Anti-KLK7 antibodies, Anti-KLK5 antibodies, multispecific Anti-KLK5 / KLK7 antibodies and methods of use

Abstract

To provide anti-KLK7 antibody, anti-KLK5 antibody, multispecific anti-KLK5 / KLK7 antibody and methods of use.SOLUTION: The disclosure provides an isolated antibody that binds to human kallikrein related peptidase 7 (KLK7), where the antibody inhibits human KLK7-mediated cleavage of a substrate of a certain amino acid sequence, and / or binds to human KLK7 with a KD of less than 10 pM, or less than 9 pM, or less than 8 pM, or less than 7 pM, or less than 6 pM, or less than 5 pM as measured by surface plasmon resonance, and the antibody binds to a specific epitope of KLK7.SELECTED DRAWING: Figure 19B

Description

Cross - reference to related applications

[0001] This application claims the benefit of priority of U.S. Provisional Patent Application No. 62 / 901,990, filed on September 18, 2019, which is hereby incorporated by reference in its entirety for all purposes.

Technical Field

[0002] The present invention relates to anti - KLK7 antibodies, anti - KLK5 antibodies, anti - KLK5 / KLK7 multispecific antibodies, and methods of using them.

Background Art

[0003] Human kallikrein - related peptidases (KLKs) are (chymo) - trypsin - like serine proteases that are expressed in various tissues such as the prostate, ovary, breast, testis, brain, and skin. KLKs belong to the subgroup of the chymotrypsin - like serine protease family S1A of clan PA(S). The 15 human KLK genes are located on chromosome 19q13.4 and constitute the largest contiguous serine protease cluster in the human genome. These genes generally consist of five coding exons and, in some cases, one or two 5' non - coding exons, encoding kallikrein - related peptidases KLK1 - KLK15. All KLK genes encode single - chain pre - proproteins containing a chymotrypsin - like or trypsin - like catalytic domain of 224 - 237 residues with approximately 40% amino acid sequence identity between KLK4 - KLK15. KLK1 and its close homologs KLK2 and KLK3 form their own clade, KLK4, 5, and 7 belong to another subgroup, while KLK6 is more similar to KLK13 and KLK14. See Debela et al., Biol Chem 389, 623 - 632 (2008).

[0004] KLK5 is a trypsin-like serine protease that appears to be most abundantly expressed in human skin, particularly in the upper spinous and granular layers of the skin. Keratinocytes undergo terminal differentiation and transform into flat brick-like structures that form a barrier against the stratum corneum, the outermost epidermal layer, and the external environment. See Debela et al., J Mol Biol, 373, 1017-1031 (2007); and Tan et al., J Med Chem. 2015 Jan 22;58(2):598-612 (2014). KLK7 is a chymotrypsin-like serine protease that is also expressed in the skin. KLK5 has been described as playing a pathological role in skin disorders such as Netherton syndrome. See Furio et al., PLOS Genet 11(9), e1005389 (2015). Netherton syndrome is caused by loss-of-function mutations in the SPINK5 gene that encodes Kazal-type serine protease inhibitor 5 (SPINK5). See Descargues et al., Nat Genet. 2005 Jan;37(1):56-65 (2004). SPINK5 has been shown to inhibit some members of the KLK serine protease family (e.g., KLK5 and KLK7). See Wang et al., Exp Dermatol.Jul;23(7):524-6 (2014). The absence of SPINK5 in Netherton syndrome results in unopposed KLK activity. Hyperactivity of KLK5 is thought to be an important factor in the pathophysiology of Netherton syndrome because KLK5 is a regulator of proteolysis in the epidermis. Excision of KLK5 and KLK7 rescues the lethality of the Netherton syndrome-like phenotype. See Briot et al., J Exp Med.May 11;206(5):1135-47 (2009); Furio et al., J Exp Med.Mar 10;211(3):499-513 (2014); and Kasparek et al., PLoS Genet.2017 Jan 17;13(1):e1006566 (2017). Netherton syndrome is a complex systemic disease with multiple effects and currently has no satisfactory treatment.

[0005] Asthma is a clinically heterogeneous disorder associated with both genetic and environmental risk factors. Heritability estimates from twin studies of asthma vary from 35% to 80%, indicating an important role in genetic risk. See, e.g., Ullemar et al., Allergy 71, 230-238 (2016). Several large-scale GWAS have been conducted on asthma and asthma-related phenotypes, and many of the identified loci, such as genes near the ORMDL3, IL13, IL1RL1, and TSLP genes, have been confirmed in multiple study groups. See, e.g., Bonnelykke et al., Nat Genet 46, 51-55 (2014). In a recent study, SNPs in the KLK4 / 5 locus that protect against the risk of low periostin asthma or type 2 hypoinflammatory asthma were identified. In the same study, it was found that KLK5 levels increase in bronchoalveolar lavage of severe asthma patients, supporting the hypothesis that KLK5 plays a role in bronchial obstruction and asthma etiology.

[0006] Despite advances in the fields of diseases such as Netherton syndrome and asthma, there is a need to identify targets and develop means to complement or enhance the effectiveness of existing therapies. SUMMARY OF THE INVENTION

