Klk5 / 7 + th2-targeting antibodies and uses thereof

Abstract

Aspects of the application provide bispecific antibodies and methods for using the same to promote barrier function and reduce inflammation and to treat conditions such as Netherton syndrome, eosinophilic esophagitis, and atopic dermatitis. In some embodiments, the bispecific antibodies comprise 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 a receptor thereof.

Description

Related applications

[0001] This application is based on 35 USC 119(e) claims priority to U.S. Provisional Application No. 63 / 578,959, filed August 25, 2023, and U.S. Provisional Application No. 63 / 549,274, filed February 2, 2024, the entire contents of each of which are incorporated herein by reference.

[0002] Reference to the electronic sequence list The contents of the electronic serial number (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] Skin contains tissue structures and cells (such as epithelial cells and immune cells), which together provide functional and physical barriers, playing a vital role in preventing allergens from entering the body and responding to pathogens. Kallikrein (KLK) regulates desquamation and innate immunity to support skin homeostasis and wound healing. In healthy skin, the outermost layer of the epidermis is regularly shed via a KLK-driven proteolytic cascade, leading to the degradation of keratinized desmosomes and desquamation. KLK5 is considered the major activator of this proteolytic cascade. Autoactivated KLK5 enzymatically converts proKLK7 and proKLK14 to their active forms and stimulates a positive feedback loop that, through KLK14, leads to the production of more proKLK5. These KLK enzymes are inhibited by endogenous serine protease inhibitors, such as lymphoepithelial Kazal-associated inhibitors. Dysregulation of KLK (including KLK5 and KLK7) is associated with skin conditions, inflammatory diseases, and cancer. For example, overactive kallikrein 5 and 7 can cause hereditary and spontaneous epidermal barrier disorders (e.g., Netherton syndrome, eosinophilic esophagitis, atopic dermatitis). Summary of the Invention

[0004] Certain aspects of this disclosure relate to the imbalance between endogenous KLK protease and related protease inhibitors leading to barrier dysfunction and inducing inflammation (e.g. Figure 1 This understanding (as shown) can lead to inflammatory disorders such as Natherton's syndrome, eosinophilic esophagitis, and atopic dermatitis. Furthermore, increased activity of T helper 2 (Th2) cytokines (e.g., IL-13 and IL-4) can further drive inflammation and lead to barrier dysfunction and related disorders (such as...). Figure 2(As shown). In some embodiments, the compositions and methods provided herein can be used to inhibit KLK5 / KLK7 and Th2 cytokine signaling (e.g., IL-13, IL-4, IL-5, IL-6, IL-9, IL-31, IL-17E (IL-25), OX40L, TSLP, etc.) to improve barrier function and reduce inflammation, which alleviates the severity of disease.

[0005] Furthermore, aspects of this 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 Th2 cytokines (e.g., IL-13, IL-4, IL-5, IL-6, IL-9, IL-31, IL-17E (IL-25), OX40L, TSLP, etc.) or their receptors. In some embodiments, such multispecific antibodies are configured such that they comprise an arm containing an active site binding to KLK5 and KLK7, and an arm binding to Th2 cytokines or their receptors. 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, regarding the KLK5 / 7 binding site within the multispecific antibody (e.g., bispecific antibody), such antibodies specifically bind to the enzyme in its active form rather than its precursor form.

[0006] In some embodiments, methods and related compositions, as well as antibodies used in the methods, are provided that can be used to inhibit the activity of KLK5 and KLK7, as well as Th2 cytokines, to improve barrier function and reduce inflammation, thereby alleviating the severity of disease. In particular, aspects of this disclosure provide bispecific antibodies, wherein one arm contains an antigen-specific binding site of a dual inhibitor 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 wherein the other arm specifically binds to and inhibits the activity of Th2 cytokines (e.g., IL-13, IL-4, IL-5, IL-6, IL-9, IL-31, IL-17E (IL-25), OX40L, TSLP, etc.) or their receptors (referred to as an anti-KLK5 / KLK7 + Th2-targeting bispecific antibody). Therefore, in some embodiments, this disclosure provides methods and related antibody compositions for treating disorders associated with KLK5 and KLK7 dysregulation and / or abnormal Th2 cytokine activity, such as Natherton syndrome, atopic dermatitis (with and without filaggrin mutations), eosinophilic esophagitis, nodular prurigo, chronic pruritus of unknown cause (CPUO), asthma (e.g., KLK5-associated asthma), and ichthyosis vulgaris.

[0007] In some embodiments, this disclosure provides a bispecific antibody comprising at least one antigen-specific binding site of a dual inhibitor antibody targeting KLK5 and KLK7, and at least one antigen-specific binding site that specifically binds to and inhibits Th2 cytokines (e.g., IL-13, IL-4, IL-5, IL-6, IL-9, IL-31, IL-17E (IL-25), OX40L, TSLP, etc.) or their receptors. In some embodiments, this disclosure provides a bispecific antibody comprising at least one antigen-specific binding site of a dual inhibitor antibody targeting KLK5 and KLK7, and at least one antigen-specific binding site that specifically binds to and inhibits IL-13 (referred to as an anti-KLK5 / KLK7 + IL-13 targeted bispecific antibody). In some embodiments, this disclosure provides a bispecific antibody comprising at least one antigen-specific binding site of a dual inhibitor antibody targeting KLK5 and KLK7 and at least one antigen-specific binding site that specifically binds to and inhibits IL-4 (referred to as an anti-KLK5 / KLK7 + IL-4 targeting bispecific antibody). Therefore, in some embodiments, this disclosure provides methods and related antibody compositions for treating disorders associated with KLK5 and KLK7 dysregulation, wherein Th2 cytokines (such as IL-13, IL-4, etc.) also play a role in the pathogenesis, such as Natherton's syndrome, atopic dermatitis (with and without filaggrin mutations), eosinophilic esophagitis, nodular prurigo, chronic pruritus of unknown cause (CPUO), asthma (e.g., KLK5-associated asthma), and ichthyosis vulgaris.

[0008] In some aspects, this disclosure provides a bispecific antibody comprising antigen-specific binding sites that specifically bind to KLK5 and KLK7 and antigen-specific binding sites that specifically bind to Th2 cytokines or their receptors.

[0009] In some embodiments, antigen-specific binding sites that specifically bind to KLK5 and KLK7 bind to the active sites of KLK5 and KLK7 and inhibit enzyme activity. In some embodiments, the antigen-specific binding sites that specifically bind to KLK5 and KLK7 comprise HC CDR1, HC CDR2, HC CDR3, LCCDR1, LC CDR2, and / or LC CDR3 of any of the antibodies listed in Tables 1a and 1b. In some embodiments, the antigen-specific binding sites that specifically bind to KLK5 and KLK7 comprise HC CDR1, HC CDR2, and HC CDR3 with heavy chain variable domains having the amino acid sequence of SEQ ID NO: 7, and LC CDR1, LC CDR2, and LC CDR3 with light chain variable domains 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 comprise 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. In some embodiments, the antigen-specific binding sites that specifically bind to KLK5 and KLK7 comprise: 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. In some embodiments, the antigen-specific binding sites that specifically bind to KLK5 and KLK7 comprise: HC CDR1, HC CDR2, and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 21; and LC CDR1, LC CDR2, and LC CDR3 of 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 comprise: 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: HCCDR1 having the amino acid sequence of SEQ ID NO: 9; HCCDR2 having the amino acid sequence of SEQ ID NO: 15; HCCDR3 having the amino acid sequence of SEQ ID NO: 16; LCCCDR1 having the amino acid sequence of SEQ ID NO: 4; LCCCDR2 having the amino acid sequence of SEQ ID NO: 5; and LCCCDR3 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 comprise: HCCDR1 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 comprises an antigen-specific binding site that specifically binds to KLK5 and KLK7, the antigen-specific binding site having a VH and / or VL of any of the antibodies listed in Table 1a. In some embodiments, the antigen-specific binding sites that specifically bind to KLK5 and KLK7 comprise: VH having the amino acid sequence of SEQ ID NO: 7; and VL 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: VH, which contains the amino acid sequence of SEQ ID NO: 13; 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 comprises: 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 comprises: 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, the antigen-specific binding site including HC CDR1, HCCDR2, HC CDR3, LC CDR1, LC CDR2 and / or LC CDR3 of any of the antibodies listed in Table 2.

[0011] In some embodiments, the Th2 cytokine is IL-13. In some embodiments, the bispecific antibody comprises 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 comprises: HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain having the amino acid sequence of SEQ ID NO: 53; and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain 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 comprises: HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain having the amino acid sequence of SEQ ID NO: 32; and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain 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 comprises: 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 comprises: 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 comprises: HC CDR1, HCCDR2, and HC CDR3 of the heavy chain variable domain having the amino acid sequence of SEQ ID NO: 114; and LC CDR1, LCCDR2, 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 comprises: 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, LCCDR2, and LCCDR3 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 comprises: 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 comprises: 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 comprises: 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 LCCDR3 having the amino acid sequence of SEQ ID NO: 66. In some embodiments, the antigen-specific binding site that specifically binds to IL-13 or IL-13R comprises: 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 comprises: 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; LCCDR1 having the amino acid sequence of SEQ ID NO: 37; LCCDR2 having the amino acid sequence of SEQ ID NO: 38; and LCCDR3 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 comprises: HC CDR1 having the amino acid sequence of SEQ ID NO: 40; HCCDR2 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 comprises: HC CDR1 having the amino acid sequence of SEQ ID NO: 46; HCCDR2 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 comprises: HC CDR1 having the amino acid sequence of SEQ ID NO: 76; HCCDR2 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 site that specifically binds to IL-13 or IL-13R comprises: HC CDR1 having the amino acid sequence of SEQ ID NO: 82; HCCDR2 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 comprises: HC CDR1 having the amino acid sequence of SEQ ID NO: 88; HCCDR2 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 comprises: HC CDR1 having the amino acid sequence of SEQ ID NO: 96; HCCDR2 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 comprises: 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 comprises: 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 comprises: 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; LCCDR2 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 comprises: HCCDR1 having the amino acid sequence of SEQ ID NO: 122; HCCDR2 having the amino acid sequence of SEQ ID NO: 123; HCCDR3 having the amino acid sequence of SEQ ID NO: 124; LCCCDR1 having the amino acid sequence of SEQ ID NO: 125; LCCCDR2 having the amino acid sequence of SEQ ID NO: 126; and LCCCDR3 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 comprises: 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 comprises: 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 LCCDR3 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 comprises: 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; LCCDR1 having the amino acid sequence of SEQ ID NO: 145; LCCDR2 having the amino acid sequence of SEQ ID NO: 146; and LCCDR3 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 comprises: 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 site that specifically binds to IL-13 or IL-13R comprises: 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 site that specifically binds to IL-13 or IL-13R comprises: 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. In some embodiments, the antigen-specific binding site that specifically binds to IL-13 or IL-13R comprises: VH having the amino acid sequence of SEQ ID NO: 53; and VL 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 comprises: VH having the amino acid sequence of SEQ ID NO: 32; and VL 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 comprises: VH, which comprises the amino acid sequence of SEQ ID NO: 74; and VL, which comprises 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 comprises: VH, which comprises the amino acid sequence of SEQ ID NO: 94; and VL, which comprises 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 comprises: VH, which comprises the amino acid sequence of SEQ ID NO: 114; and VL, which comprises 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 comprises: VH, which comprises the amino acid sequence of SEQ ID NO: 134; and VL, which comprises 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 comprises: VH, which contains the amino acid sequence of SEQ ID NO: 657; and VL, which contains 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 comprises: 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 comprises: 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 comprises: 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 comprises: 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 comprises: heavy chain variable domains HCCDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 234; and light chain variable domains LCCDR1, LC CDR2, and LC CDR3 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 comprises: heavy chain variable domains HC CDR1, HC CDR2, and HCCDR3 having the amino acid sequence of SEQ ID NO: 254; and light chain variable domains LCCDR1, LC CDR2, and LCCDR3 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 comprises: 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; LCCDR1 having the amino acid sequence of SEQ ID NO: 159; LCCDR2 having the amino acid sequence of SEQ ID NO: 160; and LCCDR3 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 comprises: 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 comprises: HC CDR1 having the amino acid sequence of SEQ ID NO: 168; HCCDR2 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 comprises: 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 comprises: 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 comprises: 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 comprises: 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; LCCDR2 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 comprises: HCCDR1 having the amino acid sequence of SEQ ID NO: 202; HCCDR2 having the amino acid sequence of SEQ ID NO: 203; HCCDR3 having the amino acid sequence of SEQ ID NO: 204; LCCCDR1 having the amino acid sequence of SEQ ID NO: 205; LCCCDR2 having the amino acid sequence of SEQ ID NO: 206; and LCCCDR3 having the amino acid sequence of SEQ ID NO: 207.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: 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 site that specifically binds to IL-4 or IL-4R comprises: 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 site that specifically binds to IL-4 or IL-4R comprises: 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 site that specifically binds to IL-4 or IL-4R comprises: 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 LCCDR3 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 comprises: 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; LCCDR1 having the amino acid sequence of SEQ ID NO: 239; LCCDR2 having the amino acid sequence of SEQ ID NO: 240; and LCCDR3 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 comprises: 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 comprises: 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 comprises: 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; LCCDR2 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: HCCDR1 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 having the amino acid sequence of SEQ ID NO: 154; and VL 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 comprises: VH having the amino acid sequence of SEQ ID NO: 174; and VL 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 comprises: VH, which comprises the amino acid sequence of SEQ ID NO: 194; and VL, which comprises 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, which comprises the amino acid sequence of SEQ ID NO: 214; and VL, which comprises 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, which comprises the amino acid sequence of SEQ ID NO: 234; and VL, which comprises 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, which comprises the amino acid sequence of SEQ ID NO: 254; and VL, which comprises 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 comprises: 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 comprises: 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 comprises: 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 comprises: 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 comprises: heavy chain variable domains HCCDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 355; and light chain variable domains LCCDR1, LC CDR2, and LC CDR3 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 comprises: heavy chain variable domains HC CDR1, HC CDR2, and HCCDR3 having the amino acid sequence of SEQ ID NO: 375; and light chain variable domains LCCDR1, LC CDR2, and LCCDR3 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 comprises: 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; LCCDR1 having the amino acid sequence of SEQ ID NO: 280; LCCDR2 having the amino acid sequence of SEQ ID NO: 281; and LCCDR3 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 comprises: 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 comprises: 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 comprises: 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 site that specifically binds to IL-5 or IL-5R comprises: 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; LCCDR2 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 site that specifically binds to IL-5 or IL-5R comprises: 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; LCCDR2 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, the antigen-specific binding site that specifically binds to IL-5 or IL-5R comprises: HCCDR1 having the amino acid sequence of SEQ ID NO: 317; HCCDR2 having the amino acid sequence of SEQ ID NO: 318; HCCDR3 having the amino acid sequence of SEQ ID NO: 319; LCCCDR1 having the amino acid sequence of SEQ ID NO: 320; LCCCDR2 having the amino acid sequence of SEQ ID NO: 321; and LCCCDR3 having the amino acid sequence of SEQ ID NO: 322. In some embodiments, the antigen-specific binding site that specifically binds to IL-5 or IL-5R comprises: 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 comprises: 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 comprises: 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 LCCDR3 having the amino acid sequence of SEQ ID NO: 342. In some embodiments, the antigen-specific binding site that specifically binds to IL-5 or IL-5R comprises: 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; LCCDR1 having the amino acid sequence of SEQ ID NO: 346; LCCDR2 having the amino acid sequence of G; and LCCDR3 having the amino acid sequence of SEQ ID NO: 348. In some embodiments, the antigen-specific binding site that specifically binds to IL-5 or IL-5R comprises: 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; LCCDR1 having the amino acid sequence of SEQ ID NO: 352; LCCDR2 having the amino acid sequence of SEQ ID NO: 353; and LCCDR3 having the amino acid sequence of SEQ ID NO: 354.In some embodiments, the antigen-specific binding site that specifically binds to IL-5 or IL-5R comprises: 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 site that specifically binds to IL-5 or IL-5R comprises: 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 comprises: 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 comprises: 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, the antigen-specific binding site that specifically binds to IL-5 or IL-5R comprises: 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; LCCDR2 having the amino acid sequence of AAS; and LC CDR3 having the amino acid sequence of SEQ ID NO: 388. In some embodiments, the antigen-specific binding site that specifically binds to IL-5 or IL-5R comprises: 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; LCCDR2 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, the antigen-specific binding site that specifically binds to IL-5 or IL-5R comprises: 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 comprises: VH, which contains the amino acid sequence of SEQ ID NO: 295; and VL, which contains 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 comprises: VH, which contains the amino acid sequence of SEQ ID NO: 315; and VL, which contains 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 comprises: VH, which contains the amino acid sequence of SEQ ID NO: 335; and VL, which contains 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 comprises: VH, which contains the amino acid sequence of SEQ ID NO: 355; and VL, which contains 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 comprises: VH, which contains the amino acid sequence of SEQ ID NO: 375; and VL, which contains 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 comprises: HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain, having the amino acid sequence of SEQ ID NO: 395; and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain, 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 comprises: 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; LCCDR1, 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, the antigen-specific binding site that specifically binds to IL-9 or IL-9R comprises: 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, the antigen-specific binding site that specifically binds to IL-9 or IL-9R comprises: HC CDR1 having the amino acid sequence of SEQ ID NO: 409; HCCDR2 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, the antigen-specific binding site that specifically binds to IL-9 or IL-9R comprises: 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 OX40L or OX40.In some embodiments, the antigen-specific binding site that specifically binds to OX40L or OX40 comprises: heavy chain variable domains HCCDR1, HCCDR2, and HCCDR3, having the amino acid sequence of SEQ ID NO: 415; and light chain variable domains LCCDR1, LCCDR2, and LCCDR3, 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 comprises: heavy chain variable domains HCCDR1, HCCDR2, and HCCDR3, having the amino acid sequence of SEQ ID NO: 435; and light chain variable domains LCCDR1, LCCDR2, and LCCDR3, 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 comprises: HC CDR1, HC CDR2, and HCCDR3 of the heavy chain variable domain having the amino acid sequence of SEQ ID NO: 819; and LC CDR1, LC CDR2, and LCCDR3 of the light chain variable domain 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 comprises: HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain having the amino acid sequence of SEQ ID NO: 839; and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain 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 comprises: HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain having the amino acid sequence of SEQ ID NO: 859; and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain having the amino acid sequence of SEQ ID NO: 860. In some embodiments, the antigen-specific binding site that specifically binds to OX40L or OX40 comprises: HCCDR1 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, the antigen-specific binding site that specifically binds to OX40L or OX40 comprises: 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, the antigen-specific binding site that specifically binds to OX40L or OX40 comprises: 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 site that specifically binds to OX40L or OX40 comprises: 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 LCCDR3 having the amino acid sequence of SEQ ID NO: 442. 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: 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; LCCDR1 having the amino acid sequence of SEQ ID NO: 446; LCCDR2 having the amino acid sequence of AAS; and LCCDR3 having the amino acid sequence of SEQ ID NO: 448.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: 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; LCCDR1 having the amino acid sequence of SEQ ID NO: 452; LCCDR2 having the amino acid sequence of SEQ ID NO: 453; and LCCDR3 having the amino acid sequence of SEQ ID NO: 454. 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: 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, the antigen-specific binding site that specifically binds to OX40L or OX40 comprises: 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, the antigen-specific binding site that specifically binds to OX40L or OX40 comprises: 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 site that specifically binds to OX40L or OX40 comprises: 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 site that specifically binds to OX40L or OX40 comprises: 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; LCCDR2 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 site that specifically binds to OX40L or OX40 comprises: 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; LCCDR2 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 site that specifically binds to OX40L or OX40 comprises: HCCDR1 having the amino acid sequence of SEQ ID NO: 861; HCCDR2 having the amino acid sequence of SEQ ID NO: 862; HCCDR3 having the amino acid sequence of SEQ ID NO: 863; LCCCDR1 having the amino acid sequence of SEQ ID NO: 864; LCCCDR2 having the amino acid sequence of SEQ ID NO: 865; and LCCCDR3 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 having the amino acid sequence of SEQ ID NO: 415; and VL 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 comprises: VH, which comprises the amino acid sequence of SEQ ID NO: 435; and VL, which comprises 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, which comprises the amino acid sequence of SEQ ID NO: 819; and VL, which comprises 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, which comprises the amino acid sequence of SEQ ID NO: 839; and VL, which comprises 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, which comprises the amino acid sequence of SEQ ID NO: 859; and VL, which comprises 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 comprises: HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain, having the amino acid sequence of SEQ ID NO: 455; and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain, 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 comprises: HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain, having the amino acid sequence of SEQ ID NO: 719; and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain, 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 comprises: 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 LCCDR3 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 comprises: 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; LCCDR1 having the amino acid sequence of SEQ ID NO: 466; LCCDR2 having the amino acid sequence of DAS; and LCCDR3 having the amino acid sequence of SEQ ID NO: 468.In some embodiments, the antigen-specific binding site that specifically binds to IL-25 or IL-25R comprises: 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; LCCDR1 having the amino acid sequence of SEQ ID NO: 472; LCCDR2 having the amino acid sequence of SEQ ID NO: 473; and LCCDR3 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 comprises: 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 comprises: 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 comprises: 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 comprises: VH, which comprises the amino acid sequence of SEQ ID NO: 455; and VL, which comprises 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 comprises: VH, which comprises the amino acid sequence of SEQ ID NO: 719; and VL, which comprises 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 comprises: HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain, having the amino acid sequence of SEQ ID NO: 475; and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain, 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 comprises: HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain, having the amino acid sequence of SEQ ID NO: 495; and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain, 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 comprises: 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 comprises: 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 site that specifically binds to IL-31 or IL-31R comprises: HCCDR1 having the amino acid sequence of SEQ ID NO: 477; HCCDR2 having the amino acid sequence of SEQ ID NO: 478; HCCDR3 having the amino acid sequence of SEQ ID NO: 479; LCCCDR1 having the amino acid sequence of SEQ ID NO: 480; LCCCDR2 having the amino acid sequence of SEQ ID NO: 481; and LCCCDR3 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 comprises: 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 comprises: 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 LCCDR3 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 comprises: 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; LCCDR1 having the amino acid sequence of SEQ ID NO: 500; LCCDR2 having the amino acid sequence of SEQ ID NO: 501; and LCCDR3 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 comprises: 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-31 or IL-31R comprises: 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-31 or IL-31R comprises: 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 comprises: 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; LCCDR2 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 comprises: 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; LCCDR2 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 comprises: HCCDR1 having the amino acid sequence of SEQ ID NO: 761; HCCDR2 having the amino acid sequence of SEQ ID NO: 762; HCCDR3 having the amino acid sequence of SEQ ID NO: 763; LCCCDR1 having the amino acid sequence of SEQ ID NO: 764; LCCCDR2 having the amino acid sequence of SEQ ID NO: 765; and LCCCDR3 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 comprises: 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 comprises: 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 comprises: 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 comprises: VH, which contains the amino acid sequence of SEQ ID NO: 495; and VL, which contains 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 comprises: VH, which contains the amino acid sequence of SEQ ID NO: 739; and VL, which contains 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 comprises: 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 comprises: HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain, having the amino acid sequence of SEQ ID NO: 575; and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain, 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 comprises: HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain, having the amino acid sequence of SEQ ID NO: 595; and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain, 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 comprises: HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain having the amino acid sequence of SEQ ID NO: 779; and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain 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 comprises: 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 site that specifically binds to IL-36 or IL-36R comprises: 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 comprises: 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 LCCDR3 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 comprises: 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; LCCDR1 having the amino acid sequence of SEQ ID NO: 600; LCCDR2 having the amino acid sequence of SEQ ID NO: 601; and LCCDR3 having the amino acid sequence of SEQ ID NO: 602. In some embodiments, the antigen-specific binding site that specifically binds to IL-36 or IL-36R comprises: 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 site that specifically binds to IL-36 or IL-36R comprises: 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 comprises: 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 comprises: 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; LCCDR2 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 comprises: VH having the amino acid sequence of SEQ ID NO: 575; and VL 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 comprises: VH, which comprises the amino acid sequence of SEQ ID NO: 595; and VL, which comprises 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 comprises: VH, which comprises the amino acid sequence of SEQ ID NO: 779; and VL, which comprises 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 comprises: HC CDR1, HC CDR2, and HCCDR3 of the heavy chain variable domain, having the amino acid sequence of SEQ ID NO: 615; and LC CDR1, LC CDR2, and LCCDR3 of the light chain variable domain, 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 comprises: HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain, having the amino acid sequence of SEQ ID NO: 635; and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain, 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 comprises: HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain having the amino acid sequence of SEQ ID NO: 879; and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain 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 comprises: HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain having the amino acid sequence of SEQ ID NO: 899; and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain 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 comprises: 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; LCCDR2 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 site that specifically binds to TSLP or TSLPR comprises: HCCDR1 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. In some embodiments, the antigen-specific binding site that specifically binds to TSLP or TSLPR comprises: HCCDR1 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 comprises: 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 comprises: 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 site that specifically binds to TSLP or TSLPR comprises: 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 LCCDR3 having the amino acid sequence of SEQ ID NO: 654. In some embodiments, the antigen-specific binding site that specifically binds to TSLP or TSLPR comprises: 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; LCCDR1 having the amino acid sequence of SEQ ID NO: 884; LCCDR2 having the amino acid sequence of SEQ ID NO: 885; and LCCDR3 having the amino acid sequence of SEQ ID NO: 886. In some embodiments, the antigen-specific binding site that specifically binds to TSLP or TSLPR comprises: 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, the antigen-specific binding site that specifically binds to TSLP or TSLPR comprises: HC CDR1 having the amino acid sequence of SEQ ID NO: 893; HCCDR2 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, the antigen-specific binding site that specifically binds to TSLP or TSLPR comprises: 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, the antigen-specific binding site that specifically binds to TSLP or TSLPR comprises: 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 comprises: 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 comprises: 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 comprises: 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 comprises: VH, which contains the amino acid sequence of SEQ ID NO: 879; and VL, which contains the amino acid sequence of SEQ ID NO: 880.In some embodiments, the antigen-specific binding site that specifically binds to TSLP or TSLPR comprises: 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 comprises: HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain, having the amino acid sequence of SEQ ID NO: 677; and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain, 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 comprises: HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain, having the amino acid sequence of SEQ ID NO: 697; and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain, 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 comprises: HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain having the amino acid sequence of SEQ ID NO: 717; and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain 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 comprises: HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain having the amino acid sequence of SEQ ID NO: 799; and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain having the amino acid sequence of SEQ ID NO: 800. In some embodiments, the antigen-specific binding site that specifically binds to IL-33 or IL-33R comprises: HCCDR1 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 site that specifically binds to IL-33 or IL-33R comprises: 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 site that specifically binds to IL-33 or IL-33R comprises: 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 comprises: 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 LCCDR3 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 comprises: 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; LCCDR1 having the amino acid sequence of SEQ ID NO: 688; LCCDR2 having the amino acid sequence of AAS; and LCCDR3 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 comprises: 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; LCCDR1 having the amino acid sequence of SEQ ID NO: 694; LCCDR2 having the amino acid sequence of SEQ ID NO: 695; and LCCDR3 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 comprises: 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 site that specifically binds to IL-33 or IL-33R comprises: 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 site that specifically binds to IL-33 or IL-33R comprises: 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 site that specifically binds to IL-33 or IL-33R comprises: 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; LCCDR2 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 site that specifically binds to IL-33 or IL-33R comprises: HCCDR1 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 comprises: HCCDR1 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 comprises: 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 comprises: VH, which contains the amino acid sequence of SEQ ID NO: 799; and VL, which contains the amino acid sequence of SEQ ID NO: 800.

