnormal KLK5, KLK7, and KLK14) that can lead to skin barrier deficiency-related diseases. [Figure 2] This graph shows that in conditions associated with epidermal barrier dysfunction, increased KLK5 / KLK7 activity leads to Th2 cell activation, which in turn further increases KLK5 / KLK7 activity. [Figure 3] Graphs show that inhibiting KLK5 / KLK7 and Th2 signaling has a more beneficial effect than targeting either pathway alone in an Nc / Nga model of atopic dermatitis. A shows that mice treated with KLK5 / KLK7-dual-Ab4 in combination with an anti-IL-4R antibody have further reduced ear thickness compared to mice treated with KLK5 / KLK7-dual-Ab4 or anti-IL-4R antibody alone. B shows that mice treated with KLK5 / KLK7-dual-Ab4 in combination with an anti-IL-4R antibody have a reduced clinical skin score compared to mice treated with KLK5 / KLK7-dual-Ab4 or anti-IL-4R antibody alone. [Figure 4A] This concerns the binding affinity of an exemplary anti-KLK5 / KLK7+IL-13 bispecific antibody (referred to as K13-0004). The KD value for binding to KLK5 is shown. [Figure 4B] This concerns the binding affinity of an exemplary anti-KLK5 / KLK7+IL-13 bispecific antibody (referred to as K13-0004). The KD value for binding to KLK7 is shown. [Figure 4C] This concerns the binding affinity of an exemplary anti-KLK5 / KLK7+IL-13 bispecific antibody (referred to as K13-0004). The KD value for binding to IL-13 is shown. [Figure 4D] This concerns the binding affinity of an exemplary anti-KLK5 / KLK7+IL-13 bispecific antibody (referred to as K13-0004). It shows inhibition of KLK5 (Figure 4D; compared with the exemplary anti-KLK5 / KLK7 dual antibody in Figure 4E). [Figure 4E] This concerns the binding affinity of an exemplary anti-KLK5 / KLK7+IL-13 bispecific antibody (referred to as K13-0004). It shows inhibition of KLK5 (Figure 4D; compared with the exemplary anti-KLK5 / KLK7 dual antibody in Figure 4E). [Figure 4F] This concerns the binding affinity of an exemplary anti-KLK5 / KLK7+IL-13 bispecific antibody (referred to as K13-0004). It shows inhibition of KLK7 (Figure 4F; compared with the exemplary anti-KLK5 / KLK7 dual antibody in Figure 4G). [Figure 4G] This concerns the binding affinity of an exemplary anti-KLK5 / KLK7+IL-13 bispecific antibody (referred to as K13-0004). It shows inhibition of KLK7 (Figure 4F; compared with the exemplary anti-KLK5 / KLK7 dual antibody in Figure 4G). [Figure 4H] This concerns the binding affinity of an exemplary anti-KLK5 / KLK7+IL-13 bispecific antibody (referred to as K13-0004). It exhibits inhibition of IL-13. [Figure 4I] This concerns the binding affinity of an exemplary anti-KLK5 / KLK7+IL-13 bispecific antibody (referred to as K13-0004). It exhibits inhibition of the extracellular matrix protein (ECM) periostin. [Figure 5A] This study concerns the inactivation of KLK5 and KLK7-mediated disruption of the primary human keratinocyte barrier. Transepithelial resistance (TEER) after treatment with various concentrations of the anti-KLK5 / KLK7 + IL-13 bispecific antibody K13-0004 is shown. [Figure 5B] This study concerns the inactivation of KLK5 and KLK7-mediated disruption of the primary human keratinocyte barrier. Transepithelial resistance (TEER) after treatment with various concentrations of KLK5 / KLK7-dual-Ab4 is shown. [Figure 5C]This study concerns the inactivation of KLK5 and KLK7-mediated disruption of the primary human keratinocyte barrier. It shows the migration of FITC-dextran dye after treatment with various concentrations of the anti-KLK5 / KLK7+IL-13 bispecific antibody K13-0004. [Figure 5D] This study concerns the inactivation of KLK5 and KLK7-mediated disruption of the primary human keratinocyte barrier. It shows the migration of FITC-dextran dye after treatment with various concentrations of KLK5 / KLK7-dual-Ab4. [Modes for carrying out the invention]

[0028] This disclosure is based, at least in part, on the development of dual inhibitory antibodies and variants thereof targeting KLK5 and KLK7. These dual inhibitory antibodies target KLK5 and KLK7 via a common, distinct antigen-specific binding site. Such dual inhibitory antibodies have high binding affinity and specificity to KLK5 and KLK7 (anti-KLK5 / KLK7 antibodies). In some embodiments, a bispecific antibody is provided in which one arm contains an antigen-specific binding site of a dual inhibitory antibody targeting KLK5 and KLK7, and the other arm specifically binds to and inhibits the activity of Th2 cytokines such as IL-13, IL-4, IL-5, IL-6, IL-9, IL-31, IL-17E (IL-25), OX40L, TSLP, or their receptors. Furthermore, methods for using anti-KLK5 / KLK7+Th2 bispecific antibodies and their variants for research, diagnostic / detection, and therapeutic applications are also provided, as well as anti-KLK5 / KLK7+Th2 bispecific antibodies for use in such methods.

[0029] The preceding and other aspects, embodiments, actions, functions, features, and embodiments of this instruction can be better understood from the following description in conjunction with the accompanying drawings.

[0030] I. Definition To administer: As used herein, the terms “to administer” or “to administer” mean to provide an antibody or a composition thereof to a subject in a physiologically and / or pharmacologically useful manner (for example, to treat a condition of the subject).

[0031] Affinity-matured antibodies: In this specification, the term “affinity-matured antibody” is used to refer to an antibody obtained by adding one or more modifications to one or more CDRs that result in improved affinity (e.g., KD, kd, or ka) of the antibody to a target antigen compared to an unmodified parent antibody. Exemplary affinity-matured antibodies may, in some embodiments, have nanomolar or even picomolar affinity to a target antigen. Various procedures are available for generating affinity-matured antibodies, including screening of combination antibody libraries prepared using biodisplay. For example, Marks et al., BioTechnology, 10:779-783 (1992) describes affinity maturation by shuffling of VH and VL domains. Random mutagenesis of CDRs and / or framework residues has been described by Barbas et al., Proc.Nat.Acad.Sci.USA, 91:3809-3813 (1994); Schier et al., Gene, 169:147-155 (1995); Yelton et al., J.Immunol., 155:1994-2004 (1995); Jackson et al., J.Immunol., 154(7):3310-3319 (1995); and Hawkins et al., J.Mol.Biol., 226:889-896 (1992). Selective mutagenesis sites and selective mutations at contact sites or hypermutation sites with activity-enhancing amino acid residues have been described in U.S. Patent No. 6,914,128 B1.

[0032] Antibody: As used herein, the term “antibody” refers to a polypeptide comprising at least one immunoglobulin variable domain containing at least one distinct antigen-specific binding site, or a portion of an immunoglobulin variable domain (a paratope or a portion thereof) containing at least one distinct antigen-specific binding site. In some embodiments, the antibody comprises at least one distinct antigen-specific binding site that specifically binds to the active site of an enzyme. In some embodiments, the antibody is a Th2-targeted antibody comprising at least one antigen-specific binding site that specifically binds to a Th2 cytokine or its receptor. In some embodiments, the antibody is a full-length antibody. In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a humanized antibody. However, in some embodiments, the antibody is a Fab fragment, an F(ab')2 fragment, an Fv fragment, or an scFv fragment. In some embodiments, the antibody is a multispecific antibody (e.g., a bispecific antibody). In some embodiments, the antibody is a nanobody derived from a camelid antibody or a nanobody derived from a shark antibody. In some embodiments, the antibody is a diabody. In some embodiments, the antibody comprises a framework having a human germline sequence. In another embodiment, the antibody comprises a heavy chain constant domain selected from the group consisting of IgG, IgG1, IgG2, IgG2A, IgG2B, IgG2C, IgG3, IgG4, IgA1, IgA2, IgD, IgM, and IgE constant domains. In some embodiments, the antibody comprises a heavy (H) chain variable region or domain (abbreviated herein as VH) and / or a light (L) chain variable region or domain (abbreviated herein as VL). In some embodiments, the antibody comprises a constant region. The immunoglobulin constant domain refers to the heavy chain constant domain or the light chain constant domain. The amino acid sequences of the human IgG heavy chain and light chain constant domain, as well as their functional mutations, are known. In some embodiments, the heavy chain constant domain of the immunoglobulin comprises an Fc region. With respect to the heavy chain, in some embodiments, the heavy chain of the antibody described herein may be an alpha (α), delta (Δ), epsilon (ε), gamma (γ), or mu (μ) heavy chain.In some embodiments, the heavy chains of the antibodies described herein may include human alpha (α), delta (Δ), epsilon (ε), gamma (γ), or mu (μ) heavy chains. In some embodiments, the antibodies described herein include human gamma-1 CH1, CH2, and / or CH3 domains. In some embodiments, the amino acid sequence of the antibody includes the amino acid sequence of the human gamma (γ) heavy chain constant region, such as those known in the art. Non-limiting examples of human constant region sequences are described in the art; see, for example, U.S. Patent No. 5,693,780 and Kabat EA et al., (1991) cited above. In some embodiments, the antibody includes a heavy chain having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or at least 99% identical to any of the heavy chain constant regions provided herein. In some embodiments, the antibody comprises a light chain having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or at least 99% identical to any of the light chain constant regions provided herein. In some embodiments, the antibody is modified, for example, via glycosylation, phosphorylation, SUMOylation, and / or methylation. In some embodiments, the antibody is a glycosylated antibody conjugated to one or more sugar or carbohydrate molecules. In some embodiments, one or more sugar or carbohydrate molecules are conjugated to the antibody via N-glycosylation, O-glycosylation, C-glycosylation, glyciation (GPI anchor attachment), and / or phosphoglycosylation. In some embodiments, one or more sugar or carbohydrate molecules are monosaccharides, disaccharides, oligosaccharides, or glycans. In some embodiments, one or more sugar or carbohydrate molecules are branched oligosaccharides or branched glycans. In some embodiments, one or more sugar or carbohydrate molecules include mannose units, glucose units, N-acetylglucosamine units, or phospholipid units. In some embodiments, the antibody is a construct comprising a polypeptide containing one or more antigen-binding fragments of the present disclosure linked to a linker polypeptide or an immunoglobulin constant domain.Linker polypeptides consist of two or more amino acid residues joined by peptide bonds and are used to link one or more antigen-binding moieties. Examples of linker polypeptides have been reported (see, for example, Holliger, P., et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, RJ, et al. (1994) Structure 2:1121-1123). Furthermore, antibodies may be part of larger immunoadhesion molecules formed by the covalent or noncovalent association of an antibody or antibody moiety with one or more other proteins or peptides. Examples of such immunoadhesion molecules include the use of streptavidin core regions to construct tetrameric scFv molecules (Kipriyanov, SM, et al. (1995) Human Antibodies and Hybridomas 6:93-101), and the use of cysteine ​​residues, marker peptides, and C-terminal polyhistidine tags to construct divalent biotinylated scFv molecules (Kipriyanov, SM, et al. (1994) Mol.Immunol.31:1047-1058).

[0033] Approximately: As used herein, the terms “approximately” or “about” refer to values ​​similar to the described reference values ​​when applied to the values ​​of one or more subjects. In certain embodiments, unless otherwise stated or evident from the content (except where such numbers may exceed 100% of the possible values), the terms “approximately” or “about” refer to a range of values ​​that fall within 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (above or below) the described reference values.

[0034] Bispecific antibodies: As used herein, the term “bispecific antibodies” refers to an antibody containing two distinct antigen-specific binding sites, or, in combination, two antibodies (covalently or noncovalently) linked, each containing two distinct antigen-specific binding sites. Non-limiting examples of the format or structure of bispecific antibodies are provided in Labrijn, AF, et al., Bispecific antibodies: a mechanistic review of the pipeline, Nature Reviews Drug Discovery volume 18, pages 585-608 (2019) and Brinkmann U and Kontermann EE, The making of bispecific antibodies, MAbs. 2017 Feb / Mar;9(2):182-212, the full contents of each of these are incorporated herein by reference.

[0035] CDR: As used herein, the term “CDR” refers to the complementarity-determining region within the antibody variable sequence. A typical antibody molecule usually contains a heavy chain variable region or heavy chain variable domain (VH) and a light chain variable region or light chain variable domain (VL) involved in antigen binding. The VH and VL regions can be further subdivided into hypervariable regions also known as “complementarity-determining regions” (“CDR”) and more conserved regions known as “framework regions” (“FR”). Each VH and VL typically consists of three CDRs and four FRs, arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The scope of the framework regions and CDRs can be precisely identified using methodologies known in the art, such as the Kabat definition, IMGT definition, Chothia definition, AbM definition, and / or contact definition, all of which are well known in the art.For example, Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, USDepartment of Health and Human Services, NIH Publication No. 91-3242, IMGT®, the international ImMunoGeneTics information system (registered trademark) http: / / www.imgt.org, Lefranc, M.-P. et al., Nucleic Acids. Res.,27:209-212(1999), Ruiz,M.et al.,Nucleic Acids Res.,28:219-221(2000),Lefranc,M.-P.,Nucleic Acids Res.,29:207-209(2001),Lefranc,M.-P.,Nucleic Acids Res.,31:307-310(2003), Lefranc, M.-P.et. al.,In Silico Biol.,5,0006(2004)[[Epub]],5:45-60(2005),Lefranc,M.-P.et al.,Nucleic Acids Res.,33:D593-597(2005),Lefranc,M.-P.et al.,Nucleic Acids Res.,37:D1006-1012(2009), Lefranc,M.-P.et al.,Nucleic Acids Res.,43:D413-422(2015),Chothia et al.,(1989)Nature 342:877,Chothia,C.et al. (1987) J. Mol. Biol. 196:901-917, Al-lazikani et al. See al(1997)J.Molec.Biol.273:927-948 and Almagro,J.Mol.Recognit.17:132-143(2004). Also see hgmp.mrc.ac.uk and bioinf.org.uk / abs. As used herein, CDR may mean CDR as defined by any method known in the art.Two antibodies having the same CDR means that the amino acid sequences of the CDRs of the two antibodies are the same, as determined by the same method, for example, the IMGT definition.

[0036] In certain embodiments, three CDRs are present in each of the variable regions of the heavy and light chains, and these are designated as CDR1, CDR2, and CDR3 with respect to each variable region. As used herein, the term “CDR set” refers to a group of three CDRs occurring in a single variable region capable of binding to an antigen. The exact boundaries of these CDRs are defined differently depending on the system. The system described by Kabat (Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987) and (1991)) not only provides a clear residue numbering system applicable to any variable region of an antibody, but also provides precise residue boundaries that define three CDRs. These CDRs are sometimes called Kabat CDRs. The sub-parts of the CDRs may be designated as L1, L2, and L3, or H1, H2, and H3, where "L" and "H" designate the light chain region and heavy chain region, respectively. These regions are sometimes called Chothia CDRs and have boundaries that overlap with Kabat CDRs. Other boundaries that define CDRs that overlap with Kabat CDRs are described by Padlan (FASEB J.9:133-139 (1995)) and MacCallum (J Mol Biol This is described in 262(5):732-45(1996). Furthermore, other CDR boundary definitions may not strictly adhere to one of the above systems and, although they overlap with Kabat CDRs, they may be shortened or extended in consideration of predictions or experimental results that certain residues or groups of residues, or even the entire CDR, do not significantly affect antigen binding. The methods used herein may utilize CDRs defined according to any of these systems, but preferred embodiments use Kabat or Chothia-defined CDRs.

[0037] CDR-transplanted antibody: As used herein, the term "CDR-transplanted antibody" refers to an antibody that contains heavy chain variable region sequences and light chain variable region sequences derived from one species, but in which one or more sequences of the VH and / or VL CDR regions are replaced with CDR sequences from another species. For example, in an antibody having mouse heavy chain variable region and light chain variable region, one or more mouse CDRs (e.g., CDR3) are replaced with human CDR sequences.

[0038] Chimeric antibody: As used herein, the term "chimeric antibody" refers to an antibody that contains a heavy chain variable region sequence and a light chain variable region sequence derived from one species and a constant region sequence derived from another species, such as an antibody in which the mouse heavy chain variable region and light chain variable region are linked to the human constant region.

[0039] Complementary: As used herein, the term “complementary” refers to the ability of two nucleotides or two sets of nucleotides to form a precise pairing. Specifically, complementarity is a term that characterizes the degree of hydrogen bond pairing that results in a bond between two nucleotides or two sets of nucleotides. For example, if a base at one position of an oligonucleotide can form a hydrogen bond with a base at a corresponding position in a target nucleic acid (e.g., mRNA), then those bases are considered complementary to each other at that position. Base pairings can include both canonical Watson-Crick base pairings and non-Watson-Crick base pairings (e.g., Wobble base pairings and Hoogsteen base pairings). For example, in some embodiments, in the case of complementary base pairing, an adenosine-type base (A) is complementary to a thymidine-type base (T) or a uracil-type base (U), a cytosine-type base (C) is complementary to a guanosine-type base (G), and universal bases such as 3-nitropyrrole or 5-nitroindole can hybridize to any A, C, U, or T and are considered complementary to them. Inosine (I) is also considered a universal base in the art and is considered complementary to any of A, C, U, or T.

[0040] Conservative amino acid substitutions: As used herein, “conservative amino acid substitutions” refer to amino acid substitutions that do not alter the relative charge or size properties of the protein being substituted. Variants can be prepared according to methods of modifying polypeptide sequences known to those skilled in the art, for example, according to references that summarize such methods, e.g., Molecular Cloning: A Laboratory Manual, J. Sambrook, et al., eds., Fourth Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2012, or according to methods found in Current Protocols in Molecular Biology, FMAusubel, et al., eds., John Wiley & Sons, Inc., New York. Conservative amino acid substitutions include substitutions made between amino acids in the following groups: (a) M, I, L, V; (b) F, Y, W; (c) K, R, H; (d) A, G; (e) S, T; (f) Q, N; and (g) E, D.

[0041] Cross-reactivity: As used herein, the term “cross-reactivity” refers to the property of a drug to specifically bind to multiple antigens of similar type or class (e.g., multiple homologous, paralogous, or orthologous antigens) with similar affinity or binding strength. For example, in some embodiments, an antibody that cross-reactive to human and non-human primate antigens of similar type or class (e.g., human KLK5 and non-human primate KLK5, human KLK7 and non-human primate KLK7) can bind to human and non-human primate antigens with similar affinity or binding strength. In some embodiments, the antibody cross-reactive to human and rodent antigens of similar type or class. In some embodiments, the antibody cross-reactive to rodent antigens and non-human primate antigens of similar type or class. In some embodiments, the antibody cross-reactive to human, non-human primate, and rodent antigens of similar type or class.

[0042] Dual-inhibitory antibody: As used herein, the term “dual-inhibitory antibody” refers to an antibody that targets at least two (e.g., 2, 3) different antigens via a common individual antigen-specific binding site and inhibits the activity of those antigens. In some embodiments, a dual-inhibitory antibody targets at least two different proteins (e.g., expressed from two different genes (e.g., endogenous genes, e.g., homologs, paralogs)) via a common individual antigen-specific binding site and inhibits the activity of at least two different proteins (e.g., enzymes such as proteases). In some embodiments, a dual-inhibitory antibody targets at least two different proteases (e.g., expressed from two different endogenous genes, e.g., KLK5 and KLK7) via a common individual antigen-specific binding site and inhibits the activity of at least two different proteases. In some embodiments, the common individual antigen-specific binding site binds to similar (e.g., homologous) domains shared between or among at least two different antigens. For example, in some embodiments, the common individual antigen-specific binding site binds to similar (e.g., homologous) catalytic domains or substrate-binding sites shared between or among at least two different enzymes, e.g., proteases. In some embodiments, the common individual antigen-specific binding site of a dual inhibitory antibody includes amino acids in one or more complementarity-determining regions of the antibody. In some embodiments, the common individual antigen-specific binding site of a dual inhibitory antibody is located within the heavy chain variable region and / or light chain variable region of the antibody. In some embodiments, the common individual antigen-specific binding site of a dual inhibitory antibody includes one or more complementarity-determining regions in the heavy chain variable region and / or light chain variable region of the antibody. In some embodiments, the common individual antigen-specific binding site of a dual inhibitory antibody includes HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 in the heavy chain and light chain variable regions of the antibody. In some embodiments, the dual inhibitory antibody specifically binds to two different proteins (e.g., KLK5 and KLK7) expressed from two different genes.

[0043] Effective dose: As used herein, “effective dose” refers to the amount of each activator (e.g., anti-KLK5 / KLK7 + Th2 cytokine-targeted bispecific antibody) required to confer a desired effect (e.g., a therapeutic effect on a target), either alone or in combination with one or more other activators. In some embodiments, the therapeutic effect is reduced KLK5 and / or KLK7 activity and / or reduced Th2 cytokine activity and / or alleviated disease (e.g., Netherton syndrome, eosinophilic esophagitis, and atopic dermatitis) or related symptoms, such as improved barrier function.

[0044] Framework: As used herein, the terms “framework” or “framework sequence” refer to the sequence remaining after removing the CDRs from the variable region. Since the precise definition of a CDR sequence can be determined by various systems, the meaning of the framework sequence is also subject to different interpretations accordingly. The six CDRs (CDR-L1, CDR-L2, and CDR-L3 of the light chain, and CDR-H1, CDR-H2, and CDR-H3 of the heavy chain) divide the framework regions of the light and heavy chains into four sub-regions (FR1, FR2, FR3, and FR4) on each chain, with CDR1 located between FR1 and FR2, CDR2 between FR2 and FR3, and CDR3 between FR3 and FR4. When a framework region is referred to by others without specifying a particular sub-region as FR1, FR2, FR3, or FR4, it represents a combination of FRs within the variable region of a single naturally occurring immunoglobulin chain. As used herein, FR represents one of four subregions, and multiple FRs represent two or more of the four subregions that constitute a framework region. Human heavy and light chain acceptor sequences are known in the art. In one embodiment, acceptor sequences known in the art may be used in the antibodies disclosed herein.

[0045] Human Antibodies: As used herein, the term “human antibody” is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of this disclosure may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-directed mutagenesis in vitro, or by somatic mutation in vivo), for example, in the CDR, specifically CDR3. However, as used herein, the term “human antibody” is not intended to include antibodies in which a CDR sequence derived from the germline of another mammalian species, such as mouse, has been transplanted into a human framework sequence.

[0046] Humanized Antibodies: As used herein, the term “humanized antibody” refers to an antibody that contains heavy and light chain variable region sequences derived from a non-human species (e.g., mouse), but in which at least a portion of the VH and / or VL sequences has been modified to be more “human-like,” i.e., more similar to human germline variable sequences. One type of humanized antibody is a CDR-transplant antibody in which a human CDR sequence is introduced into non-human VH and VL sequences to replace the corresponding non-human CDR sequence. In one embodiment, a humanized antibody is provided. Such an antibody may be produced by obtaining a mouse monoclonal antibody using conventional hybridoma technology and then humanizing it using in vitro genetic engineering, such as that disclosed in PCT Publication WO2005 / 123126 A2 by Kasaian et al.

[0047] A humanized antibody is a human immunoglobulin (recipient antibody) in which residues from the recipient's complementarity-determining region (CDR) are replaced with residues from the CDR of a non-human species (donor antibody), such as mouse, rat, or rabbit, having the desired specificity, affinity, and capabilities. In some embodiments, Fv framework region (FR) residues of the human immunoglobulin are replaced with corresponding non-human residues. Furthermore, the humanized antibody may include residues not found in the recipient antibody or the transferred CDR or framework sequence, but included to further improve and optimize the antibody's performance. Generally, a humanized antibody may include substantially all of at least one, typically two, variable domains, where all or substantially all of the CDR region corresponds to that of a non-human immunoglobulin, and all or substantially all of the FR region corresponds to that of the human immunoglobulin consensus sequence. The humanized antibody also includes, optimally, at least a portion of the immunoglobulin constant region or domain (Fc), typically at least a portion of the constant region or domain (Fc) of the human immunoglobulin. Antibodies may have modified Fc regions as described in WO99 / 58572. Other forms of humanized antibodies have one or more modified CDRs (1, 2, 3, 4, 5, 6) relative to the original antibody, also called one or more CDRs derived from one or more CDRs of the original antibody. Humanized antibodies may also undergo affinity maturation.

[0048] In some embodiments, humanization is achieved by transplanting a CDR (e.g., those shown in Table 1a or 1b) into a human variable domain (e.g., IGKV1-NL1*01 and IGHV1-3*01 human variable domains). In some embodiments, the antibodies of this disclosure are humanized variants comprising one or more amino acid substitutions (e.g., in the VH framework region) compared to any one of the VHs listed in Table 1a or 1b, and / or comprising one or more amino acid substitutions (e.g., in the VL framework region) compared to any one of the VLs listed in Table 1a or 1b.

[0049] Isolated Antibodies: As used herein, “isolated antibodies” are intended to refer to antibodies that substantially contain no other antibodies with different antigen specificities. However, isolated antibodies may, in some embodiments, exhibit cross-reactivity to other antigens. Furthermore, isolated antibodies may substantially contain no other cellular material and / or chemical substances.

[0050] Kabat Numbering: As used herein, the terms “Kabat numbering,” “Kabat definition,” and “Kabat labeling” are used synonymously. These terms, as recognized in the art, refer to a system for numbering amino acid residues that are more variable than other amino acid residues (i.e., hypervariable) in the heavy chain variable region and light chain variable region of an antibody, or in their antigen-binding regions (Kabat et al. (1971) Ann. NY Acad, Sci. 190:382-391 and Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, USD Department of Health and Human Services, NIH Publication No. 91-3242). In the heavy chain variable region, the hypervariable region ranges from amino acid positions 31-35 in CDR1, from amino acid positions 50-65 in CDR2, and from amino acid positions 95-102 in CDR3. In the case of the heavy chain variable region, the hypervariable region is located at amino acid positions 24-34 in CDR1, amino acid positions 50-56 in CDR2, and amino acid positions 89-97 in CDR3.

[0051] Multispecific antigen-binding molecule: As used herein, the term “multispecific antigen-binding molecule” refers to a molecule containing two or more antigen-specific binding sites. In some embodiments, the multispecific antigen-binding molecule is a multispecific antibody (e.g., a bispecific antibody).

[0052] Multispecific antibody: As used herein, the term “multispecific antibody” refers to an antibody comprising at least two distinct antigen-specific binding sites, or, in combination, at least two (covalently or noncovalently) linked antibodies comprising at least two distinct antigen-specific binding sites. In some embodiments, a multispecific antibody is a bispecific antibody. Non-limiting examples of the format or structure of multispecific antibodies are provided in Sawant MS, et al., Toward Drug-Like Multispecific Antibodies by Design, Int J Mol Sci. 2020 Oct 12;21(20):7496; Klein C, et al., The use of CrossMAb technology for the generation of bi- and multispecific antibodies, MAbs 2016 Aug-Sep;8(6):1010-20; and Brinkmann U and Kontermann EE, The making of bispecific antibodies, MAbs. 2017 Feb / Mar;9(2):182-212, the full contents of each of these are incorporated herein by reference.

[0053] Recombinant Antibodies: As used herein, the term “recombinant antibodies” means, for example, antibodies isolated from recombinant, combined human antibody libraries (Hoogenboom HR, (1997) TIB Tech. 15:62-70, Azzazy H., and Highsmith WE, (2002) Clin. Biochem. 35:425-445, Gavilondo JV, and Larrick JW (2002) BioTechniques 29:128-145, Hoogenboom H., and Chames P. (2000) Immunology Today 21:371-378), or antibodies isolated from animals transgenic to human immunoglobulin genes (e.g., mice) (e.g., Taylor, LD, et al. (1992) Nucl. Acids Res. 20:6287-6295, Kellermann SA., and Green LL (2002) Current Opinion). The disclosure is intended to include all antibodies prepared, expressed, produced, or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into host cells (as described in detail herein), including antibodies prepared, expressed, produced, or isolated by any other means involving splicing of human immunoglobulin gene sequences against other DNA sequences (see in Biotechnology 13:593-597, Little M. et al (2000) Immunology Today 21:364-370), or antibodies expressed using a recombinant expression vector transfected into host cells. In some embodiments, recombinant human antibodies are provided herein. In certain embodiments, such recombinant human antibodies have a variable region and a constant region derived from a human germline immunoglobulin sequence. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, if animal transgenicity for human Ig sequences is used, in vivo somatic mutagenesis), and therefore the amino acid sequences of the VH and VL regions of the recombinant antibody are derived from human germline VH and VL sequences, but may not be naturally present in vivo within the human antibody germline repertoire.One embodiment of the present disclosure provides, for example, a complete human antibody capable of binding to human KLK5 or KLK7, which can be generated using appropriate techniques, such as using a human Ig phage library, such as that disclosed in Jermutus et al., PCT Publication WO2005 / 007699A2.

[0054] Selective: As used herein, the terms “selective” or “selectively” refer to the ability of a molecule to produce an effect (e.g., inhibition, antagonism, agonization, etc.) on its target molecule compared to a reference molecule. For example, a molecule that selectively inhibits its target molecule means that this molecule can inhibit the target molecule to a degree that is distinguishable from the reference molecule in an inhibition assay or other inhibition situation. For example, with respect to an inhibitor, the term “selectively inhibiting” refers to the ability of the inhibitor to inhibit the target molecule to a degree that is distinguishable from a reference molecule that is substantially not inhibited in an inhibition assay, to a degree that enables selective inhibition of the target molecule, as described herein. After the reaction is complete, the signal produced by the inhibition of the target molecule can be measured. The maximum half-molecule inhibitor concentrations for the target molecule and the reference molecule can be calculated.