[0007] The present invention provides anti-KLK7 antibodies, anti-KLK5 antibodies, anti-KLK5 / KLK7 multispecific antibodies, and methods of using them. Embodiment 1. An isolated antibody that binds to human kallikrein-related peptidase 7 (KLK7), a) inhibits human KLK7-mediated cleavage of a substrate comprising the amino acid sequence RPKPVE-Nval-WRK (SEQ ID NO: 121), wherein Nval is norvaline; b) binds to human KLK7 with a K D of less than 10 pM, or less than 9 pM, or less than 8 pM, or less than 7 pM, or less than 6 pM, or less than 5 pM as measured by surface plasmon resonance; c) binds to an epitope within amino acids R71 - N82, K152 - S158 and / or Q211 - K222 of KLK7 (SEQ ID NO: 4); and / or d) an isolated antibody that binds to an epitope comprising one or more of amino acids H72, P73, G74, S76, Q78, N82, N157, K211 and / or T213 of KLK7 (SEQ ID NO: 4) according to chymotrypsin numbering, or an epitope comprising one or more of amino acids H91, P92, G93, S95, Q97, N101, N178, K233 and / or T235 of KLK7 Embodiment 2. An antibody that binds to human KLK7, comprising a heavy chain variable domain (VH) containing (a) CDR - H1 comprising the amino acid sequence of SEQ ID NO: 7, (b) CDR - H2 comprising the amino acid sequence of SEQ ID NO: 8, and (c) CDR - H3 comprising the amino acid sequence of SEQ ID NO: 9, and a light chain variable domain (VL) containing (d) CDR - L1 comprising the amino acid sequence of SEQ ID NO: 10, (e) CDR - L2 comprising the amino acid sequence of SEQ ID NO: 11, and (f) CDR - L3 comprising the amino acid sequence of SEQ ID NO: 12 Embodiment 3. The antibody according to Embodiment 1, comprising a heavy chain variable domain (VH) containing (a) CDR - H1 comprising the amino acid sequence of SEQ ID NO: 7, (b) CDR - H2 comprising the amino acid sequence of SEQ ID NO: 8, and (c) CDR - H3 comprising the amino acid sequence of SEQ ID NO: 9, and a light chain variable domain (VL) containing (d) CDR - L1 comprising the amino acid sequence of SEQ ID NO: 10, (e) CDR - L2 comprising the amino acid sequence of SEQ ID NO: 11, and (f) CDR - L3 comprising the amino acid sequence of SEQ ID NO: 12 Embodiment 4. The antibody according to any one of Embodiments 1 - 3, which is a monoclonal antibody Embodiment 5. The antibody according to any one of Embodiments 1 - 4, which is a humanized antibody or a chimeric antibody Embodiment 6. An antibody fragment that binds to human KLK7, of the antibody according to any one of Embodiments 1 - 5 Embodiment 7. When measured by surface plasmon resonance, a K of less than 10 pM, or less than 9 pM, or less than 8 pM, or less than 7 pM, or less than 6 pM, or less than 5 pMD binds to human KLK7; and / or has a K of less than 10 pM, or less than 9 pM, or less than 8 pM, or less than 7 pM, or less than 6 pM, or less than 5 pM when measured by surface plasmon resonance D The antibody according to any one of Embodiments 1 to 6, which binds to cynomolgus monkey KLK7. Embodiment 8. The antibody according to any one of Embodiments 1 to 7, wherein the heavy chain variable region contains FR1 having an amino acid sequence selected from SEQ ID NOs: 123 to 128, FR2 having an amino acid sequence selected from SEQ ID NOs: 130 to 133, FR3 having an amino acid sequence selected from SEQ ID NOs: 135 to 143, and / or FR4 having an amino acid sequence selected from SEQ ID NOs: 144 to 145. Embodiment 9. The antibody according to any one of Embodiments 1 to 8, wherein the light chain variable region contains FR1 having an amino acid sequence selected from SEQ ID NOs: 147 to 150, FR2 having an amino acid sequence selected from SEQ ID NOs: 152 to 154, FR3 having an amino acid sequence selected from SEQ ID NOs: 156 to 158, and / or FR4 having an amino acid sequence selected from SEQ ID NO: 160. Embodiment 10. The antibody according to any one of Embodiments 1 to 9, comprising a sequence selected from the following: (a) A VH sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 15 to 30; (b) A VL sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 31 to 38; and (c) The VH sequence defined in (a) and the VL sequence defined in (b). Embodiment 11. The antibody according to any one of Embodiments 1 to 10, comprising a sequence selected from the following: (a) A VH sequence containing an amino acid sequence selected from SEQ ID NOs: 15 to 30; (b) A VL sequence containing an amino acid sequence selected from SEQ ID NOs: 31 to 38; and (c) The VH sequence defined in (a) and the VL sequence defined in (b). Embodiment 12. An antibody according to any one of Embodiments 1 to 11, comprising the VH sequence of SEQ ID NO: 29 and the VL sequence of SEQ ID NO: 32. Embodiment 13. An antibody according to any one of Embodiments 1 to 11, comprising the VH sequence of SEQ ID NO: 30 and the VL sequence of SEQ ID NO: 38. Embodiment 14. An antibody that specifically binds to human KLK7 and comprises the VH sequence of SEQ ID NO: 29 and the VL sequence of SEQ ID NO: 32. Embodiment 15. An antibody that specifically binds to human KLK7 and comprises the VH sequence of SEQ ID NO: 30 and the VL sequence of SEQ ID NO: 38. Embodiment 16. An antibody according to any one of Embodiments 1 to 15, comprising a heavy chain constant region and a light chain constant region, wherein the heavy chain constant region comprises an S183K substitution (EU numbering) and / or an S183E substitution (EU numbering); and / or the light chain constant region comprises a V133K substitution (EU numbering) and / or a V133E substitution (EU numbering). Embodiment 17. An antibody according to any one of Embodiments 1 to 16, which is a full-length IgG1 antibody. Embodiment 18. An antibody according to Embodiment 17, comprising an N297G substitution (EU numbering). Embodiment 19. An antibody according to any one of Embodiments 16 to 18, comprising an M428L substitution (EU numbering) and / or an N434S substitution (EU numbering). Embodiment 20. When measured by surface plasmon resonance, having a K of less than 20 pM, or less than 15 pM, or less than 10 pM, less than 5 pM, or less than 3 pM, or less than 2 pM, or less than 1 pM D for binding to human KLK7, an antibody according to any one of Embodiments 1 to 19. Embodiment 21. Inhibiting human KLK7 protease activity with an IC50 of less than 5 nM, or less than 3 nM, or less than 2 nM, or less than 1 nM, an antibody according to any one of Embodiments 1 to 20. Embodiment 22. When measured by surface plasmon resonance, having a K of less than 20 pM, or less than 15 pM, or less than 10 pM, less than 5 pM, or less than 3 pM, or less than 2 pM, or less than 1 pMD which binds to human KLK7 and inhibits human KLK7 protease activity with an IC50 of less than 5 nM, or less than 3 nM, or less than 2 nM, or less than 1 nM, the antibody according to any one of Embodiments 1 to 21. Embodiment 23. The bispecific antibody according to Embodiment 21 or Embodiment 22, wherein the inhibition of human KLK7 protease activity is an inhibition of human KLK7-mediated cleavage of a substrate comprising the amino acid sequence RPKPVE-Nval-WRK (SEQ ID NO: 121), and Nval is norvaline. Embodiment 24. The antibody according to any one of Embodiments 1 to 23, which is a multispecific antibody. Embodiment 25. The antibody according to Embodiment 24, which is a bispecific antibody. Embodiment 26. An antibody that specifically binds to human KLK7 and competes with the antibody according to any one of Embodiments 1 to 25 for binding to human KLK7. Embodiment 27. The antibody according to Embodiment 26, wherein a) inhibits human KLK7-mediated cleavage of a substrate comprising the amino acid sequence RPKPVE-Nval-WRK (SEQ ID NO: 121) (wherein Nval is norvaline) with an IC50 of less than 5 nM, or less than 3 nM, or less than 2 nM, or less than 1 nM; and / or b) has a K of less than 10 pM, or less than 9 pM, or less than 8 pM, or less than 7 pM, or less than 6 pM, or less than 5 pM when measured by surface plasmon resonance D and binds to human KLK7. Embodiment 28. An isolated nucleic acid encoding the antibody according to any one of Embodiments 1 to 27. Embodiment 29. An isolated host cell comprising the nucleic acid according to Embodiment 28. Embodiment 30. An isolated host cell that expresses the antibody according to any one of Embodiments 1 to 27. Embodiment 31. A method for producing an antibody that binds to human KLK7, comprising culturing the host cell according to Embodiment 29 or Embodiment 30 under conditions suitable for the expression of the antibody. Embodiment 32. The method according to Embodiment 31, further comprising recovering the antibody from the host cell. Embodiment 33. An antibody produced by the method according to Embodiment 32. Embodiment 34. An antibody that binds to human KLK5, a) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (b) CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 40 and 41, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42, and (d) CDR-L1 comprising an amino acid sequence selected from SEQ ID NOs: 43 and 44, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (f) a light chain variable domain (VL) comprising a CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 46 to 49; or b) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising an amino acid sequence selected from SEQ ID NOs: 39 and 107, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 41, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42, and (d) CDR-L1 comprising an amino acid sequence selected from SEQ ID NOs: 43 and 44, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (f) a light chain variable domain (VL) comprising a CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 46 to 49; or c) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising an amino acid sequence selected from SEQ ID NOs: 39 and 107, (b) CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 40 and 41, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42, and (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 44, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (f) a light chain variable domain (VL) comprising a CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 46 to 49; or d) A heavy chain variable domain (VH) comprising a CDR-H1 comprising an amino acid sequence selected from SEQ ID NO: 39 and 107, (b) a CDR-H2 comprising an amino acid sequence selected from SEQ ID NO: 40 and 41, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42, and (d) a CDR-L1 comprising an amino acid sequence selected from SEQ ID NO: 43 and 44, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (f) a CDR-L3 comprising an amino acid sequence selected from SEQ ID NO: 47-49; or e) A heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 68, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 70, and (c) a CDR-H3 comprising an amino acid sequence selected from SEQ ID NO: 71 and 72, and (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74, and (f) a CDR-L3 comprising an amino acid sequence selected from SEQ ID NO: 75-78; or f) A heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 68, (b) a CDR-H2 comprising an amino acid sequence selected from SEQ ID NO: 69 and 70, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 72, and (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74, and (f) a CDR-L3 comprising an amino acid sequence selected from SEQ ID NO: 75-78; or g) An antibody comprising a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 68, (b) a CDR-H2 comprising an amino acid sequence selected from SEQ ID NO: 69 and 70, and (c) a CDR-H3 comprising an amino acid sequence selected from SEQ ID NO: 71 and 72, and (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74, and (f) a CDR-L3 comprising an amino acid sequence selected from SEQ ID NO: 76-78. Antibody according to embodiment 34, comprising a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 39, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 41, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 43, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 47. Antibody according to embodiment 34, comprising a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 68, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 70, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 72, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 76. The antibody according to any one of embodiments 34 to 36, which is a monoclonal antibody. The antibody according to any one of embodiments 34 to 37, which is a humanized antibody or a chimeric antibody. The antibody according to any one of embodiments 34 to 38, which is an antibody fragment that binds to human KLK5. Embodiment 40. When measured by surface plasmon resonance, having a K of less than 1 nM, or less than 500 pM, or less than 300 pM, or less than 200 pM, or less than 100 pM, or less than 50 pM D for binding to human KLK5 and / or having a K of less than 1 nM, or less than 500 pM, or less than 300 pM, or less than 200 pM, or less than 100 pM, or less than 50 pM D for binding to cynomolgus monkey KLK5, the antibody according to any one of embodiments 34 to 39. Embodiment 41. The antibody according to any one of embodiments 34 to 40, wherein the heavy chain variable region is a) An FR1 comprising an amino acid sequence selected from SEQ ID NO: 161, an FR2 comprising the amino acid sequences of SEQ ID NOs: 162-163, an FR3 comprising the amino acid sequence of SEQ ID NO: 164, and / or an FR4 comprising the amino acid sequence of SEQ ID NO: 165; or b) An antibody comprising an FR1 comprising the amino acid sequence of SEQ ID NO: 171, an FR2 comprising an amino acid sequence selected from SEQ ID NOs: 172-173, an FR3 comprising the amino acid sequence of SEQ ID NO: 174, and / or an FR4 comprising the amino acid sequence of SEQ ID NO: 175. Embodiment 42. An antibody according to any one of Embodiments 34-41, wherein the light chain variable region is a) An FR1 comprising the amino acid sequence of SEQ ID NO: 166, an FR2 comprising an amino acid sequence selected from SEQ ID NOs: 167-168, an FR3 comprising the amino acid sequence of SEQ ID NO: 169, and / or an FR4 comprising the amino acid sequence of SEQ ID NO: 170; or b) An antibody comprising an FR1 comprising the amino acid sequence of SEQ ID NO: 176, an FR2 comprising an amino acid sequence selected from SEQ ID NOs: 177-178, an FR3 comprising the amino acid sequence of SEQ ID NO: 179, and / or an FR4 comprising the amino acid sequence of SEQ ID NO: 180. Embodiment 43. An antibody according to any one of Embodiments 34-42, comprising a sequence selected from the following: a) A VH sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 50, 52, 53, 105, and 106; b) A VL sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 51 and 54-67; and c) The VH sequence defined in (a) and the VL sequence defined in (b); d) A VH sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 79 and 81-87; e) A VL sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 80 and 88-94; and f) The VH sequence defined in (d) and the VL sequence defined in (e). Embodiment 44. An antibody according to any one of Embodiments 34 to 43, comprising an array selected from the following: a) A VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 50, 52, 53, 105, and 106; b) A VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 51 and 54 to 67; and c) The VH sequence defined in (a) and the VL sequence defined in (b); d) A VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 79 and 81 to 87; e) A VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 80 and 88 to 94; and f) The VH sequence defined in (d) and the VL sequence defined in (e). Embodiment 45. An antibody according to any one of Embodiments 34 to 44, comprising the VH sequence of SEQ ID NO: 52 and the VL sequence of SEQ ID NO: 55. Embodiment 46. An antibody according to any one of Embodiments 34 to 44, comprising the VH sequence of SEQ ID NO: 53 and the VL sequence of SEQ ID NO: 62. Embodiment 47. An antibody that specifically binds to human KLK5, comprising the VH sequence of SEQ ID NO: 52 and the VL sequence of SEQ ID NO: 55. Embodiment 48. An antibody that specifically binds to human KLK5, comprising the VH sequence of SEQ ID NO: 53 and the VL sequence of SEQ ID NO: 62. Embodiment 49. An antibody according to any one of Embodiments 34 to 44, comprising the VH sequence of SEQ ID NO: 83 and the VL sequence of SEQ ID NO: 88. Embodiment 50. An antibody according to any one of Embodiments 34 to 44, comprising the VH sequence of SEQ ID NO: 87 and the VL sequence of SEQ ID NO: 92. Embodiment 51. An antibody that specifically binds to human KLK5, comprising the VH sequence of SEQ ID NO: 83 and the VL sequence of SEQ ID NO: 88. Embodiment 52. An antibody that specifically binds to human KLK5, comprising the VH sequence of SEQ ID NO: 87 and the VL sequence of SEQ ID NO: 92. Embodiment 53. An antibody according to any one of Embodiments 34 to 52, comprising a heavy chain constant region and a light chain constant region, wherein the heavy chain constant region comprises an S183K substitution (EU numbering) and / or an S183E substitution (EU numbering), and / or the light chain constant region comprises a V133K substitution (EU numbering) and / or a V133E substitution (EU numbering). Embodiment 54. An antibody according to any one of Embodiments 34 to 53, which is a full-length IgG1 antibody. Embodiment 55. An antibody according to Embodiment 54, comprising an N297G substitution (EU numbering). Embodiment 56. An antibody according to any one of Embodiments 53 to 55, comprising an M428L substitution (EU numbering) and / or an N434S substitution (EU numbering). Embodiment 57. An antibody according to any one of Embodiments 34 to 56, which binds to human KLK5 with a K of less than 60 pM, less than 30 pM, less than 20 pM, less than 10 pM, or less than 5 pM when measured by surface plasmon resonance. D Embodiment 58. An antibody according to any one of Embodiments 34 to 57, which inhibits human KLK5 protease activity with an IC50 of less than 5 nM, less than 3 nM, less than 2 nM, or less than 1 nM. Embodiment 59. An antibody according to any one of Embodiments 34 to 58, which binds to human KLK5 with a K of less than 60 pM, less than 30 pM, less than 20 pM, less than 10 pM, or less than 5 pM when measured by surface plasmon resonance and inhibits human KLK5 protease activity with an IC50 of less than 5 nM, less than 3 nM, less than 2 nM, or less than 1 nM. D Embodiment 60. An antibody according to Embodiment 58 or Embodiment 59, wherein the inhibition of human KLK5 protease activity is an inhibition of human KLK5-mediated cleavage of the substrate Boc-Val-Pro-Arg-AMC. Embodiment 61. An antibody according to any one of Embodiments 34 to 60, which is a multispecific antibody. Embodiment 62. An antibody according to Embodiment 61, which is a bispecific antibody. Embodiment 63. An isolated nucleic acid encoding the antibody according to any one of Embodiments 34 to 62. Embodiment 64. An isolated host cell comprising the nucleic acid according to Embodiment 63. Embodiment 65. An isolated host cell that expresses the antibody according to any one of Embodiments 34 to 62. Embodiment 66. A method for producing an antibody that binds to human KLK5, comprising culturing the host cell according to Embodiment 64 or 65 under conditions suitable for the expression of the antibody. Embodiment 67. The method according to Embodiment 66, further comprising recovering the antibody from the host cell. Embodiment 68. An antibody produced by the method according to Embodiment 67. Embodiment 69. A bispecific antibody comprising a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7, the second binding domain binds to human KLK5, and the first binding domain comprises: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 8; and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 9, and a heavy chain variable domain (VH), and (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 12, and a light chain variable domain (VL). Embodiment 70. The bispecific antibody according to Embodiment 69, wherein the first binding domain is humanized. Embodiment 71. The bispecific antibody according to Embodiment 69 or 70, wherein the first binding domain comprises a sequence selected from the following: (a) A VH sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 15 to 30; (b) A VL sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 31 to 38; and (c) The VH sequence defined in (a) and the VL sequence defined in (b). Embodiment 72. The bispecific antibody according to any one of Embodiments 69 to 71, wherein the first binding domain comprises an array selected from the following: (a) A VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 15 to 30; (b) A VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 31 to 38; and (c) The VH sequence defined in (a) and the VL sequence defined in (b). Embodiment 73. The bispecific antibody according to any one of Embodiments 69 to 72, wherein the first binding domain comprises the VH sequence of SEQ ID NO: 29 and the VL sequence of SEQ ID NO: 32. Embodiment 74. The bispecific antibody according to any one of Embodiments 69 to 72, wherein the first binding domain comprises the VH sequence of SEQ ID NO: 30 and the VL sequence of SEQ ID NO: 38. Embodiment 75. A bispecific antibody according to any one of Embodiments 69 to 74, wherein the second binding domain is a) A heavy chain variable domain (VH) comprising (a) CDR-H1 comprising an amino acid sequence selected from SEQ ID NOs: 39 and 107, (b) CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 40 and 41, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising an amino acid sequence selected from SEQ ID NOs: 43 and 44, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (f) CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 46 to 49; or b) A heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 68, (b) CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 69 and 70, and (c) CDR-H3 comprising an amino acid sequence selected from SEQ ID NOs: 71 and 72, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74, and (f) CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 75 to 78. Embodiment 76. The bispecific antibody according to any one of Embodiments 69 to 75, wherein the second binding domain comprises a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 39, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 41, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 43, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 47. Embodiment 77. The bispecific antibody according to any one of Embodiments 69 to 75, wherein the second binding domain comprises a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 68, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 70, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 72, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 76. Embodiment 78. The bispecific antibody according to any one of Embodiments 69 to 77, wherein the second binding domain is humanized. Embodiment 79. The bispecific antibody according to any one of Embodiments 75 to 78, wherein the second binding domain comprises a sequence selected from the following: a) A VH sequence having at least 95% sequence identity with an amino acid sequence selected from SEQ ID NOs: 50, 52, 53, 105, and 106; b) A VL sequence having at least 95% sequence identity with an amino acid sequence selected from SEQ ID NOs: 51 and 54 to 67; and c) The VH sequence defined in (a) and the VL sequence defined in (b); d) A VH sequence having at least 95% sequence identity with an amino acid sequence selected from SEQ ID NOs: 79 and 81 to 87; e) A VL sequence having at least 95% sequence identity with an amino acid sequence selected from SEQ ID NOs: 80 and 88 to 94; and The VH sequence defined in (d) and the VL sequence defined in (e). Embodiment 80. The bispecific antibody according to any one of Embodiments 75 to 78, wherein the second binding domain comprises a sequence selected from the following: a) A VH sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 52, 53, 105, and 106; b) A VL sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 54 to 67; and c) The VH sequence defined in (a) and the VL sequence defined in (b); d) A VH sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 81 to 87; e) A VL sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 88 to 94; and f) The VH sequence defined in (d) and the VL sequence defined in (e). Embodiment 81. The bispecific antibody according to any one of Embodiments 69 to 78, wherein the second binding domain comprises a sequence selected from the following: a) A VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 50, 52, 53, 105, and 106; b) A VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 51 and 54 to 67; and c) The VH sequence defined in (a) and the VL sequence defined in (b); d) A VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 79 and 81 to 87; e) A VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 80 and 88 to 94; and f) The VH sequence defined in (d) and the VL sequence defined in (e). Embodiment 82. The bispecific antibody according to any one of Embodiments 69 to 78, wherein the second binding domain comprises a sequence selected from the following: a) A VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 52, 53, 105, and 106; b) a VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 54 to 67; and c) the VH sequence defined in (a) and the VL sequence defined in (b); d) a VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 81 to 87; e) a VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 88 to 94; and f) the VH sequence defined in (d) and the VL sequence defined in (e). Embodiment 83. The bispecific antibody according to any one of Embodiments 69 to 79, wherein the first binding domain comprises the VH amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 30, and the VL amino acid sequence of SEQ ID NO: 32 or SEQ ID NO: 38, and the second binding domain comprises the VH sequence of SEQ ID NO: 52 or SEQ ID NO: 53, and the VL amino acid sequence of SEQ ID NO: 55 or SEQ ID NO: 62. Embodiment 84. The bispecific antibody according to Embodiment 83, wherein (i) the first binding domain comprises the VH amino acid sequence of SEQ ID NO: 29 and the VL amino acid sequence of SEQ ID NO: 32, or the VH amino acid sequence of SEQ ID NO: 30 and the VL amino acid sequence of SEQ ID NO: 38, and (ii) the second binding domain comprises the VH sequence of SEQ ID NO: 52 and the VL amino acid sequence of SEQ ID NO: 55, or the VH sequence of SEQ ID NO: 53 and the VL amino acid sequence of SEQ ID NO: 62. Embodiment 85. The bispecific antibody according to any one of Embodiments 69 to 79, wherein the first binding domain comprises the VH sequence of SEQ ID NO: 30 and the VL sequence of SEQ ID NO: 38, and the second binding domain comprises the VH sequence of SEQ ID NO: 53 and the VL sequence of SEQ ID NO: 62. Embodiment 86. A bispecific antibody comprising a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7, the second binding domain binds to human KLK5, the first binding domain comprises the heavy chain variable domain (VH) amino acid sequence of SEQ ID NO: 30 and the light chain variable domain (VL) amino acid sequence of SEQ ID NO: 38, and the second binding domain comprises the VH amino acid sequence of SEQ ID NO: 53 and the VL amino acid sequence of SEQ ID NO: 62. Embodiment 87. The bispecific antibody according to any one of Embodiments 69 to 86, wherein the first binding domain includes a first heavy chain variable domain and a first light chain variable domain, the first heavy chain variable domain is linked to a first heavy chain constant region, the first light chain variable domain is linked to a first light chain constant region, the second binding domain includes a second heavy chain variable domain and a second light chain variable domain, the second heavy chain variable domain is linked to a second heavy chain constant region, and the second light chain variable domain is linked to a second light chain constant region. Embodiment 88. The bispecific antibody according to Embodiment 87, wherein the first heavy chain constant region includes a knob mutation, and the second heavy chain constant region includes a hole mutation, or the first heavy chain constant region includes a hole mutation and the second heavy chain constant region includes a knob mutation. Embodiment 89. The bispecific antibody according to Embodiment 88, wherein the antibody is an IgG1 antibody and the knob mutation includes a T366W substitution. Embodiment 90. The bispecific antibody according to Embodiment 88 or Embodiment 89, wherein the antibody is an IgG1 antibody and the hole mutation includes at least one, at least two, or three substitutions selected from T366S, L368A, and Y407V. Embodiment 91. The bispecific antibody according to Embodiment 90, wherein the antibody is an IgG1 antibody and the hole mutation includes T366S, L368A, and Y407V substitutions. Embodiment 92. The bispecific antibody according to any one of Embodiments 87 to 91, wherein the first heavy chain constant region and / or the second heavy chain constant region includes an N297G substitution (EU numbering). Embodiment 93. The bispecific antibody according to Embodiment 92, wherein the first heavy chain constant region and the second heavy chain constant region each include an N297G substitution (EU numbering). Embodiment 94. The bispecific antibody according to any one of Embodiments 87 to 93, wherein a) The first heavy chain constant region further comprises an S183K substitution (EU numbering), the first light chain constant region comprises a V133E substitution (EU numbering), the second heavy chain constant region further comprises an S183E substitution (EU numbering), and the second light chain constant region comprises a V133K substitution (EU numbering); or b) The bispecific antibody, wherein the first heavy chain constant region further comprises an S183E substitution (EU numbering), the first light chain constant region comprises a V133K substitution (EU numbering), the second heavy chain constant region further comprises an S183K substitution (EU numbering), and the second light chain constant region comprises a V133E substitution (EU numbering). Embodiment 95. The bispecific antibody according to any one of Embodiments 87 to 94, wherein the first heavy chain constant region and / or the second heavy chain constant region further comprises at least one substitution selected from M428L and N434S (EU numbering). Embodiment 96. The bispecific antibody according to Embodiment 95, wherein the first heavy chain constant region and the second heavy chain constant region each further comprises at least one substitution selected from M428L and N434S (EU numbering). Embodiment 97. The bispecific antibody according to Embodiment 96, wherein the first heavy chain constant region and the second heavy chain constant region each further comprises M428L and N434S substitutions (EU numbering). Embodiment 98. The bispecific antibody according to any one of Embodiments 87 to 97, wherein a) the first heavy chain constant region comprises an amino acid sequence selected from SEQ ID NOs: 96, 184, 98, 186, 117, 188, 119, and 190, the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 103; the heavy chain constant region comprises an amino acid sequence selected from SEQ ID NOs: 97, 185, 99, 187, 118, 189, 120, and 191, and the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or b) The second heavy chain constant region comprises an amino acid sequence selected from SEQ ID NO: 96, 184, 98, 186, 117, 188, 119, and 190, the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the first heavy chain constant region comprises an amino acid sequence selected from SEQ ID NO: 97, 185, 99, 187, 118, 189, 120, and 191, and the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 104, a bispecific antibody. Embodiment 99. A bispecific antibody according to Embodiment 98, a) the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 96 or 184, the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 97 or 185, and the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or b) the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 98 or 186, the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 99 or 187, and the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or c) the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 96 or 184, the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 97 or 185, and the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or d) the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 98 or 186, the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 99 or 187, and the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or e) the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 118 or 189, the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 117 or 188, and the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or f) the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 120 or 191, the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 119 or 190, and the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or g) the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 118 or 189, the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 117 or 188, and the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or h) the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 120 or 191, the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 119 or 190, and the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 104, bispecific antibody. Embodiment 100. A bispecific antibody comprising a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7, the second binding domain binds to human KLK5, the first binding domain comprises the heavy chain amino acid sequence of SEQ ID NO: 108 or 192 and the light chain amino acid sequence of SEQ ID NO: 109, and the second binding domain comprises the heavy chain amino acid sequence of SEQ ID NO: 110 or 193 and the light chain amino acid sequence of SEQ ID NO: 111, bispecific antibody. Embodiment 101. A bispecific antibody comprising a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7, the second binding domain binds to human KLK5, the first binding domain comprises a heavy chain amino acid sequence of SEQ ID NO: 112 or 194 and a light chain amino acid sequence of SEQ ID NO: 113, and the second binding domain comprises a heavy chain amino acid sequence of SEQ ID NO: 114 or 195 and a light chain amino acid sequence of SEQ ID NO: 115. Embodiment 102. A bispecific antibody comprising a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7, the second binding domain binds to human KLK5, the first binding domain comprises a heavy chain amino acid sequence of SEQ ID NO: 108 and a light chain amino acid sequence of SEQ ID NO: 109, and the second binding domain comprises a heavy chain amino acid sequence of SEQ ID NO: 110 and a light chain amino acid sequence of SEQ ID NO: 111. Embodiment 103. A bispecific antibody comprising a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7, the second binding domain binds to human KLK5, the first binding domain comprises a heavy chain amino acid sequence of SEQ ID NO: 112 and a light chain amino acid sequence of SEQ ID NO: 113, and the second binding domain comprises a heavy chain amino acid sequence of SEQ ID NO: 114 and a light chain amino acid sequence of SEQ ID NO: 115. Embodiment 104. A bispecific antibody comprising a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7, the second binding domain binds to human KLK5, and the second binding domain comprises: a) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (b) CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 40 and 41, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42; and (d) a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 43 or 44, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (f) CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 46 to 49; or b) a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising an amino acid sequence selected from SEQ ID NO: 39 and 107, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 41, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising an amino acid sequence selected from SEQ ID NO: 43 and 44, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (f) a CDR-L3 comprising an amino acid sequence selected from SEQ ID NO: 46-49; or c) a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 39 or 107, (b) a CDR-H2 comprising an amino acid sequence selected from SEQ ID NO: 40 and 41, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 44, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (f) a CDR-L3 comprising an amino acid sequence selected from SEQ ID NO: 46-49; or d) a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising an amino acid sequence selected from SEQ ID NO: 39 and 107, (b) a CDR-H2 comprising an amino acid sequence selected from SEQ ID NO: 40 and 41, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising an amino acid sequence selected from SEQ ID NO: 43 and 44, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (f) a CDR-L3 comprising an amino acid sequence selected from SEQ ID NO: 47-49; or e) a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 68, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 70, and (c) a CDR-H3 comprising an amino acid sequence selected from SEQ ID NO: 71 and 72, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74, and (f) a CDR-L3 comprising an amino acid sequence selected from SEQ ID NO: 75-78; or f) A heavy chain variable domain (VH) comprising (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 68, (b) CDR-H2 containing an amino acid sequence selected from SEQ ID NO: 69 and 70, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 72, and a light chain variable domain (VL) comprising (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 73, (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 74, and (f) CDR-L3 containing an amino acid sequence selected from SEQ ID NO: 75-78; or g) A bispecific antibody comprising a heavy chain variable domain (VH) comprising (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 68, (b) CDR-H2 containing an amino acid sequence selected from SEQ ID NO: 69 and 70, and (c) CDR-H3 containing an amino acid sequence selected from SEQ ID NO: 71 and 72, and a light chain variable domain (VL) comprising (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 73, (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 74, and (f) CDR-L3 containing an amino acid sequence selected from SEQ ID NO: 76-78. Embodiment 105. The bispecific antibody according to Embodiment 104, wherein the second binding domain comprises a heavy chain variable domain (VH) comprising (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 39, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 41, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 42, and a light chain variable domain (VL) comprising (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 43, (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 45, and (f) CDR-L3 containing the amino acid sequence of SEQ ID NO: 47. Embodiment 106. The bispecific antibody according to Embodiment 104, wherein the second binding domain comprises a heavy chain variable domain (VH) comprising (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 68, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 70, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 72, and a light chain variable domain (VL) comprising (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 73, (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 74, and (f) CDR-L3 containing the amino acid sequence of SEQ ID NO: 76. The bispecific antibody according to any one of Embodiments 104 to 106, wherein the second binding domain is humanized. Embodiment 108. The bispecific antibody according to any one of Embodiments 104 to 107, wherein the second binding domain comprises a sequence selected from the following: a) A VH sequence having at least 95% sequence identity with an amino acid sequence selected from SEQ ID NOs: 50, 52, 53, 105, and 106; b) A VL sequence having at least 95% sequence identity with an amino acid sequence selected from SEQ ID NOs: 51 and 54 to 67; and c) The VH sequence defined in (a) and the VL sequence defined in (b); d) A VH sequence having at least 95% sequence identity with an amino acid sequence selected from SEQ ID NOs: 79 and 81 to 87; e) A VL sequence having at least 95% sequence identity with an amino acid sequence selected from SEQ ID NOs: 80 and 88 to 94; and f) The VH sequence defined in (d) and the VL sequence defined in (e). Embodiment 109. The bispecific antibody according to any one of Embodiments 104 to 107, wherein the second binding domain comprises a sequence selected from the following: a) A VH sequence having at least 95% sequence identity with an amino acid sequence selected from SEQ ID NOs: 52, 53, 105, and 106; b) A VL sequence having at least 95% sequence identity with an amino acid sequence selected from SEQ ID NOs: 54 to 67; and c) The VH sequence defined in (a) and the VL sequence defined in (b); d) A VH sequence having at least 95% sequence identity with an amino acid sequence selected from SEQ ID NOs: 81 to 87; e) A VL sequence having at least 95% sequence identity with an amino acid sequence selected from SEQ ID NOs: 88 to 94; and f) The VH sequence defined in (d) and the VL sequence defined in (e). Embodiment 110. The bispecific antibody according to any one of Embodiments 104 to 107, wherein the second binding domain comprises an array selected from the following: a) A VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 50, 52, 53, 105, and 106; b) A VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 51 and 54 to 67; and c) The VH sequence defined in (a) and the VL sequence defined in (b); d) A VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 79 and 81 to 87; e) A VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 80 and 88 to 94; and f) The VH sequence defined in (d) and the VL sequence defined in (e). Embodiment 111. The bispecific antibody according to any one of Embodiments 104 to 107, wherein the second binding domain comprises an array selected from the following: a) A VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 52, 53, 105, and 106; b) A VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 54 to 67; and c) The VH sequence defined in (a) and the VL sequence defined in (b); d) A VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 81 to 87; e) A VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 88 to 94; and f) The VH sequence defined in (d) and the VL sequence defined in (e). Embodiment 112. The bispecific antibody according to any one of Embodiments 104 to 107, wherein the latter half of the amino acid antibody comprises a VH sequence of SEQ ID NO: 52 or SEQ ID NO: 53 and a VL amino acid sequence of SEQ ID NO: 55 or SEQ ID NO: 62. Embodiment 113. The bispecific antibody according to Embodiment 112, wherein the latter half of the amino acid antibody comprises a VH sequence of SEQ ID NO: 52 and a VL amino acid sequence of SEQ ID NO: 55, or a VH sequence of SEQ ID NO: 53 and a VL amino acid sequence of SEQ ID NO: 62. The bispecific antibody according to any one of Embodiments 104 to 113, wherein the first binding domain is humanized. Embodiment 115. The bispecific antibody according to any one of Embodiments 104 to 114, wherein the first binding domain comprises a first heavy chain variable domain and a first light chain variable domain, the first heavy chain variable domain is linked to a first heavy chain constant region, the first light chain variable domain is linked to a first light chain constant region, the second binding domain comprises a second heavy chain variable domain and a second light chain variable domain, the second heavy chain variable domain is linked to a second heavy chain constant region, and the second light chain variable domain is linked to a second light chain constant region. Embodiment 116. The bispecific antibody according to Embodiment 115, wherein the first heavy chain constant region comprises a knob mutation, and the second heavy chain constant region comprises a hole mutation, or the first heavy chain constant region comprises a hole mutation, and the second heavy chain constant region comprises a knob mutation. Embodiment 117. The bispecific antibody according to Embodiment 116, wherein the antibody is an IgG1 antibody, and the knob mutation comprises a T366W mutation. Embodiment 118. The bispecific antibody according to Embodiment 116 or 117, wherein the antibody is an IgG1 antibody, and the hole mutation comprises at least one, at least two, or three mutations selected from T366S, L368A, and Y407V. Embodiment 119. The bispecific antibody according to Embodiment 118, wherein the antibody is an IgG1 antibody, and the hole mutation comprises T366S, L368A, and Y407V mutations. Embodiment 120. The bispecific antibody according to any one of Embodiments 115 to 119, wherein the first heavy chain constant region and / or the second heavy chain constant region comprises an N297G substitution (EU numbering). Embodiment 121. The bispecific antibody according to Embodiment 120, wherein the first heavy chain constant region and the second heavy chain constant region each comprise an N297G substitution (EU numbering). Embodiment 122. The bispecific antibody according to any one of Embodiments 115 to 121, wherein a) the first heavy chain constant region further comprises an S183K substitution (EU numbering), the first light chain constant region comprises a V133E substitution (EU numbering), the second heavy chain constant region further comprises an S183E substitution (EU numbering), and the second light chain constant region comprises a V133K substitution (EU numbering); or b) the first heavy chain constant region further comprises an S183E substitution (EU numbering), the first light chain constant region comprises a V133K substitution (EU numbering), the second heavy chain constant region further comprises an S183K substitution (EU numbering), and the second light chain constant region comprises a V133E substitution (EU numbering), a bispecific antibody. Embodiment 123. The bispecific antibody according to any one of Embodiments 115 to 122, wherein the first heavy chain constant region and / or the second heavy chain constant region further comprises at least one substitution selected from M428L and N434S (EU numbering). Embodiment 124. The bispecific antibody according to Embodiment 123, wherein the first heavy chain constant region and the second heavy chain constant region each further comprises at least one substitution selected from M428L and N434S (EU numbering). Embodiment 125. The bispecific antibody according to Embodiment 124, wherein the first heavy chain constant region and the second heavy chain constant region each further comprises an M428L and an N434S substitution (EU numbering). Embodiment 126. The bispecific antibody according to any one of Embodiments 115 to 125, a) the first heavy chain constant region comprises an amino acid sequence selected from SEQ ID NOs: 96, 184, 98, 186, 117, 188, 119, and 190, the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 103; the heavy chain constant region comprises an amino acid sequence selected from SEQ ID NOs: 97, 185, 99, 187, 118, 189, 120, and 191, and the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or b) The second heavy chain constant region comprises an amino acid sequence selected from SEQ ID NO: 96, 184, 98, 186, 117, 188, 119, and 190, the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the first heavy chain constant region comprises an amino acid sequence selected from SEQ ID NO: 97, 185, 99, 187, 118, 189, 120, and 191, and the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 104, bispecific antibody. Embodiment 127. A bispecific antibody according to Embodiment 126, a) the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 96 or 184, the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 97 or 185, and the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or b) the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 98 or 186, the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 99 or 187, and the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or c) the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 96 or 184, the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 97 or 185, and the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or d) the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 98 or 186, the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 99 or 187, and the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or e) the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 118 or 189, the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 117 or 188, and the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or f) the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 120 or 191, the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 119 or 190, and the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or g) the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 118 or 189, the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 117 or 188, and the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or h) the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 120 or 191, the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 119 or 190, and the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 104, bispecific antibody. Embodiment 128. A bispecific antibody according to any one of Embodiments 69 to 127, which binds to human KLK5 with a K of less than 60 pM, less than 30 pM, less than 20 pM, less than 10 pM or less than 5 pM when measured by surface plasmon resonance D as described in any one of Embodiments 69 to 127, which binds to human KLK5 with a K of less than 60 pM, less than 30 pM, less than 20 pM, less than 10 pM or less than 5 pM when measured by surface plasmon resonance. Embodiment 129. A bispecific antibody according to any one of Embodiments 69 to 128, which inhibits human KLK5 protease activity with an IC50 of less than 5 nM, or less than 3 nM, or less than 2 nM, or less than 1 nM. Embodiment 130. A bispecific antibody according to any one of Embodiments 69 to 128, which binds to human KLK5 with a K of less than 60 pM, less than 30 pM, less than 20 pM, less than 10 pM, or less than 5 pM when measured by surface plasmon resonance DAn antibody according to any one of embodiments 69 to 129, which binds to human KLK5 and inhibits human KLK5 protease activity with an IC50 of less than 5 nM, or less than 3 nM, or less than 2 nM, or less than 1 nM. Embodiment 131. The bispecific antibody according to embodiment 129 or embodiment 130, wherein the inhibition of human KLK5 protease activity is the inhibition of human KLK5-mediated cleavage of the substrate Boc-Val-Pro-Arg-AMC. Embodiment 132. When measured by surface plasmon resonance, K of less than 20 pM, or less than 15 pM, or less than 10 pM, 5 pM or less, or 3 pM or less, or 2 pM or less, or 1 pM or less D An antibody according to any one of embodiments 69 to 131, which binds to human KLK7. Embodiment 133. The bispecific antibody according to any one of embodiments 69 to 132, which inhibits human KLK7 protease activity with an IC50 of less than 5 nM, or less than 3 nM, or less than 2 nM, or less than 1 nM. Embodiment 134. When measured by surface plasmon resonance, K of less than 20 pM, or less than 15 pM, or less than 10 pM, 5 pM or less, or 3 pM or less, or 2 pM or less, or 1 pM or less D A bispecific antibody according to any one of embodiments 69 to 133, which binds to human KLK7 and inhibits human KLK7 protease activity with an IC50 of less than 5 nM, or less than 3 nM, or less than 2 nM, or less than 1 nM. Embodiment 135. The bispecific antibody according to embodiment 133 or embodiment 134, wherein the inhibition of human KLK7 protease activity is the inhibition of human KLK7-mediated cleavage of a substrate containing the amino acid sequence RPKPVE-Nval-WRK (SEQ ID NO: 121), and Nval is norvaline. Embodiment 136. The K of the bispecific antibody against human KLK5 D and the K of the antibody against human KLK7 D are within 3-fold, or within 2.5-fold, or within 2-fold, or within 1.5-fold of each other. The bispecific antibody according to any one of embodiments 69 to 135. Embodiment 137. An isolated nucleic acid encoding the bispecific antibody according to any one of Embodiments 69 to 136. Embodiment 138. An isolated nucleic acid encoding the first binding domain of the bispecific antibody according to any one of Embodiments 69 to 136. Embodiment 139. An isolated nucleic acid encoding the second binding domain of the bispecific antibody according to any one of Embodiments 69 to 136. Embodiment 140. An isolated host cell comprising the isolated nucleic acid according to Embodiment 137. Embodiment 141. An isolated host cell comprising the isolated nucleic acid according to Embodiment 138. Embodiment 142. An isolated host cell comprising the isolated nucleic acid according to Embodiment 139. Embodiment 143. An isolated host cell expressing the bispecific antibody according to any one of Embodiments 69 to 136. Embodiment 144. An isolated host cell expressing the first binding domain of the bispecific antibody according to any one of Embodiments 69 to 136. Embodiment 145. An isolated host cell expressing the second binding domain of the bispecific antibody according to any one of Embodiments 69 to 136. Embodiment 146. A method for producing a bispecific antibody that binds to human KLK5 and human KLK7, comprising culturing the host cell according to Embodiment 140 or Embodiment 143 under conditions suitable for the expression of the antibody. Embodiment 147. The method according to Embodiment 146, further comprising recovering the antibody from the host cell. Embodiment 148. A method for producing a bispecific antibody that binds to human KLK5 and human KLK7, comprising: (i) culturing the host cell according to Embodiment 141 or Embodiment 144 under conditions suitable for the expression of the first binding domain; and (ii) culturing the host cell according to Embodiment 142 or Embodiment 145 under conditions suitable for the expression of the second binding domain. The method according to embodiment 148, further comprising recovering the first binding domain and the second binding domain, and constructing the bispecific antibody. A pharmaceutical composition comprising the antibody according to any one of embodiments 1 to 27 and a pharmaceutically acceptable carrier. The pharmaceutical composition according to embodiment 150, further comprising an additional therapeutic agent. The pharmaceutical composition according to embodiment 151, wherein the additional therapeutic agent is a KLK5 inhibitor. The pharmaceutical composition according to embodiment 152, wherein the KLK5 inhibitor is an anti-KLK5 antibody. The pharmaceutical composition according to embodiment 153, wherein the anti-KLK5 antibody comprises a) a heavy chain variable domain (VH) comprising CDR-H1 comprising an amino acid sequence selected from SEQ ID NOs: 39 and 107, CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 40 and 41, and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42; and a light chain variable domain (VL) comprising CDR-L1 comprising an amino acid sequence selected from SEQ ID NOs: 43 and 44, CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 46 to 49; or b) a heavy chain variable domain (VH) comprising CDR-H1 comprising the amino acid sequence of SEQ ID NO: 68, CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 69 and 70, and CDR-H3 comprising an amino acid sequence selected from SEQ ID NOs: 71 and 72; and a light chain variable domain (VL) comprising CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73, CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74, and CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 75 to 78. Embodiment 155. The pharmaceutical composition according to Embodiment 153 or Embodiment 154, wherein the anti-KLK5 antibody comprises a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 39, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 41, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 43, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 47. Embodiment 156. The pharmaceutical composition according to Embodiment 153 or Embodiment 154, wherein the anti-KLK5 antibody comprises a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 68, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 70, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 72, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 76. Embodiment 157. The pharmaceutical composition according to any one of Embodiments 153 to 156, wherein the anti-KLK5 antibody is a monoclonal antibody. Embodiment 158. The pharmaceutical composition according to any one of Embodiments 153 to 157, wherein the anti-KLK5 antibody is a humanized antibody or a chimeric antibody. Embodiment 159. The pharmaceutical composition according to any one of Embodiments 153 to 158, wherein the anti-KLK5 antibody is an antibody fragment that binds to human KLK5. Embodiment 160. The pharmaceutical composition according to any one of Embodiments 153 to 159, wherein the anti-KLK5 antibody comprises a sequence selected from the following: a) A VH sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 50, 52, 53, 105, and 106; b) A VL sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 51 and 54 to 67; and c) The VH sequence defined in (a) and the VL sequence defined in (b); d) A VH sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 79 and 81-87; e) A VL sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 80 and 88-94; and f) The VH sequence defined in (d) and the VL sequence defined in (e). Embodiment 161. The pharmaceutical composition according to any one of Embodiments 153-159, wherein the anti-KLK5 antibody comprises a sequence selected from the following: a) A VH sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 52, 53, 105 and 106; b) A VL sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 54-67; and c) The VH sequence defined in (a) and the VL sequence defined in (b); d) A VH sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 81-87; e) A VL sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 88-94; and f) The VH sequence defined in (d) and the VL sequence defined in (e). Embodiment 162. The pharmaceutical composition according to any one of Embodiments 153-159, wherein the anti-KLK5 antibody comprises a sequence selected from the following: a) A VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 50, 52, 53, 105, and 106; b) A VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 51 and 54-67; and c) The VH sequence defined in (a) and the VL sequence defined in (b); d) A VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 79 and 81-87; e) A VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 80 and 88-94; and (f) The VH sequence defined in (d) and the VL sequence defined in (e). Embodiment 163. The pharmaceutical composition according to any one of Embodiments 153 to 159, wherein the anti-KLK5 antibody comprises a sequence selected from the following: a) A VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 52, 53, 105, and 106; b) A VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 54 to 67; and c) The VH sequence defined in (a) and the VL sequence defined in (b); d) A VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 81 to 87; e) A VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 88 to 94; and f) The VH sequence defined in (d) and the VL sequence defined in (e). Embodiment 164. The pharmaceutical composition according to Embodiment 153, wherein the anti-KLK5 antibody is the antibody according to any one of Embodiments 34 to 62. Embodiment 165. The pharmaceutical composition according to Embodiment 153, wherein the anti-KLK5 antibody is the antibody according to any one of Embodiments 47, 48, 51, and 52. Embodiment 166. A pharmaceutical composition comprising the antibody according to any one of Embodiments 34 to 62 and a pharmaceutically acceptable carrier. Embodiment 167. The pharmaceutical composition according to Embodiment 166, further comprising an additional therapeutic agent. Embodiment 168. The pharmaceutical composition according to Embodiment 167, wherein the additional therapeutic agent is a KLK7 inhibitor. Embodiment 169. The pharmaceutical composition according to Embodiment 168, wherein the KLK7 inhibitor is an anti-KLK7 antibody. Embodiment 170. The pharmaceutical composition according to Embodiment 169, wherein the anti-KLK7 antibody is the antibody according to any one of Embodiments 1 to 27. Embodiment 171. A pharmaceutical composition comprising the antibody according to any one of Embodiments 1 to 27, the antibody according to any one of Embodiments 34 to 62, and a pharmaceutically acceptable carrier. The pharmaceutical composition according to any one of Embodiments 150 to 171, comprising an additional therapeutic agent selected from an anti-inflammatory agent and an antibiotic. Embodiment 173. A pharmaceutical composition comprising a bispecific antibody according to any one of Embodiments 69 to 136. Embodiment 174. The pharmaceutical composition according to Embodiment 173, further comprising an additional therapeutic agent. Embodiment 175. The pharmaceutical composition according to Embodiment 174, wherein the additional therapeutic agent is an anti-inflammatory agent. Embodiment 176. The pharmaceutical composition according to any one of Embodiments 150 to 175, for topical administration. Embodiment 177. The pharmaceutical composition according to any one of Embodiments 150 to 175, for subcutaneous administration or intravenous administration. Embodiment 178. An antibody according to any one of Embodiments 1 to 27 and 34 to 62, a bispecific antibody according to any one of Embodiments 69 to 136, or a pharmaceutical composition according to any one of Embodiments 150 to 177, for use as a medicine. Embodiment 179. An antibody according to any one of Embodiments 1 to 27 and 34 to 62, a bispecific antibody according to any one of Embodiments 69 to 136, or a pharmaceutical composition according to any one of Embodiments 150 to 177, for use in the treatment of a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis, and urticaria. Embodiment 180. The antibody, bispecific antibody, or pharmaceutical composition for use according to Embodiment 179, wherein the asthma is selected from atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin-sensitive / worsening asthma, mild asthma, moderate to severe asthma, corticosteroid-naive asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, newly diagnosed untreated asthma, smoking-induced asthma, corticosteroid-uncontrolled asthma, T helper lymphocyte type 2 (Th2) asthma or type 2 (Th2) high-value asthma, or type 2 (T2)-induced asthma, eosinophilic asthma, high periostin asthma, high eosinophilic asthma, Th2 low-value asthma or non-Th2-induced asthma, low periostin asthma, and low eosinophilic asthma. The antibody, bispecific antibody, or pharmaceutical composition for use according to Embodiment 180, wherein the asthma is eosinophilic asthma. The combination of the antibody according to any one of Embodiments 1 to 27 and the antibody according to any one of Embodiments 34 to 62 for use as a medicament. The combination of the antibody according to any one of Embodiments 1 to 27 and the antibody according to any one of Embodiments 34 to 62 for use in the treatment of a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis, and urticaria. The combination according to Embodiment 183, wherein the asthma is selected from atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin-sensitive / worsening asthma, mild asthma, moderate to severe asthma, corticosteroid-naive asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, newly diagnosed untreated asthma, smoking-induced asthma, asthma uncontrolled by corticosteroids, T helper lymphocyte type 2 (Th2) asthma or type 2 (Th2) high-value asthma, or type 2 (T2)-induced asthma, eosinophilic asthma, high periostin asthma, hypereosinophilic asthma, Th2 low-value asthma or non-Th2-induced asthma, low periostin asthma, and eosinophilic asthma. The combination according to Embodiment 184, wherein the asthma is eosinophilic asthma. Use of the antibody according to any one of Embodiments 1 to 27 and 34 to 62, the bispecific antibody according to any one of Embodiments 69 to 136, or the pharmaceutical composition according to any one of Embodiments 150 to 177 in the manufacture of a medicament for treating a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis, and urticaria. Embodiment 187. The use according to Embodiment 186, wherein the asthma is selected from atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin-sensitive / worsening asthma, mild asthma, moderate to severe asthma, corticosteroid-naive asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, newly diagnosed untreated asthma, smoking-induced asthma, asthma uncontrolled by corticosteroids, T helper lymphocyte type 2 (Th2) asthma or type 2 (Th2) high-value asthma, or type 2 (T2)-induced asthma, eosinophilic asthma, high periostin asthma, hypereosinophilic asthma, Th2 low-value asthma or non-Th2-induced asthma, low periostin asthma, and hypoeosinophilic asthma. Embodiment 188. The use according to Embodiment 187, wherein the asthma is hypoeosinophilic asthma. Embodiment 189. Use of a combination of the antibody according to any one of Embodiments 1 to 27 and the antibody according to any one of Embodiments 34 to 62 in the manufacture of a medicament for treating a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis, and urticaria. Embodiment 190. The use according to Embodiment 189, wherein the asthma is selected from atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin-sensitive / worsening asthma, mild asthma, moderate to severe asthma, corticosteroid-naive asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, newly diagnosed untreated asthma, smoking-induced asthma, asthma uncontrolled by corticosteroids, T helper lymphocyte type 2 (Th2) asthma or type 2 (Th2) high-value asthma, or type 2 (T2)-induced asthma, eosinophilic asthma, high periostin asthma, hypereosinophilic asthma, Th2 low-value asthma or non-Th2-induced asthma, low periostin asthma, and hypoeosinophilic asthma. Embodiment 191. The use according to Embodiment 190, wherein the asthma is hypoeosinophilic asthma. Use of an antibody according to any one of Embodiments 1 to 27, a bispecific antibody according to any one of Embodiments 69 to 136, or a pharmaceutical composition according to any one of Embodiments 150 to 177 in the manufacture of a medicament for reducing epithelial inflammation, a medicament for reducing epithelial permeability, a medicament for reducing transepidermal water loss, a medicament for reducing skin infiltration, a medicament for reducing hyperkeratosis, a medicament for restoring the epithelial barrier, and / or a medicament for reducing skin inflammatory cytokines. Use of a combination of an antibody according to any one of Embodiments 1 to 27 and an antibody according to any one of Embodiments 34 to 62 in the manufacture of a medicament for reducing epithelial inflammation, a medicament for reducing epithelial permeability, a medicament for reducing transepidermal water loss, a medicament for reducing skin infiltration, a medicament for reducing hyperkeratosis, a medicament for restoring the epithelial barrier, and / or a medicament for reducing skin inflammatory cytokines. A method of treating an individual having a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis, and rosacea, the method comprising administering to the individual an effective amount of an antibody according to any one of Embodiments 1 to 27 and 34 to 62, a bispecific antibody according to any one of Embodiments 69 to 136, or a pharmaceutical composition according to any one of Embodiments 150 to 177. A method of treating an individual having a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis, and rosacea, the method comprising administering to the individual a) an effective amount of an antibody according to any one of Embodiments 1 to 27; and b) an effective amount of an antibody according to any one of Embodiments 34 to 62. The method according to Embodiment 195, wherein the antibody described in (a) and the antibody described in (b) are administered simultaneously. The method according to Embodiment 195, wherein the antibody described in (a) and the antibody described in (b) are administered sequentially. A method for treating an individual having a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis, and rosacea, the method comprising administering to the individual an effective amount of the bispecific antibody according to any one of Embodiments 69 to 136, or an effective amount of the pharmaceutical composition according to any one of Embodiments 150 to 177. Embodiment 199. The method according to any one of Embodiments 194 to 198, wherein the asthma is selected from atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin-sensitive / worsening asthma, mild asthma, moderate to severe asthma, corticosteroid-naive asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, newly diagnosed untreated asthma, smoking-induced asthma, asthma uncontrolled by corticosteroids, T helper lymphocyte type 2 (Th2) asthma or type 2 (Th2) high-value asthma, or type 2 (T2)-induced asthma, eosinophilic asthma, high periostin asthma, hypereosinophilic asthma, Th2 low-value asthma or non-Th2-induced asthma, low periostin asthma, and low eosinophilic asthma. Embodiment 200. The method according to Embodiment 199, wherein the asthma is low eosinophilic asthma. Embodiment 201. The method according to any one of Embodiments 194 to 198, wherein the individual has Netherton syndrome Embodiment 202. The method according to any one of Embodiments 194 to 198, wherein the individual has rosacea. Embodiment 203. The method according to any one of Embodiments 194 to 202, further comprising administering an additional therapeutic agent to the individual. Embodiment 204. The method according to Embodiment 203, wherein the additional therapeutic agent is an anti-inflammatory agent. Embodiment 205. A method for reducing epithelial inflammation, reducing epithelial permeability, reducing transepidermal water loss, reducing skin infiltration, reducing hyperkeratosis, restoring the epithelial barrier, and / or reducing skin inflammatory cytokines in an individual, comprising administering to the individual an effective amount of the antibody according to any one of Embodiments 1 to 27 and 34 to 62, the bispecific antibody according to any one of Embodiments 69 to 136, or the pharmaceutical composition according to any one of Embodiments 150 to 177 to reduce epithelial inflammation, reduce epithelial permeability, reduce transepidermal water loss, reduce skin infiltration, reduce hyperkeratosis, and / or restore the epithelial barrier. Embodiment 206. A method for reducing epithelial inflammation, reducing epithelial permeability, reducing transepidermal water loss, reducing skin infiltration, reducing hyperkeratosis, restoring the epithelial barrier, and / or reducing skin inflammatory cytokines in an individual, comprising administering to the individual a) an effective amount of the antibody according to any one of Embodiments 1 to 27; and b) an effective amount of the antibody according to any one of Embodiments 34 to 62 to reduce epithelial inflammation, reduce epithelial permeability, reduce transepidermal water loss, reduce skin infiltration, reduce hyperkeratosis, and / or restore the epithelial barrier. The method according to Embodiment 206, wherein the antibody described in (a) and the antibody described in (b) are administered simultaneously. The method according to Embodiment 206, wherein the antibody described in (a) and the antibody described in (b) are administered sequentially. Embodiment 209. A method for reducing epithelial inflammation, reducing epithelial permeability, reducing transepidermal water loss, reducing skin infiltration, reducing hyperkeratosis, restoring the epithelial barrier, and / or reducing skin inflammatory cytokines in an individual, comprising administering to the individual the bispecific antibody according to any one of Embodiments 69 to 136, or an effective amount of the pharmaceutical composition according to any one of Embodiments 150 to 177 to reduce epithelial inflammation, reduce epithelial permeability, reduce transepidermal water loss, reduce skin infiltration, reduce hyperkeratosis, and / or restore the epithelial barrier. The method according to any one of Embodiments 194 to 209, wherein the administration is subcutaneous administration or intravenous administration. The method according to any one of Embodiments 194 to 209, wherein the administration is topical administration. The method according to any one of Embodiments 194 to 209, wherein the administration is intravenous administration An isolated antibody that binds to human KLK7, wherein binding to human KLK7 results in a conformational change of human KLK7, and the conformational change allosterically results in disruption of the substrate binding site and / or active site of human KLK7. The isolated antibody according to Embodiment 213, which is a bispecific antibody. The isolated antibody according to Embodiment 214, wherein the bispecific antibody binds to human KLK7 and human KLK5. The isolated antibody according to Embodiment 215, wherein binding to human KLK5 results in a conformational change of human KLK5, and the conformational change allosterically results in disruption of the substrate binding site and / or the active site of human KLK5. The isolated antibody according to Embodiment 216, which binds to an epitope on human KLK5 comprising one or more amino acid residues selected from Pro130, Ser131, Ala132, Gly133, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Gln174A, Ile176, Asp177, Asp178, Gly184, Asp185, Lys186, Ala186A, Arg188, Asn223, Arg224, Pro225, and Lys233 according to standard protease numbering. The isolated antibody according to embodiment 217, which binds to an epitope on human KLK5 comprising one or more amino acid residues selected from the group consisting of Pro130, Ser131, Ala132, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Gln174A, Ile176, Asp177, Asp178, Arg224, and Lys233 according to standard protease numbering. The isolated antibody according to embodiment 217, which binds to an epitope on human KLK5 comprising one or more amino acid residues selected from Pro130, Ser131, Ala132, Gly133, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Gln174A, Ile176, Asp177 and Lys233 according to standard protease numbering. The isolated antibody according to embodiment 217, which binds to an epitope on human KLK5 comprising one or more amino acid residues selected from Ser131, Ala132, Gly133, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Pro173, Arg174, Gly184, Asp185, Lys186, Ala186A, Arg188, Asn223, Arg224 and Pro225 according to standard protease numbering. The isolated antibody according to any one of embodiments 213 - 220, which binds to an epitope within amino acids R71 - N82, K152 - S158 and / or Q211 - K222 of KLK7 (SEQ ID NO: 4). The isolated antibody according to any one of embodiments 213 - 221, which binds to an epitope comprising one or more of amino acids H72, P73, G74, S76, Q78, N82, N157, K211 and / or T213 of KLK7 (SEQ ID NO: 4). Embodiment 223. A bispecific antibody comprising a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7, the second binding domain binds to human KLK5, binding to human KLK7 results in a conformational change of human KLK7, and the conformational change allosterically results in disruption of the substrate binding site and / or the active site of human KLK7. A bispecific antibody. Embodiment 224. The bispecific antibody according to Embodiment 223, which, when binding to human KLK5, results in a conformational change of human KLK5, and the conformational change allosterically results in disruption of the substrate binding site and / or the active site of human KLK5. Embodiment 225. A bispecific antibody comprising a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7, the second binding domain binds to human KLK5, binding to human KLK5 results in a conformational change of human KLK5, and the conformational change allosterically results in disruption of the substrate binding site and / or the active site of human KLK5. A bispecific antibody. Embodiment 226. The bispecific antibody according to Embodiment 224 or Embodiment 225, which binds to an epitope on human KLK5 comprising one or more amino acid residues selected from Pro130, Ser131, Ala132, Gly133, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Gln174A, Ile176, Asp177, Asp178, Gly184, Asp185, Lys186, Ala186A, Arg188, Asn223, Arg224, Pro225 and Lys233 according to standard protease numbering. The isolated antibody according to embodiment 226, which binds to an epitope on human KLK5 comprising one or more amino acid residues selected from the group consisting of Pro130, Ser131, Ala132, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Gln174A, Ile176, Asp177, Asp178, Arg224, and Lys233 according to standard protease numbering. The isolated antibody according to embodiment 226, which binds to an epitope on human KLK5 comprising one or more amino acid residues selected from Pro130, Ser131, Ala132, Gly133, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Gln174A, Ile176, Asp177 and Lys233 according to standard protease numbering. The isolated antibody according to embodiment 226, which binds to an epitope on human KLK5 comprising one or more amino acid residues selected from Ser131, Ala132, Gly133, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Pro173, Arg174, Gly184, Asp185, Lys186, Ala186A, Arg188, Asn223, Arg224 and Pro225 according to standard protease numbering. The bispecific antibody according to any one of embodiments 223 to 229, which binds to an epitope within amino acids R71 - N82, K152 - S158 and / or Q211 - K222 of KLK7 (SEQ ID NO: 4). The bispecific antibody according to any one of embodiments 223 to 230, which binds to an epitope comprising one or more of amino acids H72, P73, G74, S76, Q78, N82, N157, K211 and / or T213 of KLK7 (SEQ ID NO: 4). Embodiment 232. A pharmaceutical composition comprising the antibody according to any one of Embodiments 213 to 222 and a pharmaceutically acceptable carrier. Embodiment 233. A pharmaceutical composition comprising the bispecific antibody according to any one of Embodiments 223 to 231 and a pharmaceutically acceptable carrier. Embodiment 234. An antibody according to any one of Embodiments 213 to 222, a bispecific antibody according to any one of Embodiments 223 to 231, or a pharmaceutical composition according to Embodiment 232 or Embodiment 233 for use as a medicament. Embodiment 235. An antibody according to any one of Embodiments 213 to 222, a bispecific antibody according to any one of Embodiments 223 to 231, or a pharmaceutical composition according to Embodiment 232 or Embodiment 233 for use in the treatment of a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis, and urticaria. Embodiment 236. The antibody, bispecific antibody, or pharmaceutical composition according to Embodiment 235, wherein the asthma is selected from atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin-sensitive / worsening asthma, mild asthma, moderate to severe asthma, corticosteroid-naive asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, newly diagnosed untreated asthma, smoking-induced asthma, asthma uncontrolled by corticosteroids, T helper lymphocyte type 2 (Th2) asthma or type 2 (Th2) high-value asthma, or type 2 (T2)-induced asthma, eosinophilic asthma, high periostin asthma, high eosinophilic asthma, Th2 low-value asthma or non-Th2-induced asthma, low periostin asthma, and low eosinophilic asthma. Embodiment 237. An antibody according to any one of Embodiments 213 to 222, a bispecific antibody according to any one of Embodiments 223 to 231, or a pharmaceutical composition according to Embodiment 232 or Embodiment 233 for use in reducing epithelial inflammation, reducing epithelial permeability, reducing transdermal water loss, reducing skin infiltration, reducing hyperkeratosis, restoring the epithelial barrier, and / or reducing skin inflammatory cytokines. Use of the antibody according to any one of Embodiments 213 to 222, the bispecific antibody according to any one of Embodiments 223 to 231, or the pharmaceutical composition according to Embodiment 232 or Embodiment 233 in the manufacture of a medicament for treating a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis and urticaria. Embodiment 239. The use according to Embodiment 238, wherein the asthma is selected from atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin-sensitive / worsening asthma, mild asthma, moderate to severe asthma, corticosteroid-naive asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, newly diagnosed untreated asthma, smoking-induced asthma, asthma uncontrolled by corticosteroids, T helper lymphocyte type 2 (Th2) asthma or type 2 (Th2) high-value asthma, or type 2 (T2)-induced asthma, eosinophilic asthma, high periostin asthma, hypereosinophilic asthma, Th2 low-value asthma or non-Th2-induced asthma, low periostin asthma, and hypoeosinophilic asthma. Use of the antibody according to any one of Embodiments 213 to 222, the bispecific antibody according to any one of Embodiments 223 to 231, or the pharmaceutical composition according to Embodiment 232 or Embodiment 233 in the manufacture of a medicament for reducing epithelial inflammation, reducing epithelial permeability, reducing transdermal water loss, reducing skin infiltration, reducing hyperkeratosis, restoring the epithelial barrier, and / or reducing skin inflammatory cytokines. Embodiment 241. A method for treating an individual having a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis and urticaria, the method comprising administering to the individual an effective amount of the antibody according to any one of Embodiments 213 to 222, the bispecific antibody according to any one of Embodiments 223 to 231, or the pharmaceutical composition according to Embodiment 232 or Embodiment 233. Embodiment 242. The method according to Embodiment 241, wherein the asthma is selected from the group consisting of atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin-sensitive / aggravated asthma, mild asthma, moderate to severe asthma, corticosteroid-naive asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, newly diagnosed untreated asthma, smoking-induced asthma, asthma uncontrolled by corticosteroids, T helper lymphocyte type 2 (Th2) asthma or type 2 (Th2) high-value asthma, or type 2 (T2)-induced asthma, eosinophilic asthma, high periostin asthma, hypereosinophilic asthma, Th2 low-value asthma or non-Th2-induced asthma, low periostin asthma, and hypoeosinophilic asthma. Embodiment 243. A method for reducing epithelial inflammation, reducing epithelial permeability, reducing transepidermal water loss, reducing skin infiltration, reducing hyperkeratosis, restoring the epithelial barrier, and / or reducing skin inflammatory cytokines in an individual, the method comprising administering to the individual an effective amount of the antibody according to any one of 213 to 222, the bispecific antibody according to any one of Embodiments 223 to 231, or the pharmaceutical composition according to Embodiment 232 or Embodiment 233 to reduce epithelial inflammation, reduce epithelial permeability, reduce transepidermal water loss, reduce skin infiltration, reduce hyperkeratosis, and / or restore the epithelial barrier. Embodiment 244. The antibody, bispecific antibody or pharmaceutical composition for use according to Embodiment 179 or Embodiment 235, wherein the disease is Netherton syndrome. Embodiment 245. The combination for use according to Embodiment 183, wherein the disease is Netherton syndrome. Embodiment 246. The use according to any one of Embodiments 186, 189 and 238, wherein the disease is Netherton syndrome. Embodiment 247. The use according to any one of Embodiments 192, 193 and 240, wherein the pharmaceutical is for reducing epithelial inflammation, reducing epithelial permeability, reducing transepidermal water loss, reducing skin infiltration, reducing hyperkeratosis, restoring the epithelial barrier, and / or reducing skin inflammatory cytokines in an individual having Netherton syndrome. A bispecific antibody for use in the treatment of Netherton syndrome, comprising a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7, the second binding domain binds to human KLK5, the first binding domain comprises the heavy chain amino acid sequence of SEQ ID NO: 112 or 194 and the light chain amino acid sequence of SEQ ID NO: 113, and the second binding domain comprises the heavy chain amino acid sequence of SEQ ID NO: 114 or 195 and the light chain amino acid sequence of SEQ ID NO: 115. Embodiment 249. An anti-KLK5 antibody for use in the treatment of Netherton syndrome, comprising (a) the VH sequence of SEQ ID NO: 52 and the VL sequence of SEQ ID NO: 55; or (b) the VH sequence of SEQ ID NO: 53 and the VL sequence of SEQ ID NO: 62. Embodiment 250. An anti-KLK7 antibody for use in the treatment of Netherton syndrome, comprising (a) the VH sequence of SEQ ID NO: 29 and the VL sequence of SEQ ID NO: 32; or (b) the VH sequence of SEQ ID NO: 30 and the VL sequence of SEQ ID NO: 38. Embodiment 251. An antibody combination for use in the treatment of Netherton syndrome, comprising an anti-KLK5 antibody and an anti-KLK7 antibody, wherein the anti-KLK5 antibody comprises the VH sequence of SEQ ID NO: 52 and the VL sequence of SEQ ID NO: 55, or the VH sequence of SEQ ID NO: 53 and the VL sequence of SEQ ID NO: 62, and the anti-KLK7 antibody comprises the VH sequence of SEQ ID NO: 29 and the VL sequence of SEQ ID NO: 32, or the VH sequence of SEQ ID NO: 30 and the VL sequence of SEQ ID NO: 38. Embodiment 252. A method for treating an individual having a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis, and rosacea, comprising administering to the individual an effective amount of the bispecific antibody, wherein the bispecific antibody comprises a first binding domain and a second binding domain, the first binding domain binds to human KLK7 and inhibits KLK7 protease activity, and the second binding domain binds to human KLK5 and inhibits KLK5 protease activity. A method for treating an individual having a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis, and rosacea, the method comprising administering to the individual an anti-KLK5 antibody and an anti-KLK7 antibody, wherein the anti-KLK5 antibody inhibits KLK5 protease activity and the anti-KLK7 antibody inhibits KLK7 protease activity. A method for reducing epithelial inflammation, reducing epithelial permeability, reducing transepidermal water loss, reducing skin infiltration, reducing hyperkeratosis, restoring the epithelial barrier, and / or reducing skin inflammatory cytokines in an individual, the method comprising administering to the individual a KLK5 antagonist and a KLK7 antagonist. The method according to embodiment 254, wherein the KLK5 antagonist is an anti-KLK5 antibody and / or the KLK7 antagonist is an anti-KLK7 antibody. A method for reducing epithelial inflammation, reducing epithelial permeability, reducing transepidermal water loss, reducing skin infiltration, reducing hyperkeratosis, restoring the epithelial barrier, and / or reducing skin inflammatory cytokines in an individual, the method comprising administering to the individual an effective amount of a bispecific antibody, the bispecific antibody comprising a first binding domain and a second binding domain, the first binding domain binding to human KLK7 and inhibiting KLK7 protease activity, and the second binding domain binding to human KLK5 and inhibiting KLK5 protease activity. A method for reducing epithelial inflammation, reducing epithelial permeability, reducing transepidermal water loss, reducing skin infiltration, reducing hyperkeratosis, restoring the epithelial barrier, and / or reducing skin inflammatory cytokines in an individual, the method comprising administering to the individual an anti-KLK5 antibody and an anti-KLK7 antibody, wherein the anti-KLK5 antibody inhibits KLK5 protease activity and the anti-KLK7 antibody inhibits KLK7 protease activity. Embodiment 258. A method for improving skin rash and / or scaling in an individual having Netherton syndrome, comprising administering to the individual an effective amount of a bispecific antibody, wherein the bispecific antibody comprises a first binding domain and a second binding domain, the first binding domain binds to human KLK7 to inhibit KLK7 protease activity, and the second binding domain binds to human KLK5 to inhibit KLK5 protease activity. Embodiment 259. A method for improving skin rash and / or scaling in an individual having Netherton syndrome, comprising administering to the individual an anti-KLK5 antibody and an anti-KLK7 antibody, wherein the anti-KLK5 antibody inhibits KLK5 protease activity and the anti-KLK7 antibody inhibits KLK7 protease activity. Embodiment 260. Use according to any one of Embodiments 192, 193, 240 or 247, or method according to any one of Embodiments 205, 206, 209, 243 or 254 - 257, or antibody, bispecific antibody or pharmaceutical composition for use according to Embodiment 237, wherein the skin inflammatory cytokine is one or more of IL-8, TNFα, IL-6, IL-4 and / or G-CSF. Embodiment 261. A bispecific antibody comprising a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7, the second binding domain binds to human KLK5, the first binding domain comprises the heavy chain amino acid sequence of SEQ ID NO: 194 and the light chain amino acid sequence of SEQ ID NO: 113, and the second binding domain comprises the heavy chain amino acid sequence of SEQ ID NO: 195 and the light chain amino acid sequence of SEQ ID NO: 115. Embodiment 262. A bispecific antibody comprising a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7, the second binding domain binds to human KLK5, the first binding domain comprises the heavy chain amino acid sequence of SEQ ID NO: 112 and the light chain amino acid sequence of SEQ ID NO: 113, and the second binding domain comprises the heavy chain amino acid sequence of SEQ ID NO: 195 and the light chain amino acid sequence of SEQ ID NO: 115. Embodiment 263. A bispecific antibody comprising a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7, the second binding domain binds to human KLK5, the first binding domain comprises the heavy chain amino acid sequence of SEQ ID NO: 194 and the light chain amino acid sequence of SEQ ID NO: 113, and the second binding domain comprises the heavy chain amino acid sequence of SEQ ID NO: 114 and the light chain amino acid sequence of SEQ ID NO: 115.