[0020] In some implementations, the antigen-specific binding site that specifically binds to Th2 cytokines or their receptors includes the VH and / or VL of any of the antibodies in Table 2.

[0021] In some embodiments, the bispecific antibody retains binding affinity for KLK5 and KLK7 that is no more than 20% different from that of anti-KLK5 / KLK7 antibodies containing the same CDR and / or VH / VL as the bispecific antibody. In some embodiments, the bispecific antibody retains binding affinity for Th2 targets that is no more than 20% different from that of Th2-targeting antibodies containing the same CDR and / or VH / VL as the bispecific antibody. In some embodiments, the bispecific antibody retains at least 80% inhibitory activity against KLK5 and KLK7 compared to anti-KLK5 / KLK7 antibodies containing the same CDR and / or VH / VL as the bispecific antibody. In some embodiments, the bispecific antibody retains at least 80% inhibitory activity against Th2 signaling compared to Th2-targeting antibodies containing the same CDR and / or VH / VL as the bispecific antibody.

[0022] This disclosure provides a composition comprising the bispecific antibody described herein and an acceptable vector.

[0023] In some aspects, this disclosure provides a method comprising administering to a subject a bispecific antibody or composition thereof, including the antibody described herein. In some embodiments, the subject has a skin barrier defect. In some aspects, this disclosure provides a method for treating a skin barrier defect, comprising administering to a subject an effective amount of the bispecific antibody or composition described herein. In some embodiments, the skin barrier defect is associated with Natherton's syndrome, atopic dermatitis, eosinophilic esophagitis, nodular prurigo, chronic pruritus of unknown cause (CPUO), dry skin, asthma (particularly KLK5), ichthyosis vulgaris, or itching or chronic pruritus. In some embodiments, the subject suffers from atopic dermatitis.

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

[0025] The foregoing and other aspects, embodiments, operations, functions, features, and implementations of the present invention can be more fully understood by taking into account the accompanying drawings in the following description. Attached Figure Description

[0026] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate certain embodiments and, together with the written description, serve to provide non-limiting examples of certain aspects of the compositions and methods disclosed herein.

[0027] Figure 1 This is a graph showing the activation of abnormal proteases (e.g., abnormal KLK5, KLK7, and KLK14) that lead to diseases related to skin barrier defects.

[0028] Figure 2This is a graph showing that in disorders associated with epidermal barrier dysfunction, elevated KLK5 / KLK7 activity leads to Th2 cell activation (which further increases KLK5 / KLK7 activity).

[0029] Figures 3A to 3B This figure shows that in the Nc / Nga model of atopic dermatitis, inhibiting KLK5 / KLK7 and Th2 signaling has beneficial effects beyond simply targeting either pathway. Figure 3A The results showed that mice treated with a combination of KLK5 / KLK7-Dual-Ab4 and anti-IL-4R antibody had a further reduction in ear thickness compared to mice treated with KLK5 / KLK7-Dual-Ab4 or anti-IL-4R antibody alone. Figure 3B The results showed that mice treated with a combination of KLK5 / KLK7-Dual-Ab4 and anti-IL-4R antibody had lower clinical skin scores compared to those treated with KLK5 / KLK7-Dual-Ab4 or anti-IL-4R antibody alone.

[0030] Figures 4A to 4I The binding affinity relates to an exemplary anti-KLK5 / KLK7 + IL-13 bispecific antibody (referred to as K13-0004). Figures 4A to 4C It shows the relationship with KLK5 ( Figure 4A ), KLK7 ( Figure 4B ) and IL-13 ( Figure 4C ) combined K D value. Figures 4D to 4H Showing KLK5 ( Figure 4D ;and Figure 4E Comparison of exemplary anti-KLK5 / KLK7 biantibodies), KLK7 ( Figure 4F ;and Figure 4G Comparison of exemplary anti-KLK5 / KLK7 biantibodies), IL-13 ( Figure 4H ) and extracellular matrix proteins (ECM) periosteal proteins ( Figure 4I The inhibition of ).

[0031] Figures 5A to 5D It involves eliminating KLK5 and KLK7-mediated primary human keratinocyte barrier disruption. Figure 5A The results showed the effects of different concentrations of the anti-KLK5 / KLK7 + IL-13 bispecific antibody K13-0004. Figure 5A ) or different concentrations of KLK5 / KLK7-dual-Ab4 ( Figure 5B Transepithelial resistance (TEER) after treatment. Figures 5C to 5D The results showed the effects of different concentrations of the anti-KLK5 / KLK7 + IL-13 bispecific antibody K13-0004. Figure 5C ) or different concentrations of KLK5 / KLK7-dual-Ab4 ( Figure 5D Migration of FITC-dextran dyes after treatment. Detailed Implementation

[0032] This disclosure is based, at least in part, on the development of dual inhibitor antibodies and variants thereof targeting KLK5 and KLK7. These dual inhibitor antibodies target KLK5 and KLK7 through a common, unique antigen-specific binding site. Such dual inhibitor antibodies exhibit high binding affinity and specificity for KLK5 and KLK7 (anti-KLK5 / KLK7 antibodies). In some embodiments, a bispecific antibody is provided, wherein one arm comprises an antigen-specific binding site of the dual inhibitor antibody targeting KLK5 and KLK7, and wherein 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, etc.) or their receptors. Methods for using anti-KLK5 / KLK7+Th2 bispecific antibodies and variants thereof in research, diagnostic / detection, and therapeutic applications are also provided, as well as anti-KLK5 / KLK7+Th2 bispecific antibodies for use in such methods.

[0033] The foregoing and other aspects, embodiments, operations, functions, features, and implementations of the present invention can be more fully understood by taking into account the accompanying drawings in the following description.

[0034] I. Definition Administration: As used herein, the term “administering / administration” means to provide an antibody or a combination thereof to a subject in a physiologically and / or pharmacologically useful manner (e.g., to treat a subject’s condition).

[0035] Affinity-maturating antibody: The term "affinity-maturating antibody" is used herein to refer to an antibody having one or more alterations in one or more CDRs, which, compared to a parent antibody without said alterations, result in an improvement in the antibody's affinity (e.g., KD, kd, or ka) for the target antigen. In some embodiments, exemplary affinity-maturating antibodies may have nanomolar or even picomolar affinity for the target antigen. Various procedures are available for generating affinity-maturating antibodies, including screening combinatorial antibody libraries already prepared using biodisplay. For example, Marks et al., BioTechnology, 10: 779-783 (1992) describe affinity maturation achieved through VH and VL domain shuffling. The following literature describes random mutagenesis of CDR and / or framework residues: 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). US Patent No. 6,914,128 B1 describes selective mutagenesis using amino acid residues that enhance activity at selective mutagenesis sites and at contact or hypermutation sites.

[0036] Antibody: As used herein, the term "antibody" refers to a polypeptide comprising at least one immunoglobulin variable domain containing at least one unique antigen-specific binding site; or a portion of an immunoglobulin variable domain (e.g., a complementary site or a portion thereof) containing at least one unique antigen-specific binding site. In some embodiments, the antibody comprises at least one unique antigen-specific binding site that specifically binds to the active site of an enzyme. In some embodiments, the antibody is a Th2-targeting 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 a 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 camel antibody or a shark antibody. In some embodiments, the antibody is a bifunctional antibody. 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 domain. An immunoglobulin constant domain refers to a heavy chain or light chain constant domain. The amino acid sequences of the human IgG heavy chain and light chain constant domains and their functional variations are known. In some embodiments, the immunoglobulin heavy chain constant domain comprises an Fc region. Regarding the heavy chain, in some embodiments, the heavy chain of the antibody described herein may be an α (alpha), Δ (delta), ε (epsilon), γ (gamma), or µ (mu) heavy chain. In some embodiments, the heavy chain of the antibody described herein may comprise a human α (alpha), Δ (delta), ε (epsilon), γ (gamma), or μ (mu) heavy chain. In some embodiments, the antibody described herein comprises human γ1 CH1, CH2, and / or CH3 domains. In some embodiments, the amino acid sequence of the antibody comprises the amino acid sequence of the human γ (gamma) heavy chain constant region, such as any sequence known in the art. Non-limiting examples of human constant region sequences have been described in the art, for example, see U.S. Patent No. 5,693,780 and Kabat EA et al., (1991), ibid.In some embodiments, the antibody comprises a heavy chain containing an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or at least 99% identity with any of the heavy chain constant regions provided herein. In some embodiments, the antibody comprises a light chain containing an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or at least 99% identity with any of the light chain constant regions provided herein. 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, the one or more sugar or carbohydrate molecules are conjugated to the antibody via N-glycosylation, O-glycosylation, C-glycosylation, glypiation (GPI anchoring), and / or phosphoglycosylation. In some embodiments, the one or more sugar or carbohydrate molecules are monosaccharides, disaccharides, oligosaccharides, or polysaccharides. In some embodiments, the one or more sugar or carbohydrate molecules are branched-chain oligosaccharides or branched-chain polysaccharides. In some embodiments, the 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 this disclosure linked to a linker polypeptide or an immunoglobulin constant domain. The linker polypeptide comprises two or more amino acid residues linked by peptide bonds and is 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, the antibody may be a portion of a larger immunoadhesion molecule formed by covalent or non-covalent association of the antibody or antibody moiety with one or more other proteins or peptides. Examples of such immunoadhesion molecules include the preparation of tetrameric scFv molecules using the streptavidin core region (Kipriyanov, SM et al. (1995) Human Antibodies and Hybridomas 6:93-101) and the preparation of divalent and biotinylated scFv molecules using cysteine ​​residues, biomarker peptides, and C-terminal multihistidine tags (Kipriyanov, SM et al. (1994) Mol. Immunol. 31:1047-1058).

[0037] Approximately: As used herein, the terms “approximately” or “about” when applied to one or more values ​​of interest refer to a value similar to a specified reference value. In some embodiments, unless otherwise stated or clearly apparent from the context (unless such a figure would exceed 100% of a possible value), the terms “approximately” or “about” refer to a range of values ​​within 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the stated reference value in either direction (greater or less).

[0038] Bispecific antibody: As used herein, the term "bispecific antibody" refers to an antibody containing two distinct antigen-specific binding sites or two linked (covalent or non-covalent) antibodies that together contain two distinct antigen-specific binding sites. Non-limiting examples of bispecific antibody forms or structures are provided by Labrijn, AF, et al. Bispecific antibodies: a mechanistic review of the pipeline Nature Reviews Drug Discovery, Vol. 18, pp. 585-608 (2019) and Brinkmann U and Kontermann EE, The making of bispecific antibodies In MAbs. Feb / Mar 2017;9(2):182-212, the entire contents of each of them are incorporated herein by reference.

[0039] CDR: As used herein, the term "CDR" refers to the complementarity-determining region within the variable sequence of an antibody. A typical antibody molecule contains a heavy chain variable region or heavy chain variable domain (VH) and a light chain variable region or light chain variable domain (VL), which are typically involved in antigen binding. The VH and VL regions can be further subdivided into hypervariable regions (also known as "complementarity-determining regions" ("CDRs")) interspersed with more conserved regions (called "frame regions" ("FRs")). Each VH and VL typically consists of three CDRs and four FRs, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The extent of the frame regions and CDRs can be precisely identified using methods 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.See, for example, Kabat, E.A. et al. (1991), Sequences of Proteins of Immunological Interest, 5th Edition, Department of Health and Human Services, NIH Publication No. 91-3242; IMGT®, the international ImMunoGeneTics information system® 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. (1997) J. Molec. Biol. 273:927-948; and Almagro, J. Mol. Recognit. 17:132-143 (2004). See also hgmp.mrc.ac.uk and bioinf.org.uk / abs. As used herein, CDR can refer to a CDR defined by any method known in the art. Two antibodies having the same CDR means that the two antibodies have the same amino acid sequence of the CDR, as determined by the same method (e.g., IMGT definition).

[0040] In some implementations, each variable region of the heavy and light chains contains three CDRs, designated CDR1, CDR2, and CDR3 for each variable region. As used herein, the term "CDR set" refers to a group of three CDRs present in a single variable region capable of binding the 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 definitive residue numbering system applicable to any variable region of an antibody, but also provides precise residue boundaries defining three CDRs. These CDRs can be referred to as Kabat CDRs. Sub-regions of a CDR can be designated as L1, L2, and L3 or H1, H2, and H3, where “L” and “H” designate the light chain region and the heavy chain region, respectively. These regions can be referred to as Chothia CDRs, whose boundaries overlap with Kabat CDRs. Padlan (FASEB J.9:133-139 (1995)) and MacCallum (J Mol Biol 262(5):732-45 (1996)) describe other boundaries defining CDRs that overlap with Kabat CDRs. Other CDR boundary definitions may not strictly follow one of the systems described above, but will still overlap with Kabat CDRs. CDRs overlap, however, they may shorten or lengthen based on predictions or experimental findings that specific residues or groups of residues, or even the entire CDR, do not significantly affect antigen binding. The methods used herein can utilize CDRs defined according to any of these systems, although preferred embodiments use CDRs defined by Kabat or Chothia.

[0041] CDR transplantation antibody: As used herein, the term “CDR transplantation antibody” refers to an antibody that contains heavy and light chain variable region sequences from one species, but in which one or more of the CDR regions of VH and / or VL are replaced by a CDR sequence from another species, such as an antibody having murine heavy and light chain variable regions in which one or more of the murine CDRs (e.g., CDR3) have been replaced by a human CDR sequence.

[0042] Chimeric antibody: As used herein, the term “chimeric antibody” refers to an antibody that comprises heavy and light chain variable region sequences from one species and constant region sequences from another species, such as antibodies with murine heavy and light chain variable regions linked to human constant regions.

[0043] Complementarity: As used herein, the term “complementarity” refers to the ability of two nucleotides or groups of nucleotides to pair precisely. In particular, complementarity is a term characterizing the degree of hydrogen bond pairing that binds two nucleotides or groups of nucleotides together. For example, if a base at a position of an oligonucleotide is able to hydrogen bond with a base at a corresponding position of a target nucleic acid (e.g., mRNA), the bases are considered complementary to each other at that position. Base pairing can include canonical Watson-Crick base pairing and non-Watson-Crick base pairing (e.g., wobble base pairing and Hoogsteen base pairing). For example, in some embodiments, for complementary base pairing, an adenosine base (A) is complementary to a thymidine base (T) or a uracil base (U), a cytosine base (C) is complementary to a guanosine base (G), and universal bases such as 3-nitropyrrole or 5-nitroindole can hybridize with 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 believed to be complementary to any A, C, U or T.

[0044] Amino acid substitution: As used herein, “conservative amino acid substitution” refers to an amino acid substitution that does not alter the relative charge or size characteristics of the protein to which the substitution is made. Variants can be prepared according to methods known to those skilled in the art for altering polypeptide sequences, as seen in references compiling such methods: e.g., *Molecular Cloning: A Laboratory Manual*, J. Sambrook et al., 4th ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2012; or *Current Protocols in Molecular Biology*, FM Ausubel et al., John Wiley & Sons, Inc., New York. Conservative substitution of amino acids includes substitutions between amino acids within 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.

[0045] Cross-reactivity: As used herein, the term "cross-reactivity" refers to the ability of an agent to specifically bind with similar affinity or co-affinity to up to one similar type or class of antigens (e.g., antigens of multiple homologs, paralogs, or orthologs). For example, in some embodiments, antibodies that are cross-reactive with similar types or classes of human and non-human primate antigens (e.g., human KLK5 and non-human primate KLK5, human KLK7 and non-human primate KLK7) are able to bind to human and non-human primate antigens with similar affinity or co-affinity. In some embodiments, antibodies are cross-reactive with similar types or classes of human and rodent antigens. In some embodiments, antibodies are cross-reactive with similar types or classes of rodent and non-human primate antigens. In some embodiments, antibodies are cross-reactive with similar types or classes of human, non-human primate, and rodent antigens.

[0046] Dual-inhibitor antibody: As used herein, the term "dual-inhibitor antibody" refers to an antibody that targets at least two (e.g., two, three) different antigens through a common, unique antigen-specific binding site and inhibits the activity of those antigens. In some embodiments, a dual-inhibitor antibody targets at least two different proteins (e.g., expressed by two different genes (e.g., endogenous genes, such as homologs, parahomologs)) through a common, unique 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-inhibitor antibody targets at least two different proteases (e.g., expressed by two different endogenous genes (e.g., KLK5 and KLK7)) through a common, unique antigen-specific binding site and inhibits the activity of at least two different proteases. In some embodiments, the common, unique antigen-specific binding site binds to a similar (e.g., homologous) domain shared between or therein of at least two different antigens. For example, in some embodiments, the common, unique antigen-specific binding site binds to a similar (e.g., homologous) catalytic domain or substrate binding site shared between or therein of at least two different enzymes (e.g., proteases). In some embodiments, the common unique antigen-specific binding site of the dual inhibitor antibody comprises amino acids from one or more complementarity-determining regions of the antibody. In some embodiments, the common unique antigen-specific binding site of the dual inhibitor antibody is located within the heavy chain variable region and / or light chain variable region of the antibody. In some embodiments, the common unique antigen-specific binding site of the dual inhibitor antibody comprises one or more complementarity-determining regions from the heavy chain variable region and / or light chain variable region of the antibody. In some embodiments, the common unique antigen-specific binding site of the dual inhibitor antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LCCDR2, and LC CDR3 from the heavy chain variable region and light chain variable region of the antibody. In some embodiments, the dual inhibitor antibody specifically binds to two different proteins expressed by two different genes (e.g., KLK5 and KLK7).

[0047] Effective amount: As used herein, "effective amount" refers to the amount of each active agent (e.g., anti-KLK5 / KLK7+ Th2 cytokine targeting a bispecific antibody) required, alone or in combination with one or more other active agents, to impart the desired effect (e.g., a therapeutic effect on a subject). In some embodiments, the therapeutic "effect" is a reduction in KLK5 and / or KLK7 activity and / or a reduction in Th2 cytokine activity and / or an alleviation of disease (e.g., Natherton's syndrome, eosinophilic esophagitis, and atopic dermatitis) or related symptoms, such as improved barrier function.

[0048] Frame: As used herein, the term “frame” or “frame sequence” refers to the remaining sequence in the variable region after subtracting the CDR. Because the exact definition of a CDR sequence can be determined by different systems, the meaning of a frame sequence may be interpreted differently. The six CDRs (CDR-L1, CDR-L2, and CDR-L3 for the light chain, and CDR-H1, CDR-H2, and CDR-H3 for the heavy chain) further divide the frame region on both the light and heavy chains into four subregions (FR1, FR2, FR3, and FR4) on each chain, where CDR1 is located between FR1 and FR2, CDR2 between FR2 and FR3, and CDR3 between FR3 and FR4. Without specifying a particular subregion as FR1, FR2, FR3, or FR4, the frame region, as used by others, represents a combination of FRs within the variable region of a single naturally occurring immunoglobulin chain. As used herein, FR represents one of the four subregions, and FRs represent two or more of the four subregions that constitute the frame region. Human heavy chain and light chain receptor sequences are known in the art. In one embodiment, receptor sequences known in the art can be used in the antibodies disclosed herein.

[0049] Human Antibody: As used herein, the term "human antibody" is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. 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-specific mutagenesis in vitro or by somatic mutations in vivo), such as in CDRs, and particularly 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 (e.g., mouse) has been grafted onto a human frame sequence.

[0050] Humanized Antibodies: As used herein, the term "humanized antibody" refers to an antibody containing 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 altered to be more "human-like," i.e., more similar to human germline variable sequences. One type of humanized antibody is a CDR transplantation antibody, in which a human CDR sequence is introduced into non-human VH and VL sequences to replace the corresponding non-human CDR sequences. In one embodiment, a humanized antibody is provided. Such antibodies can be produced by obtaining murine monoclonal antibodies using conventional hybridoma techniques, followed by humanization using in vitro genetic engineering, such as those disclosed in PCT Publication No. WO 2005 / 123126 A2 by Kasaian et al.

[0051] Humanized antibodies are human immunoglobulins (recipient antibodies) in which residues of the complementarity-determining region (CDR) from the recipient are replaced by residues of the CDR from a non-human species (donor antibody) (such as mouse, rat, or rabbit) having the desired specificity, affinity, and capability. In some embodiments, Fv frame region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may include residues not found in either the recipient antibody or the input CDR or frame sequence, but such residues are included for further refinement and optimization of antibody performance. Generally, humanized antibodies will contain at least one and typically substantially all of two variable domains, wherein all or substantially all of the CDR regions correspond to those of non-human immunoglobulins, and all or substantially all of the FR regions are those of the human immunoglobulin common sequence. Optionally, humanized antibodies will also contain 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 an Fc region modified as described in WO 99 / 58572. Other forms of humanized antibodies have one or more CDRs (one, two, three, four, five, or six) that are altered relative to the original antibody, referred to as one or more CDRs derived from one or more CDRs of the original antibody. Humanized antibodies may also involve affinity maturation.

[0052] In some implementations, CDRs (e.g., as shown in Table 1a or Table 1b) are transplanted into human variable structural domains (e.g., IGKV1-NL1). 01 and IGHV1-3 Humanization is achieved in the variable domain (01). In some embodiments, the antibody of this disclosure is a humanized variant containing one or more amino acid substitutions (e.g., in the VH frame region) compared to any of the VH listed in Table 1a or Table 1b, and / or containing one or more amino acid substitutions (e.g., in the VL frame region) compared to any of the VL listed in Table 1a or Table 1b.

[0053] Isolated antibody: As used herein, "isolated antibody" refers to an antibody that is substantially free of other antibodies with different antigen specificities. However, in some embodiments, isolated antibodies may be cross-reactive to other antigens. Furthermore, isolated antibodies may be substantially free of other cellular material and / or chemicals.

[0054] Kabat Numbering: As used herein, the terms “Kabat numbering,” “Kabat definition,” and “Kabat labeling” are used interchangeably. These terms, as recognized in the art, refer to a system for numbering amino acid residues that are more variable (i.e., hypervariable) than other amino acid residues in the heavy and light chain variable regions of an antibody or its antigen-binding moiety (Kabat et al. (1971) Ann. NY Acad, Sci. 190:382-391 and Kabat, EA et al. (1991) Sequences of Proteins of Immunological Interest, 5th ed., US Department of Health and Human Services, NIH Publication No. 91-3242). For the heavy chain variable region, the hypervariable region ranges from amino acid positions 31 to 35 of CDR1, amino acid positions 50 to 65 of CDR2, and amino acid positions 95 to 102 of CDR3. For the light chain variable regions, the range of the hypervariable regions is between amino acid positions 24 to 34 of CDR1, amino acid positions 50 to 56 of CDR2, and amino acid positions 89 to 97 of CDR3.

[0055] 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).

[0056] Multispecific antibody: As used herein, the term "multispecific antibody" refers to an antibody containing at least two unique antigen-specific binding sites or at least two linked (covalent or non-covalent) antibodies that together contain at least two unique antigen-specific binding sites. In some embodiments, a multispecific antibody is a bispecific antibody. Non-limiting examples of the form or structure of multispecific antibodies are provided by 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 August to September 2016;8(6):1010-20; and Brinkmann U and Kontermann EE, The making of bispecific antibodies In MAbs. Feb / Mar 2017;9(2):182-212, the entire contents of each of them are incorporated herein by reference.

[0057] Recombinant Antibody: As used herein, the term “recombinant antibody” is intended to include all antibodies prepared, expressed, generated, or isolated by recombinant means, such as antibodies expressed using recombinant expression vectors transfected into host cells (described in more detail in this disclosure), including, for example, antibodies isolated from recombinant 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), and antibodies isolated from animals (e.g., mice) transgenic to target human immunoglobulin genes (see, for example, Taylor, LD et al. (1992) Nucl. Acids Res.). 20:6287-6295; Kellermann SA. and Green LL (2002) Current Opinion in Biotechnology 13:593-597; Little M. et al. (2000) Immunology Today 21:364-370) or antibodies prepared, expressed, produced, or isolated by any other means involving splicing human immunoglobulin gene sequences into other DNA sequences. In some embodiments, recombinant human antibodies are provided herein. In some embodiments, such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in some embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when using animals transgenic to target human Ig sequences, in vivo somatic cell mutagenesis), and thus the amino acid sequences of the VH and VL regions of the recombinant antibody are sequences that, although derived from and associated with human germline VH and VL sequences, may not be naturally present in the in vivo human antibody germline library. One embodiment of this disclosure provides a fully human antibody (e.g., a fully human antibody capable of binding to human KLK5 or KLK7) which can be generated using appropriate techniques, such as, but not limited to, using human Ig phage libraries, such as those disclosed in Jermutus et al., PCT Publication No. WO2005 / 007699 A2.

[0058] Selectivity: As used herein, the term "selective" or "selectively" refers to the ability of a molecule to influence its target molecule (e.g., inhibit, antagonize, agonize, etc.) compared to a reference molecule. For example, a molecule that selectively inhibits its target molecule means that the molecule is able to inhibit its target molecule to a degree different from that of a reference molecule in an inhibition assay or other inhibitory setting. For example, with respect to inhibitors, the term "selectively inhibiting" refers to the ability of an inhibitor to inhibit its target molecule to a degree different from that of a reference molecule that is substantially uninhibited in an inhibition assay, for example, to the extent that selective inhibition of the target molecule is permitted, as described herein. Once the reaction is terminated, the signal generated by inhibiting the target molecule can be measured. The half-maximum inhibitor concentrations of the target molecule and the reference molecule can be calculated.