[0055] Specific binding: As used herein, the term “specifically binding” refers to the ability of a molecule to bind to a binding partner with a degree of affinity or binding strength that enables the molecule to be used to distinguish the binding partner from a suitable control in a binding assay or other binding situation. With respect to an antibody, the term “specifically binding” refers to the ability of an antibody to bind to a specific antigen with a certain degree of affinity or binding strength compared to a suitable reference antigen(s), as described herein, enabling the antibody to be used to distinguish a particular antigen from other antigens. In some embodiments, the K of the antibody to bind to a target D However, at least about 10 -4 M, 10 -5 M, 10 -6 M, 10 -7 M, 10 -8M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12 M, 10 -13 When M is 10 or less, the antibody binds specifically to the target. In some embodiments, the antibody binds specifically to KLK5 or KLK7. In some embodiments, the antibody binds specifically to a Th2 cytokine (e.g., IL-13, IL-4, IL-5, IL-6, IL-9, IL-31, IL-17E (IL-25), OX40L, TSLP, etc.) or its receptor. In some embodiments, the bispecific antibody comprises an antigen-binding site that binds specifically to KLK5 and KLK7 and an antigen-binding site that binds specifically to a Th2 cytokine (e.g., IL-13, IL-4, IL-5, IL-6, IL-9, IL-31, IL-17E (IL-25), OX40L, TSLP, etc.) or its receptor.

[0056] Subject: As used herein, the term "subject" refers to a mammal. In some embodiments, the subject is a non-human primate or a rodent. In some embodiments, the subject is a human. In some embodiments, the subject is a patient having or suspected of having a disease, e.g., a human patient.

[0057] Th2-targeted antibody: As used herein, the term "Th2-targeted antibody" refers to an antibody that binds to a Th2 cytokine or its receptor. In some embodiments, the Th2-targeted antibody inhibits Th2 cytokine-mediated signaling. In some embodiments, the Th2-targeted antibody suppresses Th2 cytokine-mediated inflammation.

[0058] Treatment: As used herein, the terms “to treat” or “treatment” refer to the application or administration of a composition comprising one or more activators (e.g., anti-KLK5 / KLK7+Th2 bispecific antibodies) to a subject having a target disease or disorder, symptoms of a disease / disorder, or a predisposition to a disease or disorder, with the aim of curing, healing, reducing, mitigating, modifying, correcting, improving, or influencing the disease, symptoms of a disease or disorder, or a predisposition to a disease or disorder. Mitigation of a target disease / disorder includes delaying or preventing the onset or progression of the disease, or reducing the severity of the disease. It will be understood that “to treat” or reference to treatment may also refer to an antibody comprising a KLK5 / KLK7+Th2 bispecific antibody for use in such a manner.

[0059] II. Antibodies (a) Targeting KLK5 and KLK7 In some embodiments, dual inhibitory antibodies targeting KLK5 and KLK7 (referred to as anti-KLK5 / KLK7 antibodies) are antibodies specific to both kallikrein-5 (KLK5) and KLK7 via a common specific antigen-binding site. Dual inhibitory KLK5 / KLK7 antibodies are described in PCT / US2024 / 019231, the entirety of which is incorporated herein by reference. In some embodiments herein, antibodies are provided that bind with high specificity and affinity to KLK5 (e.g., human KLK5, or mouse KLK5) and KLK7 (e.g., human KLK7, or mouse KLK7) via a common antigen-binding site. In some embodiments herein, the anti-KLK5 / KLK7 antibodies specifically bind to the KLK5 epitope that is or will be exposed to the antibody, and to the KLK7 epitope that is or will be exposed to the antibody. In some embodiments, the anti-KLK5 / KLK7 antibodies described herein bind to the active sites of KLK5 and KLK7. In some embodiments, the anti-KLK5 / KLK7 antibodies provided herein specifically bind to KLK5 and KLK7 from humans, non-human primates, mice, rats, etc. In some embodiments, the anti-KLK5 / KLK7 antibodies provided herein specifically bind to human KLK5. In some embodiments, the anti-KLK5 / LKL7 antibodies provided herein specifically bind to mouse KLK5. In some embodiments, the anti-KLK5 / KLK7 antibodies provided herein specifically bind to human KLK7. In some embodiments, the anti-KLK5 / LKL7 antibodies provided herein specifically bind to mouse KLK7. In some embodiments, this specification provides a multispecific antibody comprising an arm having an antigen-specific binding site of a dual inhibitory antibody targeting KLK5 and KLK7, and an arm having an antigen-specific binding site that specifically binds to a Th2 cytokine (e.g., IL-13, IL-4, IL-5, IL-6, IL-9, IL-31, IL-17E (IL-25), OX40L, TSLP, etc.) or its receptor.For example, in some embodiments, a bispecific antibody is provided herein that comprises an arm having an antigen-specific binding site for a biinhibitory antibody targeting KLK5 and KLK, and an arm having an antigen-specific binding site that specifically binds to a Th2 cytokine (e.g., IL-13, IL-4, IL-5, IL-6, IL-9, IL-31, IL-17E (IL-25), OX40L, TSLP, etc.).

[0060] In some embodiments, the anti-KLK5 / KLK7 antibody is not a bispecific antibody or bispecific antigen-binding molecule in which KLK5 binding is conferred by one binding site within the antibody and KLK7 binding is conferred by a different binding site within the antibody.

[0061] In some embodiments, the anti-KLK5 / KLK7 antibodies described herein may be characterized by reference to certain functional properties. In some embodiments, the anti-KLK5 / KLK7 antibodies described herein specifically bind to KLK5 and KLK7. In some embodiments, the anti-KLK5 / KLK7 antibodies specifically bind to the active forms of KLK5 and KLK7. In some embodiments, the anti-KLK5 / KLK7 antibodies do not bind to the inactive forms (proforms) of KLK5 and KLK7. In some embodiments, the antibody specifically binds to the active forms of KLK5 and KLK7, but does not specifically bind to the inactive forms of KLK5 or KLK7. In some embodiments, the antibody detectably binds to the active forms of KLK5 and KLK7, but does not detectably bind to the inactive forms of KLK5 or KLK7 under the same or equivalent conditions. In some embodiments, anti-KLK5 / KLK7 antibodies inhibit KLK5 and KLK7 protease activity. In some embodiments, anti-KLK5 / KLK7 antibodies are not cleaved by KLK5 or KLK7 when bound to them. In some embodiments, anti-KLK5 / KLK7 antibodies compete with SPINK5 and / or leupeptin for binding to the active sites of KLK5 and KLK7. In some embodiments, anti-KLK5 / KLK7 antibodies reduce keratosis and desquamation. In some embodiments, anti-KLK5 / KLK7 antibodies reduce stratum corneum thickness. In some embodiments, anti-KLK5 / KLK7 antibodies reduce inflammation and epidermal effects.

[0062] Kallikrein-5, also known as stratum corneum trypsinase (SCTE), is a serine protease expressed in the epidermis, encoded by the KLK5 gene. The KLK5 gene is one of 15 kallikrein subfamily members located in a cluster on the chromosome. Its expression is upregulated by estrogen and progestin. KLK5 is expressed in the stratum granulosum and stratum corneum. In some embodiments, KLK5 controls epidermal desquamation. In some embodiments, KLK5 controls epidermal desquamation in conjunction with other members of the kallikrein family proteases (e.g., KLK7 and / or KLK14). In some embodiments, KLK5 degrades proteins that make up the epidermis (e.g., stratum corneum, stratum clearusa, stratum granulosum, stratum spinosum, or stratum basale). In some embodiments, KLK5 degrades proteins that form the stratum corneum and / or granular layer (e.g., cornodesmosine (CDSN), desmoglein 1 (DSG1), and desmocolin 1 (DSC1)). In the epidermis (e.g., granular layer and stratum corneum), KLK5 is expressed as pro-KLK5, an inactive form (sometimes called proform or pro-form), which can self-activate itself. Once activated, KLK5 can convert both pro-KLK7 and pro-KLK14 to their active forms via proteolytic cleavage. Subsequently, active KLK14 can activate newly generated pro-KLK5, thus forming a positive feedback loop (see, for example, Nauroy et al., Kallikreins: Essential epidermal messengers for regulation of the skin microenvironment during homeostasis, repair and disease, Matrix Biol Plus. 2019;6-7:100019). KLK7 and KLK14 also degrade proteins that form the stratum corneum and / or granular layer (e.g., cornodesmosine (CDSN), desmoglein 1 (DSG1), and desmocolin 1 (DSC1)).Structural proteins such as CDSN, DSG1, and DSC1 are adhesion proteins in the extracellular portion of corneodesmosomes, which are junctional structures that mediate the adhesion of keratinocytes. Degradation of these proteins on the epidermal surface leads to desquamation, which can result in skin barrier defects (e.g., stratum corneum exfoliation, decreased permeability barrier, allergies, and inflammation). KLK5 and KLK7 are involved in this process (see, for example, Caubet et al., Degradation of Corneodesmosome Proteins by Two Serine Proteases of the Kallikrein Family, SCTE / KLK5 / hK5 and SCCE / KLK7 / hK7, Journal of Investigative Dermatology, Volume 122, Issue 5, May 2004, Pages 1235-1244). Inhibition of KLK5 and / or KLK7 promotes improved skin barrier integrity and reduced inflammation (e.g., Chavarria-Smith et al., Dual antibody inhibition of KLK5 and KLK7 for Netherton syndrome and atopic dermatitis, SCIENCE TRANSLATIONAL MEDICINE, 14 Dec 2022, Vol14, Issue 675).

[0063] Kallikrein-7 is a serine protease encoded by the KLK7 gene in humans. KLK7 is characterized as a stratum corneum chymotriptic enzyme (SCCE). It is the seventh member of the human kallikrein family, which includes 15 homologous serine proteases located on chromosome 19. KLK7 is secreted as an inactive zymogen (e.g., in the granular layer of the epidermis) and requires proteolytic cleavage to be activated. In some embodiments, KLK5 or matryptase activates KLK7. Once activated, KLK7 can cleave proteins that form the stratum corneum and / or granular layer (e.g., corneodesmosine (CDSN), desmoglein 1 (DSG1), and desmocolin 1 (DSC1)) (see, for example, Caubet et al. (May 2004). Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family, SCTE / KLK5 / hK5 and SCCE / KLK7 / hK7. The Journal of Investigative Dermatology. 122(5):1235-1244). These proteins constitute the extracellular component of corneodesmosomes, which are intercellular adhesion structures that connect intermediate filaments of adjacent cells in the stratum corneum. In some embodiments, proteolysis of keratinodesmosomes leads to epidermal desquamation (i.e., the shedding of keratinocytes from the outer layer of the epidermis). In some embodiments, the combined roles of KLK5 and KLK7 suggest that the KLK cutaneous cascade is responsible for regulating desquamation. KLK7 is a chymotrypsin-like serine protease that cleaves proteins at tyrosine, phenylalanine, or leucine residues. In some embodiments, dysregulation of KLK7 is linked to several skin disorders, including atopic dermatitis, psoriasis, and Netherton syndrome. These diseases are characterized by excessively dry, scaly, and inflamed skin due to a breakdown of skin homeostasis and normal barrier function.

[0064] In some embodiments, the anti-KLK5 / KLK7 antibodies described herein specifically bind to epitopes on human KLK5. Exemplary amino acid sequences of human KLK5 are described in NCBI accession numbers NP_001070959.1, NP_001070960.1, or NP_036559.1, and UniProt accession numbers: Q8IU55, Q6S9W8, M0QXX2, Q9P0G3, A0A2I2MP48, or A0A2I2MP49, and these entire sequences are incorporated herein by reference.

[0065] In some embodiments, the anti-KLK5 / KLK7 antibodies described herein specifically bind to epitopes on mouse KLK5. Exemplary amino acid sequences of mouse KLK5 are described in NCBI accession numbers NP_081082.1, XP_006541213.1, XP_006541214.1, XP_006541215.1, XP_036009294.1, or XP_036009295.1, and UniProt accession number P15945, or Q9D140, and these entire sequences are incorporated herein by reference.

[0066] In some embodiments, the anti-KLK5 / KLK7 antibodies described herein specifically bind to an epitope on human KLK7 via the same antigen-binding site that binds to KLK5 (e.g., human KLK5 or mouse KLK5). Exemplary amino acid sequences of human KLK7 are described in NCBI accession numbers NP_001193982.1, NP_001230055.1, NP_005037.1, NP_644806.1, and UniProt accession numbers: M0QYU8, Q6DTY1, X2J289, X2J4X7, A0A024R4H6, P49862, A0A2H4GDB2, and A0A2H4GDB6, the entirety of which are incorporated herein by reference.

[0067] In some embodiments, the anti-KLK5 / KLK7 antibodies described herein specifically bind to an epitope on mouse KLK7 via the same antigen-binding site that binds to KLK5 (e.g., human KLK5 or mouse KLK5). Exemplary amino acid sequences of mouse KLK7 are described in NCBI accession number NP_036002.1 and UniProt accession number Q91VE3, and these entire sequences are incorporated herein by reference.

[0068] In some embodiments, the anti-KLK5 / KLK7 antibody described herein specifically binds to an epitope on KLK5 (e.g., the active site of the enzyme, also known as the catalytic domain / pocket of human KLK5 or mouse KLK5) and an epitope on KLK7 (e.g., the catalytic domain / pocket of human KLK7 or mouse KLK7). In some embodiments, the anti-KLK5 / KLK7 antibody described herein prevents KLK5 (e.g., human or mouse KLK5) and KLK7 (e.g., human or mouse KLK7) from cleaving their substrates. In some embodiments, the anti-KLK5 antibody described herein binds to fragments of KLK5 (e.g., human or mouse KLK5) and fragments of KLK7 (e.g., human or mouse KLK7). Fragments of KLK5 and / or KLK7 (e.g., human or mouse) may be approximately 5 to 425 amino acids, 10 to 400 amino acids, 50 to 350 amino acids, 100 to 300 amino acids, 150 to 250 amino acids, 200 to 300 amino acids, 75 to 150 amino acids, 25 to 100 amino acids, or 10 to 30 amino acids in length. Without intending to be bound by any particular theory, in some embodiments, the heavy chain (HC) complementarity-determining region 3 (CDR3) of any one of the anti-KLK5 / KLK7 antibodies described herein inhibits KLK5 (e.g., human or mouse KLK5) and KLK7 (e.g., human or mouse KLK7) by binding to the catalytic domain / pocket of KLK5.

[0069] In some embodiments, the anti-KLK5 / KLK7 antibodies described herein inhibit KLK5 protease activity, KLK7 protease activity, or protease activity of both KLK5 and KLK7. In some embodiments, the anti-KLK5 / KLK7 antibodies inhibit KLK5 cleavage of BOC-Val-Pro-Arg-AMC with an IC50 of less than 30 nM, less than 25 nM, less than 20 nM, less than 15 nM, less than 10 nM, less than 5 nM, less than 3 nM, less than 2.5 nM, less than 2 nM, or less than 1.5 nM, less than 1 nM, less than 0.5 nM, less than 0.3 nM, less than 0.25 nM, less than 0.2 nM, or less than 0.1 nM. In some embodiments, the anti-KLK5 / KLK7 antibody is expressed in the following concentrations: 0.1nM-30nM, 0.1nM-20nM, 0.1nM-10nM, 0.1nM-5nM, 0.1nM-2.5nM, 0.1nM-2nM, 0.1nM-1nM, 0.1nM-0.5nM, 0.1nM-0.25nM, 0.1nM-50nM, 0.1nM-40nM, 0.1nM-30nM, 0.1nM-20nM, 0.1nM-10nM. M, 0.1nM~5nM, 0.1nM~2.5nM, 0.1nM~2nM, 0.1nM~1nM, 0.1nM~0.9nM, 0.1nM~0.8nM, 0.1nM~0.7nM, 0.1nM~0. 6nM, 0.1nM~0.5nM, 0.1nM~0.4nM, 0.1nM~0.3nM, 0.1nM~0.25nM, 0.1nM~0.2nM, 0.1nM~0.15nM, 0.15nM~0.2n M, 0.15nM~0.25nM, 0.15nM~0.3nM, 0.15nM~0.4nM, 0.15nM~0.5nM, 0.15nM~1nM, 0.2nM~30nM, 0.2nM~20nM, 0.2nM~10nM, 0.2nM~5nM, 0.2nM~2.5nM, 0.2nM~2nM, 0.2nM~1nM, 0.2nM~0.5nM, 0.2nM~0.2nM, 0.2nM~50nM, 0 .2nM~40nM, 0.2nM~30nM, 0.2nM~20nM, 0.2nM~10nM, 0.2nM~5nM, 0.2nM~2.5nM, 0.2nM~2nM, 0.2nM~1nM, 0.2 nM~0.9nM, 0.2nM~0.8nM, 0.2nM~0.7nM, 0.2nM~0.6nM, 0.2nM~0.5nM, 0.2nM~0.4nM, 0.2nM~0.3nM, 0.2nM~0.25nM, 1nM~30nM, 1nM~20nM, 1nM~10nM, 1nM~5nM, 1nM~2.5nM, 1nM~2nM, 1nM~3nM, 1nM~5.5nM, 1.5nM~2nM, 1.5nM~3nM, 1.5nM~5.5nM, 2nM~5nM, 2nM~4nM, 2nM~5.5nM, 3nM~5.5nM, 4nM~5.5nM, 3nM~30nM, 3nM~20nM, 3 nM~10nM, 3nM~5nM, 3nM~2.5nM, 3nM~4nM, 3nM~5.5nM, 5nM~30nM, 5nM~20nM, 5nM~10nM, 5nM~9nM, 5nM~8nM , 5nM~7nM, 5nM~6nM, 5nM~5.5nM, 10nM~30nM, 10nM~25nM, 10nM~20nM, 10nM~18nM, 10nM~15nM, 10nM~12nM, 12nM~20nM, 12nM~25nM, 12nM~16nM, 12nM~18nM, 12nM~20nM, 12nM~24nM, 12nM~28nM, 12nM~30nM, 15nM~3 0nM, 15nM~25nM, 15nM~20nM, 15nM~18nM, 18nM~30nM, 18nM~25nM, 18nM~20nM, 20nM~30nM, 20nM~25nM, 20n It inhibits the cleavage of KLK5 (e.g., human KLK5 or mouse KLK5) in BOC-Val-Pro-Arg-AMC with an IC50 in the range of M~22nM, 20nM~24nM, 20nM~26nM, 22nM~30nM, 22nM~25nM, 22nM~28nM, 24nM~30nM, 24nM~25nM, 24nM~26nM, or 24nM~28nM. In some embodiments, the anti-KLK5 / KLK7 antibody inhibits KLK7 cleavage of KHLF-AMC with an IC50 of less than 6 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2.5 nM, less than 2 nM, or less than 1.5 nM, less than 1 nM, less than 0.5 nM, less than 0.4 nM, less than 0.3 nM, less than 0.2 nM, less than 0.16 nM, less than 0.1 nM, or less than 0.05 nM. In some embodiments, the anti-KLK5 / KLK7 antibody is expressed in concentrations of 0.1nM to 30nM, 0.1nM to 20nM, 0.1nM to 10nM, 0.1nM to 5nM, 0.1nM to 2.5nM, 0.1nM to 2nM, 0.1nM to 1nM, 0.1nM to 0.5nM, 0.1nM to 0.25nM, 0.1nM to 50nM, and 0.1nM~40nM、0.1nM~30nM、0.1nM~20nM、0.1nM~10nM、0.1nM~5nM、0.1nM~2.5nM、0.1nM~2nM、0.1nM~1nM、0.1nM~0.9nM、0.1nM~0.8nM、0.1nM~0.7nM、0.1nM~0.6nM、0.1nM~0.5nM、0.1nM~0.4nM、0.1nM~0.3nM、0.1nM~0.25nM、0.1nM~0.2nM、0.1nM~0.15nM、0.15nM~0.2nM、0.15nM~0.25nM、0.15nM~0.3nM、0.15nM~0.4nM、0.15nM~0.5nM、0.15nM~1nM、0.2nM~30nM、0.2nM~20nM、0.2nM~10nM、0.2nM~5nM、0.2nM~2.5nM、0.2nM~2nM、0.2nM~1nM、0.2nM~0.5nM、0.2nM~0.2nM、0.2nM~50nM、0.2nM~40nM、0.2nM~30nM、0.2nM~20nM、0.2nM~10nM、0.2nM~5nM、0.2nM~2.5nM、0.2nM~2nM、0.2nM~1nM、0.2nM~0.9nM、0.2nM~0.8nM、0.2nM~0.7nM、0.2nM~0.6nM、0.2nM~0.5nM、0.2nM~0.4nM、0.2nM~0.3nM、0.2nM~0.25nM、1nM~30nM、1nM~20nM、1nM~10nM、1nM~5nM、1nM~2.5nM、1nM~2nM、1nM~3nM、1nM~5.5nM、1.5nM~2nM、1.5nM~3nM、1.5nM~5.5nM、2nM~5nM、2nM~4nM、2nM~5.5nM、3nM~5.5nM、4nM~5.5nM、3nM~30nM、3nM~20nM、3nM~10nM、3nM~5nM、3nM~2.5nM、3nM~4nM、3nM~5.5nM、5nM~30nM、5nM~20nM、5nM~10nM、5nM~9nM、5nM~8nM、5nM~7nM、5nM~6nM、5nM~5.5nM, 10nM~30nM, 10nM~25nM, 10nM~20nM, 10nM~18nM, 10nM~15nM, 10nM~12nM, 12nM~20nM, 12nM~25nM, 12nM~16nM, 12nM~18nM, 12nM~20nM, 12nM~24nM, 12nM~28nM, 12nM~30nM, 15nM~30nM, 15nM~25nM, 15nM~20nM, 15nM~18nM, 18nM~ IC50 values ​​within the ranges of 30nM, 18nM-25nM, 18nM-20nM, 20nM-30nM, 20nM-25nM, 20nM-22nM, 20nM-24nM, 20nM-26nM, 20nM-28nM, 22nM-30nM, 22nM-25nM, 22nM-28nM, 24nM-30nM, 24nM-25nM, 24nM-26nM, or 24nM-28nM inhibit KLK7 cleavage of KHLF-AMC.

[0070] In some embodiments, the anti-KLK5 / KLK7 antibody described herein specifically binds to the active forms of KLK5, KLK7, or KLK5 and KLK7. In some embodiments, the anti-KLK5 / KLK7 antibody described herein does not bind to the inactive forms of KLK5, KLK7, or KLK5 and KLK7. In some embodiments, the anti-KLK5 / KLK7 antibody described herein specifically binds to the active sites of KLK5, KLK7, or KLK5 and KLK7. In some embodiments, the anti-KLK5 / KLK7 antibody described herein specifically binds to the active form of KLK5, the active form of KLK7, or the active forms of KLK5 and KLK7, but does not specifically bind to the inactive form of KLK5, the inactive form of KLK7, or the inactive forms of KLK5 and KLK7. In some embodiments, the anti-KLK5 / KLK7 antibodies described herein are detectably bound to the active form of KLK5, the active form of KLK7, or the active forms of both KLK5 and KLK7, but are not detectably bound to the inactive form of KLK5, the inactive form of KLK7, or the inactive forms of both KLK5 and KLK7 under the same or equivalent conditions. The active site of KLK5 and / or KLK7 is the site on which the KLK5 and / or KLK7 substrate molecule binds and is cleaved. The active site may also be known as the catalytic domain or catalytic triresidue. In some embodiments, the active site of KLK5 or KLK7 (i.e., the catalytic domain or catalytic triresidue) consists of the amino acids Ser195, His57, and Asp102 of KLK5 or KLK7 (see, for example, Goettig et al., Natural and synthetic inhibitors of kallikrein-related peptidases (KLKs), Biochimie. 2010 Nov;92(11):1546-1567).

[0071] In some embodiments, the antibodies described herein are optimized versions (e.g., affinity-mature) of the parent antibody. In some embodiments, the antibodies described herein are at least about 10 -4 M, at least about 10 -5 M, at least about 10 -6 M, at least about 10 -7M, at least about 10 -8 M, at least about 10 -9 M, at least about 10 -10 M, at least about 10 -11 M, at least about 10 -12 M, at least about 10 -13 M, or lower binding affinity (e.g., K D The antibodies specifically bind KLK5 (e.g., human or mouse KLK5) and KLK7 (e.g., human or mouse KLK7) as shown by [the specified method]. In some embodiments, the antibodies described herein are 1 × 10⁶ -10 M~5×10 -9 M, 1×10 -10 M~1×10 -9 M, 5×10 -10 ~1 × 10 -9 M, 5×10 -11 ~1 × 10 -10 M, 1×10 -11 ~5×10 -10 M, or 5×10 -13 ~1 × 10 -12 Binding affinity of M (e.g., K DThe antibodies specifically bind to KLK5 (e.g., human or mouse KLK5) and KLK7 (e.g., human or mouse KLK7) (as shown by [representation]). For example, the antibodies of this disclosure can bind to KLK5 proteins (e.g., human or mouse KLK5) and KLK7 (e.g., human or mouse KLK7) with affinities of 1 pM to 500 nM, e.g., 50 pM to 100 nM, 500 pM to 500 pM, 500 pM to 1 nM, 1 nM to 5 nM, 1 nM to 10 nM, 5 nM to 25 nM, 10 nM to 50 nM, 50 nM to 100 nM, and 100 nM to 500 nM. This disclosure also includes antibodies that compete with any of the antibodies described herein for binding to KLK5 protein (e.g., human or mouse KLK5) and KLK7 protein (e.g., human or mouse KLK7) and have affinities of 100 nM or less (e.g., 80 nM or less, 50 nM or less, 20 nM or less, 10 nM or less, 1 nM or less, 500 pM or less, 50 pM or less, or 5 pM or less). The affinity and binding reaction rate of the antibodies can be tested using any suitable method, including but not limited to biosensor technologies (e.g., OCTET or BIACORE). In some embodiments, the antibodies described herein have K in the sub-nanomole range. D It connects to KLK5 and KLK7.

[0072] Binding affinity (or binding specificity) can be determined by a variety of methods, including equilibrium dialysis, equilibrium binding, gel filtration, ELISA, surface plasmon resonance (SPR), fluorescence-activated cell sorting (FACS), or spectroscopy (e.g., using fluorescence assays). Exemplary conditions for evaluating binding affinity are HBS-P buffer (10 mM HEPES pH 7.4, 150 mM NaCl, 0.005% (v / v) surfactant P2O) and PBS buffer (10 mM PO4-3, 137 mM NaCl, and 2.7 mM KCl). Using these techniques, the concentration of the binding protein can be measured as a function of the target protein concentration. Generally, the concentration of the binding protein ([[binding]]) is given by the following formula: The binding rate is related to the concentration of the free target protein (free protein) because [[binding]] = [[free]] / (Kd + [[free]]).

[0073] K A While it is not always necessary to make an accurate determination, obtaining a quantitative measure of affinity determined using methods such as ELISA or FACS analysis is useful, as it indicates that K A Since it is proportional to the activity, it may be sufficient, and therefore can be used for comparisons to determine whether a higher affinity is, for example, twice as high, to obtain a qualitative measurement of affinity, or to infer affinity by activity in a functional assay (e.g., an in vitro or in vivo assay).

[0074] Exemplary anti-KLK5 / KLK7 antibody sequences (e.g., heavy chain (HC) sequence and light chain (LC) sequence, heavy chain variable domain (VH) and light chain variable domain (VL), and CDR sequence) are provided in Tables 1a and 1b. [Table 1a-1] [Table 1a-2]

[0075] In some embodiments, certain amino acid positions in the antibodies described herein (e.g., amino acids in the VH / VL region and / or CDR region) are substitutable, and this substitution results in an antibody having substantially similar binding and biological activity (e.g., substantially similar binding affinity, binding specificity, protease inhibitory activity, anti-inflammatory activity, or a combination thereof) to the reference antibody. To identify substitutable positions in an antibody, the amino acid sequence of that antibody is compared to the sequences of other antibodies belonging to the same group as that antibody. If the identity of that amino acid varies among related antibodies of different groups at any particular position, that position is a substitutable position in the antibody. In other words, a substitutable position is a position where the identity of the amino acid varies among related antibodies. Positions containing constant amino acids are not substitutable positions.

[0076] In some embodiments, the above method may be used to provide a consensus antibody sequence. In such a consensus sequence, non-substitutable positions are indicated by the amino acids present at those positions, and substitutable positions are indicated by "X".

[0077] Depending on how the antibody is adopted, X may be a) any amino acid, b) any amino acid present at that position in any of the related antibodies within that group, or a conservatively substituted variant thereof, or c) any amino acid present at that position in any of the related antibodies within that group. Any antibody having a sequence encompassed by consensus should bind to the same antigen as any of the related antibodies.

[0078] In some embodiments, the methods described above may be employed in a method for designing and producing variants of a parent antibody that at least maintain (e.g., maintain or increase) the antigen-binding activity of the parent antibody. Antibodies containing substitutions at substitutable positions can be produced and tested, and therefore substitutions at those positions should not significantly reduce the antibody's binding activity. Generally, antibody variants of a parent antibody have an antigen-binding affinity of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% (e.g., at least 150%, at least 200%, at least 500%, at least 1000%, and typically up to at least 10,000%) of the parent antibody's binding affinity to a particular antigen.