Brief Description of the Drawings

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BEST MODE FOR CARRYING OUT THE INVENTION

[0028] I. Definitions For the purposes of this specification, "acceptor human framework" is a framework that includes the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as defined below. An acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may contain the same amino acid sequence or may contain changes to the amino acid sequence. In some embodiments, the number of amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some aspects, the VL acceptor human framework is identical in sequence to a VL human immunoglobulin framework sequence or a human consensus framework sequence.

[0029] "Affinity" refers to the total strength of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects the 1:1 interaction between the members of a binding pair (e.g., an antibody and an antigen). The affinity of molecule X for its partner Y can generally be represented by the dissociation constant (K D ). Affinity can be measured by common methods known in the art, including the methods described herein. Specific illustrative and exemplary methods for measuring binding affinity are described below.

[0030] An "affinity matured" antibody is an antibody that has one or more changes in one or more complementarity determining regions (CDRs) compared to the parent antibody that has no changes, and such modifications improve the affinity of the antibody for the antigen.

[0031] The terms "anti-KLK7 antibody" and "antibody that binds to KLK7" refer to antibodies that can bind to KLK7, such as human KLK7, with sufficient affinity to be useful as diagnostic and / or therapeutic agents when the antibody targets KLK7. In one aspect, the degree of binding of the anti-KLK7 antibody to unrelated non-KLK7 proteins is less than about 10% of the binding of the antibody to KLK7, as measured, for example, by surface plasmon resonance (SPR). In certain aspects, the antibody that binds to KLK7 has a dissociation constant (K -8 ) of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM (e.g., 10 -8 M or less, such as 10 -13 M to 10 -9 M, such as 10 -13 M to 10 D M). When the antibody has a K D of 1 μM or less, the antibody is said to "specifically bind" to KLK7. In certain aspects, the anti-KLK7 antibody binds to an epitope of KLK7 that is conserved among KLK7s of different species.

[0032] The terms "anti-KLK5 antibody" and "antibody that binds to KLK5" refer to antibodies that can bind to KLK5, such as human KLK5, with sufficient affinity to be useful as diagnostic and / or therapeutic agents when the antibody targets KLK5. In one aspect, the degree of binding of the anti-KLK5 antibody to unrelated non-KLK5 proteins is less than about 10% of the binding of the antibody to KLK5, as measured, for example, by surface plasmon resonance (SPR). In certain aspects, the antibody that binds to KLK5 has a dissociation constant (K -8 ) of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM (e.g., 10 -8 M or less, such as 10 -13 M to 10 -9 M, such as 10 -13 M to 10 D M). When the antibody has a K DAn antibody is said to "specifically bind" to KLK5 if it has the following structure: In certain embodiments, an anti-KLK5 antibody binds to an epitope of KLK5 that is conserved among KLK5 of different species.

[0033] The terms "anti-KLK5 / KLK7 antibody" and "antibody that binds KLK5 and KLK7" refer to a multispecific antibody that can bind KLK7 and KLK5 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting KLK7 and / or KLK5. In one embodiment, the extent of binding of an anti-KLK5 / KLK7 antibody to an unrelated non-KLK5 / non-KLK7 protein is less than about 10% of the binding of the antibody to KLK7 or KLK5, as measured, for example, by surface plasmon resonance (SPR). In certain embodiments, an antibody that binds KLK7 and KLK5 has a binding affinity of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM, or ≦0.001 nM (e.g., 10 -8 M or less, e.g. 10 -8 M~10 -13 M, for example 10 -9 M~10 -13 Dissociation constant (K D ) The antibody has a K D An antibody is said to "specifically bind" to a target protein if it has a specific binding domain. In certain embodiments, an anti-KLK5 / KLK7 antibody binds to an epitope of KLK7 that is conserved among KLK7 from different species. In some embodiments, an anti-KLK5 / KLK7 antibody binds to an epitope of KLK5 that is conserved among KLK5 from different species.

[0034] The term "antibody" is used herein in the broadest sense and encompasses a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired antigen-binding activity.

[0035] "Antibody fragment" refers to a molecule other than an intact antibody that includes a portion of an intact antibody that binds to an antigen to which the intact antibody binds. Examples of antibody fragments include Fv, Fab, Fab’, Fab’-SH, F(ab’) 2 ; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv and scFab); single-domain antibodies (dAb); and multispecific antibodies formed from antibody fragments, but are not limited thereto. For a review of specific antibody fragments, see Holliger and Hudson, Nature Biotechnology 23:1126-1136 (2005).

[0036] As used herein, the "binding domain" of an antibody refers to a portion of a variable domain sufficient to bind to an antigen. In some embodiments, the binding domain includes heavy chain (HC) CDR1, CDR2, and CDR3, as well as light chain (LC) CDR1, CDR2, and CDR3. In some embodiments, the binding domain includes heavy chain (HC) CDR1, FR2, CDR2, FR3, and CDR3, as well as light chain (LC) CDR1, FR2, CDR2, FR3, and CDR3.

[0037] The term "epitope" refers to a site on any antigen, whether proteinaceous or non-proteinaceous, to which an anti-KLK7 antibody or an anti-KLK5 antibody binds. Epitopes can be formed from either contiguous stretches of amino acids (linear epitopes) or can include non-contiguous amino acids (structural epitopes), for example, formed by being spatially proximal due to folding of the antigen (i.e., by the tertiary folding of a proteinaceous antigen). Linear epitopes are typically still bound by an antibody even after exposure of the proteinaceous antigen to a denaturing agent, whereas conformational epitopes are typically destroyed by treatment with a denaturing agent. An epitope contains at least 3, at least 4, at least 5, at least 6, at least 7, or 8-10 amino acids in a unique spatial structure.

[0038] Screening for antibodies that bind to a particular epitope (i.e., antibodies that bind to the same epitope) can be performed using methods conventional in the art, such as, but not limited to, alanine scanning, peptide blotting (Meth. Mol. Biol. 248 (2004) 443-463), peptide cleavage analysis, epitope excision, epitope extraction, chemical modification of the antigen (see Prot. Sci. 9 (2000) 487-496), and cross-blocking (see "Antibodies", Harlow and Lane, Cold Spring Harbor Press, Cold Spring Harb., NY).

[0039] Antigen structure-based antibody profiling (ASAP), also known as modified-assisted profiling (MAP), allows for the acceptance of a number of monoclonal antibodies that specifically bind to KLK7 or KLK5 based on the binding profile of each antibody to a chemically or enzymatically modified antigen surface (see, e.g., U.S. Patent Application Publication No. 2004 / 0101920). Each sorted antibody binds to the same epitope, which may be a distinct epitope that is clearly different from the epitopes represented by other sorts or a unique epitope that partially overlaps.

[0040] In addition, competitive binding can be used to readily determine whether an antibody binds to the same KLK7 epitope as an anti-KLK7 antibody or competes with the anti-KLK7 antibody for binding. For example, a reference anti-KLK7 antibody and an "antibody that binds to the same epitope" refer to an antibody that blocks the binding of the reference anti-KLK7 antibody to the antigen by 50% or more in a competition assay. Conversely, the reference antibody inhibits the binding of the antibody to the antigen by 50% or more in a competition assay. Also, for example, to determine whether an antibody binds to the same epitope as a reference anti-KLK7 antibody, the reference antibody is bound to KLK7 under saturation conditions. After removing the excess reference anti-KLK7 antibody, the ability of the subject anti-KLK7 antibody to bind to KLK7 is evaluated. If the anti-KLK7 antibody can bind to KLK7 after the saturation binding of the reference anti-KLK7 antibody, it can be concluded that the subject anti-KLK7 antibody binds to a different epitope from the reference anti-KLK7 antibody. However, if the subject anti-KLK7 antibody cannot bind to KLK7 after the saturation binding of the reference anti-KLK7 antibody, the subject anti-KLK7 antibody may bind to the same epitope as the epitope bound by the reference anti-KLK7 antibody. To confirm whether this antibody binds to the same epitope or is only sterically hindered from binding, conventional experiments can be used (such as peptide mutations, ELISA, RIA, surface plasmon resonance, flow cytometry, or binding analysis using other quantitative or qualitative antibody binding assays available in the art). This assay should be performed in two setups, i.e., with both antibodies being saturation antibodies. In both settings, if only the first (saturation) antibody can bind to KLK7, it can be concluded that the subject anti-KLK7 antibody and the reference anti-KLK7 antibody compete for binding to KLK7.

[0041] Similarly, competitive binding can be used to readily determine whether an antibody binds to the same epitope of KLK5 as the anti-KLK5 antibody or competes with the anti-KLK5 antibody for binding. For example, a "same epitope-binding antibody" as the reference anti-KLK5 antibody refers to an antibody that inhibits the binding of the reference anti-KLK5 antibody to the antigen by 50% or more in a competition assay, and conversely, the reference antibody inhibits the binding of the antibody to the antigen by 50% or more in a competition assay. Also, for example, to determine whether an antibody binds to the same epitope as the reference anti-KLK5 antibody, the reference antibody is bound to KLK5 under saturation conditions. After removing the excess reference anti-KLK5 antibody, the ability of the anti-KLK5 antibody in question to bind to KLK5 is evaluated. If the anti-KLK5 antibody can bind to KLK5 after the saturation binding of the reference anti-KLK5 antibody, it can be concluded that the anti-KLK5 antibody in question binds to a different epitope than the reference anti-KLK5 antibody. However, if the anti-KLK5 antibody in question cannot bind to KLK5 after the saturation binding of the reference anti-KLK5 antibody, the anti-KLK5 antibody in question may bind to the same epitope as the epitope bound by the reference anti-KLK5 antibody. To confirm whether this antibody binds to the same epitope or is only sterically hindered from binding, conventional experiments can be used (such as peptide mutations, ELISA, RIA, surface plasmon resonance, flow cytometry, or binding analysis using other quantitative or qualitative antibody binding assays available in the art). This assay should be performed in two setups, i.e., with both antibodies being saturation antibodies. In both settings, if only the first (saturation) antibody can bind to KLK5, it can be concluded that the anti-KLK5 antibody in question and the reference anti-KLK5 antibody compete for binding to KLK5.

[0042] In some embodiments, two antibodies bind to the same epitope or overlapping epitopes if, when one antibody is present at a 1-fold, 5-fold, 10-fold, 20-fold, or 100-fold excess, it inhibits the binding of the other antibody by at least 50%, at least 75%, at least 90%, or even 99% or more, as measured in a competitive binding assay (see, e.g., Junghans et al., Cancer Res. 50 (1990) 1495-1502).

[0043] In some embodiments, two antibodies are considered to bind to the same epitope if essentially all amino acid mutations in the antigen that reduce or eliminate the binding of one antibody also reduce or eliminate the binding of the other antibody. Two antibodies are considered to have "overlapping epitopes" if only a subset of the amino acid mutations that reduce or eliminate the binding of one antibody reduce or eliminate the binding of the other antibody.

[0044] The term "chimeric" antibody refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species and the remaining portion of the heavy and / or light chain is derived from a different source or species.

[0045] The "class" of an antibody refers to the type of constant domain or constant region carried by its heavy chain. There are five main classes of antibodies, namely IgA, IgD, IgE, IgG, and IgM, and some of these can be further divided into subclasses (isotypes), e.g., IgG 1 , IgG 2 , IgG 3 , IgG 4 , IgA 1 , and IgA 2 can be further divided. In certain embodiments, the antibody is of the IgG 1 isotype. In certain embodiments, the antibody is of the IgG isotype having the P329G, L234A, and L235A mutations to reduce the Fc region effector function 1 . In other embodiments, the antibody is of the IgG 2 isotype. In certain embodiments, the antibody is of the IgG 4An IgG having an S228P mutation in the hinge region to improve antibody stability 4 It is of an isotype. The heavy chain constant domains corresponding to different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively. The light chain of an antibody may be assigned to either of two types called κ (kappa) and λ (lambda) based on the amino acid sequence of its constant domain.

[0046] "Effector function" refers to the biological activity resulting from the Fc region of an antibody and varies depending on the antibody isotype. Examples of antibody effector functions include the following: C1q binding and complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g., B cell receptors); and B cell activation.

[0047] The "effective amount" of an agent, e.g., a pharmaceutical composition, refers to the amount effective in the dosage and for the period required to achieve the desired therapeutic or prophylactic result.

[0048] The term "Fc region" as used herein is used to define the C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. This term includes native sequence Fc regions and variant Fc regions. In one aspect, the human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl terminus of the heavy chain. However, antibodies produced by a host cell may be subject to post-translational cleavage of one or more, particularly one or two, amino acids from the C-terminus of the heavy chain. Thus, expression of a particular nucleic acid molecule encoding a full-length heavy chain may result in antibodies produced by a host cell that contain either the full-length heavy chain or a cleaved variant of the full-length heavy chain. This may be the case even where the final two C-terminal amino acids of the heavy chain are glycine (G446) and lysine (K447, numbering according to the EU index). Thus, the C-terminal lysine (Lys447) of the Fc region, or the C-terminal glycine (Gly446) and lysine (Lys447) may or may not be present. Thus, for example, "full-length IgG1" includes IgG1 that has Gly446 and Lys447, or does not have Lys447, or does not have both Gly446 and Lys447. The amino acid sequence of the heavy chain containing the Fc region is represented herein without the C-terminal glycine-lysine dipeptide, unless otherwise indicated. In one aspect, the heavy chain containing the Fc region as specified herein and included in an antibody according to the invention may include Gly446 and Lys447 (numbering according to the EU index). In one aspect, the heavy chain containing the Fc region as specified herein and included in an antibody according to the invention may include Gly446 (numbering according to the EU index). Unless otherwise indicated herein, the numbering of amino acid residues in the Fc region or constant region follows the EU numbering system, also called the EU index, described in Kabat et al., "Sequences of Proteins of Immunological Interest", 5th Edition, Public Health Service, National Institutes of Health, Bethesda, Maryland (1991).

[0049] The term "framework" or "FR" refers to variable domain residues other than complementarity determining regions (CDRs). The FRs of the variable domain generally consist of four FR domains, FR1, FR2, FR3, and FR4. Thus, CDR and FR sequences generally occur in the following sequences in VH (or VL): FR1-CDR-H1 (CDR-L1)-FR2-CDR-H2 (CDR-L2)-FR3-CDR-H3 (CDR-L3)-FR4.

[0050] The terms "full-length antibody", "intact antibody", and "whole antibody" are used interchangeably herein to refer to an antibody having a structure substantially the same as a native antibody structure or having a heavy chain that contains an Fc region as defined herein.

[0051] The terms "host cell", "host cell line", and "host cell culture" are used interchangeably and refer to a cell into which an exogenous nucleic acid has been introduced, including progeny of such cell. Host cells include "transformants" and "transformed cells", which include the progeny of the primary transformed cell and progeny derived from the host cell regardless of the number of passages. The progeny may not be completely identical to the parental cell in terms of nucleic acid content and may include mutations. Progeny of mutants having the same function or biological activity as that originally screened or selected in the transformed cell are included herein.

[0052] A "human antibody" is one that possesses an amino acid sequence corresponding to the amino acid sequence of an antibody produced by a human or human cell or derived from a non-human source that utilizes a human antibody repertoire or other human antibody coding sequences. This definition of a human antibody specifically excludes humanized antibodies that contain non-human antigen-binding residues.

[0053] The "human consensus framework" is a framework that represents the most commonly occurring amino acid residues in the selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup such as those in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda MD (1991), vols. 1-3. In one aspect, for VL, the subgroup is subgroup kappa I as in Kabat et al. above. In one aspect, for VH, the subgroup is subgroup III of Kabat et al. above

[0054] A "humanized" antibody refers to a chimeric antibody that contains amino acid residues derived from non-human CDRs and amino acid residues derived from human FRs. In certain aspects, a humanized antibody substantially comprises all of at least one, typically two, variable domains, in which all or substantially all of the CDRs correspond to the CDRs of a non-human antibody and all or substantially all of the FRs correspond to the FRs of a human antibody. A humanized antibody may optionally include at least a portion of the antibody constant region derived from a human antibody. The "humanized form" of an antibody, e.g., a non-human antibody, refers to the antibody that has been humanized

[0055] As used herein, the terms "hypervariable region" or "HVR" mean each of the regions of an antibody variable domain that are hypervariable within the sequence and that determine antigen-binding specificity, e.g., the "complementary determining regions" (CDRs)

[0056] Generally, an antibody contains six CDRs, three in VH (CDR-H1, CDR-H2, CDR-H3) and three in VL (CDR-L1, CDR-L2, CDR-L3). Exemplary CDRs herein include the following: (a) Hypervariable loops occurring at amino acid residues 26 - 32 (L1), 50 - 52 (L2), 91 - 96 (L3), 26 - 32 (H1), 53 - 55 (H2) and 96 - 101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901 - 917 (1987)); (b) CDRs present at amino acid residues 24 - 34 (L1), 50 - 56 (L2), 89 - 97 (L3), 31 - 35b (H1), 50 - 65 (H2) and 95 - 102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)); and (c) Antigen contacts occurring at amino acid residues 27c - 36 (L1), 46 - 55 (L2), 89 - 96 (L3), 30 - 35b (H1), 47 - 58 (H2) and 93 - 101 (H3) (MacCallum et al. J. Mol. Biol. 262:732 - 745 (1996)).

[0057] Unless otherwise indicated, CDRs are determined according to Kabat et al. above. One of ordinary skill in the art will understand that the CDR designations can be determined according to Chothia above, MacCallum above, or any other scientifically - approved nomenclature system. In one aspect, CDR residues include those identified in FIGS. 1 - 3 or elsewhere in this specification.

[0058] An "immunoconjugate" is an antibody conjugated to one or more heterologous molecules, including but not limited to cytotoxic agents.

[0059] The "individual" or "subject" is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the individual or subject is a human.

[0060] An "isolated" antibody is one that has been separated from the components of its natural environment. In some embodiments, the antibody is purified until it has a purity greater than 95% or greater than 99%, as determined by, for example, electrophoretic (e.g., SDS-PAGE, isoelectric focusing electrophoresis (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC) methods. For a review of methods for assessing antibody purity, see, for example, Flatman et al., J. Chromatogr. B848:79-87 (2007).

[0061] The term "linked", when used in the context of two polypeptides, means that the polypeptides are part of the same amino acid sequence. The two linked polypeptides can be separated by additional amino acid sequences; that is, they need not be contiguous or directly linked to each other.

[0062] The term "nucleic acid molecule" or "polynucleotide" includes any compound and / or substance that contains a polymer of nucleotides. Each nucleotide is composed of a base, specifically, a purine base or a pyrimidine base (i.e., cytosine (C), guanine (G), adenine (A), thymine (T) or uracil (U)), a sugar (i.e., deoxyribose or ribose), and a phosphate group. Often, nucleic acid molecules are described by their base sequences, whereby the bases represent the primary structure (linear structure) of the nucleic acid molecule. The sequence of bases is typically represented as 5' to 3'. As used herein, the term nucleic acid molecule includes deoxyribonucleic acid (DNA), e.g., complementary DNA (cDNA) and genomic DNA, ribonucleic acid (RNA), particularly messenger RNA (mRNA), synthetic forms of DNA or RNA, and hybrid polymers containing two or more of these molecules. Nucleic acid molecules may be linear or circular. In addition, the term nucleic acid molecule includes both sense and antisense strands, as well as both single-stranded and double-stranded forms. Further, the nucleic acid molecules described herein may contain naturally occurring nucleotides or non-naturally occurring nucleotides. Examples of non-naturally occurring nucleotides that include derivatized sugars or phosphate backbone linkages or chemically modified residues include modified nucleotide bases. Nucleic acid molecules also include, for example, DNA molecules and RNA molecules that are suitable as vectors for the direct expression of the antibodies of the present invention in vitro and / or in vivo in a host or patient. Such DNA (e.g., cDNA) or RNA (e.g., mRNA) vectors may or may not be modified. For example, mRNA may be chemically modified to enhance the stability of the RNA vector and / or the expression of the encoded molecule so that the mRNA can be injected into a subject to produce an antibody in vivo. (See, e.g., Stadler et al., Nature Medicine 2017, published online June 12, 2017, doi:10.1038 / nm.4356 or European Patent No. 2101823B1.)

[0063] "Isolated" nucleic acid refers to a nucleic acid molecule that has been separated from the components of its natural environment.

[0064] Isolated nucleic acids include nucleic acid molecules that are present extrachromosomally or at a chromosomal location different from their native chromosomal location within a cell that normally contains the nucleic acid molecule. "Isolated nucleic acid encoding an anti-KLK7 antibody" refers to one or more nucleic acid molecules encoding the heavy and light chains (or fragments thereof) of an anti-KLK7 antibody, such nucleic acid molecules in a single vector or separate vectors, and such nucleic acid molecules present at one or more locations within a host cell.

[0065] "Isolated nucleic acid encoding an anti-KLK5 antibody" refers to one or more nucleic acid molecules encoding the heavy and light chains (or fragments thereof) of an anti-KLK5 antibody, such nucleic acid molecules in a single vector or separate vectors, and such nucleic acid molecules present at one or more locations within a host cell.

[0066] "Isolated nucleic acid encoding an anti-KLK5 / KLK7 bispecific antibody" refers to one or more nucleic acid molecules encoding the heavy and light chains (or fragments thereof) of an anti-KLK5 / KLK7 bispecific antibody, such nucleic acid molecules in a single vector or separate vectors, and such nucleic acid molecules present at one or more locations within a host cell.

[0067] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies comprising the population are identical and / or bind the same epitope, except for variant antibodies that may occur naturally or during the production of a monoclonal antibody preparation, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier "monoclonal" indicates the characteristic of the antibody as being obtained from a substantially homogeneous population of antibodies and should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies according to the present invention can be made by a variety of techniques including, but not limited to, the hybridoma method, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals that include all or part of the human immunoglobulin loci, and such methods and other exemplary methods for making monoclonal antibodies described herein are included but not limited to.

[0068] A "naked antibody" refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or a radioactive label. A naked antibody may be present in a pharmaceutical composition.

[0069] The term "native antibody" refers to immunoglobulin molecules that exist natively with various structures. For example, native IgG antibodies are approximately 150,000 Dalton heterotetrameric glycoproteins, including those in which two identical light chains and two identical heavy chains are disulfide-bonded. From the N-terminus to the C-terminus, each heavy chain has a variable domain (VH), also called the variable heavy domain or heavy chain variable region, followed by three constant heavy domains (CH1, CH2, and CH3). Similarly, from the N-terminus to the C-terminus, each light chain has a variable domain (VL), also called the variable light domain or light chain variable region, followed by a constant light (CL) domain.

[0070] The term "package insert" is used to refer to the instructions customarily included in the commercial package of a therapeutic product and includes information regarding indications, use, dosage, administration, combination therapy, contraindications and / or warnings for such a therapeutic product.

[0071] The "percent amino acid sequence identity" to a reference polypeptide sequence is defined, for the purpose of alignment, as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in the reference polypeptide sequence, after aligning the sequences, introducing gaps if necessary to achieve the maximum sequence identity, and without considering any conservative substitutions as part of the sequence identity. Alignments for determining the percent amino acid sequence identity can be achieved in a variety of ways within the skill in the art, for example, using publicly available computer software such as BLAST, BLAST-2, Clustal W, Megalign (DNASTAR) software or the FASTA program package. One of ordinary skill in the art can determine appropriate parameters for alignment of sequences, including any algorithms necessary to achieve the maximum alignment over the entire length of the sequences being compared. Alternatively, the value of the identity rate can be generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was created by Genentech, Inc., the source code of which is filed in the user documentation of the United States Copyright Office (Washington D.C., 20559), registered under United States Copyright Registration No. TXU510087, and described in International Publication No. WO 2001 / 007611.

[0072] Unless otherwise specified, for the purposes of this specification, the value of the amino acid sequence identity rate is generated using the ggsearch program of the FASTA package version 36.3.8c, or subsequently using the BLOSUM50 comparison matrix. The FASTA program package is disclosed in W.R. Pearson and D.J. Lipman (1988), "Improved Tools for Biological Sequence Analysis", PNAS 85:2444-2448; W.R. Pearson (1996) "Effective protein sequence comparison" Meth. Enzymol. 266:227-258; and Pearson et al., (1997) Genomics 46:24-36, and is publicly available from www.fasta.bioch.virginia.edu / fasta_www2 / fasta_down.shtml or www.ebi.ac.uk / Tools / sss / fasta. Alternatively, use a public server accessible at fasta.bioch.virginia.edu / fasta_www2 / index.cgi, use the ggsearch (global protein:protein) program and default options (BLOSUM50; open: -10; ext: -2; Ktup = 2) to ensure global rather than local alignment and compare sequences. The amino acid identity rate is given in the output alignment header.

[0073] The terms "pharmaceutical composition" or "pharmaceutical formulation" refer to a preparation that is in a form such that the biological activity of the active ingredient contained therein is effective, and that does not contain additional ingredients that are unacceptably toxic to the subject to whom the pharmaceutical composition will be administered.

[0074] Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0075] As used herein, the terms "KLK5" and "kallikrein-related peptidase 5" refer to any native KLK5 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise specified. This term encompasses "full-length" unprocessed KLK5, as well as any form of KLK5 resulting from intracellular processing. This term also encompasses naturally occurring variants of KLK5, such as splice variants or allelic variants. The amino acid sequence of an exemplary human precursor KLK5 protein is shown in SEQ ID NO: 1 (UniProtKB / Swiss-Prot: Q9Y337.3). The amino acid sequence of an exemplary human mature KLK5 protein lacking the signal peptide (amino acids 1-22) and the propeptide (amino acids 23-66) is shown in SEQ ID NO: 2. The amino acid sequence of an exemplary cynomolgus monkey precursor KLK5 protein is shown in SEQ ID NO: 100 (UniProtKB: A0A2K5W0T6). The amino acid sequence of an exemplary cynomolgus monkey mature KLK5 protein lacking the signal peptide (amino acids 1-22) and the propeptide (amino acids 23-64) is shown in SEQ ID NO: 101.

[0076] As used herein, the terms "KLK7" and "kallikrein-related peptidase 7" refer to any native KLK7 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise specified. This term encompasses "full-length" unprocessed KLK7, as well as any form of KLK7 resulting from intracellular processing. This term also encompasses naturally occurring variants of KLK7, such as splice variants or allelic variants. The amino acid sequence of an exemplary human precursor KLK7 protein is shown in SEQ ID NO: 3 (UniProtKB / Swiss-Prot: P49862.1). The amino acid sequence of an exemplary human mature KLK7 protein lacking the signal peptide (amino acids 1-22) and propeptide (amino acids 23-29) is shown in SEQ ID NO: 4. The amino acid sequence of an exemplary cynomolgus monkey precursor KLK7 protein is shown in SEQ ID NO: 5 (UniProtKB: G7PYG2). The amino acid sequence of an exemplary cynomolgus monkey mature KLK7 protein lacking the signal peptide (amino acids 1-21) and propeptide (amino acids 22-29) is shown in SEQ ID NO: 6.