[0059] Specific binding: As used herein, the term "specific binding" refers to the ability of a molecule to bind to a conjugate with a degree of affinity or cohesion such that the molecule can be used in a binding assay or other binding context to distinguish the conjugate from an appropriate control. With respect to antibodies, the term "specific binding" refers to the ability of an antibody to bind to a specific antigen with a degree of affinity or cohesion relative to the binding of an antibody to one or more appropriate reference antigens, such that the antibody can be used to distinguish the specific antigen from other antigens, as described herein. In some embodiments, if the antibody binds to the K of the target... D It is at least about 10 -4 M, 10 -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12 M, 10 -13 If M is lower than 0, the antibody specifically binds to the target. In some embodiments, the antibody specifically binds to KLK5 or KLK7. In some embodiments, the antibody specifically binds to Th2 cytokines (e.g., IL-13, IL-4, IL-5, IL-6, IL-9, IL-31, IL-17E (IL-25), OX40L, TSLP, etc.) or their receptors. In some embodiments, the bispecific antibody comprises antigen-binding sites that specifically bind to KLK5 and KLK7 and antigen-binding sites that specifically bind to Th2 cytokines (e.g., IL-13, IL-4, IL-5, IL-6, IL-9, IL-31, IL-17E (IL-25), OX40L, TSLP, etc.) or their receptors.

[0060] Subject: As used herein, the term "subject" refers to a mammal. In some embodiments, the subject is a non-human primate or rodent. In some embodiments, the subject is a human. In some embodiments, the subject is a patient, such as a person who has or is suspected of having a disease.

[0061] Th2-targeting antibody: As used herein, the term "Th2-targeting antibody" refers to an antibody that binds to Th2 cytokines or their receptors. In some embodiments, Th2-targeting antibodies inhibit Th2 cytokine-mediated signaling. In some embodiments, Th2-targeting antibodies inhibit Th2 cytokine-mediated inflammation.

[0062] Treatment: As used herein, the term "treatment" refers to the application or administration of a composition comprising one or more active agents (e.g., an anti-KLK5 / KLK7+Th2 bispecific antibody) to a subject suffering from a target disease or condition, symptoms of the disease / condition, or susceptibility to the disease / condition, with the aim of curing, healing, alleviating, mitigating, altering, remedying, reducing, improving, or influencing the disease, its symptoms, or susceptibility. Alleviating a target disease / condition includes delaying or preventing the development or progression of the disease, or reducing its severity. It should be understood that references to treatment may also refer to antibodies, including KLK5 / KLK7+Th2 bispecific antibodies used in such methods.

[0063] II. Antibodies (a) KLK5 and KLK7 targeting In some embodiments, dual inhibitor antibodies targeting KLK5 and KLK7 (referred to as anti-KLK5 / KLK7 antibodies) are antibodies that are specific to both kallikrein-5 (KLK5) and KLK7 through a common specific antigen-binding site. Dual inhibitor KLK5 / KLK7 antibodies are described in PCT / US2024 / 019231, the entire contents of which are incorporated herein by reference. In some aspects, this document provides antibodies that bind to KLK5 (e.g., human KLK5 or mouse KLK5) and KLK7 (e.g., human KLK7 or mouse KLK7) with high specificity and affinity through a common antigen-binding site. In some embodiments, the anti-KLK5 / KLK7 antibodies described herein specifically bind to both a KLK5 epitope exposed to or becoming exposed to the antibody and a KLK7 epitope exposed to or becoming exposed to the antibody. In some embodiments, the anti-KLK5 / KLK7 antibody described herein binds to the active sites of KLK5 and KLK7. In some embodiments, the anti-KLK5 / KLK7 antibody provided herein specifically binds to KLK5 and KLK7 derived from humans, non-human primates, mice, rats, etc. In some embodiments, the anti-KLK5 / KLK7 antibody provided herein specifically binds to human KLK5. In some embodiments, the anti-KLK5 / KLK7 antibody provided herein specifically binds to mouse KLK5. In some embodiments, the anti-KLK5 / KLK7 antibody provided herein specifically binds to human KLK7. In some embodiments, the anti-KLK5 / KLK7 antibody provided herein specifically binds to mouse KLK7. In some embodiments, this document provides a multispecific antibody comprising an arm having an antigen-specific binding site for a dual inhibitor antibody targeting KLK5 and KLK7, and an arm having an antigen-specific binding site specifically binding to Th2 cytokines (e.g., IL-13, IL-4, IL-5, IL-6, IL-9, IL-31, IL-17E (IL-25), OX40L, TSLP, etc.) or their receptors. For example, in some embodiments, this document provides a bispecific antibody comprising an arm having an antigen-specific binding site for a dual inhibitor antibody targeting KLK5 and KLK, and an arm having an antigen-specific binding site specifically binding to Th2 cytokines (e.g., IL-13, IL-4, IL-5, IL-6, IL-9, IL-31, IL-17E (IL-25), OX40L, TSLP, etc.).

[0064] In some implementations, the anti-KLK5 / KLK7 antibody is not a bispecific antibody or a bispecific antigen-binding molecule, wherein KLK5 binding is conferred by one binding site within the antibody and KLK7 binding is conferred by another binding site within the antibody.

[0065] In some embodiments, the anti-KLK5 / KLK7 antibodies described herein can 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 (precursor) forms 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 undetectably binds to the inactive forms of KLK5 or KLK7 under the same or equivalent conditions. In some embodiments, the anti-KLK5 / KLK7 antibodies inhibit the activity of KLK5 and KLK7 proteases. In some embodiments, when an anti-KLK5 / KLK7 antibody binds to KLK5 or KLK7, it is not cleaved by KLK5 or KLK7. In some embodiments, the anti-KLK5 / KLK7 antibody competes with SPINK5 and / or leucine for binding to the active sites of KLK5 and KLK7. In some embodiments, the anti-KLK5 / KLK7 antibody reduces hyperkeratosis and desquamation. In some embodiments, the anti-KLK5 / KLK7 antibody reduces stratum corneum thickness. In some embodiments, the anti-KLK5 / KLK7 antibody reduces inflammation and epidermal effects.

[0066] Kallikrein-5 (also known as stratum corneum trypsin (SCTE)) is a serine protease expressed in the epidermis, encoded by the KLK5 gene. The KLK5 gene is one of fifteen members of the kallikrein subfamily located on a chromosome cluster. Its expression is upregulated by estrogen and progesterone. KLK5 is expressed in the granular layer and stratum corneum. In some embodiments, KLK5 regulates epidermal desquamation. In some embodiments, KLK5 regulates epidermal desquamation in conjunction with another member of the kallikrein family of proteases (e.g., KLK7 and / or KLK14). In some embodiments, KLK5 degrades proteins that form the epidermis (e.g., stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, or stratum basale). In some embodiments, KLK5 degrades proteins that form the stratum corneum and / or stratum granulosum (e.g., corneal lockstrand protein (CDSN), desmosome core glycoprotein 1 (DSG1), and desmosome glialin 1 (DSC1), etc.). In the epidermis (e.g., the granular layer and stratum corneum), KLK5 is expressed in an inactive form (sometimes referred to as the proform / pro-form) proKLK5 and is self-activated. When activated, KLK5 can be proteolytically cleaved, converting both proKLK7 and proKLK14 into their active forms. The active KLK14 can then activate the newly generated proKLK5, creating a positive feedback loop (see, for example, Nauroy et al., Kallikreins: Essentialepidermal 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., corneal chain-locked protein (CDSN), desmosome core glycoprotein 1 (DSG1), and desmosome glialin 1 (DSC1), etc.). Structural proteins (such as CDSN, DSG1, and DSC1) are adhesion proteins of the extracellular portion of keratinocytes, which are connective structures that mediate keratinocyte adhesion. Degradation of these proteins at the epidermal surface leads to desquamation, which can result in skin barrier defects (e.g., stratum corneum shedding, decreased barrier permeability, 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, Vol. 122, No. 5, May 2004, pp. 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 (December 14, 2022, Volume 14, Issue 675).

[0067] Kallikrein-7 is a serine protease encoded by the KLK7 gene in humans. KLK7 is characterized as stratum corneum chymotrypsin (SCCE). [It is the seventh member of the human kallikrein family, which includes fifteen homologous serine proteases located on chromosome 19. KLK7 is secreted as an inactive zymogen (e.g., in the granular layer of the epidermis), thus requiring activation for proteolytic cleavage. In some embodiments, KLK7 is activated by KLK5 or a matrix enzyme. Once active, KLK7 is able to cleave proteins that form the stratum corneum and / or granular layer (e.g., corneal chain-locked protein (CDSN), desmosome core glycoprotein 1 (DSG1), and desmosome glialin 1 (DSC1), etc.) (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 keratinocytes, which are intercellular adhesion structures consisting of intermediate filaments connecting adjacent cells in the stratum corneum. In some embodiments, proteolysis of keratinocytes leads to epidermal desquamation (i.e., the shedding of keratinocytes from the outer layer of the epidermis). In some embodiments, the combined action of KLK5 and KLK7 suggests that the KLK skin cascade is responsible for coordinating desquamation. KLK7 is a chymotrypsin-like serine protease that cleaves proteins at tyrosine, phenylalanine, or leucine residues. In some embodiments, dysregulation of KLK7 is associated with several skin conditions, including atopic dermatitis, psoriasis, and Natherton's syndrome. These conditions are characterized by excessive dryness, scaling, and inflammation of the skin due to disruption of skin homeostasis and proper barrier function.

[0068] 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 shown in the following: NCBI accession numbers NP_001070959.1, NP_001070960.1, or NP_036559.1, and UniProt accession numbers Q8IU55, Q6S9W8, M0QXX2, Q9P0G3, A0A2I2MP48, or A0A2I2MP49, the entire sequences of which are incorporated herein by reference.

[0069] In some embodiments, the anti-KLK5 / KLK7 antibody described herein specifically binds to an epitope on mouse KLK5. Exemplary amino acid sequences of mouse KLK5 are shown in the following: 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, the entire sequences of which are incorporated herein by reference.

[0070] In some embodiments, the anti-KLK5 / KLK7 antibodies described herein specifically bind to epitopes 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 shown in the following: 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 entire sequences of which are incorporated herein by reference.

[0071] In some embodiments, the anti-KLK5 / KLK7 antibodies described herein specifically bind to epitopes 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 shown in the following: NCBI Registry No. NP_036002.1 and UniProt Registry No. Q91VE3, the entire sequences of which are incorporated herein by reference.

[0072] In some embodiments, the anti-KLK5 / KLK7 antibody described herein specifically binds to epitopes on KLK5 (e.g., the active site of an enzyme, also referred to as the catalytic domain / pocket of human KLK5 or mouse KLK5) and epitopes 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 KLK7 (e.g., human or mouse KLK7). The length of the KLK5 and / or KLK7 (e.g., human or mouse) fragments can be between about 5 and about 425 amino acids, about 10 and about 400 amino acids, about 50 and about 350 amino acids, about 100 and about 300 amino acids, about 150 and about 250 amino acids, about 200 and about 300 amino acids, about 75 and about 150 amino acids, about 25 and about 100 amino acids, or about 10 and about 30 amino acids. Without wishing to be bound by any particular theory, in some embodiments, the heavy chain (HC) complementarity-determining region 3 (CDR3) of either 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.

[0073] In some embodiments, the anti-KLK5 / KLK7 antibody described herein inhibits KLK5 protease activity, KLK7 protease activity, or both KLK5 and KLK7 protease activities. In some embodiments, the anti-KLK5 / KLK7 antibody inhibits 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 implementations, the anti-KLK5 / KLK7 antibody is present in concentrations of 0.1 nM to 30 nM, 0.1 nM to 20 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 2.5 nM, 0.1 nM to 2 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.1 nM to 0.25 nM, 0.1 nM to 50 nM, 0.1 nM to 40 nM, 0.1 nM to 30 nM, 0.1 nM to 20 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 2.5 nM, 0.1 nM to 2 nM, 0.1 nM to 1 nM, 0.1 nM to 0.9 nM, 0.1 nM to 0.8 nM, and 0.1 nM to 0.7 nM. nM, 0.1 nM to 0.6 nM, 0.1 nM to 0.5 nM, 0.1 nM to 0.4 nM, 0.1 nM to 0.3 nM, 0.1 nM to 0.25 nM, 0.1 nM to 0.2 nM, 0.1 nM to 0.15 nM, 0.15 nM to 0.2 nM, 0.15 nM to 0.25 nM, 0.15 nM to 0.3 nM, 0.15 nM to 0.4 nM, 0.15 nM to 0.5 nM, 0.15 nM to 1 nM, 0.2 nM to 30 nM, 0.2 nM to 20 nM, 0.2 nM to 10 nM, 0.2 nM to 5 nM, 0.2 nM to 2.5 nM, 0.2 nM to 2 nM, 0.2 nM to 1 nM, 0.2 nM to 0.5 nM, 0.2 nM to 0.2 nM, 0.2 nM to 50 nM, 0.2 nM to 40 nM, 0.2 nM to 30 nM, 0.2 nM to 20 nM, 0.2 nM to 10 nM, 0.2 nM to 5 nM, 0.2 nM to 2.5 nM, 0.2 nM to 2 nM, 0.2 nM to 1 nM, 0.2 nM to 0.9 nM, 0.2 nM to 0.8 nM, 0.2 nM to 0.7 nM, 0.2 nM to 0.6 nM, 0.2 nM to 0.5 nM, 0.2 nM to 0.4 nM, 0.2 nM to 0.3 nM, 0.2 nM to 0.25 nM, 1 nM to 30 nM, 1 nM to 20 nM, 1 nM to 10 nM, 1 nM to 5 nM, 1 nM to 2.5 nM, 1 nM to 2 nM, 1 nM to 3 nM, 1 nM to 5.5 nM, 1.5 nM to 2 nM, 1.5 nM to 3 nM, 1.5 nM to 5.5 nM, 2 nM to 5 nM, 2 nM to 4 nM, 2 nM to 5.5 nM, 3 nM to 5.5 nM, 4 nM to 5.5 nM, 3 nM to 30 nM, 3 nM to 20 nM, 3 nM to 10 nM, 3 nM to 5 nM, 3 nM to 2.5 nM, 3 nM to 4 nM, 3 nM to 5.5 nM, 5 nM to 30 nM, 5 nM to 20 nM, 5 nM to 10 nM, 5 nM to 9 nM, 5 nM to 8 nM, 5 nM to 7 nM, 5 nM to 6 nM, 5 nM to 5.5 nM, 10 nM to 30 nM, 10 nM to 25 nM, 10 nM to 20 nM, 10 nM to 18 nM, 10 nM to 15 nM, 10 nM to 12 nM, 12 nM to 20 nM, 12 nM to 25 nM, 12 nM to 16 nM, 12 nM to 18 nM, 12 nM to 20 nM, 12 nM to 24 nM, 12 nM to 28 nM, 12 nM to 30 IC50 values ​​in the ranges of nM, 15 nM to 30 nM, 15 nM to 25 nM, 15 nM to 20 nM, 15 nM to 18 nM, 18 nM to 30 nM, 18 nM to 25 nM, 18 nM to 20 nM, 20 nM to 30 nM, 20 nM to 25 nM, 20 nM to 22 nM, 20 nM to 24 nM, 20 nM to 26 nM, 20 nM to 28 nM, 22 nM to 30 nM, 22 nM to 25 nM, 22 nM to 28 nM, 24 nM to 30 nM, 24 nM to 25 nM, 24 nM to 26 nM, or 24 nM to 28 nM inhibit the cleavage of KLK5 (e.g., human KLK5 or mouse KLK5) by BOC-Val-Pro-Arg-AMC. In some implementations, the anti-KLK5 / KLK7 antibody is present in amounts 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, or less than 0.IC50 at 16 nM, less than 0.1 nM, or less than 0.05 nM inhibits KLK7 cutting of KHLF-AMC. In some implementations, the anti-KLK5 / KLK7 antibody is present in concentrations of 0.1 nM to 30 nM, 0.1 nM to 20 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 2.5 nM, 0.1 nM to 2 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.1 nM to 0.25 nM, 0.1 nM to 50 nM, 0.1 nM to 40 nM, 0.1 nM to 30 nM, 0.1 nM to 20 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 2.5 nM, 0.1 nM to 2 nM, 0.1 nM to 1 nM, 0.1 nM to 0.9 nM, 0.1 nM to 0.8 nM, and 0.1 nM to 0.7 nM. nM, 0.1 nM to 0.6 nM, 0.1 nM to 0.5 nM, 0.1 nM to 0.4 nM, 0.1 nM to 0.3 nM, 0.1 nM to 0.25 nM, 0.1 nM to 0.2 nM, 0.1 nM to 0.15 nM, 0.15 nM to 0.2 nM, 0.15 nM to 0.25 nM, 0.15 nM to 0.3 nM, 0.15 nM to 0.4 nM, 0.15 nM to 0.5 nM, 0.15 nM to 1 nM, 0.2 nM to 30 nM, 0.2 nM to 20 nM, 0.2 nM to 10 nM, 0.2 nM to 5 nM, 0.2 nM to 2.5 nM, 0.2 nM to 2 nM, 0.2 nM to 1 nM, 0.2 nM to 0.5 nM, 0.2 nM to 0.2 nM, 0.2 nM to 50 nM, 0.2 nM to 40 nM, 0.2 nM to 30 nM, 0.2 nM to 20 nM, 0.2 nM to 10 nM, 0.2 nM to 5 nM, 0.2 nM to 2.5 nM, 0.2 nM to 2 nM, 0.2 nM to 1 nM, 0.2 nM to 0.9 nM, 0.2 nM to 0.8 nM, 0.2 nM to 0.7 nM, 0.2 nM to 0.6 nM, 0.2 nM to 0.5 nM, 0.2 nM to 0.4 nM, 0.2 nM to 0.3 nM, 0.2 nM to 0.25 nM, 1 nM to 30 nM, 1 nM to 20 nM, 1 nM to 10 nM, 1 nM to 5 nM, 1 nM to 2.5 nM, 1 nM to 2 nM, 1 nM to 3 nM, 1 nM to 5.5 nM, 1.5 nM to 2 nM, 1.5 nM to 3 nM, 1.5 nM to 5.5 nM, 2 nM to 5 nM, 2 nM to 4 nM, 2 nM to 5.5 nM, 3 nM to 5.5 nM, 4 nM to 5.5 nM, 3 nM to 30 nM, 3 nM to 20 nM, 3 nM to 10 nM, 3 nM to 5 nM, 3 nM to 2.5 nM, 3 nM to 4 nM, 3 nM to 5.5 nM, 5 nM to 30 nM, 5 nM to 20 nM, 5 nM to 10 nM, 5 nM to 9 nM, 5 nM to 8 nM, 5 nM to 7 nM, 5 nM to 6 nM, 5 nM to 5.5 nM, 10 nM to 30 nM, 10 nM to 25 nM, 10 nM to 20 nM, 10 nM to 18 nM, 10 nM to 15 nM, 10 nM to 12 nM, 12 nM to 20 nM, 12 nM to 25 nM, 12 nM to 16 nM, 12 nM to 18 nM, 12 nM to 20 nM, 12 nM to 24 nM, 12 nM to 28 nM, 12 nM to 30 nM, 15 nM to 30 nM, 15 nM to 25 nM, 15 nM to 20 nM, 15 nM to 18 nM, 18 nM to 30 nM, 18 nM to 25 nM, 18 nM to 20 nM, 20 nM to 30 nM, 20 nM to 25 nM, 20 nM to 22 nM, 20 nM to 24 nM, 20 nM to 26 nM, 20 nM to 28 nM, 22 nM to 30 nM, 22 nM to 25 nM, 22 nM to 28 nM, 24 nM to 30 nM IC50 suppresses KLK7 cleavage of KHLF-AMC in the ranges of nM, 24 nM to 25 nM, 24 nM to 26 nM, or 24 nM to 28 nM.

[0074] 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 forms of KLK5, KLK7, or KLK5 and KLK7, but does not specifically bind to the inactive forms of KLK5, KLK7, or KLK5 and KLK7. In some embodiments, the anti-KLK5 / KLK7 antibody described herein detectably binds to the active form of KLK5, the active form of KLK7, or both active forms of KLK5 and active forms of KLK7, but undetectably binds to the inactive form of KLK5, the inactive form of KLK7, or both active forms of KLK5 and inactive forms of KLK7 under the same or equivalent conditions. The active site of KLK5 and / or KLK7 is the site at which the KLK5 and / or KLK7 substrate molecule binds for cleavage. The active site may also be referred to as a catalytic domain or catalytic triad. In some embodiments, the active site of KLK5 or KLK7 (i.e., the catalytic domain or catalytic triad) 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 . November 2010; 92(11): 1546-1567).

[0075] In some embodiments, the antibodies described herein are optimized forms of parental antibodies (e.g., affinity-matured). In some embodiments, the antibodies described herein have a concentration of at least about 10... -4 M, at least about 10 -5 M, at least about 10 -6 M, at least about 10 -7 M, 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 smaller binding affinity (e.g., as by K)D The antibody (as indicated) specifically binds to KLK5 (e.g., human or mouse KLK5) and KLK7 (e.g., human or mouse KLK7). In some embodiments, the antibody described herein is in 1×10 -10 M and 5×10 -9 Between M, 1×10 -10 M and 1×10 -9 Between M, 5×10 -10 With 1×10 -9 Between M, 5×10 -11 With 1×10 -10 M, 1×10 -11 With 5×10 - 10 Between M or 5×10 -13 With 1×10 -12 The binding affinity between M (e.g., as by K) D The antibodies of this disclosure can specifically bind to KLK5 (e.g., human or mouse KLK5) and KLK7 (e.g., human or mouse KLK7), as indicated. 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 an affinity between 1 pM and 500 nM, such as between 50 pM and 100 nM, 500 pM and 50 nM, 1 pM and 100 pM, 10 pM and 100 pM, 50 pM and 100 pM, 100 pM and 500 nM, 500 pM and 1 nM, 1 nM and 5 nM, 1 nM and 10 nM, 5 nM and 25 nM, 10 nM and 50 nM, 50 nM and 100 nM, and 100 nM and 500 nM. This disclosure also includes antibodies that compete with any of the antibodies described herein for binding to the KLK5 protein (e.g., human or mouse KLK5) and KLK7 (e.g., human or mouse KLK7) and have an affinity 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 kinetics 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 are expressed in sub-nanomolar K... D Combined with KLK5 and KLK7.

[0076] 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 spectroscopic methods (e.g., using fluorescence assays). Exemplary conditions for assessing binding affinity are in HBS-P buffer (10 mM HEPES pH 7.4, 150 mM NaCl, 0.005% (v / v) surfactant P20) and PBS buffer (10 mM PO4-3, 137 mM NaCl, and 2.7 mM KCl). These techniques can be used to measure the concentration of the bound protein as a function of the target protein concentration. The concentration of the bound protein ([[bound]]) is generally correlated with the concentration of the free target protein ([[free]]), as shown in the following formula: [[Binding]] = [[Free]] / (Kd + [[Free]]) However, it is not always necessary to determine K precisely. A Because sometimes you get K A A quantitative measurement of affinity proportional to the amount of affinity (e.g., determined using methods such as ELISA or FACS analysis) is sufficient and can therefore be used for comparison, such as determining whether a higher affinity is, for example, 2 times higher, to obtain a qualitative measurement of affinity, or to obtain an inference of affinity, such as by activity in a functional assay (e.g., in vitro or in vivo assay).

[0077] Tables 1a and 1b provide exemplary anti-KLK5 / KLK7 antibody sequences (e.g., heavy chain (HC) and light chain (LC) sequences, heavy chain variable domain (VH) and light chain variable domain (VL) sequences, and CDR sequences).

[0078] Table 1a. Examples of anti-KLK5 / KLK7 antibodies In some embodiments, certain amino acid positions in the antibody described herein (e.g., amino acids in the VH / VL region and / or CDR region) are substituted, and this substitution results in the antibody having substantially similar binding and biological activities to a reference antibody (e.g., substantially similar binding affinity, binding specificity, protease activity inhibitory activity, anti-inflammatory activity, or combinations thereof). To identify substituted positions of an antibody, the amino acid sequence of that antibody is compared with the sequences of other antibodies belonging to the same group as that antibody. If the identity of that amino acid changes at any particular position among different related antibodies in a group, that position is a substituted position of that antibody. In other words, a substituted position is a position where the identity of the amino acid differs between related antibodies. Positions containing constant amino acids are non-substituted positions.

[0079] In some embodiments, the above method can be used to provide a shared antibody sequence. In such a shared sequence, non-substitutable positions are indicated by the amino acids present at those positions, and substitutable positions are indicated by "X".

[0080] Depending on how the antibody is used, X can be a) any amino acid, b) any amino acid present at that position in any of the relevant antibodies in the group, or a variant thereof with a conserved substitution, or c) any amino acid present at that position in any of the relevant antibodies in the group. Any antibody having a sequence covered by a common denominator should bind to the same antigen as any of the relevant antibodies.

[0081] In some embodiments, the above-described methods can be used in the design and preparation of variants of the parent antibody that at least maintain (e.g., maintain or increase) the antigen-binding activity of the parent antibody. Because antibodies containing substitutions at substituted sites have already been produced and tested, substitutions at those sites can be performed knowing that they will not significantly reduce the binding activity of the antibody. Typically, the antigen-binding affinity of the antibody variant of the parent antibody is 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% of the binding affinity of the parent antibody to a specific antigen (e.g., at least 150%, at least 200%, at least 500%, at least 1000%, typically up to at least 10,000%).

[0082] In some embodiments, the substitutable position of the parent antibody can be substituted by: a) any of 20 naturally occurring amino acids to produce a random substitution; b) an amino acid having similar biochemical properties to an amino acid already present at the substitutable position to produce a conserved substitution; c) an amino acid present at the same position as in the associated antibody to produce a directed substitution; or d) an amino acid present at the same position in a similar human antibody to produce a humanized substitution. Substitution can occur at any portion of the antibody variable region (including any frame region or CDR). In some embodiments, a single substitutable amino acid can be substituted. However, in other embodiments, multiple substitutable amino acids (e.g., up to about 5 or 10 or more) can be substituted. In a particular embodiment, the type of substitution that can occur at each substitutable position can be indicated by the type of amino acid present at that position in the associated antibody. For example, if an unrelated amino acid (e.g., Ala, Gly, Cys, Glu, and Thr) is present at a position in a group of associated antibodies, then any amino acid can be substituted at that position without significantly reducing the antibody binding activity. Exemplary amino acid substitutions for the anti-KLK5 / KLK7 antibodies described herein are shown in Table 1b: Table 1b. Exemplary amino acid substitutions in anti-KLK5 / KLK7 antibodies

[0083] In some embodiments, the antibodies of this disclosure comprise HC CDR1, which comprises the amino acid sequence GSISSX1DYYWX2 (SEQ ID NO: 28), wherein X1 is S, D, or L, and X2 is G or V; HC CDR2, which comprises the amino acid sequence SIX3YX4X5X6TYYX7PSLKS (SEQ ID NO: 29), wherein 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, which comprises the amino acid sequence ARGRPLGYGAX8HX9YYGMDV (SEQ ID NO: 30), wherein X8 is R or K, or X9 is Y or D; LC CDR1, which comprises the amino acid sequence SEQ ID NO: 4; LC CDR2, which comprises the amino acid sequence SEQ ID NO: 5; and / or LC CDR3, which comprises QQSPX 10 The amino acid sequence of FPPLT (SEQ ID NO: 31), where X 10 It is either P or Y.