[0079] In some embodiments, the substitutable positions of the parent antibody may be substituted by: a) any of 20 naturally occurring amino acids to produce a random substitution; b) an amino acid with biochemical properties similar to an amino acid already present at the substitutable position to produce a conservative substitution; c) an amino acid present at the same position in the related antibody to produce a designated substitution; or d) an amino acid present at the same position in a similar human antibody to produce a humanization substitution. Substitutions may occur in any portion of the antibody variable region, including any framework region or CDR. In certain embodiments, a single substitutable amino acid may be substituted. However, in other embodiments, multiple substitutable amino acids (e.g., up to about 5 or 10 or more) may be substituted. In certain embodiments, the type of substitution that can be performed at each substitutable position may be indicated by the type of amino acid present at that position in the related antibody. For example, if an unrelated amino acid (e.g., Ala, Gly, Cys, Glu, and Thr) is present at a particular position in the group of related antibodies, any amino acid can be substituted at that position without significantly reducing the antibody's binding activity. Exemplary amino acid substitutions of anti-KLK5 / KLK7 antibodies described herein are shown in Table 1b: [Table 1b]

[0080] In some embodiments, the antibodies of this disclosure include HC CDR1 containing the amino acid sequence GSISSX1DYYWX2 (SEQ ID NO: 28) (where X1 is S, D, or L, and X2 is G or V), HC CDR2 containing the amino acid sequence SIX3YX4X5X6TYYX7PSLKS (SEQ ID NO: 29) (where X3 is Y or D, X4 is S, F, or Y, X5 is G or A, X6 is S or D, or X7 is N or S), HC CDR3 containing the amino acid sequence ARGRPLGYGAX8HX9YYGMDV (SEQ ID NO: 30) (where X8 is R or K, or X9 is Y or D), LC CDR1 containing the amino acid sequence of SEQ ID NO: 4, LC CDR2 containing the amino acid sequence of SEQ ID NO: 5, and / or QQSPX 10 FPPLT(Sequence ID 31)(X 10 It contains LC CDR3 containing the amino acid sequence of P or Y.

[0081] In some embodiments, the antibody of the Disclosure comprises one or more HC CDR (e.g., HC CDR1, HC CDR2, or HC CDR3) amino acid sequences from any one of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b. In some embodiments, the antibody of the Disclosure comprises an HC CDR3 amino acid sequence from any one of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b. In some embodiments, the antibody of the Disclosure comprises HC CDR1, HC CDR2, and HC CDR3 provided for any one of the (elected) antibodies selected from Tables 1a and 1b. In some embodiments, the antibody of the Disclosure comprises an LC CDR3 amino acid sequence from any one of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b. In some embodiments, the antibody of the Disclosure comprises one or more LC CDR (e.g., LC CDR1, LC CDR2, or LC CDR3) amino acid sequences from any one of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b. In some embodiments, the antibody of the Disclosure comprises LC CDR1, LC CDR2, and LC CDR3 provided for any one of the anti-KLK5 antibodies selected from Tables 1a and 1b.

[0082] In some embodiments, the antibodies of this disclosure include HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 provided for any one of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b. In some embodiments, the heavy chain CDR3 domain and / or light chain CDR3 domain of the antibody may play a particularly important role in the antibody's binding specificity / affinity to the antigen. Therefore, the antibodies of this disclosure may include at least the heavy chain CDR3 and / or light chain CDR3 of any one of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b.

[0083] Any variant of the exemplary anti-KLK5 / KLK7 antibody disclosed herein is also within the scope of this disclosure. The variant may contain one or more amino acid residue mutations in the VH and / or VL, or in one or more of the HC CDRs and / or one or more of the LC CDRs, compared to the reference antibody, but retain substantially similar binding activity and biological activity (e.g., substantially similar binding affinity, binding specificity, protease inhibitory activity, anti-inflammatory activity, or a combination thereof) to the reference antibody.

[0084] In some embodiments, the antibody of this disclosure has one or more CDR (e.g., HC CDR or LC CDR) sequences substantially similar to any of HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 from one of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b. In some embodiments, the positions of one or more CDRs along the VH (e.g., HC CDR1, HC CDR2, or HC CDR3) and / or VL (e.g., LC CDR1, LC CDR2, or LC CDR3) regions of the antibodies described herein can be mutated by only 1, 2, 3, 4, 5, or 6 amino acid positions, as long as specific binding to KLK5 (e.g., human or mouse KLK5) and KLK7 (e.g., human or mouse KLK7) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% of the binding of the original antibody from which it is derived). For example, in some embodiments, the position defining the CDR of any antibody described herein can be mutated by shifting the N-terminal and / or C-terminal boundary of the CDR by 1, 2, 3, 4, 5, or 6 amino acids relative to any one of the CDR positions of the antibodies described herein, insofar as specific binding of KLK5 (e.g., human or mouse KLK5) and KLK7 (e.g., human or mouse KLK7) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% of the binding of the original antibody from which it originates).In another embodiment, the length of one or more CDRs along the VH (e.g., HC CDR1, HC CDR2, or HC CDR3) and / or VL (e.g., LC CDR1, LC CDR2, or LC CDR3) regions of the antibodies described herein may be mutated (e.g., shortened or lengthened) by only 1, 2, 3, 4, 5, or more amino acids, as long as immunospecific binding to KLK5 (e.g., human or mouse KLK5) and KLK7 (e.g., human or mouse KLK7) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% of the binding of the original antibody from which it is derived).

[0085] Therefore, in some embodiments, the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 described herein may be 1, 2, 3, 4, or 5 amino acids shorter than one or more of the CDRs described herein (e.g., CDRS from any of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b), as long as specific binding to KLK5 (e.g., human or mouse KLK5) and KLK7 (e.g., human or mouse KLK7) is maintained (e.g., substantially maintained by at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% compared to the binding of the original antibody from which it is derived). In some embodiments, the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 described herein may be 1, 2, 3, 4, or 5 amino acids or longer than one or more of the CDRs described herein (e.g., CDRs from any of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b), provided that specific binding to KLK5 (e.g., human or mouse KLK5) and KLK7 (e.g., human or mouse KLK7) is maintained (e.g., substantially maintained by at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% compared to the binding of the original antibody from which it is derived). In some embodiments, the amino portions of HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 described herein can be extended by 1, 2, 3, 4, or 5 amino acids or more compared to one or more of the CDRs described herein (e.g., CDRs from any of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b), provided that specific binding to KLK5 (e.g., human or mouse KLK5) and KLK7 (e.g., human or mouse KLK7) is maintained (e.g., substantially maintained by at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% compared to the binding of the original antibody from which it is derived).In some embodiments, the carboxyl portions of HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 described herein can be extended by 1, 2, 3, 4, or 5 amino acids or more compared to one or more of the CDRs described herein (e.g., CDRs from any of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b), provided that specific binding to KLK5 (e.g., human or mouse KLK5) and KLK7 (e.g., human or mouse KLK7) is maintained (e.g., substantially maintained by at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% compared to the binding of the original antibody from which it is derived). In some embodiments, the amino portion of HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 described herein can be shortened by 1, 2, 3, 4, or 5 amino acids or more compared to one or more of the CDRs described herein (e.g., CDRs from any of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b), as long as specific binding to KLK5 (e.g., human or mouse KLK5) and KLK7 (e.g., human or mouse KLK7) is maintained (e.g., substantially maintained by at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% compared to the binding of the original antibody from which it is derived). In some embodiments, the carboxyl portions of HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 described herein can be shortened by 1, 2, 3, 4, or 5 amino acids or more compared to one or more of the CDRs described herein (e.g., CDRs from any of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b), as long as specific binding to KLK5 (e.g., human or mouse KLK5) and KLK7 (e.g., human or mouse KLK7) is maintained (e.g., substantially maintained by at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% compared to the binding of the original antibody from which it is derived).To confirm whether specific binding to KLK5 (e.g., human or mouse KLK5) and KLK7 (e.g., human or mouse KLK7) is maintained, any method can be used, such as using the binding assays and conditions described in the Art.

[0086] In some examples, the antibodies of this disclosure have one or more CDR (e.g., HC CDR or LC CDR) sequences substantially similar to any one of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b. For example, the antibodies described herein may contain one or more CDR sequences from any of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b, containing up to 5, 4, 3, 2, or 1 amino acid residue mutations compared to the corresponding CDR region of any one of the CDRs provided herein (e.g., CDRs from any of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b), insofar as specific binding to KLK5 (e.g., human or mouse KLK5) and KLK7 (e.g., human or mouse KLK7) is maintained (e.g., substantially maintained by at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% compared to the binding of the original antibody from which it is derived). In some embodiments, any amino acid mutations in any of the CDRs provided herein may be conservative mutations. Conservative mutations can be introduced into a CDR at a position where the residue is unlikely to be involved in interaction with KLK5 (e.g., human or mouse KLK5) and / or KLK7 (e.g., human or mouse KLK7) when determined, for example, based on the crystal structure. Some aspects of this disclosure provide antibodies comprising one or more heavy chain variable (VH) domains and / or light chain variable (VL) domains provided herein. In some embodiments, any VH domain provided herein comprises one or more of the HC CDR sequences provided herein (e.g., HC CDR1, HC CDR2, and HC CDR3), which are, for example, any of the HC CDR sequences provided for any one of the anti-KLK5 / KLK7 selected from Tables 1a and 1b. In some embodiments, each VL domain provided herein comprises one or more of the LC CDR sequences provided herein (e.g., LC CDR1, LC CDR2, and LC CDR3), which are, for example, any of the LC CDR sequences provided for any one of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b.

[0087] In some embodiments, the antibodies of the Disclosure include any antibody comprising a heavy chain variable domain and / or light chain variable domain of any one anti-KLK5 / KLK7 antibody selected from Tables 1a and 1b, as well as variants thereof. In some embodiments, the antibodies of the Disclosure include any antibody comprising a pair of heavy chain variable and light chain variable regions of any anti-KLK5 / KLK7 antibody selected from Tables 1a and 1b.

[0088] Aspects of this disclosure provide antibodies comprising heavy chain variable (VH) domain amino acid sequences and / or light chain variable (VL) domain amino acid sequences homologous to any of the amino acid sequences described herein. In some embodiments, the antibody comprises a heavy chain variable sequence or light chain variable sequence that is at least 75% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to any one of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b. In some embodiments, the homologous heavy chain variable amino acid sequences and / or light chain variable amino acid sequences are not mutated in any of the CDR sequences provided herein. For example, in some embodiments, the degree of sequence variation (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) may occur within the heavy chain variable sequence and / or light chain variable sequence, excluding any of the CDR sequences provided herein. In some embodiments, the antibodies provided herein include a heavy chain variable sequence and a light chain variable sequence that include a framework sequence which is at least 75% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the framework sequence of any anti-KLK5 / KLK7 antibody selected from Tables 1a and 1b.

[0089] In some embodiments, the antibody of the Disclosure is a humanized antibody (e.g., a humanized variant containing one or more CDRs from Tables 1a and 1b). In some embodiments, the antibody of the Disclosure comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, which are the same as HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 shown in Tables 1a and 1b, and includes a humanized heavy chain variable region and / or a humanized light chain variable region.

[0090] In some embodiments, the antibody of the Disclosure is a humanized antibody comprising a VH containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH of any of the anti-KLK5 / KLK7 antibodies listed in Tables 1a and 1b. Alternatively or additionally, the antibody of the Disclosure is a humanized antibody comprising a VL containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to any one of the VL of any of the anti-KLK5 / KLK7 antibodies listed in Tables 1a and 1b.

[0091] In some embodiments, the anti-KLK5 / KLK7 antibody of the present disclosure comprises heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 7. Alternatively or additionally, the anti-KLK5 / KLK7 antibody of the present disclosure comprises light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 8.

[0092] In some embodiments, the anti-KLK5 / KLK7 antibody of the present disclosure includes HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, HC CDR3 having the amino acid sequence of SEQ ID NO: 3, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 6.

[0093] In some embodiments, the anti-KLK5 / KLK7 antibodies of the Disclosure comprise HC CDR1, HC CDR2, and HC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 3. Wherever used in the Disclosure, “collectively” means that the total number of amino acid mutations in all three heavy chain CDRs is within a defined range. Alternatively or additionally, the anti-KLK5 / KLK7 antibodies of the Disclosure comprise LC CDR1, LC CDR2, and LC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 6.

[0094] In some embodiments, the anti-KLK5 / KLK7 antibody of the present disclosure comprises HC CDR1, HC CDR2, and HC CDR3 which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-KLK5 / KLK7 antibodies of the present disclosure include LC CDR1, LC CDR2, and LC CDR3 which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 6.

[0095] In some embodiments, the anti-KLK5 / KLK7 antibody of the present disclosure includes HC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 1; HC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR2 having the amino acid sequence of SEQ ID NO: 2; and / or HC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-KLK5 / KLK7 antibodies of this disclosure include LC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 4; LC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR2 having the amino acid sequence of SEQ ID NO: 5; and / or LC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR3 having the amino acid sequence of SEQ ID NO: 6.

[0096] In some embodiments, the anti-KLK5 / KLK7 antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 7. Alternatively or additionally, the anti-KLK5 / KLK7 antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 8.

[0097] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure includes a VH containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH described in SEQ ID NO: 7. Alternatively or additionally, the anti-KLK5 / KLK7 antibody of this disclosure includes a VL containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VL described in SEQ ID NO: 8.

[0098] In some embodiments, the anti-KLK5 / KLK7 antibody of the present disclosure includes a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the VH described in SEQ ID NO: 7. Alternatively or additionally, the anti-KLK5 / KLK7 antibody of the present disclosure includes a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the VL described in SEQ ID NO: 8.

[0099] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 13. Alternatively or additionally, the anti-KLK5 / KLK7 antibody of this disclosure comprises LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 14.

[0100] In some embodiments, the anti-KLK5 / KLK7 antibody of the present disclosure includes HC CDR1 having the amino acid sequence of SEQ ID NO: 9, HC CDR2 having the amino acid sequence of SEQ ID NO: 10, HC CDR3 having the amino acid sequence of SEQ ID NO: 11, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 12.

[0101] In some embodiments, the anti-KLK5 / KLK7 antibodies of this disclosure comprise HC CDR1, HC CDR2, and HC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 9, HC CDR2 having the amino acid sequence of SEQ ID NO: 10, and HC CDR3 having the amino acid sequence of SEQ ID NO: 11. As used anywhere in this disclosure, “collectively” means that the total number of amino acid mutations in all three heavy chain CDRs is within a defined range. Alternatively or additionally, the anti-KLK5 / KLK7 antibodies of this disclosure comprise LC CDR1, LC CDR2, and LC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 12.

[0102] In some embodiments, the anti-KLK5 / KLK7 antibodies of the present disclosure include HC CDR1, HC CDR2, and HC CDR3, which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to HC CDR1 having the amino acid sequence of SEQ ID NO: 9, HC CDR2 having the amino acid sequence of SEQ ID NO: 10, and HC CDR3 having the amino acid sequence of SEQ ID NO: 11. Alternatively or additionally, the anti-KLK5 / KLK7 antibodies of the present disclosure include LC CDR1, LC CDR2, and LC CDR3 which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 12.

[0103] In some embodiments, the anti-KLK5 / KLK7 antibody of the present disclosure includes HC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO. 9; HC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR2 having the amino acid sequence of SEQ ID NO. 10; and / or HC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR3 having the amino acid sequence of SEQ ID NO. 11. Alternatively or additionally, the anti-KLK5 / KLK7 antibodies of this disclosure include LC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 4; LC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR2 having the amino acid sequence of SEQ ID NO: 5; and / or LC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR3 having the amino acid sequence of SEQ ID NO: 12.

[0104] In some embodiments, the anti-KLK5 / KLK7 antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 13. Alternatively or additionally, the anti-KLK5 / KLK7 antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 14.

[0105] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure includes a VH containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH described in SEQ ID NO. 13. Alternatively or additionally, the anti-KLK5 / KLK7 antibody of this disclosure includes a VL containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VL described in SEQ ID NO. 14.

[0106] In some embodiments, the anti-KLK5 / KLK7 antibody of the present disclosure includes a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the VH described in SEQ ID NO: 13. Alternatively or additionally, the anti-KLK5 / KLK7 antibody of the present disclosure includes a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the VL described in SEQ ID NO: 14.

[0107] In some embodiments, the anti-KLK5 / KLK7 antibody of the present disclosure comprises HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 17. Alternatively or additionally, the anti-KLK5 / KLK7 antibody of the present disclosure comprises LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 14.

[0108] In some embodiments, the anti-KLK5 / KLK7 antibody of the present disclosure includes HC CDR1 having the amino acid sequence of SEQ ID NO: 9, HC CDR2 having the amino acid sequence of SEQ ID NO: 15, HC CDR3 having the amino acid sequence of SEQ ID NO: 16, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 12.

[0109] In some embodiments, the anti-KLK5 / KLK7 antibodies of this disclosure comprise HC CDR1, HC CDR2, and HC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 9, HC CDR2 having the amino acid sequence of SEQ ID NO: 15, and HC CDR3 having the amino acid sequence of SEQ ID NO: 16. As used anywhere in this disclosure, “collectively” means that the total number of amino acid mutations in all three heavy chain CDRs is within a defined range. Alternatively or additionally, the anti-KLK5 / KLK7 antibodies of this disclosure comprise LC CDR1, LC CDR2, and LC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 12.

[0110] In some embodiments, the anti-KLK5 / KLK7 antibodies of the present disclosure include HC CDR1, HC CDR2, and HC CDR3, which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to HC CDR1 having the amino acid sequence of SEQ ID NO: 9, HC CDR2 having the amino acid sequence of SEQ ID NO: 15, and HC CDR3 having the amino acid sequence of SEQ ID NO: 16. Alternatively or additionally, the anti-KLK5 / KLK7 antibodies of the present disclosure include LC CDR1, LC CDR2, and LC CDR3 which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 12.

[0111] In some embodiments, the anti-KLK5 / KLK7 antibody of the present disclosure includes HC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO. 9; HC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR2 having the amino acid sequence of SEQ ID NO. 15; and / or HC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR3 having the amino acid sequence of SEQ ID NO. 16. Alternatively or additionally, the anti-KLK5 / KLK7 antibodies of this disclosure include LC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 4; LC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR2 having the amino acid sequence of SEQ ID NO: 5; and / or LC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR3 having the amino acid sequence of SEQ ID NO: 12.

[0112] In some embodiments, the anti-KLK5 / KLK7 antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 17. Alternatively or additionally, the anti-KLK5 / KLK7 antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 14.

[0113] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure includes a VH containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH described in SEQ ID NO. 17. Alternatively or additionally, the anti-KLK5 / KLK7 antibody of this disclosure includes a VL containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VL described in SEQ ID NO. 14.

[0114] In some embodiments, the anti-KLK5 / KLK7 antibody of the present disclosure includes a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the VH described in SEQ ID NO: 17. Alternatively or additionally, the anti-KLK5 / KLK7 antibody of the present disclosure includes a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the VL described in SEQ ID NO: 14.

[0115] In some embodiments, the anti-KLK5 / KLK7 antibody of the present disclosure comprises heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 21. Alternatively or additionally, the anti-KLK5 / KLK7 antibody of the present disclosure comprises light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 14.

[0116] In some embodiments, the anti-KLK5 / KLK7 antibody of the present disclosure includes HC CDR1 having the amino acid sequence of SEQ ID NO: 18, HC CDR2 having the amino acid sequence of SEQ ID NO: 19, HC CDR3 having the amino acid sequence of SEQ ID NO: 20, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 12.

[0117] In some embodiments, the anti-KLK5 / KLK7 antibodies of this disclosure comprise HC CDR1, HC CDR2, and HC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 18, HC CDR2 having the amino acid sequence of SEQ ID NO: 19, and HC CDR3 having the amino acid sequence of SEQ ID NO: 20. As used anywhere in this disclosure, “collectively” means that the total number of amino acid mutations in all three heavy chain CDRs is within a defined range. Alternatively or additionally, the anti-KLK5 / KLK7 antibodies of this disclosure comprise LC CDR1, LC CDR2, and LC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 12.

[0118] In some embodiments, the anti-KLK5 / KLK7 antibodies of the present disclosure include HC CDR1, HC CDR2, and HC CDR3, which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to HC CDR1 having the amino acid sequence of SEQ ID NO: 18, HC CDR2 having the amino acid sequence of SEQ ID NO: 19, and HC CDR3 having the amino acid sequence of SEQ ID NO: 20. Alternatively or additionally, the anti-KLK5 / KLK7 antibodies of the present disclosure include LC CDR1, LC CDR2, and LC CDR3 which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 12.

[0119] In some embodiments, the anti-KLK5 / KLK7 antibody of the present disclosure includes HC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO. 18; HC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR2 having the amino acid sequence of SEQ ID NO. 19; and / or HC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR3 having the amino acid sequence of SEQ ID NO. 20. Alternatively or additionally, the anti-KLK5 / KLK7 antibodies of this disclosure include LC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 4; LC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR2 having the amino acid sequence of SEQ ID NO: 5; and / or LC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR3 having the amino acid sequence of SEQ ID NO: 12.

[0120] In some embodiments, the anti-KLK5 / KLK7 antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 21. Alternatively or additionally, the anti-KLK5 / KLK7 antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 14.

[0121] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure includes a VH containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH described in SEQ ID NO. 21. Alternatively or additionally, the anti-KLK5 / KLK7 antibody of this disclosure includes a VL containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VL described in SEQ ID NO. 14.

[0122] In some embodiments, the anti-KLK5 / KLK7 antibody of the present disclosure includes a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the VH described in SEQ ID NO: 21. Alternatively or additionally, the anti-KLK5 / KLK7 antibody of the present disclosure includes a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the VL described in SEQ ID NO: 14.

[0123] The antibodies described herein may be in any antibody form, including but not limited to intact (i.e., full-length) antibodies, their antigen-binding fragments (Fab, F(ab'), F(ab')2, Fv, etc.), single-chain antibodies, bispecific antibodies, or nanobodies. In some embodiments, the anti-KLK5 / KLK7 antibody described herein is scFv. In some embodiments, the anti-KLK5 / KLK7 antibody described herein is scFv-Fab (e.g., scFv fused to a portion of the constant region).

[0124] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure is a chimeric antibody, which may include a heavy chain constant region and a light chain constant region derived from a human antibody. A chimeric antibody refers to an antibody having a variable region or a portion of a variable region derived from a first species and a constant region derived from a second species. Typically, in these chimeric antibodies, both the light chain and heavy chain variable regions mimic the variable regions of an antibody derived from one species of mammal (e.g., a non-human mammal such as a mouse, rabbit, and rat), while the constant region is homologous to the sequence in an antibody derived from another mammal, such as a human. In some embodiments, amino acid modifications may occur in the variable region and / or the constant region.

[0125] In some embodiments, the antibodies of this disclosure comprise the VL domain and / or VH domain of any one of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b, and include a constant region comprising the amino acid sequence of the constant region of an IgG, IgE, IgM, IgD, IgA, or IgY immunoglobulin molecule, any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or any subclass (e.g., IgG2a and IgG2b) immunoglobulin molecule. Non-limiting examples of human constant regions have been described in the Art; see, for example, Kabat EA et al., (1991), cited above.

[0126] In some embodiments, the light chain of any of the anti-KLK5 / KLK7 antibodies described herein may further comprise a light chain constant region (CL), which may be any CL known in the Art. In some examples, the CL is a kappa light chain. In other examples, the CL is a lambda light chain. In some embodiments, the CL is a kappa light chain.

[0127] Other antibody heavy chain constant regions and light chain constant regions are well known in the art and are provided, for example, in the IMGT database (www.imgt.org) or www.vbase2.org / vbstat.php, both of which are incorporated herein by reference.

[0128] In some embodiments, conservative mutations may be introduced into the antibody sequence (e.g., CDR or framework sequence) at a position where the residue is unlikely to be involved in interaction with the target antigen (e.g., human or mouse KLK5 and / or human or mouse KLK7), for example, if determined based on the crystal structure. In some embodiments, one, two or more mutations (e.g., amino acid substitutions) may be introduced into the Fc region (numbered according to the Kabat numbering system (e.g., the EU index in Kabat), for example, the CH2 domain (residues 231-340 of human IgG1) and / or the CH3 domain (residues 341-447 of human IgG1) and / or the hinge region) of the anti-KLK5 / KLK7 antibody described herein to modify one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding and / or antigen-dependent cytotoxicity.

[0129] In some embodiments, one, two, or more mutations (e.g., amino acid substitutions) are introduced into the hinge region of the Fc region (CH1 domain) to modify (e.g., increase or decrease) the number of cysteine ​​residues in the hinge region, as described, for example, in U.S. Patent No. 5,677,425. Modifying the number of cysteine ​​residues in the hinge region of the CH1 domain can, for example, promote light and heavy chain assembly, or modify antibody stability (e.g., increase or decrease), or promote linker conjugation.

[0130] In some embodiments, one, two, or more mutations (e.g., amino acid substitutions) are introduced into the Fc region of the antibodies described herein (numbered according to the Kabat numbering system (e.g., the EU index in Kabat), for example, the CH2 domain (residues 231-340 of human IgG1) and / or the CH3 domain (residues 341-447 of human IgG1) and / or the hinge region) to increase or decrease the affinity of the antibody to Fc receptors (e.g., activated Fc receptors) on the surface of effector cells. Mutations in the Fc region of antibodies that decrease or increase the affinity of an antibody to Fc receptors, and techniques for introducing such mutations into Fc receptors or fragments thereof, are known to those skilled in the art. Examples of antibody mutations at the Fc receptor that can be made to alter the affinity of an antibody to the Fc receptor are described, for example, in Smith P et al., (2012) PNAS 109:6181-6186, U.S. Patent No. 6,737,056, and International Publication Nos. WO02 / 060919, WO98 / 23289, and WO97 / 34631, which are incorporated herein by reference.

[0131] In some embodiments, one, two, or more amino acid mutations (i.e., substitutions, insertions, or deletions) are introduced into the IgG constant domain or its FcRn binding fragment (preferably an Fc or hinge-Fc domain fragment) to modify (e.g., decrease or increase) the in vivo half-life of the antibody. See, for example, International Publication Nos. WO02 / 060919, WO98 / 23289, and WO97 / 34631, and U.S. Patents 5,869,046, 6,121,022, 6,277,375, and 6,165,745 for examples of mutations that modify (e.g., decrease or increase) the in vivo half-life of the antibody.

[0132] In some embodiments, one, two, or more amino acid mutations (i.e., substitutions, insertions, or deletions) are introduced into the IgG constant domain or its FcRn binding fragment (preferably an Fc or hinge-Fc domain fragment) to reduce the half-life of the anti-KLK5 / KLK7 antibody in vivo. In some embodiments, one, two, or more amino acid mutations (i.e., substitutions, insertions, or deletions) are introduced into the IgG constant domain or its FcRn binding fragment (preferably an Fc or hinge-Fc domain fragment) to increase the half-life of the antibody in vivo. In some embodiments, the antibody may have one or more amino acid mutations (e.g., substitutions) in a second constant (CH2) domain (residues 231-340 of human IgG1) and / or a third constant (CH3) domain (residues 341-447 of human IgG1), numbered according to the EU index in Kabat (Kabat EA et al., (1991), cited above). In some embodiments, the constant region of IgG1 of the antibodies described herein, numbered according to the EU index as set forth in Kabat, includes a methionine (M) to tyrosine (Y) substitution at position 252, a serine (S) to threonine (T) substitution at position 254, and a threonine (T) to glutamic acid (E) substitution at position 256. See U.S. Patent No. 7,658,921, which is incorporated herein by reference. This type of mutant IgG is called the “YTE variant” and has been shown to exhibit a 4-fold increased half-life compared to the wild-type version of the same antibody (see Dall'Acqua WF et al., (2006) J Biol Chem 281:23514-24). In some embodiments, the antibody includes an IgG constant domain that contains one, two, three or more amino acid substitutions of amino acid residues at positions 251–257, 285–290, 308–314, 385–389, and 428–436, numbered according to the EU index as found in Kabat.

[0133] In some embodiments, the antibody includes an Fc region that has been modified, for example, by introducing substitutions of M428L and / or N434A, for the purpose of extending the half-life. Non-limiting examples of such Fc variants that affect the circulating half-life are provided in Saunders KO, Conceptual Approaches to Modulating Antibody Effector Functions and Circulation Half-Life, Front Immunol. 2019;10:1296, which is incorporated herein by reference.

[0134] In some embodiments, the effector function(s) of an anti-KLK5 / KLK7 antibody is modified by introducing one, two, or more amino acid substitutions into the IgG constant domain Fc region, for example, by introducing Leu234Ala and Leu235Ala mutations (commonly referred to as LALA mutations). The effector ligand whose affinity is modified may be, for example, the Fc receptor or the C1 component of complement. This technique is described in U.S. Patents 5,624,821 and 5,648,260. In some embodiments, deletion or inactivation of the constant domain (via point mutation or other means) can reduce the binding of the circulating antibody to the Fc receptor, thereby increasing tumor localization. For a description of mutations that delete or inactivate the constant domain and thereby increase tumor localization, see, for example, U.S. Patents 5,585,097 and 8,591,886. In some embodiments, one or more amino acid substitutions may be introduced into the Fc region of the antibodies described herein to remove potential glycosylation sites on the Fc region, thereby reducing Fc receptor binding (see, for example, Shields RL et al., (2001) J Biol Chem 276:6591-604).

[0135] In some embodiments, one or more amino acids in the constant region of the anti-KLK5 / KLK7 antibody described herein can be replaced with different amino acid residues, thereby giving the antibody modified C1q binding and / or reduced or ineffective complement-dependent cell-mediated cytotoxicity (CDC). This technique is described in detail in U.S. Patent No. 6,194,551 (Idusogie et al). In some embodiments, one or more amino acid residues in the N-terminal region of the CH2 domain of the antibody described herein are modified, thereby altering the antibody's ability to immobilize complement. This technique is further described in International Publication No. WO94 / 29351. In some embodiments, the Fc region of the antibody described herein is modified to increase the antibody's ability to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) and / or increase the antibody's affinity for the Fcγ receptor. This technique is further described in International Publication No. WO00 / 42072.