[0077] As used herein, "treatment" (and its grammatical variations, e.g., "treat" or "treating") refers to a clinical intervention in a trial to alter the natural course of a disease in an individual being treated, which can be performed for prophylaxis or during the course of clinical pathology. Desired effects of treatment include, but are not limited to, prevention of the onset or recurrence of the disease, alleviation of symptoms, attenuation of any direct or indirect pathological consequences of the disease, prevention of metastasis, reduction of the rate of disease progression, remission or palliation of symptoms, and improved prognosis or recovery. In some embodiments, the antibodies of the invention are used to delay the onset of a disease or to slow the progression of a disease.

[0078] The term "variable region" or "variable domain" refers to the domain of the heavy or light chain of an antibody that is involved in the binding of the antibody to an antigen. The variable domains of the heavy and light chains of a native antibody (VH and VL, respectively) generally have a similar structure, and each domain contains four conserved framework regions (FRs) and three complementarity-determining regions (CDRs). See, for example, Kindt et al., Kuby Immunology, 6 th ed. W.H. Freeman and Co., page 91 (2007). The variable domain can include the heavy chain (HC) CDR1-FR2-CDR2-FR3-CDR3, with or without all or part of FR1 and / or FR4; and the light chain (LC) CDR1-FR2-CDR2-FR3-CDR3, with or without all or part of FR1 and / or FR4. That is, the variable domain may lack part of FR1 and / or FR4 as long as it retains antigen-binding activity. A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, an antibody that binds a particular antigen may be isolated by using the VH or VL domain of the antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, for example, Portolano et al., J. Immunol. 150:880-887, 1993; Clarkson et al., Nature 352:624-628, 1991.

[0079] The term "vector" as used herein refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is ligated. This term includes vectors as self-replicating nucleic acid structures and vectors that are incorporated into the genome of a host cell into which the vector has been introduced. A particular vector can direct the expression of a nucleic acid operably linked thereto. Such a vector is referred to herein as an "expression vector." II. Compositions and Methods

[0080] In one aspect, the present invention is based in part on the finding that both KLK5 and KLK7 can play a role in epithelial barrier permeability. Thus, it can be shown that by inhibiting both KLK5 and KLK7, the efficacy is improved in the treatment of conditions associated with excessive epithelial barrier permeability. In certain aspects, antibodies that bind to KLK5 are provided. In certain aspects, antibodies that bind to KLK7 are provided. In certain aspects, bispecific antibodies that bind to both KLK5 and KLK7 are provided. The antibodies of the present invention are useful, for example, in the diagnosis or treatment of Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis and rosacea. A. Exemplary anti-KLK7 antibodies

[0081] In one aspect, the present invention provides an antibody that binds to KLK7. In one aspect, the present invention provides an antibody that binds to KLK7. In one aspect, the present invention provides an antibody that specifically binds to KLK7. In certain aspects, the anti-KLK7 antibody inhibits KLK7 protease activity. In some embodiments, the anti-KLK7 antibody inhibits human KLK7-mediated cleavage of a substrate comprising the amino acid sequence RPKPVE-Nval-WRK (Nval is norvaline) (SEQ ID NO: 121). In some embodiments, the anti-KLK7 antibody inhibits human KLK7-mediated cleavage of a substrate comprising the amino acid sequence RPKPVE-Nval-WRK (Nval is norvaline) (SEQ ID NO: 121) with an IC50 of less than 5 nM, or less than 3 nM, or less than 2 nM, or less than 1 nM. In some embodiments, the anti-KLK7 antibody inhibits human KLK7-mediated cleavage of a substrate comprising the amino acid sequence RPKPVE-Nval-WRK (Nval is norvaline) (SEQ ID NO: 121) with an IC50 of 5 nM or less, or 3 nM or less, or 2 nM or less, or 1 nM or less. In some embodiments, the anti-KLK7 antibody has a K of less than 20 pM, less than 10 pM, or less than 9 pM, or less than 8 pM, or less than 7 pM, or less than 6 pM, or less than 5 pM, or less than 3 pM, or less than 2 pM, or less than 1 pM when measured by surface plasmon resonance DIt binds to human KLK7. In some embodiments, the anti-KLK7 antibody has a K of 20 pM or less, 10 pM or less, or 9 pM or less, or 8 pM or less, or 7 pM or less, or 6 pM or less, or 5 pM or less, or 3 pM or less, or 2 pM or less, or 1 pM or less when measured by surface plasmon resonance. D It binds to human KLK7.

[0082] In some embodiments, the anti-KLK7 antibody binds to an epitope within amino acids R71 - N82, K152 - S158, and / or Q211 - K222 of KLK7. Here, the amino acids are numbered according to SEQ ID NO: 4. In some embodiments, the anti-KLK7 antibody contacts at least one amino acid within amino acids R71 - N82, contacts at least one amino acid within amino acids K152 - S158, and contacts at least one amino acid within amino acids Q211 - K222 of KLK7 as numbered according to SEQ ID NO: 4. In some embodiments, the anti-KLK7 antibody binds to an epitope comprising one or more of amino acids H72, P73, G74, S76, Q78, N82, N157, K211 and / or T213 of KLK7 numbered according to SEQ ID NO: 4. In some embodiments, the anti-KLK7 antibody binds to an epitope comprising one or more of amino acids H91, P92, G93, S95, Q97, N101, N178, K233, and / or T235 of KLK7 according to chymotrypsin numbering. In some embodiments, the anti-KLK7 antibody binds to an epitope comprising amino acids H72, P73, G74, S76, Q78, N82, N157, K211 and T213 of KLK7 numbered according to SEQ ID NO: 4. In some embodiments, the anti-KLK7 antibody binds to an epitope comprising amino acids H91, P92, G93, S95, Q97, N101, N178, K233, and T235 of KLK7 according to chymotrypsin numbering.

[0083] In some embodiments, when the anti-KLK7 antibody binds to KLK7, a conformational change of human KLK7 is brought about, and this conformational change allosterically results in the disruption of the substrate binding site and / or the active site of human KLK7.

[0084] In some embodiments, the anti-KLK7 antibody does not bind to KLK5. In some embodiments, the anti-KLK7 antibody does not bind to KLK1, KLK4, KLK5, KLK11, and KLK14. In some embodiments, the anti-KLK7 antibody binds to human KLK7 and cynomolgus monkey KLK7.

[0085] In one aspect, the present invention provides an anti-KLK7 antibody comprising at least 1, at least 2, at least 3, at least 4, at least 5, and / or all 6 CDRs selected from: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 12.

[0086] In one aspect, the present invention provides an antibody comprising at least one, at least two, or all three VH CDR sequences selected from: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 8; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 9. In one aspect, the antibody comprises CDR-H3 comprising the amino acid sequence of SEQ ID NO: 9. In another aspect, the antibody comprises CDR-H3 comprising the amino acid sequence of SEQ ID NO: 9 and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 12. In a further aspect, the antibody comprises CDR-H3 comprising the amino acid sequence of SEQ ID NO: 9, CDR-L3 comprising the amino acid sequence of SEQ ID NO: 12, and CDR-H2 comprising the amino acid sequence of SEQ ID NO: 8. In a further aspect, the antibody comprises: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 8; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 9.

[0087] In another aspect, the present invention provides an antibody comprising at least one, at least two, or all three VL CDR sequences selected from: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 12. In one aspect, the antibody comprises: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 12.

[0088] In another aspect, the antibody of the present invention comprises a VH domain comprising at least one, at least two and / or all three VH CDR sequences selected from: (a) (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 7, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 8, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 9; and a VL domain comprising at least one, at least two and / or all three VL CDR sequences selected from: (b) (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 10, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 11, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 12.

[0089] In another aspect, the present invention provides an antibody comprising: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 12.

[0090] In any of the aspects provided herein, the anti-KLK7 antibody is humanized. In one aspect, the anti-KLK7 antibody further comprises an acceptor human framework, such as a human immunoglobulin framework or a human consensus framework.

[0091] In one aspect, the anti-KLK7 antibody comprises a VH domain comprising one or more heavy chain framework sequences selected from: (a) heavy chain framework region 1 (HC-FR1) of SEQ ID NOs: 123-128; (b) heavy chain framework region 2 (HC-FR2) of SEQ ID NOs: 130-133; (c) heavy chain framework region 3 (HC-FR3) of SEQ ID NOs: 135-143; and (d) heavy chain framework region 4 (HC-FR4) of SEQ ID NOs: 144-145.

[0092] In another aspect, the anti-KLK7 antibody comprises a VH domain comprising HC-FR1 of SEQ ID NOs: 123-128. In another aspect, the anti-KLK7 antibody comprises a VH domain comprising HC-FR2 of SEQ ID NOs: 130-133. In another aspect, the anti-KLK7 antibody comprises a VH domain comprising HC-FR3 of SEQ ID NOs: 135-143. In another aspect, the anti-KLK7 antibody comprises a VH domain comprising HC-FR4 of SEQ ID NOs: 144-145.

[0093] In another aspect, the anti-KLK7 antibody comprises a VH domain comprising HC-FR1 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 123-128. In one aspect, the VH domain comprises HC-FR1 having at least 95% sequence identity to SEQ ID NOs: 123-128. In another aspect, the VH domain comprises HC-FR1 having at least 98% sequence identity to SEQ ID NOs: 123-128.

[0094] In another aspect, the anti-KLK7 antibody comprises a VH domain comprising HC-FR2 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 130-133. In one aspect, the VH domain comprises HC-FR2 having at least 95% sequence identity to SEQ ID NOs: 130-133. In another aspect, the VH domain comprises HC-FR2 having at least 98% sequence identity to SEQ ID NOs: 130-133.

[0095] In another aspect, the anti-KLK7 antibody comprises a VH domain comprising HC-FR3 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 135-143. In one aspect, the VH domain comprises HC-FR3 having at least 95% sequence identity to SEQ ID NOs: 135-143. In another aspect, the VH domain comprises HC-FR3 having at least 98% sequence identity to SEQ ID NOs: 135-143.

[0096] In another aspect, the anti-KLK7 antibody comprises a VH domain comprising an HC-FR4 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 144-145. In one aspect, the VH domain comprises an HC-FR4 having at least 95% sequence identity to SEQ ID NOs: 144-145. In another aspect, the VH domain comprises an HC-FR4 having at least 98% sequence identity to SEQ ID NOs: 144-145.

[0097] In one aspect, the anti-KLK7 antibody comprises a VL domain comprising one or more light chain framework sequences selected from (a) light chain framework region 1 (LC-FR1) of SEQ ID NOs: 147-150, (b) light chain framework region 2 (LC-FR2) of SEQ ID NOs: 152-154, (c) light chain framework region 3 (LC-FR3) of SEQ ID NOs: 156-158, and (d) light chain framework region 4 (LC-FR4) of SEQ ID NO: 160.

[0098] In another aspect, the anti-KLK7 antibody comprises a VL domain comprising LC-FR1 of SEQ ID NOs: 147-150. In another aspect, the anti-KLK7 antibody comprises a VL domain comprising LC-FR2 of SEQ ID NOs: 152-154. In another aspect, the anti-KLK7 antibody comprises a VL domain comprising LC-FR3 of SEQ ID NOs: 156-158. In another aspect, the anti-KLK7 antibody comprises a VL domain comprising LC-FR4 of SEQ ID NO: 160.

[0099] In another aspect, the anti-KLK7 antibody comprises a VL domain comprising an LC-FR1 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 147-150. In one aspect, the VL domain comprises an LC-FR1 having at least 95% sequence identity to SEQ ID NOs: 147-150. In another aspect, the VL domain comprises an LC-FR1 having at least 98% sequence identity to SEQ ID NOs: 147-150.

[0100] In another aspect, the anti-KLK7 antibody comprises a VL domain comprising an LC-FR2 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 152-154. In one aspect, the VL domain comprises an LC-FR2 having at least 95% sequence identity to SEQ ID NOs: 152-154. In another aspect, the VL domain comprises an LC-FR2 having at least 98% sequence identity to SEQ ID NOs: 152-154.

[0101] In another aspect, the anti-KLK7 antibody comprises a VL domain comprising an LC-FR3 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 156-158. In one aspect, the VL domain comprises an LC-FR3 having at least 95% sequence identity to SEQ ID NOs: 156-158. In another aspect, the VL domain comprises an LC-FR3 having at least 98% sequence identity to SEQ ID NOs: 156-158.

[0102] In another aspect, the anti-KLK7 antibody comprises a VL domain comprising an LC-FR4 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 160. In one aspect, the VL domain comprises an LC-FR1 having at least 95% sequence identity to SEQ ID NO: 160. In another aspect, the VL domain comprises an LC-FR1 having at least 98% sequence identity to SEQ ID NO: 160.

[0103] In another aspect, the anti-KLK7 antibody comprises one or more CDR sequences of VH selected from SEQ ID NOs: 13 and 15-30. In another embodiment, the anti-KLK7 antibody comprises one or more CDR sequences of VL selected from SEQ ID NOs: 14 and 31-38. In another embodiment, the anti-KLK7 antibody comprises CDR sequences of VH selected from SEQ ID NOs: 13 and 15-30, and CDR sequences of VL selected from SEQ ID NOs: 14 and 31-38.

[0104] In a further aspect, the anti-KLK7 antibody comprises the CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of VH selected from SEQ ID NOs: 13 and 15-30, and the CDR-L1, CDR-L2 and CDR-L3 amino acid sequences of VL selected from SEQ ID NOs: 14 and 31-38.

[0105] In one aspect, the anti-KLK7 antibody comprises one or more heavy chain CDR amino acid sequences of VH selected from SEQ ID NOs: 13 and 15-30, and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequence of VH selected from SEQ ID NOs: 13 and 15-30. In one aspect, the anti-KLK7 antibody comprises three heavy chain CDR amino acid sequences of VH selected from SEQ ID NOs: 13 and 15-30, and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequence of VH selected from SEQ ID NOs: 13 and 15-30. In one aspect, the anti-KLK7 antibody comprises three heavy chain CDR amino acid sequences of VH selected from SEQ ID NOs: 13 and 15-30, and a framework having at least 95% sequence identity to the framework amino acid sequence of VH selected from SEQ ID NOs: 13 and 15-30. In another aspect, the anti-KLK7 antibody comprises three heavy chain CDR amino acid sequences of VH selected from SEQ ID NOs: 13 and 15-30, and a framework having at least 98% sequence identity to the framework amino acid sequence of VH selected from SEQ ID NOs: 13 and 15-30.

[0106] In one aspect, the anti-KLK7 antibody comprises one or more light chain CDR amino acid sequences of VL selected from SEQ ID NO: 14 and 31-38, and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequence of VL selected from SEQ ID NO: 14 and 31-38. In one aspect, the anti-KLK7 antibody comprises three light chain CDR amino acid sequences of VL selected from SEQ ID NO: 14 and 31-38, and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequence of VL selected from SEQ ID NO: 14 and 31-38. In one aspect, the anti-KLK7 antibody comprises three light chain CDR amino acid sequences of VL selected from SEQ ID NO: 14 and 31-38, and a framework having at least 95% sequence identity to the framework amino acid sequence of VL selected from SEQ ID NO: 14 and 31-38. In another aspect, the anti-KLK7 antibody comprises three light chain CDR amino acid sequences of VL selected from SEQ ID NO: 14 and 31-38, and in particular a framework having at least 98% sequence identity to the framework amino acid sequence of VL selected from SEQ ID NO: 14 and 31-38.

[0107] In one aspect, the anti-KLK7 antibody comprises: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 11; (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 12, and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from SEQ ID NOs: 13 and 15-30, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from SEQ ID NOs: 14 and 31-38. In one aspect, the VH domain has at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 13 and 15-30. In one aspect, the VL domain has at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 14 and 31-38.

[0108] In one aspect, the anti-KLK7 antibody comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 12, and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from SEQ ID NOs: 13 and 15-30, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from SEQ ID NOs: 14 and 31-38, and the antibody specifically binds to KLK7. In one aspect, the VH domain has at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 13 and 15-30. In one aspect, the VL domain has at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 14 and 31-38. In one aspect, the antibody binds to KLK7 with a dissociation constant (K D ) of 10 pM or less, or 9 pM or less, or 8 pM or less, or 7 pM or less, or 6 pM or less, or 5 pM or less when measured by surface plasmon resonance. In one aspect, the antibody binds to KLK7 with a dissociation constant (K D ) of 10 pM or less, or 9 pM or less, or 8 pM or less, or 7 pM or less, or 6 pM or less, or 5 pM or less when measured by surface plasmon resonance.

[0109] In another aspect, the anti-KLK7 antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from SEQ ID NOs: 13 and 15-30. In one aspect, the anti-KLK7 antibody comprises a heavy chain variable domain (VH) sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 13 and 15-30. In certain aspects, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity includes substitutions (e.g., conservative substitutions), insertions, or deletions as compared to a reference sequence, but the anti-KLK7 antibody comprising such a sequence retains the ability to bind to KLK7. In certain aspects, 1 to 10 total amino acids are substituted, inserted, and / or deleted in the amino acid sequence selected from SEQ ID NOs: 13 and 15-30. In some aspects, the substitutions, insertions, or deletions occur in regions outside of the CDRs (i.e., in the FRs). Optionally, the anti-KLK7 antibody comprises a VH sequence of an amino acid sequence selected from SEQ ID NOs: 13 and 15-30 and includes post-translational modifications of such a sequence. Optionally, the anti-KLK7 antibody comprises a VH sequence of SEQ ID NO: 29 or 30 and includes post-translational modifications of such a sequence. In certain aspects, the VH comprises one, two, or three CDRs selected from (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 7, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 8, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 9. In another aspect, provided is an anti-KLK7 antibody comprising a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from SEQ ID NOs: 14 and 31-38. In one aspect, the anti-KLK7 antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 14 and 31-38.In certain embodiments, VL sequences having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity, compared to a reference sequence, include substitutions (e.g., conservative substitutions), insertions, or deletions, but an anti-KLK7 antibody comprising such a sequence retains the ability to bind to KLK7. In certain embodiments, in the amino acid sequences selected from SEQ ID NO: 14 and 31-38, a total of 1-10 amino acids are substituted, inserted, and / or deleted. In certain embodiments, the substitutions, insertions or deletions occur in regions outside the CDRs (i.e., FRs). Optionally, the anti-KLK7 antibody comprises a VL sequence of an amino acid sequence selected from SEQ ID NO: 14 and 31-38, including post-translational modifications of the sequence. Optionally, the anti-KLK7 antibody comprises a VL sequence of SEQ ID NO: 32 or 38, including post-translational modifications of the sequence. In certain embodiments, the VL comprises one, two, or three CDRs selected from: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 10, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 11, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 12.

[0110] In another embodiment, an anti-KLK7 antibody is provided that comprises a VH sequence as in any of the embodiments provided above and a VL sequence as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH and VL sequences of SEQ ID NO: 29 and SEQ ID NO: 32, respectively, including post-translational modifications of the sequences. In one embodiment, the antibody comprises the VH and VL sequences of SEQ ID NO: 30 and SEQ ID NO: 38, respectively, including post-translational modifications of the sequences.

[0111] In a further embodiment, the invention provides an antibody that binds to the same epitope as an anti-KLK7 antibody provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as an anti-KLK7 antibody comprising the VH sequence of SEQ ID NO: 29 and the VL sequence of SEQ ID NO: 32.

[0112] In a further embodiment, the invention provides an antibody that competes with an anti-KLK7 antibody provided herein for binding to KLK7.

[0113] In a further aspect of the invention, an anti-KLK7 antibody according to any of the above aspects is a monoclonal antibody including a chimeric antibody, a humanized antibody or a human antibody. In one aspect, the anti-KLK7 antibody is an antibody fragment, for example, Fv, Fab, Fab’, scFv, diabody, or F(ab’) 2 fragment. In another aspect, the antibody is a full-length antibody, for example, an intact IgG1 antibody or other antibody class or isotype defined herein.

[0114] In a further aspect, an anti-KLK7 antibody according to any of the above aspects may incorporate any of the features, alone or in combination, as described in Sections 1-8 below. B. Exemplary anti-KLK5 antibodies

[0115] In one aspect, the invention provides an antibody that binds to KLK5. In one aspect, an isolated antibody that binds to KLK5 is provided. In one aspect, the invention provides an antibody that specifically binds to KLK5. In certain aspects, the anti-KLK5 antibody inhibits KLK5 protease activity. In some embodiments, the anti-KLK5 antibody inhibits human KLK5-mediated cleavage of the substrate Boc-Val-Pro-Arg-AMC. In some embodiments, the anti-KLK5 antibody inhibits human KLK5-mediated cleavage of the substrate Boc-Val-Pro-Arg-AMC with an IC50 of less than 5 nM, or less than 3 nM, or less than 2 nM, or less than 1 nM. In some embodiments, the anti-KLK5 antibody inhibits human KLK5-mediated cleavage of the substrate Boc-Val-Pro-Arg-AMC with an IC50 of 5 nM or less, or 3 nM or less, or 2 nM or less, or 1 nM or less. In some embodiments, the anti-KLK5 antibody binds to KLK5 with a K of less than 60 pM, less than 30 pM, less than 20 pM, less than 10 pM, or less than 5 pM as measured by surface plasmon resonance. D In some embodiments, the anti-KLK5 antibody binds to KLK5 with a K of less than 60 pM, less than 30 pM, less than 20 pM, less than 10 pM, or less than 5 pM as measured by surface plasmon resonance. D In some embodiments, the anti-KLK5 antibody binds to KLK5 with a K of less than 60 pM, less than 30 pM, less than 20 pM, less than 10 pM, or less than 5 pM as measured by surface plasmon resonance.

[0116] In some embodiments, when the anti-KLK5 antibody binds to human KLK5, it causes a conformational change in human KLK5, and this conformational change allosterically results in disruption of the substrate binding site and / or the active site of human KLK5.

[0117] In some embodiments, the anti-KLK5 antibody binds to an epitope on human KLK5 comprising one or more amino acid residues selected from Pro130, Ser131, Ala132, Gly133, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Gln174A, Ile176, Asp177, Asp178, Gly184, Asp185, Lys186, Ala186A, Arg188, Asn223, Arg224, Pro225, and Lys233 according to standard protease numbering (P113, S114, A115, G116, V145, L146, S147, Q148, K149, R150, E152, D153, A154, Y155, P156, R157, Q158, I159, D160, D161, G167, D168, K169, A170, R172, N204, R205, P206, and K214: consecutive numbering of SEQ ID NO: 2). See, for example, PCT Publication No. WO 2019 / 178316A1. In some embodiments, the anti-KLK5 antibody binds to an epitope on human KLK5 comprising one or more amino acid residues selected from the group consisting of Pro130, Ser131, Ala132, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Gln174A, Ile176, Asp177, Asp178, Arg224, and Lys233 according to standard protease numbering. In some embodiments, the anti-KLK5 antibody binds to an epitope on human KLK5 comprising one or more amino acid residues selected from Pro130, Ser131, Ala132, Gly133, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Gln174A, Ile176, Asp177, and Lys233 according to standard protease numbering.In some embodiments, the anti-KLK5 antibody binds to an epitope on human KLK5 that includes one or more amino acid residues selected from Ser131, Ala132, Gly133, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Pro173, Arg174, Gly184, Asp185, Lys186, Ala186A, Arg188, Asn223, Arg224, and Pro225 according to standard protease numbering.

[0118] In some embodiments, the anti-KLK5 antibody does not bind to KLK7. In some embodiments, the anti-KLK5 antibody does not bind to KLK1, KLK4, KLK7, KLK11, or KLK14. In some embodiments, the anti-KLK5 antibody binds to human KLK5 and cynomolgus monkey KLK5. Antibody hu.10C5-H28L5 and variants

[0119] In one aspect, the present invention provides an anti-KLK5 antibody comprising at least 1, at least 2, at least 3, at least 4, at least 5, or all 6 CDRs selected from: (a) CDR-H1 comprising the amino acid sequences of SEQ ID NOs: 39 and 107; (b) CDR-H2 comprising the amino acid sequences of SEQ ID NOs: 40 and 41; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42; (d) CDR-L1 comprising the amino acid sequences of SEQ ID NOs: 43 and 44; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45; and (f) CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 46-49.

[0120] In one aspect, the present invention provides an antibody comprising at least one, at least two, or all three VH CDR sequences selected from: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 39; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 41; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42. In a further aspect, the antibody comprises: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 39; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 41; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42.

[0121] In another aspect, the present invention provides an antibody comprising at least one, at least two, or all three VL CDR sequences selected from: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 43; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 47. In one aspect, the antibody comprises: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 43; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 47.

[0122] In one aspect, the present invention provides an antibody comprising at least one, at least two, or all three VH CDR sequences selected from: (a) CDR-H1 comprising the amino acid sequences of SEQ ID NOs: 39 and 107; (b) CDR-H2 comprising the amino acid sequences of SEQ ID NOs: 40 and 41; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42. In another aspect, the antibody comprises CDR-H1 comprising the amino acid sequence of SEQ ID NO: 39, CDR-H2 comprising the amino acid sequence of SEQ ID NO: 41, and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42.

[0123] In another aspect, the present invention provides an antibody comprising at least one, at least two, or all three VL CDR sequences selected from: (a) CDR-L1 comprising the amino acid sequences of SEQ ID NOs: 43 and 44; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45; and (c) CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 46 to 49. In one aspect, the antibody comprises: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 43; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 47.

[0124] In another aspect, the antibody of the present invention comprises: (a) a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from: (i) CDR-H1 comprising the amino acid sequences of SEQ ID NOs: 39 and 107, (ii) CDR-H2 comprising the amino acid sequences of SEQ ID NOs: 40 and 41, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42; and (b) a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from: (i) CDR-L1 comprising the amino acid sequences of SEQ ID NOs: 43 and 44, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (iii) CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 46 to 49.

[0125] In another aspect, the present invention provides an antibody comprising: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 39; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 41; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 43; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 47.

[0126] In any of the aspects provided herein, the anti-KLK5 antibody is humanized. In one aspect, the anti-KLK5 antibody further comprises an acceptor human framework, such as a human immunoglobulin framework or a human consensus framework.

[0127] In one aspect, the anti-KLK5 antibody comprises a VH domain comprising one or more heavy chain framework sequences selected from (a) heavy chain framework region 1 (HC-FR1) of SEQ ID NO: 161, (b) heavy chain framework regions 2 (HC-FR2) of SEQ ID NOs: 162-163, (c) heavy chain framework region 3 (HC-FR3) of SEQ ID NO: 164, and (d) heavy chain framework region 4 (HC-FR4) of SEQ ID NO: 165.

[0128] In another aspect, the anti-KLK5 antibody comprises a VH domain comprising HC-FR1 of SEQ ID NO: 161. In another aspect, the anti-KLK5 antibody comprises a VH domain comprising HC-FR2 of SEQ ID NOs: 162-163. In another aspect, the anti-KLK5 antibody comprises a VH domain comprising HC-FR3 of SEQ ID NO: 164. In another aspect, the anti-KLK5 antibody comprises a VH domain comprising HC-FR4 of SEQ ID NO: 165.

[0129] In another aspect, the anti-KLK5 antibody comprises a VH domain comprising HC-FR1 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 161. In one aspect, the VH domain comprises HC-FR1 having at least 95% sequence identity to SEQ ID NO: 161.

[0130] In another aspect, the VH domain comprises HC-FR1 having at least 98% sequence identity to SEQ ID NO: 161. In another aspect, the anti-KLK5 antibody comprises a VH domain comprising HC-FR2 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 162-163. In one aspect, the VH domain comprises HC-FR2 having at least 95% sequence identity to SEQ ID NOs: 162-163. In another aspect, the VH domain comprises HC-FR2 having at least 98% sequence identity to SEQ ID NOs: 162-163.

[0131] In another aspect, the anti-KLK5 antibody comprises a VH domain comprising an HC-FR3 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with SEQ ID NO: 164. In one aspect, the VH domain comprises an HC-FR3 having at least 95% sequence identity with SEQ ID NO: 164. In another aspect, the VH domain comprises an HC-FR3 having at least 98% sequence identity with SEQ ID NO: 164.

[0132] In another aspect, the anti-KLK5 antibody comprises a VH domain comprising an HC-FR4 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with SEQ ID NO: 165. In one aspect, the VH domain comprises an HC-FR4 having at least 95% sequence identity with SEQ ID NO: 165. In another aspect, the VH domain comprises an HC-FR4 having at least 98% sequence identity with SEQ ID NO: 165.

[0133] In one aspect, the anti-KLK5 antibody comprises a VL domain comprising one or more light chain framework sequences selected from (a) the light chain framework region 1 (LC-FR1) of SEQ ID NO: 166, (b) the light chain framework regions 2 (LC-FR2) of SEQ ID NOs: 167-168, (c) the light chain framework region 3 (LC-FR3) of SEQ ID NO: 169, and (d) the light chain framework region 4 (LC-FR4) of SEQ ID NO: 170.

[0134] In another aspect, the anti-KLK5 antibody comprises a VL domain comprising the LC-FR1 of SEQ ID NO: 166. In another aspect, the anti-KLK5 antibody comprises a VL domain comprising the LC-FR2 of SEQ ID NOs: 167-168. In another aspect, the anti-KLK5 antibody comprises a VL domain comprising the LC-FR3 of SEQ ID NO: 169. In another aspect, the anti-KLK5 antibody comprises a VL domain comprising the LC-FR4 of SEQ ID NO: 170.

[0135] In another aspect, the anti-KLK5 antibody comprises a VL domain comprising an LC-FR1 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 166. In one aspect, the VL domain comprises an LC-FR1 having at least 95% sequence identity to SEQ ID NO: 166. In another aspect, the VL domain comprises an LC-FR1 having at least 98% sequence identity to SEQ ID NO: 166.

[0136] In another aspect, the anti-KLK5 antibody comprises a VL domain comprising an LC-FR2 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOS: 167-168. In one aspect, the VL domain comprises an LC-FR2 having at least 95% sequence identity to SEQ ID NOS: 167-168. In another aspect, the VL domain comprises an LC-FR2 having at least 98% sequence identity to SEQ ID NOS: 167-168.

[0137] In another aspect, the anti-KLK5 antibody comprises a VL domain comprising an LC-FR3 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 169. In one aspect, the VL domain comprises an LC-FR3 having at least 95% sequence identity to SEQ ID NO: 169. In another aspect, the VL domain comprises an LC-FR3 having at least 98% sequence identity to SEQ ID NO: 169.

[0138] In another aspect, the anti-KLK5 antibody comprises a VL domain comprising an LC-FR4 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 170. In one aspect, the VL domain comprises an LC-FR4 having at least 95% sequence identity to SEQ ID NO: 170. In another aspect, the VL domain comprises an LC-FR4 having at least 98% sequence identity to SEQ ID NO: 170.

[0139] In another aspect, the anti-KLK5 antibody comprises one or more of the CDR sequences of VH of SEQ ID NO: 50, 52, 53, 105, or 106. In another embodiment, the anti-KLK5 antibody comprises one or more of the CDR sequences of VL of SEQ ID NO: 51 or 54-57. In another embodiment, the anti-KLK5 antibody comprises the CDR sequences of VH of SEQ ID NO: 50, 52, 53, 105, or 106, and the CDR sequences of VL of SEQ ID NO: 51 or 54-57.

[0140] In a further aspect, the anti-KLK5 antibody comprises the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of the VH domain of SEQ ID NO: 50, 52, 53, 105, or 106, and the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of the VL domain of SEQ ID NO: 51 or 54-57.

[0141] In one aspect, the anti-KLK5 antibody comprises one or more of the heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 50, 52, 53, 105, or 106, and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO: 50, 52, 53, 105, or 106. In one aspect, the anti-KLK5 antibody comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 50, 52, 53, 105, or 106, and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO: 50, 52, 53, 105, or 106. In one aspect, the anti-KLK5 antibody comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 50, 52, 53, 105, or 106, and a framework having at least 95% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO: 50, 52, 53, 105, or 106. In another aspect, the anti-KLK5 antibody comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 50, 52, 53, 105, or 106, and a framework having at least 98% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO: 50, 52, 53, 105, or 106.

[0142] In one aspect, the anti-KLK5 antibody comprises one or more of the light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 51 or 54-57 and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO: 51 or 54-57. In one aspect, the anti-KLK5 antibody comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 51 or 54-57 and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO: 51 or 54-57. In one aspect, the anti-KLK5 antibody comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 51 or 54-57 and a framework having at least 95% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO: 51 or 54-57. In another aspect, the anti-KLK5 antibody comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 51 or 54-57 and a framework having particularly at least at least 98% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO: 50, 52, 53, 105, and 106.

[0143] In one aspect, the anti-KLK5 antibody comprises: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 39 or 107; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 40 or 41; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 43 or 44; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45; and (f) CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 46-49, and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequences of SEQ ID NOs: 50, 52, 53, 105, and 106, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequences of SEQ ID NOs: 51 and 54-67. In one aspect, the VH domain has at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 50, 52, 53, 105, and 106. In one aspect, the VL domain has at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 51 and 54-67.

[0144] In one aspect, the anti-KLK5 antibody comprises: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 39 or 107; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 40 or 41; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 43 or 44; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NOs: 46-49, and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequences of SEQ ID NOs: 50, 52, 53, 105 and 106, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequences of SEQ ID NOs: 51 and 54-67; and specifically binds to KLK5. In one aspect, the VH domain has at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 50, 52, 53, 105, and 106. In one aspect, the VL domain has at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 51 and 54-67. In one aspect, the antibody binds to KLK5 with a dissociation constant (K D ) that is decreased by up to 10-fold or increased by up to 10-fold compared to the dissociation constant (K D ) of an antibody comprising the VH sequence of SEQ ID NOs: 50, 52, 53, 105 and 106 and the VL sequence of SEQ ID NOs: 51 and 54-67.

[0145] In another aspect, the anti-KLK5 antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequences of SEQ ID NOs: 50, 52, 53, 105, and 106. In one aspect, the anti-KLK5 antibody comprises a heavy chain variable domain (VH) sequence having at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 50, 52, 53, 105, and 106. In certain aspects, the VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity includes substitutions (e.g., conservative substitutions), insertions, or deletions as compared to the reference sequence, but the anti-KLK5 antibody comprising the sequence retains the ability to bind to KLK5. In certain aspects, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NOs: 50, 52, 53, 105, and 106. In some aspects, the substitutions, insertions, or deletions occur in regions outside of the CDRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VH sequence of SEQ ID NOs: 50, 52, 53, 105, and 106, including post-translational modifications of the sequence. In certain aspects, the VH comprises at least 1, at least 2, or all 3 CDRs selected from (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 39 or 107, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 40 or 41, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42. In another aspect, provided is an anti-KLK5 antibody comprising a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequences of SEQ ID NOs: 51 and 54-67. In one aspect, the anti-KLK5 antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 51 and 54-67.In certain embodiments, VL sequences having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity, compared to a reference sequence, include substitutions (e.g., conservative substitutions), insertions, or deletions, and an anti-KLK5 antibody comprising such a sequence retains the ability to bind to KLK5. In certain embodiments, 1 to 10 total amino acids are substituted, inserted, and / or deleted in SEQ ID NOs: 51 and 54-67. In certain embodiments, the substitution, insertion, or deletion occurs in a region outside of the CDRs (i.e., FR). Optionally, the anti-KLK5 antibody comprises the VL sequences of SEQ ID NOs: 51 and 54-67, including post-translational modifications of such sequences. In certain embodiments, the VL comprises at least 1, at least 2, or all 3 CDRs selected from: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 43 or 44, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (c) CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 46-49.