[0084] In some embodiments, the antibodies of this disclosure comprise one or more of the HC CDRs (e.g., HC CDR1, HC CDR2, or HC CDR3) from any of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b. In some embodiments, the antibodies of this disclosure comprise the HC CDR3 amino acid sequence from any of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b. In some embodiments, the antibodies of this disclosure comprise the HC CDR1, HC CDR2, and HC CDR3 as provided for any of the antibodies selected from Tables 1a and 1b. In some embodiments, the antibodies of this disclosure comprise the LC CDR3 amino acid sequence from any of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b. In some embodiments, the antibodies of this disclosure comprise one or more of the LC CDRs (e.g., LC CDR1, LC CDR2, or LC CDR3) from any of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b. In some embodiments, the antibodies disclosed herein comprise LC CDR1, LC CDR2, and LCCDR3 as provided for any of the anti-KLK5 antibodies selected from Tables 1a and 1b.

[0085] In some embodiments, the antibodies of this disclosure comprise HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 as provided for any of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b. In some embodiments, the CDR3 domains of the antibody heavy chain and / or light chain may play a particularly important role in the antibody's binding specificity / affinity to the antigen. Therefore, the antibodies of this disclosure may at least comprise the heavy chain and / or light chain CDR3 of any of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b.

[0086] Variants of any of the exemplary anti-KLK5 / KLK7 antibodies disclosed herein are also within the scope of this disclosure. Variants may contain one or more amino acid residue variations in VH and / or VL, or in one of the HC CDRs, or in one of the LC CDRs, while retaining substantially similar binding and biological activities to the reference antibody (e.g., substantially similar binding affinity, binding specificity, protease activity, inhibitory activity, anti-inflammatory activity, or combinations thereof).

[0087] In some embodiments, the antibody of this disclosure has one or more CDR (e.g., HC CDR or LC CDR) sequences that are substantially similar to any of the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 and / or LC CDR3 sequences selected from the anti-KLK5 / KLK7 antibodies of 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 antibody described herein may vary by one, two, three, four, five or six 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 maintaining, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% binding to the original antibody from which it is derived). For example, in some embodiments, the position of the CDR defining any antibody described herein can be varied by shifting the N-terminal and / or C-terminal boundary of the CDR by one, two, three, four, five, or six amino acids relative to the CDR position of any of the antibodies described herein, 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 maintaining, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived). 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, LCCDR2, or LC CDR3) regions of the antibody described herein may vary (e.g., shorten or lengthen) by one, two, three, four, five, or more amino acids, as long as immune-specific binding to KLK5 (e.g., human or mouse KLK5) and KLK7 (e.g., human or mouse KLK7) is maintained (e.g., substantially maintaining, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% binding to the original antibody from which it is derived).

[0088] Therefore, in some embodiments, the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LCCDR2 and / or LC CDR3 described herein may be one, two, three, four, five or more amino acids shorter than one of the CDRs described herein or (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 maintaining binding relative to the original antibody from which it is derived, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%). In some embodiments, the HC CDR1, HC CDR2, HC CDR3, LCCDR1, LC CDR2 and / or LC CDR3 described herein may be one, two, three, four, five or more amino acids longer than one of the CDRs described herein or (e.g., a CDR 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 maintaining binding relative to the original antibody from which it is derived, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%). In some embodiments, the amino moiety of the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 and / or LC CDR3 described herein may be extended by one, two, three, four, five or more amino acids compared to one of the CDRs described herein or (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 maintaining binding relative to the original antibody from which it is derived, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%).In some embodiments, the carboxyl moiety of HCCDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 and / or LC CDR3 described herein may be extended by one, two, three, four, five or more amino acids compared to one of the CDRs described herein or (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 maintaining binding relative to the original antibody from which it is derived, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%). In some embodiments, the amino moiety of the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 and / or LC CDR3 described herein may be shortened by one, two, three, four, five or more amino acids compared to one of the CDRs described herein or (e.g., the CDR 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 maintaining binding relative to the original antibody from which it is derived, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%). In some embodiments, the carboxyl moiety of the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 described herein may be shortened by one, two, three, four, five, or more amino acids compared to one of the CDRs described herein or (e.g., the CDR 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 maintaining binding relative to the original antibody from which it is derived, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%). Any method may be used to determine whether specific binding to KLK5 (e.g., human or mouse KLK5) and KLK7 (e.g., human or mouse KLK7) is maintained, for example, using binding assays and conditions described in the art.

[0089] In some embodiments, the antibodies of this disclosure have one or more CDR (e.g., HC CDR or LC CDR) sequences that are substantially similar to any of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b. For example, the antibodies described herein may include one or more CDR sequences from any of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b, which contain up to 5, 4, 3, 2, or 1 amino acid residue variations compared to the corresponding CDR region in any of the CDRs provided 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 maintaining binding relative to the original antibody from which it is derived, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%). In some embodiments, any amino acid variation in any of the CDRs provided herein may be a conserved variation. A conserved variation may be introduced at a location where residues are unlikely to interact with KLK5 (e.g., human or mouse KLK5) and / or KLK7 (e.g., human or mouse KLK7), for example, as determined based on the crystal structure. Some aspects of this disclosure provide antibodies comprising one or more of the heavy chain variable (VH) and / or light chain variable (VL) domains provided herein. In some embodiments, any of the VH domains provided herein includes one or more of the HC CDR sequences provided herein (e.g., HC CDR1, HC CDR2, and HCCDR3), for example, any of the HC CDR sequences provided from any of the anti-KLK5 / KLK7 sequences in Tables 1a and 1b. In some embodiments, any of the VL domains provided herein includes one or more of the LC CDR sequences provided herein (e.g., LC CDR1, LC CDR2, and LC CDR3), for example, any of the HC CDR sequences provided in any of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b.

[0090] In some embodiments, the antibodies of this disclosure include any antibody comprising a heavy chain variable domain and / or a light chain variable domain of any of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b and their variants. In some embodiments, the antibodies of this disclosure include any antibody comprising a heavy chain variable pair and a light chain variable pair of any of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b.

[0091] This disclosure provides antibodies having heavy chain variable (VH) 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 having 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%) identity to any of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b. In some embodiments, the homologous heavy chain variable amino acid sequence and / or light chain variable amino acid sequence remains unchanged within 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 appear in heavy chain variable sequences and / or light chain variable sequences other than any of the CDR sequences provided herein. In some embodiments, the antibodies provided herein comprise heavy chain variable sequences and light chain variable sequences containing a frame sequence having 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%) identity with any anti-KLK5 / KLK7 antibody selected from Tables 1a and 1b.

[0092] In some embodiments, the antibodies of this disclosure are humanized antibodies (e.g., humanized variants containing one or more CDRs of Tables 1a and 1b). In some embodiments, the antibodies of this disclosure comprise the same HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 as shown in Tables 1a and 1b, and comprise humanized heavy chain variable regions and / or humanized light chain variable regions.

[0093] In some embodiments, the antibody of this disclosure is a humanized antibody comprising a VH containing no more than 20 amino acid variations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the VH of any anti-KLK5 / KLK7 antibody listed in Tables 1a and 1b. Alternatively, the antibody of this disclosure is a humanized antibody comprising a VL containing no more than 20 amino acid variations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the VL of any anti-KLK5 / KLK7 antibody listed in Tables 1a and 1b.

[0094] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises HC CDR1, HC CDR2, and HC CDR3 having a heavy chain variable domain of the amino acid sequence of SEQ ID NO: 7. Alternatively, the anti-KLK5 / KLK7 antibody of this disclosure comprises LC CDR1, LC CDR2, and LC CDR3 having a light chain variable domain of the amino acid sequence of SEQ ID NO: 8.

[0095] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises 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.

[0096] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises HC CDR1, HC CDR2, and HC CDR3, which together contain no more than 5 amino acid variations (e.g., no more than 5, 4, 3, 2, or 1 amino acid variation) 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. As used anywhere in this disclosure, “total” means that the total number of amino acid variations in all three heavy chain CDRs is within the defined range. Alternatively, the anti-KLK5 / KLK7 antibody of this disclosure comprises LC CDR1, LC CDR2, and LC CDR3, which together contain no more than 5 amino acid variations (e.g., no more than 5, 4, 3, 2, or 1 amino acid variation) 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.

[0097] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises HC CDR1, HC CDR2, and HC CDR3, all of which are 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, the anti-KLK5 / KLK7 antibody of this disclosure comprises LC CDR1, LC CDR2, and LCCDR3, all of which are 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.

[0098] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises: HC CDR1 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 1; HC CDR2 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) compared to HC CDR2 having the amino acid sequence of SEQ ID NO: 2; and / or HCCDR3 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) compared to HC CDR3 having the amino acid sequence of SEQ ID NO: 3. Alternatively, the anti-KLK5 / KLK7 antibody of this disclosure comprises: an LC CDR1 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) compared to an LC CDR1 having the amino acid sequence of SEQ ID NO: 4; an LC CDR2 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) compared to an LC CDR2 having the amino acid sequence of SEQ ID NO: 5; and / or an LC CDR3 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) compared to an LC CDR3 having the amino acid sequence of SEQ ID NO: 6.

[0099] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises VH containing the amino acid sequence of SEQ ID NO: 7. Alternatively, the anti-KLK5 / KLK7 antibody of this disclosure comprises VL containing the amino acid sequence of SEQ ID NO: 8.

[0100] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises a VH containing no more than 20 amino acid variations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the VH shown in SEQ ID NO: 7. Alternatively, the anti-KLK5 / KLK7 antibody of this disclosure comprises a VL containing no more than 20 amino acid variations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the VL shown in SEQ ID NO: 8.

[0101] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises VH, said VH containing 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%) of the amino acid sequence identical to that of VH as shown in SEQ ID NO: 7. Alternatively, the anti-KLK5 / KLK7 antibody of this disclosure comprises VL, said VL containing 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%) of the amino acid sequence of VL as shown in SEQ ID NO: 8.

[0102] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3, having the amino acid sequence of SEQ ID NO: 13. Alternatively, the anti-KLK5 / KLK7 antibody of this disclosure comprises light chain variable domains LC CDR1, LC CDR2, and LC CDR3, having the amino acid sequence of SEQ ID NO: 14.

[0103] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises 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.

[0104] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises HC CDR1, HC CDR2, and HC CDR3, which together contain no more than 5 amino acid variations (e.g., no more than 5, 4, 3, 2, or 1 amino acid variation) 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, “total” means the total number of amino acid variations in all three heavy chain CDRs is within the specified range. Alternatively, the anti-KLK5 / KLK7 antibody of this disclosure comprises LC CDR1, LC CDR2, and LC CDR3, which together contain no more than 5 amino acid variations (e.g., no more than 5, 4, 3, 2, or 1 amino acid variation) 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.

[0105] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises HC CDR1, HC CDR2, and HC CDR3, all of which are 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, the anti-KLK5 / KLK7 antibody of this disclosure comprises LC CDR1, LC CDR2, and LCCDR3, all of which are 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.

[0106] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises: HC CDR1 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 9; HC CDR2 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) compared to HC CDR2 having the amino acid sequence of SEQ ID NO: 10; and / or HCCDR3 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) compared to HC CDR3 having the amino acid sequence of SEQ ID NO: 11. Alternatively, the anti-KLK5 / KLK7 antibody of this disclosure comprises: an LC CDR1 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) compared to an LC CDR1 having the amino acid sequence of SEQ ID NO: 4; an LC CDR2 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) compared to an LC CDR2 having the amino acid sequence of SEQ ID NO: 5; and / or an LC CDR3 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) compared to an LC CDR3 having the amino acid sequence of SEQ ID NO: 12.

[0107] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises VH containing the amino acid sequence of SEQ ID NO: 13. Alternatively, the anti-KLK5 / KLK7 antibody of this disclosure comprises VL containing the amino acid sequence of SEQ ID NO: 14.

[0108] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises a VH containing no more than 20 amino acid variations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the VH shown in SEQ ID NO: 13. Alternatively, the anti-KLK5 / KLK7 antibody of this disclosure comprises a VL containing no more than 20 amino acid variations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the VL shown in SEQ ID NO: 14.

[0109] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises VH, said VH containing 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%) of the amino acid sequence identical to that of VH as shown in SEQ ID NO: 13. Alternatively, the anti-KLK5 / KLK7 antibody of this disclosure comprises VL, said VL containing 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%) of the amino acid sequence identical to that of VL as shown in SEQ ID NO: 14.

[0110] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3, having the amino acid sequence of SEQ ID NO: 17. Alternatively, the anti-KLK5 / KLK7 antibody of this disclosure comprises light chain variable domains LC CDR1, LC CDR2, and LC CDR3, having the amino acid sequence of SEQ ID NO: 14.

[0111] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises 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.

[0112] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises HC CDR1, HC CDR2, and HC CDR3, which together contain no more than 5 amino acid variations (e.g., no more than 5, 4, 3, 2, or 1 amino acid variation) 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, “total” means the total number of amino acid variations in all three heavy chain CDRs is within the specified range. Alternatively, the anti-KLK5 / KLK7 antibody of this disclosure comprises LC CDR1, LC CDR2, and LC CDR3, which together contain no more than 5 amino acid variations (e.g., no more than 5, 4, 3, 2, or 1 amino acid variation) 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.

[0113] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises HC CDR1, HC CDR2, and HC CDR3, all of which are 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, the anti-KLK5 / KLK7 antibody of this disclosure comprises LC CDR1, LC CDR2, and LCCDR3, all of which are 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.

[0114] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises: HC CDR1 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 9; HC CDR2 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) compared to HC CDR2 having the amino acid sequence of SEQ ID NO: 15; and / or HCCDR3 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) compared to HC CDR3 having the amino acid sequence of SEQ ID NO: 16. Alternatively, the anti-KLK5 / KLK7 antibody of this disclosure comprises: an LC CDR1 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) compared to an LC CDR1 having the amino acid sequence of SEQ ID NO: 4; an LC CDR2 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) compared to an LC CDR2 having the amino acid sequence of SEQ ID NO: 5; and / or an LC CDR3 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) compared to an LC CDR3 having the amino acid sequence of SEQ ID NO: 12.

[0115] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises VH containing the amino acid sequence of SEQ ID NO: 17. Alternatively, the anti-KLK5 / KLK7 antibody of this disclosure comprises VL containing the amino acid sequence of SEQ ID NO: 14.

[0116] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises a VH containing no more than 20 amino acid variations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the VH shown in SEQ ID NO: 17. Alternatively, the anti-KLK5 / KLK7 antibody of this disclosure comprises a VL containing no more than 20 amino acid variations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the VL shown in SEQ ID NO: 14.

[0117] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises VH, said VH containing 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%) of the amino acid sequence identical to that of the VH shown in SEQ ID NO: 17. Alternatively, the anti-KLK5 / KLK7 antibody of this disclosure comprises VL, said VL containing 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%) of the amino acid sequence identical to that of the VL shown in SEQ ID NO: 14.

[0118] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3, having the amino acid sequence of SEQ ID NO: 21. Alternatively, the anti-KLK5 / KLK7 antibody of this disclosure comprises light chain variable domains LC CDR1, LC CDR2, and LC CDR3, having the amino acid sequence of SEQ ID NO: 14.

[0119] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises 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.

[0120] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises HC CDR1, HC CDR2, and HC CDR3, which together contain no more than 5 amino acid variations (e.g., no more than 5, 4, 3, 2, or 1 amino acid variation) 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, “total” means the total number of amino acid variations in all three heavy chain CDRs is within the specified range. Alternatively, the anti-KLK5 / KLK7 antibody of this disclosure comprises LC CDR1, LC CDR2, and LC CDR3, which together contain no more than 5 amino acid variations (e.g., no more than 5, 4, 3, 2, or 1 amino acid variation) 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.

[0121] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises HC CDR1, HC CDR2, and HC CDR3, all of which are 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, the anti-KLK5 / KLK7 antibody of this disclosure comprises LC CDR1, LC CDR2, and LCCDR3, all of which are 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.

[0122] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises: HC CDR1 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 18; HC CDR2 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) compared to HC CDR2 having the amino acid sequence of SEQ ID NO: 19; and / or HCCDR3 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) compared to HC CDR3 having the amino acid sequence of SEQ ID NO: 20. Alternatively, the anti-KLK5 / KLK7 antibody of this disclosure comprises: an LC CDR1 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) compared to an LC CDR1 having the amino acid sequence of SEQ ID NO: 4; an LC CDR2 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) compared to an LC CDR2 having the amino acid sequence of SEQ ID NO: 5; and / or an LC CDR3 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) compared to an LC CDR3 having the amino acid sequence of SEQ ID NO: 12.

[0123] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises VH containing the amino acid sequence of SEQ ID NO: 21. Alternatively, the anti-KLK5 / KLK7 antibody of this disclosure comprises VL containing the amino acid sequence of SEQ ID NO: 14.

[0124] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises a VH containing no more than 20 amino acid variations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the VH shown in SEQ ID NO: 21. Alternatively, the anti-KLK5 / KLK7 antibody of this disclosure comprises a VL containing no more than 20 amino acid variations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the VL shown in SEQ ID NO: 14.

[0125] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure comprises VH, said VH containing 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%) of the amino acid sequence identical to that of VH as shown in SEQ ID NO: 21. Alternatively, the anti-KLK5 / KLK7 antibody of this disclosure comprises VL, said VL containing 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%) of the amino acid sequence identical to that of VL as shown in SEQ ID NO: 14.

[0126] The antibodies described herein can be in any antibody form, including but not limited to full-length antibodies, their antigen-binding fragments (such as Fab, F(ab'), F(ab')2, Fv), single-chain antibodies, bispecific antibodies, or nanobodies. In some embodiments, the anti-KLK5 / KLK7 antibody described herein is an scFv. In some embodiments, the anti-KLK5 / KLK7 antibody described herein is an scFv-Fab (e.g., an scFv fused to a portion of a constant region).

[0127] In some embodiments, the anti-KLK5 / KLK7 antibody of this disclosure is a chimeric antibody, which may include a heavy constant region and a light constant region derived from a human antibody. A chimeric antibody is an antibody having a variable region or a portion of a variable region from a first species and a constant region from a second species. Typically, in these chimeric antibodies, the variable regions of both the light and heavy chains mimic the variable regions of antibodies derived from one mammalian species (e.g., non-human mammals such as mice, rabbits, and rats), while the constant portion is sequence homologous to an antibody derived from another mammal (such as a human). In some embodiments, amino acid modifications may be made in the variable and / or constant regions.

[0128] In some embodiments, the antibody of this disclosure comprises a VL domain and / or a VH domain selected from any of the anti-KLK5 / KLK7 antibodies selected from Tables 1a and 1b, and includes a constant region comprising the amino acid sequence of the constant region of an immunoglobulin molecule of IgG, IgE, IgM, IgD, IgA, or IgY, any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) or any subclass (e.g., IgG2a and IgG2b). Non-limiting examples of human constant regions have been described in the art, see, for example, Kabat EA et al., (1991), ibid.

[0129] In some embodiments, the light chain of either of the anti-KLK5 / KLK7 antibodies described herein may further include a light chain constant region (CL), which may be any CL known in the art. In some instances, the CL is a κ light chain. In other instances, the CL is a λ light chain. In some embodiments, the CL is a κ light chain.

[0130] Other antibody heavy chain constant regions and light chain constant regions are well known in the art, for example, those provided in the IMGT database (www.imgt.org) or www.vbase2.org / vbstat.php, both of which are incorporated herein by reference.

[0131] In some embodiments, conserved mutations may be introduced into antibody sequences (e.g., CDRs or framework sequences) at sites where residues are unlikely to interact with the target antigen (e.g., human or mouse KLK5 and / or human or mouse KLK7), for example, as determined by crystal structure. In some embodiments, one, two, or more mutations (e.g., amino acid substitutions) are introduced into the Fc region of the anti-KLK5 / KLK7 antibody described herein (e.g., in 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, which are numbered according to the Kabat numbering system (e.g., Kabat's EU index)) to alter one or more functional properties of the antibody, such as serum half-life, complement binding, Fc receptor binding, and / or antigen-dependent cytotoxicity.

[0132] 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) such that the number of cysteine ​​residues in the hinge region is altered (e.g., increased or decreased), as described, for example, in U.S. Patent No. 5,677,425. The number of cysteine ​​residues in the hinge region of the CH1 domain can be altered to, for example, promote the assembly of light and heavy chains, or alter (e.g., increase or decrease) antibody stability, or promote linker conjugation.

[0133] In some embodiments, one, two, or more mutations (e.g., amino acid substitutions) are introduced into the Fc region of the antibody described herein (e.g., in 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, where numbering is performed according to the Kabat numbering system (e.g., Kabat's EU index)) to increase or decrease the antibody's affinity for 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 antibody's affinity for Fc receptors, and techniques for introducing such mutations into Fc receptors or fragments thereof, are known to those skilled in the art. Examples of mutations in the Fc receptor of antibodies that can alter the affinity of antibodies for 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 Patent Publications Nos. WO 02 / 060919, WO 98 / 23289, and WO 97 / 34631, which are incorporated herein by reference.

[0134] In some embodiments, one, two, or more amino acid mutations (i.e., substitution, insertion, or deletion) are introduced into the constant domain of IgG or its FcRn binding fragment (preferably an Fc or hinge-Fc domain fragment) to alter (e.g., reduce or increase) the half-life of the antibody in vivo. Examples of mutations that alter (e.g., reduce or increase) the half-life of the antibody in vivo can be found, for example, International Publications WO 02 / 060919, WO 98 / 23289, and WO 97 / 34631, and U.S. Patents 5,869,046, 6,121,022, 6,277,375, and 6,165,745.

[0135] In some embodiments, one, two, or more amino acid mutations (i.e., substitution, insertion, or deletion) are introduced into the constant domain of IgG or its FcRn binding fragment (preferably 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., substitution, insertion, or deletion) are introduced into the constant domain of IgG or its FcRn binding fragment (preferably 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., substitution) in the second constant (CH2) domain (residues 231-340 of human IgG1) and / or the third constant (CH3) domain (residues 341-447 of human IgG1), which are numbered according to Kabat's EU index (Kabat EA et al., (1991), ibid.). In some embodiments, the constant region of the antibody IgG1 described herein comprises 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, numbered according to the Kabat EU index. See U.S. Patent No. 7,658,921, which is incorporated herein by reference. This type of mutant IgG, referred to as the “YTE mutant,” has been shown to exhibit a fourfold increase in half-life compared to the wild-type of the same antibody (see Dall'Acqua WF et al., (2006) J Biol Chem 281: 23514-24). In some embodiments, the antibody comprises an IgG constant domain comprising one, two, three, or more amino acid substitutions at positions 251-257, 285-290, 308-314, 385-389, and 428-436, numbered according to the Kabat EU index.

[0136] In some implementations, for example by introducing M428L and / or N434A substitutions, the antibody comprises an Fc region that has been engineered for the purpose of extending the half-life. Non-limiting examples of Fc variants affecting the half-life in circulation are provided in Saunders KO, Conceptual Approaches to Modulating Antibody Effector Functions and Circulation Half-Life, Front Immunol. 2019; 10: 1296, the contents of which are incorporated herein by reference.

[0137] In some embodiments, for example, by introducing Leu234Ala and Leu235Ala mutations (commonly referred to as LALA mutations), one, two, or more amino acid substitutions are introduced into the Fc region of the IgG constant domain to alter the effector function of anti-KLK5 / KLK7 antibodies. The effector ligand whose affinity is altered can be, for example, an Fc receptor or a C1 component of complement. This approach is described in more detail in U.S. Patent Nos. 5,624,821 and 5,648,260. In some embodiments, the deletion or inactivation of the constant domain (through point mutations or other means) can reduce Fc receptor binding of circulating antibodies, thereby increasing tumor localization. For a description of mutations that delete or inactivate the constant domain and thus increase tumor localization, see, for example, U.S. Patent Nos. 5,585,097 and 8,591,886. In some implementations, one or more amino acid substitutions may be introduced into the Fc region of the antibody described herein to remove potential glycosylation sites on the Fc region, which may reduce Fc receptor binding (see, for example, Shields RL et al., (2001) J Biol Chem 276: 6591-604).

[0138] In some embodiments, one or more amino groups in the constant region of the anti-KLK5 / KLK7 antibody described herein may be replaced with different amino acid residues, such that the antibody exhibits altered Clq binding and / or reduced or eliminated complement-dependent cytotoxicity (CDC). This method is described in more 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 altered, thereby changing the antibody's ability to fix complement. This method is further described in International Publication No. WO 94 / 29351. In some embodiments, the Fc region of the antibody described herein is modified to increase the antibody's ability to mediate antibody-dependent cytotoxicity (ADCC) and / or increase the antibody's affinity for the Fcγ receptor. This method is further described in International Publication No. WO 00 / 42072.

[0139] In some embodiments, the antibody comprises an Fc variant containing amino acid substitutions for L234A, L235E, and P329G, which are numbered according to the EU index. In some embodiments, antibodies comprising Fc variants exhibit reduced affinity for one or more, or each, of FcyRJ, FcyRIIA, FcyRIIIA, and Clq compared to antibodies comprising the wild-type human Fc region. Examples of such Fc variants are provided in International Patent Application Publication No. WO 2021 / 055669, entitled "FC VARIANTS WITH REDUCEDEFFECTOR FUNCTION," published March 25, 2021; and U.S. Patent Application Publication No. US 2021-0087271, entitled "FC VARIANTS WITH REDUCED EFFECTOR FUNCTION," published March 25, 2021, the contents of which are incorporated herein by reference.

[0140] In some embodiments, the heavy chain domain sequence and / or light chain variable domain sequence of the antibodies provided herein can be used to generate, for example, CDR-grafted, chimeric, humanized, or complexed human antibodies or antigen-binding fragments, as described elsewhere herein. As will be understood by those skilled in the art, any variant, CDR-grafted, chimeric, humanized, or complexed antibody derived from any of the antibodies provided herein can be used in the compositions and methods described herein and will maintain the ability to specifically bind to KLK5 and KLK7 such that the variant, CDR-grafted, chimeric, humanized, or complexed antibody 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 relative to the original antibody from which it is derived.

[0141] In some embodiments, the antibodies provided herein contain mutations that confer the desired properties to the antibody. For example, to avoid potential complications due to Fab-arm exchange (which is known to occur in natural IgG4 mAb), the antibodies provided herein may contain a stable 'Adair' mutation (ngal 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 number; residue 241 Kabat number) is converted to proline, producing an IgG1-like hinge sequence. Therefore, any of the antibodies may contain a stable 'Adair' mutation.