[0136] In some embodiments, the antibody comprises an Fc variant containing amino acid substitutions L234A, L235E, and P329G, in which case the numbering follows the EU index. In some embodiments, the antibody comprising the Fc variant exhibits reduced affinity for one or more or each of FcyRJ, FcyRIIA, FcyRIIIA, and Clq compared to the antibody comprising the wild-type human Fc region. Examples of such Fc variants are provided in International Patent Application Publication No. WO2021 / 055669, title, FC VARIANTS WITH REDUCED EFFECTOR FUNCTION, published March 25, 2021, and U.S. Patent Application Publication No. US2021-0087271, title, FC VARIANTS WITH REDUCED EFFECTOR FUNCTION, published March 25, 2021, the contents of which are incorporated herein by reference.

[0137] In some embodiments, as described elsewhere herein, variable domain(s) sequences(s) of the heavy and / or light chains of the antibodies provided herein can be used to generate, for example, CDR-implanted, chimeric, humanized, or compound human antibodies or antigen-binding fragments. As will be understood by those skilled in the art, any variant, CDR-implanted, chimeric, humanized, or compound antibody derived from any of the antibodies provided herein may be useful in the compositions and methods described herein, and the variant, CDR-implanted, chimeric, humanized, or compound antibody will maintain the ability to specifically bind to KLK5 and KLK7 such that it has at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or more binding to KLK5 and KLK7 compared to the original antibody from which it is derived.

[0138] In some embodiments, the antibodies provided herein include mutations that confer desirable properties to the antibody. For example, to avoid potential complications from Fab-arm exchange, which are known to occur with natural IgG4 mAbs, the antibodies provided herein may include a stabilizing "Adair" mutation (Angal S., et al., “A single amino acid substitution abolishes the heterogeneity of chimeric mouse / human (IgG4) antibody,” Mol Immunol 30, 105-108; 1993), in which serine 228 (EU numbering; residue 241 Kabat numbering) is converted to proline, resulting in an IgG1-like hinge sequence. Thus, any of the antibodies may include a stabilizing "Adair" mutation.

[0139] In some embodiments, the antibody is modified, for example, by glycosylation, phosphorylation, SUMOylation, and / or methylation. In some embodiments, the antibody is a glycosylated antibody conjugated to one or more sugar or carbohydrate molecules. In some embodiments, one or more sugar or carbohydrate molecules are conjugated to the antibody via N-glycosylation, O-glycosylation, C-glycosylation, glyciation (GPI anchor attachment), and / or phosphoglycosylation. In some embodiments, one or more sugar or carbohydrate molecules are monosaccharides, disaccharides, oligosaccharides, or glycans. In some embodiments, one or more sugar or carbohydrate molecules are branched oligosaccharides or branched glycans. In some embodiments, one or more sugar or carbohydrate molecules include mannose units, glucose units, N-acetylglucosamine units, N-acetylgalactosamine units, galactose units, fucose units, or phospholipid units. In some embodiments, there are about 1-10, about 1-5, about 5-10, about 1-4, about 1-3, or about 2 sugar molecules. In some embodiments, the glycosylated antibody is completely or partially glycosylated. In some embodiments, the antibody is glycosylated by chemical reaction or enzymatic means. In some embodiments, the antibody is glycosylated in vitro or intracellularly and, optionally, an enzyme in the N or O glycosylation pathway, such as glycosyltransferase, may be deficient. In some embodiments, the antibody is functionalized with sugar molecules or carbohydrate molecules as described in International Patent Application Publication No. WO2014065661, published May 1, 2014, titled "Modified antibody, antibody-conjugate and process for the preparation thereof".

[0140] In some embodiments, any one of the anti-KLK5 / KLK7 antibodies described herein may include a signal peptide (e.g., an N-terminal signal peptide) in the heavy chain sequence and / or light chain sequence. In some embodiments, the anti-KLK5 / KLK7 antibody described herein includes either a VH sequence or a VL sequence, either an IgG heavy chain sequence or a light chain sequence, or either an F(ab') heavy chain sequence or a light chain sequence described herein, and further includes a signal peptide (e.g., an N-terminal signal peptide).

[0141] (b) Th2 targeting Conditions associated with barrier dysfunction are characterized by barrier disruption and Th2-driven inflammation, mediated by Th2 cytokines and their receptors, such as IL-13, IL-13 receptor (IL-13R), IL-4, IL-4R, IL-5, IL-5R, IL-6, IL-6R, IL-9, IL-9R, IL-31, IL-31R, IL-17E (IL-25), IL-17ER (IL-25R), IL-33, IL-33R, IL-36, IL-36R, OX40L, OX40, TSLP, and TSLPR. In some cases, unregulated KLK activity in the epidermis leads to activation of Th2 cells and subsequent secretion of Th2 cytokines. Elevated Th2 cytokine levels can further contribute to KLK hyperactivation (Figure 2). Therapeutic antibodies are being developed to suppress Th2 cytokine-mediated inflammation by targeting Th2 cytokines and / or their respective receptors (referred to as Th2-targeted antibodies), such as anti-IL-13 antibodies and anti-IL-4R antibodies.

[0142] In some embodiments, the antibodies provided herein include at least one antigen-specific binding site that specifically binds to a Th2 cytokine or its receptor. In some embodiments, such Th2 cytokines or receptors include, but are not limited to, IL-13, IL-13 receptor (IL-13R), IL-4, IL-4R, IL-5, IL-5R, IL-6, IL-6R, IL-9, IL-9R, IL-31, IL-31R, IL-17E (IL-25), IL-17ER (IL-25R), IL-33, IL-33R, IL-36, IL-36R, OX40L, OX40, TSLP, and TSLPR. Antibodies targeting Th2 cytokines or their receptors include, but are not limited to, anti-IL-13 antibodies, anti-IL-13R antibodies, anti-IL-4 antibodies, anti-IL-4R antibodies, anti-IL-5 antibodies, anti-IL-5R antibodies, anti-IL-6 antibodies, anti-IL-6R antibodies, anti-IL-9 antibodies, anti-IL-9 antibodies, anti-IL-31 antibodies, anti-IL-31R antibodies, anti-IL-17E antibodies, anti-IL-17ER antibodies, anti-IL-31 antibodies, anti-IL-31R antibodies, anti-IL-36R antibodies, anti-IL-36R antibodies, anti-OX40L antibodies, anti-OX40 antibodies, anti-TSLP antibodies, or anti-TSLPR antibodies. Any suitable Th2-targeting antibody can be used in methods and compositions, but are not limited to, those listed in Table 2. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 Table 2-19 Table 2-20 Table 2-21 Table 2-22 Table 2-23 Table 2-24 Table 2-25 Table 2-26 Table 2-27 Table 2-28 Table 2-29 Table 2-30 Table 2-31 Table 2-32 Table 2-33 Table 2-34 Table 2-35 Table 2-36 Table 2-37

[0143] In some embodiments, the Th2-targeted antibody includes an antigen-specific binding site for IL-13 or its receptor. 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US2014341913, published November 20, 2014, title Methods And Compositions For Treating Asthma Using Anti-IL-13 Antibodies; US2014348855, published November 27, 2014, title Antibody Formulations; US2015225479, published August 13, 2015, title Anti-IL-4 / Anti-IL-13 Bispecific Antibody / Polyglutamate Formulations; US2015266962, published September 24, 2015, title: Anti-IL-13 Receptor Alpha2 Antibodies And Antibody-Drug Conjugates;US2016075777, published March 17, 2016, title: Anti-IL-4 / Anti-IL-13 Bispecific Antibody Formulations; US2016319012, published November 3, 2016, title: Methods And Compositions Comprising Purified Recombinant Polypeptides; US2017145089, published May 25, 2017, title: Anti-IL4-IL13 Bispecific Antibodies; WO17191627, published November 9, 2017, title: Antibodies To Interleukin13 Receptor Alpha-1 (IL-13R Alpha1) And Uses Thereof; US2017334985, published November 23, 2017, title: Anti-IL-13 / IL-17 Bispecific Antibodies And Uses Thereof;WO19096219, published May 23, 2019, title: Humanized Anti-IL-13 Antibody And Preparation Method And Use; Thereof;US2019247303, published August 15, 2019, title: Inhalable Powder Composition Comprising IL-13 Antibody;US2019309059, published October 10, 2019, title: IL-13 Antibody And Preparation Method And Use; Thereof;US2020165347, published May 28, 2020, title: Method Of Treatment Using IL-13R Antibody;US2021277131, published September 9, 2021, title: Treatment Employing Anti-IL-L3R Antibody Or Binding Fragment Thereof;US2021380674, published December 9, 2021, title: Methods Of Treatment Of Diseases In Which IL-13 Activity Is Detrimental Using Anti-IL-13 Antibodies;US2022033508, published February 3, 2022, title: Anti-IL-13R Alpha2 Antibodies; WO22174808, published August 25, 2022, title: Antibody Against IL-13Ra2 And Use Thereof; US2022305104, published September 29, 2022, title: Methods Of Treating Atopic Dermatitis; US2023002484, published January 5, 2023, title: Treatment Of Atopic Dermatitis Employing Anti-IL-13Ra1 Antibody Or Binding Fragment Thereof; WO23287590, published January 19, 2023, title: IL-13 Antibodies For The Treatment Of Atopic Dermatitis;WO23019260, published on February 16, 2023, titled IL-13 Antibodies For The Treatment Of Atopic Dermatitis;WO23023497, published on February 23, 2023, titled Anti-IL-13 Antibody Formulation;US2023084464, published on March 16, 2023, titled Antibody With Binding Specificity For Human IL-13;US2023087378, published on March 23, 2023, titled Multi-Specific Antibody With Binding Specificity For Human IL-13 And Il-17;WO23075700, 05 / 04 / published on May 4, 2023, titled Anti-IL-13R Antibody Formulation; WO23075702, published May 4, 2023, title: Anti-IL-13R Antibody Formulation; US2023183364, published June 15, 2023, title: Anti-IL13R-Alpha2 Antibodies, Antigen-Binding Fragments And Uses Thereof; WO23163659, published August 31, 2023, title: Glycosylated Form Of Anti-IL13R Antibody;US2023357381, published November 9, 2023, titled Multispecific Antibodies Targeting IL-13 And Il-18;WO23215769, published November 9, 2023, titled IL-13 Antibodies For The Treatment Of Atopic Dermatitis;WO23245187, published December 21, 2023, titled Antibodies That Bind Interleukin13 A; nd Methods Of Use; WO24043837, published February 29, 2024, title: High Concentration Anti-IL13R Antibody Formulation; US2024117030, published April 11, 2024, title: Multispecific Antibodies And Uses Thereof; US2024158521, published May 16, 2024, title: DNA-Encoded Bispecific Antibodies Targeting IL13Ra2 And Methods Of Use In Cancer Therapeutics; WO08140455, published November 20, 2008, title: Treatment Of Radiation And Chemo-Therapy Induced Fibrosis Using Novel Anti-IL13 Monoclonal Antibodies; and WO24099310, published May 16, 2024, title: Anti-IL-13 Long-Acting Nanobody Sequence And Use It includes antigen-specific binding sites for IL-13 or IL-13R derived from anti-IL-13 / anti-IL-13R antibodies described thereof (the descriptions of anti-IL-13 antibodies in each of these are incorporated herein by reference).

[0144] In some embodiments, the Th2-targeted antibody includes an antigen-specific binding site for IL-4 or its receptor. In some embodiments, the Th2-targeted antibody is any known anti-IL-4 or its receptor, e.g., US5552304, published September 3, 1996, title: cDNA Clones Coding For Human Protein Exhibiting A Broad Cellular Activity Spectrum (Human Interleukin-4); US5676940, published October 14, 1997, title: Method Of Reducing Immunoglobulin E Responses; US5985280, published November 16, 1999, title: Diagnosis And / Or Therapy Of Tumours Using Monoclonal Antibodies Specific For The Human IL-4 Receptor; US6358509, published March 19, 2002, title: Antibody Antagonists Of Human Interleukin-4; US5863537, published January 26, 1999, title: Humanized Monoclonal Antibodies Against Human Interleukin-4; WO9414975, released July 7, 1994, title Monoclonal Antibodies Against The Human Interleukin-4 Receptor And Hybridomas Producing The Same; US5928904, released July 27, 1999, title DNA Encoding Recombinant IL4 Antibodies Useful In Treatment Of IL4 Mediated Disorders; US5597710, released January 28, 1997, title Humanized Monoclonal Antibodies Against Human Interleukin-4;US5783181, published July 21, 1998, title: Therapeutic Uses Of Fusion Proteins Between Mutant IL-4 / IL-13 Antagonists And Immunoglobulins; US2002002132, published January 3, 2002, title: Use Of Interleukin-4 Antagonists And Compositions Thereof; US2007274996, published November 29, 2007, title: Antibodies That Bind Interleukin-4 Receptor; US2008241160, published October 2, 2008, title: Human Monoclonal Antibodies Against Human IL-4; US2010297110, published November 25, 2010, title: Antibody Specific For Human IL-4 For The Treatment Of Cancer; US2008160035, published July 3, 2008, Title: High Affinity Human Antibodies To Human IL-4 Receptor; US2010226923, published September 9, 2010, Title: Antibodies That Bind IL-4 And / Or IL-13 And Their Uses; US2012097565, published April 26, 2012, Title: Stabilized Formulations Containing Anti-Interleukin-4 Receptor (IL-4R) Antibodies; US2014056920, published February 27, 2014, Title: Methods For Treating Or Preventing Asthma By Administering An IL-4R Antagonist; US2014072583, published March 13, 2014, Title: Methods For Treating Atopic Dermatitis By Administering an IL-4R Antagonist;US2016207995, published July 21, 2016, title: Anti-IL-4 Antibodies And Bispecific Antibodies And Uses Thereof; US2016075777, published March 17, 2016, title: Anti-IL-4 / Anti-IL-13 Bispecific Antibody Formulations; US2014356372, published December 4, 2014, title: Methods For Treating Allergy And Enhancing Allergen-Specific Immunotherapy By Administering An IL-4R Inhibitor; US2015017176, published January 15, 2015, title: Methods For Treating Eosinophilic Esophagitis By Administering An IL-4R Inhibitor; US2015225479, published August 13, 2015, title: Anti-IL-4 / Anti-IL-13 Bispecific Antibody / Polyglutamate Formulations; US2017145089, published May 25, 2017, title: Anti-IL4-IL13 Bispecific Antibodies; US2017281769, published October 5, 2017, title: Stable Anti-IL-4Ra Formulation; US2018346580, published December 6, 2018, title: Antibodies To Canine Interleukin-4 Receptor Alpha; US2019177408, published June 13, 2019, title: Antibody For Binding To Interleukin4 Receptor;US2022081485, published March 17, 2022, title Anti-IL-4R Antibody And Use Thereof;WO19148405, published August 8, 2019, title IL-4R Antibody And Use Thereof;US2022073631, published March 10, 2022, title: Monoclonal Antibody Against Human Interleukin-4 Receptor Alpha And Use Thereof; US2021238294, published August 5, 2021, title: Human IL-4R Binding Antibody, Antigen Binding Fragment Thereof, And Medical Use Thereof; US2021206861, published July 8, 2021, title: Antibodies Binding To Human IL-4R, Preparation Method Therefor And Use Thereof; US2021403580, published December 30, 2021, title: Human Antibody Having High Affinity To Human IL-4 Receptor Alpha, And Use Thereof; US2023295312, published September 21, 2023, title: Antibody Against Human IL-4Ra And Use Thereof; US2022162328, published May 26, 2022, title Interleukin-4 Receptor Antibody And Application Thereof; US2022348666, published November 3, 2022, title Liquid Composition Comprising Antibody Of Human Interleukin-4 Receptor Alpha; US2022411519, published December 29, 2022, title Anti-IL-4R Single-Domain Antibody And Use Thereof; US2023053131, published February 16, 2023, title Antibodies To Canine Interleukin-4 Receptor Alpha; US2023088052, published March 23, 2023, title Pharmaceutical Composition Containing Anti-IL-4R Antibody And Use Thereof;US2023105029, published April 6, 2023, title: Antibodies Binding IL4R And Uses Thereof; US2024067738, published February 29, 2024, title: Anti-IL4 Receptor Antibodies For Veterinary Use; US2023203172, published June 29, 2023, title: Anti-Human Interleukin-4 Receptor Alpha Antibody And Preparation Method And Application Thereof; US2023167180, published June 1, 2023, title: Antibody Binding With Specific Epitope In Human IL-4R Alpha And Applications Of Antibody; WO21254221, published December 23, 2021, title: Stable Liquid Preparation Of Anti-IL-4R Monoclonal Antibodies; US2023279124, published September 7, 2023, title: Fusion Protein Comprising Ige Fc Receptor Alpha Subunit Extracellular Domain And Anti-IL-4R Antibody, And Use Thereof; US2023357415, published November 9, 2023, title: Bispecific Antibody Simultaneously Binding To Interleukin-4 Receptor Alpha Subunit And Interleukin-5 Receptor Alpha Subunit, And Use Thereof; US2023374144, published November 23, 2023, title: Antibodies Specifically Recognizing Interleukin-4 Receptor Alpha And Uses Thereof; US2023279123, published September 7, 2023, title: Humanized Anti-IL-4Ra Single Domain Antibody And Application Thereof;US2024075158, published March 7, 2024, title: Complex Of Anti-IL-4R Antibody Or Antigen-Binding Fragment Thereof And Medical Use Thereof; WO23011502, published February 9, 2023, title: Stable Formulation Comprising Anti-IL-4R Antibody; US2023064378, published March 2, 2023, title: Human Interleukin-4 Receptor Alpha Antibodies; WO23025217, published March 2, 2023, title: Pharmaceutical Composition Of Anti-IL4R Antibody And Use Thereof; WO23191665, published October 5, 2023, title: Antibodies To Human IL-4R Having Reduced Immunogenicity And App; This includes antigen-specific binding sites for IL-4 or IL-4R derived from anti-IL-4 / anti-IL-4R antibodies described in: lication Thereof;US2024024472, published January 25, 2024, title: Anti-Interleukin-4 Receptor (IL-4R) Antibody Formulations;US2024100176, published March 28, 2024, title: Human Interleukin-4 Receptor Alpha Antibody Glucocorticoid Conjugates;and WO24061279, published March 28, 2024, title: Recombinant Bispecific Antibodies Targeting TSLP And IL4R (the descriptions of anti-IL-4 or anti-IL-4R antibodies in each of these are incorporated herein by reference).

[0145] In some embodiments, the Th2-targeted antibody includes an antigen-specific binding site for OX40L or its receptor. In some embodiments, the Th2-targeted antibody is any known anti-OX40L or its receptor, e.g., US2006002929, published January 5, 2006, title Monoclonal Antibodies; US7291331, published November 6, 2007, title Methods Of Treating OX40 Medicated Recall Immune Responses; US2009053230, published February 26, 2009, title Anti-OX40L Antibodies And Methods Using Same; US7501496, published March 10, 2009, title Anti-OX40L Antibodies; US2010098712, published April 22, 2010, title Pharmaceutical Formulation Of An Antibody Against OX40L; US2010136030, published June 3, 2010, title: Antagonist OX40 Antibodies And Their Use In The Treatment Of Inflammatory And Autoimmune Diseases; US2010196359, published August 5, 2010, title: Human Monoclonal Antibody Human Cd134 (OX40) And Methods Of Making And Using Same; US2010254978, published October 7, 2010, title: Antibody Molecules Having Specificity For Human OX40; US2013018175, published January 17, 2013, title: Single Variable Domain Antibodies Against OX40L, Constructs And Therapeutic Use; US2013183315, published July 18, 2013, title: Antibodies That Bind To OX40 and Their Uses;US2013243772, published September 19, 2013, title: Antibody Molecules Having Specificity For Human OX40; US2013280275, published October 24, 2013, title: Anti-OX40 Antibodies And Methods Of Using The Same; US2014377284, published December 25, 2014, title: Humanized Anti-Cd134(OX40) Antibodies And Uses Thereof; US2015307617, published October 29, 2015, title: Anti-OX40 Antibodies And Methods Of Use; WO16002820, published January 7, 2016, title: Novel Anti-Human OX40 Ligand Antibody, And Anti-Influenza Drug Comprising Same; US2016137740, published May 19, 2016, title Humanized Anti-OX40 Antibodies And Uses Thereof; US2016347847, published December 1, 2016, title Anti-OX40 Antibodies And Methods Of Use Thereof; US2016347849, published December 1, 2016, title Antibodies Against OX40 And Uses Thereof; US2016368997, published December 22, 2016, title Antibodies, Uses And Methods; WO17096281, published June 8, 2017, title Anti-OX40 Antibodies And Methods Of Use Thereof; WO17134292, published August 10, 2017, title Anti-OX40 Antagonistic Antibodies For The Treatment Of Atopic Dermatitis; US2017349661, published December 7, 2017, title: Antagonistic Anti-OX40L Antibodies And Methods Of Their Use;US2018171023, published June 21, 2018, title: Anti-OX40 Antibodies And Their Uses; US2021206864, published July 8, 2021, title: Anti-OX40 Antagonistic Antibodies And Dosage For The Treatment Of OX40-Mediated Disorders; US2021214453, published July 15, 2021, title: Anti-OX40 Antagonistic Antibodies For The Treatment Of Autoimmune Diseases; WO22042692, published March 3, 2022, title: Anti-OX40 Antibody Having Low Toxicity, And Pharmaceutical Composition And Use Thereof; US2023151105, published May 18, 2023, title: Anti-OX40 Antibody And Uses Thereof;WO23109901, published June 22, 2023, title: Anti-OX40 Antibodies And Methods Of Use;WO23109976, published June 22, 2023, title: Antibody Against OX40 And Medical Use;Thereof;US2024182594, published June 6, 2024, title: Uses Of Antagonist, Non-Depleting OX40 Antibodies;US2024209104, published June 27, 2024, title: Anti-OX40 Antibody, And Pharmaceutical Composition And Application;Thereof;US2024209107, published June 27, 2024, title: Cd28 / OX40 Bispecific Antibodies;This includes antigen-specific binding sites for OX40L or OX40 derived from the anti-OX40L / anti-OX40 antibody described in US2024270859, published August 15, 2024, titled Anti-OX40L Antibody, Anti-OX40L / Anti-TNFa Bispecific Antibody, And Uses Thereof (the descriptions of anti-OX40L or anti-OX40 antibodies in each of these are incorporated herein by reference).

[0146] In some embodiments, the Th2-targeted antibody includes an antigen-specific binding site to TSLP or its receptor. In some embodiments, the Th2-targeted antibody is any known anti-TSLP or its receptor, e.g., US2009186022, published July 23, 2009, title Organic Compounds; US2010166766, published July 1, 2010, title Engineered Anti-TSLP Antibody; US2011020369, published January 27, 2011, title Engineered Anti-TSLP Antibodies; US2012020988, published January 26, 2012, title Antibodies Specifically Binding To Human TSLPR And Methods Of Use; US2012219565, published August 30, 2012, title Engineered Anti-TSLP Antibody; US2014227250, published August 14, 2014, title Stable Formulations Of Antibodies To TSLP; US2016046720, published February 18, 2016, title: Novel Anti-Human TSLP Receptor Antibody; US2017066823, published March 9, 2017, title: Thymic Stromal Lymphopoietin (TSLP) - Binding Molecules And Methods Of Using The Molecules; US2018296669, published October 18, 2018, title: Treatment Of Asthma With Anti-TSLP Antibody; US2019111129, published April 18, 2019, title: Pharmaceutical Composition Comprising Anti-Human TSLP Receptor Antibody; US2021121406, published April 29, 2021, title: Dry Powder Formulations Of Thymic Stromal Lymphopoietin(TSLP)-Binding Antibodies And Methods Of Use Thereof;WO21155634, published August 12, 2021, title: Anti-Human-TSLP Antibody And Use Thereof; WO22184074, published September 9, 2022, title: Pharmaceutical Composition Containing Anti-TSLP Antibody; US2022289833, published September 15, 2022, title: Antibodies Binding TSLP And Uses Thereof; US2022340654, published October 27, 2022, title: Antibody Capable Of Binding To Thymic Stromal Lymphopoietin And Use Thereof; US2022363781, published November 17, 2022, title: Anti-TSLP Antibody And Uses Thereof;WO22253147, published December 8, 2022, title: Anti-Thymic Stromal Lymphopoietin (TSLP) Antibody And Use Thereof;WO23028612, published March 2, 2023, title: Anti-TSLPPR(Crlf2) Antibodies;US2023073888, published March 9, 2023, title: Treatment Of Atopic Dermatitis With Anti-TSLP Antibody;WO23029281, published March 9, 2023, title: Anti-Human TSLP Monoclonal Antibody And Use Thereof;US2023078678, published March 16, 2023, title: Formulations Of Human Anti-TSLP Antibodies And Methods Of Treating Atopic Dermatitis; US2023081261, published March 16, 2023, title: Formulations Of Human Anti-TSLP Antibodies And Methods Of Using The Same;US2023082287, published March 16, 2023, title: Methods Of Treating An Inflammatory Or Obstructive Airway Disease Using Anti-TSLP Antibody; WO23070948, published May 4, 2023, title: Preparation Method For Concentrated Solution Containing Anti-Human Thymic Stromal Lymphopoietin (TSLP) Monoclonal Antibody, And Liquid Preparation; WO23098491, published June 8, 2023, title: Anti-TSLP Monoclonal Antibody, Antigen-Binding Fragment Thereof And Use Thereof; WO23116925, published June 29, 2023, title: Novel Anti-TSLP Antibodies; WO23142309, published August 3, 2023, title: Anti-TSLP Nanobody And Use Thereof;US2024016931, published January 18, 2024, title: Anti-TSLP Antibody Pharmaceutical Composition And Use Thereof;WO24061279, published March 28, 2024, title: Recombinant Bispecific Antibodies Targeting TSLP And Il4R;US2024117030, published April 11, 2024, title: Multispecific Antibodies And Uses Thereof;US2024132581, published April 25, 2024, title: Antibodies Against Human TSLP And Use Thereof;WO24092064, published May 2, 2024, title: Anti-TSLP Antibody Compositions And Uses Thereof;US2024173405, published May 30, 2024, title: Pharmaceutical Compositions Comprising Anti-Human TSLP Receptor Antibodies And Methods Of Using The Same; US2024182558, published June 6, 2024, title: Modified Anti-TSLP Antibodies; US2024190951, published June 13, 2024, title: Anti-TSLP Antibody Compositions And Uses Thereof; WO24146630, published July 11, 2024, title: Method For Treating Asthma By Using TSLP Antibody; WO24152881, published July 25, 2024, title: Anti-TSLP Antibody And Use Thereof; and WO24163978, published August 8, 2024, title: Treatment Of It includes an antigen-specific binding site for TSLP or TSLPR derived from an anti-TSLP / anti-TSLPR antibody described in Chronic Rhinosinusitis With Anti-TSLP Antibody (the descriptions of anti-TSLP or anti-TSLPR antibodies in each of these are incorporated herein by reference).

[0147] In some embodiments, the Th2-targeted antibody includes an antigen-specific binding site for IL-5 or its receptor. In some embodiments, the Th2-targeted antibody is any known anti-IL-5 or its receptor, e.g., US5683892, published November 4, 1997, title: DNA Encoding Recombinant IL-5 Antagonists Useful In Treatment Of IL-5 Mediated Disorders; US5976821, published November 2, 1999, title: Monoclonal Antibodies Specific For Human Interleukin-5; US5998586, published December 7, 1999, title: Interleukin-5 Specific Recombinant Antibodies; US6018032, published January 25, 2000, title: Antibody Against Human Interleukin-5-Receptor Alpha Chain; US6056957, published May 2, 2000, title: Humanized Monoclonal Antibodies Against Human Interleukin-5; US6451982, published September 17, 2002, title: Design, Cloning And Expression Of Humanized Monoclonal Antibodies Against Human Interleukin-5; US2003194404, published October 16, 2003, title: Human Monoclonal Antibodies To Interleukin-5 And Methods And Compositions Comprising Same; US6720155, published April 13, 2004, title: Monoclonal Antibody Inhibitor Of Gm-Csf, Il-3, IL-5 And Other Cytokines, And Uses Thereof; US2005226867, published October 13, 2005, title: IL-5R-Specific Antibody Composition;US2009252723, published October 8, 2009, title: Remedy For Endometriosis; US2010086547, published April 8, 2010, title: Methods For Administering Anti-IL-5 Antibodies; US2010291073, published November 18, 2010, title: Methods Of Reducing Eosinophil Levels; US2011020339, published January 27, 2011, title: Methods Of Treatment; US2015118249, published April 30, 2015, title: Stable, Aqueous Antibody Formulations; US2018155434, published June 7, 2018, title: Therapeutic Agent And Therapeutic Method For Pulmonary Hypertension; US2018186873, published July 5, 2018, title Anti-IL-5 Antibodies; US2018251539, published September 6, 2018, title Biopharmaceutical Compositions; US2020262909, published August 20, 2020, title IL-5 Antibody, Antigen Binding Fragment Thereof, And Medical Application Therefor; US2020291121, published September 17, 2020, title Anti-IL-5Ralpha Monoclonal Antibody; US2020399382, published December 24, 2020, title Combined Antagonists Against IL-5 / IL-5R And Either IL-4 / IL-4R Or Il-13 / Il-13R;US2021171621, published June 10, 2021, title: Monoclonal Antibody Binding To Human IL-5, Preparation Method Therefor And Use Thereof;WO21249373, published December 16, 2021, title: Stable High-Concentration Anti-Human IL-5 Monoclonal Antibody Liquid Preparation; US2022010008, published January 13, 2022, title: Anti-Human Interleukin 5 (IL-5) Monoclonal Antibody And Use Thereof; US2022144937, published May 12, 2022, title: Pharmaceutical Composition Containing Antibody Against IL-5 And Use Thereof; US2022193238, published June 23, 2022, title: Anti-IL5R Antibody Formulations; US2023357415, published November 9, 2023, title: Bispecific Antibody Simultaneously Binding To Interleukin-4 Receptor Alpha Subunit And Interleukin-5 It includes an antigen-specific binding site for IL-5 or IL-5R derived from the anti-IL-5 / anti-IL-5R described in Receptor Alpha Subunit, And Use Thereof; US2023399395, published December 14, 2023, titled Anti-IL-5 Nanoantibody And Use Thereof; US2023416380, published December 28, 2023, titled Antibody Binding Human IL-5R Alpha And Use Thereof; and US2024115698, published April 11, 2024, titled Anti-IL-5 Antibody Formulation, Preparation Method Therefor And Use Thereof (the descriptions of anti-IL-5 or anti-IL-5R antibodies in each of these are incorporated herein by reference).