[0146] In another embodiment, an anti-KLK5 antibody is provided that comprises a VH sequence as in any of the embodiments provided above and a VL sequence as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH and VL sequences of SEQ ID NOs: 50, 52, 53, 105, and 106 and SEQ ID NOs: 51 and 54-67, including post-translational modifications of such sequences.

[0147] In a further embodiment, the invention provides an antibody that binds to the same epitope as an anti-KLK5 antibody provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising the VH sequences of SEQ ID NOs: 50, 52, 53, 105, and 106 and the VL sequences of SEQ ID NOs: 51 and 54-67.

[0148] In a further embodiment of the invention, the anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody comprising a chimeric antibody, a humanized antibody, or a human antibody. In one embodiment, the anti-KLK5 antibody is an antibody fragment, e.g., Fv, Fab, Fab’, scFv, diabody, or F(ab’) 2It is a fragment. In another aspect, the antibody is a full-length antibody, such as an intact IgG1 antibody or another antibody class or isotype as defined herein.

[0149] In a further aspect, an anti-KLK5 antibody according to any of the above aspects may incorporate any of the features, alone or in combination, as described in Sections 1-8 below. Antibody hu.9H5-H14L4 and variants

[0150] In one aspect, the present invention provides an anti-KLK5 antibody comprising at least 1, at least 2, at least 3, at least 4, at least 5, or all 6 CDRs selected from: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 68; (b) CDR-H2 comprising the amino acid sequences of SEQ ID NO: 69 and 70; (c) CDR-H3 comprising the amino acid sequences of SEQ ID NO: 71 and 72; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74; and (f) CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 75-78.

[0151] In one aspect, the present invention provides an antibody comprising at least 1, at least 2, or all 3 VH CDR sequences selected from: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 68; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 70; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 72. In a further aspect, the antibody comprises: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 68; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 70; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 72.

[0152] In another aspect, the present invention provides an antibody comprising at least one, at least two / or all three VL CDR sequences selected from: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 76. In one aspect, the antibody comprises: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 76.

[0153] In another aspect, the antibody of the present invention comprises: (a) a VH domain comprising at least one, at least two / or all three VH CDR sequences selected from: (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 68, (ii) CDR-H2 comprising the amino acid sequences of SEQ ID NOs: 69 and 70, and (iii) CDR-H3 comprising the amino acid sequences of SEQ ID NOs: 71 and 72; and (b) a VL domain comprising at least one, at least two / or all three VL CDR sequences selected from: (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74, and (c) CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 75-78.

[0154] In another aspect, the present invention provides an antibody comprising: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 68; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 70; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 72; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 76.

[0155] In any of the aspects provided herein, the anti-KLK5 antibody is humanized. In one aspect, the anti-KLK5 antibody further comprises an acceptor human framework, such as a human immunoglobulin framework or a human consensus framework.

[0156] In one aspect, the anti-KLK5 antibody comprises a VH domain comprising one or more heavy chain framework sequences selected from (a) heavy chain framework region 1 (HC-FR1) of SEQ ID NO: 171, (b) heavy chain framework region 2 (HC-FR2) of SEQ ID NOs: 172-173, (c) heavy chain framework region 3 (HC-FR3) of SEQ ID NO: 174, and (d) heavy chain framework region 4 (HC-FR4) of SEQ ID NO: 175.

[0157] In another aspect, the anti-KLK5 antibody comprises a VH domain comprising HC-FR1 of SEQ ID NO: 171. In another aspect, the anti-KLK5 antibody comprises a VH domain comprising HC-FR2 of SEQ ID NO: 172 or 173. In another aspect, the anti-KLK5 antibody comprises a VH domain comprising HC-FR3 of SEQ ID NO: 174. In another aspect, the anti-KLK5 antibody comprises a VH domain comprising HC-FR4 of SEQ ID NO: 175.

[0158] In another aspect, the anti-KLK5 antibody comprises a VH domain comprising HC-FR1 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 171. In one aspect, the VH domain comprises HC-FR1 having at least 95% sequence identity to SEQ ID NO: 171. In another aspect, the VH domain comprises HC-FR1 having at least 98% sequence identity to SEQ ID NO: 171.

[0159] In another aspect, the anti-KLK5 antibody comprises a VH domain comprising HC-FR2 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 172 or 173. In one aspect, the VH domain comprises HC-FR2 having at least 95% sequence identity to SEQ ID NO: 172 or 173. In another aspect, the VH domain comprises HC-FR2 having at least 98% sequence identity to SEQ ID NO: 172 or 173.

[0160] In another aspect, the anti-KLK5 antibody comprises a VH domain comprising an HC-FR3 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 174. In one aspect, the VH domain comprises an HC-FR3 having at least 95% sequence identity to SEQ ID NO: 174. In another aspect, the VH domain comprises an HC-FR3 having at least 98% sequence identity to SEQ ID NO: 174.

[0161] In another aspect, the anti-KLK5 antibody comprises a VH domain comprising an HC-FR4 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 175. In one aspect, the VH domain comprises an HC-FR4 having at least 95% sequence identity to SEQ ID NO: 175. In another aspect, the VH domain comprises an HC-FR4 having at least 98% sequence identity to SEQ ID NO: 175.

[0162] In one aspect, the anti-KLK5 antibody comprises a VL domain comprising one or more light chain framework sequences selected from (a) the light chain framework region 1 (LC-FR1) of SEQ ID NO: 176, (b) the light chain framework regions 2 (LC-FR2) of SEQ ID NOs: 177-178, (c) the light chain framework region 3 (LC-FR3) of SEQ ID NO: 179, and (d) the light chain framework region 4 (LC-FR4) of SEQ ID NO: 180.

[0163] In another aspect, the anti-KLK5 antibody comprises a VL domain comprising the LC-FR1 of SEQ ID NO: 176. In another aspect, the anti-KLK5 antibody comprises a VL domain comprising the LC-FR2 of SEQ ID NOs: 177-178. In another aspect, the anti-KLK5 antibody comprises a VL domain comprising the LC-FR3 of SEQ ID NO: 179. In another aspect, the anti-KLK5 antibody comprises a VL domain comprising the LC-FR4 of SEQ ID NO: 180.

[0164] In another aspect, the anti-KLK5 antibody comprises a VL domain comprising an LC-FR1 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 176. In one aspect, the VL domain comprises an LC-FR1 having at least 95% sequence identity to SEQ ID NO: 176. In another aspect, the VL domain comprises an LC-FR1 having at least 98% sequence identity to SEQ ID NO: 176.

[0165] In another aspect, the anti-KLK5 antibody comprises a VL domain comprising an LC-FR2 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 177 or 178. In one aspect, the VL domain comprises an LC-FR2 having at least 95% sequence identity to SEQ ID NO: 177 or 178. In another aspect, the VL domain comprises an LC-FR2 having at least 98% sequence identity to SEQ ID NO: 177 or 178.

[0166] In another aspect, the anti-KLK5 antibody comprises a VL domain comprising an LC-FR3 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 179. In one aspect, the VL domain comprises an LC-FR3 having at least 95% sequence identity to SEQ ID NO: 179. In another aspect, the VL domain comprises an LC-FR3 having at least 98% sequence identity to SEQ ID NO: 179.

[0167] In another aspect, the anti-KLK5 antibody comprises a VL domain comprising an LC-FR4 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 180. In one aspect, the VL domain comprises an LC-FR1 having at least 95% sequence identity to SEQ ID NO: 180. In another aspect, the VL domain comprises an LC-FR1 having at least 98% sequence identity to SEQ ID NO: 180.

[0168] In another aspect, the anti-KLK5 antibody comprises one or more of the CDR sequences of VH of SEQ ID NO: 79 or 81-87. In another embodiment, the anti-KLK5 antibody comprises one or more of the CDR sequences of VL of SEQ ID NO: 80 or 88-94. In another embodiment, the anti-KLK5 antibody comprises the CDR sequences of VH of SEQ ID NO: 79 or 81-87 and the CDR sequences of VL of SEQ ID NO: 80 or 88-94.

[0169] In a further aspect, the anti-KLK5 antibody comprises the CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of the VH domain of SEQ ID NO: 79 or 81-87, and the CDR-L1, CDR-L2 and CDR-L3 amino acid sequences of the VL domain of SEQ ID NO: 80 or 88-94.

[0170] In one aspect, the anti-KLK5 antibody comprises one or more of the heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 79 or 81-87, and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO: 79 or 81-87. In one aspect, the anti-KLK5 antibody comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 79 or 81-87, and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO: 79 or 81-87. In one aspect, the anti-KLK5 antibody comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 79 or 81-87, and a framework having at least 95% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO: 79 or 81-87. In another aspect, the anti-KLK5 antibody comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 79 or 81-87, and a framework having at least 98% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO: 79 or 81-87.

[0171] In one aspect, the anti-KLK5 antibody comprises one or more of the light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 80 or 88-94, and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO: 80 or 88-94. In one aspect, the anti-KLK5 antibody comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 80 or 88-94, and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO: 80 or 88-94. In one aspect, the anti-KLK5 antibody comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 80 or 88-94, and a framework having at least 95% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO: 80 or 88-94. In another aspect, the anti-KLK5 antibody comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 80 or 88-94, and in particular a framework having at least 98% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO: 80 or 88-94.

[0172] In one aspect, the anti-KLK5 antibody comprises: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 68; (b) CDR-H2 comprising the amino acid sequences of SEQ ID NO: 69-70; (c) CDR-H3 comprising the amino acid sequences of SEQ ID NO: 71-72; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74; and (f) CDR-L3 comprising the amino acid sequences of SEQ ID NO: 75-78, and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 79 or 81-87, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 80 or 88-94. In one aspect, the VH domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 79 or 81-87. In one aspect, the VL domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 80 or 88-94.

[0173] In one aspect, the anti-KLK5 antibody comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 68; (b) CDR-H2 comprising the amino acid sequences of SEQ ID NO: 69-70; (c) CDR-H3 comprising the amino acid sequences of SEQ ID NO: 71-72; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74; and (f) CDR-L3 comprising the amino acid sequences of SEQ ID NO: 75-78, and has a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 79 or 81-87, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 80 or 88-94, and specifically binds to KLK5. In one aspect, the VH domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 79 or 81-87. In one aspect, the VL domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 80 or 88-94. In one aspect, the antibody binds to KLK5 with a dissociation constant (K D ) that is decreased by a maximum of 10-fold or increased by a maximum of 10-fold compared to the dissociation constant (K D ) of an antibody comprising the VH sequence of SEQ ID NO: 79 or 81-87 and the VL sequence of SEQ ID NO: 80 or 88-94.

[0174] In another aspect, the anti-KLK5 antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 79 or 81-87. In one aspect, the anti-KLK5 antibody comprises a heavy chain variable domain (VH) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 79 or 81-87. In certain aspects, the VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity comprises substitutions (e.g., conservative substitutions), insertions, or deletions as compared to the reference sequence, but the anti-KLK5 antibody comprising such sequence retains the ability to bind to KLK5. In certain aspects, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 79 or 81-87. In some aspects, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VH sequence of SEQ ID NO: 79 or 81-87, including post-translational modifications of the sequence. In certain aspects, the VH comprises one, two, or three CDRs selected from (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 68, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 69-70, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 71-72. In another aspect, provided is an anti-KLK5 antibody comprising a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 80 or 88-94. In one aspect, the anti-KLK5 antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 80 or 88-94. In certain aspects, the VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity comprises substitutions (e.g., conservative substitutions), insertions, or deletions as compared to the reference sequence, but the anti-KLK5 antibody comprising such sequence retains the ability to bind to KLK5.In certain embodiments, 1 to 10 amino acids in total are substituted, inserted, and / or deleted in SEQ ID NO: 80 or 88 - 94. In certain embodiments, the substitution, insertion, or deletion occurs in a region outside the CDR (i.e., FR). Optionally, the anti - KLK5 antibody comprises the VL sequence of SEQ ID NO: 80 or 88 - 94, including post - translational modifications of the sequence. In certain embodiments, VL comprises one, two, or three CDRs selected from: (a) CDR - L1 comprising the amino acid sequence of SEQ ID NO: 73, (b) CDR - L2 comprising the amino acid sequence of SEQ ID NO: 74, and (c) CDR - L3 comprising the amino acid sequences of SEQ ID NO: 75 - 78.

[0175] In another embodiment, an anti - KLK5 antibody is provided that comprises a VH sequence as in any of the embodiments provided above and a VL sequence as in any of the embodiments provided above. In one embodiment, the antibody comprises VH and VL sequences of SEQ ID NO: 79 or 81 - 87 and SEQ ID NO: 80 or 88 - 94, respectively, including post - translational modifications of the sequences.

[0176] In a further embodiment, the present invention provides an antibody that binds to the same epitope as the anti - KLK5 antibody provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as an anti - KLK5 antibody comprising a VH sequence of SEQ ID NO: 79 or 81 - 87 and a VL sequence of SEQ ID NO: 80 or 88 - 94.

[0177] In a further embodiment of the present invention, the anti - KLK5 antibody according to any of the above embodiments is a monoclonal antibody comprising a chimeric antibody, a humanized antibody, or a human antibody. In one embodiment, the anti - KLK5 antibody is an antibody fragment, such as Fv, Fab, Fab’, scFv, diabody, or F(ab’) 2 fragment. In another embodiment, the antibody is a full - length antibody, such as an intact IgG1 antibody or another antibody class or isotype defined herein.

[0178] In a further embodiment, the anti - KLK5 antibody according to any of the above embodiments may incorporate any of the features, alone or in combination, as described in Sections 1 - 8 below. C. Exemplary Anti-KLK5 / KLK7 Bispecific Antibodies

[0179] In one aspect, the invention provides a bispecific antibody that binds to both KLK5 and KLK7. In some embodiments, a bispecific antibody that binds to both KLK5 and KLK7 is provided. In some embodiments, the bispecific (e.g., bispecific) antibody inhibits both KLK5 protease activity and KLK7 protease activity. In some embodiments, the bispecific (e.g., bispecific) antibody has a K D for binding to KLK5 of less than 60 pM, less than 30 pM, less than 20 pM, less than 10 pM, or less than 5 pM as measured by surface plasmon resonance. In some embodiments, the bispecific (e.g., bispecific) antibody has a K D for binding to KLK7 of less than 20 pM, less than 10 pM, or less than 9 pM, or less than 8 pM, or less than 7 pM, or less than 6 pM, or less than 5 pM, or less than 3 pM, or less than 2 pM, or less than 1 pM as measured by surface plasmon resonance. In some embodiments, the bispecific (e.g., bispecific) antibody has a K D for binding to KLK5 of 60 pM or less, 30 pM or less, 20 pM or less, 10 pM or less, or 5 pM or less as measured by surface plasmon resonance. In some embodiments, the bispecific (e.g., bispecific) antibody has a K D for binding to KLK7 of less than 20 pM, less than 10 pM, or less than 9 pM, or less than 8 pM, or less than 7 pM, or less than 6 pM, or less than 5 pM, or less than 3 pM, or less than 2 pM, or less than 1 pM as measured by surface plasmon resonance.

[0180] In some embodiments, the anti-KLK5 / KLK7 multispecific antibody inhibits human KLK7 protease activity and inhibits human KLK5 protease activity. In some embodiments, the anti-KLK5 / KLK7 multispecific antibody inhibits human KLK7-mediated cleavage of a substrate comprising the amino acid sequence RPKPVE-Nval-WRK (where Nval is norvaline) (SEQ ID NO: 121) with an IC50 of less than 5 nM, or less than 3 nM, or less than 2 nM, or less than 1 nM. In some embodiments, the anti-KLK5 / KLK7 multispecific antibody inhibits human KLK5-mediated cleavage of the substrate Boc-Val-Pro-Arg-AMC with an IC50 of less than 5 nM, or less than 3 nM, or less than 2 nM, or less than 1 nM. In some embodiments, the anti-KLK5 / KLK7 multispecific antibody inhibits human KLK7-mediated cleavage of a substrate comprising the amino acid sequence RPKPVE-Nval-WRK (where Nval is norvaline) (SEQ ID NO: 121) with an IC50 of 5 nM or less, or 3 nM or less, or 2 nM or less, or 1 nM or less. In some embodiments, the anti-KLK5 / KLK7 multispecific antibody inhibits human KLK5-mediated cleavage of the substrate Boc-Val-Pro-Arg-AMC with an IC50 of 5 nM or less, or 3 nM or less, or 2 nM or less, or 1 nM or less. In some embodiments, the K D of the multispecific antibody against human KLK5 and the K D of the antibody against human KLK7 are within 3-fold of each other, or within 2.5-fold of each other, or within 2-fold of each other, or within 1.5-fold of each other.

[0181] In some aspects, the multispecific antibody that binds to both KLK5 and KLK7 comprises a first binding domain that binds to KLK7 and a second binding domain that binds to KLK5.

[0182] In some embodiments, a multispecific antibody that binds to both KLK5 and KLK7, when binding to human KLK5, results in a conformational change of human KLK5, and this conformational change allosterically results in disruption of the substrate binding site and / or active site of human KLK5. In some embodiments, a multispecific antibody that binds to both KLK5 and KLK7, when binding to human KLK7, results in a conformational change of human KLK7, and this conformational change allosterically results in disruption of the substrate binding site and / or active site of human KLK7.

[0183] In some embodiments, the first binding domain comprises an anti-KLK7 antibody binding domain as described herein. For example, in some such embodiments, the first binding domain comprises: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 12. As a further non-limiting example, in some embodiments, the first binding domain comprises: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 12, and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from SEQ ID NOs: 13 and 15-30, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from SEQ ID NOs: 14 and 31-38. In some embodiments, the first binding domain comprises the VH and VL sequences of SEQ ID NOs: 29 and 32, respectively, including post-translational modifications of the sequences. In some embodiments, the first binding domain comprises the VH and VL sequences of SEQ ID NOs: 30 and 38, respectively, including post-translational modifications of the sequences.

[0184] In some embodiments, the second binding domain comprises an anti-KLK5 antibody binding domain as described herein. For example, in some such embodiments, the second binding domain comprises (a) CDR-H1 comprising an amino acid sequence selected from SEQ ID NOs: 39 and 107, (b) CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 40 and 41, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42, and (d) CDR-L1 comprising an amino acid sequence selected from SEQ ID NOs: 43 and 44, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (f) a light chain variable domain (VL) comprising a CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 46-49. As a further non-limiting example, in some embodiments, the second binding domain comprises (a) CDR-H1 comprising an amino acid sequence selected from SEQ ID NOs: 39 and 107, (b) CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 40 and 41, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42, and (d) CDR-L1 comprising an amino acid sequence selected from SEQ ID NOs: 43 and 44, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (f) a light chain variable domain (VL) comprising a CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 46-49, a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from SEQ ID NOs: 50, 52, 53, 105, and 106, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from SEQ ID NOs: 51 and 54-67. In some embodiments, the second binding domain comprises the VH and VL sequences of SEQ ID NOs: 52 and 55, respectively, including post-translational modifications of the sequences. In some embodiments, the second binding domain comprises the VH and VL sequences of SEQ ID NOs: 53 and 62, respectively, including post-translational modifications of the sequences.

[0185] In some embodiments, the second binding domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 68, a CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 69 and 70, and a CDR-H3 comprising an amino acid sequence selected from SEQ ID NOs: 71 and 72, and a light chain variable domain (VL) comprising a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74, and a CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 75-78. As a further non-limiting example, in some embodiments, the second binding domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 68, a CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 69 and 70, and a CDR-H3 comprising an amino acid sequence selected from SEQ ID NOs: 71 and 72, and a light chain variable domain (VL) comprising a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74, and a CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 75-78, a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from SEQ ID NOs: 79 and 81-87, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from SEQ ID NOs: 80 and 88-94. In some embodiments, the second binding domain comprises the VH and VL sequences of SEQ ID NOs: 83 and 88, respectively, including post-translational modifications of the sequences. In some embodiments, the second binding domain comprises the VH and VL sequences of SEQ ID NOs: 87 and 92, respectively, including post-translational modifications of the sequences.

[0186] In some embodiments, a multispecific antibody (e.g., a bispecific antibody) is provided in which a first binding domain binds to KLK7, a second binding domain binds to KLK5, the first binding domain is an anti-KLK7 antibody binding domain provided herein, and the second binding domain is an anti-KLK5 binding domain provided herein. In some such embodiments, the first binding domain

[0187] In some embodiments, the first binding domain comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 12; and the second binding domain comprises (a) CDR-H1 comprising an amino acid sequence selected from SEQ ID NOs: 39 and 107, (b) CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 40 and 41, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42, and (d) CDR-L1 comprising an amino acid sequence selected from SEQ ID NOs: 43 and 44, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (f) a light chain variable domain (VL) comprising a CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 46-49. In some embodiments, the first binding domain comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 12; and the second binding domain comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 68, (b) CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 69 and 70, and (c) CDR-H3 comprising an amino acid sequence selected from SEQ ID NOs: 71 and 72, and (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74, and (f) a light chain variable domain (VL) comprising a CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 75-78.

[0188] In some embodiments, the first binding domain comprises: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 12, and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from SEQ ID NOs: 13 and 15-30, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from SEQ ID NOs: 14 and 31-38; the second binding domain comprises: a light chain variable domain (VL) comprising (a) CDR-H1 comprising an amino acid sequence selected from SEQ ID NOs: 39 and 107, (b) CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 40 and 41, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42, and (d) CDR-L1 comprising an amino acid sequence selected from SEQ ID NOs: 43 and 44, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (f) CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 46-49, and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from SEQ ID NOs: 50, 52, 53, 105, and 106, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from SEQ ID NOs: 51 and 54-67.

[0189] In some embodiments, the first binding domain comprises a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from SEQ ID NOs: 13 and 15 - 30, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from SEQ ID NOs: 14 and 31 - 38, wherein the VH domain comprises: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 12; and the second binding domain comprises a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from SEQ ID NOs: 79 and 81 - 87, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from SEQ ID NOs: 80 and 88 - 94, wherein the light chain variable domain (VL) comprises: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 68; (b) CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 69 and 70; (c) CDR-H3 comprising an amino acid sequence selected from SEQ ID NOs: 71 and 72; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74; and (f) CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 75 - 78.

[0190] In some embodiments, the bispecific anti-KLK5 / KLK7 antibody comprises a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7, the second binding domain binds to human KLK5, the first binding domain comprises a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 7, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 8, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 9, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 10, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 11, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 12; the second binding domain comprises a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 39, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 41, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 43, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 47.

[0191] In some embodiments, the bispecific anti-KLK5 / KLK7 antibody comprises a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7, the second binding domain binds to human KLK5, the first binding domain comprises a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 7, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 8, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 9, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 10, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 11, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 12; the second binding domain comprises a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 68, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 70, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 72, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 76.

[0192] In some embodiments, the bispecific anti-KLK5 / KLK7 antibody comprises a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7, the second binding domain binds to human KLK5, (i) the first binding domain comprises the VH amino acid sequence of SEQ ID NO: 29 and the VL amino acid sequence of SEQ ID NO: 32, or the VH amino acid sequence of SEQ ID NO: 30 and the VL amino acid sequence of SEQ ID NO: 38; (ii) the second binding domain comprises the VH sequence of SEQ ID NO: 52 and the VL amino acid sequence of SEQ ID NO: 55, or the VH sequence of SEQ ID NO: 53 and the VL amino acid sequence of SEQ ID NO: 62.

[0193] In some embodiments, the first binding domain comprises the VH sequence of SEQ ID NO: 30 and the VL sequence of SEQ ID NO: 38, and the second binding domain comprises the VH sequence of SEQ ID NO: 53 and the VL sequence of SEQ ID NO: 62. In some embodiments, the bispecific anti-KLK5 / KLK7 antibody comprises a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7, the second binding domain binds to human KLK5, and (i) the first binding domain comprises the VH amino acid sequence of SEQ ID NO: 29 and the VL amino acid sequence of SEQ ID NO: 32, or comprises the VH amino acid sequence of SEQ ID NO: 30 and the VL amino acid sequence of SEQ ID NO: 38; (ii) the second binding domain comprises the VH sequence of SEQ ID NO: 83 and the VL amino acid sequence of SEQ ID NO: 88, or comprises the VH sequence of SEQ ID NO: 87 and the VL amino acid sequence of SEQ ID NO: 92.

[0194] In some embodiments, the first binding domain comprises the VH sequence of SEQ ID NO: 30 and the VL sequence of SEQ ID NO: 38, and the second binding domain comprises the VH sequence of SEQ ID NO: 87 and the VL sequence of SEQ ID NO: 92. In some embodiments, the bispecific anti-KLK5 / KLK7 antibody comprises a first binding domain that binds to KLK7 and a second binding domain that binds to KLK5, wherein the first binding domain comprises a first heavy chain variable region and a first light chain variable region, and the second binding domain comprises a second heavy chain variable region and a second light chain variable region. In some such embodiments, the first heavy chain variable region comprises a Q39E substitution (Kabat numbering), the first light chain variable region comprises a Q38K substitution (Kabat numbering); the second heavy chain variable region comprises a Q39K substitution (Kabat numbering), and the second light chain variable region comprises a Q38E substitution (Kabat numbering). In some embodiments, the first heavy chain variable region comprises a Q39K substitution (Kabat numbering), the first light chain variable region comprises a Q38E substitution (Kabat numbering); the second heavy chain variable region comprises a Q39E substitution (Kabat numbering), and the second light chain variable region comprises a Q38K substitution (Kabat numbering). In some embodiments, the Q39E / Q38K and Q39K / Q38E substitutions reduce heavy and light chain mispairing of the bispecific antibody.

[0195] In some embodiments, the first binding domain comprises a first heavy chain variable domain linked to a first heavy chain constant region and a first light chain variable domain linked to a first light chain constant region; the second binding domain comprises a second heavy chain variable domain linked to a second heavy chain constant region and a second light chain variable domain linked to a second light chain constant region. In some such embodiments, the first heavy chain constant region comprises an S183K substitution (EU numbering), the first light chain constant region comprises a V133E substitution (EU numbering), the second heavy chain constant region comprises an S183E substitution (EU numbering), and the second light chain constant region comprises a V133K substitution (EU numbering). In some embodiments, the first heavy chain constant region comprises an S183E substitution (EU numbering), the first light chain constant region comprises a V133K substitution (EU numbering), the second heavy chain constant region comprises an S183K substitution (EU numbering), and the second light chain constant region comprises a V133E substitution (EU numbering). In some embodiments, the S183K / V133E and S183E / V133K substitutions reduce heavy and light chain mispairing of the bispecific antibody.

[0196] In some embodiments, the bispecific anti-KLK5 / KLK7 antibody comprises Q39E / Q38K and Q39K / Q38E substitutions in the binding domains and S183K / V133E and S183E / V133K substitutions in the constant regions. See, for example, International Publication No. WO 2016 / 172485, which is hereby incorporated by reference in its entirety for any purpose. A non-limiting exemplary schematic of the bispecific antibody is shown in FIG. 15.

[0197] In some embodiments, a bispecific anti-KLK5 / KLK7 antibody is provided that comprises a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7, the second binding domain binds to human KLK5, the first binding domain comprises the heavy chain amino acid sequence of SEQ ID NO: 108 or 192, and the light chain amino acid sequence of SEQ ID NO: 109, and the second binding domain comprises the heavy chain amino acid sequence of SEQ ID NO: 114 or 195, and the light chain amino acid sequence of SEQ ID NO: 111. In some embodiments, a bispecific anti-KLK5 / KLK7 antibody is provided that comprises a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7, the second binding domain binds to human KLK5, the first binding domain comprises the heavy chain amino acid sequence of SEQ ID NO: 112 or 194, and the light chain amino acid sequence of SEQ ID NO: 113, and the second binding domain comprises the heavy chain amino acid sequence of SEQ ID NO: 110 or 193, and the light chain amino acid sequence of SEQ ID NO: 115.

[0198] In some embodiments, a bispecific anti-KLK5 / KLK7 antibody is provided that comprises a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7, the second binding domain binds to human KLK5, the first binding domain comprises the heavy chain amino acid sequence of SEQ ID NO: 108 or 192, and the light chain amino acid sequence of SEQ ID NO: 109, and the second binding domain comprises the heavy chain amino acid sequence of SEQ ID NO: 114 or 195, and the light chain amino acid sequence of SEQ ID NO: 111. In some embodiments, a bispecific anti-KLK5 / KLK7 antibody is provided that comprises a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7, the second binding domain binds to human KLK5, the first binding domain comprises the heavy chain amino acid sequence of SEQ ID NO: 112 or 194, and the light chain amino acid sequence of SEQ ID NO: 113, and the second binding domain comprises the heavy chain amino acid sequence of SEQ ID NO: 110 or 193, and the light chain amino acid sequence of SEQ ID NO: 115.

[0199] In some embodiments, a bispecific anti-KLK5 / KLK7 antibody is provided that comprises a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7, the second binding domain binds to human KLK5, the first binding domain comprises the heavy chain amino acid sequence of SEQ ID NO: 194 and the light chain amino acid sequence of SEQ ID NO: 113, and the second binding domain comprises the heavy chain amino acid sequence of SEQ ID NO: 195 and the light chain amino acid sequence of SEQ ID NO: 115.

[0200] In some embodiments, a bispecific anti-KLK5 / KLK7 antibody is provided that comprises a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7, the second binding domain binds to human KLK5, the first binding domain comprises the heavy chain amino acid sequence of SEQ ID NO: 112 and the light chain amino acid sequence of SEQ ID NO: 113, and the second binding domain comprises the heavy chain amino acid sequence of SEQ ID NO: 195 and the light chain amino acid sequence of SEQ ID NO: 115.

[0201] In some embodiments, a bispecific anti-KLK5 / KLK7 antibody is provided that comprises a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7, the second binding domain binds to human KLK5, the first binding domain comprises the heavy chain amino acid sequence of SEQ ID NO: 194 and the light chain amino acid sequence of SEQ ID NO: 113, and the second binding domain comprises the heavy chain amino acid sequence of SEQ ID NO: 114 and the light chain amino acid sequence of SEQ ID NO: 115.

[0202] In a further aspect, a multispecific antibody according to any of the above aspects may incorporate any of the features described in Sections 1-8 below, alone or in combination. 1. Antibody affinity

[0203] In certain aspects, the antibodies provided herein have an affinity of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM or ≤0.001 nM (e.g., 10 -8 M or less, e.g., 10 -8 M to 10 -13 M, e.g., 10 -9M~10 -13 dissociation constant (K D ) of M).

[0204] In one embodiment, K D is measured using surface plasmon resonance. In one embodiment, K D is measured using a BIAcore( 登録商標 ) surface plasmon resonance assay such as a BIAcore (trademark) T200 or BIAcore (trademark) 8K assay. For example, an assay using BIAcore (trademark) 8K (BIAcore, Inc., Piscataway, NJ) is performed at 25° C. or 37° C. on a protein A chip with an immobilized antibody at approximately 300 response units (RU). Serial 10-fold dilutions of an antigen (e.g., human KLK7 or human KLK5) are injected into HBS-P buffer at 37° C. at a flow rate of 100 μL / min. Alternatively, serial 10-fold dilutions of the antigen are injected into HBS-P buffer at 25° C. at a flow rate of 30 μL / min. The association rate (ka) and dissociation rate (kd) are calculated using a 1:1 Langmuir binding model (BIAcore (trademark) T200 evaluation software version 2.0). The equilibrium dissociation constant (KD) is calculated as the ratio kd / ka.

[0205] In one embodiment, K D is measured by a radiolabeled antigen binding assay (RIA). In one embodiment, the RIA is performed using the Fab version of the antibody of interest and its antigen. For example, the solution binding affinity of the Fab for the antigen is measured by equilibrating the Fab with a minimal concentration of ( 125 I)-labeled antigen in the presence of a titration series of unlabeled antigen and then capturing the bound antigen on a plate coated with an anti-Fab antibody (see, e.g., Chen et al., "J. Mol. Biol." Vol. 293, pp. 865-881 (1999)). To establish assay conditions, MICROTITER (登録商標)A multiwell plate (Thermo Scientific) is coated overnight with 5 μg / mL of capture anti-Fab antibody (Cappel Labs) in 50 mM sodium carbonate (pH 9.6), and then blocked with 2% (w / v) bovine serum albumin in PBS for 2 - 5 hours at room temperature (approximately 23°C). In a non-adsorptive plate (Nunc #269620), 100 pM or 26 pM of 125 I]-antigen is mixed with serial dilutions of the Fab of interest (e.g., consistent with the evaluation of anti-VEGF antibody Fab-12 in Presta et al., "Cancer Res." Vol. 57, pp. 4593 - 4599 (1997)). The Fab of interest is then incubated overnight; however, the incubation may be continued for a longer period (e.g., about 65 hours) to reach equilibrium. The mixture is then transferred to the capture plate for incubation at room temperature (e.g., for 1 hour). The solution is then removed and the plate is washed 8 times with 0.1% polysorbate 20 (TWEEN-20 (登録商標) ) in PBS. Once the plate is dry, 150 μL / well of scintillant (MICROSCINT-20 (商標) , Packard) is added and the plate is counted on a TOPCOUNT (商標) gamma counter (Packard) for 10 minutes. The concentration of each Fab that results in 20% or less of the maximum binding is selected for use in the competitive binding assay. 2. Antibody Fragments

[0206] In some embodiments, the antibodies provided herein are antibody fragments.

[0207] In one embodiment, the antibody fragment is Fab, Fab’, Fab’-SH or F(ab’) 2Fragment, particularly a Fab fragment. When an intact antibody is digested with papain, in addition to the variable domains of the heavy and light chains (VH and VL, respectively, in that order), the constant domain of the light chain (CL) and the first constant domain of the heavy chain (CH1), each containing two identical antigen-binding fragments (so-called "Fab" fragments) are obtained. Thus, a "Fab fragment" is an antibody fragment having a light chain containing a VL domain and a CL domain, and a heavy chain containing a VH domain and a CH1 domain. A "Fab' fragment" differs from a Fab fragment by adding residues at the carboxy terminus of the CH1 domain containing one or more cysteines from the antibody hinge region. Fab'-SH is a Fab' fragment in which the cysteine residue(s) of the constant domain retains a free thiol group. Treatment with pepsin yields an F(ab') 2 fragment having two antigen-binding sites (two Fab fragments) and a portion of the Fc region. For an explanation of Fab and F(ab') 2 fragments with increased in vivo half-life containing salvage receptor binding epitope residues, see U.S. Patent No. 5,869,046.

[0208] In another aspect, the antibody fragment is a diabody, triabody, or tetrabody. A "diabody" is an antibody fragment having two antigen-binding sites that can be bivalent or bispecific. See, for example, European Patent No. 404,097, International Publication No. 1993 / 01161, Hudson et al., Nat. Med. 9:129-134 (2003), and Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993). Triabodies and tetrahedrons are also described in Hudson et al., Nat. Med. 9:129-134 (2003).