[0142] 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, the one or more sugar or carbohydrate molecules are conjugated to the antibody via N-glycosylation, O-glycosylation, C-glycosylation, glypiation (GPI anchoring), and / or phosphoglycosylation. In some embodiments, the one or more sugar or carbohydrate molecules are monosaccharides, disaccharides, oligosaccharides, or polysaccharides. In some embodiments, the one or more sugar or carbohydrate molecules are branched oligosaccharides or branched polysaccharides. In some embodiments, the one or more sugar or carbohydrate molecules include mannose units, glucose units, N-acetylglucosamine units, N-acetylglucosamine units, galactose units, fucose units, or phospholipid units. In some embodiments, about 1-10, about 1-5, about 5-10, about 1-4, about 1-3, or about 2 sugar molecules are present. In some embodiments, the glycosylated antibody is fully or partially glycosylated. In some embodiments, the antibody is glycosylated by a chemical reaction or enzymatic process. In some embodiments, the antibody is glycosylated in vitro or intracellularly, and the cells may optionally lack enzymes in the N-glycosylation or O-glycosylation pathway, such as glycosyltransferases. In some embodiments, the antibody is functionalized with sugar or carbohydrate molecules, as described in the following literature: International Patent Application Publication WO2014065661, published May 1, 2014, entitled "Modified antibody, antibody-conjugate and process for the preparation thereof".

[0143] In some embodiments, any of the anti-KLK5 / KLK7 antibodies described herein may include a signal peptide (e.g., an N-terminal signal peptide) in the heavy chain and / or light chain sequence. In some embodiments, the anti-KLK5 / KLK7 antibodies described herein comprise any of the VH and VL sequences described herein, any of the IgG heavy chain and light chain sequences, or any of the F(ab') heavy chain and light chain sequences, and further comprise a signal peptide (e.g., an N-terminal signal peptide).

[0144] (b) Th2 targeting Disorders associated with barrier dysfunction are characterized by barrier disruption and T helper cell 2 (Th2)-driven inflammation, such as inflammation mediated by Th2 cytokines and their receptors, including 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, TSLPR, etc. In some cases, unregulated KLK activity in the epidermis leads to and / or is associated with Th2 cell activation, resulting in the secretion of Th2 cytokines. Elevated Th2 cytokine levels may further lead to KLK overactivation. Figure 2 Therapeutic antibodies have been developed to inhibit Th2 cytokine-mediated inflammation by targeting Th2 cytokines and / or their respective receptors (called Th2-targeting antibodies) (e.g., anti-IL-13 antibodies, anti-IL-4R antibodies, etc.).

[0145] In some embodiments, the antibodies provided herein comprise 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-9R 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-36 antibodies, anti-IL-36R antibodies, anti-OX40L antibodies, anti-OX40 antibodies, anti-TSLP antibodies, or anti-TSLPR antibodies. Any suitable Th2-targeting antibody may be used in the methods and compositions described, including but not limited to those described in Table 2.

[0146] Table 2: Examples of Th2-targeting antibodies

[0147] In some embodiments, the Th2-targeting antibody contains an antigen-specific binding site for IL-13 or its receptor. In some embodiments, the Th2-targeting antibody contains an antigen-specific binding site for IL-13 or IL-13R derived from any known anti-IL-13 or its receptor, such as the anti-IL-13 / anti-IL-13R antibodies described below: WO2005062972, published on July 14, 2005, entitled “Treatment of cancer with novel anti-il 13 monoclonal antibodies”; WO 2005062967, published on July 14, 2005, entitled “Novel anti-il 13 antibodies and uses thereof”; WO 2008140455, published on May 15, 2007, entitled “Treatment of radiation and chemotherapy-induced fibrosis using novel anti-il 13 monoclonal antibody”. Antibodies; WO2023245187, published on December 21, 2023, titled "Antibodies that bind interleukin 13 and methods of use"; US6703488, published on March 9, 2004, titled "Antibody / Receptor Targeting Moiety For Enhanced Delivery Of Armed Ligand"; US2005058645, published on March 17, 2005, titled "Monoclonal Antibody Against Interleukin-13 Receptor Alpha 1 (IL-13Ralpha1)"; US2005154192, published on July 14, 2005, titled "Anti-IL13 Receptor Alpha 1 Neutralizing Antibody"; US2006099652, published on May 11, 2006, titled "IL..." 13 Receptor Alpha 2 Antibody And Methods Of Use; US2006140948, published on June 29, 2006, and titled Fully Human Monoclonal Antibodies To IL-13;US2006263356, published on November 23, 2006, titled "Antibodies Against IL-13 Receptor Alpha1 And Uses Thereof"; US2007048785, published on March 1, 2007, titled "Anti-IL-13 Antibodies And Complexes"; US2007128192, published on June 7, 2007, titled "Human Antibody Molecules For IL-13"; WO07080174, published on July 19, 2007, titled "Immunoglobulins"; US2007258979, published on November 8, 2007, titled "Chimeric And Humanised Monoclonal Antibodies Against Interleukin-13; US2008008648, published January 10, 2008, titled Treatment Of Cancer With A Novel Anti-IL13 Monoclonal Antibody; US2008044420, published February 21, 2008, titled Anti-IL-13 Antibodies, Compositions, Methods and Uses; US2008166343, published July 10, 2008, titled High Affinity Antibody Antagonists Of Interleukin-13 Receptor Alpha 1; US2008171014, published July 17, 2008, titled Interleukin-13 Binding Proteins; US2008248048, published on October 9, 2008, entitled Interleukin-13 Antibody Composition; US2008267959, published on October 30, 2008, entitled Anti-IL13 Human Antibodies; US2009060906, published on March 5, 2009, entitled Anti-IL-13 Antibody Formulations And Uses Thereof;US2009148905, published on June 11, 2009, titled "Antigen-Binding Constructs"; US2009285799, published on November 19, 2009, titled "Antibody Antagonists Of Interleukin-13 Receptor Alpha1"; WO09138413, published on November 19, 2009, titled "Single Domain Antibodies That Bind IL-13"; US2010226923, published on September 9, 2010, titled "Antibodies That Bind IL-4 And / Or IL-13 And Their Uses"; US2010260773, published on October 14, 2010, titled "Antibody Molecules Having Binding Specificity For Humans". IL-13; US2011052597, published March 3, 2011, titled "Anti-IL-13R Alpha1 Antibodies And Their Uses Thereof"; US2011206687, published August 25, 2011, titled "Isolation And Purification Of Anti-IL-13 Antibodies Using Protein A Affinity Chromatography"; US2012045438, published February 23, 2012, titled "Engineered Anti-IL-13 Antibodies, Compositions, Methods And Uses"; US2012093830, published April 19, 2012, titled "Single Domain Antibodies That Bind IL-13"; WO13103783, published July 11, 2013, titled "Murine..." IL-13 Antibodies; US2014341913, which was published on November 20, 2014, and its title is Methods And Compositions For Treating Asthma Using Anti-IL-13 Antibodies;US2014348855, published on November 27, 2014, titled "Antibody Formulations"; US2015225479, published on August 13, 2015, titled "Anti-IL-4 / Anti-IL-13 Bispecific Antibody / Polyglutamate Formulations"; US2015266962, published on September 24, 2015, titled "Anti-IL-13 Receptor Alpha 2 Antibodies And Antibody-Drug Conjugates"; US2016075777, published on March 17, 2016, titled "Anti-IL-4 / Anti-IL-13 Bispecific Antibody Formulations"; US2016319012, published on November 3, 2016, titled "Methods And Compositions". Comprising Purified Recombinant Polypeptides; US2017145089, published May 25, 2017, entitled Anti-IL4-IL 13 Bispecific Antibodies; WO17191627, published November 9, 2017, entitled Antibodies To Interleukin 13 Receptor Alpha-1 (IL-13R Alpha 1) And Uses Thereof; US2017334985, published November 23, 2017, entitled Anti-IL-13 / IL-17 Bispecific Antibodies And Uses Thereof; WO19096219, published May 23, 2019, entitled Humanized Anti-IL-13 Antibody And Preparation Method And Use Thereof; US2019247303, published on August 15, 2019, entitled Inhalable Powder Composition Comprising IL-13 Antibody; US2019309059, published on October 10, 2019, entitled IL-13 Antibody And Preparation Method And Use Thereof;US2020165347, published on May 28, 2020, titled "Method Of Treatment Using IL-13R Antibody"; US2021277131, published on September 9, 2021, titled "Treatment Employing Anti-IL-13R Antibody Or Binding Fragment Thereof"; US2021380674, published on December 9, 2021, titled "Methods Of Treatment Of Diseases In Which IL-13 Activity Is Detrimental Using Anti-IL-13 Antibodies"; US2022033508, published on February 3, 2022, titled "Anti-IL13R Alpha2 Antibodies"; WO22174808, published on August 25, 2022, titled "Antibody Against..." IL-13Ra2 and Use Thereof; US2022305104, published on September 29, 2022, titled "Methods of Treating Atopic Dermatitis"; US2023002484, published on January 5, 2023, titled "Treatment of Atopic Dermatitis Employing Anti-IL-13Ra1 Antibody Or Binding Fragment Thereof"; WO23287590, published on January 19, 2023, titled "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". Dermatitis; WO23023497, published on February 23, 2023, and titled Anti-IL-13 Antibody Formulation; US2023084464, published on March 16, 2023, and titled Antibody With Binding Specificity For Human IL-13;US2023087378, published on March 23, 2023, is titled "Multi-Specific Antibody With Binding Specificity For Human IL-13 and IL-17"; WO23075700, published on May 4, 2023, is titled "Anti-IL-13R Antibody Formulation"; WO23075702, published on May 4, 2023, is titled "Anti-IL-13R Antibody Formulation"; US2023183364, published on June 15, 2023, is titled "Anti-IL13R-Alpha2 Antibodies, Antigen-Binding Fragments And Uses Thereof"; WO23163659, published on August 31, 2023, is titled "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 Interleukin 13 And Methods Of Use; WO24043837, published February 29, 2024, titled High Concentration Anti-IL13R Antibody Formulation; US2024117030, published April 11, 2024, titled Multispecific Antibodies And Uses Thereof; US2024158521, published on May 16, 2024, and titled "Dna-Encoded Bispecific Antibodies Targeting IL13Ra2 And Methods Of Use In Cancer Therapeutics";WO08140455, published on November 20, 2008, entitled "Treatment Of Radiation And Chemo-Therapy Induced Fibrosis Using Novel Anti-IL-13 Monoclonal Antibodies"; and WO24099310, published on May 16, 2024, entitled "Anti-IL-13 Long-Acting Nanobody Sequence And Use Thereof," the descriptions of anti-IL-13 antibodies in each of these publications are incorporated herein by reference.

[0148] In some embodiments, the Th2-targeting antibody contains an antigen-specific binding site for IL-4 or its receptor. In some embodiments, the Th2-targeting antibody contains an antigen-specific binding site for IL-4 or IL-4R derived from any known anti-IL-4 or its receptor, such as the anti-IL-4 / anti-IL-4R antibodies described below: US5552304, published September 3, 1996, entitled *cDNA Clones Coding For Human Protein Exhibiting A BroadCellular Activity Spectrum (Human Interleukin-4)*; US5676940, published October 14, 1997, entitled *Method Of Reducing Immunoglobulin E Responses*; and US5985280, published November 16, 1999, entitled *Diagnosis And / Or Therapy Of Tumours Using Monoclonal Antibodies Specific For The Human IL-4*. Receptor; US6358509, published March 19, 2002, titled "Antibody Antagonists Of Human Interleukin-4"; US5863537, published January 26, 1999, titled "Humanized Monoclonal Antibodies Against Human Interleukin-4"; WO9414975, published July 7, 1994, titled "Monoclonal Antibodies Against The Human Interleukin-4 Receptor And Hybridomas Producing The Same"; US5928904, published July 27, 1999, titled "DNA Encoding Recombinant IL4 Antibodies Useful In Treatment Of IL4 Mediated Disorders"; US5597710, published January 28, 1997, titled "Humanized Monoclonal Antibodies Against Human Interleukin-4". Interleukin-4;US5783181, published on July 21, 1998, is titled "Therapeutic Uses Of Fusion Proteins Between Mutant IL-4 / IL-13 Antagonists And Immunoglobulins"; US2002002132, published on January 3, 2002, is titled "Use Of Interleukin-4 Antagonists And Compositions Thereof"; US2007274996, published on November 29, 2007, is titled "Antibodies That Bind Interleukin-4 Receptor"; US2008241160, published on October 2, 2008, is titled "Human Monoclonal Antibodies Against Human IL-4"; US2010297110, published on November 25, 2010, is titled "Antibody Specific For Humans". IL-4 For The Treatment of Cancer; US2008160035, published on July 3, 2008, titled "High Affinity Human Antibodies To Human IL-4 Receptor"; US2010226923, published on September 9, 2010, titled "Antibodies That Bind IL-4 And / Or IL-13 And Their Uses"; US2012097565, published on April 26, 2012, titled "Stabilized Formulations Containing Anti-Interleukin-4 Receptor (IL-4R) Antibodies"; US2014056920, published on February 27, 2014, titled "Methods For Treating Or Preventing Asthma By Administering An IL-4R Antagonist; US2014072583, published on March 13, 2014, and titled "Methods For Treating Atopic Dermatitis By Administering An IL-4R Antagonist";US2016207995, published on July 21, 2016, is titled "Anti-IL-4 Antibodies And Bispecific Antibodies And Uses Thereof"; US2016075777, published on March 17, 2016, is titled "Anti-IL-4 / Anti-IL-13 Bispecific Antibody Formulations"; US2014356372, published on December 4, 2014, is titled "Methods For Treating Allergy And Enhancing Allergen-Specific Immunotherapy By Administering An IL-4R Inhibitor"; US2015017176, published on January 15, 2015, is titled "Methods For Treating Eosinophilic Esophagitis By Administering An IL-4R Inhibitors: US2015225479, published August 13, 2015, entitled Anti-IL-4 / Anti-IL-13 Bispecific Antibody / Polyglutamate Formulations; US2017145089, published May 25, 2017, entitled Anti-IL4-IL-13 Bispecific Antibodies; US2017281769, published October 5, 2017, entitled Stable Anti-IL-4Ra Formulation; US2018346580, published December 6, 2018, entitled Antibodies To Canine Interleukin-4 Receptor Alpha; US2019177408, published June 13, 2019, entitled Antibody For Binding To Interleukin 4 Receptor; US2022081485, published on March 17, 2022, and titled Anti-IL-4R Antibody And Use Thereof; WO19148405, published on August 8, 2019, and titled IL-4R Antibody And Use Thereof;US2022073631, published on March 10, 2022, is titled "Monoclonal Antibody Against Human Interleukin-4 Receptor Alpha And Use Thereof"; US2021238294, published on August 5, 2021, is titled "Human IL-4R Binding Antibody, Antigen Binding Fragment Thereof, And Medical Use Thereof"; US2021206861, published on July 8, 2021, is titled "Antibodies Binding To Human IL-4R, Preparation Method Therefor And Use Thereof"; US2021403580, published on December 30, 2021, is titled "Human Antibody Having High Affinity To Human IL-4 Receptor Alpha, And Use Thereof". Thereof; US2023295312, published on September 21, 2023, entitled "Antibody Against Human IL-4Ra And Use Thereof"; US2022162328, published on May 26, 2022, entitled "Interleukin-4 Receptor Antibody And Application Thereof"; US2022348666, published on November 3, 2022, entitled "Liquid Composition Comprising Antibody Of Human Interleukin-4 Receptor Alpha"; US2022411519, published on December 29, 2022, entitled "Anti-IL-4R Single-Domain Antibody And Use Thereof"; US2023053131, published on February 16, 2023, entitled "Antibodies To Canine Interleukin-4 Receptor Alpha".US2023088052, published on March 23, 2023, entitled "Pharmaceutical Composition Containing Anti-IL-4R Antibody And Use Thereof"; US2023105029, published on April 6, 2023, entitled "Antibodies Binding IL4R And Uses Thereof"; US2024067738, published on February 29, 2024, entitled "Anti-IL4 Receptor Antibodies For Veterinary Use"; US2023203172, published on June 29, 2023, entitled "Anti-Human Interleukin-4 Receptor Alpha Antibody And Preparation Method And Application Thereof"; US2023167180, published on June 1, 2023, entitled "Antibody Binding With Specific Epitope In Human IL-4R Alpha and Applications of Antibody; WO21254221, published on December 23, 2021, entitled Stable Liquid Preparation Of Anti-IL-4R Monoclonal Antibodies; US2023279124, published on September 7, 2023, entitled Fusion Protein Comprising Ige Fc Receptor Alpha Subunit Extracellular Domain And Anti-IL-4R Antibody, And Use Thereof; US2023357415, published on November 9, 2023, entitled Bispecific Antibody Simultaneously Binding To Interleukin-4 Receptor Alpha Subunit And Interleukin-5 Receptor Alpha Subunit, And Use Thereof;US2023374144, published on November 23, 2023, entitled "Antibodies Specifically Recognizing Interleukin-4 Receptor Alpha And Uses Thereof"; US2023279123, published on September 7, 2023, entitled "Humanized Anti-IL-4R Single Domain Antibody And Application Thereof"; US2024075158, published on March 7, 2024, entitled "Complex Of Anti-IL-4R Antibody Or Antigen-Binding Fragment Thereof And Medical Use Thereof"; WO23011502, published on February 9, 2023, entitled "Stable Formulation Comprising Anti-IL-4R Antibody"; US2023064378, published on March 2, 2023, entitled "Human Interleukin-4 Receptor". Alpha Antibodies; WO23025217, published on March 2, 2023, entitled "Pharmaceutical Composition Of Anti-IL4R Antibody And Use Thereof"; WO23191665, published on October 5, 2023, entitled "Antibodies To Human IL-4R Having Reduced Immunogenicity And Application Thereof"; US2024024472, published on January 25, 2024, entitled "Anti-Interleukin-4 Receptor (IL-4R) Antibody Formulations"; US2024100176, published on March 28, 2024, entitled "Human Interleukin-4 Receptor Alpha Antibody Glucocorticoid Conjugates";And WO24061279, published on March 28, 2024, entitled "Recombinant Bispecific Antibodies Targeting TSLP And IL4R," the contents of each of which describing anti-IL-4 or anti-IL-4R antibodies are incorporated herein by reference.

[0149] In some embodiments, the Th2-targeting antibody contains an antigen-specific binding site for OX40L or its receptor. In some embodiments, the Th2-targeting antibody contains an antigen-specific binding site for OX40L or OX40 derived from any known anti-OX40L or its receptor, such as the anti-OX40L / anti-OX40 antibodies described below: US2006002929, published January 5, 2006, entitled Monoclonal Antibodies; US7291331, published November 6, 2007, entitled Methods Of Treating OX40 Medicated Recall Immune Responses; US2009053230, published February 26, 2009, entitled Anti-OX40L Antibodies And Methods Using Same; US7501496, published March 10, 2009, entitled Anti-OX40L Antibodies; US2010098712, published April 22, 2010, entitled Pharmaceutical Formulation Of An Antibody Against OX40L; US2010136030, published June 3, 2010, entitled Antiagonist OX40 Antibodies And Their Use In The Treatment Of Inflammatory And Autoimmune Diseases; US2010196359, published August 5, 2010, entitled Human Monoclonal Antibody Human Cd134 (OX40) And Methods Of Making And Using Same; US2010254978, published October 7, 2010, entitled Antibody Molecules Having Specificity For Human OX40; US2013018175, published on January 17, 2013, and titled Single Variable Domain Antibodies Against OX40L, Constructs And Therapeutic Use;US2013183315, published on July 18, 2013, is titled "Antibodies That Bind To OX40 And Their Uses"; US2013243772, published on September 19, 2013, is titled "Antibody Molecules Having Specificity For Human OX40"; US2013280275, published on October 24, 2013, is titled "Anti-OX40 Antibodies And Methods Of Using The Same"; US2014377284, published on December 25, 2014, is titled "Humanized Anti-Cd134 (OX40) Antibodies And Uses Thereof"; US2015307617, published on October 29, 2015, is titled "Anti-OX40 Antibodies And Methods Of Use; WO16002820, published January 7, 2016, titled "Novel Anti-Human OX40 Lig and Antibody, And Anti-Influenza Drug Comprising Same"; US2016137740, published May 19, 2016, titled "Humanized Anti-OX40 Antibodies And Uses Thereof"; US2016347847, published December 1, 2016, titled "Anti-OX40 Antibodies And Methods Of Use Thereof"; US2016347849, published December 1, 2016, titled "Antibodies Against OX40 And Uses Thereof"; US2016368997, published December 22, 2016, titled "Antibodies, Uses And Methods; WO17096281, published on June 8, 2017, and titled Anti-OX40 Antibodies And Methods of Use Thereof;WO17134292, published on August 10, 2017, is titled "Anti-OX40 Antagonistic Antibodies For The Treatment of Atopic Dermatitis"; US2017349661, published on December 7, 2017, is titled "Antagonistic Anti-OX40L Antibodies And Methods Of Their Use"; US2018171023, published on June 21, 2018, is titled "Anti-OX40 Antibodies And Their Uses"; US2021206864, published on July 8, 2021, is titled "Anti-OX40 Antagonistic Antibodies And Dosage For The Treatment of Atopic Dermatitis". OX40-Mediated Disorders; US2021214453, published on July 15, 2021, entitled "Anti-OX40 Antagonistic Antibodies For The Treatment Of Autoimmune Diseases"; WO22042692, published on March 3, 2022, entitled "Anti-OX40 Antibody Having Low Toxicity, And Pharmaceutical Composition And Use Thereof"; US2023151105, published on May 18, 2023, entitled "Anti-OX40 Antibody And Uses Thereof"; WO23109901, published on June 22, 2023, entitled "Anti-OX40 Antibodies And Methods Of Use"; WO23109976, published on June 22, 2023, entitled "Antibody Against OX40 And Medical Use". Thereof; US2024182594, which was published on June 6, 2024, and is titled Uses Of Antagonist, Non-Depleting OX40 Antibodies;US2024209104, published on June 27, 2024, entitled "Anti-OX40 Antibody, And Pharmaceutical Composition And Application Thereof"; US2024209107, published on June 27, 2024, entitled "Cd28 / OX40 Bispecific Antibodies"; and US2024270859, published on August 15, 2024, entitled "Anti-OX40L Antibody, Anti-OX40L / Anti-TNFα Bispecific Antibody, And Uses Thereof," all descriptions of anti-OX40L or anti-OX40 antibodies in each of these publications are incorporated herein by reference.

[0150] In some embodiments, the Th2-targeting antibody contains an antigen-specific binding site for TSLP or its receptor. In some embodiments, the Th2-targeting antibody contains an antigen-specific binding site for TSLP or TSLPR derived from any known anti-TSLP or its receptor, such as the anti-TSLP / anti-TSLPR antibodies described below: US2009186022, published July 23, 2009, entitled *Organic Compounds*; US2010166766, published July 1, 2010, entitled *Engineered Anti-TSLP Antibody*; US2011020369, published January 27, 2011, entitled *Engineered Anti-TSLPR Antibodies*; US2012020988, published January 26, 2012, entitled *Antibodies Specifically Binding To Human TSLPR And Methods*. Of Use; US2012219565, published August 30, 2012, titled Engineered Anti-TSLP Antibody; US2014227250, published August 14, 2014, titled Stable Formulations of Antibodies To TSLP; US2016046720, published February 18, 2016, titled Novel Anti-Human TSLP Receptor Antibody; US2017066823, published March 9, 2017, titled Thymic Stromal Lymphopoietin (TSLP) - Binding Molecules And Methods Of Using The Molecules; US2018296669, published October 18, 2018, titled Treatment of Asthma With Anti-TSLP Antibody; US2019111129, which was announced on April 18, 2019, and its title is Pharmaceutical Composition Comprising Anti-Human TSLP Receptor Antibody;US2021121406, published on April 29, 2021, entitled "Dry Powder Formulations Of Thymic Stromal Lymphopoietin (TSLP) - Binding Antibodies And Methods Of Use Thereof"; WO21155634, published on August 12, 2021, entitled "Anti-Human-TSLP Antibody And Use Thereof"; WO22184074, published on September 9, 2022, entitled "Pharmaceutical Composition Containing Anti-TSLP Antibody"; US2022289833, published on September 15, 2022, entitled "Antibodies Binding TSLP And Uses Thereof"; US2022340654, published on October 27, 2022, entitled "Antibody Capable Of Binding To Thymic Stromal Lymphopoietin And Use Thereof; US2022363781, published on November 17, 2022, entitled Anti-TSLP Antibody And Uses Thereof; WO22253147, published on December 8, 2022, entitled Anti-Thymic Stromal Lymphopoietin (TSLP) Antibody And Use Thereof; WO23028612, published on March 2, 2023, entitled Anti-TSLPR (Crlf2) Antibodies; US2023073888, published on March 9, 2023, entitled Treatment Of Atopic Dermatitis With Anti-TSLP Antibody; WO23029281, published on March 9, 2023, entitled Anti-Human TSLP Monoclonal Antibody And Use Thereof;US2023078678, published on March 16, 2023, is titled "Formulations of Human Anti-TSLP Antibodies and Methods of Treating Atopic Dermatitis"; US2023081261, published on March 16, 2023, is titled "Formulations of Human Anti-TSLP Antibodies and Methods of Using The Same"; US2023082287, published on March 16, 2023, is titled "Methods of Treating An Inflammatory or Obstructive Airway Disease Using Anti-TSLP Antibody"; WO23070948, published on May 4, 2023, is titled "Preparation Method For Concentrated Solution Containing Anti-Human Thymic Stromal Lymphopoietin (TSLP) Monoclonal Antibody, And Liquid". Preparation; WO23098491, published on June 8, 2023, entitled Anti-TSLP Monoclonal Antibody, Antigen-Binding Fragment Thereof and Use Thereof; WO23116925, published on June 29, 2023, entitled Novel Anti-TSLP Antibodies; WO23142309, published on August 3, 2023, entitled Anti-TSLP Nanobody and Use Thereof; US2024016931, published on January 18, 2024, entitled Anti-TSLP Antibody Pharmaceutical Composition and Use Thereof; WO24061279, published on March 28, 2024, entitled Recombinant Bispecific Antibodies Targeting TSLP and Il4R;US2024117030, published on April 11, 2024, is titled "Multispecific Antibodies And Uses Thereof"; US2024132581, published on April 25, 2024, is titled "Antibodies Against Human TSLP And Use Thereof"; WO24092064, published on May 2, 2024, is titled "Anti-TSLP Antibody Compositions And Uses Thereof"; US2024173405, published on May 30, 2024, is titled "Pharmaceutical Compositions Comprising Anti-Human TSLP Receptor Antibodies And Methods Of Using The Same"; US2024182558, published on June 6, 2024, is titled "Modified Anti-TSLP". Antibodies; US2024190951, published June 13, 2024, entitled Anti-TSLP Antibody Compositions And Uses Thereof; WO24146630, published July 11, 2024, entitled Method For Treating Asthma By Using TSLP Antibody; WO24152881, published July 25, 2024, entitled Anti-TSLP Antibody And Use Thereof; and WO24163978, published August 8, 2024, entitled Treatment Of Chronic Rhinosinusitis With Anti-TSLP Antibody, all descriptions of anti-TSLP or anti-TSLP antibodies in each of these publications are incorporated herein by reference.