[0148] In some embodiments, the Th2-targeted antibody includes an antigen-specific binding site for IL-9 or its receptor. In some embodiments, the Th2-targeted antibody is any known anti-IL-9 or its receptor, e.g., US5789237, published August 4, 1998, title: Nucleic Acid Sequences Coding For Or Complementary To Nucleic Acid Sequences Coding For Interleukin9 Receptor; US5908839, published June 1, 1999, title: Asthma Associated Factors As Targets For Treating Atopic Allergies Including Asthma And Related Disorders; US2003219439, published November 27, 2003, title: Recombinant Anti-Interleukin-9 Antibodies; US2005002934, published January 6, 2005, title: Recombinant IL-9 Antibodies And Uses This includes antigen-specific binding sites for IL-9 or IL-9R derived from anti-IL-9 / anti-IL-9R antibodies described in Thereof;US2005260204, published November 24, 2005, titled Anti-IL-9 Antibody Formulations And Uses Thereof;WO23246570, published December 28, 2023, titled Interleukin-9 Antibody And Use Thereof; and US2024109960, published April 4, 2024, titled Anti-IL-9 Antibodies And Methods Of Use Thereof (the descriptions of anti-IL-9 or anti-IL-9R antibodies in each of these are incorporated herein by reference).

[0149] In some embodiments, the Th2-targeted antibody includes an antigen-specific binding site for IL-25 or its receptor. In some embodiments, the Th2-targeted antibody is any known anti-IL-25 or its receptor, e.g., US2010028343, published February 4, 2010, title ILL17 Homologous Polypeptides And Therapeutic Uses Thereof; US2010129380, published May 27, 2010, title Antibodies Against IL-25; US7771719, published August 10, 2010, title Pharmaceutical Compositions, Kits, And Therapeutic Uses Of Antagonist Antibodies To IL-17E; US2011250195, published October 13, 2011, title Antibodies Against IL-25; US2011318353, published December 29, 2011, title Humanized IL-25 Antibodies; US2016083466, published March 24, 2016, titled Anti-IL-25 Antibodies And Uses Thereof; US2020291105, published September 17, 2020, titled Neutralizing Monoclonal Antibodies To IL-25 And Uses Thereof; US2021332123, published October 28, 2021, titled Anti-IL-25 Antibodies And Use Thereof; and WO23060144, published April 13, 2023, titled Monoclonal Antibodies To IL-25 And Uses Thereof (the content describing anti-IL-25 or anti-IL-25R antibodies in each of these is incorporated herein by reference), which include antigen-specific binding sites for IL-25 or IL-25R.

[0150] In some embodiments, the Th2-targeted antibody includes an antigen-specific binding site for IL-31 or its receptor. In some embodiments, the Th2-targeted antibody is any known anti-IL-31 or its receptor, e.g., US2006275296, published December 7, 2006, titled IL-31 Monoclonal Antibodies And Methods Of Use; US2007160610, published July 12, 2007, titled Methods Of Treating Pain And Inflammation In Neuronal Tissue Using IL-31 Antagonists; US2009208494, published August 20, 2009, titled Humanized Antibody Molecules Specific For IL-31; US2013022616, published January 24, 2013, titled Interleukin-31 Monoclonal Antibody; and US2024043547, published February 8, 2024, titled Antibody Variable Domains That Bind It includes an antigen-specific binding site for IL-31 or IL-31R derived from an anti-IL-31 / anti-IL-31R antibody described in IL-31 (the descriptions of anti-IL-31 or anti-IL-31R antibodies in each of these are incorporated herein by reference).

[0151] In some embodiments, the Th2-targeted antibody includes an antigen-specific binding site to IL-33 or its receptor. In some embodiments, the Th2-targeted antibody is any known anti-IL-33 or its receptor, e.g., US2003124624, published July 3, 2003, titled Monoclonal Antibody And Method And Kit For Immunoassay Of Soluble Human ST2; US2012213774, published August 23, 2012, titled Antibodies Against Human IL33R And Uses Thereof; US2014004107, published January 2, 2014, titled ST2 Antigen Binding Proteins; US2014271658, published September 18, 2014, titled Anti-IL-33 Antibodies And Uses Thereof; US2016168242, published June 16, 2016, titled Anti-Interleukin-33 Antibodies And Uses Thereof; US2016289322, published October 6, 2016, title: Human Anti-IL-33 Neutralizing Monoclonal Antibody; US2016333090, published November 17, 2016, title: Antibodies Directed Against Interleukin-33 (IL-33); US2018037644, published February 8, 2018, title: Anti-IL-33 Antibodies, Compositions, Methods And Uses Thereof; US2018118821, published May 3, 2018, title: Anti-IL-33 Antibodies And Uses Thereof; US2019202907, published July 4, 2019, title: Method Of Treating Systemic Fibrotic Disorders Using An IL-33 / Tnf Bispecific Antibody;US2019225682, published July 25, 2019, title: Method Of Treating Localized Fibrotic Disorders Using An IL-33 / Tnf Bispecific Antibody; WO20061571, published March 26, 2020, title: Anti-IL-33 Antibody For Use In Treating Eosinophilic Asthma; US2020190182, published June 18, 2020, title: IL-33 Antagonist-Containing Therapeutic Agent For Endometriosis; US2020297845, published September 24, 2020, title: Stabilized Formulations Containing Anti-IL-33 Antibodies; WO21017071, published February 4, 2021, title: Anti-Human ST2 Antibody And Use Thereof;US2021284725, published September 16, 2021, title: Anti-Interleukin-33 Antibodies And Uses Thereof;US2022041709, published February 10, 2022, title: Human Anti-IL-33 Monoclonal Antibody-Containing Pharmaceutical Composition;WO22039455, published February 24, 2022, title: Antibody Or Antigen-Binding Fragment Thereof That Specifically Binds To IL-33;WO23025932, published March 2, 2023, title: Treatment Of Chronic Obstructive Pulmonary Disease With An Anti-Interleukin-33 Antibody;WO23029280, published March 9, 2023, title: Anti-Human Interleukin-33 Monoclonal Antibody And Use Thereof;WO23077685, published May 11, 2023, title: Method For Preparing Concentrated Solution Comprising Monoclonal Antibody Against Human Interleukin-33 And Liquid Preparation; WO23086807, published May 19, 2023, title: Anti-Interleukin-33 Antibodies And Uses Thereof; US2023174638, published June 8, 2023, title: Formulations Of Anti-IL-33 Antibodies; US2023220086, published July 13, 2023, title: Anti-ST2 Antibody And Application Thereof; US2023399394, published December 14, 2023, title: Antibody Binding To Human IL-33, Preparation Method Therefor, And Use Thereof; and WO24042212, published February 29, 2024, titled Treatment Of Asthma With An Anti-Interleukin-33 Antibody (the descriptions of anti-IL-33 or anti-IL33R antibodies in each of these are incorporated herein by reference), which include antigen-specific binding sites for IL-33 or IL-33R derived from anti-IL-33 / anti-IL-33R antibodies.

[0152] In some embodiments, the Th2-targeted antibody includes an antigen-specific binding site for IL-6 or its receptor. In some embodiments, the Th2-targeted antibody is any known anti-IL-6 or its receptor, e.g., US2002037523, published March 28, 2002, title IL-6-Like Polynucleotides, Polypeptides, And Antibodies; US2002187150, published December 12, 2002, title Preventive And / Or Therapeutic Agent For Systemic Lupus Erythematosus Comprising Anti-IL-6 Receptor Antibody As An Active Ingredient; US2006134113, published June 22, 2006, title Preventive Or Therapeutic Agent For Sensitized T Cell-Mediated Diseases Comprising IL-6 Antagonist As An Active Ingredient; US2006188502, published August 24, 2006, title Anti-IL-6 Antibodies, Compositions, Methods And Uses; US2006240012, published October 26, 2006, title: Human Antihuman Interleukin-6 Antibody And Fragment Of Antibody; US2006251653, published November 9, 2006, title: Methods For Treating Interleukin-6 Related Diseases; US2006257407, published November 16, 2006, title: Anti-IL-6 Antibodies, Compositions, Methods And Uses; US2007036785, published February 15, 2007, title: Pharmaceutical Composition For Treatment Of Diseases Caused By IL-6 Production;US2007154481, published July 5, 2007, title: Antibody Molecules Having Specificity For Human IL-6; 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US2018022801, published January 25, 2018, title: Antibodies To IL-6 And Use Thereof; US2018066046, published March 8, 2018, title: Anti-IL-6 Antibodies For The Treatment Of Arthritis; US2018092999, published April 5, 2018, title: Antibodies To IL-6 And Use Thereof;US2018100013, published April 12, 2018, title: Antibodies To IL-6 And Use Thereof; US2018186874, published July 5, 2018, title: Antibodies To IL-6 And Use Thereof; US2018201668, published July 19, 2018, title: In Vivo Imaging Using Anti-IL-6 Antibodies; US2018201675, published July 19, 2018, title: Antibodies To IL-6 And Use Thereof; US2018371079, published December 27, 2018, title: Antibodies To IL-6 And Use Thereof; US2019023780, published January 24, 2019, title: Anti-IL-6 Antibodies For The Treatment Of Oral Mucositis; US2019083665, published March 21, 2019, Title: Antibodies To IL-6 And Use Thereof; US2019192692, published June 27, 2019, Title: DNA Monoclonal Antibodies Targeting IL-6 And Cd126; US2019194312, published June 27, 2019, Title: IL-6 Antibodies; 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[0153] In some embodiments, the Th2-targeted antibody comprises HC CDR1, HC CDR2, HC CDR3 of either the anti-IL-13 antibody or the anti-IL-13R antibody from Table 2 (VH), and LC CDR1, LC CDR2, and LC CDR3 of either the anti-IL-13 antibody or the anti-IL-13R antibody from Table 2 (VL). In some embodiments, the Th2-targeted antibody comprises either the anti-IL-13 antibody from Table 2 (VH), and either the anti-IL-13 antibody from Table 2 (VL). In some embodiments, the Th2-targeted antibody comprises either the anti-IL-13 antibody from Table 2 (VH), and either the anti-IL-13 antibody from Table 2 (VL). In some embodiments, the Th2-targeted antibody includes HC CDR1, HC CDR2, HC CDR3 of lebrikizumab, and LC CDR1, LC CDR2, and LC CDR3 of lebrikizumab. In some embodiments, the Th2-targeted antibody includes VH of lebrikizumab and VL of lebrikizumab. In some embodiments, the Th2-targeted antibody includes HC CDR1, HC CDR2, HC CDR3 of tralokinumab, and LC CDR1, LC CDR2, and LC CDR3 of tralokinumab. In some embodiments, the Th2-targeted antibody includes VH of tralokinumab and VL of tralokinumab. In some embodiments, the Th2-targeted antibody includes HC CDR1, HC CDR2, HC CDR3 of evrasakimab, and LC CDR1, LC CDR2, and LC CDR3 of evrasakimab. In some embodiments, the Th2-targeting antibody includes evrasakimab VH and evrasakimab VL. In some embodiments, the Th2-targeting antibody includes sendakimab HC CDR1, HC CDR2, HC CDR3, and sendakimab LC CDR1, LC CDR2, and LC CDR3. In some embodiments, the Th2-targeting antibody includes sendakimab VH and sendakimab VL.In some embodiments, the Th2-targeting antibody includes HC CDR1, HC CDR2, HC CDR3 of dectrecumab, and LC CDR1, LC CDR2, and LC CDR3 of dectrecumab. In some embodiments, the Th2-targeting antibody includes VH of dectrecumab and VL of dectrecumab. In some embodiments, the Th2-targeting antibody includes HC CDR1, HC CDR2, HC CDR3 of APG777, and LC CDR1, LC CDR2, and LC CDR3 of APG777. In some embodiments, the Th2-targeting antibody includes VH of APG777 and VL of APG777.

[0154] In some embodiments, the Th2-targeted antibody includes an antigen-specific binding site for IL-4 or its receptor. In some embodiments, the Th2-targeted antibody includes HC CDR1, HC CDR2, HC CDR3 of either the anti-IL-4 antibody or the anti-IL-4R antibody from Table 2 (VH), and LC CDR1, LC CDR2, and LC CDR3 of either the anti-IL-4 antibody or the anti-IL-4R antibody from Table 2 (VL). In some embodiments, the Th2-targeted antibody includes either the anti-IL-4 antibody or the anti-IL-4R antibody from Table 2 (VH), and either the anti-IL-4 antibody or the anti-IL-4R antibody from Table 2 (VL). In some embodiments, the Th2-targeted antibody includes HC CDR1, HC CDR2, HC CDR3 of dupilumab, and LC CDR1, LC CDR2, and LC CDR3 of dupilumab. In some embodiments, the Th2-targeted antibody includes dupilumab (VH) and dupilumab (VL). In some embodiments, the Th2-targeting antibody includes HC CDR1, HC CDR2, HC CDR3 of pascolizumab, and LC CDR1, LC CDR2, and LC CDR3 of pascolizumab. In some embodiments, the Th2-targeting antibody includes VH of pascolizumab and VL of pascolizumab. In some embodiments, the Th2-targeting antibody includes HC CDR1, HC CDR2, HC CDR3 of AMG 317, and LC CDR1, LC CDR2, and LC CDR3 of AMG 317. In some embodiments, the Th2-targeting antibody includes VH of AMG 317 and VL of AMG 317. In some embodiments, the Th2-targeting antibody includes HC CDR1, HC CDR2, HC CDR3 of stabokivart, and LC CDR1, LC CDR2, and LC CDR3 of stabokivart. In some embodiments, the Th2-targeting antibody includes stabokivat VH and stabokivat VL. In some embodiments, the Th2-targeting antibody includes rademiquivat HC CDR1, HC CDR2, HC CDR3, and rademiquivat LC CDR1, LC CDR2, and LC CDR3. In some embodiments, the Th2-targeting antibody includes rademiquivat VH and rademiquivat VL.In some embodiments, the Th2-targeted antibody includes manfidokimab HC CDR1, HC CDR2, HC CDR3, and manfidokimab LC CDR1, LC CDR2, and LC CDR3. In some embodiments, the Th2-targeted antibody includes manfidokimab VH and manfidokimab VL.

[0155] In some embodiments, the Th2-targeted antibody includes an antigen-specific binding site for IL-5 or its receptor. In some embodiments, the Th2-targeted antibody includes HC CDR1, HC CDR2, HC CDR3 of the VH of either the anti-IL-5 antibody or the anti-IL-5R antibody from Table 2, and LC CDR1, LC CDR2, and LC CDR3 of the VL of either the anti-IL-5 antibody or the anti-IL-5R antibody from Table 2. In some embodiments, the Th2-targeted antibody includes the VH of either the anti-IL-5 antibody or the anti-IL-5R antibody from Table 2, and the VL of either the anti-IL-5 antibody or the anti-IL-5R antibody from Table 2. In some embodiments, the Th2-targeted antibody includes HC CDR1, HC CDR2, HC CDR3 of benralizumab, and LC CDR1, LC CDR2, and LC CDR3 of benralizumab. In some embodiments, the Th2-targeting antibody includes benralizumab VH and benralizumab VL. In some embodiments, the Th2-targeting antibody includes mepolizumab HC CDR1, HC CDR2, HC CDR3, and mepolizumab LC CDR1, LC CDR2, and LC CDR3. In some embodiments, the Th2-targeting antibody includes mepolizumab VH and mepolizumab VL. In some embodiments, the Th2-targeting antibody includes reslizumab HC CDR1, HC CDR2, HC CDR3, and reslizumab LC CDR1, LC CDR2, and LC CDR3. In some embodiments, the Th2-targeting antibody includes reslizumab VH and reslizumab VL. In some embodiments, the Th2-targeting antibody includes HC CDR1, HC CDR2, HC CDR3 of depemoquimab, and LC CDR1, LC CDR2, and LC CDR3 of depemoquimab. In some embodiments, the Th2-targeting antibody includes VH of depemoquimab and VL of depemoquimab. In some embodiments, the Th2-targeting antibody includes HC CDR1, HC CDR2, HC CDR3 of clone 601 described by WO2019120,060 or WO2021249,373, and LC CDR1, LC CDR2, and LC CDR3 of clone 601 described by WO2019120,060 or WO2021249,373.In some embodiments, the Th2-targeting antibody includes VH of clone 601 as described by WO2019120,060 or WO2021249,373, and VL of clone 601 as described by WO2019120,060 or WO2021249,373. In some embodiments, the Th2-targeting antibody includes HC CDR1, HC CDR2, HC CDR3 of Traviquivat, and LC CDR1, LC CDR2, and LC CDR3 of Traviquivat. In some embodiments, the Th2-targeting antibody includes VH of Traviquivat and VL of Traviquivat.

[0156] In some embodiments, the Th2-targeted antibody includes an antigen-specific binding site for IL-9 or its receptor. In some embodiments, the Th2-targeted antibody includes HC CDR1, HC CDR2, HC CDR3 of the VH of either the anti-IL-9 antibody or the anti-IL-9R antibody from Table 2, and LC CDR1, LC CDR2, and LC CDR3 of the VL of either the anti-IL-9 antibody or the anti-IL-9R antibody from Table 2. In some embodiments, the Th2-targeted antibody includes the VH of either the anti-IL-9 antibody or the anti-IL-9R antibody from Table 2, and the VL of either the anti-IL-9 antibody or the anti-IL-9R antibody from Table 2. In some embodiments, the Th2-targeted antibody includes HC CDR1, HC CDR2, HC CDR3 of enokizumab, and LC CDR1, LC CDR2, and LC CDR3 of enokizumab. In some embodiments, the Th2-targeting antibody comprises enokizumab VH and enokizumab VL.

[0157] In some embodiments, the Th2-targeted antibody includes an antigen-specific binding site for OX40 or its ligand. In some embodiments, the Th2-targeted antibody includes HC CDR1, HC CDR2, HC CDR3 of either the anti-OX40 antibody or the anti-OX40L antibody from Table 2 (VH), and LC CDR1, LC CDR2, and LC CDR3 of either the anti-OX40 antibody or the anti-OX40L antibody from Table 2 (VL). In some embodiments, the Th2-targeted antibody includes either the anti-OX40 antibody or the anti-OX40L antibody from Table 2 (VH), and either the anti-OX40 antibody or the anti-OX40L antibody from Table 2 (VL). In some embodiments, the Th2-targeted antibody includes HC CDR1, HC CDR2, HC CDR3 of locatin limab, and LC CDR1, LC CDR2, and LC CDR3 of locatin limab. In some embodiments, the Th2-targeted antibody includes locatinlimab VH and locatinlimab VL. In some embodiments, the Th2-targeted antibody includes oxerumab HC CDR1, HC CDR2, HC CDR3, and oxerumab LC CDR1, LC CDR2, and LC CDR3. In some embodiments, the Th2-targeted antibody includes oxerumab VH and oxerumab VL. In some embodiments, the Th2-targeted antibody includes terazolimab HC CDR1, HC CDR2, HC CDR3, and terazolimab LC CDR1, LC CDR2, and LC CDR3. In some embodiments, the Th2-targeted antibody includes terazolimab VH and terazolimab VL. In some embodiments, the Th2-targeting antibody includes amriterimab HC CDR1, HC CDR2, HC CDR3, and amriterimab LC CDR1, LC CDR2, and LC CDR3. In some embodiments, the Th2-targeting antibody includes amriterimab VH and amriterimab VL. In some embodiments, the Th2-targeting antibody includes IMG-007 HC CDR1, HC CDR2, HC CDR3, and IMG-007 LC CDR1, LC CDR2, and LC CDR3. In some embodiments, the Th2-targeting antibody includes IMG-007 VH and IMG-007 VL.

[0158] In some embodiments, the Th2-targeted antibody includes an antigen-specific binding site for IL-25 (also known as IL-17E) or its receptor. In some embodiments, the Th2-targeted antibody includes HC CDR1, HC CDR2, HC CDR3 of the VH of either the anti-IL-25 antibody or the anti-IL-25R antibody from Table 2, and LC CDR1, LC CDR2, and LC CDR3 of the VL of either the anti-IL-25 antibody or the anti-IL-25R antibody from Table 2. In some embodiments, the Th2-targeted antibody includes the VH of either the anti-IL-25 antibody or the anti-IL-25R antibody from Table 2, and the VL of either the anti-IL-25 antibody or the anti-IL-25R antibody from Table 2. In some embodiments, the Th2-targeted antibody includes HC CDR1, HC CDR2, HC CDR3 of brodalumab, and LC CDR1, LC CDR2, and LC CDR3 of brodalumab. In some embodiments, the Th2-targeting antibody includes brodalumab VH and brodalumab VL. In some embodiments, the Th2-targeting antibody includes LNR125 HC CDR1, HC CDR2, HC CDR3, and LNR125 LC CDR1, LC CDR2, and LC CDR3. In some embodiments, the Th2-targeting antibody includes LNR125 VH and LNR125 VL.

[0159] In some embodiments, the Th2-targeted antibody includes an antigen-specific binding site for IL-31 or its receptor. In some embodiments, the Th2-targeted antibody includes HC CDR1, HC CDR2, HC CDR3 of the VH of either the anti-IL-31 antibody or the anti-IL-31R antibody from Table 2, and LC CDR1, LC CDR2, and LC CDR3 of the VL of either the anti-IL-31 antibody or the anti-IL-31R antibody from Table 2. In some embodiments, the Th2-targeted antibody includes the VH of either the anti-IL-31 antibody or the anti-IL-31R antibody from Table 2, and the VL of either the anti-IL-31 antibody or the anti-IL-31R antibody from Table 2. In some embodiments, the Th2-targeted antibody includes HC CDR1, HC CDR2, HC CDR3 of nemolizumab, and LC CDR1, LC CDR2, and LC CDR3 of nemolizumab. In some embodiments, the Th2-targeting antibody includes nemolizumab VH and nemolizumab VL. In some embodiments, the Th2-targeting antibody includes bixarelimab HC CDR1, HC CDR2, HC CDR3, and bixarelimab LC CDR1, LC CDR2, and LC CDR3. In some embodiments, the Th2-targeting antibody includes bixarelimab VH and bixarelimab VL. In some embodiments, the Th2-targeting antibody includes NM26-2198 HC CDR1, HC CDR2, HC CDR3, and NM26-2198 LC CDR1, LC CDR2, and LC CDR3. In some embodiments, the Th2-targeting antibody includes NM26-2198 VH and NM26-2198 VL. In some embodiments, the Th2-targeting antibody includes HC CDR1, HC CDR2, HC CDR3 of BMS-981164, and LC CDR1, LC CDR2, and LC CDR3 of BMS-981164. In some embodiments, the Th2-targeting antibody includes VH of BMS-981164 and VL of BMS-981164.

[0160] In some embodiments, the Th2-targeted antibody includes an antigen-specific binding site for IL-36 or its receptor. In some embodiments, the Th2-targeted antibody includes HC CDR1, HC CDR2, HC CDR3 of the VH of either the anti-IL-36 antibody or the anti-IL-36R antibody from Table 2, and LC CDR1, LC CDR2, and LC CDR3 of the VL of either the anti-IL-36 antibody or the anti-IL-36R antibody from Table 2. In some embodiments, the Th2-targeted antibody includes the VH of either the anti-IL-36 antibody or the anti-IL-36R antibody from Table 2, and the VL of either the anti-IL-36 antibody or the anti-IL-36R antibody from Table 2. In some embodiments, the Th2-targeted antibody includes HC CDR1, HC CDR2, HC CDR3 of spesorimab, and LC CDR1, LC CDR2, and LC CDR3 of spesorimab. In some embodiments, the Th2-targeted antibody includes the VH and VL forms of spesolimab. In some embodiments, the Th2-targeted antibody includes the HC CDR1, HC CDR2, and HC CDR3 forms of imsidlimab, as well as the LC CDR1, LC CDR2, and LC CDR3 forms of imsidlimab. In some embodiments, the Th2-targeted antibody includes the VH and VL forms of imsidlimab. In some embodiments, the Th2-targeted antibody includes the HC CDR1, HC CDR2, and HC CDR3 forms of HB0034, as well as the LC CDR1, LC CDR2, and LC CDR3 forms of HB0034. In some embodiments, the Th2-targeted antibody includes the VH and VL forms of HB0034.

[0161] In some embodiments, the Th2-targeted antibody includes an antigen-specific binding site for thymic interstitial lymphocyte neogenesis factor (TSLP) or its receptor. In some embodiments, the Th2-targeted antibody includes HC CDR1, HC CDR2, HC CDR3 of either the anti-TSLP antibody or the anti-TSLPR antibody VH of Table 2, and LC CDR1, LC CDR2, and LC CDR3 of either the anti-TSLP antibody or the anti-TSLPR antibody VL of Table 2. In some embodiments, the Th2-targeted antibody includes either the anti-TSLP antibody or the anti-TSLPR antibody VH of Table 2, and either the anti-TSLP antibody or the anti-TSLPR antibody VL of Table 2. In some embodiments, the Th2-targeted antibody includes HC CDR1, HC CDR2, HC CDR3 of tezeperumab, and LC CDR1, LC CDR2, and LC CDR3 of tezeperumab. In some embodiments, the Th2-targeted antibody includes tezeperumab VH and tezeperumab VL. In some embodiments, the Th2-targeted antibody includes eclarimab HC CDR1, HC CDR2, HC CDR3, and eclarimab LC CDR1, LC CDR2, and LC CDR3. In some embodiments, the Th2-targeted antibody includes eclarimab VH and eclamimab VL. In some embodiments, the Th2-targeted antibody includes BSI-045B HC CDR1, HC CDR2, HC CDR3, and BSI-045B LC CDR1, LC CDR2, and LC CDR3. In some embodiments, the Th2-targeted antibody includes BSI-045B VH and BSI-045B VL. In some embodiments, the Th2-targeting antibody includes HC CDR1, HC CDR2, HC CDR3 of CM326, and LC CDR1, LC CDR2, and LC CDR3 of CM326. In some embodiments, the Th2-targeting antibody includes VH of CM326 and VL of CM326.

[0162] In some embodiments, the Th2-targeted antibody includes an antigen-specific binding site for IL-33 or its receptor. In some embodiments, the Th2-targeted antibody includes HC CDR1, HC CDR2, HC CDR3 of either the anti-IL-33 antibody or the anti-IL-33R antibody VH of Table 2, and LC CDR1, LC CDR2, and LC CDR3 of either the anti-IL-33 antibody or the anti-IL-33R antibody VL of Table 2. In some embodiments, the Th2-targeted antibody includes either the anti-IL-33 antibody or the anti-IL-33R antibody VH of Table 2, and either the anti-IL-33 antibody or the anti-IL-33R antibody VL of Table 2. In some embodiments, the Th2-targeted antibody includes HC CDR1, HC CDR2, HC CDR3 of tozolakimab, and LC CDR1, LC CDR2, and LC CDR3 of tozolakimab. In some embodiments, the Th2-targeting antibody includes tozolacimab VH and tozolacimab VL. In some embodiments, the Th2-targeting antibody includes itepecimab HC CDR1, HC CDR2, HC CDR3, and itepecimab LC CDR1, LC CDR2, and LC CDR3. In some embodiments, the Th2-targeting antibody includes itepecimab VH and itepecimab VL. In some embodiments, the Th2-targeting antibody includes etokimab HC CDR1, HC CDR2, HC CDR3, and etokimab LC CDR1, LC CDR2, and LC CDR3. In some embodiments, the Th2-targeting antibody includes etokimab VH and etokimab VL. In some embodiments, the Th2-targeting antibody includes HC CDR1, HC CDR2, HC CDR3 of PF-07264660, and LC CDR1, LC CDR2, and LC CDR3 of PF-07264660. In some embodiments, the Th2-targeting antibody includes VH of PF-07264660 and VL of PF-07264660.

[0163] (c) Multispecific antibody In some embodiments, the antibodies provided herein are multispecific antibodies (e.g., bispecific antibodies). For example, in some embodiments, one or more anti-KLK5 / KLK7 antibodies may be combined with one or more different anti-KLK5 / KLK7 antibodies to produce multispecific or bispecific anti-KLK5 / KLK7 antibodies. For example, one or more anti-KLK5 / KLK7 antibodies described herein (Tables 1a and 1b) can be combined with one or more different anti-KLK5 / KLK7 antibodies described herein (Tables 1a and 1b) to produce multispecific antibodies.