[0209] In a further aspect, the antibody fragment is a single-chain Fab fragment. A "single-chain Fab fragment" or "scFab" is a polypeptide consisting of an antibody heavy-chain variable domain (VH), an antibody heavy-chain constant domain 1 (CH1), an antibody light-chain variable domain (VL), an antibody light-chain constant domain (CL), and a linker, and the antibody domains and the linker are in the following order from the N-terminus to the C-terminus: a) VH-CH1-linker-VL-CL, b) VL-CL-linker-VH-CH1, c) VH-CL-linker-VL-CH1, or d) VL-CH1-linker-VH-CL. In particular, the linker is a polypeptide of at least 30 amino acids, preferably 32 to 50 amino acids. The single-chain Fab fragment is stabilized by a native disulfide bond between the CL domain and the CH1 domain. In addition, these single-chain Fab fragments can be further stabilized by the formation of interchain disulfide bonds via the insertion of cysteine residues (e.g., positions 44 of the variable heavy chain and 100 of the variable light chain according to Kabat numbering).

[0210] In another aspect, the antibody fragment is a single-chain variable fragment (scFv). A "single-chain variable fragment" or "scFv" is a fusion protein of the variable domains of the heavy chain (VH) and light chain (VL) of an antibody connected by a linker. In particular, the linker is a short polypeptide of 10 to 25 amino acids, usually rich in glycine for flexibility and serine or threonine for solubility, and can connect the N-terminus of VH to the C-terminus of VL or vice versa. This protein can retain the specificity of the original antibody despite the removal of the constant region and the introduction of a linker. For a review of scFv fragments, see, for example, Pluckthun, The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenberg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994). See also International Publication No. 93 / 16185 and U.S. Patent Nos. 5,571,894 and 5,587,458.

[0211] In another aspect, the antibody fragment is a single domain antibody. A "single domain antibody" is an antibody fragment that includes all or part of the heavy chain variable domain of an antibody, or all or part of the light chain variable domain. In certain aspects, the single domain antibody is a human single domain antibody (see, e.g., U.S. Patent No. 6,248,516 B1 to Domantis, Inc., Waltham, MA).

[0212] Antibody fragments can be made by a variety of techniques including, but not limited to, proteolytic digestion of intact antibodies described herein and recombinant production by recombinant host cells (e.g., E. coli). 3. Chimeric and Humanized Antibodies

[0213] In certain aspects, the antibodies provided herein are chimeric antibodies. Certain chimeric antibodies are described, for example, in U.S. Patent No. 4,816,567 and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984). In one example, a chimeric antibody includes a non-human variable region (e.g., a variable region derived from a non-human primate such as a mouse, rat, hamster, rabbit, or monkey) and a human constant region. In a further example, a chimeric antibody is a "class switched" antibody in which the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include their antigen-binding fragments.

[0214] In certain embodiments, the chimeric antibody is a humanized antibody. Typically, non-human antibodies are humanized to reduce their immunogenicity in humans while retaining the specificity and affinity of the parental non-human antibody. Usually, a humanized antibody contains one or more variable domains in which the CDR (or a portion thereof) is derived from a non-human antibody and the FR (or a portion thereof) is derived from a human antibody sequence. Optionally, the humanized antibody also contains at least a portion of a human constant region. In some embodiments, some FR residues in the humanized antibody are replaced with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived) to, for example, restore or improve antibody specificity or affinity.

[0215] Humanized antibodies and methods of making them are reviewed in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008) and further described below: Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat’l Acad. Sci. USA 86:10029-10033 (1989); U.S. Pat. Nos. 5,821,337, 7,527,791, 6,982,321 and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (description of specificity-determining region (SDR) grafting); Padlan, Mol. Immunol. 28:489-498 (1991) (description of resurfacing); Dall’Acqua et al., Methods 36:43-60 (2005) (description of FR shuffling); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (description of the “guided selection” approach to FR shuffling).

[0216] Human framework regions that can be used for humanization include, but are not limited to, the following: framework regions selected using the "best fit" method (see, e.g., Sims et al., J. Immunol. 151:2296 (1993)); framework regions derived from consensus sequences of human antibodies of certain subgroups of the light or heavy chain variable regions (see, e.g., Carter et al., Proc. Natl. Acad. Sci. USA, 89:4285 (1992); and Presta et al., J. Immunol., 151:2623 (1993)); human mature (somatic mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)); and framework regions derived from screening of FR libraries (see, e.g., Baca et al., J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271:22611-22618 (1996)). 4. Human Antibodies

[0217] In some embodiments, the antibodies provided herein are human antibodies. Human antibodies can be made using a variety of techniques known in the art. Human antibodies are generally described in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5:368-74 (2001) and Lonberg, Curr. Opin. Immunol. 20:450-459 (2008).

[0218] Human antibodies can be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies having human variable regions in response to an antigen challenge. Such animals typically contain all or part of the human immunoglobulin locus that replaces the endogenous immunoglobulin locus, or exist extrachromosomally, or are randomly integrated into the chromosomes of the animal. In such transgenic mice, the endogenous immunoglobulin locus is generally inactivated. For a review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005). Also see, for example, U.S. Patent Nos. 6,075,181 and 6,150,584, which describe the XENOMOUSE (商標) technology; U.S. Patent No. 5,770,429, which describes the HuMab® technology; U.S. Patent No. 7,041,870, which describes the K-M MOUSE® technology; and U.S. Patent Application Publication No. 2007 / 0061900, which describes the VelociMouse® technology. The human variable regions from intact antibodies produced by such animals may be further modified, for example, by combining them with different human constant regions.

[0219] In addition, human antibodies can be produced by methods using hybridomas. Human myeloma cell lines and mouse-human heteromyeloma cell lines for producing human monoclonal antibodies have been described. (See, for example, Kozbor J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J. Immunol., 147:86 (1991)). Human antibodies generated via human B-cell hybridoma technology are also described in Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006). Further methods include, for example, U.S. Patent No. 7,189,826 (describing the production of monoclonal human IgM antibodies from hybridoma cell lines), and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (describing human-human hybridomas). Human hybridoma technology (trioma technology) is also described in Histology and Histopathology, 20(3):927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27(3):185-91 (2005).

[0220] Human antibodies can also be generated by isolating variable domain sequences selected from a human-derived phage display library. Such variable domain sequences can then be combined with desired human constant domains. Techniques for selecting human antibodies from antibody libraries are described below. 5. Antibodies from Libraries

[0221] In some embodiments, the antibodies provided herein are obtained from libraries. The antibodies of the invention can be isolated by screening a combinatorial library for antibodies having one or more desired activities. Methods for screening combinatorial libraries are reviewed, for example, by Lerner et al. in Nature Reviews 16:498-508 (2016). For example, various methods are known in the art for generating phage display libraries and screening such libraries for antibodies having desired binding properties. Such methods are found, for example, in mAbs 8:1177-1194 (2016); Frenzel et al. in Human Vaccines and Immunotherapeutics 8:1817-1828 (2012); and Zhao et al. in Critical Reviews in Biotechnology 36:276-289 (2016), as well as Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., eds., Human Press, Totowa, NJ, 2001) and Marks and Bradbury in Methods in Molecular Biology 248:161-175 (Lo, ed., Human Press, Totowa, NJ, 2003).

[0222] In certain phage display methods, repertoires of VH and VL genes are individually cloned by polymerase chain reaction (PCR), randomly recombined in a phage library, and then can be screened for antigen-binding phage as described by Winter et al. in Annual Review of Immunology 12:433-455 (1994). Phage typically display antibody fragments as either single-chain Fv (scFv) fragments or Fab fragments. Libraries from immunogens provide high-affinity antibodies to the immunogen without the need to construct hybridomas. Alternatively, naive repertoires can be cloned (e.g., from humans) to obtain a single source of antibodies against a wide range from non-self to self-antigens without immunization, as described by Griffiths et al. in EMBO Journal 12:725-734 (1993). Finally, naive libraries can also be made synthetically by cloning unrearranged V gene segments from stem cells and using PCR primers containing random sequences to encode highly variable CDR3 regions and achieve rearrangement in vitro, as described by Hoogenboom and Winter in Journal of Molecular Biology 227:381-388 (1992). Patent publications describing human antibody phage libraries include, for example: U.S. Patent Nos. 5,750,373, 7,985,840, 7,785,903, and 8,679,490, as well as U.S. Patent Application Publication Nos. 2005 / 0079574, 2007 / 0117126, 2007 / 0237764, and 2007 / 0292936.

[0223] Further examples of methods known in the art for screening a combinatorial library for antibodies having a desired activity(ies) include ribosome and mRNA display, as well as methods for display and selection of antibodies in bacteria, mammalian cells, insect cells or yeast cells. Methods for yeast surface display are reviewed, for example, in Scholler et al., Methods in Molecular Biology 503:135-56(2012) and Cherf et al., Methods in Molecular biology 1319:155-175(2015) as well as Zhao et al., Methods in Molecular Biology 889:73-84(2012). Methods for ribosome display are described, for example, in He et al., Nucleic Acids Research 25:5132-5134(1997) and Hanes et al., PNAS 94:4937-4942(1997).

[0224] Antibodies or antibody fragments isolated from a human antibody library are considered herein to be human antibodies or human antibody fragments. 6. Multispecific antibodies

[0225] In certain embodiments, the antibodies provided herein are multispecific antibodies, e.g., bispecific antibodies. A multispecific antibody is a monoclonal antibody having binding specificities for at least two different sites, i.e., different epitopes on different antigens or different epitopes on the same antigen. In certain embodiments, the multispecific antibody has three or more binding specificities. In certain embodiments, one of the binding specificities is for KLK7 and the other specificities are for any other antigen. In certain embodiments, one of the binding specificities is for KLK7 and the other specificity is for KLK5. In certain embodiments, the bispecific antibody can bind to two (or more) different epitopes of an antigen. The multispecific antibody can be prepared as a full-length antibody or an antibody fragment.

[0226] Techniques for making multispecific antibodies include, but are not limited to, recombinant co-expression of two immunoglobulin heavy chain-light chain pairs having different specificities (Milstein and Cuello, Nature 305:537 (1983)) and "knob-in-hole" engineering (see, e.g., U.S. Patent No. 5,731,168 and Atwell et al., J. Mol. Biol. 270:26 (1997)). Non-limiting exemplary knob-in-hole substitutions include T366W (knob) and T366S / L368A / Y407V (hole). In some embodiments, the knob-in-hole substitution is in the IgG1 constant domain.

[0227] Multispecific antibodies can also be made by manipulating the electrostatic steering effect for making antibody Fc-heterodimeric molecules. See, e.g., International Publication No. WO 2009 / 089004, Dillon et al., Mab, 9(2):213-230 (2017). As a non-limiting example, in a bispecific antibody comprising two heavy chain variable regions and two light chain variable regions, the first heavy chain variable region can include a Q39E substitution (Kabat numbering), and the first light chain variable region can include a Q38K substitution (Kabat numbering). The second heavy chain variable region can include a Q39K substitution (Kabat numbering), and the second light chain variable region can include a Q38E substitution (Kabat numbering). In some embodiments, the Q39E / Q38K and Q39K / Q38E substitutions reduce heavy and light chain mispairing of the bispecific antibody. Similarly, the first heavy chain constant region can include an S183K substitution (EU numbering), the first light chain constant region can include a V133E substitution (EU numbering), the second heavy chain constant region can include an S183E substitution (EU numbering), and the second light chain constant region can include a V133K substitution (EU numbering). In some embodiments, the S183K / V133E and S183E / V133K substitutions reduce heavy and light chain mispairing of the bispecific antibody. In some embodiments, the bispecific antibody comprises Q39E / Q38K and Q39K / Q38E substitutions in the binding domain and S183K / V133E and S183E / V133K substitutions in the constant region.

[0228] In some embodiments, the bispecific antibody comprises both knob-in-hole substitutions and electrostatic substitutions. See, e.g., International Publication No. WO 2016 / 172485, which is hereby incorporated by reference in its entirety for any purpose. A non-limiting, exemplary schematic of a bispecific antibody is shown in FIG. 15.

[0229] Accordingly, in some embodiments, there is provided a multispecific antibody comprising: a) a first heavy chain / light chain pair that binds to a first antigen and comprises a first heavy chain polypeptide (H1) and a first light chain polypeptide (L1); and b) a second heavy chain / light chain pair that binds to a second antigen and comprises a second heavy chain polypeptide (H2) and a second light chain polypeptide (L2), wherein each H1 and H2 comprises a heavy chain variable domain (VH) and a heavy chain constant domain (CH1), and each L1 and L2 comprises a light chain variable domain (VL) and a light chain constant domain (CL), wherein the CH1 domain of H1 comprises an amino acid substitution at S183 (EU numbering), the CL domain of L1 comprises an amino acid substitution at V133 (EU numbering); the VH domain of H1 comprises an amino acid substitution at position Q39, the VL domain of L1 comprises an amino acid substitution at position Q38, and / or the VH domain of H2 comprises an amino acid substitution at position Q39, and the VL domain of L2 comprises an amino acid substitution at position Q38 (all Kabat numbering). In some embodiments, the VH domain of H1 comprises an amino acid substitution at Q39 (Kabat numbering), and the VL domain of L1 comprises an amino acid substitution at Q38 (Kabat numbering). In some embodiments, the CH1 domain of H2 comprises an amino acid substitution at S183 (EU numbering), and the CL domain of L2 comprises an amino acid substitution at V133 (EU numbering). In some embodiments, the VH domain of H2 further comprises an amino acid substitution at position Q39, and the VL domain of L2 further comprises an amino acid substitution at position Q38 (Kabat numbering). In some embodiments, the CH1 domain of H1 comprises the S183K mutation, the CL of L1 comprises the V133E mutation, the CH1 of H2 comprises the S183E mutation, and the CL domain of L2 comprises the V133K mutation. In some embodiments, the VH domain of H1 comprises the Q39E mutation, the VL domain of L1 comprises the Q38K mutation, the VH domain of H2 comprises the Q39K mutation, and the VL domain of L2 comprises the Q38E mutation (all Kabat numbering).

[0230] Multispecific antibodies can also be produced by cross-linking two or more antibodies or fragments (see, e.g., U.S. Patent No. 4,676,980 and Brennan et al., Science, 229:81 (1985)); production of bispecific antibodies using leucine zippers (see, e.g., Kostelny et al., J. Immunol., 148(5):1547-1553 (1992) and International Publication No. 2011 / 034605); use of common light chain technology to avoid light chain mispairing problems (see, e.g., International Publication No. 98 / 50431); use of "diabody" technology to produce bispecific antibody fragments (see, e.g., Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993)); and use of single-chain Fv (sFv) dimers (see, e.g., Gruber et al., J. Immunol., 152:5368 (1994)); and can be made, for example, by the preparation of trispecific antibodies as described in, e.g., Tutt et al., J. Immunol. 147:60 (1991).

[0231] Also included herein are engineered antibodies having three or more antigen-binding sites, such as "Octopus antibodies" (see, e.g., International Publication Nos. 2001 / 77342 and 2008 / 024715). Other examples of multispecific antibodies having three or more antigen-binding sites can be found in International Publication Nos. 2010 / 115589, 2010 / 112193, 2010 / 136172, 2010 / 145792 and 2013 / 026831. Bispecific antibodies or antigen-binding fragments thereof also include "dual action FAb" or "DAF" that include antigen-binding sites that bind to KLK7 as well as another different antigen, such as KLK5 (see, e.g., U.S. Patent Application Publication No. 2008 / 0069820 and International Publication No. 2015 / 095539).

[0232] Multispecific antibodies can also be provided in an asymmetric form with domain crossovers in one or more binding arms of the same antigen specificity, i.e., by exchanging VH / VL domains (see, e.g., WO 2009 / 080252 and WO 2015 / 150447), CH1 / CL domains (see WO 2009 / 080253), or complete Fab arms (see WO 2009 / 080251, WO 2016 / 016299, Schaefer et al., PNAS, 108(2011)1187-1191, and Klein at al., MAbs 8(2016)1010-20). In one aspect, the multispecific antibody comprises a cross Fab fragment. The terms "cross Fab fragment" or "xFab fragment" or "cross-over Fab fragment" refer to a Fab fragment in which either the variable or constant regions of the heavy and light chains have been exchanged. A cross Fab fragment comprises a polypeptide chain composed of a light chain variable region (VL) and a heavy chain constant region 1 (CH1), and a polypeptide chain composed of a heavy chain variable region (VH) and a light chain constant region (CL). The asymmetric Fab arms can also be engineered by introducing charged or uncharged amino acid mutations at the domain interface to direct correct Fab pairing. See, e.g., WO 2016 / 172485.

[0233] Various further molecular formats of multispecific antibodies are known in the art and are included herein (see, e.g., Spiess et al., Mol Immunol 67(2015)95-106).

[0234] Examples of bispecific antibody formats that may be useful for this purpose include the so-called "BiTE" (bispecific T cell engager) molecules in which two scFv molecules are fused by a flexible linker (see, for example, International Publication Nos. 2004 / 106381, 2005 / 061547, 2007 / 042261 and 2008 / 119567, Nagorsen and Baeuerle, Exp Cell Res 317, 1255-1260 (2011)); diabodies (Holliger et al., Prot Eng 9, 299-305 (1996)) and derivatives thereof, such as tandem diabodies ("TandAb"; Kipriyanov et al., J Mol Biol 293, 41-56 (1999)); "DART" (dual affinity retargeting) molecules that are based on the diabody format but feature a C-terminal disulfide bridge for stabilization (Johnson et al., J Mol Biol 399, 436-449 (2010)), and so-called triomabs, which are fully hybrid mouse / rat IgG molecules (reviewed in Seimetz et al., Cancer Treat Rev 36, 458-467 (2010)), but are not limited thereto. Specific T cell bispecific antibody formats included herein are described in International Publication Nos. 2013 / 026833, 2013 / 026839, 2016 / 020309; Bacac et al., Oncoimmunology 5(8)(2016)e1203498. 7. Antibody Variant

[0235] In certain embodiments, amino acid sequence variants of the antibodies provided herein are contemplated. For example, it may be desirable to alter the binding affinity and / or other biological properties of an antibody. Amino acid sequence variants of the antibody may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody or by peptide synthesis. Such modifications include, for example, deletions from, and / or insertions into, and / or substitutions of residues within the amino acid sequence of the antibody. Any combination of deletions, insertions and substitutions can be made to arrive at the final construct, so long as the final construct possesses the desired characteristics (e.g., antigen binding). a) Substitution, insertion, and deletion variants

[0236] In certain embodiments, antibody variants having one or more amino acid substitutions are provided. Sites of interest for substitution mutagenesis include the CDRs and FRs. Conservative substitutions are shown in Table 1 under the heading “preferred substitutions”. More substantial changes are provided in Table 1 under the heading “exemplary substitutions” and as further described below with reference to amino acid side chain classes. Amino acid substitutions can be introduced into the antibody of interest and the product screened for the desired activity, e.g., retained / improved antigen binding, decreased immunogenicity, or improved ADCC or CDC. JPEG2025087672000002.jpg129170

[0237] Amino acids can be classified according to common side-chain properties. (1) Hydrophobic: norleucine, Met, Ala, Val, Leu, Ile; (2) Neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) Acidic: Asp, Glu; (4) Basic: His, Lys, Arg; (5) Residues that influence chain orientation: Gly, Pro; (6) Aromatic: Trp, Tyr, Phe.

[0238] Non-conservative substitutions would involve exchanging a member of one of these classes for a member of another class.

[0239] Certain substitution variants involve replacing one or more hypervariable region residues of a parent antibody (e.g., a humanized or human antibody). Generally, the resulting variants selected for further study will have a modification (e.g., an improvement) in a particular biological property (e.g., increased affinity, decreased immunogenicity) compared to the parent antibody and / or will substantially retain a particular biological property of the parent antibody. Exemplary substitution variants are affinity matured antibodies, which can be readily made, for example, using phage display-based affinity maturation techniques as described herein. Briefly, one or more CDR residues are mutated, the variant antibodies are displayed on phage, and screened for a particular biological activity (e.g., binding affinity).

[0240] To improve antibody affinity, for example, modifications (such as substitutions) may be made in the CDRs. Such modifications can be made at CDR “hot spots,” i.e., residues encoded by codons that mutate frequently during the somatic maturation process (e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and / or at residues that contact the antigen, and the resulting variant VH or VL is tested for binding affinity. Affinity maturation by construction and reselection from a secondary library is described, for example, in Hoogenboom's Methods in Molecular Biology 178:1-37 (edited by O'Brien et al., Human Press, Totowa, NJ, (2001)). In some aspects of affinity maturation, diversity is introduced into the variable genes selected for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis). A secondary library is then created. This library is then screened to identify antibody variants having the desired affinity. Another method of introducing diversity involves a CDR-directed approach in which several CDR residues (e.g., 4-6 residues at a time) are randomized. CDR residues involved in antigen binding can be specifically identified, for example, using alanine-scanning mutagenesis or modeling. In particular, CDR-H3 and CDR-L3 are often targeted.

[0241] In certain aspects, substitutions, insertions, or deletions can occur within one or more CDRs so long as such modifications do not substantially reduce the ability of the antibody to bind to its antigen. For example, conservative changes (such as the conservative substitutions provided herein) that do not substantially reduce binding affinity can be made in the CDRs. Such modifications can be, for example, outside of the antigen contact residues in the CDRs. In the specific variant VH and VL sequences described above, each CDR is either unmodified or has one, two, or three or fewer amino acid substitutions.

[0242] A useful method for identifying residues or regions of an antibody that can be targets for mutagenesis is what is called "alanine scanning mutagenesis" as described in Cunningham and Wells (1989) Science, 244:1081-1085. In this method, residues or groups of residues of target residues (e.g., charged residues such as arg, asp, his, lys, and glu) are identified and substituted with neutral or negatively charged amino acids (e.g., alanine or polyalanine) to determine whether the interaction between the antibody and the antigen is affected. Further substitutions may be introduced at amino acid positions that show functional sensitivity to the initial substitution. Alternatively, or in addition, the crystal structure of the antigen-antibody complex may be used to identify the contact points between the antibody and the antigen. Such contact residues and adjacent residues may be targeted as candidates for substitution or removed. Variants may be screened to determine whether they have the desired properties.

[0243] Amino acid sequence insertions include amino-terminal and / or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing over 100 residues, as well as in-sequence insertions of one or more amino acid residues. Examples of terminal insertions include antibodies having an N-terminal methionyl residue. Other insertion variants of the antibody molecule include fusions of the antibody to an enzyme (e.g., ADEPT (for antibody-directed enzyme prodrug therapy) or a polypeptide, which increases the serum half-life of the antibody. b) Glycosylation variants

[0244] In certain embodiments, the antibodies provided herein are altered to increase or decrease the degree of glycosylation of the antibody. Addition or deletion of glycosylation sites to the antibody can be conveniently achieved by modifying the amino acid sequence such that one or more glycosylation sites are created or removed.

[0245] When the antibody contains an Fc region, the oligosaccharides bound thereto can be altered. Natural antibodies produced by mammalian cells typically contain branched, biantennary oligosaccharides that are generally bound by N-linkage to Asn297 of the CH2 domain of the Fc region. See, e.g., Wright et al. TIBTECH 15:26-32 (1997). The oligosaccharides can include various carbohydrates such as mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, as well as fucose bound to the GlcNAc of the "stem" of the biantennary oligosaccharide structure. In some embodiments, modification of the oligosaccharides in the antibodies of the invention may be performed to generate antibody variants having certain improved properties.

[0246] In one aspect, provided is an antibody variant having an oligosaccharide structure that is a non-fucosylated oligosaccharide, i.e., lacking a fucose moiety (either directly or indirectly) linked to the Fc region. Such non-fucosylated oligosaccharides (also referred to as "afucosylated" oligosaccharides) are in particular N-linked oligosaccharides lacking a fucose residue with a first GlcNAc attached to the stem of the biantennary oligosaccharide structure. In one aspect, provided is an antibody variant having an increased ratio of non-fucosylated oligosaccharides in the Fc region as compared to the endogenous or parental antibody. For example, the proportion of non-fucosylated oligosaccharides may be at least about 20%, at least about 40%, at least about 60%, at least about 80%, or in some cases about 100% (i.e., no fucosylated oligosaccharides are present). The proportion of non-fucosylated oligosaccharides is, for example, the (average) amount of oligosaccharides lacking a fucose residue relative to the total of all oligosaccharides attached to Asn297 (e.g., complex, hybrid, and high mannose structures), measured by the MALDI-TOF mass spectrometry method described in WO 2006 / 082515. Asn297 refers to the asparagine residue located at position approximately 297 of the Fc region (EU numbering of Fc region residues); however, Asn297 may also be located at approximately ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in the antibody. Such antibodies having an increased proportion of non-fucosylated oligosaccharides in the Fc region may have improved FcγRIIIa receptor binding and / or improved effector function, particularly improved ADCC function. See, for example, US Patent Application Publication Nos. 2003 / 0157108; 2004 / 0093621.

[0247] Examples of cell lines capable of producing antibodies with reduced fucosylation include Lec13 CHO cells with insufficient protein fucosylation (Ripka et al., Arch. Biochem. Biophys. 249:533-545 (1986); US Patent Application Publication No. 2003 / 0157108; and International Publication No. 2004 / 056312, particularly Example 11), and knockout cell lines, such as FUT8 knockout CHO cells of the alpha-1,6-fucosyltransferase gene (see, for example, Yamane-Ohnuki et al., Biotech. Bioeng. 87:614-622 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688 (2006); and International Publication No. 2003 / 085107), or cells with reduced or abolished GDP-fucose synthesis or transporter protein activity (see, for example, US Patent Application Publication Nos. 2004259150, 2005031613, 2004132140, 2004110282).

[0248] In a further aspect, the antibody variant is provided, for example, with a bisected oligosaccharide in which the bisected oligosaccharide bound to the Fc region of the antibody is bisected by GlcNAc. Such antibody variants can have reduced fucosylation and / or improved ADCC function as described above. Examples of such antibody variants are described, for example, in Umana et al., Nat Biotechnol 17,176-180 (1999); Ferrara et al., Biotechn Bioeng 93,851-861 (2006); International Publication Nos. 99 / 54342, 2004 / 065540, 2003 / 011878.

[0249] Antibody variants having at least one galactose residue of the oligosaccharide attached to the Fc region are also provided. Such antibody variants may improve the function of CDC. Such antibody variants are described, for example, in International Publication Nos. 1997 / 30087, 1998 / 58964, and 1999 / 22764. c) Fc region variant

[0250] In certain embodiments, one or more amino acid modifications may be introduced into the Fc region of the antibodies presented herein, thereby creating Fc region variants. Fc region variants include human Fc region sequences (e.g., human IgG 1 , IgG 2 , IgG 3 or IgG 4 Fc region) that contain amino acid modifications (e.g., substitutions) at one or more amino acid positions.

[0251] In certain embodiments, the invention contemplates antibody variants that have some, but not all, effector functions, such that they are desirable candidates for applications where the in vivo half-life of the antibody is important but certain effector functions, such as complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC), are unnecessary or harmful. To confirm a reduction or loss of CDC and / or ADCC activity, in vitro and / or in vivo cytotoxicity assays can be performed. For example, an Fc receptor (FcR) binding assay can be run to confirm that the antibody lacks FcR binding (and thus is likely to lack ADCC activity), but retains FcRn binding ability. NK cells, which are the major cells mediating ADCC, express only FcRIII, while monocytes express FcRI, FcRII, and FcRIII. The expression of FcRs in hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991). Non-limiting examples of in vitro assays for evaluating the ADCC activity of a molecule of interest are described in U.S. Patent No. 5,500,362 (see, e.g., Hellstrom, I. et al., Proc. Nat’l Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom, I et al., Proc. Nat’l Acad. Sci. USA 82:1499-1502 (1985); 5,821,337 (Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)). Alternatively, a non-radioactive assay method may be employed (e.g., ACTI™ non-radioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc. Mountain View, CA), and CytoTox96 (登録商標)Please refer to the non-radioactive cytotoxicity test method (Promega, Madison, WI). Effector cells useful for such assays include peripheral blood mononuclear cells (PBMC) and natural killer (NK) cells. Alternatively, or in addition, the ADCC activity of the molecule of interest can be evaluated in vivo, for example, in an animal model, as described in Clynes et al., Proc. Nat’l Acad. Sci. USA 95:652-656 (1998). Also, a C1q binding assay may be performed to confirm that the antibody cannot bind to C1q and lacks CDC activity. See, for example, C1q and C3c binding ELISAs of WO 2006 / 029879 and WO 2005 / 100402. A CDC assay can be performed to evaluate complement activation (see, for example, Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996); Cragg, M. S. et al., Blood 101:1045-1052 (2003); and Cragg, M. S. and M. J. Glennie, Blood 103:2738-2743 (2004)), and measurements of FcRn binding and in vivo clearance / half-life can also be performed using methods known in the art (see, for example, Petkova, S. B. et al., Int’l. Immunol. 18(12):1759-1769 (2006); WO 2013 / 120929).

[0252] Antibodies with reduced effector function include antibodies having one or more substitutions at residues 238, 265, 269, 270, 297, 327, and 329 in the Fc region (U.S. Patent No. 6,737,056). Such Fc mutants include Fc mutants having substitutions at two or more of amino acid positions 265, 269, 270, 297, and 327, including the so-called "DANA" Fc mutant in which residues 265 and 297 are substituted with alanine (U.S. Patent No. 7,332,581).

[0253] Certain antibody variants with improved or decreased binding to FcR are described. (See, for example, U.S. Patent No. 6,737,056; International Publication No. 2004 / 056312, and Shields et al., J. Biol. Chem. 9(2):6591-6604 (2001).)

[0254] In certain embodiments, the antibody variant comprises an Fc region having one or more amino acid substitutions that improve ADCC, such as substitutions at positions 298, 333 and / or 334 of the Fc region (EU numbering of residues).

[0255] In certain embodiments, the antibody variant comprises an Fc region having one or more amino acid substitutions that reduce FcγR binding, such as positions 234 and 235 of the Fc region (EU numbering of residues). In one embodiment, the substitutions are L234A and L235A (LALA). In certain embodiments, the antibody variant is a human IgG 1 Fc region further comprises D265A and / or P329G in the Fc region derived from the Fc region.

[0256] In one embodiment, the substitutions are in a human IgG 1 L234A, L235A, and P329G (LALA-PG) in the Fc region derived from the human IgG Fc region. (See, for example, International Publication No. 2012 / 130831.) In another embodiment, the substitutions are in a human IgG 1 L234A, L235A, and D265A (LALA-DA) in the Fc region derived from the human IgG Fc region. In some embodiments, changes (i.e., either improvement or decrease) in C1q binding and / or complement-dependent cytotoxicity (CDC) occur within the Fc region, as described, for example, in U.S. Patent No. 6,194,551, International Publication No. 99 / 51642, and Idusogie et al., J. Immunol. 164:4178-4184 (2000).

[0257] Antibodies that play a role in transferring maternal IgG to the fetus, with an increased half-life and improved binding to the neonatal Fc receptor (FcRn) (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)) are described in US Patent Application Publication No. 2005 / 0014934 (Hinton et al.). Those antibodies contain an Fc region having one or more substitutions that improve the binding of the Fc region to FcRn. Such Fc variants include those having a substitution at one or more of Fc region residues: 238, 252, 254, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424, 428 or 434, for example, those having a substitution at Fc region residue 434 (see, e.g., US Patent No. 7,371,826; Dall’Acqua, W.F., et al. J. Biol. Chem. 281 (2006) 23514-23524). In some embodiments, the antibodies provided herein contain the substitutions M428L and / or N434S, e.g., M428L and N434S (“LS”).

[0258] The Fc region residues essential for mouse Fc-mouse FcRn interaction have been identified by site-directed mutagenesis (see, for example, Dall’Acqua, W.F. et al. J. Immunol 169 (2002) 5171-5180). Residues I253, H310, H433, N434, and H435 (EU index numbering) are involved in the interaction (Medesan, C. et al., Eur. J. Immunol. 26 (1996) 2533; Firan, M. et al, Int. Immunol. 13 (2001) 993; Kim, J.K. et al, Eur. J. Immunol. 24 (1994) 542). Residues I253, H310, and H435 were found to be crucial for the interaction of human Fc with mouse FcRn (Kim, J.K. et al, Eur. J. Immunol. 29 (1999) 2819). Studies of the human Fc-human FcRn complex have shown that residues I253, S254, H435, and Y436 are crucial for the interaction (Firan, M. et al, Int. Immunol. 13 (2001) 993; Shields, R.L. et al, J. Biol. Chem. 276 (2001) 6591-6604). In Yeung, Y.A., et al. (J. Immunol. 182 (2009) 7667-7671), various mutations in residues 248-259, and 301-317, and 376-382, and 424-437 have been reported and investigated.

[0259] In certain embodiments, the antibody variant comprises an Fc region having one or more amino acid substitutions that reduce FcRn binding, such as mutations at positions 253, and / or 310, and / or 435 (EU numbering of residues) of the Fc region. In certain embodiments, the antibody variant comprises an Fc region having amino acid substitutions at positions 253, 310, and 435. In one embodiment, the substitutions are I253A, H310A, and H435A in an Fc region derived from the human IgG1 Fc region. See, for example, Grevys, A. et al, J. Immunol. 194 (2015) 5497-5508.

[0260] Comprises an Fc region having one or more amino acid substitutions that reduce FcRn binding, such as mutations at Fc region positions 310, and / or 433, and / or 436 (EU numbering of residues). In certain embodiments, the antibody variant comprises an Fc region having amino acid substitutions at positions 310, 433 and 436. In one embodiment, the substitutions are H310A, H433A and Y436A in the Fc region derived from the human IgG1 Fc region. See, for example, WO 2014 / 177460.)

[0261] In certain embodiments, the antibody variant comprises an Fc region having one or more amino acid substitutions that increase FcRn binding, such as mutations at Fc region positions 252, and / or 254, and / or 256 (EU numbering of residues). In certain embodiments, the antibody variant comprises an Fc region having amino acid substitutions at positions 252, 254, and 256. In one embodiment, the substitutions are M252Y, S254T, and T256E in the Fc region derived from the human IgG 1 Fc region. For other examples of variants of the Fc region, see also Duncan & Winter, Nature 322:738-40 (1988); U.S. Patent No. 5,648,260; U.S. Patent No. 5,624,821; and WO 94 / 29351.)