[0151] In some implementations, Th2-targeting antibodies contain an antigen-specific binding site for IL-5 or its receptor. In some implementations, the Th2-targeting antibody comprises an antigen-specific binding site for IL-5 or IL-5R derived from any known anti-IL-5 or its receptor, such as the anti-IL-5 / anti-IL-5R antibodies described below: US5683892, published November 4, 1997, entitled "DNA Encoding Recombinant IL-5 Antagonists Useful In Treatment Of IL-5 Mediated Disorders"; US5976821, published November 2, 1999, entitled "Monoclonal Antibodies Specific For Human Interleukin-5"; US5998586, published December 7, 1999, entitled "Interleukin-5 Specific Recombinant Antibodies"; and US6018032, published January 25, 2000, entitled "Antibody Against Human Interleukin-5-Receptor Alpha". Chain; US6056957, published on May 2, 2000, entitled Humanized Monoclonal Antibodies Against Human Interleukin-5; US6451982, published on September 17, 2002, entitled Design, Cloning And Expression Of Humanized Monoclonal Antibodies Against Human Interleukin-5; US2003194404, published on October 16, 2003, entitled Human Monoclonal Antibodies To Interleukin-5 And Methods And Compositions Comprising Same; US6720155, published on April 13, 2004, entitled Monoclonal Antibody Inhibitor Of Gm-Csf, Il-3, IL-5 And Other Cytokines, And Uses Thereof;US2005226867, published on October 13, 2005, titled "IL-5R-Specific Antibody Composition"; US2009252723, published on October 8, 2009, titled "Remedy for Endometriosis"; US2010086547, published on April 8, 2010, titled "Methods for Administering Anti-IL-5 Antibodies"; US2010291073, published on November 18, 2010, titled "Methods of Reducing Eosinophil Levels"; US2011020339, published on January 27, 2011, titled "Methods of Treatment"; US2015118249, published on April 30, 2015, titled "Stable". Aqueous Antibody Formulations; US2018155434, published June 7, 2018, titled "Therapeutic Agent and Therapeutic Method For Pulmonary Hypertension"; US2018186873, published July 5, 2018, titled "Anti-IL-5 Antibodies"; US2018251539, published September 6, 2018, titled "Biopharmaceutical Compositions"; US2020262909, published August 20, 2020, titled "IL-5 Antibody, Antigen Binding Fragment Thereof, And Medical Application Thereof"; US2020291121, published September 17, 2020, titled "Anti-IL-5 Ralpha". Monoclonal Antibody; US2020399382, published on December 24, 2020, and entitled Combined AntagonistsAgainst IL-5 / IL-5R And Either Il-4 / Il-4R Or Il-13 / Il-13R;US2021171621, published on June 10, 2021, is titled "Monoclonal Antibody Binding To Human IL-5, Preparation Method Therefor And Use Thereof"; WO21249373, published on December 16, 2021, is titled "Stable High-Concentration Anti-Human IL-5 Monoclonal Antibody Liquid Preparation"; US2022010008, published on January 13, 2022, is titled "Anti-Human Interleukin 5 (IL-5) Monoclonal Antibody And Use Thereof"; US2022144937, published on May 12, 2022, is titled "Pharmaceutical Composition Containing Antibody Against IL-5 And Use". Thereof; US2022193238, published on June 23, 2022, entitled "Anti-IL5R Antibody Formulations"; US2023357415, published on November 9, 2023, entitled "Bispecific Antibody Simultaneously Binding To Interleukin-4 Receptor Alpha Subunit And Interleukin-5 Receptor Alpha Subunit, And Use Thereof"; US2023399395, published on December 14, 2023, entitled "Anti-IL5 Nanoantibody And Use Thereof"; US2023416380, published on December 28, 2023, entitled "Antibody Binding Human IL-5R Alpha And Use Thereof; and US2024115698, published on April 11, 2024, entitled Anti-IL-5 Antibody Formulation, Preparation Method Therefor And Use Thereof, the contents of which describe anti-IL-5 or anti-IL-5R antibodies are incorporated herein by reference.

[0152] In some embodiments, the Th2-targeting antibody contains an antigen-specific binding site for IL-9 or its receptor. In some embodiments, the Th2-targeting antibody contains an antigen-specific binding site for IL-9 or IL-9R derived from any known anti-IL-9 or its receptor, such as the anti-IL-9 / anti-IL-9R antibodies described below: US5789237, published August 4, 1998, entitled *Nucleic Acid Sequences Coding For Or Complementary To Nucleic Acid Sequences Coding For Interleukin 9 Receptor*; US5908839, published June 1, 1999, entitled *Asthma Associated Factors As Targets For Treating Atopic Allergies Including Asthma And Related Disorders*; and US2003219439, published November 27, 2003, entitled *Recombinant Anti-Interleukin-9*. Antibodies; US2005002934, published January 6, 2005, entitled Recombinant IL-9 Antibodies And Uses Thereof; US2005260204, published November 24, 2005, entitled Anti-IL-9 Antibody Formulations And Uses Thereof; WO23246570, published December 28, 2023, entitled Interleukin-9 Antibody And Use Thereof; and US2024109960, published April 4, 2024, entitled Anti-IL-9 Antibodies And Methods Of Use Thereof, the contents of each of which describe anti-IL-9 or anti-IL-9R antibodies are incorporated herein by reference.

[0153] In some implementations, Th2-targeting antibodies contain an antigen-specific binding site for IL-25 or its receptor. In some implementations, the Th2-targeting antibody comprises an antigen-specific binding site for IL-25 or IL-25R derived from any known anti-IL-25 or its receptor, such as the anti-IL-25 / anti-IL-25R antibodies described below: US2010028343, published February 4, 2010, entitled "ILL17 Homologous Polypeptides And Therapeutic Uses Thereof"; US2010129380, published May 27, 2010, entitled "Antibodies Against IL-25"; US7771719, published August 10, 2010, entitled "Pharmaceutical Compositions, Kits, And Therapeutic Uses Of Antagonist Antibodies To IL-17E"; and US2011250195, published October 13, 2011, entitled "Antibodies Against..." IL-25; US2011318353, published on December 29, 2011, entitled "Humanized IL-25 Antibodies"; US2016083466, published on March 24, 2016, entitled "Anti-IL-25 Antibodies And Uses Thereof"; US2020291105, published on September 17, 2020, entitled "Neutralizing Monoclonal Antibodies To IL-25 And Uses Thereof"; US2021332123, published on October 28, 2021, entitled "Anti-IL-25 Antibodies And Uses Thereof"; and WO23060144, published on April 13, 2023, entitled "Monoclonal Antibodies To IL-25 And..." All descriptions of anti-IL-25 or anti-IL-25R antibodies in each of the UsesThereof documents are incorporated herein by reference.

[0154] In some implementations, the Th2-targeting antibody contains an antigen-specific binding site for IL-31 or its receptor. In some implementations, the Th2-targeting antibody comprises an antigen-specific binding site for IL-31 or IL-31R derived from any known anti-IL-31 or its receptor, such as the anti-IL-31 / anti-IL-31R antibodies described below: US2006275296, published December 7, 2006, entitled IL-31 Monoclonal Antibodies And Methods Of Use; US2007160610, published July 12, 2007, entitled Methods Of Treating Pain And Inflammation In Neuronal Tissue Using IL-31 Antagonists; US2009208494, published August 20, 2009, entitled Humanized Antibody Molecules Specific For IL-31; and US2013022616, published January 24, 2013, entitled Interleukin-31. Monoclonal Antibody; and US2024043547, published on February 8, 2024, entitled Antibody Variable Domains That Bind IL-31, the contents of each of which describing anti-IL-31 or anti-IL-31R antibodies are incorporated herein by reference.

[0155] In some implementations, Th2-targeting antibodies contain an antigen-specific binding site for IL-33 or its receptor. In some implementations, the Th2-targeting antibody comprises an antigen-specific binding site for IL-33 or IL-33R derived from any known anti-IL-33 or its receptor, such as the anti-IL-33 / anti-IL-33R antibodies described below: US2003124624, published July 3, 2003, entitled Monoclonal Antibody And Method And Kit For Immunoassay Of Soluble Human ST2; US2012213774, published August 23, 2012, entitled Antibodies Against Human IL33R And Uses Thereof; US2014004107, published January 2, 2014, entitled ST2 Antigen Binding Proteins; and US2014271658, published September 18, 2014, entitled Anti-IL-33 Antibodies And Uses. Thereof; US2016168242, published on June 16, 2016, entitled "Anti-Interleukin-33 Antibodies And Uses"; US2016289322, published on October 6, 2016, entitled "Human Anti-IL-33 Neutralizing Monoclonal Antibody"; US2016333090, published on November 17, 2016, entitled "Antibodies Directed Against Interleukin-33 (IL-33)"; US2018037644, published on February 8, 2018, entitled "Anti-IL-33 Antibodies, Compositions, Methods and Uses"; US2018118821, published on May 3, 2018, entitled "Anti-IL-33 Antibodies And..." Uses of the Theof; US2019202907, published on July 4, 2019, and titled "Method Of Treating Systemic Fibrotic Disorders Using An IL-33 / Tnf Bispecific Antibody";US2019225682, published on July 25, 2019, is titled "Method Of Treating Localized Fibrotic Disorders Using An IL-33 / Tnf Bispecific Antibody"; WO20061571, published on March 26, 2020, is titled "Anti-IL-33 Antibody For Use In Treating Eosinophilic Asthma"; US2020190182, published on June 18, 2020, is titled "IL-33 Antagonist-Containing Therapeutic Agent For Endometriosis"; US2020297845, published on September 24, 2020, is titled "Stabilized Formulations Containing Anti-IL-33". Antibodies; WO21017071, published on February 4, 2021, entitled Anti-Human ST2 Antibody And Use Thereof; US2021284725, published on September 16, 2021, entitled Anti-Interleukin-33 Antibodies And Uses Thereof; US2022041709, published on February 10, 2022, entitled Human Anti-IL-33 Monoclonal Antibody-Containing Pharmaceutical Composition; WO22039455, published on February 24, 2022, entitled Antibody Or Antigen-Binding Fragment Thereof That Specifically Binds To IL-33; WO23025932, published on March 2, 2023, entitled Treatment Of Chronic Obstructive Pulmonary Disease With An Anti-Interleukin-33 Antibody; WO23029280, which was published on March 9, 2023, and is titled Anti-Human Interleukin-33 Monoclonal Antibody And Use Thereof;WO23077685, published on May 11, 2023, entitled "Method For Preparing Concentrated Solution Comprising Monoclonal Antibody Against Human Interleukin-33 And Liquid Preparation"; WO23086807, published on May 19, 2023, entitled "Anti-Interleukin-33 Antibodies And Uses Thereof"; US2023174638, published on June 8, 2023, entitled "Formulations Of Anti-IL-33 Antibodies"; US2023220086, published on July 13, 2023, entitled "Anti-ST2 Antibody And Application Thereof"; US2023399394, published on December 14, 2023, entitled "Antibody Binding To Human IL-33, Preparation Method Thereof, And Use" Thereof; and WO24042212, published on February 29, 2024, entitled Treatment Of Asthma With An Anti-Interleukin-33 Antibody, the descriptions of anti-IL-33 or anti-IL33R antibodies in each of these publications are incorporated herein by reference.

[0156] In some implementations, Th2-targeting antibodies contain an antigen-specific binding site for IL-6 or its receptor. In some implementations, the Th2-targeting antibody comprises an antigen-specific binding site for IL-6 or IL-6R derived from any known anti-IL-6 or its receptor, such as the anti-IL-6 / anti-IL-6R antibodies described below: US2002037523, published March 28, 2002, entitled IL-6-Like Polynucleotides, Polypeptides, and Antibodies; US2002187150, published December 12, 2002, entitled Preventive And / Or Therapeutic Agent For Systemic Lupus Erythematosus Comprising Anti-IL-6 Receptor Antibody As An Active Ingredient; US2006134113, published June 22, 2006, entitled Preventive Or Therapeutic Agent For Sensitized T Cell-Mediated Diseases Comprising IL-6 Antagonist As An Active Ingredients; US2006188502, published August 24, 2006, entitled "Anti-IL-6 Antibodies, Compositions, Methods and Uses"; US2006240012, published October 26, 2006, entitled "Human Antihuman Interleukin-6 Antibody and Fragment Of Antibody"; US2006251653, published November 9, 2006, entitled "Methods For Treating Interleukin-6 Related Diseases"; US2006257407, published November 16, 2006, entitled "Anti-IL-6 Antibodies, Compositions, Methods and Uses"; US2007036785, published February 15, 2007, entitled "Pharmaceutical Composition For Treatment Of Diseases". Caused by IL-6 Production;US2007154481, published on July 5, 2007, is titled "Antibody Molecules Having Specificity For Human IL-6"; US2007178098, published on August 2, 2007, is titled "Interleukin-6 Antagonists"; US2007280945, published on December 6, 2007, is titled "High Affinity Antibodies To Human IL-6 Receptor"; US2008075726, published on March 27, 2008, is titled "Anti-IL-6 Monoclonal Antibodies And Uses Thereof"; and US2008145367, published on June 19, 2008, is titled "Methods Of Treating Osteoarthritis With IL-6". Antagonists; US2008188401, published August 7, 2008, titled Compounds; US2009028784, published January 29, 2009, titled Antibodies To IL-6 And Use Thereof; US2009220499, published September 3, 2009, titled Agents For Suppressing Damage To Transplanted Islets After Islet Transplantation; US2009220500, published September 3, 2009, titled Agents For Treating Cardiopathy; US2009297436, published December 3, 2009, titled Antibodies To IL-6 And Use Thereof; US2009297513, published on December 3, 2009, entitled Antibodies To IL-6 And Use; Thereof; US2009317402, published on December 24, 2009, entitled Antibodies To IL-6 And Their Uses;US2010098709, published on April 22, 2010, entitled "Antibodies Specific For The Complex Of Interleukin-6 And The Interleukin-6 Receptor"; US2010129357, published on May 27, 2010, entitled "Antibodies To IL-6 And Use Thereof"; US2010138945, published on June 3, 2010, entitled "Humanized Anti-IL-6 Antibodies"; US2010150829, published on June 17, 2010, entitled "Antibodies To IL-6 And Use Thereof"; US2010158859, published on June 24, 2010, entitled "Antagonists Of IL-6 To Prevent Or Treat Cachexia, Weakness, Fatigue". And / Or Fever; US2010247523, published on September 30, 2010, entitled "Subtypes Of Humanized Antibody Against Interleukin-6 Receptor"; US2010290993, published on November 18, 2010, entitled "Antibodies To IL-6 And Use Thereof"; US2011002936, published on January 6, 2011, entitled "Anti-IL-6 / IL-6R Antibodies And Methods Of Use Thereof"; US2011059080, published on March 10, 2011, entitled "Use Of An Anti-IL6 Antibody To Decrease Hepcidin In Cancer Patients"; US2011098450, published on April 28, 2011, entitled "Antibody Molecules; US2011171241, published on July 14, 2011, and entitled Stabilized Formulations Containing Anti-Interleukin-6 (IL-6) Antibodies;US2011293622, published on December 1, 2011, is titled "Antibodies To IL-6 And Use Thereof"; US2012009177, published on January 12, 2012, is titled "Gene Expression Markers For Predicting Response To Interleukin-6 Receptor-Inhibiting Monoclonal Antibody Drug Treatment"; US2012014955, published on January 19, 2012, is titled "Antagonists Of IL-6 To Raise Albumin And / Or Lower Crop"; US2012034212, published on February 9, 2012, is titled "Human Anti-IL-6 Antibodies With Extended In VivoHalf-Life And Their Use In Treatment Of Oncology, Autoimmune Diseases And Inflammatory". Diseases; US2012077731, published March 29, 2012, titled "AminoAcid Sequences Directed Against IL-6R And Polypeptides Comprising the Same For The Treatment of IL-6R Related Diseases and Disorders"; US2012121594, published May 17, 2012, titled "Anti-IL-6 Antibodies For The Treatment of Arthritis"; US2012128626, published May 24, 2012, titled "Anti-IL-6 Antibodies For The Treatment of Anemia"; US2012142900, published June 7, 2012, titled "Antibodies To IL-6 And Use Thereof; US2012189629, which was published on July 26, 2012, and its title is Anti-IL-6 Antibodies For The Treatment Of Oral Mucositis;US2012225060, published on September 6, 2012, is titled "Anti-IL-6 Receptor Antibodies And Methods Of Use"; US2012301460, published on November 29, 2012, is titled "Subcutaneously Administered Anti-IL-6 Receptor Antibody"; US2013017575, published on January 17, 2013, is titled "Nucleic Acids Encoding Anti-IL-6 Antibodies Of Defined Epitopic Specificity"; US2013028860, published on January 31, 2013, is titled "Antagonists Of IL-6 To Prevent Or Treat Cachexia, Weakness, Fatigue And / or Fever; US2013034554, published on February 7, 2013, entitled "Antibodies To IL-6 And Use Thereof"; US2013224201, published on August 29, 2013, entitled "Antibodies To IL-6 And Use Thereof"; US2014079702, published on March 20, 2014, entitled "Antagonists Of IL-6 To Raise Albumin And / Or Lower Cripple"; US2014112935, published on April 24, 2014, entitled "Antibodies To Interleukin-6 And Use Thereof"; US2014127209, published on May 8, 2014, entitled "Antibody". Derivatives; US2014363430, published on December 11, 2014, and entitled "Activatable Antibodies That Bind Interleukin-6 Receptor And Methods of Use Thereof";US2015125450, published on May 7, 2015, is titled "Bispecific Antibodies That Neutralize Both TnF-Alpha And IL-6: Novel Therapeutic Agent For Autoimmune Disease"; US2015132224, published on May 14, 2015, is titled "Antibodies To IL-6 And Use Thereof"; US2015197567, published on July 16, 2015, is titled "Antibodies To IL-6 And Use Thereof"; US2015259413, published on September 17, 2015, is titled "Antibodies To IL-6 And Use Thereof"; US2015273058, published on October 1, 2015, is titled "Antagonists Of IL-6 To Prevent Or Treat Cachexia". Weakness, Fatigue, and / or Fever; US2015274822, published October 1, 2015, titled "Antagonists Of IL-6 To Raise Albumin And / or Lower Cripple"; US2015274823, published October 1, 2015, titled "Antibodies To IL-6 And Use Thereof"; US2015337036, published November 26, 2015, titled "Antibodies To IL-6 And Use Thereof"; US2015344558, published December 3, 2015, titled "Anti-IL-6 Antibodies For The Treatment Of Arthritis"; US2015368337, published December 24, 2015, titled "Anti-IL-6 Antibodies For..." The Treatment of Oral Mucositis; US2016130340, published on May 12, 2016, and titled Dosing Regimens Using Anti-IL-6 Antibodies For The Treatment Of Rheumatoid And Psoriatic Arthritis;US2016326252, published November 10, 2016, titled "Treatment of IL-6R Related Diseases"; US2016340423, published November 24, 2016, titled "Anti-IL-6 Antibodies For The Treatment of Anemia"; US2017115307, published April 27, 2017, titled "Antibodies To IL-6 And Use Thereof"; US2017166646, published June 15, 2017, titled "Compositions Comprising IL6R Antibodies For The Treatment of Uveitis And Macular Edema And Methods Of Using Same"; US2017291950, published October 12, 2017, titled "Method For Treating Multiloculated Hydrocephalus By Administering an Anti-IL-6 Receptor Antibody; US2018022801, published January 25, 2018, titled "Antibodies To IL-6 And Use Thereof"; US2018066046, published March 8, 2018, titled "Anti-IL-6 Antibodies For The Treatment Of Arthritis"; US2018092999, published April 5, 2018, titled "Antibodies To IL-6 And Use Thereof"; US2018100013, published April 12, 2018, titled "Antibodies To IL-6 And Use Thereof"; US2018186874, published July 5, 2018, titled "Antibodies To IL-6 And Use Thereof". Thereof; US2018201668, published on July 19, 2018, entitled "In Vivo Imaging Using Anti-IL-6 Antibodies"; US2018201675, published on July 19, 2018, entitled "Antibodies To IL-6 And Use Thereof";US2018371079, published on December 27, 2018, titled "Antibodies To IL-6 And Use Thereof"; US2019023780, published on January 24, 2019, titled "Anti-IL-6 Antibodies For The Treatment Of Oral Mucositis"; US2019083665, published on March 21, 2019, titled "Antibodies To IL-6 And Use Thereof"; US2019192692, published on June 27, 2019, titled "Dna Monoclonal Antibodies Targeting IL-6 And Cd126"; US2019194312, published on June 27, 2019, titled "IL-6..." Antibodies; US2019194313, published on June 27, 2019, entitled "Antibody Or An Antigen-Binding Fragment Thereof Capable Of Binding To A Human Receptor Of Interleukin-6"; US2019218300, published on July 18, 2019, entitled "Liquid Pharmaceutical Composition"; US2019270806, published on September 5, 2019, entitled "IL-6 Antibodies And Fusion Constructs And Conjugates Thereof"; US2019315854, published on October 17, 2019, entitled "Antibodies, Composition And Kits Comprising Same, And Methods Of Use Thereof"; US2020040074, published on February 6, 2020, entitled "Antibodies To IL-6" And Use Thereof; US2020087391, published on March 19, 2020, and titled Antibodies To IL-6 And Use Thereof; US2020108140, published on April 9, 2020, and titled Antibodies To IL-6 And Use Thereof;US2020140539, published on May 7, 2020, is titled "Anti-IL-6 Antibodies For The Treatment of Anemia"; US2020165295, published on May 28, 2020, is titled "Method For Purifying Anti-IL-6 Receptor Antibodies"; US2020299391, published on September 24, 2020, is titled "Anti-IL-6 Receptor Antibody - Containing Medicinal Composition For Preventing Post-Surgical Adhesion"; and US2020339693, published on October 29, 2020, is titled "Compositions and Methods For Treating Juvenile Idiopathic Arthritis; US2020369774, published November 26, 2020, titled "IL-6R Antibody And Antigen Binding Fragment Thereof And Medical Use"; US2021070853, published March 11, 2021, titled "Use Of Anti-IL-6 Antibody, EG, Clazakizumab For Desensitization Of Solid Organ Transplant Recipients And / Or For Preventing, Stabilizing Or Reducing Antibody Mediated Rejection (Abmr)"; US2021246201, published August 12, 2021, titled "Antibodies To IL-6 And Use Thereof"; US2021284743, published September 16, 2021, titled "Compositions Of IL-6 / IL-6R Antibodies And Methods Of Use". Thereof; US2021332126, which was published on October 28, 2021, and is titled Anti-IL-6 Antibodies For The Treatment Of Oral Mucositis;US2021395357, published on December 23, 2021, is titled "Humanized Monoclonal Antibodies Against Interleukin-6, Encoding Genes And Uses Thereof"; US2022040301, published on February 10, 2022, is titled "Anti-IL-6 Antibody Formulation"; US2022071901, published on March 10, 2022, is titled "A Liquid Formulation Of Humanized Antibody For Treating IL-6-Mediated Diseases"; and US2022220210, published on July 14, 2022, is titled "Anti-IL-6 Receptor Antibody - Containing Inhibitor For Inhibiting Deterioration Of Bbb". Functions; US2022396615, published on December 15, 2022, entitled "Anti-Human IL6 Monoclonal Antibodies, Preparation Method Therefor And Use Thereof"; US2023167182, published on June 1, 2023, entitled "Antibodies Binding IL6R And Uses Thereof"; US2023174640, published on June 8, 2023, entitled "Use Of Anti-IL-6 Antibody, EG, Clazakizumab For Treatment / Prevention Of Ards Associated With Coronavirus (Covid-19) Infection"; US2023174657, published on June 8, 2023, entitled "Compositions Comprising An Antibody Against Interleukin-6 Receptor For The Treatment Of Rheumatoid Arthritis And Methods Of Using Same;US2024209076, published on June 27, 2024, is titled "Use Of IL-6 Antibodies And Vegf Traps, And Fusion Constructs And Conjugates Thereof"; US5559012, published on September 24, 1996, is titled "Therapeutic, IL-6 Antibody Kits, And Process For Their Preparation"; US5618700, published on April 8, 1997, is titled "IL-6 Specific Monoclonal Antibodies, Hybridomas Therefor And Methods Of Making And Using Same"; US5795965, published on August 18, 1998, is titled "Reshaped Human To Human Interleukin-6 Receptor"; US5856135, published on January 5, 1999, is titled "Reshaped Human Antibody To Human Interleukin-6; US5888510, published on March 30, 1999, entitled "Chronic Rheumatoid Arthritis Therapy Containing IL-6 Antagonist As Effective Component"; US6261560, published on July 17, 2001, entitled "Method For Inhibiting Muscle Protein Proteolysis With Antibodies To Interleukin-6 Receptor"; US6723319, published on April 20, 2004, entitled "Method Of Treating Inflammatory Intestinal Diseases Containing As The Ingredient IL-6 Receptors Antibodies"; US8440196, published on May 14, 2013, entitled "Treatment For Pancreatitis Using IL-6 Receptor Antagonist Antibodies".US8632778, published on January 21, 2014, entitled "Stabilized Anti-Interleukin-6 Receptor Antibody-Containing Preparations"; WO08144763, published on November 27, 2008, entitled "Antibodies To IL-6 And Use Thereof"; WO09109584, published on September 11, 2009, entitled "Antibody Binding Only To IL6-SIL6R Complex"; WO10065072, published on June 10, 2010, entitled "Antagonists Of IL-6 To Raise Albumin And / Or Lower Cripple"; WO10065078, published on June 10, 2010, entitled "Antagonists Of IL-6 To Prevent Or Treat Cachexia, Weakness, Fatigue And / Or..." Fever; WO11066369, published on June 3, 2011, titled "Antagonists Of IL-6 To Raise Albumin And / Or Lower Cripple"; WO11066371, published on June 3, 2011, titled "Antibodies To IL-6 And Use Thereof"; WO12071554, published on May 31, 2012, titled "Anti-IL-6 Antibodies For The Treatment Of Oral Mucositis"; WO12071561, published on May 31, 2012, titled "Anti-IL-6 Antibodies For The Treatment Of Anemia"; WO15116852, published on August 6, 2015, titled "Methods For Treating Rheumatoid Arthritis By Administering An IL-6R Antibody; WO18029182, which was published on February 15, 2018, and is titled IL-6R Single Variable Domain Antibodies For Treatment Of IL-6R Related Diseases;WO21164107, published on August 26, 2021, is titled "Novel Application Of IL-6 Receptor Antibodies"; WO22037606, published on February 24, 2022, is titled "Liquid Formulations Comprising High Concentrations Humanized Antibodies For Treating IL-6 Related Diseases"; WO22179432, published on September 1, 2022, is titled "Antibody Fusion Proteins Targeting IL-6 Receptor And Angiogenic Factors"; WO23020563, published on February 23, 2023, is titled "Liquid Formulations Comprising High Concentrations Humanized Antibodies For Treating IL-6 Related Diseases"; and WO23217933, published on November 16, 2023, is titled "Antibody That Binds To Vegf-A and IL-6 and Methods of Use; WO24036385, published on February 22, 2024, entitled Treatment of Myocarditis By Administration of Anti-Interleukin-6 Antibodies; WO24093652, published on May 10, 2024, entitled Application of Nanobody Targeting On IL-6R; WO24170583, published on August 22, 2024, entitled Antibodies Binding To Human Interleukin-6 Receptor; and WO9509873, published on April 13, 1995, entitled A Monoclonal Anti-Human IL-6 Receptor Antibody, the descriptions of anti-IL-6 or anti-IL-6R antibodies in each of these are incorporated herein by reference.