[0164] In some embodiments, one or more anti-KLK5 / KLK7 antibodies may be combined with any other suitable therapeutic antibody to generate multispecific or bispecific anti-KLK5 / KLK7 / additional target antibodies. For example, the anti-KLK5 / KLK7 antibodies described herein (Tables 1a and 1b) can be combined with any suitable antibody (e.g., the Th2-targeted antibodies described in Table 2) to generate bispecific antibodies. Such additional therapeutic antibodies include, but are not limited to, anti-IL4R antibodies (e.g., dupilumab), anti-IL-13 antibodies, TNF inhibitors (e.g., anti-TNF antibodies), IL-12 / 23 antibodies, IL-17 antibodies, adalimumab, infliximab, golimumab, ustekinumab, secukinumab, ixekizumab, brodalumab, abatacept, tidrakizumab-asmn, risankisumab-rzaa, and guselkumab.

[0165] In some embodiments, the disclosure provides a bispecific antibody comprising at least one antigen-specific binding site that specifically binds to KLK5 and KLK7, and at least one antigen-specific binding site that specifically binds to a T helper cell 2 (Th2) cytokine (i.e., a cytokine produced by Th2 cells) or its receptor. In some embodiments, the Th2 cytokines include, but are not limited to, IL-13, IL-4, IL-5, IL-9, IL-31, IL-17E (IL-25), IL-33, OX40, IL-36, JAG1, and TSLP. In some embodiments, the at least one antigen-specific binding site that specifically binds to a T helper cell 2 (Th2) cytokine or its receptor does not target IL-13, IL-17, IL-5, or IL-4. In some embodiments, at least one antigen-specific binding site that specifically binds to a T helper cell 2 (Th2) cytokine or its receptor binds to IL-9, IL-31, IL-33, OX40, IL-36, JAG1, and TSLP.

[0166] Table 6 below shows possible arm configurations for anti-KLK5 / KLK7+Th2 targeted bispecific antibodies. In some embodiments, the anti-KLK5 / KLK7+Th2 targeted bispecific antibody includes one arm comprising a CDR and / or VH and / or VL, the sequence of which is derived from, corresponds to, or is the same as, the CDR and / or VH and / or VL sequence of the antibodies listed in the left column of Table 6; and a second arm comprising a CDR and / or VH / VL, the sequence of which is derived from, corresponds to, or is the same as, the CDR and / or VH and / or VL sequence of the antibodies listed in the corresponding row in the right column of Table 6 or another suitable antibody disclosed herein. The CDR and VH / VL of each antibody are listed in Tables 1a and 2. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8] [Table 6-9]

[0167] In some embodiments, the anti-KLK5 / KLK7+Th2 targeted bispecific antibody comprises one arm containing a CDR and / or VH / VL whose sequence is derived from, corresponds to, or is identical to, the sequence of the CDR and / or VH / VL of the anti-KLK5 / KLK7 antibody listed in Table 1a, and a second arm containing a CDR and / or VH / VL whose sequence is derived from, corresponds to, or is identical to, the sequence of the CDR and / or VH / VL of the anti-IL-13 or anti-IL-13R antibody listed in Table 2, Table 6, or elsewhere in this specification. In some embodiments, the anti-KLK5 / KLK7+Th2 bispecific antibody may comprise one arm containing an antigen-specific binding site that targets KLK5 and KLK7, and a second arm containing an antigen-specific binding site that does not target IL-13 or IL-13R.

[0168] In some embodiments, the anti-KLK5 / KLK7+Th2 targeted bispecific antibody comprises one arm containing a CDR and / or VH / VL whose sequence is derived from, corresponds to, or is identical to, the sequence of the CDR and / or VH / VL of the anti-KLK5 / KLK7 antibody listed in Table 1a, and a second arm containing a CDR and / or VH / VL whose sequence is derived from, corresponds to, or is identical to, the sequence of the CDR and / or VH / VL of the anti-IL-4 or anti-IL4R antibody listed in Table 2, Table 6, or elsewhere in this specification. In some embodiments, the anti-KLK5 / KLK7+Th2 bispecific antibody may comprise one arm containing an antigen-specific binding site that targets KLK5 and KLK7, and a second arm containing an antigen-specific binding site that does not target IL-4 or IL-4R.

[0169] In some embodiments, the anti-KLK5 / KLK7+Th2 targeted bispecific antibody comprises one arm containing a CDR and / or VH / VL whose sequence is derived from, corresponds to, or is identical to, the sequence of the CDR and / or VH / VL of the anti-KLK5 / KLK7 antibody listed in Table 1a, and a second arm containing a CDR and / or VH / VL whose sequence is derived from, corresponds to, or is identical to, the sequence of the CDR and / or VH / VL of the anti-IL-5 or anti-IL-5R antibody listed in Table 2, Table 6, or elsewhere in this specification. In some embodiments, the anti-KLK5 / KLK7+Th2 bispecific antibody may comprise one arm containing an antigen-specific binding site that targets KLK5 and KLK7, and a second arm containing an antigen-specific binding site that does not target IL-5 or IL-5R.

[0170] In some embodiments, the anti-KLK5 / KLK7+Th2 targeted bispecific antibody comprises one arm containing a CDR and / or VH / VL whose sequence is derived from, corresponds to, or is identical to, the sequence of the CDR and / or VH / VL of the anti-KLK5 / KLK7 antibody listed in Table 1a, and a second arm containing a CDR and / or VH / VL whose sequence is derived from, corresponds to, or is identical to, the sequence of the CDR and / or VH / VL of the anti-IL-25 or anti-IL-25R antibody listed in Table 2, Table 6, or elsewhere in this specification. In some embodiments, the anti-KLK5 / KLK7+Th2 bispecific antibody may comprise one arm containing an antigen-specific binding site that targets KLK5 and KLK7, and a second arm containing an antigen-specific binding site that does not target IL-25 or IL-25R.

[0171] In some embodiments, the anti-KLK5 / KLK7+Th2 targeted bispecific antibody comprises one arm containing a CDR and / or VH / VL whose sequence is derived from, corresponds to, or is identical to, the sequence of the CDR and / or VH / VL of the anti-KLK5 / KLK7 antibody listed in Table 1a, and a second arm containing a CDR and / or VH / VL whose sequence is derived from, corresponds to, or is identical to, the sequence of the CDR and / or VH / VL of the anti-IL-9 or anti-IL9R antibody listed in Table 2, Table 6, or elsewhere in this specification. In some embodiments, the anti-KLK5 / KLK7+Th2 bispecific antibody may comprise one arm containing an antigen-specific binding site that targets KLK5 and KLK7, and a second arm containing an antigen-specific binding site that does not target IL-9 or IL-9R.

[0172] In some embodiments, the anti-KLK5 / KLK7+Th2 targeted bispecific antibody comprises one arm containing a CDR and / or VH / VL whose sequence is derived from, corresponds to, or is identical to, the sequence of the CDR and / or VH / VL of the anti-KLK5 / KLK7 antibody listed in Table 1a, and a second arm containing a CDR and / or VH / VL whose sequence is derived from, corresponds to, or is identical to, the sequence of the CDR and / or VH / VL of the anti-OX40L or anti-OX40 antibody listed in Table 2, Table 6, or elsewhere in this specification. In some embodiments, the anti-KLK5 / KLK7+Th2 bispecific antibody may comprise one arm containing an antigen-specific binding site that targets KLK5 and KLK7, and a second arm containing an antigen-specific binding site that does not target OX40L or OX40.

[0173] In some embodiments, the anti-KLK5 / KLK7+Th2 targeted bispecific antibody comprises one arm containing a CDR and / or VH / VL whose sequence is derived from, corresponds to, or is identical to, the sequence of the CDR and / or VH / VL of the anti-KLK5 / KLK7 antibody listed in Table 1a, and a second arm containing a CDR and / or VH / VL whose sequence is derived from, corresponds to, or is identical to, the sequence of the CDR and / or VH / VL of the anti-IL-31 or anti-IL-31R antibody listed in Table 2, Table 6, or elsewhere in this specification. In some embodiments, the anti-KLK5 / KLK7+Th2 bispecific antibody may comprise one arm containing an antigen-specific binding site that targets KLK5 and KLK7, and a second arm containing an antigen-specific binding site that does not target IL-31 or IL-31R.

[0174] In some embodiments, the anti-KLK5 / KLK7+Th2 targeted bispecific antibody comprises one arm containing a CDR and / or VH / VL whose sequence is derived from, corresponds to, or is identical to, the sequence of the CDR and / or VH / VL of an anti-KLK5 / KLK7 antibody listed in Table 1a, and a second arm containing a CDR and / or VH / VL whose sequence is derived from, corresponds to, or is identical to, the sequence of the CDR and / or VH / VL of an anti-TSLP or anti-TSLPR antibody listed in Table 2, Table 6, or elsewhere in this specification. In some embodiments, the anti-KLK5 / KLK7+Th2 bispecific antibody may comprise one arm containing an antigen-specific binding site that targets KLK5 and KLK7, and a second arm containing an antigen-specific binding site that does not target TSLPR or TSLPR.

[0175] In some embodiments, the anti-KLK5 / KLK7+Th2 targeted bispecific antibody comprises one arm containing a CDR and / or VH / VL whose sequence is derived from, corresponds to, or is identical to, the sequence of the CDR and / or VH / VL of an anti-KLK5 / KLK7 antibody listed in Table 1a, and a second arm containing a CDR and / or VH / VL whose sequence is derived from, corresponds to, or is identical to, the sequence of the CDR and / or VH / VL of an anti-IL-33 or anti-IL-33R antibody listed in Table 2, Table 6, or elsewhere in this specification. In some embodiments, the anti-KLK5 / KLK7+Th2 bispecific antibody may comprise one arm containing an antigen-specific binding site that targets KLK5 and KLK7, and a second arm containing an antigen-specific binding site that does not target IL-33 or IL-33R.

[0176] In some embodiments, the anti-KLK5 / KLK7+Th2 targeted bispecific antibody comprises one arm containing a CDR and / or VH / VL whose sequence is derived from, corresponds to, or is identical to, the sequence of the CDR and / or VH / VL of an anti-KLK5 / KLK7 antibody listed in Table 1a, and a second arm containing a CDR and / or VH / VL whose sequence is derived from, corresponds to, or is identical to, the sequence of the CDR and / or VH / VL of an anti-IL-6 or anti-IL-6R antibody listed in Table 2, Table 6, or elsewhere in this specification. In some embodiments, the anti-KLK5 / KLK7+Th2 bispecific antibody may comprise one arm containing an antigen-specific binding site that targets KLK5 and KLK7, and a second arm containing an antigen-specific binding site that does not target IL-6 or IL-6R.

[0177] In some embodiments, the bispecific antibodies described herein include at least one antigen-specific binding site that specifically binds to KLK5 and KLK7 (e.g., KLK5 / KLK7-dual-Ab4) and at least one antigen-specific binding site that specifically binds to IL-13 or IL-13R (e.g., either of the anti-IL-13 or anti-IL-13 antibodies described herein). Such bispecific antibodies are referred to as anti-KLK5 / KLK7+IL-13 bispecific antibodies. Such antigen-specific binding sites may be derived from, correspond to, or be the same as, either one of the anti-KLK5 / KLK7 antibodies or IL-13 / IL-13R targeted antibodies disclosed herein.

[0178] Interleukin (IL)-13 is a cytokine involved in the pathogenesis of skin barrier diseases (e.g., atopic dermatitis (AD)). In some embodiments, IL-13 is a driver of type 2 T helper inflammation. In some embodiments, IL-13 is overexpressed in the lesioned skin of subjects with skin barrier disease. In some embodiments, upon release in the peripheral skin, IL-13 activates its receptors, recruits inflammatory cells, and / or modifies the skin microbiome. In some embodiments, IL-13 also reduces the expression of epidermal barrier proteins and activates sensory nerves that mediate itch transmission signals. In some embodiments, blocking IL-13 signaling in combination with KLK5 / KLK7 inhibition is effective in treating any of the diseases described herein.

[0179] In some embodiments, the anti-KLK5 / KLK7+IL-13 bispecific antibody described herein includes at least one antigen-specific binding site that specifically binds to the active sites of KLK5 and KLK7. In some embodiments, the anti-KLK5 / KLK7+IL-13 bispecific antibody described herein includes at least one antigen-specific binding site that specifically binds to KLK5 and KLK7, which are binding sites of dual inhibitory antibodies that specifically bind to KLK5 and KLK7 (e.g., any one of KLK5 / KLK7-dual-Ab1, KLK5 / KLK7-dual-Ab2, KLK5 / KLK7-dual-Ab3, or KLK5 / KLK7-dual-Ab1). In some embodiments, the anti-KLK5 / KLK7+IL-13 bispecific antibody comprises one arm containing at least one antigen-specific binding site that specifically binds to KLK5 and KLK7, including one of the antibodies listed in Tables 1a and 1b (e.g., any one of KLK5 / KLK7-dual-Ab1, KLK5 / KLK7-dual-Ab2, KLK5 / KLK7-dual-Ab3, KLK5 / KLK7-dual-Ab4), and one of the anti-IL-13 or anti-IL-13R antibodies listed in Table 2, including HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3, and one of the anti-IL-13 or anti-IL-13R antibodies listed in Table 2, including HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3, and one of the anti-IL-13 or anti-IL-13R antibodies listed in Table 2. The anti-KLK5 / KLK7-IL-13 bispecific antibody comprises one arm containing at least one antigen-specific binding site that specifically binds to IL-13 or IL-13R containing CDR3. In some embodiments, the anti-KLK5 / KLK7-IL-13 bispecific antibody comprises a VH that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to one of the VHs listed in Tables 1a and 1b (e.g., any one of KLK5 / KLK7-dual-Ab1, KLK5 / KLK7-dual-Ab2, KLK5 / KLK7-dual-Ab3, KLK5 / KLK7-dual-Ab1),An arm containing at least one antigen-specific binding site that specifically binds to KLK5 and KLK7, comprising a VL that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to one VL of any of the antibodies listed in Tables 1a and 1b (e.g., any one of KLK5 / KLK7-dual-Ab1, KLK5 / KLK7-dual-Ab2, KLK5 / KLK7-dual-Ab3, or KLK5 / KLK7-dual-Ab1), and at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to one VL of any of the antibodies listed in Tables 1a and 1b (e.g., KLK5 / KLK7-dual-Ab1, KLK5 / KLK7-dual-Ab2, KLK5 / KLK7-dual-Ab3, or any one of KLK5 / KLK7-dual-Ab1), and at least 80% (e.g., It includes a VH that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical, and / or an arm containing at least one antigen-specific binding site that specifically binds to IL-13 or IL-13R, including a VL that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to one VL of any of the anti-IL-13 or anti-IL-13R antibodies listed in Table 2.

[0180] In some embodiments, an anti-KLK5 / KLK7+IL-13 bispecific antibody comprising at least one antigen-specific binding site that specifically binds to KLK5 and KLK7 comprises heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 7, and light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 8. In some embodiments, an anti-KLK5 / KLK7+IL-13 bispecific antibody comprising at least one antigen-specific binding site that specifically binds to KLK5 and KLK7 comprises heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 13, and light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 14.

[0181] In some embodiments, an anti-KLK5 / KLK7+IL-13 bispecific antibody comprising at least one antigen-specific binding site that specifically binds to KLK5 and KLK7 comprises heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 17, and light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 14.

[0182] In some embodiments, an anti-KLK5 / KLK7+IL-13 bispecific antibody comprising at least one antigen-specific binding site that specifically binds to KLK5 and KLK7 comprises heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 21, and light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 14.

[0183] In some embodiments, an anti-KLK5 / KLK7+IL-13 bispecific antibody comprising at least one antigen-specific binding site that specifically binds to KLK5 and KLK7 includes HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, HC CDR3 having the amino acid sequence of SEQ ID NO: 3, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 6. In some embodiments, an anti-KLK5 / KLK7+IL-13 bispecific antibody comprising at least one antigen-specific binding site that specifically binds to KLK5 and KLK7 includes HC CDR1 having the amino acid sequence of SEQ ID NO: 9, HC CDR2 having the amino acid sequence of SEQ ID NO: 10, HC CDR3 having the amino acid sequence of SEQ ID NO: 11, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, an anti-KLK5 / KLK7+IL-13 bispecific antibody comprising at least one antigen-specific binding site that specifically binds to KLK5 and KLK7 includes HC CDR1 having the amino acid sequence of SEQ ID NO: 9, HC CDR2 having the amino acid sequence of SEQ ID NO: 15, HC CDR3 having the amino acid sequence of SEQ ID NO: 16, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, an anti-KLK5 / KLK7+IL-13 bispecific antibody comprising at least 18 antigen-specific binding sites that specifically bind to KLK5 and KLK7 includes HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 19, HC CDR3 having the amino acid sequence of SEQ ID NO: 20, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 12.

[0184] In some embodiments, an anti-KLK5 / KLK7+IL-13 bispecific antibody containing at least one antigen-specific binding site that specifically binds to KLK5 and KLK7 includes a VH containing the amino acid sequence of SEQ ID NO: 7 and a VL containing the amino acid sequence of SEQ ID NO: 8. In some embodiments, an anti-KLK5 / KLK7+IL-13 bispecific antibody containing at least one antigen-specific binding site that specifically binds to KLK5 and KLK7 includes a VH containing the amino acid sequence of SEQ ID NO: 13 and a VL containing the amino acid sequence of SEQ ID NO: 14. In some embodiments, an anti-KLK5 / KLK7+IL-13 bispecific antibody containing at least one antigen-specific binding site that specifically binds to KLK5 and KLK7 includes a VH containing the amino acid sequence of SEQ ID NO: 17, and a VL containing the amino acid sequences of LC CDR1, LC CDR2, and SEQ ID NO: 14. In some embodiments, an anti-KLK5 / KLK7+IL-13 bispecific antibody containing at least one antigen-specific binding site that specifically binds to KLK5 and KLK7 includes VH containing the amino acid sequence of SEQ ID NO: 21 and VL containing the amino acid sequence of SEQ ID NO: 14.

[0185] In some embodiments, the anti-KLK5 / KLK7+IL-13 bispecific antibody includes at least one antigen-specific binding site that specifically binds to IL-13. In some embodiments, the anti-KLK5 / KLK7+IL-13 bispecific antibody includes an antigen-specific binding site to IL-13 derived from any known anti-IL-13 or its receptor, e.g., the anti-IL-13 / anti-IL-13R antibody described in WO2005062972, WO2005062967, WO2008140455, or WO2023245187 (the anti-IL-13 antibody in each of them is incorporated herein by reference). In some embodiments, an anti-KLK5 / KLK7+IL-13 bispecific antibody containing at least one antigen-specific binding site that specifically binds to IL-13 or IL-13R includes one of the anti-IL-13 antibodies or anti-IL-13R antibodies listed in Table 2: HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / o...

Claims

1. A bispecific antibody comprising an antigen-specific binding site that specifically binds to KLK5 and KLK7, and an antigen-specific binding site that specifically binds to a Th2 cytokine or its receptor.

2. The bispecific antibody according to claim 1, wherein the antigen-specific binding sites that specifically bind to KLK5 and KLK7 bind to the active sites of KLK5 and KLK7 and inhibit the activity of the enzymes.

3. The bispecific antibody according to claim 1 or 2, wherein the antigen-specific binding site that specifically binds to KLK5 and KLK7 comprises one of the antibodies listed in Tables 1a and 1b: HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3.

4. The antigen-specific binding sites that specifically bind to KLK5 and KLK7 are (a) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 7, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 8, (b) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 13, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 14, (c) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 17, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 14, or (d) A bispecific antibody according to any one of claims 1 to 3, comprising HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 21, and LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO:

14.

5. The antigen-specific binding sites that specifically bind to KLK5 and KLK7 are (a) HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, HC CDR3 having the amino acid sequence of SEQ ID NO: 3, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 6 (b) HC CDR1 having the amino acid sequence of SEQ ID NO: 9, HC CDR2 having the amino acid sequence of SEQ ID NO: 10, HC CDR3 having the amino acid sequence of SEQ ID NO: 11, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 12 (c) HC CDR1 having the amino acid sequence of SEQ ID NO: 9, HC CDR2 having the amino acid sequence of SEQ ID NO: 15, HC CDR3 having the amino acid sequence of SEQ ID NO: 16, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 12, or (d) A bispecific antibody according to any one of claims 1 to 4, comprising HC CDR1 having the amino acid sequence of SEQ ID NO: 18, HC CDR2 having the amino acid sequence of SEQ ID NO: 19, HC CDR3 having the amino acid sequence of SEQ ID NO: 20, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO:

12.

6. The bispecific antibody according to any one of claims 1 to 5, wherein the antigen-specific binding site that specifically binds to KLK5 and KLK7 is the VH and / or VL of any one of the antibodies listed in Table 1a.

7. The antigen-specific binding sites that specifically bind to KLK5 and KLK7 are (a) VH containing the amino acid sequence of SEQ ID NO: 7, and VL containing the amino acid sequence of SEQ ID NO: 8, (b) VH containing the amino acid sequence of SEQ ID NO: 13, and VL containing the amino acid sequence of SEQ ID NO: 14, (c) VH containing the amino acid sequence of SEQ ID NO: 17, and VL containing the amino acid sequence of SEQ ID NO: 14, or (d) A bispecific antibody according to any one of claims 1 to 6, comprising VH containing the amino acid sequence of SEQ ID NO: 21 and VL containing the amino acid sequence of SEQ ID NO:

14.

8. A bispecific antibody according to any one of claims 1 to 7, wherein the antigen-specific binding site that specifically binds to the Th2 cytokine or its receptor comprises one of the antibodies listed in Table 2: HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3.

9. The bispecific antibody according to any one of claims 1 to 8, wherein the Th2 cytokine is IL-13.

10. The antigen-specific binding site that specifically binds to IL-13 or IL-13R is (a) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 53, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 54, (b) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 32, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 33, (c) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 74, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 75, (d) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 94, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 95, (e) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 114, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 115, (f) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 134, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 135, or (g) The bispecific antibody according to claim 9, comprising HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 657, and LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO:

658.

11. The antigen-specific binding site that specifically binds to Il-13 or IL-13R is (a) HC CDR1 having the amino acid sequence of SEQ ID NO: 55, HC CDR2 having the amino acid sequence of SEQ ID NO: 56, HC CDR3 having the amino acid sequence of SEQ ID NO: 57, LC CDR1 having the amino acid sequence of SEQ ID NO: 58, LC CDR2 having the amino acid sequence of SEQ ID NO: 59, and LC CDR3 having the amino acid sequence of SEQ ID NO: 60 (b) HC CDR1 having the amino acid sequence of SEQ ID NO: 61, HC CDR2 having the amino acid sequence of SEQ ID NO: 62, HC CDR3 having the amino acid sequence of SEQ ID NO: 63, LC CDR1 having the amino acid sequence of SEQ ID NO: 64, LC CDR2 having the amino acid sequence of SEQ ID NO: 65, and LC CDR3 having the amino acid sequence of SEQ ID NO: 66 (c) HC CDR1 having the amino acid sequence of SEQ ID NO: 67, HC CDR2 having the amino acid sequence of SEQ ID NO: 68, HC CDR3 having the amino acid sequence of SEQ ID NO: 69, LC CDR1 having the amino acid sequence of SEQ ID NO: 70, LC CDR2 having the amino acid sequence of SEQ ID NO: 71, and LC CDR3 having the amino acid sequence of SEQ ID NO: 72 (d) HC CDR1 having the amino acid sequence of SEQ ID NO: 34, HC CDR2 having the amino acid sequence of SEQ ID NO: 35, HC CDR3 having the amino acid sequence of SEQ ID NO: 36, LC CDR1 having the amino acid sequence of SEQ ID NO: 37, LC CDR2 having the amino acid sequence of SEQ ID NO: 38, and LC CDR3 having the amino acid sequence of SEQ ID NO: 39 (e) HC CDR1 having the amino acid sequence of SEQ ID NO: 40, HC CDR2 having the amino acid sequence of SEQ ID NO: 41, HC CDR3 having the amino acid sequence of SEQ ID NO: 42, LC CDR1 having the amino acid sequence of SEQ ID NO: 43, LC CDR2 having the amino acid sequence of SEQ ID NO: 44, and LC CDR3 having the amino acid sequence of SEQ ID NO: 45 (f) HC CDR1 having the amino acid sequence of SEQ ID NO: 46, HC CDR2 having the amino acid sequence of SEQ ID NO: 47, HC CDR3 having the amino acid sequence of SEQ ID NO: 48, LC CDR1 having the amino acid sequence of SEQ ID NO: 49, LC CDR2 having the amino acid sequence of SEQ ID NO: 50, and LC CDR3 having the amino acid sequence of SEQ ID NO: 51 (g) HC CDR1 having the amino acid sequence of SEQ ID NO: 76, HC CDR2 having the amino acid sequence of SEQ ID NO: 77, HC CDR3 having the amino acid sequence of SEQ ID NO: 78, LC CDR1 having the amino acid sequence of SEQ ID NO: 79, LC CDR2 having the amino acid sequence of SEQ ID NO: 80, and LC CDR3 having the amino acid sequence of SEQ ID NO:

81. (h) HC CDR1 having the amino acid sequence of SEQ ID NO: 82, HC CDR2 having the amino acid sequence of SEQ ID NO: 83, HC CDR3 having the amino acid sequence of SEQ ID NO: 84, LC CDR1 having the amino acid sequence of SEQ ID NO: 85, LC CDR2 having the amino acid sequence of SEQ ID NO: 86, and LC CDR3 having the amino acid sequence of SEQ ID NO: 87 (i) HC CDR1 having the amino acid sequence of SEQ ID NO: 88, HC CDR2 having the amino acid sequence of SEQ ID NO: 89, HC CDR3 having the amino acid sequence of SEQ ID NO: 90, LC CDR1 having the amino acid sequence of SEQ ID NO: 91, LC CDR2 having the amino acid sequence of SEQ ID NO: 92, and LC CDR3 having the amino acid sequence of SEQ ID NO: 93 (j) HC CDR1 having the amino acid sequence of SEQ ID NO: 96, HC CDR2 having the amino acid sequence of SEQ ID NO: 97, HC CDR3 having the amino acid sequence of SEQ ID NO: 98, LC CDR1 having the amino acid sequence of SEQ ID NO: 99, LC CDR2 having the amino acid sequence of SEQ ID NO: 100, and LC CDR3 having the amino acid sequence of SEQ ID NO: 101 (k) HC CDR1 having the amino acid sequence of SEQ ID NO: 102, HC CDR2 having the amino acid sequence of SEQ ID NO: 103, HC CDR3 having the amino acid sequence of SEQ ID NO: 104, LC CDR1 having the amino acid sequence of SEQ ID NO: 105, LC CDR2 having the amino acid sequence of SEQ ID NO: 106, and LC CDR3 having the amino acid sequence of SEQ ID NO: 107 (l) HC CDR1 having the amino acid sequence of SEQ ID NO: 108, HC CDR2 having the amino acid sequence of SEQ ID NO: 109, HC CDR3 having the amino acid sequence of SEQ ID NO: 110, LC CDR1 having the amino acid sequence of SEQ ID NO: 111, LC CDR2 having the amino acid sequence of SEQ ID NO: 112, and LC CDR3 having the amino acid sequence of SEQ ID NO: 113 (m) HC CDR1 having the amino acid sequence of SEQ ID NO: 116, HC CDR2 having the amino acid sequence of SEQ ID NO: 117, HC CDR3 having the amino acid sequence of SEQ ID NO: 118, LC CDR1 having the amino acid sequence of SEQ ID NO: 119, LC CDR2 having the amino acid sequence of SEQ ID NO: 120, and LC CDR3 having the amino acid sequence of SEQ ID NO:

121. (n) HC CDR1 having the amino acid sequence of SEQ ID NO: 122, HC CDR2 having the amino acid sequence of SEQ ID NO: 123, HC CDR3 having the amino acid sequence of SEQ ID NO: 124, LC CDR1 having the amino acid sequence of SEQ ID NO: 125, LC CDR2 having the amino acid sequence of SEQ ID NO: 126, and LC CDR3 having the amino acid sequence of SEQ ID NO: 127 (o) HC CDR1 having the amino acid sequence of SEQ ID NO: 128, HC CDR2 having the amino acid sequence of SEQ ID NO: 129, HC CDR3 having the amino acid sequence of SEQ ID NO: 130, LC CDR1 having the amino acid sequence of SEQ ID NO: 131, LC CDR2 having the amino acid sequence of SEQ ID NO: 132, and LC CDR3 having the amino acid sequence of SEQ ID NO: 133 (p) HC CDR1 having the amino acid sequence of SEQ ID NO: 136, HC CDR2 having the amino acid sequence of SEQ ID NO: 137, HC CDR3 having the amino acid sequence of SEQ ID NO: 138, LC CDR1 having the amino acid sequence of SEQ ID NO: 139, LC CDR2 having the amino acid sequence of SEQ ID NO: 140, and LC CDR3 having the amino acid sequence of SEQ ID NO:

141. (q) HC CDR1 having the amino acid sequence of SEQ ID NO: 142, HC CDR2 having the amino acid sequence of SEQ ID NO: 143, HC CDR3 having the amino acid sequence of SEQ ID NO: 144, LC CDR1 having the amino acid sequence of SEQ ID NO: 145, LC CDR2 having the amino acid sequence of SEQ ID NO: 146, and LC CDR3 having the amino acid sequence of SEQ ID NO: 147 (r) HC CDR1 having the amino acid sequence of SEQ ID NO: 148, HC CDR2 having the amino acid sequence of SEQ ID NO: 149, HC CDR3 having the amino acid sequence of SEQ ID NO: 150, LC CDR1 having the amino acid sequence of SEQ ID NO: 151, LC CDR2 having the amino acid sequence of SEQ ID NO: 152, and LC CDR3 having the amino acid sequence of SEQ ID NO: 153 (s) HC CDR1 having the amino acid sequence of SEQ ID NO: 655, HC CDR2 having the amino acid sequence of SEQ ID NO: 41, HC CDR3 having the amino acid sequence of SEQ ID NO: 42, LC CDR1 having the amino acid sequence of SEQ ID NO: 43, LC CDR2 having the amino acid sequence of SEQ ID NO: 44, and LC CDR3 having the amino acid sequence of SEQ ID NO: 45, or (t) A bispecific antibody according to claim 9 or 10, comprising HC CDR1 having the amino acid sequence of SEQ ID NO: 656, HC CDR2 having the amino acid sequence of SEQ ID NO: 47, HC CDR3 having the amino acid sequence of SEQ ID NO: 48, LC CDR1 having the amino acid sequence of SEQ ID NO: 49, LC CDR2 having the amino acid sequence of SEQ ID NO: 50, and LC CDR3 having the amino acid sequence of SEQ ID NO:

51.