[0262] The C-terminus of the heavy chain of an antibody as reported herein may be a complete C-terminus ending with the amino acid residue PGK. The C-terminus of the heavy chain may be a shortened C-terminus with one or two of the C-terminal amino acid residues removed. In one preferred embodiment, the C-terminus of the heavy chain is the shortened C-terminal end PG. In one embodiment of all the embodiments reported herein, an antibody comprising a heavy chain comprising the C-terminal CH3 domain as specified herein comprises a C-terminal glycine-lysine dipeptide (amino acid positions G446 and K447, EU index numbering). In one embodiment of all the embodiments reported herein, an antibody comprising a heavy chain comprising the C-terminal CH3 domain as specified herein comprises a C-terminal glycine residue (G446, EU index numbering of amino acid positions). d) Cysteine-engineered antibody variants

[0263] In certain embodiments, it may be desirable to generate a cysteine-engineered antibody in which one or more residues of the antibody are replaced with cysteine residues, e.g., a THIOMAB (商標) When this is the case. In certain embodiments, the residues being replaced occur at accessible sites of the antibody. By replacing these residues with cysteine, reactive thiol groups are thereby positioned at accessible sites of the antibody and can be used to conjugate the antibody to other sites, such as a drug site or a linker-drug site, to create an immunoconjugate, as further described herein. Cysteine-engineered antibodies can be generated, for example, as described in U.S. Pat. Nos. 7,521,541, 8,30,930, 7,855,275, 9,000,130, or International Publication No. 2016040856. e) Antibody derivatives

[0264] In certain embodiments, the antibodies provided herein can be further modified to contain additional non-proteinaceous moieties that are known in the art and readily available. Suitable sites for derivatization of the antibody include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), copolymers of ethylene glycol / propropylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene / maleic anhydride copolymer, polyamino acids (either homopolymers or random copolymers), and dextran or poly(n-vinyl pyrrolidone) polyethylene glycol, polypropylene glycol homopolymers, polypropylene oxide / ethylene oxide copolymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may be advantageous during production due to its stability in water. The polymer may have any molecular weight, may be branched, or may be unbranched. The number of polymers attached to the antibody may vary and, when more than one polymer is attached, the polymers may be the same molecule or different molecules. In general, the number and / or type of polymer used for derivatization can be determined based on considerations such as, but not limited to, the particular properties or functions of the antibody to be improved, whether the antibody derivative is to be used therapeutically under defined conditions, and the like. 8. Immunoconjugate

[0265] The invention also provides an immunoconjugate comprising an antibody conjugated (chemically linked) to one or more therapeutic agents such as a cytotoxic agent, a chemotherapeutic agent, a drug, a growth inhibitor, a toxin (e.g., a protein toxin, an enzymatically active toxin of bacterial, fungal, plant or animal origin, or a fragment thereof), or a radioisotope.

[0266] In one aspect, the immunoconjugate is an antibody-drug conjugate (ADC) in which an antibody is conjugated to one or more of the aforementioned therapeutic agents. The antibody is typically linked to one or more of the therapeutic agents using a linker. An overview of ADC technology, including examples of therapeutic agents and drugs and linkers, is described in Pharmacol Review 68:3-19 (2016).

[0267] In another aspect, the immunoconjugate comprises an antibody conjugated to an enzymatically active toxin or fragments thereof, as described herein. These include, but are not limited to, diphtheria A chain, non-binding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, α-sarcin, ricin from castor bean, dianthin protein, protein from Phytolacca americana (PAPI, PAPII, and PAP-S), tricothecin inhibitor, curcin, crotin, saponin inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and trichothecene.

[0268] In another aspect, the immunoconjugate comprises an antibody as described herein conjugated to a radioactive atom to form a radioactive conjugate. A variety of radioisotopes are available for the production of radioactive substances. Examples include At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212, and radioactive isotopes of Lu. When a radioactive substance is used for detection, it may include radioactive atoms for scintigraphy studies, such as Tc99m or I123, or spin labels for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, MRI), such as iodine 123 again, iodine 131, indium 111, fluorine 19, carbon 13, nitrogen 15, oxygen 17, gadolinium, manganese or iron.

[0269] Conjugates of antibodies and cytotoxic agents can be prepared, for example, using various bifunctional protein coupling agents: N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), iminothiolane (IT), bifunctional derivatives of imidoesters (dimethyl adipimidate HCl, etc.), active esters (disuccinimidyl suberate, etc.), aldehydes (glutaraldehyde, etc.), bis-azide compounds (bis(p-azidobenzoyl)hexanediamine, etc.), bis-diazonium derivatives (bis-(p-diazoniumbenzoyl)-ethylenediamine, etc.), diisocyanates (toluene 2,6-diisocyanate, etc.), and di-active fluorine compounds (1,5-difluoro-2,4-dinitrobenzene, etc.). For example, as described by Vitetta et al., Science 238:1098 (1987), ricin immunotoxin can be prepared. Carbon 14-labeled 1-isothiocyanatobenzyl-3-methyldiethylenetriaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugating radionuclides to antibodies. See International Publication No. 94 / 11026. The linker may be a "cleavable linker" that promotes the release of the cytotoxic drug intracellularly. For example, acid-labile linkers, peptidase-sensitive linkers, photolabile linkers, dimethyl linkers or disulfide-containing linkers (Chari et al., "Cancer Res." Vol. 52, pp. 127-131 (1992); U.S. Patent No. 5,208,020) can be used.

[0270] The immunoconjugates or ADCs of this specification are prepared with cross-linking reagent reagents including, but not limited to, commercially available ones (e.g., from Pierce Biotechnology, Inc., Rockford, IL., U.S.A), BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, and sulfo-SMPB, and SVSB (succinimidyl-(4-vinylsulfone)benzoate), and such conjugates are explicitly contemplated, but not limited to, these. D. Recombinant Methods and Compositions

[0271] Antibodies can be produced using recombinant methods and compositions, as described, for example, in U.S. Patent No. 4,816,567. For these methods, one or more isolated nucleic acids encoding the antibody are provided.

[0272] In the case of native antibodies or native antibody fragments that require two nucleic acids, one is for the light chain or a fragment thereof, and one is for the heavy chain or a fragment thereof. Such nucleic acids encode an amino acid ...

Claims

1. 1. An isolated antibody that binds to human kallikrein-related peptidase 7 (KLK7), a) inhibits human KLK7-mediated cleavage of a substrate comprising the amino acid sequence RPKPVE-Nval-WRK (SEQ ID NO: 121), where Nval is norvaline; and / or b) a K of less than 10 pM, or less than 9 pM, or less than 8 pM, or less than 7 pM, or less than 6 pM, or less than 5 pM, as measured by surface plasmon resonance Ｄ binds to human KLK7 with c) binds to an epitope within amino acids R71 to N82, K152 to S158, and / or Q211 to K222 of KLK7 (SEQ ID NO:4); and / or d) An isolated antibody that binds to an epitope comprising one or more of amino acids H72, P73, G74, S76, Q78, N82, N157, K211 and / or T213 of KLK7 (SEQ ID NO:4).

2. An antibody that binds to human KLK7, An antibody comprising: (a) a heavy chain variable domain (VH) containing CDR-H1 comprising the amino acid sequence of SEQ ID NO:7, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:8, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:9; and (d) a light chain variable domain (VL) containing CDR-L1 comprising the amino acid sequence of SEQ ID NO:10, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:11, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:

12.

3. The antibody of claim 1, comprising a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 7, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 8, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 9, and a light chain variable domain (VL) comprising (c) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 10, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 11, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:

12.

4. The antibody according to any one of claims 1 to 3, which is a monoclonal antibody.

5. The antibody according to any one of claims 1 to 4, which is a humanized antibody or a chimeric antibody.

6. The antibody according to any one of claims 1 to 5, which is an antibody fragment that binds to human KLK7.

7. A K of less than 10 pM, or less than 9 pM, or less than 8 pM, or less than 7 pM, or less than 6 pM, or less than 5 pM as measured by surface plasmon resonance. Ｄ and / or has a K of less than 10 pM, or less than 9 pM, or less than 8 pM, or less than 7 pM, or less than 6 pM, or less than 5 pM as measured by surface plasmon resonance. Ｄ The antibody according to any one of claims 1 to 6, which binds to cynomolgus KLK7 at

8. The antibody of any one of claims 1 to 7, wherein the heavy chain variable region comprises FR1 comprising an amino acid sequence selected from SEQ ID NOs: 123 to 128, FR2 comprising an amino acid sequence selected from SEQ ID NOs: 130 to 133, FR3 comprising an amino acid sequence selected from SEQ ID NOs: 135 to 143, and / or FR4 comprising an amino acid sequence selected from SEQ ID NOs: 144 to 145.

9. The antibody of any one of claims 1 to 8, wherein the light chain variable region comprises FR1 comprising an amino acid sequence selected from SEQ ID NOs: 147-150, FR2 comprising an amino acid sequence selected from SEQ ID NOs: 152-154, FR3 comprising an amino acid sequence selected from SEQ ID NOs: 156-158, and / or FR4 comprising an amino acid sequence selected from SEQ ID NO:

160.

10. The antibody of any one of claims 1 to 9, comprising a sequence selected from: (a) a VH sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 15-30; (b) a VL sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 31-38; and (c) The VH sequence defined in (a) and the VL sequence defined in (b).

11. The antibody of any one of claims 1 to 10, comprising a sequence selected from: (a) a VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 15-30; (b) a VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 31-38; and (c) The VH sequence defined in (a) and the VL sequence defined in (b).

12. An antibody according to any one of claims 1 to 11, comprising the VH sequence of SEQ ID NO:29 and the VL sequence of SEQ ID NO:

32.

13. An antibody according to any one of claims 1 to 11, comprising the VH sequence of SEQ ID NO: 30 and the VL sequence of SEQ ID NO:

38.

14. An antibody that specifically binds to human KLK7, comprising the VH sequence of SEQ ID NO:29 and the VL sequence of SEQ ID NO:

32.

15. An antibody that specifically binds to human KLK7, comprising the VH sequence of SEQ ID NO:30 and the VL sequence of SEQ ID NO:

38.

16. 16. The antibody of any one of claims 1 to 15, comprising a heavy chain constant region and a light chain constant region, wherein the heavy chain constant region comprises a S183K substitution (EU numbering) and / or a S183E substitution (EU numbering); and / or the light chain constant region comprises a V133K substitution (EU numbering) and / or a V133E substitution (EU numbering).

17. The antibody of any one of claims 1 to 16, which is a full-length IgG1 antibody.

18. 18. The antibody of claim 17, comprising an N297G substitution (EU numbering).

19. The antibody of any one of claims 16 to 18, comprising an M428L substitution (EU numbering) and / or an N434S substitution (EU numbering).

20. A K of less than 20 pM, or less than 15 pM, or less than 10 pM, or less than 5 pM, or less than 3 pM, or less than 2 pM, or less than 1 pM as measured by surface plasmon resonance. Ｄ The antibody of any one of claims 1 to 19, which binds to human KLK7 at

21. 21. The antibody of any one of claims 1 to 20, which inhibits human KLK7 protease activity with an IC50 of less than 5 nM, or less than 3 nM, or less than 2 nM, or less than 1 nM.

22. A K of less than 20 pM, or less than 15 pM, or less than 10 pM, or less than 5 pM, or less than 3 pM, or less than 2 pM, or less than 1 pM as measured by surface plasmon resonance. Ｄ 22. The antibody of any one of claims 1 to 21, which binds to human KLK7 with an IC50 of less than 5 nM, or less than 3 nM, or less than 2 nM, or less than 1 nM, and inhibits human KLK7 protease activity with an IC50 of less than 5 nM, or less than 3 nM, or less than 2 nM, or less than 1 nM.

23. The antibody of claim 21 or claim 22, wherein the inhibition of human KLK7 protease activity is inhibition of human KLK7-mediated cleavage of a substrate comprising the amino acid sequence RPKPVE-Nval-WRK (sequence number 121), wherein Nval is norvaline.

24. The antibody according to any one of claims 1 to 23, which is a multispecific antibody.

25. The antibody of claim 24 which is a bispecific antibody.

26. An antibody that specifically binds to human KLK7 and competes with the antibody of any one of claims 1 to 25 for binding to human KLK7.

27. 27. The antibody of claim 26, c) inhibits human KLK7-mediated cleavage of a substrate comprising the amino acid sequence RPKPVE-Nval-WRK (SEQ ID NO: 121), where Nval is norvaline, with an IC50 of less than 5 nM, or less than 3 nM, or less than 2 nM, or less than 1 nM; and / or d) a K of less than 10 pM, or less than 9 pM, or less than 8 pM, or less than 7 pM, or less than 6 pM, or less than 5 pM, as measured by surface plasmon resonance. Ｄ An antibody that binds to human KLK7 at

28. An isolated nucleic acid encoding an antibody according to any one of claims 1 to 27.

29. 29. An isolated host cell comprising the nucleic acid of claim 28.

30. An isolated host cell expressing the antibody of any one of claims 1 to 27.

31. 31. A method for producing an antibody that binds to human KLK7, comprising culturing a host cell according to claim 29 or claim 30 under conditions suitable for expression of said antibody.

32. 32. The method of claim 31, further comprising recovering the antibody from the host cell.

33. 33. An antibody produced by the method of claim 32.

34. An antibody that binds to human KLK5, a) a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (b) a CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 40 and 41, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising an amino acid sequence selected from SEQ ID NOs: 43 and 44, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (f) a CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 46-49; or b) a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising an amino acid sequence selected from SEQ ID NOs: 39 and 107, (b) a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 41, and (c) a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 42, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising an amino acid sequence selected from SEQ ID NOs: 43 and 44, (e) a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 45, and (f) a CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 46-49; or c) a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising an amino acid sequence selected from SEQ ID NOs: 39 and 107, (b) a CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 40 and 41, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 44, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (f) a CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 46-49; or d) a heavy chain variable domain (VH) comprising: (a) a CDR-H1 comprising an amino acid sequence selected from SEQ ID NOs: 39 and 107; (b) a CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 40 and 41; and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42; and a light chain variable domain (VL) comprising: (d) a CDR-L1 comprising an amino acid sequence selected from SEQ ID NOs: 43 and 44; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45; and (f) a CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 47-49; or e) a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:68, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO:70, and (c) a CDR-H3 comprising an amino acid sequence selected from SEQ ID NOs:71 and 72, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO:73, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO:74, and (f) a CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs:75-78; or f) a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:68, (b) a CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs:69 and 70, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO:72, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO:73, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO:74, and (f) a CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs:75-78; or g) an antibody comprising a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:68, (b) a CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs:69 and 70, and (c) a CDR-H3 comprising an amino acid sequence selected from SEQ ID NOs:71 and 72, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO:73, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO:74, and (f) a CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs:76-78.

35. The antibody of claim 34, comprising a heavy chain variable domain (VH) comprising: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 39, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 41, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42, and a light chain variable domain (VL) comprising: (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 43, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:

47.

36. The antibody of claim 34, comprising a heavy chain variable domain (VH) comprising: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:68, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:70, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:72, and a light chain variable domain (VL) comprising: (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:73, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:74, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:

76.

37. The antibody according to any one of claims 34 to 36, which is a monoclonal antibody.

38. The antibody according to any one of claims 34 to 37, which is a humanized or chimeric antibody.

39. The antibody of any one of claims 34 to 38, which is an antibody fragment that binds to human KLK5.

40. K of less than 1 nM, or less than 500 pM, or less than 300 pM, or less than 200 pM, or less than 100 pM, or less than 50 pM as measured by surface plasmon resonance Ｄ and / or a K of less than 1 nM, or less than 500 pM, or less than 300 pM, or less than 200 pM, or less than 100 pM, or less than 50 pM as measured by surface plasmon resonance. Ｄ The antibody of any one of claims 34 to 39, which binds to cynomolgus KLK5 at

41. The antibody of any one of claims 34 to 40, wherein the heavy chain variable region comprises: a) FR1 comprising an amino acid sequence selected from SEQ ID NO: 161, FR2 comprising an amino acid sequence of SEQ ID NO: 162-163, FR3 comprising an amino acid sequence of SEQ ID NO: 164, and / or FR4 comprising an amino acid sequence of SEQ ID NO: 165; or b) An antibody comprising FR1 comprising the amino acid sequence of SEQ ID NO: 171, FR2 comprising an amino acid sequence selected from SEQ ID NOs: 172-173, FR3 comprising the amino acid sequence of SEQ ID NO: 174, and / or FR4 comprising the amino acid sequence of SEQ ID NO:

175.

42. 42. The antibody of claim 34, wherein the light chain variable region comprises: a) FR1 comprising the amino acid sequence of SEQ ID NO: 166, FR2 comprising an amino acid sequence selected from SEQ ID NOs: 167-168, FR3 comprising the amino acid sequence of SEQ ID NO: 169, and / or FR4 comprising the amino acid sequence of SEQ ID NO: 170; or b) An antibody comprising FR1 comprising the amino acid sequence of SEQ ID NO: 176, FR2 comprising an amino acid sequence selected from SEQ ID NOs: 177-178, FR3 comprising the amino acid sequence of SEQ ID NO: 179, and / or FR4 comprising the amino acid sequence of SEQ ID NO:

180.

43. The antibody of any one of claims 34 to 42, comprising a sequence selected from: a) a VH sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 50, 52, 53, 105 and 106; b) a VL sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 51 and 54-67; and c) the VH sequence defined in (a) and the VL sequence defined in (b); d) a VH sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 79 and 81-87; e) a VL sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 80 and 88-94; and f) The VH sequence defined in (d) and the VL sequence defined in (e).

44. The antibody of any one of claims 34 to 43, comprising a sequence selected from: a) a VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 50, 52, 53, 105, and 106; b) a VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 51 and 54-67; and c) the VH sequence defined in (a) and the VL sequence defined in (b); d) a VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 79 and 81-87; e) a VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 80 and 88-94; and f) The VH sequence defined in (d) and the VL sequence defined in (e).

45. An antibody according to any one of claims 34 to 44, comprising the VH sequence of SEQ ID NO: 52 and the VL sequence of SEQ ID NO:

55.

46. An antibody according to any one of claims 34 to 44, comprising the VH sequence of SEQ ID NO: 53 and the VL sequence of SEQ ID NO:

62.

47. An antibody that specifically binds to human KLK5, comprising the VH sequence of SEQ ID NO:52 and the VL sequence of SEQ ID NO:

55.

48. An antibody that specifically binds to human KLK5, comprising the VH sequence of SEQ ID NO:53 and the VL sequence of SEQ ID NO:

62.

49. An antibody according to any one of claims 34 to 44, comprising the VH sequence of SEQ ID NO: 83 and the VL sequence of SEQ ID NO:

88.

50. An antibody according to any one of claims 34 to 44, comprising the VH sequence of SEQ ID NO: 87 and the VL sequence of SEQ ID NO:

92.

51. An antibody that specifically binds to human KLK5, comprising the VH sequence of SEQ ID NO:83 and the VL sequence of SEQ ID NO:

88.

52. An antibody that specifically binds to human KLK5, comprising the VH sequence of SEQ ID NO:87 and the VL sequence of SEQ ID NO:

92.

53. 53. The antibody of any one of claims 34 to 52, comprising a heavy chain constant region and a light chain constant region, wherein the heavy chain constant region comprises a S183K substitution (EU numbering) and / or a S183E substitution (EU numbering), and / or the light chain constant region comprises a V133K substitution (EU numbering) and / or a V133E substitution (EU numbering).

54. The antibody of any one of claims 34 to 53, which is a full-length IgG1 antibody.

55. 55. The antibody of claim 54, comprising an N297G substitution (EU numbering).

56. 56. The antibody of any one of claims 53 to 55, comprising an M428L substitution (EU numbering) and / or an N434S substitution (EU numbering).

57. K of less than 60 pM, less than 30 pM, less than 20 pM, less than 10 pM, or less than 5 pM as measured by surface plasmon resonance. Ｄ The antibody of any one of claims 34 to 56, which binds to human KLK5 at

58. 58. The antibody of any one of claims 34 to 57, which inhibits human KLK5 protease activity with an IC50 of less than 5 nM, or less than 3 nM, or less than 2 nM, or less than 1 nM.

59. K of less than 60 pM, less than 30 pM, less than 20 pM, less than 10 pM, or less than 5 pM as measured by surface plasmon resonance. Ｄ 59. The antibody of any one of claims 34 to 58, which binds to human KLK5 with an IC50 of less than 5 nM, or less than 3 nM, or less than 2 nM, or less than 1 nM and inhibits human KLK5 protease activity with an IC50 of less than 5 nM, or less than 3 nM, or less than 2 nM, or less than 1 nM.

60. 60. The antibody of claim 58 or claim 59, wherein the inhibition of human KLK5 protease activity is inhibition of human KLK5-mediated cleavage of the substrate Boc-Val-Pro-Arg-AMC.

61. The antibody of any one of claims 34 to 60, which is a multispecific antibody.

62. 62. The antibody of claim 61 which is a bispecific antibody.

63. An isolated nucleic acid encoding an antibody according to any one of claims 34 to 62.

64. 64. An isolated host cell comprising the nucleic acid of claim 63.

65. An isolated host cell expressing an antibody according to any one of claims 34 to 62.

66. 66. A method for producing an antibody that binds to human KLK5, comprising culturing a host cell according to claim 64 or 65 under conditions suitable for expression of said antibody.

67. 67. The method of claim 66, further comprising recovering the antibody from the host cell.

68. 68. An antibody produced by the method of claim 67.

69. A bispecific antibody comprising a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7 and the second binding domain binds to human KLK5, the first binding domain comprising a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:7, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:8, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:9, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:10, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:11, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:

12.

70. 70. The bispecific antibody of claim 69, wherein the first binding domain is humanized.

71. The bispecific antibody of claim 69 or claim 70, wherein the first binding domain comprises a sequence selected from: (a) a VH sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 15-30; (b) a VL sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 31-38; and (c) The VH sequence defined in (a) and the VL sequence defined in (b).

72. The bispecific antibody of any one of claims 69 to 71, wherein the first binding domain comprises a sequence selected from: (a) a VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 15-30; (b) a VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 31-38; and (c) The VH sequence defined in (a) and the VL sequence defined in (b).

73. 73. The bispecific antibody of any one of claims 69 to 72, wherein the first binding domain comprises the VH sequence of SEQ ID NO: 29 and the VL sequence of SEQ ID NO:

32.

74. 73. The bispecific antibody of any one of claims 69 to 72, wherein the first binding domain comprises the VH sequence of SEQ ID NO: 30 and the VL sequence of SEQ ID NO:

38.

75. 75. The bispecific antibody of any one of claims 69 to 74, wherein the second binding domain comprises: a) a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising an amino acid sequence selected from SEQ ID NOs: 39 and 107, (b) a CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 40 and 41, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising an amino acid sequence selected from SEQ ID NOs: 43 and 44, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (f) a CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 46-49; or b) a pharmaceutical composition comprising a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:68, (b) a CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs:69 and 70, and (c) a CDR-H3 comprising an amino acid sequence selected from SEQ ID NOs:71 and 72, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO:73, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO:74, and (f) a CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs:75-78.

76. 76. The bispecific antibody of any one of claims 69 to 75, wherein the second binding domain comprises a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 39, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 41, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 43, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:

47.

77. 76. The bispecific antibody of any one of claims 69 to 75, wherein the second binding domain comprises a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 68, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 70, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 72, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:

76.

78. 78. The bispecific antibody of any one of claims 69 to 77, wherein the second binding domain is humanized.

79. The bispecific antibody of any one of claims 75 to 78, wherein the second binding domain comprises a sequence selected from: a) a VH sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 50, 52, 53, 105 and 106; b) a VL sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 51 and 54-67; and c) the VH sequence defined in (a) and the VL sequence defined in (b); d) a VH sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 79 and 81-87; e) a VL sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 80 and 88-94; and f) The VH sequence defined in (d) and the VL sequence defined in (e).

80. The bispecific antibody of any one of claims 75 to 78, wherein the second binding domain comprises a sequence selected from: a) a VH sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 52, 53, 105 and 106; b) a VL sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 54-67; and c) the VH sequence defined in (a) and the VL sequence defined in (b); d) a VH sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 81-87; e) a VL sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 88-94; and f) The VH sequence defined in (d) and the VL sequence defined in (e).

81. The bispecific antibody of any one of claims 69 to 78, wherein the second binding domain comprises a sequence selected from: a) a VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 50, 52, 53, 105, and 106; b) a VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 51 and 54-67; and c) the VH sequence defined in (a) and the VL sequence defined in (b); d) a VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 79 and 81-87; e) a VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 80 and 88-94; and f) The VH sequence defined in (d) and the VL sequence defined in (e).

82. The bispecific antibody of any one of claims 69 to 78, wherein the second binding domain comprises a sequence selected from: a) a VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 52, 53, 105, and 106; b) a VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 54-67; and c) the VH sequence defined in (a) and the VL sequence defined in (b); d) a VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 81-87; e) a VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 88-94; and f) The VH sequence defined in (d) and the VL sequence defined in (e).

83. 80. The bispecific antibody of any one of claims 69 to 79, wherein the first binding domain comprises the VH amino acid sequence of SEQ ID NO:29 or SEQ ID NO:30, and the VL amino acid sequence of SEQ ID NO:32 or SEQ ID NO:38, and the second binding domain comprises the VH sequence of SEQ ID NO:52 or SEQ ID NO:53, and the VL amino acid sequence of SEQ ID NO:55 or SEQ ID NO:

62.

84. 84. The bispecific antibody of claim 83, wherein (i) the first binding domain comprises a VH amino acid sequence of SEQ ID NO:29 and a VL amino acid sequence of SEQ ID NO:32, or comprises a VH amino acid sequence of SEQ ID NO:30 and a VL amino acid sequence of SEQ ID NO:38, and (ii) the second binding domain comprises a VH sequence of SEQ ID NO:52 and a VL amino acid sequence of SEQ ID NO:55, or comprises a VH sequence of SEQ ID NO:53 and a VL amino acid sequence of SEQ ID NO:

62.

85. 80. The bispecific antibody of any one of claims 69 to 79, wherein the first binding domain comprises the VH sequence of SEQ ID NO: 30 and the VL sequence of SEQ ID NO: 38, and the second binding domain comprises the VH sequence of SEQ ID NO: 53 and the VL sequence of SEQ ID NO:

62.

86. A bispecific antibody comprising a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7 and the second binding domain binds to human KLK5, the first binding domain comprising a heavy chain variable domain (VH) amino acid sequence of SEQ ID NO:30 and a light chain variable domain (VL) amino acid sequence of SEQ ID NO:38, and the second binding domain comprising a VH amino acid sequence of SEQ ID NO:53 and a VL amino acid sequence of SEQ ID NO:

62.

87. 87. The bispecific antibody of any one of claims 69 to 86, wherein the first binding domain comprises a first heavy chain variable domain and a first light chain variable domain, the first heavy chain variable domain linked to a first heavy chain constant region, the first light chain variable domain linked to a first light chain constant region, the second binding domain comprises a second heavy chain variable domain and a second light chain variable domain, the second heavy chain variable domain linked to a second heavy chain constant region, and the second light chain variable domain linked to a second light chain constant region.

88. 88. The bispecific antibody of claim 87, wherein the first heavy chain constant region comprises a knob mutation and the second heavy chain constant region comprises a hole mutation, or the first heavy chain constant region comprises a hole mutation and the second heavy chain constant region comprises a knob mutation.

89. 89. The bispecific antibody of claim 88, wherein the antibody is an IgG1 antibody and the knob mutation comprises a T366W substitution.

90. 90. A bispecific antibody according to claim 88 or claim 89, wherein the antibody is an IgG1 antibody and the hole mutations comprise at least one, at least two / or three substitutions selected from T366S, L368A and Y407V.

91. 91. The bispecific antibody of claim 90, wherein said antibody is an IgG1 antibody and said hole mutations comprise T366S, L368A and Y407V substitutions.

92. 92. The bispecific antibody of any one of claims 87 to 91, wherein the first heavy chain constant region and / or the second heavy chain constant region comprises a N297G substitution (EU numbering).

93. 93. The bispecific antibody of claim 92, wherein the first heavy chain constant region and the second heavy chain constant region each comprise a N297G substitution (EU numbering).

94. A bispecific antibody according to any one of claims 87 to 93, a) the first heavy chain constant region further comprises a S183K substitution (EU numbering), the first light chain constant region comprises a V133E substitution (EU numbering), the second heavy chain constant region further comprises a S183E substitution (EU numbering), and the second light chain constant region comprises a V133K substitution (EU numbering); or b) A bispecific antibody, wherein the first heavy chain constant region further comprises a S183E substitution (EU numbering), the first light chain constant region comprises a V133K substitution (EU numbering), the second heavy chain constant region further comprises a S183K substitution (EU numbering), and the second light chain constant region comprises a V133E substitution (EU numbering).

95. 95. The bispecific antibody of any one of claims 87 to 94, wherein the first heavy chain constant region and / or the second heavy chain constant region further comprises at least one substitution selected from M428L and N434S (EU numbering).

96. 96. The bispecific antibody of claim 95, wherein the first heavy chain constant region and the second heavy chain constant region each further comprise at least one substitution selected from M428L and N434S (EU numbering).

97. 97. The bispecific antibody of claim 96, wherein the first heavy chain constant region and the second heavy chain constant region further comprise M428L and N434S substitutions (EU numbering), respectively.

98. A bispecific antibody according to any one of claims 87 to 97, a) the first heavy chain constant region comprises an amino acid sequence selected from SEQ ID NOs: 96, 184, 98, 186, 117, 188, 119, and 190, and the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 103; the heavy chain constant region comprises an amino acid sequence selected from SEQ ID NOs: 97, 185, 99, 187, 118, 189, 120, and 191, and the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or b) a bispecific antibody, wherein the second heavy chain constant region comprises an amino acid sequence selected from SEQ ID NOs: 96, 184, 98, 186, 117, 188, 119, and 190, the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the first heavy chain constant region comprises an amino acid sequence selected from SEQ ID NOs: 97, 185, 99, 187, 118, 189, 120, and 191, and the first light chain constant region comprises the amino acid sequence of SEQ ID NO:

104.

99. 99. A bispecific antibody according to claim 98, a) the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 96 or 184, the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 97 or 185, and the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or b) the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 98 or 186, the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 99 or 187, and the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or c) the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 96 or 184, the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 97 or 185, and the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or d) the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 98 or 186, the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 99 or 187, and the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or e) the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 118 or 189, the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 117 or 188, and the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or f) the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 120 or 191, the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 119 or 190, and the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or g) the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 118 or 189, the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 117 or 188, and the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or h) A bispecific antibody, wherein the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 120 or 191, the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 119 or 190, and the first light chain constant region comprises the amino acid sequence of SEQ ID NO:

104.

100. A bispecific antibody comprising a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7 and the second binding domain binds to human KLK5, the first binding domain comprising a heavy chain amino acid sequence of SEQ ID NO: 108 or 192 and a light chain amino acid sequence of SEQ ID NO: 109, and the second binding domain comprising a heavy chain amino acid sequence of SEQ ID NO: 110 or 193 and a light chain amino acid sequence of SEQ ID NO:

111.

101. A bispecific antibody comprising a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7 and the second binding domain binds to human KLK5, the first binding domain comprising a heavy chain amino acid sequence of SEQ ID NO: 112 or 194 and a light chain amino acid sequence of SEQ ID NO: 113, and the second binding domain comprising a heavy chain amino acid sequence of SEQ ID NO: 114 or 195 and a light chain amino acid sequence of SEQ ID NO:

115.

102. A bispecific antibody comprising a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7 and the second binding domain binds to human KLK5, the first binding domain comprising a heavy chain amino acid sequence of SEQ ID NO: 108 and a light chain amino acid sequence of SEQ ID NO: 109, and the second binding domain comprising a heavy chain amino acid sequence of SEQ ID NO: 110 and a light chain amino acid sequence of SEQ ID NO:

111.

103. A bispecific antibody comprising a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7 and the second binding domain binds to human KLK5, the first binding domain comprising a heavy chain amino acid sequence of SEQ ID NO: 112 and a light chain amino acid sequence of SEQ ID NO: 113, and the second binding domain comprising a heavy chain amino acid sequence of SEQ ID NO: 114 and a light chain amino acid sequence of SEQ ID NO:

115.

104. A bispecific antibody comprising a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7 and the second binding domain binds to human KLK5, and the second binding domain is a) a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (b) a CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 40 and 41, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 43 or 44, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (f) a CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 46-49; or b) a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising an amino acid sequence selected from SEQ ID NOs: 39 and 107, (b) a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 41, and (c) a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 42, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising an amino acid sequence selected from SEQ ID NOs: 43 and 44, (e) a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 45, and (f) a CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 46-49; or c) a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 39 or 107, (b) a CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 40 and 41, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 44, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (f) a CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 46-49; or d) a heavy chain variable domain (VH) comprising: (a) a CDR-H1 comprising an amino acid sequence selected from SEQ ID NOs: 39 and 107; (b) a CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 40 and 41; and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42; and a light chain variable domain (VL) comprising: (d) a CDR-L1 comprising an amino acid sequence selected from SEQ ID NOs: 43 and 44; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45; and (f) a CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 47-49; or e) a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:68, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO:70, and (c) a CDR-H3 comprising an amino acid sequence selected from SEQ ID NOs:71 and 72, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO:73, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO:74, and (f) a CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs:75-78; or f) a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:68, (b) a CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs:69 and 70, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO:72, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO:73, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO:74, and (f) a CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs:75-78; or g) an antibody comprising a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:68, (b) a CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs:69 and 70, and (c) a CDR-H3 comprising an amino acid sequence selected from SEQ ID NOs:71 and 72, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO:73, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO:74, and (f) a CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs:76-78.

105. 105. The bispecific antibody of claim 104, wherein the second binding domain comprises a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 39, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 41, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 43, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:

47.

106. 105. The bispecific antibody of claim 104, wherein the second binding domain comprises a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 68, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 70, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 72, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 73, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 74, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:

76.

107. The bispecific antibody of any one of claims 104 to 106, wherein the second binding domain is humanized.

108. The bispecific antibody of any one of claims 104 to 107, wherein the second binding domain comprises a sequence selected from: a) a VH sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 50, 52, 53, 105 and 106; b) a VL sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 51 and 54-67; and c) the VH sequence defined in (a) and the VL sequence defined in (b); d) a VH sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 79 and 81-87; e) a VL sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 80 and 88-94; and f) The VH sequence defined in (d) and the VL sequence defined in (e).

109. The bispecific antibody of any one of claims 104 to 107, wherein the second binding domain comprises a sequence selected from: a) a VH sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 52, 53, 105 and 106; b) a VL sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 54-67; and c) the VH sequence defined in (a) and the VL sequence defined in (b); d) a VH sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 81-87; e) a VL sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 88-94; and f) The VH sequence defined in (d) and the VL sequence defined in (e).

110. The bispecific antibody of any one of claims 104 to 107, wherein the second binding domain comprises a sequence selected from: a) a VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 50, 52, 53, 105, and 106; b) a VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 51 and 54-67; and c) the VH sequence defined in (a) and the VL sequence defined in (b); d) a VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 79 and 81-87; e) a VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 80 and 88-94; and f) The VH sequence defined in (d) and the VL sequence defined in (e).

111. The bispecific antibody of any one of claims 104 to 107, wherein the second binding domain comprises a sequence selected from: a) a VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 52, 53, 105, and 106; b) a VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 54-67; and c) the VH sequence defined in (a) and the VL sequence defined in (b); d) a VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 81-87; e) a VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 88-94; and f) The VH sequence defined in (d) and the VL sequence defined in (e).

112. The bispecific antibody according to any one of claims 104 to 107, wherein the latter half of the amino acid antibody comprises the VH sequence of SEQ ID NO: 52 or SEQ ID NO: 53, and the VL amino acid sequence of SEQ ID NO: 55 or SEQ ID NO:

62.

113. The bispecific antibody of claim 112, wherein the latter half of the amino acid antibody comprises the VH sequence of SEQ ID NO: 52 and the VL amino acid sequence of SEQ ID NO: 55, or the VH sequence of SEQ ID NO: 53 and the VL amino acid sequence of SEQ ID NO:

62.