[0157] In some embodiments, the Th2-targeting antibody comprises the HC CDR1, HC CDR2, and HC CDR3 of the VH of any of the anti-IL-13 antibodies or anti-IL-13R antibodies listed in Table 2, and the LC CDR1, LC CDR2, and LC CDR3 of the VL of any of the anti-IL-13 antibodies or anti-IL-13R antibodies listed in Table 2. In some embodiments, the Th2-targeting antibody comprises the VH and VL of any of the anti-IL-13 antibodies listed in Table 2. In some embodiments, the Th2-targeting antibody comprises the HC CDR1, HC CDR2, and HC CDR3 of anluzumab, and the LC CDR1, LCCDR2, and LC CDR3 of anluzumab. In some embodiments, the Th2-targeting antibody comprises the VH and VL of anluzumab. In some embodiments, the Th2-targeting antibody comprises HC CDR1, HC CDR2, HC CDR3 and LC CDR1, LC CDR2, and LC CDR3 of leridgecizumab. In some embodiments, the Th2-targeting antibody comprises VH and VL of leridgecizumab. In some embodiments, the Th2-targeting antibody comprises HC CDR1, HC CDR2, HC CDR3 and LC CDR1, LC CDR2, and LC CDR3 of trorocalumab. In some embodiments, the Th2-targeting antibody comprises VH and VL of trorocalumab. In some embodiments, the Th2-targeting antibody comprises HC CDR1, HC CDR2, HC CDR3 and LC CDR1, LC CDR2, and LC CDR3 of ixazolizumab. In some embodiments, the Th2-targeting antibody comprises VH and VL of ixazolizumab. In some embodiments, the Th2-targeting antibody comprises HC CDR1, HC CDR2, HC CDR3 of sendazumab and LC CDR1, LC CDR2, and LC CDR3 of sendazumab. In some embodiments, the Th2-targeting antibody comprises VH and VL of sendazumab. In some embodiments, the Th2-targeting antibody comprises HC CDR1, HC CDR2, HC CDR3 of detkumab and LC CDR1, LC CDR2, and LC CDR3 of detkumab. In some embodiments, the Th2-targeting antibody comprises VH and VL of detkumab. In some embodiments, the Th2-targeting antibody comprises 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 comprises VH and VL of APG777.

[0158] In some embodiments, the Th2-targeting antibody contains an antigen-specific binding site for IL-4 or its receptor. In some embodiments, the Th2-targeting antibody contains the HCCDR1, HC CDR2, and HC CDR3 of the VH of any of the anti-IL-4 antibodies or anti-IL-4R antibodies in Table 2, and the LC CDR1, LC CDR2, and LC CDR3 of the VL of any of the anti-IL-4 antibodies or anti-IL-4R antibodies in Table 2. In some embodiments, the Th2-targeting antibody contains the VH of any of the anti-IL-4 antibodies or anti-IL-4R antibodies in Table 2 and the VL of any of the anti-IL-4 antibodies or anti-IL-4R antibodies in Table 2. In some embodiments, the Th2-targeting antibody contains the HC CDR1, HC CDR2, and HC CDR3 of dupilumab, and the LCCDR1, LC CDR2, and LC CDR3 of dupilumab. In some embodiments, the Th2-targeting antibody contains the VH of dupilumab and the VL of dupilumab. In some embodiments, the Th2-targeting antibody comprises HC CDR1, HC CDR2, HCCDR3 of pacocilizumab and LC CDR1, LC CDR2, and LC CDR3 of pacocilizumab. In some embodiments, the Th2-targeting antibody comprises VH and VL of pacocilizumab. In some embodiments, the Th2-targeting antibody comprises HCCDR1, 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 comprises VH and VL of AMG 317. In some embodiments, the Th2-targeting antibody comprises HC CDR1, HC CDR2, HC CDR3 of sprozimab and LC CDR1, LC CDR2, and LC CDR3 of sprozimab. In some embodiments, the Th2-targeting antibody comprises VH and VL of sprozimab. In some embodiments, the Th2-targeting antibody comprises HC CDR1, HC CDR2, HC CDR3 and LC CDR1, LC CDR2 and LC CDR3 of ledeqibaimab. In some embodiments, the Th2-targeting antibody comprises VH and VL of ledeqibaimab. In some embodiments, the Th2-targeting antibody comprises HC CDR1, HC CDR2, HCCDR3 and LC CDR1, LC CDR2 and LC CDR3 of mandozizumab. In some embodiments, the Th2-targeting antibody comprises VH and VL of mandozizumab.

[0159] In some embodiments, the Th2-targeting antibody contains an antigen-specific binding site for IL-5 or its receptor. In some embodiments, the Th2-targeting antibody contains the HCCDR1, HC CDR2, and HC CDR3 of the VH of any of the anti-IL-5 antibodies or anti-IL-5R antibodies listed in Table 2, and the LC CDR1, LC CDR2, and LC CDR3 of the VL of any of the anti-IL-5 antibodies or anti-IL-5R antibodies listed in Table 2. In some embodiments, the Th2-targeting antibody contains the VH of any of the anti-IL-5 antibodies or anti-IL-5R antibodies listed in Table 2 and the VL of any of the anti-IL-5 antibodies or anti-IL-5R antibodies listed in Table 2. In some embodiments, the Th2-targeting antibody contains the HC CDR1, HC CDR2, and HC CDR3 of benzodiazepine and the LC CDR1, LC CDR2, and LC CDR3 of benzodiazepine. In some embodiments, the Th2-targeting antibody contains the VH of benzodiazepine and the VL of benzodiazepine. In some embodiments, the Th2-targeting antibody comprises HC CDR1, HC CDR2, HC CDR3 and LC CDR1, LC CDR2, and LC CDR3 of mepolizumab. In some embodiments, the Th2-targeting antibody comprises VH and VL of mepolizumab. In some embodiments, the Th2-targeting antibody comprises HC CDR1, HCCDR2, HC CDR3 and LC CDR1, LC CDR2, and LC CDR3 of retalizumab. In some embodiments, the Th2-targeting antibody comprises VH and VL of retalizumab. In some embodiments, the Th2-targeting antibody comprises HC CDR1, HC CDR2, HC CDR3 and LC CDR1, LC CDR2, and LC CDR3 of dmoxicillin. In some embodiments, the Th2-targeting antibody comprises VH and VL of dmoxicillin. In some embodiments, the Th2-targeting antibody comprises HC CDR1, HC CDR2, and HCCDR3 of clone 601 described by WO2019120,060 or WO2021249,373, and LC CDR1, LC CDR2, and LCCDR3 of clone 601 described by WO2019120,060 or WO2021249,373. In some embodiments, the Th2-targeting antibody comprises VH of clone 601 described by WO2019120,060 or WO2021249,373, and VL of clone 601 described by WO2019120,060 or WO2021249,373.In some embodiments, the Th2-targeting antibody comprises HC CDR1, HC CDR2, HC CDR3 of tericitabimab and LCCDR1, LC CDR2, and LC CDR3 of tericitabimab. In some embodiments, the Th2-targeting antibody comprises VH and VL of tericitabimab.

[0160] In some embodiments, the Th2-targeting antibody contains an antigen-specific binding site for IL-9 or its receptor. In some embodiments, the Th2-targeting antibody contains the HCCDR1, HC CDR2, and HC CDR3 of the VH of any of the anti-IL-9 antibodies or anti-IL-9R antibodies listed in Table 2, and the LCCDR1, LC CDR2, and LC CDR3 of the VL of any of the anti-IL-9 antibodies or anti-IL-9R antibodies listed in Table 2. In some embodiments, the Th2-targeting antibody contains the VH of any of the anti-IL-9 antibodies or anti-IL-9R antibodies listed in Table 2 and the VL of any of the anti-IL-9 antibodies or anti-IL-9R antibodies listed in Table 2. In some embodiments, the Th2-targeting antibody contains the HC CDR1, HC CDR2, and HC CDR3 of enokaimib monoclonal antibody, and the LCCDR1, LC CDR2, and LC CDR3 of enokaimib monoclonal antibody. In some embodiments, the Th2-targeting antibody contains the VH and VL of enokaimib monoclonal antibody.

[0161] In some embodiments, the Th2-targeting antibody contains an antigen-specific binding site for OX40 or its ligand. In some embodiments, the Th2-targeting antibody contains the HCCDR1, HC CDR2, and HC CDR3 of the VH of any of the anti-OX40 or anti-OX40L antibodies listed in Table 2, and the LCCDR1, LC CDR2, and LC CDR3 of the VL of any of the anti-OX40 or anti-OX40L antibodies listed in Table 2. In some embodiments, the Th2-targeting antibody contains the VH of any of the anti-OX40 or anti-OX40L antibodies listed in Table 2 and the VL of any of the anti-OX40 or anti-OX40L antibodies listed in Table 2. In some embodiments, the Th2-targeting antibody contains the HC CDR1, HC CDR2, and HC CDR3 of rocatinib, and the LCCDR1, LC CDR2, and LC CDR3 of rocatinib. In some embodiments, the Th2-targeting antibody contains the VH and VL of rocatinib. In some embodiments, the Th2-targeting antibody comprises HC CDR1, HCCDR2, HC CDR3 of oxeructumab and LC CDR1, LC CDR2, and LC CDR3 of oxeructumab. In some embodiments, the Th2-targeting antibody comprises VH and VL of oxeructumab. In some embodiments, the Th2-targeting antibody comprises HC CDR1, HC CDR2, HC CDR3 of trazolimumab and LC CDR1, LC CDR2, and LC CDR3 of trazolimumab. In some embodiments, the Th2-targeting antibody comprises VH and VL of trazolimumab. In some embodiments, the Th2-targeting antibody comprises HC CDR1, HC CDR2, HC CDR3 of amilorimab and LCCDR1, LC CDR2, and LC CDR3 of amilorimab. In some embodiments, the Th2-targeting antibody comprises VH and VL of amilorimab. In some embodiments, the Th2-targeting antibody comprises HC CDR1, HC CDR2, HC CDR3 of IMG-007 and LC CDR1, LC CDR2, and LC CDR3 of IMG-007. In some embodiments, the Th2-targeting antibody comprises VH and VL of IMG-007.

[0162] In some embodiments, the Th2-targeting antibody comprises an antigen-specific binding site for IL-25 (also known as IL-17E) or its receptor. In some embodiments, the Th2-targeting antibody comprises the HC CDR1, HC CDR2, and HC CDR3 of the VH of any of the anti-IL-25 antibodies or anti-IL-25R antibodies listed in Table 2, and the LC CDR1, LC CDR2, and LC CDR3 of the VL of any of the anti-IL-25 antibodies or anti-IL-25R antibodies listed in Table 2. In some embodiments, the Th2-targeting antibody comprises the VH of any of the anti-IL-25 antibodies or anti-IL-25R antibodies listed in Table 2 and the VL of any of the anti-IL-25 antibodies or anti-IL-25R antibodies listed in Table 2. In some embodiments, the Th2-targeting antibody comprises the HC CDR1, HC CDR2, and HCCDR3 of brolmumabala, and the LC CDR1, LC CDR2, and LC CDR3 of brolmumabala. In some embodiments, the Th2-targeting antibody comprises the VH and VL of brolemumab. In some embodiments, the Th2-targeting antibody comprises HC CDR1, HC CDR2, HC CDR3 of LNR125 and LC CDR1, LC CDR2, and LC CDR3 of LNR125. In some embodiments, the Th2-targeting antibody comprises the VH and VL of LNR125.

[0163] In some embodiments, the Th2-targeting antibody contains an antigen-specific binding site for IL-31 or its receptor. In some embodiments, the Th2-targeting antibody contains the HC CDR1, HC CDR2, and HC CDR3 of the VH of any of the anti-IL-31 antibodies or anti-IL-31R antibodies listed in Table 2, and the LC CDR1, LC CDR2, and LC CDR3 of the VL of any of the anti-IL-31 antibodies or anti-IL-31R antibodies listed in Table 2. In some embodiments, the Th2-targeting antibody contains the VH of any of the anti-IL-31 antibodies or anti-IL-31R antibodies listed in Table 2 and the VL of any of the anti-IL-31 antibodies or anti-IL-31R antibodies listed in Table 2. In some embodiments, the Th2-targeting antibody contains the HC CDR1, HC CDR2, and HC CDR3 of nemolizumab, and the LC CDR1, LC CDR2, and LC CDR3 of nemolizumab. In some embodiments, the Th2-targeting antibody contains the VH and VL of nemolizumab. In some embodiments, the Th2-targeting antibody comprises HC CDR1, HC CDR2, HC CDR3 of vesarelimab and LC CDR1, LC CDR2, and LC CDR3 of vesarelimab. In some embodiments, the Th2-targeting antibody comprises VH and VL of vesarelimab. In some embodiments, the Th2-targeting antibody comprises HC CDR1, HC CDR2, HC CDR3 of NM26-2198 and LC CDR1, LC CDR2, and LCCDR3 of NM26-2198. In some embodiments, the Th2-targeting antibody comprises VH and VL of NM26-2198. In some embodiments, the Th2-targeting antibody comprises HC CDR1, HC CDR2, HC CDR3 of BMS-981164 and LCCDR1, LC CDR2, and LC CDR3 of BMS-981164. In some implementations, the Th2-targeting antibody comprises the VH and VL of BMS-981164.

[0164] In some embodiments, the Th2-targeting antibody contains an antigen-specific binding site for IL-36 or its receptor. In some embodiments, the Th2-targeting antibody contains the HC CDR1, HC CDR2, and HC CDR3 of the VH of any of the anti-IL-36 antibodies or anti-IL-36R antibodies listed in Table 2, and the LC CDR1, LC CDR2, and LC CDR3 of the VL of any of the anti-IL-36 antibodies or anti-IL-36R antibodies listed in Table 2. In some embodiments, the Th2-targeting antibody contains the VH of any of the anti-IL-36 antibodies or anti-IL-36R antibodies listed in Table 2 and the VL of any of the anti-IL-36 antibodies or anti-IL-36R antibodies listed in Table 2. In some embodiments, the Th2-targeting antibody contains the HC CDR1, HC CDR2, and HC CDR3 of sapristallizumab, and the LC CDR1, LC CDR2, and LC CDR3 of sapristallizumab. In some embodiments, the Th2-targeting antibody contains the VH and VL of sapristallizumab. In some embodiments, the Th2-targeting antibody comprises HC CDR1, HC CDR2, HC CDR3 of emisilimab and LC CDR1, LC CDR2, and LC CDR3 of emisilimab. In some embodiments, the Th2-targeting antibody comprises VH and VL of emisilimab. In some embodiments, the Th2-targeting antibody comprises HC CDR1, HC CDR2, HC CDR3 of HB0034 and LC CDR1, LC CDR2, and LC CDR3 of HB0034. In some embodiments, the Th2-targeting antibody comprises VH and VL of HB0034.

[0165] In some embodiments, the Th2-targeting antibody comprises an antigen-specific binding site for thymic stromal lymphopoietin (TSLP) or its receptor. In some embodiments, the Th2-targeting antibody comprises the HC CDR1, HC CDR2, and HC CDR3 of the VH of any of the anti-TSLP or anti-TSLPR antibodies listed in Table 2, and the LC CDR1, LC CDR2, and LC CDR3 of the VL of any of the anti-TSLP or anti-TSLPR antibodies listed in Table 2. In some embodiments, the Th2-targeting antibody comprises the VH of any of the anti-TSLP or anti-TSLPR antibodies listed in Table 2 and the VL of any of the anti-TSLP or anti-TSLPR antibodies listed in Table 2. In some embodiments, the Th2-targeting antibody comprises the HC CDR1, HC CDR2, and HC CDR3 of tazepluzumab, and the LC CDR1, LC CDR2, and LC CDR3 of tazepluzumab. In some embodiments, the Th2-targeting antibody comprises the VH of tazepluzumab and the VL of tazepluzumab. In some embodiments, the Th2-targeting antibody comprises HC CDR1, HC CDR2, HC CDR3 of eclalimumab and LC CDR1, LC CDR2, and LCCDR3 of eclalimumab. In some embodiments, the Th2-targeting antibody comprises VH and VL of eclalimumab. In some embodiments, the Th2-targeting antibody comprises HC CDR1, HC CDR2, HC CDR3 of BSI-045B and LCCDR1, LC CDR2, and LC CDR3 of BSI-045B. In some embodiments, the Th2-targeting antibody comprises VH and VL of BSI-045B. In some embodiments, the Th2-targeting antibody comprises 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 comprises VH and VL of CM326.

[0166] In some embodiments, the Th2-targeting antibody contains an antigen-specific binding site for IL-33 or its receptor. In some embodiments, the Th2-targeting antibody contains the HC CDR1, HC CDR2, and HC CDR3 of the VH of any of the anti-IL-33 antibodies or anti-IL-33R antibodies listed in Table 2, and the LC CDR1, LC CDR2, and LC CDR3 of the VL of any of the anti-IL-33 antibodies or anti-IL-33R antibodies listed in Table 2. In some embodiments, the Th2-targeting antibody contains the VH of any of the anti-IL-33 antibodies or anti-IL-33R antibodies listed in Table 2 and the VL of any of the anti-IL-33 antibodies or anti-IL-33R antibodies listed in Table 2. In some embodiments, the Th2-targeting antibody contains the HC CDR1, HC CDR2, and HC CDR3 of toledizumab, and the LC CDR1, LC CDR2, and LC CDR3 of toledizumab. In some embodiments, the Th2-targeting antibody contains the VH and VL of toledizumab. In some embodiments, the Th2-targeting antibody comprises HC CDR1, HC CDR2, HCCDR3 of etanercumab and LC CDR1, LC CDR2, and LC CDR3 of etanercumab. In some embodiments, the Th2-targeting antibody comprises VH and VL of etanercumab. In some embodiments, the Th2-targeting antibody comprises HCCDR1, HC CDR2, HC CDR3 of etozymezumab and LC CDR1, LC CDR2, and LC CDR3 of etozymezumab. In some embodiments, the Th2-targeting antibody comprises VH and VL of etozymezumab. In some embodiments, the Th2-targeting antibody comprises HC CDR1, HC CDR2, HC CDR3 of PF-07264660 and LC CDR1, LC CDR2, and LCCDR3 of PF-07264660. In some implementations, the Th2-targeting antibody comprises the VH and VL of PF-07264660.

[0167] (c) Multispecific antibodies 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) may be combined with one or more different anti-KLK5 / KLK7 antibodies described herein (Tables 1a and 1b) to produce multispecific antibodies.

[0168] In some implementations, one or more anti-KLK5 / KLK7 antibodies can be combined with any other suitable therapeutic antibody to produce multispecific or bispecific anti-KLK5 / KLK7 / additional target antibodies. For example, anti-KLK5 / KLK7 antibodies as described herein (Tables 1a and 1b) can be combined with any suitable antibody (e.g., Th2-targeting antibodies as described in Table 2) to produce 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.

[0169] In some aspects, this 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 T helper cell 2 (Th2) cytokines (i.e., cytokines produced by Th2 cells) or their receptors. In some embodiments, 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, at least one antigen-specific binding site that specifically binds to T helper cell 2 (Th2) cytokines or their receptors 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 T helper cell 2 (Th2) cytokines or their receptors binds to IL-9, IL-31, IL-33, OX40, IL-36, JAG1, and TSLP.

[0170] Table 6 below shows the possible arm configurations of the anti-KLK5 / KLK7+Th2 targeting bispecific antibody. In some embodiments, the anti-KLK5 / KLK7+Th2 targeting bispecific antibody includes an arm containing a CDR and / or VH and / or VL, the sequence of which is derived from or corresponds to or is identical to the CDR and / or VH and / or VL sequences of the antibodies listed in the left column of Table 6, and a second arm containing a CDR and / or VH / VL, the sequence of which is derived from or corresponds to or is identical to the CDR and / or VH and / or VL sequences of the antibody listed in the corresponding row in the right column of Table 6 or another suitable antibody disclosed herein. The CDRs and VH / VLs of the various antibodies are listed in Tables 1a and 2.

[0171] Table 6: Arm configuration of anti-KLK5 / KLK7 + Th2 bispecific antibody

[0172] In some embodiments, the anti-KLK5 / KLK7 + Th2 targeting bispecific antibody includes an arm comprising a CDR and / or VH / VL pair, the sequence of which is derived from or corresponds to, or is identical to, the CDR and / or VH / VL sequences of the anti-KLK5 / KLK7 antibodies listed in Table 1a, and a second arm comprising a CDR and / or VH / VL, the sequence of which is derived from or corresponds to, or is identical to, the CDR and / or VH / VL sequences of the anti-IL-13 or anti-IL-13R antibodies listed in Table 2, Table 6, or elsewhere herein. In some embodiments, the anti-KLK5 / KLK7 + Th2 bispecific antibody may include an arm comprising an antigen-specific binding site targeting KLK5 and KLK7, and a second arm comprising an antigen-specific binding site not targeting IL-13 or IL-13R.

[0173] In some embodiments, the anti-KLK5 / KLK7+Th2 targeting bispecific antibody includes an arm comprising a CDR and / or VH / VL pair, the sequence of which is derived from or corresponds to, or is identical to, the CDR and / or VH / VL sequences of the anti-KLK5 / KLK7 antibodies listed in Table 1a, and a second arm comprising a CDR and / or VH / VL, the sequence of which is derived from or corresponds to, or is identical to, the CDR and / or VH / VL sequences of the anti-IL-4 or anti-IL4R antibodies listed in Table 2, Table 6, or elsewhere herein. In some embodiments, the anti-KLK5 / KLK7+Th2 bispecific antibody may include an arm comprising antigen-specific binding sites targeting KLK5 and KLK7, and a second arm comprising antigen-specific binding sites not targeting IL-4 or IL-4R.

[0174] In some embodiments, the anti-KLK5 / KLK7+Th2 targeting bispecific antibody includes an arm comprising a CDR and / or VH / VL pair, the sequence of which is derived from or corresponds to, or is identical to, the CDR and / or VH / VL sequences of the anti-KLK5 / KLK7 antibodies listed in Table 1a, and a second arm comprising a CDR and / or VH / VL, the sequence of which is derived from or corresponds to, or is identical to, the CDR and / or VH / VL sequences of the anti-IL-5 or anti-IL-5R antibodies listed in Table 2, Table 6, or elsewhere herein. In some embodiments, the anti-KLK5 / KLK7+Th2 bispecific antibody may include an arm comprising an antigen-specific binding site targeting KLK5 and KLK7, and a second arm comprising an antigen-specific binding site not targeting IL-5 or IL-5R.

[0175] In some embodiments, the anti-KLK5 / KLK7+Th2 targeting bispecific antibody includes an arm comprising a CDR and / or VH / VL pair, the sequence of which is derived from or corresponds to, or is identical to, the CDR and / or VH / VL sequences of the anti-KLK5 / KLK7 antibodies listed in Table 1a, and a second arm comprising a CDR and / or VH / VL, the sequence of which is derived from or corresponds to, or is identical to, the CDR and / or VH / VL sequences of the anti-IL-25 or anti-IL-25R antibodies listed in Table 2, Table 6, or elsewhere herein. In some embodiments, the anti-KLK5 / KLK7+Th2 bispecific antibody may include an arm comprising an antigen-specific binding site targeting KLK5 and KLK7, and a second arm comprising an antigen-specific binding site not targeting IL-25 or IL-25R.

[0176] In some embodiments, the anti-KLK5 / KLK7+Th2 targeting bispecific antibody includes an arm comprising a CDR and / or VH / VL pair, the sequence of which is derived from or corresponds to, or is identical to, the CDR and / or VH / VL sequences of the anti-KLK5 / KLK7 antibodies listed in Table 1a, and a second arm comprising a CDR and / or VH / VL, the sequence of which is derived from or corresponds to, or is identical to, the CDR and / or VH / VL sequences of the anti-IL-9 or anti-IL9R antibodies listed in Table 2, Table 6, or elsewhere herein. In some embodiments, the anti-KLK5 / KLK7+Th2 bispecific antibody may include an arm comprising an antigen-specific binding site targeting KLK5 and KLK7, and a second arm comprising an antigen-specific binding site not targeting IL-9 or IL-9R.

[0177] In some embodiments, the anti-KLK5 / KLK7 + Th2 targeting bispecific antibody includes an arm comprising a CDR and / or VH / VL pair, the sequence of which is derived from or corresponds to, or is identical to, the CDR and / or VH / VL sequences of the anti-KLK5 / KLK7 antibodies listed in Table 1a, and a second arm comprising a CDR and / or VH / VL, the sequence of which is derived from or corresponds to, or is identical to, the CDR and / or VH / VL sequences of the anti-OX40L or anti-OX40 antibodies listed in Table 2, Table 6, or elsewhere herein. In some embodiments, the anti-KLK5 / KLK7 + Th2 bispecific antibody may include an arm comprising antigen-specific binding sites targeting KLK5 and KLK7, and a second arm comprising antigen-specific binding sites not targeting OX40L or OX40.