12. The antigen-specific binding site that specifically binds to IL-13 or IL-13R is (a) VH containing the amino acid sequence of SEQ ID NO: 53, and VL containing the amino acid sequence of SEQ ID NO: 54, (b) VH containing the amino acid sequence of SEQ ID NO: 32, and VL containing the amino acid sequence of SEQ ID NO: 33, (c) VH containing the amino acid sequence of SEQ ID NO: 74, and VL containing the amino acid sequence of SEQ ID NO: 75 (d) VH containing the amino acid sequence of SEQ ID NO: 94, and VL containing the amino acid sequence of SEQ ID NO: 95 (e) VH containing the amino acid sequence of SEQ ID NO: 114, and VL containing the amino acid sequence of SEQ ID NO: 115, (f) VH containing the amino acid sequence of SEQ ID NO: 134, and VL containing the amino acid sequence of SEQ ID NO: 135; or (g) A bispecific antibody according to any one of claims 9 to 11, comprising VH containing the amino acid sequence of SEQ ID NO: 657 and VL containing the amino acid sequence of SEQ ID NO:

658.

13. The bispecific antibody according to any one of claims 1 to 8, wherein the Th2 cytokine is IL-4.

14. The antigen-specific binding site that specifically binds to IL-4 or IL-4R is (a) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 154, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 155, (b) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 174, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 175, (c) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 194, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 195, (d) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 214, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 215, (e) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 234, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 235, or (f) The bispecific antibody according to claim 13, comprising HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 254, and LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO:

255.

15. The antigen-specific binding site that specifically binds to IL-4 or IL-4R is (a) HC CDR1 having the amino acid sequence of SEQ ID NO: 156, HC CDR2 having the amino acid sequence of SEQ ID NO: 157, HC CDR3 having the amino acid sequence of SEQ ID NO: 158, LC CDR1 having the amino acid sequence of SEQ ID NO: 159, LC CDR2 having the amino acid sequence of SEQ ID NO: 160, and LC CDR3 having the amino acid sequence of SEQ ID NO: 161 (b) HC CDR1 having the amino acid sequence of SEQ ID NO: 162, HC CDR2 having the amino acid sequence of SEQ ID NO: 163, HC CDR3 having the amino acid sequence of SEQ ID NO: 164, LC CDR1 having the amino acid sequence of SEQ ID NO: 165, LC CDR2 having the amino acid sequence of LGS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 167 (c) HC CDR1 having the amino acid sequence of SEQ ID NO: 168, HC CDR2 having the amino acid sequence of SEQ ID NO: 169, HC CDR3 having the amino acid sequence of SEQ ID NO: 170, LC CDR1 having the amino acid sequence of SEQ ID NO: 171, LC CDR2 having the amino acid sequence of SEQ ID NO: 172, and LC CDR3 having the amino acid sequence of SEQ ID NO:

173. (d) HC CDR1 having the amino acid sequence of SEQ ID NO: 176, HC CDR2 having the amino acid sequence of SEQ ID NO: 177, HC CDR3 having the amino acid sequence of SEQ ID NO: 178, LC CDR1 having the amino acid sequence of SEQ ID NO: 179, LC CDR2 having the amino acid sequence of SEQ ID NO: 180, and LC CDR3 having the amino acid sequence of SEQ ID NO: 181 (e) HC CDR1 having the amino acid sequence of SEQ ID NO: 182, HC CDR2 having the amino acid sequence of SEQ ID NO: 183, HC CDR3 having the amino acid sequence of SEQ ID NO: 184, LC CDR1 having the amino acid sequence of SEQ ID NO: 185, LC CDR2 having the amino acid sequence of AAS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 187 (f) HC CDR1 having the amino acid sequence of SEQ ID NO: 188, HC CDR2 having the amino acid sequence of SEQ ID NO: 189, HC CDR3 having the amino acid sequence of SEQ ID NO: 190, LC CDR1 having the amino acid sequence of SEQ ID NO: 191, LC CDR2 having the amino acid sequence of SEQ ID NO: 192, and LC CDR3 having the amino acid sequence of SEQ ID NO: 193 (g) HC CDR1 having the amino acid sequence of SEQ ID NO: 196, HC CDR2 having the amino acid sequence of SEQ ID NO: 197, HC CDR3 having the amino acid sequence of SEQ ID NO: 198, LC CDR1 having the amino acid sequence of SEQ ID NO: 199, LC CDR2 having the amino acid sequence of SEQ ID NO: 200, and LC CDR3 having the amino acid sequence of SEQ ID NO:

201. (h) HC CDR1 having the amino acid sequence of SEQ ID NO: 202, HC CDR2 having the amino acid sequence of SEQ ID NO: 203, HC CDR3 having the amino acid sequence of SEQ ID NO: 204, LC CDR1 having the amino acid sequence of SEQ ID NO: 205, LC CDR2 having the amino acid sequence of SEQ ID NO: 206, and LC CDR3 having the amino acid sequence of SEQ ID NO: 207, (i) HC CDR1 having the amino acid sequence of SEQ ID NO: 208, HC CDR2 having the amino acid sequence of SEQ ID NO: 209, HC CDR3 having the amino acid sequence of SEQ ID NO: 210, LC CDR1 having the amino acid sequence of SEQ ID NO: 211, LC CDR2 having the amino acid sequence of GAS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 213 (j) HC CDR1 having the amino acid sequence of SEQ ID NO: 216, HC CDR2 having the amino acid sequence of SEQ ID NO: 217, HC CDR3 having the amino acid sequence of SEQ ID NO: 218, LC CDR1 having the amino acid sequence of SEQ ID NO: 219, LC CDR2 having the amino acid sequence of SEQ ID NO: 220, and LC CDR3 having the amino acid sequence of SEQ ID NO:

221. (k) HC CDR1 having the amino acid sequence of SEQ ID NO: 222, HC CDR2 having the amino acid sequence of SEQ ID NO: 223, HC CDR3 having the amino acid sequence of SEQ ID NO: 224, LC CDR1 having the amino acid sequence of SEQ ID NO: 225, LC CDR2 having the amino acid sequence of YTS, and LC CDR3 having the amino acid sequence of SEQ ID NO:

227. (l) HC CDR1 having the amino acid sequence of SEQ ID NO: 228, HC CDR2 having the amino acid sequence of SEQ ID NO: 229, HC CDR3 having the amino acid sequence of SEQ ID NO: 230, LC CDR1 having the amino acid sequence of SEQ ID NO: 231, LC CDR2 having the amino acid sequence of SEQ ID NO: 232, and LC CDR3 having the amino acid sequence of SEQ ID NO:

233. (m) HC CDR1 having the amino acid sequence of SEQ ID NO: 236, HC CDR2 having the amino acid sequence of SEQ ID NO: 237, HC CDR3 having the amino acid sequence of SEQ ID NO: 238, LC CDR1 having the amino acid sequence of SEQ ID NO: 239, LC CDR2 having the amino acid sequence of SEQ ID NO: 240, and LC CDR3 having the amino acid sequence of SEQ ID NO:

241. (n) HC CDR1 having the amino acid sequence of SEQ ID NO: 242, HC CDR2 having the amino acid sequence of SEQ ID NO: 243, HC CDR3 having the amino acid sequence of SEQ ID NO: 244, LC CDR1 having the amino acid sequence of SEQ ID NO: 245, LC CDR2 having the amino acid sequence of SEQ ID NO: 246, and LC CDR3 having the amino acid sequence of SEQ ID NO:

247. (o) HC CDR1 having the amino acid sequence of SEQ ID NO: 248, HC CDR2 having the amino acid sequence of SEQ ID NO: 249, HC CDR3 having the amino acid sequence of SEQ ID NO: 250, LC CDR1 having the amino acid sequence of SEQ ID NO: 251, LC CDR2 having the amino acid sequence of SEQ ID NO: 252, and LC CDR3 having the amino acid sequence of SEQ ID NO: 253 (p) HC CDR1 having the amino acid sequence of SEQ ID NO: 256, HC CDR2 having the amino acid sequence of SEQ ID NO: 257, HC CDR3 having the amino acid sequence of SEQ ID NO: 258, LC CDR1 having the amino acid sequence of SEQ ID NO: 259, LC CDR2 having the amino acid sequence of SEQ ID NO: 260, and LC CDR3 having the amino acid sequence of SEQ ID NO:

261. (q) HC CDR1 having the amino acid sequence of SEQ ID NO: 262, HC CDR2 having the amino acid sequence of SEQ ID NO: 263, HC CDR3 having the amino acid sequence of SEQ ID NO: 264, LC CDR1 having the amino acid sequence of SEQ ID NO: 265, LC CDR2 having the amino acid sequence of SEQ ID NO: 267, and LC CDR3 having the amino acid sequence of SEQ ID NO: 268, or (r) A bispecific antibody according to claim 13 or 14, comprising HC CDR1 having the amino acid sequence of SEQ ID NO: 269, HC CDR2 having the amino acid sequence of SEQ ID NO: 270, HC CDR3 having the amino acid sequence of SEQ ID NO: 271, LC CDR1 having the amino acid sequence of SEQ ID NO: 272, LC CDR2 having the amino acid sequence of SAS, and LC CDR3 having the amino acid sequence of SEQ ID NO:

274.

16. The antigen-specific binding site that specifically binds to IL-4 or IL-4R is (a) VH containing the amino acid sequence of SEQ ID NO: 154, and VL containing the amino acid sequence of SEQ ID NO: 155, (b) VH containing the amino acid sequence of SEQ ID NO: 174, and VL containing the amino acid sequence of SEQ ID NO: 175, (c) VH containing the amino acid sequence of SEQ ID NO: 194, and VL containing the amino acid sequence of SEQ ID NO: 195, (d) VH containing the amino acid sequence of SEQ ID NO: 214, and VL containing the amino acid sequence of SEQ ID NO: 215, (e) VH containing the amino acid sequence of SEQ ID NO: 234, and VL containing the amino acid sequence of SEQ ID NO: 235, (f) A bispecific antibody according to any one of claims 13 to 15, comprising VH containing the amino acid sequence of SEQ ID NO: 254 and VL containing the amino acid sequence of SEQ ID NO:

255.

17. The bispecific antibody according to any one of claims 1 to 8, wherein the Th2 cytokine is IL-5.

18. The antigen-specific binding site that specifically binds to IL-5 or IL-5R is (a) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 275, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 276, (b) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 295, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 296, (c) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 315, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 316, (d) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 335, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 336, (e) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 355, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 356, or (f) The bispecific antibody according to claim 17, comprising HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 375, and LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO:

376.

19. The antigen-specific binding site that specifically binds to IL-5 or IL-5R is (a) HC CDR1 having the amino acid sequence of SEQ ID NO: 277, HC CDR2 having the amino acid sequence of SEQ ID NO: 278, HC CDR3 having the amino acid sequence of SEQ ID NO: 279, LC CDR1 having the amino acid sequence of SEQ ID NO: 280, LC CDR2 having the amino acid sequence of SEQ ID NO: 281, and LC CDR3 having the amino acid sequence of SEQ ID NO: 282 (b) HC CDR1 having the amino acid sequence of SEQ ID NO: 283, HC CDR2 having the amino acid sequence of SEQ ID NO: 284, HC CDR3 having the amino acid sequence of SEQ ID NO: 285, LC CDR1 having the amino acid sequence of SEQ ID NO: 286, LC CDR2 having the amino acid sequence of SEQ ID NO: 287, and LC CDR3 having the amino acid sequence of SEQ ID NO: 288 (c) HC CDR1 having the amino acid sequence of SEQ ID NO: 289, HC CDR2 having the amino acid sequence of SEQ ID NO: 290, HC CDR3 having the amino acid sequence of SEQ ID NO: 291, LC CDR1 having the amino acid sequence of SEQ ID NO: 292, LC CDR2 having the amino acid sequence of SEQ ID NO: 293, and LC CDR3 having the amino acid sequence of SEQ ID NO: 294 (d) HC CDR1 having the amino acid sequence of SEQ ID NO: 297, HC CDR2 having the amino acid sequence of SEQ ID NO: 298, HC CDR3 having the amino acid sequence of SEQ ID NO: 299, LC CDR1 having the amino acid sequence of SEQ ID NO: 300, LC CDR2 having the amino acid sequence of SEQ ID NO: 301, and LC CDR3 having the amino acid sequence of SEQ ID NO: 302 (e) HC CDR1 having the amino acid sequence of SEQ ID NO: 303, HC CDR2 having the amino acid sequence of SEQ ID NO: 304, HC CDR3 having the amino acid sequence of SEQ ID NO: 305, LC CDR1 having the amino acid sequence of SEQ ID NO: 306, LC CDR2 having the amino acid sequence of GAS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 308 (f) HC CDR1 having the amino acid sequence of SEQ ID NO: 309, HC CDR2 having the amino acid sequence of SEQ ID NO: 310, HC CDR3 having the amino acid sequence of SEQ ID NO: 311, LC CDR1 having the amino acid sequence of SEQ ID NO: 312, LC CDR2 having the amino acid sequence of SEQ ID NO: 313, and LC CDR3 having the amino acid sequence of SEQ ID NO: 314 (g) HC CDR1 having the amino acid sequence of SEQ ID NO: 317, HC CDR2 having the amino acid sequence of SEQ ID NO: 318, HC CDR3 having the amino acid sequence of SEQ ID NO: 319, LC CDR1 having the amino acid sequence of SEQ ID NO: 320, LC CDR2 having the amino acid sequence of SEQ ID NO: 321, and LC CDR3 having the amino acid sequence of SEQ ID NO:

322. (h) HC CDR1 having the amino acid sequence of SEQ ID NO: 323, HC CDR2 having the amino acid sequence of SEQ ID NO: 324, HC CDR3 having the amino acid sequence of SEQ ID NO: 325, LC CDR1 having the amino acid sequence of SEQ ID NO: 326, LC CDR2 having the amino acid sequence of GANN, and LC CDR3 having the amino acid sequence of SEQ ID NO:

328. (i) HC CDR1 having the amino acid sequence of SEQ ID NO: 329, HC CDR2 having the amino acid sequence of SEQ ID NO: 330, HC CDR3 having the amino acid sequence of SEQ ID NO: 331, LC CDR1 having the amino acid sequence of SEQ ID NO: 332, LC CDR2 having the amino acid sequence of SEQ ID NO: 333, and LC CDR3 having the amino acid sequence of SEQ ID NO: 334 (j) HC CDR1 having the amino acid sequence of SEQ ID NO: 337, HC CDR2 having the amino acid sequence of SEQ ID NO: 338, HC CDR3 having the amino acid sequence of SEQ ID NO: 339, LC CDR1 having the amino acid sequence of SEQ ID NO: 340, LC CDR2 having the amino acid sequence of SEQ ID NO: 341, and LC CDR3 having the amino acid sequence of SEQ ID NO: 342 (k) HC CDR1 having the amino acid sequence of SEQ ID NO: 343, HC CDR2 having the amino acid sequence of SEQ ID NO: 344, HC CDR3 having the amino acid sequence of SEQ ID NO: 345, LC CDR1 having the amino acid sequence of SEQ ID NO: 346, LC CDR2 having the amino acid sequence of G, and LC CDR3 having the amino acid sequence of SEQ ID NO:

348. (l) HC CDR1 having the amino acid sequence of SEQ ID NO: 349, HC CDR2 having the amino acid sequence of SEQ ID NO: 350, HC CDR3 having the amino acid sequence of SEQ ID NO: 351, LC CDR1 having the amino acid sequence of SEQ ID NO: 352, LC CDR2 having the amino acid sequence of SEQ ID NO: 353, and LC CDR3 having the amino acid sequence of SEQ ID NO: 354 (m) HC CDR1 having the amino acid sequence of SEQ ID NO: 357, HC CDR2 having the amino acid sequence of SEQ ID NO: 358, HC CDR3 having the amino acid sequence of SEQ ID NO: 359, LC CDR1 having the amino acid sequence of SEQ ID NO: 360, LC CDR2 having the amino acid sequence of SEQ ID NO: 361, and LC CDR3 having the amino acid sequence of SEQ ID NO:

362. (n) HC CDR1 having the amino acid sequence of SEQ ID NO: 363, HC CDR2 having the amino acid sequence of SEQ ID NO: 364, HC CDR3 having the amino acid sequence of SEQ ID NO: 365, LC CDR1 having the amino acid sequence of SEQ ID NO: 366, LC CDR2 having the amino acid sequence of RAD, and LC CDR3 having the amino acid sequence of SEQ ID NO:

368. (o) HC CDR1 having the amino acid sequence of SEQ ID NO: 369, HC CDR2 having the amino acid sequence of SEQ ID NO: 370, HC CDR3 having the amino acid sequence of SEQ ID NO: 371, LC CDR1 having the amino acid sequence of SEQ ID NO: 372, LC CDR2 having the amino acid sequence of SEQ ID NO: 373, and LC CDR3 having the amino acid sequence of SEQ ID NO: 374 (p) HC CDR1 having the amino acid sequence of SEQ ID NO: 377, HC CDR2 having the amino acid sequence of SEQ ID NO: 378, HC CDR3 having the amino acid sequence of SEQ ID NO: 379, LC CDR1 having the amino acid sequence of SEQ ID NO: 380, LC CDR2 having the amino acid sequence of SEQ ID NO: 381, and LC CDR3 having the amino acid sequence of SEQ ID NO:

382. (q) HC CDR1 having the amino acid sequence of SEQ ID NO: 383, HC CDR2 having the amino acid sequence of SEQ ID NO: 384, HC CDR3 having the amino acid sequence of SEQ ID NO: 385, LC CDR1 having the amino acid sequence of SEQ ID NO: 386, LC CDR2 having the amino acid sequence of AAS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 388, or (r) A bispecific antibody according to claim 17 or 18, comprising HC CDR1 having the amino acid sequence of SEQ ID NO: 389, HC CDR2 having the amino acid sequence of SEQ ID NO: 390, HC CDR3 having the amino acid sequence of SEQ ID NO: 391, LC CDR1 having the amino acid sequence of SEQ ID NO: 392, LC CDR2 having the amino acid sequence of SEQ ID NO: 393, and LC CDR3 having the amino acid sequence of SEQ ID NO:

394.

20. The antigen-specific binding site that specifically binds to IL-5 or IL-5R is (a) VH containing the amino acid sequence of SEQ ID NO: 275, and VL containing the amino acid sequence of SEQ ID NO: 276, (b) VH containing the amino acid sequence of SEQ ID NO: 295, and VL containing the amino acid sequence of SEQ ID NO: 296, (c) VH containing the amino acid sequence of SEQ ID NO: 315, and VL containing the amino acid sequence of SEQ ID NO: 316, (d) VH containing the amino acid sequence of SEQ ID NO: 335, and VL containing the amino acid sequence of SEQ ID NO: 336, (e) VH containing the amino acid sequence of SEQ ID NO: 355, and VL containing the amino acid sequence of SEQ ID NO: 356, (f) A bispecific antibody according to any one of claims 17 to 19, comprising VH containing the amino acid sequence of SEQ ID NO: 375 and VL containing the amino acid sequence of SEQ ID NO:

376.

21. The bispecific antibody according to any one of claims 1 to 8, wherein the Th2 cytokine is IL-9.

22. The antigen-specific binding site that specifically binds to IL-9 or IL-9R is (a) The bispecific antibody according to claim 21, comprising HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 395, and LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO:

396.

23. The antigen-specific binding site that specifically binds to IL-9 or IL-9R is (a) HC CDR1 having the amino acid sequence of SEQ ID NO: 397, HC CDR2 having the amino acid sequence of SEQ ID NO: 398, HC CDR3 having the amino acid sequence of SEQ ID NO: 399, LC CDR1 having the amino acid sequence of SEQ ID NO: 400, LC CDR2 having the amino acid sequence of SEQ ID NO: 401, and LC CDR3 having the amino acid sequence of SEQ ID NO: 402 (b) HC CDR1 having the amino acid sequence of SEQ ID NO: 403, HC CDR2 having the amino acid sequence of SEQ ID NO: 404, HC CDR3 having the amino acid sequence of SEQ ID NO: 405, LC CDR1 having the amino acid sequence of SEQ ID NO: 406, LC CDR2 having the amino acid sequence of GTS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 408, or (c) A bispecific antibody according to claim 21 or 22, comprising HC CDR1 having the amino acid sequence of SEQ ID NO: 409, HC CDR2 having the amino acid sequence of SEQ ID NO: 410, HC CDR3 having the amino acid sequence of SEQ ID NO: 411, LC CDR1 having the amino acid sequence of SEQ ID NO: 412, LC CDR2 having the amino acid sequence of SEQ ID NO: 413, and LC CDR3 having the amino acid sequence of SEQ ID NO:

414.

24. The antigen-specific binding site that specifically binds to IL-9 or IL-9R is (a) A bispecific antibody according to any one of claims 21 to 23, comprising VH containing the amino acid sequence of SEQ ID NO: 395 and VL containing the amino acid sequence of SEQ ID NO:

396.

25. The bispecific antibody according to any one of claims 1 to 8, wherein the Th2 cytokine is OX40L.

26. The antigen-specific binding site that specifically binds to OX40L or OX40 is (a) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 415, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 416, (b) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 435, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 436, (c) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 819, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 820, (d) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 839, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 840, or (e) The bispecific antibody according to claim 25, comprising HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 859, and LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO:

860.

27. The antigen-specific binding site that specifically binds to OX40L or OX40 is (a) HC CDR1 having the amino acid sequence of SEQ ID NO: 417, HC CDR2 having the amino acid sequence of SEQ ID NO: 418, HC CDR3 having the amino acid sequence of SEQ ID NO: 419, LC CDR1 having the amino acid sequence of SEQ ID NO: 420, LC CDR2 having the amino acid sequence of SEQ ID NO: 421, and LC CDR3 having the amino acid sequence of SEQ ID NO: 422 (b) HC CDR1 having the amino acid sequence of SEQ ID NO: 423, HC CDR2 having the amino acid sequence of SEQ ID NO: 424, HC CDR3 having the amino acid sequence of SEQ ID NO: 425, LC CDR1 having the amino acid sequence of SEQ ID NO: 426, LC CDR2 having the amino acid sequence of GAS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 428 (c) HC CDR1 having the amino acid sequence of SEQ ID NO: 429, HC CDR2 having the amino acid sequence of SEQ ID NO: 430, HC CDR3 having the amino acid sequence of SEQ ID NO: 431, LC CDR1 having the amino acid sequence of SEQ ID NO: 432, LC CDR2 having the amino acid sequence of SEQ ID NO: 433, and LC CDR3 having the amino acid sequence of SEQ ID NO: 434 (d) HC CDR1 having the amino acid sequence of SEQ ID NO: 437, HC CDR2 having the amino acid sequence of SEQ ID NO: 438, HC CDR3 having the amino acid sequence of SEQ ID NO: 439, LC CDR1 having the amino acid sequence of SEQ ID NO: 440, LC CDR2 having the amino acid sequence of SEQ ID NO: 441, and LC CDR3 having the amino acid sequence of SEQ ID NO: 442 (e) HC CDR1 having the amino acid sequence of SEQ ID NO: 443, HC CDR2 having the amino acid sequence of SEQ ID NO: 444, HC CDR3 having the amino acid sequence of SEQ ID NO: 445, LC CDR1 having the amino acid sequence of SEQ ID NO: 446, LC CDR2 having the amino acid sequence of AAS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 448 (f) HC CDR1 having the amino acid sequence of SEQ ID NO: 449, HC CDR2 having the amino acid sequence of SEQ ID NO: 450, HC CDR3 having the amino acid sequence of SEQ ID NO: 451, LC CDR1 having the amino acid sequence of SEQ ID NO: 452, LC CDR2 having the amino acid sequence of SEQ ID NO: 453, and LC CDR3 having the amino acid sequence of SEQ ID NO: 454 (g) HC CDR1 having the amino acid sequence of SEQ ID NO: 821, HC CDR2 having the amino acid sequence of SEQ ID NO: 822, HC CDR3 having the amino acid sequence of SEQ ID NO: 823, LC CDR1 having the amino acid sequence of SEQ ID NO: 824, LC CDR2 having the amino acid sequence of SEQ ID NO: 825, and LC CDR3 having the amino acid sequence of SEQ ID NO:

826. (h) HC CDR1 having the amino acid sequence of SEQ ID NO: 827, HC CDR2 having the amino acid sequence of SEQ ID NO: 828, HC CDR3 having the amino acid sequence of SEQ ID NO: 829, LC CDR1 having the amino acid sequence of SEQ ID NO: 830, LC CDR2 having the amino acid sequence of ATS, and LC CDR3 having the amino acid sequence of SEQ ID NO:

832. (i) HC CDR1 having the amino acid sequence of SEQ ID NO: 833, HC CDR2 having the amino acid sequence of SEQ ID NO: 834, HC CDR3 having the amino acid sequence of SEQ ID NO: 835, LC CDR1 having the amino acid sequence of SEQ ID NO: 836, LC CDR2 having the amino acid sequence of SEQ ID NO: 837, and LC CDR3 having the amino acid sequence of SEQ ID NO: 838 (j) HC CDR1 having the amino acid sequence of SEQ ID NO: 841, HC CDR2 having the amino acid sequence of SEQ ID NO: 842, HC CDR3 having the amino acid sequence of SEQ ID NO: 843, LC CDR1 having the amino acid sequence of SEQ ID NO: 844, LC CDR2 having the amino acid sequence of SEQ ID NO: 845, and LC CDR3 having the amino acid sequence of SEQ ID NO: 846 (k) HC CDR1 having the amino acid sequence of SEQ ID NO: 847, HC CDR2 having the amino acid sequence of SEQ ID NO: 848, HC CDR3 having the amino acid sequence of SEQ ID NO: 849, LC CDR1 having the amino acid sequence of SEQ ID NO: 850, LC CDR2 having the amino acid sequence of AAS, and LC CDR3 having the amino acid sequence of SEQ ID NO:

852. (l) HC CDR1 having the amino acid sequence of SEQ ID NO: 853, HC CDR2 having the amino acid sequence of SEQ ID NO: 854, HC CDR3 having the amino acid sequence of SEQ ID NO: 855, LC CDR1 having the amino acid sequence of SEQ ID NO: 856, LC CDR2 having the amino acid sequence of SEQ ID NO: 857, and LC CDR3 having the amino acid sequence of SEQ ID NO:

858. (m) HC CDR1 having the amino acid sequence of SEQ ID NO: 861, HC CDR2 having the amino acid sequence of SEQ ID NO: 862, HC CDR3 having the amino acid sequence of SEQ ID NO: 863, LC CDR1 having the amino acid sequence of SEQ ID NO: 864, LC CDR2 having the amino acid sequence of SEQ ID NO: 865, and LC CDR3 having the amino acid sequence of SEQ ID NO:

866. (n) HC CDR1 having the amino acid sequence of SEQ ID NO: 867, HC CDR2 having the amino acid sequence of SEQ ID NO: 868, HC CDR3 having the amino acid sequence of SEQ ID NO: 869, LC CDR1 having the amino acid sequence of SEQ ID NO: 870, LC CDR2 having the amino acid sequence of RAS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 872, or (o) A bispecific antibody according to claim 25 or 26, comprising HC CDR1 having the amino acid sequence of SEQ ID NO: 873, HC CDR2 having the amino acid sequence of SEQ ID NO: 874, HC CDR3 having the amino acid sequence of SEQ ID NO: 875, LC CDR1 having the amino acid sequence of SEQ ID NO: 876, LC CDR2 having the amino acid sequence of SEQ ID NO: 878, and LC CDR3 having the amino acid sequence of SEQ ID NO:

872.

28. The antigen-specific binding site that specifically binds to OX40L or OX40 is (a) VH containing the amino acid sequence of SEQ ID NO: 415, and VL containing the amino acid sequence of SEQ ID NO: 416, (b) VH containing the amino acid sequence of SEQ ID NO: 435, and VL containing the amino acid sequence of SEQ ID NO: 436, (c) VH containing the amino acid sequence of SEQ ID NO: 819, and VL containing the amino acid sequence of SEQ ID NO: 820, (d) VH containing the amino acid sequence of SEQ ID NO: 839, and VL containing the amino acid sequence of SEQ ID NO: 840, or (e) A bispecific antibody according to any one of claims 25 to 27, comprising VH containing the amino acid sequence of SEQ ID NO: 859 and VL containing the amino acid sequence of SEQ ID NO:

860.

29. The bispecific antibody according to any one of claims 1 to 8, wherein the Th2 cytokine is IL-25.

30. The antigen-specific binding site that specifically binds to IL-25 or IL-25R is (a) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 455, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 456, or (b) The bispecific antibody according to claim 29, comprising HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 719, and LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO:

720.