114. The bispecific antibody of any one of claims 104 to 113, wherein the first binding domain is humanized.

115. 115. The bispecific antibody of any one of claims 104 to 114, wherein the first binding domain comprises a first heavy chain variable domain and a first light chain variable domain, the first heavy chain variable domain linked to a first heavy chain constant region, the first light chain variable domain linked to a first light chain constant region, the second binding domain comprises a second heavy chain variable domain and a second light chain variable domain, the second heavy chain variable domain linked to a second heavy chain constant region, and the second light chain variable domain linked to a second light chain constant region.

116. The bispecific antibody of claim 115, wherein the first heavy chain constant region comprises a knob mutation and the second heavy chain constant region comprises a hole mutation, or the first heavy chain constant region comprises a hole mutation and the second heavy chain constant region comprises a knob mutation.

117. 117. The bispecific antibody of claim 116, wherein the antibody is an IgG1 antibody and the knob mutation comprises a T366W mutation.

118. 118. The bispecific antibody of claim 116 or 117, wherein the antibody is an IgG1 antibody and the hole mutations comprise at least one, at least two / or three mutations selected from T366S, L368A and Y407V.

119. The bispecific antibody of claim 118, wherein the antibody is an IgG1 antibody and the hole mutations include T366S, L368A and Y407V mutations.

120. 120. The bispecific antibody of any one of claims 115 to 119, wherein the first heavy chain constant region and / or the second heavy chain constant region comprises a N297G substitution (EU numbering).

121. 121. The bispecific antibody of claim 120, wherein the first heavy chain constant region and the second heavy chain constant region each comprise a N297G substitution (EU numbering).

122. A bispecific antibody according to any one of claims 115 to 121, a) the first heavy chain constant region further comprises a S183K substitution (EU numbering), the first light chain constant region comprises a V133E substitution (EU numbering), the second heavy chain constant region further comprises a S183E substitution (EU numbering), and the second light chain constant region comprises a V133K substitution (EU numbering); or b) A bispecific antibody, wherein the first heavy chain constant region further comprises a S183E substitution (EU numbering), the first light chain constant region comprises a V133K substitution (EU numbering), the second heavy chain constant region further comprises a S183K substitution (EU numbering), and the second light chain constant region comprises a V133E substitution (EU numbering).

123. 123. The bispecific antibody of any one of claims 115 to 122, wherein the first heavy chain constant region and / or the second heavy chain constant region further comprises at least one substitution selected from M428L and N434S (EU numbering).

124. 124. The bispecific antibody of claim 123, wherein the first heavy chain constant region and the second heavy chain constant region each further comprise at least one substitution selected from M428L and N434S (EU numbering).

125. 125. The bispecific antibody of claim 124, wherein the first heavy chain constant region and the second heavy chain constant region further comprise M428L and N434S substitutions, respectively (EU numbering).

126. A bispecific antibody according to any one of claims 115 to 125, a) the first heavy chain constant region comprises an amino acid sequence selected from SEQ ID NOs: 96, 184, 98, 186, 117, 188, 119, and 190, and the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 103; the heavy chain constant region comprises an amino acid sequence selected from SEQ ID NOs: 97, 185, 99, 187, 118, 189, 120, and 191, and the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or b) a bispecific antibody, wherein the second heavy chain constant region comprises an amino acid sequence selected from SEQ ID NOs: 96, 184, 98, 186, 117, 188, 119, and 190, the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the first heavy chain constant region comprises an amino acid sequence selected from SEQ ID NOs: 97, 185, 99, 187, 118, 189, 120, and 191, and the first light chain constant region comprises the amino acid sequence of SEQ ID NO:

104.

127. 127. The bispecific antibody of claim 126, a) the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 96 or 184, the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 97 or 185, and the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or b) the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 98 or 186, the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 99 or 187, and the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or c) the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 96 or 184, the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 97 or 185, and the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or d) the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 98 or 186, the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 99 or 187, and the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or e) the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 118 or 189, the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 117 or 188, and the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or f) the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 120 or 191, the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 119 or 190, and the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or g) the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 118 or 189, the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 117 or 188, and the first light chain constant region comprises the amino acid sequence of SEQ ID NO: 104; or h) A bispecific antibody, wherein the second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 120 or 191, the second light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, the first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 119 or 190, and the first light chain constant region comprises the amino acid sequence of SEQ ID NO:

104.

128. K of less than 60 pM, less than 30 pM, less than 20 pM, less than 10 pM, or less than 5 pM as measured by surface plasmon resonance. Ｄ The bispecific antibody of any one of claims 69 to 127, which binds to human KLK5 at the C3 domain.

129. 129. The bispecific antibody of any one of claims 69 to 128, which inhibits human KLK5 protease activity with an IC50 of less than 5 nM, or less than 3 nM, or less than 2 nM, or less than 1 nM.

130. K of less than 60 pM, less than 30 pM, less than 20 pM, less than 10 pM, or less than 5 pM as measured by surface plasmon resonance. Ｄ and inhibits human KLK5 protease activity with an IC50 of less than 5 nM, or less than 3 nM, or less than 2 nM, or less than 1 nM.

131. The bispecific antibody of claim 129 or claim 130, wherein the inhibition of human KLK5 protease activity is inhibition of human KLK5-mediated cleavage of the substrate Boc-Val-Pro-Arg-AMC.

132. A K of less than 20 pM, or less than 15 pM, or less than 10 pM, or less than 5 pM, or less than 3 pM, or less than 2 pM, or less than 1 pM as measured by surface plasmon resonance. Ｄ The antibody of any one of claims 69 to 131, which binds to human KLK7 at

133. 133. The bispecific antibody of any one of claims 69 to 132, which inhibits human KLK7 protease activity with an IC50 of less than 5 nM, or less than 3 nM, or less than 2 nM, or less than 1 nM.

134. A K of less than 20 pM, or less than 15 pM, or less than 10 pM, or less than 5 pM, or less than 3 pM, or less than 2 pM, or less than 1 pM as measured by surface plasmon resonance. Ｄ and inhibits human KLK7 protease activity with an IC50 of less than 5 nM, or less than 3 nM, or less than 2 nM, or less than 1 nM.

135. 135. The bispecific antibody of claim 133 or claim 134, wherein the inhibition of human KLK7 protease activity is inhibition of human KLK7-mediated cleavage of a substrate comprising the amino acid sequence RPKPVE-Nval-WRK (SEQ ID NO: 121), wherein Nval is norvaline.

136. The K of the bispecific antibody against human KLK5 Ｄ and the K of said antibody against human KLK7 Ｄ are within 3-fold, or within 2.5-fold, or within 2-fold, or within 1.5-fold of each other.

137. 137. An isolated nucleic acid encoding a bispecific antibody according to any one of claims 69 to 136.

138. 137. An isolated nucleic acid encoding the first binding domain of the bispecific antibody of any one of claims 69 to 136.

139. 137. An isolated nucleic acid encoding the second binding domain of the bispecific antibody of any one of claims 69 to 136.

140. 138. An isolated host cell comprising the isolated nucleic acid of claim 137.

141. 139. An isolated host cell comprising the isolated nucleic acid of claim 138.

142. 140. An isolated host cell comprising the isolated nucleic acid of claim 139.

143. An isolated host cell expressing a bispecific antibody according to any one of claims 69 to 136.

144. 137. An isolated host cell expressing the first binding domain of the bispecific antibody of any one of claims 69 to 136.

145. 137. An isolated host cell expressing the second binding domain of the bispecific antibody of any one of claims 69 to 136.

146. A method for producing a bispecific antibody that binds to human KLK5 and human KLK7, comprising culturing a host cell according to claim 140 or claim 143 under conditions suitable for expression of the antibody.

147. 147. The method of claim 146, further comprising recovering the antibody from the host cell.

148. A method for producing a bispecific antibody that binds to human KLK5 and human KLK7, comprising: (i) culturing a host cell described in claim 141 or claim 144 under conditions suitable for expression of the first binding domain; and (ii) culturing a host cell described in claim 142 or claim 145 under conditions suitable for expression of the second binding domain.

149. 149. The method of claim 148, further comprising recovering the first binding domain and the second binding domain and constructing the bispecific antibody.

150. A pharmaceutical composition comprising the antibody of any one of claims 1 to 27 and a pharma- ceutically acceptable carrier.

151. 151. The pharmaceutical composition of claim 150, further comprising an additional therapeutic agent.

152. The pharmaceutical composition of claim 151, wherein the additional therapeutic agent is a KLK5 inhibitor.

153. The pharmaceutical composition of claim 152, wherein the KLK5 inhibitor is an anti-KLK5 antibody.

154. 154. The pharmaceutical composition of claim 153, wherein the anti-KLK5 antibody is a) a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising an amino acid sequence selected from SEQ ID NOs: 39 and 107, (b) a CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 40 and 41, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising an amino acid sequence selected from SEQ ID NOs: 43 and 44, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (f) a CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 46-49; or b) a pharmaceutical composition comprising a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:68, (b) a CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs:69 and 70, and (c) a CDR-H3 comprising an amino acid sequence selected from SEQ ID NOs:71 and 72, and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO:73, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO:74, and (f) a CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs:75-78.

155. The pharmaceutical composition of claim 153 or claim 154, wherein the anti-KLK5 antibody comprises a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 39, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 41, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 43, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:

47.

156. The pharmaceutical composition of claim 153 or claim 154, wherein the anti-KLK5 antibody comprises a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:68, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:70, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:72, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:73, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:74, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:

76.

157. The pharmaceutical composition of any one of claims 153 to 156, wherein the anti-KLK5 antibody is a monoclonal antibody.

158. The pharmaceutical composition of any one of claims 153 to 157, wherein the anti-KLK5 antibody is a humanized or chimeric antibody.

159. The pharmaceutical composition of any one of claims 153 to 158, wherein the anti-KLK5 antibody is an antibody fragment that binds to human KLK5.

160. The pharmaceutical composition of any one of claims 153 to 159, wherein the anti-KLK5 antibody comprises a sequence selected from: a) a VH sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 50, 52, 53, 105 and 106; b) a VL sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 51 and 54-67; and c) the VH sequence defined in (a) and the VL sequence defined in (b); d) a VH sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 79 and 81-87; e) a VL sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 80 and 88-94; and f) The VH sequence defined in (d) and the VL sequence defined in (e).

161. The pharmaceutical composition of any one of claims 153 to 159, wherein the anti-KLK5 antibody comprises a sequence selected from: a) a VH sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 52, 53, 105 and 106; b) a VL sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 54-67; and c) the VH sequence defined in (a) and the VL sequence defined in (b); d) a VH sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 81-87; e) a VL sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 88-94; and f) The VH sequence defined in (d) and the VL sequence defined in (e).

162. The pharmaceutical composition of any one of claims 153 to 159, wherein the anti-KLK5 antibody comprises a sequence selected from: a) a VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 50, 52, 53, 105, and 106; b) a VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 51 and 54-67; and c) the VH sequence defined in (a) and the VL sequence defined in (b); d) a VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 79 and 81-87; e) a VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 80 and 88-94; and f) The VH sequence defined in (d) and the VL sequence defined in (e).

163. The pharmaceutical composition of any one of claims 153 to 159, wherein the anti-KLK5 antibody comprises a sequence selected from: a) a VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 52, 53, 105, and 106; b) a VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 54-67; and c) the VH sequence defined in (a) and the VL sequence defined in (b); d) a VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 81-87; e) a VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 88-94; and f) The VH sequence defined in (d) and the VL sequence defined in (e).

164. The pharmaceutical composition of claim 153, wherein the anti-KLK5 antibody is an antibody according to any one of claims 34 to 62.

165. The pharmaceutical composition of claim 153, wherein the anti-KLK5 antibody is an antibody described in any one of claims 47, 48, 51, and 52.

166. A pharmaceutical composition comprising the antibody of any one of claims 34 to 62 and a pharma- ceutically acceptable carrier.

167. The pharmaceutical composition of claim 166, further comprising an additional therapeutic agent.

168. The pharmaceutical composition of claim 167, wherein the additional therapeutic agent is a KLK7 inhibitor.

169. The pharmaceutical composition of claim 168, wherein the KLK7 inhibitor is an anti-KLK7 antibody.

170. The pharmaceutical composition of claim 169, wherein the anti-KLK7 antibody is an antibody according to any one of claims 1 to 27.

171. A pharmaceutical composition comprising an antibody according to any one of claims 1 to 27, an antibody according to any one of claims 34 to 62, and a pharma- ceutically acceptable carrier.

172. 172. The pharmaceutical composition of any one of claims 150 to 171, comprising an additional therapeutic agent selected from an anti-inflammatory agent and an antibiotic.

173. A pharmaceutical composition comprising a bispecific antibody according to any one of claims 69 to 136.

174. The pharmaceutical composition of claim 173, further comprising an additional therapeutic agent.

175. The pharmaceutical composition of claim 174, wherein the additional therapeutic agent is an anti-inflammatory agent.

176. 176. The pharmaceutical composition of any one of claims 150 to 175, for topical administration.

177. The pharmaceutical composition according to any one of claims 150 to 175, for subcutaneous or intravenous administration.

178. An antibody according to any one of claims 1 to 27 and 34 to 62, a bispecific antibody according to any one of claims 69 to 136, or a pharmaceutical composition according to any one of claims 150 to 177, for use as a medicament.

179. An antibody according to any one of claims 1 to 27 and 34 to 62, a bispecific antibody according to any one of claims 69 to 136, or a pharmaceutical composition according to any one of claims 150 to 177, for use in the treatment of a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis and rosacea.

180. 180. The antibody, bispecific antibody or pharmaceutical composition for use according to claim 179, wherein the asthma is selected from atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin-sensitive / exacerbated asthma, mild asthma, moderate-to-severe asthma, corticosteroid-naive asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, newly diagnosed untreated asthma, smoking-induced asthma, corticosteroid-uncontrolled asthma, T helper lymphocyte type 2 (Th2) asthma or type 2 (Th2) high asthma or type 2 (T2) driven asthma, eosinophilic asthma, periostin high asthma, high eosinophilic asthma, Th2 low or non-Th2 driven asthma, periostin low asthma, and low eosinophilic asthma.

181. The antibody, bispecific antibody or pharmaceutical composition for use according to claim 180, wherein the asthma is hypoeosinophilic asthma.

182. A combination of an antibody according to any one of claims 1 to 27 with an antibody according to any one of claims 34 to 62 for use as a medicament.

183. A combination of an antibody according to any one of claims 1 to 27 with an antibody according to any one of claims 34 to 62 for use in the treatment of a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis and rosacea.

184. 184. The combination for use of claim 183, wherein the asthma is selected from atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin-sensitive / exacerbated asthma, mild asthma, moderate-to-severe asthma, corticosteroid-naive asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, newly diagnosed untreated asthma, smoking-induced asthma, corticosteroid-uncontrolled asthma, T helper lymphocyte type 2 (Th2) asthma or type 2 (Th2) high asthma or type 2 (T2) driven asthma, eosinophilic asthma, periostin high asthma, high eosinophilic asthma, Th2 low or non-Th2 driven asthma, periostin low asthma, and low eosinophilic asthma.

185. The combination of claim 184, wherein the asthma is hypoeosinophilic asthma.

186. Use of an antibody according to any one of claims 1 to 27 and 34 to 62, a bispecific antibody according to any one of claims 69 to 136, or a pharmaceutical composition according to any one of claims 150 to 177 in the manufacture of a medicament for the treatment of a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis and rosacea.

187. 187. The use of claim 186, wherein the asthma is selected from atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin-sensitive / exacerbated asthma, mild asthma, moderate-to-severe asthma, corticosteroid-naive asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, newly diagnosed untreated asthma, smoking-induced asthma, corticosteroid-uncontrolled asthma, T helper lymphocyte type 2 (Th2) asthma or type 2 (Th2) high asthma or type 2 (T2) driven asthma, eosinophilic asthma, periostin high asthma, high eosinophilic asthma, Th2 low or non-Th2 driven asthma, periostin low asthma, and low eosinophilic asthma.

188. The use of claim 187, wherein the asthma is hypoeosinophilic asthma.

189. Use of a combination of an antibody according to any one of claims 1 to 27 and an antibody according to any one of claims 34 to 62 in the manufacture of a medicament for treating a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis and rosacea.

190. 190. The use of claim 189, wherein the asthma is selected from atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin-sensitive / exacerbated asthma, mild asthma, moderate-to-severe asthma, corticosteroid-naive asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, newly diagnosed untreated asthma, smoking-induced asthma, corticosteroid-uncontrolled asthma, T helper lymphocyte type 2 (Th2) asthma or type 2 (Th2) high asthma or type 2 (T2) driven asthma, eosinophilic asthma, periostin high asthma, high eosinophilic asthma, Th2 low or non-Th2 driven asthma, periostin low asthma, and low eosinophilic asthma.

191. The use of claim 190, wherein the asthma is hypoeosinophilic asthma.

192. Use of an antibody according to any one of claims 1 to 27 and 34 to 62, a bispecific antibody according to any one of claims 69 to 136, or a pharmaceutical composition according to any one of claims 150 to 177 in the manufacture of a medicament for reducing epithelial inflammation, for reducing epithelial permeability, for reducing transepidermal water loss, for reducing skin infiltration, for reducing parakeratinization, for restoring the epithelial barrier and / or for reducing skin inflammatory cytokines.

193. Use of a combination of an antibody according to any one of claims 1 to 27 and an antibody according to any one of claims 34 to 62 in the manufacture of a medicament for reducing epithelial inflammation, for reducing epithelial permeability, for reducing transepidermal water loss, for reducing skin infiltration, for reducing parakeratinization, for restoring the epithelial barrier and / or for reducing skin inflammatory cytokines.

194. A method of treating an individual having a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis and rosacea, comprising administering to said individual an effective amount of an antibody according to any one of claims 1 to 27 and 34 to 62, a bispecific antibody according to any one of claims 69 to 136 or a pharmaceutical composition according to any one of claims 150 to 177.

195. 11. A method of treating an individual having a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis and rosacea, comprising administering to the individual: a) an effective amount of an antibody according to any one of claims 1 to 27; and b) an effective amount of an antibody according to any one of claims 34 to 62.

196. The method of claim 195, wherein the antibody of (a) and the antibody of (b) are administered simultaneously.

197. The method of claim 195, wherein the antibody of (a) and the antibody of (b) are administered sequentially.

198. 19. A method of treating an individual having a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis and rosacea, comprising administering to said individual an effective amount of a bispecific antibody according to any one of claims 69 to 136, or an effective amount of a pharmaceutical composition according to any one of claims 150 to 177.

199. 200. The method of any one of claims 194 to 198, wherein the asthma is selected from atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin-sensitive / exacerbated asthma, mild asthma, moderate-to-severe asthma, corticosteroid-naive asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, newly diagnosed untreated asthma, smoking-induced asthma, corticosteroid-uncontrolled asthma, T helper lymphocyte type 2 (Th2) asthma or type 2 (Th2) high asthma, or type 2 (T2) driven asthma, eosinophilic asthma, periostin high asthma, eosinophilic asthma, Th2 low or non-Th2 driven asthma, periostin low asthma, and hypoeosinophilic asthma.

200. 200. The method of claim 199, wherein the asthma is hypoeosinophilic asthma.

201. 200. The method of any one of claims 194 to 198, wherein the individual has Netherton Syndrome.

202. 200. The method of any one of claims 194 to 198, wherein the individual has rosacea.

203. 203. The method of any one of claims 194-202, further comprising administering to the individual an additional therapeutic agent.

204. The method of claim 203, wherein the additional therapeutic agent is an anti-inflammatory agent.

205. 176. A method for reducing epithelial inflammation, reducing epithelial permeability, reducing transepidermal water loss, reducing skin infiltration, reducing parakeratinization, restoring the epithelial barrier and / or reducing skin inflammatory cytokines in an individual, comprising administering to said individual an effective amount of an antibody according to any one of claims 1 to 27 and 34 to 62, a bispecific antibody according to any one of claims 69 to 136 or a pharmaceutical composition according to any one of claims 150 to 177 to reduce epithelial inflammation, reduce epithelial permeability, reduce transepidermal water loss, reduce skin infiltration, reduce parakeratinization and / or restore the epithelial barrier.

206. 11. A method for reducing epithelial inflammation, reducing epithelial permeability, reducing transepidermal water loss, reducing skin infiltration, reducing parakeratinization, restoring the epithelial barrier, and / or reducing skin inflammatory cytokines in an individual, comprising administering to the individual: a) an effective amount of an antibody described in any one of claims 1 to 27; and b) an effective amount of an antibody described in any one of claims 34 to 62, thereby reducing epithelial inflammation, reducing epithelial permeability, reducing transepidermal water loss, reducing skin infiltration, reducing parakeratinization, and / or restoring the epithelial barrier.

207. The method of claim 206, wherein the antibody described in (a) and the antibody described in (b) are administered simultaneously.

208. The method of claim 206, wherein the antibody described in (a) and the antibody described in (b) are administered sequentially.

209. 176. A method of reducing epithelial inflammation, reducing epithelial permeability, reducing transepidermal water loss, reducing skin infiltration, reducing parakeratinization and / or restoring the epithelial barrier in an individual, comprising administering to said individual a bispecific antibody according to any one of claims 69 to 136, or an effective amount of a pharmaceutical composition according to any one of claims 150 to 177, to reduce epithelial inflammation, reduce epithelial permeability, reduce transepidermal water loss, reducing skin infiltration, reducing parakeratinization and / or restoring the epithelial barrier.

210. The method of any one of claims 194 to 209, wherein said administration is subcutaneous or intravenous.

211. The method of any one of claims 194 to 209, wherein said administering is topical.

212. The method of any one of claims 194 to 209, wherein the administration is intravenous.

213. An isolated antibody that binds to human KLK7, which upon binding to human KLK7 causes a conformational change in human KLK7, and which allosterically results in the destruction of the substrate binding site and / or active site of human KLK7.

214. 214. The isolated antibody of claim 213, which is a bispecific antibody.

215. The isolated antibody of claim 214, wherein the bispecific antibody binds to human KLK7 and human KLK5.

216. The isolated antibody of claim 215, which upon binding to human KLK5, causes a conformational change in human KLK5, and said conformational change allosterically results in the disruption of the substrate binding site and / or the active site of human KLK5.

217. 217. The isolated antibody of claim 216, which binds to an epitope on human KLK5 that includes one or more amino acid residues selected from Pro130, Ser131, Ala132, Gly133, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Gln174A, Ile176, Asp177, Asp178, Gly184, Asp185, Lys186, Ala186A, Arg188, Asn223, Arg224, Pro225, and Lys233, according to standard protease numbering.

218. The isolated antibody of claim 217, which binds to an epitope on human KLK5 that contains one or more amino acid residues selected from the group consisting of Pro130, Ser131, Ala132, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Gln174A, Ile176, Asp177, Asp178, Arg224, and Lys233, according to standard protease numbering.

219. The isolated antibody of claim 217, which binds to an epitope on human KLK5 that includes one or more amino acid residues selected from Pro130, Ser131, Ala132, Gly133, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Gln174A, Ile176, Asp177 and Lys233, according to standard protease numbering.

220. The isolated antibody of claim 217, which binds to an epitope on human KLK5 that includes one or more amino acid residues selected from Ser131, Ala132, Gly133, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Pro173, Arg174, Gly184, Asp185, Lys186, Ala186A, Arg188, Asn223, Arg224 and Pro225 according to standard protease numbering.

221. 221. The isolated antibody of any one of claims 213-220, which binds to an epitope within amino acids R71-N82, K152-S158 and / or Q211-K222 of KLK7 (SEQ ID NO:4).

222. 222. The isolated antibody of any one of claims 213-221, which binds to an epitope comprising one or more of amino acids H72, P73, G74, S76, Q78, N82, N157, K211 and / or T213 of KLK7 (SEQ ID NO:4).

223. A bispecific antibody comprising a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7 and the second binding domain binds to human KLK5, and upon binding to human KLK7, causes a conformational change in human KLK7, and the conformational change allosterically results in the destruction of the substrate binding site and / or active site of human KLK7.

224. The bispecific antibody of claim 223, which upon binding to human KLK5, induces a conformational change in human KLK5, and said conformational change allosterically results in the disruption of the substrate binding site and / or active site of human KLK5.

225. A bispecific antibody comprising a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7 and the second binding domain binds to human KLK5, and upon binding to human KLK5, causes a conformational change in human KLK5, and the conformational change allosterically results in the destruction of the substrate binding site and / or active site of human KLK5.

226. 226. The bispecific antibody of claim 224 or claim 225, which binds to an epitope on human KLK5 comprising one or more amino acid residues selected from Pro130, Ser131, Ala132, Gly133, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Gln174A, Ile176, Asp177, Asp178, Gly184, Asp185, Lys186, Ala186A, Arg188, Asn223, Arg224, Pro225 and Lys233 according to standard protease numbering.

227. The isolated antibody of claim 226, which binds to an epitope on human KLK5 that contains one or more amino acid residues selected from the group consisting of Pro130, Ser131, Ala132, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Gln174A, Ile176, Asp177, Asp178, Arg224, and Lys233, according to standard protease numbering.

228. The isolated antibody of claim 226, which binds to an epitope on human KLK5 that includes one or more amino acid residues selected from Pro130, Ser131, Ala132, Gly133, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Gln174A, Ile176, Asp177 and Lys233, according to standard protease numbering.

229. The isolated antibody of claim 226, which binds to an epitope on human KLK5 that includes one or more amino acid residues selected from Ser131, Ala132, Gly133, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Pro173, Arg174, Gly184, Asp185, Lys186, Ala186A, Arg188, Asn223, Arg224 and Pro225 according to standard protease numbering.

230. 230. The bispecific antibody of any one of claims 223 to 229, which binds to an epitope within amino acids R71 to N82, K152 to S158 and / or Q211 to K222 of KLK7 (SEQ ID NO: 4).

231. 231. The bispecific antibody of any one of claims 223 to 230, which binds to an epitope comprising one or more of amino acids H72, P73, G74, S76, Q78, N82, N157, K211 and / or T213 of KLK7 (SEQ ID NO: 4).

232. A pharmaceutical composition comprising an antibody according to any one of claims 213 to 222 and a pharma- ceutically acceptable carrier.

233. 232. A pharmaceutical composition comprising the bispecific antibody of any one of claims 223 to 231 and a pharma- ceutically acceptable carrier.

234. An antibody according to any one of claims 213 to 222, a bispecific antibody according to any one of claims 223 to 231 or a pharmaceutical composition according to claim 232 or claim 233 for use as a medicament.

235. An antibody according to any one of claims 213 to 222, a bispecific antibody according to any one of claims 223 to 231, or a pharmaceutical composition according to claim 232 or claim 233, for use in the treatment of a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis and rosacea.

236. 236. The antibody, bispecific antibody or pharmaceutical composition of claim 235, wherein the asthma is selected from atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin-sensitive / exacerbated asthma, mild asthma, moderate-to-severe asthma, corticosteroid-naive asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, newly diagnosed untreated asthma, smoking-induced asthma, corticosteroid-uncontrolled asthma, T helper lymphocyte type 2 (Th2) asthma or type 2 (Th2) high asthma or type 2 (T2) driven asthma, eosinophilic asthma, periostin high asthma, high eosinophilic asthma, Th2 low or non-Th2 driven asthma, periostin low asthma, and low eosinophilic asthma.

237. The antibody of any one of claims 213 to 222, the bispecific antibody of any one of claims 223 to 231 or the pharmaceutical composition of claim 232 or claim 233 for use in reducing epidermal inflammation, reducing epithelial permeability, reducing transepidermal water loss, reducing skin infiltration, reducing parakeratinization, restoring the epithelial barrier and / or reducing skin inflammatory cytokines.

238. Use of an antibody according to any one of claims 213 to 222, a bispecific antibody according to any one of claims 223 to 231, or a pharmaceutical composition according to claim 232 or claim 233, in the manufacture of a medicament for the treatment of a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis and rosacea.

239. 239. The use of claim 238, wherein the asthma is selected from atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin-sensitive / exacerbated asthma, mild asthma, moderate-to-severe asthma, corticosteroid-naive asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, newly diagnosed untreated asthma, smoking-induced asthma, corticosteroid-uncontrolled asthma, T helper lymphocyte type 2 (Th2) asthma or type 2 (Th2) high asthma or type 2 (T2) driven asthma, eosinophilic asthma, periostin high asthma, high eosinophilic asthma, Th2 low or non-Th2 driven asthma, periostin low asthma, and low eosinophilic asthma.

240. Use of an antibody according to any one of claims 213 to 222, a bispecific antibody according to any one of claims 223 to 231 or a pharmaceutical composition according to claim 232 or claim 233 in the manufacture of a medicament for reducing epithelial inflammation, for reducing epithelial permeability, for reducing transepidermal water loss, for reducing skin infiltration, for reducing parakeratinization, for restoring the epithelial barrier and / or for reducing skin inflammatory cytokines.

241. A method of treating an individual having a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis and rosacea, comprising administering to said individual an effective amount of an antibody according to any one of claims 213 to 222, a bispecific antibody according to any one of claims 223 to 231, or a pharmaceutical composition according to claim 232 or claim 233.

242. 242. The method of claim 241, wherein the asthma is selected from atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin-sensitive / exacerbated asthma, mild asthma, moderate-to-severe asthma, corticosteroid-naive asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, newly diagnosed untreated asthma, smoking-induced asthma, corticosteroid-uncontrolled asthma, T helper lymphocyte type 2 (Th2) asthma or type 2 (Th2) high asthma or type 2 (T2) driven asthma, eosinophilic asthma, periostin high asthma, eosinophilic asthma, Th2 low or non-Th2 driven asthma, periostin low asthma, and hypoeosinophilic asthma.

243. 233。 Method for reducing epithelial inflammation, reducing epithelial permeability, reducing transepidermal water loss, reducing skin infiltration, reducing parakeratinization, restoring the epithelial barrier and / or reducing skin inflammatory cytokines in an individual, comprising administering to the individual an effective amount of an antibody according to any one of claims 213 to 222, a bispecific antibody according to any one of claims 223 to 231, or a pharmaceutical composition according to claim 232 or claim 233, to reduce epithelial inflammation, reduce epithelial permeability, reduce transepidermal water loss, reduce skin infiltration, reduce parakeratinization and / or restore the epithelial barrier.

244. The antibody, bispecific antibody or pharmaceutical composition for use according to claim 179 or claim 235, wherein the disease is Netherton Syndrome.

245. The combination for use according to claim 183, wherein the disease is Netherton Syndrome.

246. The use according to any one of claims 186, 189 and 238, wherein the disease is Netherton Syndrome.

247. The use of any one of claims 192, 193 and 240, wherein the medicament is for reducing epidermal inflammation, reducing epithelial permeability, reducing transepidermal water loss, reducing skin infiltration, reducing parakeratinization, restoring the epithelial barrier, and / or reducing skin inflammatory cytokines in an individual.

248. 1. A bispecific antibody for use in the treatment of Netherton syndrome, comprising a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7 and the second binding domain binds to human KLK5, the first binding domain comprising a heavy chain amino acid sequence of SEQ ID NO: 112 or 194 and a light chain amino acid sequence of SEQ ID NO: 113, and the second binding domain comprising a heavy chain amino acid sequence of SEQ ID NO: 114 or 195 and a light chain amino acid sequence of SEQ ID NO:

115.

249. 1. An anti-KLK5 antibody for use in treating Netherton syndrome, comprising: (a) the VH sequence of SEQ ID NO:52 and the VL sequence of SEQ ID NO:55; or (b) the VH sequence of SEQ ID NO:53 and the VL sequence of SEQ ID NO:

62.

250. An anti-KLK7 antibody for use in treating Netherton syndrome, comprising: (a) the VH sequence of SEQ ID NO:29 and the VL sequence of SEQ ID NO:32; or (b) the VH sequence of SEQ ID NO:30 and the VL sequence of SEQ ID NO:

38.

251. An antibody combination for use in the treatment of Netherton syndrome, comprising an anti-KLK5 antibody and an anti-KLK7 antibody, wherein the anti-KLK5 antibody comprises a VH sequence of SEQ ID NO:52 and a VL sequence of SEQ ID NO:55, or a VH sequence of SEQ ID NO:53 and a VL sequence of SEQ ID NO:62, and the anti-KLK7 antibody comprises a VH sequence of SEQ ID NO:29 and a VL sequence of SEQ ID NO:32, or a VH sequence of SEQ ID NO:30 and a VL sequence of SEQ ID NO:

38.

252. 1. A method of treating an individual having a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis and rosacea, comprising administering to the individual an effective amount of the bispecific antibody, wherein the bispecific antibody comprises a first binding domain and a second binding domain, wherein the first binding domain binds to human KLK7 and inhibits KLK7 protease activity, and the second binding domain binds to human KLK5 and inhibits KLK5 protease activity.

253. A method of treating an individual having a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis and rosacea, comprising administering to the individual an anti-KLK5 antibody and an anti-KLK7 antibody, wherein the anti-KLK5 antibody inhibits KLK5 protease activity and the anti-KLK7 antibody inhibits KLK7 protease activity.

254. A method for reducing epithelial inflammation, reducing epithelial permeability, reducing transepidermal water loss, reducing skin infiltration, reducing parakeratinization, restoring the epithelial barrier, and / or reducing skin inflammatory cytokines in an individual, comprising administering to the individual a KLK5 antagonist and a KLK7 antagonist.

255. The method of claim 254, wherein the KLK5 antagonist is an anti-KLK5 antibody and / or the KLK7 antagonist is an anti-KLK7 antibody.

256. A method of reducing epithelial inflammation, reducing epithelial permeability, reducing transepidermal water loss, reducing skin infiltration, reducing parakeratinization, restoring the epithelial barrier, and / or reducing skin inflammatory cytokines in an individual, comprising administering to the individual an effective amount of a bispecific antibody, the bispecific antibody comprising a first binding domain and a second binding domain, the first binding domain binds to human KLK7 and inhibits KLK7 protease activity, and the second binding domain binds to human KLK5 and inhibits KLK5 protease activity.

257. A method for reducing epithelial inflammation, reducing epithelial permeability, reducing transepidermal water loss, reducing skin infiltration, reducing parakeratinization, restoring the epithelial barrier, and / or reducing skin inflammatory cytokines in an individual, comprising administering to the individual an anti-KLK5 antibody and an anti-KLK7 antibody, wherein the anti-KLK5 antibody inhibits KLK5 protease activity and the anti-KLK7 antibody inhibits KLK7 protease activity.

258. A method of ameliorating skin rash and / or scaling in an individual with Netherton Syndrome, comprising administering to the individual an effective amount of a bispecific antibody, the bispecific antibody comprising a first binding domain and a second binding domain, the first binding domain binds to human KLK7 and inhibits KLK7 protease activity, and the second binding domain binds to human KLK5 and inhibits KLK5 protease activity.

259. A method for improving skin rash and / or scaling in an individual with Netherton syndrome, comprising administering to the individual an anti-KLK5 antibody and an anti-KLK7 antibody, wherein the anti-KLK5 antibody inhibits KLK5 protease activity and the anti-KLK7 antibody inhibits KLK7 protease activity.

260. The use according to any one of claims 192, 193, 240 or 247, or the method according to any one of claims 205, 206, 209, 243 or 254-257, or the antibody, bispecific antibody or pharmaceutical composition for use according to claim 237, wherein said skin inflammatory cytokines are one or more of IL-8, TNFα, IL-6, IL-4 and / or G-CSF.

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