[0178] In some embodiments, the anti-KLK5 / KLK7+Th2 targeting bispecific antibody includes an arm comprising a CDR and / or VH / VL pair, the sequence of which is derived from or corresponds to, or is identical to, the CDR and / or VH / VL sequences of the anti-KLK5 / KLK7 antibodies listed in Table 1a, and a second arm comprising a CDR and / or VH / VL, the sequence of which is derived from or corresponds to, or is identical to, the CDR and / or VH / VL sequences of the anti-IL-31 or anti-IL-31R antibodies listed in Table 2, Table 6, or elsewhere herein. In some embodiments, the anti-KLK5 / KLK7+Th2 bispecific antibody may include an arm comprising an antigen-specific binding site targeting KLK5 and KLK7, and a second arm comprising an antigen-specific binding site not targeting IL-31 or IL-31R.

[0179] In some embodiments, the anti-KLK5 / KLK7+Th2 targeting bispecific antibody includes an arm comprising a CDR and / or VH / VL pair, the sequence of which is derived from or corresponds to, or is identical to, the CDR and / or VH / VL sequences of the anti-KLK5 / KLK7 antibodies listed in Table 1a, and a second arm comprising a CDR and / or VH / VL, the sequence of which is derived from or corresponds to, or is identical to, the CDR and / or VH / VL sequences of the anti-TSLP or anti-TSLPR antibodies listed in Table 2, Table 6, or elsewhere herein. In some embodiments, the anti-KLK5 / KLK7+Th2 bispecific antibody may include an arm comprising an antigen-specific binding site targeting both KLK5 and KLK7, and a second arm comprising an antigen-specific binding site not targeting TSLPR or TSLPR-specific binding sites.

[0180] In some embodiments, the anti-KLK5 / KLK7+Th2 targeting bispecific antibody includes an arm comprising a CDR and / or VH / VL pair, the sequence of which is derived from or corresponds to, or is identical to, the CDR and / or VH / VL sequences of the anti-KLK5 / KLK7 antibodies listed in Table 1a, and a second arm comprising a CDR and / or VH / VL, the sequence of which is derived from or corresponds to, or is identical to, the CDR and / or VH / VL sequences of the anti-IL-33 or anti-IL-33R antibodies listed in Table 2, Table 6, or elsewhere herein. In some embodiments, the anti-KLK5 / KLK7+Th2 bispecific antibody may include an arm comprising an antigen-specific binding site targeting KLK5 and KLK7, and a second arm comprising an antigen-specific binding site not targeting IL-33 or IL-33R.

[0181] In some embodiments, the anti-KLK5 / KLK7+Th2 targeting bispecific antibody includes an arm comprising a CDR and / or VH / VL pair, the sequence of which is derived from or corresponds to, or is identical to, the CDR and / or VH / VL sequences of the anti-KLK5 / KLK7 antibodies listed in Table 1a, and a second arm comprising a CDR and / or VH / VL, the sequence of which is derived from or corresponds to, or is identical to, the CDR and / or VH / VL sequences of the anti-IL-6 or anti-IL-6R antibodies listed in Table 2, Table 6, or elsewhere herein. In some embodiments, the anti-KLK5 / KLK7+Th2 bispecific antibody may include an arm comprising an antigen-specific binding site targeting KLK5 and KLK7, and a second arm comprising an antigen-specific binding site not targeting IL-6 or IL-6R.

[0182] In some embodiments, the bispecific antibodies described herein comprise 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., any 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. These antigen-specific binding sites may be derived from or correspond to any of the anti-KLK5 / KLK7 antibodies and IL-13 / IL-13R targeting antibodies disclosed herein, or be identical to them.

[0183] Interleukin (IL)-13 is a cytokine involved in the pathogenesis of skin barrier diseases, such as atopic dermatitis (AD). In some embodiments, IL-13 is a driver of type 2 T helper cell inflammation. In some embodiments, IL-13 is overexpressed in the lesioned skin of a subject with a skin barrier disease. In some embodiments, upon release in the peripheral skin, IL-13 activates its receptors, recruits inflammatory cells, and / or alters the skin microbiota. In some embodiments, IL-13 also reduces the expression of epidermal barrier proteins and activates sensory nerves mediating itch transmission signals. In some embodiments, blocking IL-13 signaling in combination with inhibition of KLK5 / KLK7 is effective in treating any of the diseases described herein.

[0184] In some embodiments, the anti-KLK5 / KLK7 + IL-13 bispecific antibody described herein comprises 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 comprises at least one antigen-specific binding site that specifically binds to KLK5 and KLK7, which is a binding site of a dual inhibitor antibody that specifically binds to KLK5 and KLK7 (e.g., any one of KLK5 / KLK7-Dual-Ab1, KLK5 / KLK7-Dual-Ab2, KLK5 / KLK7-Dual-Ab3, KLK5 / KLK7-Dual-Ab1). In some embodiments, the anti-KLK5 / KLK7 + IL-13 bispecific antibody comprises an arm containing at least one antigen-specific binding site specifically binding to both KLK5 and KLK7, said antigen-specific binding site comprising HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 of any of the antibodies listed in Tables 1a and 1b (e.g., any of KLK5 / KLK7-Dual-Ab1, KLK5 / KLK7-Dual-Ab2, KLK5 / KLK7-Dual-Ab3, KLK5 / KLK7-Dual-Ab4), and an arm containing at least one antigen-specific binding site specifically binding to IL-13 or IL-13R, said antigen-specific binding site comprising HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 of any of the anti-IL-13 or anti-IL-13R antibodies listed in Table 2. CDR2 and / or LC CDR3.In some embodiments, the anti-KLK5 / KLK7-IL-13 bispecific antibody includes an arm comprising at least one antigen-specific binding site that specifically binds to both KLK5 and KLK7, said antigen-specific binding site comprising a VH of at least 80% with any of the antibodies listed in Tables 1a and 1b (e.g., KLK5 / KLK7-Dual-Ab1, KLK5 / KLK7-Dual-Ab2, KLK5 / KLK7-Dual-Ab3, KLK5 / KLK7-Dual-Ab1). (e.g., 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 to any of the antibodies listed in Tables 1a and 1b (e.g., any of KLK5 / KLK7-Dual-Ab1, KLK5 / KLK7-Dual-Ab2, KLK5 / KLK7-Dual-Ab3, KLK5 / KLK7-Dual-Ab1). (e.g., a VL with 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%) identity with any of the anti-IL-13 or anti-IL-13R antibodies listed in Table 2, and / or a VL with at least 80% identity with any of the anti-IL-13 or anti-IL-13R antibodies listed in Table 2. (For example, VL of 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%) identity.

[0185] In some embodiments, the anti-KLK5 / KLK7 + IL-13 bispecific antibody comprising at least one antigen-specific binding site specifically binding to KLK5 and KLK7 comprises: HC CDR1, HC CDR2, and HCCDR3 of the heavy chain variable domain having the amino acid sequence of SEQ ID NO: 7; and LC CDR1, LC CDR2, and LCCDR3 of the light chain variable domain having the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-KLK5 / KLK7 + IL-13 bispecific antibody comprising at least one antigen-specific binding site specifically binding to KLK5 and KLK7 comprises: HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain having the amino acid sequence of SEQ ID NO: 13; and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain having the amino acid sequence of SEQ ID NO: 14.

[0186] In some embodiments, the anti-KLK5 / KLK7+IL-13 bispecific antibody comprising at least one antigen-specific binding site that specifically binds to KLK5 and KLK7 comprises: HC CDR1, HC CDR2, and HCCDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 17; and LC CDR1, LC CDR2, and LCCDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO: 14.

[0187] In some embodiments, the anti-KLK5 / KLK7 + IL-13 bispecific antibody comprising at least one antigen-specific binding site specifically binding to KLK5 and KLK7 comprises: HC CDR1, HC CDR2, and HCCDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 21; and LC CDR1, LC CDR2, and LCCDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO: 14.

[0188] In some embodiments, the anti-KLK5 / KLK7 + IL-13 bispecific antibody comprising at least one antigen-specific binding site specifically binding to KLK5 and KLK7 comprises: 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 anti-KLK5 / KLK7 + IL-13 bispecific antibody comprising at least one antigen-specific binding site specifically binding to KLK5 and KLK7 comprises: 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 anti-KLK5 / KLK7 + IL-13 bispecific antibody comprising at least one antigen-specific binding site specifically binding to KLK5 and KLK7 comprises: 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 anti-KLK5 / KLK7 + IL-13 bispecific antibody comprising at least one antigen-specific binding site specifically binding to KLK5 and KLK7 comprises: 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.

[0189] In some embodiments, the anti-KLK5 / KLK7 + IL-13 bispecific antibody comprising at least one antigen-specific binding site specifically binding to KLK5 and KLK7 comprises: VH, which comprises the amino acid sequence of SEQ ID NO: 7; and VL, which comprises the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-KLK5 / KLK7 + IL-13 bispecific antibody comprising at least one antigen-specific binding site specifically binding to KLK5 and KLK7 comprises: VH, which comprises the amino acid sequence of SEQ ID NO: 13; and VL, which comprises the amino acid sequence of SEQ ID NO: 14. In some embodiments, the anti-KLK5 / KLK7 + IL-13 bispecific antibody comprising at least one antigen-specific binding site specifically binding to KLK5 and KLK7 comprises: VH, which comprises the amino acid sequence of SEQ ID NO: 17; and LC CDR1, LC CDR2, and VL, which comprise the amino acid sequence of SEQ ID NO: 14. 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 compr...

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 Th2 cytokines or their receptors.

2. The bispecific antibody of 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 enzyme activity.

3. The bispecific antibody of claim 1 or 2, wherein the antigen-specific binding sites that specifically bind to KLK5 and KLK7 comprise HC CDR1, HC CDR2, HC CDR3, LCCDR1, LC CDR2 and / or LC CDR3 of any of the antibodies listed in Tables 1a and 1b.

4. The bispecific antibody according to any one of claims 1 to 3, wherein the antigen-specific binding sites that specifically bind to KLK5 and KLK7 comprise: (a) HC CDR1, HC CDR2, and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 7, and LC CDR1, LC CDR2, and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

8. (b) HC CDR1, HC CDR2 and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 13, and LC CDR1, LC CDR2 and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

14. (c) HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain, having the amino acid sequence of SEQ ID NO: 17, and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain, having the amino acid sequence of SEQ ID NO: 14; or (d) HC CDR1, HC CDR2 and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 21, and LC CDR1, LC CDR2 and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

14.

5. The bispecific antibody according to any one of claims 1 to 4, wherein the antigen-specific binding sites that specifically bind to KLK5 and KLK7 comprise: (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) 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 sites specifically binding to KLK5 and KLK7 are VH and / or VL of any of the antibodies listed in Table 1a.

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

8. The 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 any of the antibodies listed in Table 2, namely HC CDR1, HCCDR2, 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 bispecific antibody of claim 9, wherein the antigen-specific binding site that specifically binds to IL-13 or IL-13R comprises: (a) HC CDR1, HC CDR2, and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 53, and LC CDR1, LC CDR2, and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

54. (b) HC CDR1, HC CDR2 and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 32, and LC CDR1, LC CDR2 and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO: 33; (c) HC CDR1, HC CDR2 and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 74, and LC CDR1, LC CDR2 and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

75. (d) HC CDR1, HC CDR2 and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 94, and LC CDR1, LC CDR2 and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO: 95; (e) HC CDR1, HC CDR2 and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 114, and LC CDR1, LC CDR2 and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

115. (f) HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domains, having the amino acid sequence of SEQ ID NO: 134, and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domains, having the amino acid sequence of SEQ ID NO: 135; or (g) HC CDR1, HC CDR2 and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 657, and LC CDR1, LC CDR2 and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

658.

11. The bispecific antibody of claim 9 or 10, wherein the antigen-specific binding site that specifically binds to IL-13 or IL-13R comprises: (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) 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 bispecific antibody according to any one of claims 9 to 11, wherein the antigen-specific binding site that specifically binds to IL-13 or IL-13R comprises: (a) VH, which contains the amino acid sequence of SEQ ID NO: 53; and VL, which contains the amino acid sequence of SEQ ID NO: 54; (b) VH, which contains the amino acid sequence of SEQ ID NO: 32; and VL, which contains the amino acid sequence of SEQ ID NO: 33; (c) VH, which contains the amino acid sequence of SEQ ID NO: 74; and VL, which contains the amino acid sequence of SEQ ID NO: 75; (d) VH, which contains the amino acid sequence of SEQ ID NO: 94; and VL, which contains the amino acid sequence of SEQ ID NO: 95; (e) VH, which contains the amino acid sequence of SEQ ID NO: 114; and VL, which contains the amino acid sequence of SEQ ID NO: 115; (f) VH, comprising the amino acid sequence of SEQ ID NO: 134; and VL, comprising the amino acid sequence of SEQ ID NO: 135; or (g) VH, which contains the amino acid sequence of SEQ ID NO: 657; and VL, which contains 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 bispecific antibody of claim 13, wherein the antigen-specific binding site that specifically binds to IL-4 or IL-4R comprises: (a) HC CDR1, HC CDR2, and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 154, and LC CDR1, LC CDR2, and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

155. (b) HC CDR1, HC CDR2 and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 174, and LC CDR1, LC CDR2 and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

175. (c) HC CDR1, HC CDR2 and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 194, and LC CDR1, LC CDR2 and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO: 195; (d) HC CDR1, HC CDR2 and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 214, and LC CDR1, LC CDR2 and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

215. (e) HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domains, having the amino acid sequence of SEQ ID NO: 234, and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domains, having the amino acid sequence of SEQ ID NO: 235; or (f) HC CDR1, HC CDR2 and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 254, and LC CDR1, LC CDR2 and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

255.

15. The bispecific antibody of claim 13 or 14, wherein the antigen-specific binding site that specifically binds to IL-4 or IL-4R comprises: (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) 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 bispecific antibody of any one of claims 13 to 15, wherein the antigen-specific binding site that specifically binds to IL-4 or IL-4R comprises: (a) VH, which contains the amino acid sequence of SEQ ID NO: 154; and VL, which contains the amino acid sequence of SEQ ID NO: 155; (b) VH, which contains the amino acid sequence of SEQ ID NO: 174; and VL, which contains the amino acid sequence of SEQ ID NO: 175; (c) VH, which contains the amino acid sequence of SEQ ID NO: 194; and VL, which contains the amino acid sequence of SEQ ID NO: 195; (d) VH, which contains the amino acid sequence of SEQ ID NO: 214; and VL, which contains the amino acid sequence of SEQ ID NO: 215; (e) VH, comprising the amino acid sequence of SEQ ID NO: 234; and VL, comprising the amino acid sequence of SEQ ID NO: 235; or (f) VH, which contains the amino acid sequence of SEQ ID NO: 254; and VL, which contains 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 bispecific antibody of claim 17, wherein the antigen-specific binding site that specifically binds to IL-5 or IL-5R comprises: (a) HC CDR1, HC CDR2, and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 275, and LC CDR1, LC CDR2, and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

276. (b) HC CDR1, HC CDR2 and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 295, and LC CDR1, LC CDR2 and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

296. (c) HC CDR1, HC CDR2 and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 315, and LC CDR1, LC CDR2 and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

316. (d) HC CDR1, HC CDR2 and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 335, and LC CDR1, LC CDR2 and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO: 336; (e) HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domains, having the amino acid sequence of SEQ ID NO: 355, and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domains, having the amino acid sequence of SEQ ID NO: 356; or (f) HC CDR1, HC CDR2 and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 375, and LC CDR1, LC CDR2 and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

376.

19. The bispecific antibody of claim 17 or 18, wherein the antigen-specific binding site that specifically binds to IL-5 or IL-5R comprises: (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 GAN; 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, which has 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) 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, which has the amino acid sequence of SEQ ID NO:

394.

20. The bispecific antibody of any one of claims 17 to 19, wherein the antigen-specific binding site that specifically binds to IL-5 or IL-5R comprises: (a) VH, which contains the amino acid sequence of SEQ ID NO: 275; and VL, which contains the amino acid sequence of SEQ ID NO: 276; (b) VH, which contains the amino acid sequence of SEQ ID NO: 295; and VL, which contains the amino acid sequence of SEQ ID NO: 296; (c) VH, which contains the amino acid sequence of SEQ ID NO: 315; and VL, which contains the amino acid sequence of SEQ ID NO: 316; (d) VH, which contains the amino acid sequence of SEQ ID NO: 335; and VL, which contains the amino acid sequence of SEQ ID NO: 336; (e) VH, comprising the amino acid sequence of SEQ ID NO: 355; and VL, comprising the amino acid sequence of SEQ ID NO: 356; or (f) VH, which contains the amino acid sequence of SEQ ID NO: 375; and VL, which contains 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 bispecific antibody of claim 21, wherein the antigen-specific binding site that specifically binds to IL-9 or IL-9R comprises: (a) HC CDR1, HC CDR2, and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 395, and LC CDR1, LC CDR2, and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

396.

23. The bispecific antibody of claim 21 or 22, wherein the antigen-specific binding site that specifically binds to IL-9 or IL-9R comprises: (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) 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 bispecific antibody of any one of claims 21 to 23, wherein the antigen-specific binding site that specifically binds to IL-9 or IL-9R comprises: (a) VH, which contains the amino acid sequence of SEQ ID NO: 395; and VL, which contains 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 bispecific antibody of claim 25, wherein the antigen-specific binding site that specifically binds to OX40L or OX40 comprises: (a) HC CDR1, HC CDR2, and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 415, and LC CDR1, LC CDR2, and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

416. (b) HC CDR1, HC CDR2 and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 435, and LC CDR1, LC CDR2 and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

436. (c) HC CDR1, HC CDR2 and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 819, and LC CDR1, LC CDR2 and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

820. (d) HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domains, having the amino acid sequence of SEQ ID NO: 839, and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domains, having the amino acid sequence of SEQ ID NO: 840; or (e) HC CDR1, HC CDR2 and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 859, and LC CDR1, LC CDR2 and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

860.

27. The bispecific antibody of claim 25 or 26, wherein the antigen-specific binding site that specifically binds to OX40L or OX40 comprises: (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) 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 bispecific antibody of any one of claims 25 to 27, wherein the antigen-specific binding site that specifically binds to OX40L or OX40 comprises: (a) VH, which contains the amino acid sequence of SEQ ID NO: 415; and VL, which contains the amino acid sequence of SEQ ID NO: 416; (b) VH, which contains the amino acid sequence of SEQ ID NO: 435; and VL, which contains the amino acid sequence of SEQ ID NO: 436; (c) VH, which contains the amino acid sequence of SEQ ID NO: 819; and VL, which contains the amino acid sequence of SEQ ID NO: 820; (d) VH, comprising the amino acid sequence of SEQ ID NO: 839; and VL, comprising the amino acid sequence of SEQ ID NO: 840; or (e) VH, which contains the amino acid sequence of SEQ ID NO: 859; and VL, which contains 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 bispecific antibody of claim 29, wherein the antigen-specific binding site that specifically binds to IL-25 or IL-25R comprises: (a) HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain, having the amino acid sequence of SEQ ID NO: 455, and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain, having the amino acid sequence of SEQ ID NO: 456; or (b) HC CDR1, HC CDR2 and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 719, and LC CDR1, LC CDR2 and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

720.

31. The bispecific antibody of claim 29 or 30, wherein the antigen-specific binding site that specifically binds to IL-25 or IL-25R comprises: (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) 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 bispecific antibody of any one of claims 29 to 31, wherein the antigen-specific binding site that specifically binds to IL-25 or IL-25R comprises: (a) VH, comprising the amino acid sequence of SEQ ID NO: 455; and VL, comprising the amino acid sequence of SEQ ID NO: 456; or (b) VH, which contains the amino acid sequence of SEQ ID NO: 719; and VL, which contains 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 bispecific antibody of claim 33, wherein the antigen-specific binding site that specifically binds to IL-31 or IL-31R comprises: (a) HC CDR1, HC CDR2, and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 475, and LC CDR1, LC CDR2, and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

476. (b) HC CDR1, HC CDR2 and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 495, and LC CDR1, LC CDR2 and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

496. (c) HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domains, having the amino acid sequence of SEQ ID NO: 739, and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domains, having the amino acid sequence of SEQ ID NO: 740; or (d) HC CDR1, HC CDR2 and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 759, and LC CDR1, LC CDR2 and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

760.

35. The bispecific antibody of claim 33 or 34, wherein the antigen-specific binding site that specifically binds to IL-31 or IL-31R comprises: (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, which has 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) 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, which has the amino acid sequence of SEQ ID NO:

778.

36. The bispecific antibody of any one of claims 33 to 35, wherein the antigen-specific binding site that specifically binds to IL-31 or IL31R comprises: (a) VH, which contains the amino acid sequence of SEQ ID NO: 475; and VL, which contains the amino acid sequence of SEQ ID NO: 476; (b) VH, which contains the amino acid sequence of SEQ ID NO: 495; and VL, which contains the amino acid sequence of SEQ ID NO: 496; (c) VH, comprising the amino acid sequence of SEQ ID NO: 739; and VL, comprising the amino acid sequence of SEQ ID NO: 740; or (d) 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.

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

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

576. (b) HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domains, having the amino acid sequence of SEQ ID NO: 595, and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domains, having the amino acid sequence of SEQ ID NO: 596; or (c) HC CDR1, HC CDR2 and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 779, and LC CDR1, LC CDR2 and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

780.

39. The bispecific antibody of claim 37 or 38, wherein the antigen-specific binding site that specifically binds to IL-36 or IL-36R comprises: (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) 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 bispecific antibody of any one of claims 37 to 39, wherein the antigen-specific binding site that specifically binds to IL-36 or IL-36R comprises: (a) VH, which contains the amino acid sequence of SEQ ID NO: 575; and VL, which contains the amino acid sequence of SEQ ID NO: 576; (b) VH, comprising the amino acid sequence of SEQ ID NO: 595; and VL, comprising the amino acid sequence of SEQ ID NO: 596; or (c) VH, which contains the amino acid sequence of SEQ ID NO: 779; and VL, which contains 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 bispecific antibody of claim 41, wherein the antigen-specific binding site that specifically binds to TSLP or TSLPR comprises: (a) HC CDR1, HC CDR2, and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 615, and LC CDR1, LC CDR2, and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

616. (b) HC CDR1, HC CDR2 and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 635, and LC CDR1, LC CDR2 and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

636. (c) HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domains, having the amino acid sequence of SEQ ID NO: 879, and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domains, having the amino acid sequence of SEQ ID NO: 880; or (d) HC CDR1, HC CDR2 and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 899, and LC CDR1, LC CDR2 and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

900.

43. The bispecific antibody of claim 41 or 42, wherein the antigen-specific binding site that specifically binds to TSLP or TSLPR comprises: (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, which has 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) 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, which has the amino acid sequence of SEQ ID NO:

918.

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

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

46. ​​The bispecific antibody of claim 45, wherein the antigen-specific binding site that specifically binds to IL-33 or IL-33R comprises: (a) HC CDR1, HC CDR2, and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 677, and LC CDR1, LC CDR2, and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

678. (b) HC CDR1, HC CDR2 and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 697, and LC CDR1, LC CDR2 and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

698. (c) HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domains, having the amino acid sequence of SEQ ID NO: 717, and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domains, having the amino acid sequence of SEQ ID NO: 718; or (d) HC CDR1, HC CDR2 and HC CDR3 of heavy chain variable domains having the amino acid sequence of SEQ ID NO: 799, and LC CDR1, LC CDR2 and LC CDR3 of light chain variable domains having the amino acid sequence of SEQ ID NO:

800.

47. The bispecific antibody of claim 45 or 46, wherein the antigen-specific binding site that specifically binds to IL-33 or IL-33R comprises: (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, which has 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, which has 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) 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, which has the amino acid sequence of SEQ ID NO:

818.

48. The bispecific antibody of any one of claims 45 to 47, wherein the antigen-specific binding site that specifically binds to IL-33 or IL-33R comprises: (a) VH, comprising the amino acid sequence of SEQ ID NO: 677; and VL, comprising the amino acid sequence of SEQ ID NO: 678; or (b) VH, which contains the amino acid sequence of SEQ ID NO: 799; and VL, which contains 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 VH and / or VL of any of the antibodies in Table 2.

50. The bispecific antibody according to any one of claims 1 to 49, wherein the binding affinity of the bispecific antibody for KLK5 and KLK7 is not more than 20% different from that of an anti-KLK5 / KLK7 antibody comprising 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 binding affinity of the bispecific antibody to a Th2 target is not more than 20% different from that of a Th2-targeting antibody comprising 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% inhibitory activity against KLK5 and KLK7 relative to an anti-KLK5 / KLK7 antibody comprising 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% inhibitory activity against Th2 signaling relative to a Th2-targeting antibody comprising the same CDR and / or VH / VL as the bispecific antibody.

54. A composition comprising a bispecific antibody as described in any one of claims 1 to 53, and an acceptable carrier.

55. A method comprising administering to a subject a bispecific antibody as described in any one of claims 1 to 53 or a composition as described in claim 54.

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

57. A method for treating skin barrier defects, the method comprising administering to a subject an effective amount of a bispecific antibody as described in any one of claims 1 to 53 or a composition as described in claim 54.

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

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

60. The method of claims 55 to 59, wherein the application reduces ear thickness by more than 30% relative to the administration of a Th2-targeting antibody comprising the same CDR and / or VH / VL as the bispecific antibody to a subject.

61. The method of any one of claims 55 to 60, wherein the application reduces ear thickness by more than 30% relative to the administration of a subject to a Th2-targeting antibody comprising the same CDR and / or VH / VL as the bispecific antibody.

62. The method of any one of claims 55 to 61, wherein the administration reduces skin erythema / bleeding by more than 30% relative to the administration of a Th2-targeting antibody comprising the same CDR and / or VH / VL as the bispecific antibody to a subject.

63. The method of any one of claims 55 to 62, wherein the administration reduces skin erythema / bleeding by more than 30% relative to the administration of a Th2-targeting antibody comprising the same CDR and / or VH / VL as the bispecific antibody to a subject.

64. The method of any one of claims 55 to 63, wherein the administration reduces skin erythema / bleeding by more than 30% relative to the administration of a Th2-targeting antibody comprising the same CDR and / or VH / VL as the bispecific antibody to a subject.

65. The method of any one of claims 55 to 64, wherein the application reduces skin abrasion / erosion by more than 30% relative to the administration of a Th2-targeting antibody comprising the same CDR and / or VH / VL as the bispecific antibody to a subject.

66. The method of any one of claims 55 to 65, wherein the application reduces skin peeling / dryness by more than 30% relative to the administration of a Th2-targeting antibody comprising the same CDR and / or VH / VL as the bispecific antibody to a subject.

67. The method of any one of claims 55 to 66, wherein the application reduces skin peeling / dryness by more than 30% relative to the administration of a Th2-targeting antibody comprising the same CDR and / or VH / VL as the bispecific antibody to a subject.

68. The method of any one of claims 55 to 67, wherein the administration reduces skin edema by more than 30% relative to the administration of a Th2-targeting antibody comprising the same CDR and / or VH / VL as the bispecific antibody to a subject.

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

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