31. The antigen-specific binding site that specifically binds to IL-25 or IL-25R is (a) HC CDR1 having the amino acid sequence of SEQ ID NO: 457, HC CDR2 having the amino acid sequence of SEQ ID NO: 458, HC CDR3 having the amino acid sequence of SEQ ID NO: 459, LC CDR1 having the amino acid sequence of SEQ ID NO: 460, LC CDR2 having the amino acid sequence of SEQ ID NO: 461, and LC CDR3 having the amino acid sequence of SEQ ID NO: 462 (b) HC CDR1 having the amino acid sequence of SEQ ID NO: 463, HC CDR2 having the amino acid sequence of SEQ ID NO: 464, HC CDR3 having the amino acid sequence of SEQ ID NO: 465, LC CDR1 having the amino acid sequence of SEQ ID NO: 466, LC CDR2 having the amino acid sequence of DAS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 468 (c) HC CDR1 having the amino acid sequence of SEQ ID NO: 469, HC CDR2 having the amino acid sequence of SEQ ID NO: 470, HC CDR3 having the amino acid sequence of SEQ ID NO: 471, LC CDR1 having the amino acid sequence of SEQ ID NO: 472, LC CDR2 having the amino acid sequence of SEQ ID NO: 473, and LC CDR3 having the amino acid sequence of SEQ ID NO: 474 (d) HC CDR1 having the amino acid sequence of SEQ ID NO: 721, HC CDR2 having the amino acid sequence of SEQ ID NO: 722, HC CDR3 having the amino acid sequence of SEQ ID NO: 723, LC CDR1 having the amino acid sequence of SEQ ID NO: 724, LC CDR2 having the amino acid sequence of SEQ ID NO: 725, and LC CDR3 having the amino acid sequence of SEQ ID NO: 726 (e) HC CDR1 having the amino acid sequence of SEQ ID NO: 727, HC CDR2 having the amino acid sequence of SEQ ID NO: 728, HC CDR3 having the amino acid sequence of SEQ ID NO: 729, LC CDR1 having the amino acid sequence of SEQ ID NO: 730, LC CDR2 having the amino acid sequence of RTS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 732, or (f) A bispecific antibody according to claim 29 or 30, comprising HC CDR1 having the amino acid sequence of SEQ ID NO: 733, HC CDR2 having the amino acid sequence of SEQ ID NO: 734, HC CDR3 having the amino acid sequence of SEQ ID NO: 735, LC CDR1 having the amino acid sequence of SEQ ID NO: 736, LC CDR2 having the amino acid sequence of SEQ ID NO: 737, and LC CDR3 having the amino acid sequence of SEQ ID NO:

738.

32. The antigen-specific binding site that specifically binds to IL-25 or IL-25R is (a) VH containing the amino acid sequence of SEQ ID NO: 455, and VL containing the amino acid sequence of SEQ ID NO: 456, (b) A bispecific antibody according to any one of claims 29 to 31, comprising VH containing the amino acid sequence of SEQ ID NO: 719 and VL containing the amino acid sequence of SEQ ID NO:

720.

33. The bispecific antibody according to any one of claims 1 to 8, wherein the Th2 cytokine is IL-31.

34. The antigen-specific binding site that specifically binds to IL-31 or IL-31R is (a) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 475, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 476, (b) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 495, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 496, (c) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 739, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 740, or (d) The bispecific antibody according to claim 33, comprising HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 759, and LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO:

760.

35. The antigen-specific binding site that specifically binds to IL-31 or IL-31R is (a) HC CDR1 having the amino acid sequence of SEQ ID NO: 477, HC CDR2 having the amino acid sequence of SEQ ID NO: 478, HC CDR3 having the amino acid sequence of SEQ ID NO: 479, LC CDR1 having the amino acid sequence of SEQ ID NO: 480, LC CDR2 having the amino acid sequence of SEQ ID NO: 481, and LC CDR3 having the amino acid sequence of SEQ ID NO: 482 (b) HC CDR1 having the amino acid sequence of SEQ ID NO: 483, HC CDR2 having the amino acid sequence of SEQ ID NO: 484, HC CDR3 having the amino acid sequence of SEQ ID NO: 485, LC CDR1 having the amino acid sequence of SEQ ID NO: 486, LC CDR2 having the amino acid sequence of SEQ ID NO: 487, and LC CDR3 having the amino acid sequence of SEQ ID NO: 488 (c) HC CDR1 having the amino acid sequence of SEQ ID NO: 489, HC CDR2 having the amino acid sequence of SEQ ID NO: 490, HC CDR3 having the amino acid sequence of SEQ ID NO: 491, LC CDR1 having the amino acid sequence of SEQ ID NO: 492, LC CDR2 having the amino acid sequence of SEQ ID NO: 493, and LC CDR3 having the amino acid sequence of SEQ ID NO: 494 (d) HC CDR1 having the amino acid sequence of SEQ ID NO: 497, HC CDR2 having the amino acid sequence of SEQ ID NO: 498, HC CDR3 having the amino acid sequence of SEQ ID NO: 499, LC CDR1 having the amino acid sequence of SEQ ID NO: 500, LC CDR2 having the amino acid sequence of SEQ ID NO: 501, and LC CDR3 having the amino acid sequence of SEQ ID NO: 502 (e) HC CDR1 having the amino acid sequence of SEQ ID NO: 503, HC CDR2 having the amino acid sequence of SEQ ID NO: 504, HC CDR3 having the amino acid sequence of SEQ ID NO: 505, LC CDR1 having the amino acid sequence of SEQ ID NO: 506, LC CDR2 having the amino acid sequence of NIN, and LC CDR3 having the amino acid sequence of SEQ ID NO:

508. (f) HC CDR1 having the amino acid sequence of SEQ ID NO: 509, HC CDR2 having the amino acid sequence of SEQ ID NO: 510, HC CDR3 having the amino acid sequence of SEQ ID NO: 511, LC CDR1 having the amino acid sequence of SEQ ID NO: 512, LC CDR2 having the amino acid sequence of SEQ ID NO: 513, and LC CDR3 having the amino acid sequence of SEQ ID NO: 514 (g) HC CDR1 having the amino acid sequence of SEQ ID NO: 741, HC CDR2 having the amino acid sequence of SEQ ID NO: 742, HC CDR3 having the amino acid sequence of SEQ ID NO: 743, LC CDR1 having the amino acid sequence of SEQ ID NO: 744, LC CDR2 having the amino acid sequence of SEQ ID NO: 745, and LC CDR3 having the amino acid sequence of SEQ ID NO:

746. (h) HC CDR1 having the amino acid sequence of SEQ ID NO: 747, HC CDR2 having the amino acid sequence of SEQ ID NO: 748, HC CDR3 having the amino acid sequence of SEQ ID NO: 749, LC CDR1 having the amino acid sequence of SEQ ID NO: 750, LC CDR2 having the amino acid sequence of QAS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 752 (i) HC CDR1 having the amino acid sequence of SEQ ID NO: 753, HC CDR2 having the amino acid sequence of SEQ ID NO: 754, HC CDR3 having the amino acid sequence of SEQ ID NO: 755, LC CDR1 having the amino acid sequence of SEQ ID NO: 756, LC CDR2 having the amino acid sequence of SEQ ID NO: 757, and LC CDR3 having the amino acid sequence of SEQ ID NO: 758 (j) HC CDR1 having the amino acid sequence of SEQ ID NO: 761, HC CDR2 having the amino acid sequence of SEQ ID NO: 762, HC CDR3 having the amino acid sequence of SEQ ID NO: 763, LC CDR1 having the amino acid sequence of SEQ ID NO: 764, LC CDR2 having the amino acid sequence of SEQ ID NO: 765, and LC CDR3 having the amino acid sequence of SEQ ID NO: 766 (k) HC CDR1 having the amino acid sequence of SEQ ID NO: 767, HC CDR2 having the amino acid sequence of SEQ ID NO: 768, HC CDR3 having the amino acid sequence of SEQ ID NO: 770, LC CDR1 having the amino acid sequence of SEQ ID NO: 346, LC CDR2 having the amino acid sequence of NAK, and LC CDR3 having the amino acid sequence of SEQ ID NO: 772, or (l) A bispecific antibody according to claim 33 or 34, comprising HC CDR1 having the amino acid sequence of SEQ ID NO: 773, HC CDR2 having the amino acid sequence of SEQ ID NO: 774, HC CDR3 having the amino acid sequence of SEQ ID NO: 775, LC CDR1 having the amino acid sequence of SEQ ID NO: 776, LC CDR2 having the amino acid sequence of SEQ ID NO: 777, and LC CDR3 having the amino acid sequence of SEQ ID NO:

778.

36. The antigen-specific binding site that specifically binds to IL-31 or IL-31R is (a) VH containing the amino acid sequence of SEQ ID NO: 475, and VL containing the amino acid sequence of SEQ ID NO: 476, (b) VH containing the amino acid sequence of SEQ ID NO: 495, and VL containing the amino acid sequence of SEQ ID NO: 496, (c) VH containing the amino acid sequence of SEQ ID NO: 739, and VL containing the amino acid sequence of SEQ ID NO: 740, or (d) A bispecific antibody according to any one of claims 33 to 35, comprising VH containing the amino acid sequence of SEQ ID NO: 759 and VL containing the amino acid sequence of SEQ ID NO:

760.

37. The bispecific antibody according to any one of claims 1 to 8, wherein the Th2 cytokine is IL-36.

38. The antigen-specific binding site that specifically binds to IL-36 or IL-36R is (a) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 575, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 576, (b) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 595, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 596, or (c) The bispecific antibody according to claim 37, comprising HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 779, and LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO:

780.

39. The antigen-specific binding site that specifically binds to IL-36 or IL-36R is (a) HC CDR1 having the amino acid sequence of SEQ ID NO: 577, HC CDR2 having the amino acid sequence of SEQ ID NO: 578, HC CDR3 having the amino acid sequence of SEQ ID NO: 579, LC CDR1 having the amino acid sequence of SEQ ID NO: 580, LC CDR2 having the amino acid sequence of SEQ ID NO: 581, and LC CDR3 having the amino acid sequence of SEQ ID NO: 582 (b) HC CDR1 having the amino acid sequence of SEQ ID NO: 583, HC CDR2 having the amino acid sequence of SEQ ID NO: 584, HC CDR3 having the amino acid sequence of SEQ ID NO: 585, LC CDR1 having the amino acid sequence of SEQ ID NO: 586, LC CDR2 having the amino acid sequence of RTS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 588 (c) HC CDR1 having the amino acid sequence of SEQ ID NO: 589, HC CDR2 having the amino acid sequence of SEQ ID NO: 590, HC CDR3 having the amino acid sequence of SEQ ID NO: 591, LC CDR1 having the amino acid sequence of SEQ ID NO: 592, LC CDR2 having the amino acid sequence of SEQ ID NO: 593, and LC CDR3 having the amino acid sequence of SEQ ID NO:

594. (d) HC CDR1 having the amino acid sequence of SEQ ID NO: 597, HC CDR2 having the amino acid sequence of SEQ ID NO: 598, HC CDR3 having the amino acid sequence of SEQ ID NO: 599, LC CDR1 having the amino acid sequence of SEQ ID NO: 600, LC CDR2 having the amino acid sequence of SEQ ID NO: 601, and LC CDR3 having the amino acid sequence of SEQ ID NO: 602 (e) HC CDR1 having the amino acid sequence of SEQ ID NO: 603, HC CDR2 having the amino acid sequence of SEQ ID NO: 604, HC CDR3 having the amino acid sequence of SEQ ID NO: 605, LC CDR1 having the amino acid sequence of SEQ ID NO: 606, LC CDR2 having the amino acid sequence of QMS, and LC CDR3 having the amino acid sequence of SEQ ID NO:

608. (f) HC CDR1 having the amino acid sequence of SEQ ID NO: 609, HC CDR2 having the amino acid sequence of SEQ ID NO: 610, HC CDR3 having the amino acid sequence of SEQ ID NO: 611, LC CDR1 having the amino acid sequence of SEQ ID NO: 612, LC CDR2 having the amino acid sequence of SEQ ID NO: 613, and LC CDR3 having the amino acid sequence of SEQ ID NO: 614 (g) HC CDR1 having the amino acid sequence of SEQ ID NO: 781, HC CDR2 having the amino acid sequence of SEQ ID NO: 782, HC CDR3 having the amino acid sequence of SEQ ID NO: 783, LC CDR1 having the amino acid sequence of SEQ ID NO: 784, LC CDR2 having the amino acid sequence of SEQ ID NO: 785, and LC CDR3 having the amino acid sequence of SEQ ID NO: 786, or (h) A bispecific antibody according to claim 37 or 38, comprising HC CDR1 having the amino acid sequence of SEQ ID NO: 787, HC CDR2 having the amino acid sequence of SEQ ID NO: 788, HC CDR3 having the amino acid sequence of SEQ ID NO: 789, LC CDR1 having the amino acid sequence of SEQ ID NO: 790, LC CDR2 having the amino acid sequence of STS, and LC CDR3 having the amino acid sequence of SEQ ID NO:

792.

40. The antigen-specific binding site that specifically binds to IL-36 or IL-36R is (a) VH containing the amino acid sequence of SEQ ID NO: 575, and VL containing the amino acid sequence of SEQ ID NO: 576, (b) VH containing the amino acid sequence of SEQ ID NO: 595, and VL containing the amino acid sequence of SEQ ID NO: 596, (c) A bispecific antibody according to any one of claims 37 to 39, comprising VH containing the amino acid sequence of SEQ ID NO: 779 and VL containing the amino acid sequence of SEQ ID NO:

780.

41. The bispecific antibody according to any one of claims 1 to 8, wherein the Th2 cytokine is TSLP.

42. The antigen-specific binding site that specifically binds to TSLP or TSLPR is (a) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 615, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 616, (b) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 635, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 636, (c) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 879, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 880, or (d) The bispecific antibody according to claim 41, comprising HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 899, and LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO:

900.

43. The antigen-specific binding site that specifically binds to TSLP or TSLPR is (a) HC CDR1 having the amino acid sequence of SEQ ID NO: 617, HC CDR2 having the amino acid sequence of SEQ ID NO: 618, HC CDR3 having the amino acid sequence of SEQ ID NO: 619, LC CDR1 having the amino acid sequence of SEQ ID NO: 620, LC CDR2 having the amino acid sequence of SEQ ID NO: 621, and LC CDR3 having the amino acid sequence of SEQ ID NO: 622 (b) HC CDR1 having the amino acid sequence of SEQ ID NO: 623, HC CDR2 having the amino acid sequence of SEQ ID NO: 624, HC CDR3 having the amino acid sequence of SEQ ID NO: 625, LC CDR1 having the amino acid sequence of SEQ ID NO: 626, LC CDR2 having the amino acid sequence of DDS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 628 (c) HC CDR1 having the amino acid sequence of SEQ ID NO: 629, HC CDR2 having the amino acid sequence of SEQ ID NO: 630, HC CDR3 having the amino acid sequence of SEQ ID NO: 631, LC CDR1 having the amino acid sequence of SEQ ID NO: 632, LC CDR2 having the amino acid sequence of SEQ ID NO: 633, and LC CDR3 having the amino acid sequence of SEQ ID NO: 634, or (d) HC CDR1 having the amino acid sequence of SEQ ID NO: 637, HC CDR2 having the amino acid sequence of SEQ ID NO: 638, HC CDR3 having the amino acid sequence of SEQ ID NO: 639, LC CDR1 having the amino acid sequence of SEQ ID NO: 640, LC CDR2 having the amino acid sequence of SEQ ID NO: 641, and LC CDR3 having the amino acid sequence of SEQ ID NO: 642 (e) HC CDR1 having the amino acid sequence of SEQ ID NO: 643, HC CDR2 having the amino acid sequence of SEQ ID NO: 644, HC CDR3 having the amino acid sequence of SEQ ID NO: 645, LC CDR1 having the amino acid sequence of SEQ ID NO: 646, LC CDR2 having the amino acid sequence of GDN, and LC CDR3 having the amino acid sequence of SEQ ID NO:

648. (f) HC CDR1 having the amino acid sequence of SEQ ID NO: 649, HC CDR2 having the amino acid sequence of SEQ ID NO: 650, HC CDR3 having the amino acid sequence of SEQ ID NO: 651, LC CDR1 having the amino acid sequence of SEQ ID NO: 652, LC CDR2 having the amino acid sequence of SEQ ID NO: 653, and LC CDR3 having the amino acid sequence of SEQ ID NO: 654 (g) HC CDR1 having the amino acid sequence of SEQ ID NO: 881, HC CDR2 having the amino acid sequence of SEQ ID NO: 882, HC CDR3 having the amino acid sequence of SEQ ID NO: 883, LC CDR1 having the amino acid sequence of SEQ ID NO: 884, LC CDR2 having the amino acid sequence of SEQ ID NO: 885, and LC CDR3 having the amino acid sequence of SEQ ID NO:

886. (h) HC CDR1 having the amino acid sequence of SEQ ID NO: 887, HC CDR2 having the amino acid sequence of SEQ ID NO: 888, HC CDR3 having the amino acid sequence of SEQ ID NO: 889, LC CDR1 having the amino acid sequence of SEQ ID NO: 890, LC CDR2 having the amino acid sequence of FAR, and LC CDR3 having the amino acid sequence of SEQ ID NO: 892 (i) HC CDR1 having the amino acid sequence of SEQ ID NO: 893, HC CDR2 having the amino acid sequence of SEQ ID NO: 894, HC CDR3 having the amino acid sequence of SEQ ID NO: 895, LC CDR1 having the amino acid sequence of SEQ ID NO: 896, LC CDR2 having the amino acid sequence of SEQ ID NO: 897, and LC CDR3 having the amino acid sequence of SEQ ID NO: 898 (j) HC CDR1 having the amino acid sequence of SEQ ID NO: 901, HC CDR2 having the amino acid sequence of SEQ ID NO: 902, HC CDR3 having the amino acid sequence of SEQ ID NO: 903, LC CDR1 having the amino acid sequence of SEQ ID NO: 904, LC CDR2 having the amino acid sequence of SEQ ID NO: 905, and LC CDR3 having the amino acid sequence of SEQ ID NO: 906 (k) HC CDR1 having the amino acid sequence of SEQ ID NO: 907, HC CDR2 having the amino acid sequence of SEQ ID NO: 908, HC CDR3 having the amino acid sequence of SEQ ID NO: 909, LC CDR1 having the amino acid sequence of SEQ ID NO: 910, LC CDR2 having the amino acid sequence of FAK, and LC CDR3 having the amino acid sequence of SEQ ID NO: 912, or (l) A bispecific antibody according to claim 41 or 42, comprising HC CDR1 having the amino acid sequence of SEQ ID NO: 913, HC CDR2 having the amino acid sequence of SEQ ID NO: 914, HC CDR3 having the amino acid sequence of SEQ ID NO: 915, LC CDR1 having the amino acid sequence of SEQ ID NO: 916, LC CDR2 having the amino acid sequence of SEQ ID NO: 917, and LC CDR3 having the amino acid sequence of SEQ ID NO:

918.

44. The antigen-specific binding site that specifically binds to TSLP or TSLPR is (a) VH containing the amino acid sequence of SEQ ID NO: 615, and VL containing the amino acid sequence of SEQ ID NO: 616, (b) VH containing the amino acid sequence of SEQ ID NO: 635, and VL containing the amino acid sequence of SEQ ID NO: 636, (c) VH containing the amino acid sequence of SEQ ID NO: 879, and VL containing the amino acid sequence of SEQ ID NO: 880, or (d) A bispecific antibody according to any one of claims 41 to 43, comprising VH containing the amino acid sequence of SEQ ID NO: 899 and VL containing the amino acid sequence of SEQ ID NO:

900.

45. The bispecific antibody according to any one of claims 1 to 8, wherein the Th2 cytokine is IL-33.

46. The antigen-specific binding site that specifically binds to IL-33 or IL-33R is (a) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 677, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 678, (b) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 697, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 698, (c) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 717, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 718, or (d) The bispecific antibody according to claim 45, comprising HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 799, and LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO:

800.

47. The antigen-specific binding site that specifically binds to IL-33 or IL-33R is (a) HC CDR1 having the amino acid sequence of SEQ ID NO: 659, HC CDR2 having the amino acid sequence of SEQ ID NO: 660, HC CDR3 having the amino acid sequence of SEQ ID NO: 661, LC CDR1 having the amino acid sequence of SEQ ID NO: 662, LC CDR2 having the amino acid sequence of SEQ ID NO: 663, and LC CDR3 having the amino acid sequence of SEQ ID NO: 664 (b) HC CDR1 having the amino acid sequence of SEQ ID NO: 665, HC CDR2 having the amino acid sequence of SEQ ID NO: 666, HC CDR3 having the amino acid sequence of SEQ ID NO: 667, LC CDR1 having the amino acid sequence of SEQ ID NO: 668, LC CDR2 having the amino acid sequence of RDT, and LC CDR3 having the amino acid sequence of SEQ ID NO: 670 (c) HC CDR1 having the amino acid sequence of SEQ ID NO: 671, HC CDR2 having the amino acid sequence of SEQ ID NO: 672, HC CDR3 having the amino acid sequence of SEQ ID NO: 673, LC CDR1 having the amino acid sequence of SEQ ID NO: 674, LC CDR2 having the amino acid sequence of SEQ ID NO: 675, and LC CDR3 having the amino acid sequence of SEQ ID NO:

676. (d) HC CDR1 having the amino acid sequence of SEQ ID NO: 679, HC CDR2 having the amino acid sequence of SEQ ID NO: 680, HC CDR3 having the amino acid sequence of SEQ ID NO: 681, LC CDR1 having the amino acid sequence of SEQ ID NO: 682, LC CDR2 having the amino acid sequence of SEQ ID NO: 683, and LC CDR3 having the amino acid sequence of SEQ ID NO: 684 (e) HC CDR1 having the amino acid sequence of SEQ ID NO: 685, HC CDR2 having the amino acid sequence of SEQ ID NO: 686, HC CDR3 having the amino acid sequence of SEQ ID NO: 687, LC CDR1 having the amino acid sequence of SEQ ID NO: 688, LC CDR2 having the amino acid sequence of AAS, and LC CDR3 having the amino acid sequence of SEQ ID NO: 690 (f) HC CDR1 having the amino acid sequence of SEQ ID NO: 691, HC CDR2 having the amino acid sequence of SEQ ID NO: 692, HC CDR3 having the amino acid sequence of SEQ ID NO: 693, LC CDR1 having the amino acid sequence of SEQ ID NO: 694, LC CDR2 having the amino acid sequence of SEQ ID NO: 695, and LC CDR3 having the amino acid sequence of SEQ ID NO: 696 (g) HC CDR1 having the amino acid sequence of SEQ ID NO: 699, HC CDR2 having the amino acid sequence of SEQ ID NO: 700, HC CDR3 having the amino acid sequence of SEQ ID NO: 701, LC CDR1 having the amino acid sequence of SEQ ID NO: 702, LC CDR2 having the amino acid sequence of SEQ ID NO: 703, and LC CDR3 having the amino acid sequence of SEQ ID NO:

704. (h) HC CDR1 having the amino acid sequence of SEQ ID NO: 705, HC CDR2 having the amino acid sequence of SEQ ID NO: 706, HC CDR3 having the amino acid sequence of SEQ ID NO: 707, LC CDR1 having the amino acid sequence of SEQ ID NO: 708, LC CDR2 having the amino acid sequence of WAS, and LC CDR3 having the amino acid sequence of SEQ ID NO:

710. (i) HC CDR1 having the amino acid sequence of SEQ ID NO: 711, HC CDR2 having the amino acid sequence of SEQ ID NO: 712, HC CDR3 having the amino acid sequence of SEQ ID NO: 713, LC CDR1 having the amino acid sequence of SEQ ID NO: 714, LC CDR2 having the amino acid sequence of SEQ ID NO: 715, and LC CDR3 having the amino acid sequence of SEQ ID NO: 716 (j) HC CDR1 having the amino acid sequence of SEQ ID NO: 801, HC CDR2 having the amino acid sequence of SEQ ID NO: 802, HC CDR3 having the amino acid sequence of SEQ ID NO: 803, LC CDR1 having the amino acid sequence of SEQ ID NO: 804, LC CDR2 having the amino acid sequence of SEQ ID NO: 805, and LC CDR3 having the amino acid sequence of SEQ ID NO: 806 (k) HC CDR1 having the amino acid sequence of SEQ ID NO: 807, HC CDR2 having the amino acid sequence of SEQ ID NO: 808, HC CDR3 having the amino acid sequence of SEQ ID NO: 809, LC CDR1 having the amino acid sequence of SEQ ID NO: 810, LC CDR2 having the amino acid sequence of FTN, and LC CDR3 having the amino acid sequence of SEQ ID NO: 812, or (l) A bispecific antibody according to claim 45 or 46, comprising HC CDR1 having the amino acid sequence of SEQ ID NO: 813, HC CDR2 having the amino acid sequence of SEQ ID NO: 814, HC CDR3 having the amino acid sequence of SEQ ID NO: 815, LC CDR1 having the amino acid sequence of SEQ ID NO: 816, LC CDR2 having the amino acid sequence of SEQ ID NO: 817, and LC CDR3 having the amino acid sequence of SEQ ID NO:

818.

48. The antigen-specific binding site that specifically binds to IL-33 or IL-33R is (a) VH containing the amino acid sequence of SEQ ID NO: 677, and VL containing the amino acid sequence of SEQ ID NO: 678, or (b) A bispecific antibody according to any one of claims 45 to 47, comprising VH containing the amino acid sequence of SEQ ID NO: 799 and VL containing the amino acid sequence of SEQ ID NO:

800.

49. The bispecific antibody according to any one of claims 1 to 5, wherein the antigen-specific binding site that specifically binds to the Th2 cytokine or its receptor is the VH and / or VL of any one of the antibodies in Table 2.

50. The bispecific antibody according to any one of claims 1 to 49, wherein the bispecific antibody maintains a binding affinity for KLK5 and KLK7 that is 20% or less lower than that of an anti-KLK5 / KLK7 antibody containing the same CDR and / or VH / VL as the bispecific antibody.

51. The bispecific antibody according to any one of claims 1 to 50, wherein the bispecific antibody maintains a binding affinity to the Th2 target that is 20% or less lower than that of a Th2-targeted antibody containing the same CDR and / or VH / VL as the bispecific antibody.

52. The bispecific antibody according to any one of claims 1 to 51, wherein the bispecific antibody retains at least 80% of the inhibitory activity against KLK5 and KLK7 compared to an anti-KLK5 / KLK7 antibody containing the same CDR and / or VH / VL as the bispecific antibody.

53. The bispecific antibody according to any one of claims 1 to 52, wherein the bispecific antibody retains at least 80% of the inhibitory activity against Th2 signaling compared to a Th2-targeted antibody containing the same CDR and / or VH / VL as the bispecific antibody.

54. A composition comprising a bispecific antibody according to any one of claims 1 to 53 and an acceptable carrier.

55. A method comprising administering a bispecific antibody according to any one of claims 1 to 53 or the composition according to claim 54 to a target.

56. The method according to claim 55, wherein the subject has a skin barrier defect.

57. A method for treating a skin barrier defect, comprising administering an effective amount to a target of a bispecific antibody according to any one of claims 1 to 53 or a composition according to claim 54.

58. The method according to claim 56 or 57, wherein the skin barrier defect is associated with Netherton syndrome, atopic dermatitis, eosinophilic esophagitis, prurigo nodularis, chronic pruritus of unknown cause (CPUO), dry skin, asthma (especially KLK5), ichthyosis vulgaris, or itching or chronic itching.

59. The method according to any one of claims 55 to 58, wherein the subject has atopic dermatitis.

60. The method according to any one of claims 55 to 59, wherein the administration reduces ear thickness by more than 30% compared to a subject administered with a Th2-targeted antibody containing the same CDR and / or VH / VL as the bispecific antibody.

61. The method according to any one of claims 55 to 60, wherein the administration reduces ear thickness by more than 30% compared to a subject administered with a Th2-targeted antibody containing the same CDR and / or VH / VL as the bispecific antibody.

62. The method according to any one of claims 55 to 61, wherein the administration reduces skin erythema / hemorrhage by more than 30% compared to subjects administered with a Th2-targeted antibody containing the same CDR and / or VH / VL as the bispecific antibody.

63. The method according to any one of claims 55 to 62, wherein the administration reduces skin erythema / hemorrhage by more than 30% compared to subjects administered with a Th2-targeted antibody containing the same CDR and / or VH / VL as the bispecific antibody.

64. The method according to any one of claims 55 to 63, wherein the administration reduces skin erythema / hemorrhage by more than 30% compared to subjects administered with a Th2-targeted antibody containing the same CDR and / or VH / VL as the bispecific antibody.

65. The method according to any one of claims 55 to 64, wherein the administration reduces skin peeling / erosion by more than 30% compared to subjects administered with a Th2-targeted antibody containing the same CDR and / or VH / VL as the bispecific antibody.

66. The method according to any one of claims 55 to 65, wherein the administration reduces skin scaling / dryness by more than 30% compared to subjects administered with a Th2-targeted antibody containing the same CDR and / or VH / VL as the bispecific antibody.

67. The method according to any one of claims 55 to 66, wherein the administration reduces skin scaling / dryness by more than 30% compared to subjects administered with a Th2-targeted antibody containing the same CDR and / or VH / VL as the bispecific antibody.

68. The method according to any one of claims 55 to 67, wherein the administration reduces skin edema by more than 30% compared to subjects administered with a Th2-targeted antibody containing the same CDR and / or VH / VL as the bispecific antibody.

69. The method according to any one of claims 55 to 68, wherein the administration reduces skin edema by more than 30% compared to a subject administered with a Th2-targeted antibody containing the same CDR and / or VH / VL as the bispecific antibody.

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