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

Abstract

The present invention provides anti-KLK7 antibodies, anti-KLK5 antibodies, anti-KLK5 / KLK7 multispecific antibodies, and methods of using them.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 901,990, filed September 18, 2019, which is incorporated herein 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 technology]

[0003] Human kallikrein-related peptidases (KLKs) are (chymo)trypsin-like serine proteases expressed in various tissues, including the prostate, ovary, breast, testis, brain, and skin. KLKs belong to the chymotrypsin-like serine protease family S1A subgroup of clan PA(S). The 15 human KLK genes, located on chromosome 19q13.4, 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 the kallikrein-related peptidases KLK1 through KLK15. All KLK genes encode single-chain preproproteins containing chymotrypsin-like or trypsin-like catalytic domains of 224–237 residues, with approximately 40% amino acid sequence identity between KLK4 and KLK15. KLK1 and its close homologs KLK2 and KLK3 form their own clade, while KLK4, 5, and 7 belong to a separate 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, where keratinocytes undergo terminal differentiation to transform into flattened, brick-like structures that form the stratum corneum, the outermost epidermal layer and a barrier against 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 skin. It has been described that KLK5 plays 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, which 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 several members of the KLK serine protease family (e.g., KLK5 and KLK7). See Wang et al., Exp Dermatol. Jul;23(7):524-6 (2014). Lack of SPINK5 in Netherton syndrome results in unopposed KLK activity. KLK5 hyperactivity is thought to be a key factor in the pathophysiology of Netherton syndrome because KLK5 is a regulator of protein degradation in the epidermis. Ablation 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. Estimates of heritability from twin studies of asthma vary from 35% to 80%, indicating a significant role for genetic risk. See, for example, Ullemar et al., Allergy 71, 230-238 (2016). Several large-scale GWAS studies have been conducted on asthma and asthma-related phenotypes, and many of the identified loci, such as those near the ORMDL3, IL13, IL1RL1, and TSLP genes, have been confirmed in multiple study populations. See, for example, Bonnelykke et al., Nat Genet 46, 51-55 (2014). Recent studies have identified SNPs in the KLK4 / 5 locus that are protective for the risk of low periostin asthma or type 2 low-inflammatory asthma. In the same study, KLK5 levels were found to be increased in bronchoalveolar lavage of patients with severe asthma, supporting the hypothesis that KLK5 plays a role in bronchial obstruction and asthma pathogenesis.

[0006] Despite advances in the field of diseases such as Netherton syndrome and asthma, there is a need to identify targets and develop tools that can complement or enhance the effectiveness of existing treatments. 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), comprising: a) inhibits human KLK7-mediated cleavage of a substrate containing the amino acid sequence RPKPVE-Nval-WRK (SEQ ID NO: 121), where Nval is norvaline; 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; 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 (sequence number 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 having the amino acid sequence of SEQ ID NO: 7, (b) CDR-H2 having the amino acid sequence of SEQ ID NO: 8, and (c) CDR-H3 having the amino acid sequence of SEQ ID NO: 9; and a light chain variable domain (VL) containing (d) CDR-L1 having the amino acid sequence of SEQ ID NO: 10, (e) CDR-L2 having the amino acid sequence of SEQ ID NO: 11, and (f) CDR-L3 having the amino acid sequence of SEQ ID NO: 12. Embodiment 3. The antibody of embodiment 1, comprising a heavy chain variable domain (VH) comprising (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 light chain variable domain (VL) comprising (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. Embodiment 4. The antibody of any one of embodiments 1 to 3, which is a monoclonal antibody. Embodiment 5. The antibody of any one of embodiments 1 to 4, which is a humanized or chimeric antibody. Embodiment 6. The antibody of any one of embodiments 1 to 5, which is an antibody fragment that binds to human KLK7. Embodiment 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 7. The antibody of any one of embodiments 1 to 6, which binds to cynomolgus monkey KLK7 at 1000 bp. Embodiment 8. An antibody described in any one of embodiments 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. Embodiment 9. An antibody described in any one of embodiments 1 to 8, wherein the light chain variable region comprises FR1 comprising an amino acid sequence selected from SEQ ID NOs: 147 to 150, FR2 comprising an amino acid sequence selected from SEQ ID NOs: 152 to 154, FR3 comprising an amino acid sequence selected from SEQ ID NOs: 156 to 158, and / or FR4 comprising an amino acid sequence selected from SEQ ID NO: 160. Embodiment 10. The antibody of 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) VH sequence defined in (a) and VL sequence defined in (b). Embodiment 11. The antibody of any one of embodiments 1 to 10, comprising a sequence 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) VH sequence defined in (a) and VL sequence defined in (b). Embodiment 12. The antibody of any one of embodiments 1 to 11, comprising a VH sequence of SEQ ID NO: 29 and a VL sequence of SEQ ID NO: 32. Embodiment 13. The antibody of any one of embodiments 1 to 11, comprising a VH sequence of SEQ ID NO: 30 and a VL sequence of SEQ ID NO: 38. Embodiment 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. Embodiment 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. Embodiment 16. The antibody of 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 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). Embodiment 17. The antibody of any one of embodiments 1 to 16, which is a full-length IgG1 antibody. Embodiment 18. The antibody of embodiment 17, comprising an N297G substitution (EU numbering). Embodiment 19. The antibody of any one of embodiments 16 to 18, comprising an M428L substitution (EU numbering) and / or an N434S substitution (EU numbering). Embodiment 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 20. The antibody of any one of embodiments 1 to 19, which binds to human KLK7 at the sigma-positive region. Embodiment 2. The antibody of any one of embodiments 1 to 20, which inhibits human KLK7 protease activity with an IC50 of less than 1.5 nM, or less than 3 nM, or less than 2 nM, or less than 1 nM. Embodiment 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 embodiments 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. Embodiment 23. The bispecific antibody of embodiment 21 or embodiment 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 (SEQ ID NO: 121), wherein Nval is norvaline. Embodiment 24. The antibody of any one of embodiments 1 to 23, which is a multispecific antibody. Embodiment 25. The antibody of embodiment 24, which is a bispecific antibody. Embodiment 26: An antibody that specifically binds to human KLK7 and competes with the antibody of any one of Embodiments 1 to 25 for binding to human KLK7. Embodiment 27. The antibody of embodiment 26, 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, 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) 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. Embodiment 28. An isolated nucleic acid encoding the antibody of any one of embodiments 1 to 27. Embodiment 29. An isolated host cell comprising the nucleic acid of embodiment 28. Embodiment 30. An isolated host cell expressing an 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 of embodiment 29 or embodiment 30 under conditions suitable for expression of the antibody. Embodiment 32 The method of embodiment 31, further comprising recovering the antibody from the host cell. Embodiment 33. An antibody produced by the method of embodiment 32. Embodiment 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 to 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 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 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 to 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 to 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 (d) a light chain variable domain (VL) comprising: (a) 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 to 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 to 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 to 78; or g) An antibody comprising a heavy chain variable domain (VH) comprising (a) a CDR-H1 having the amino acid sequence of SEQ ID NO: 68, (b) a CDR-H2 having an amino acid sequence selected from SEQ ID NOs: 69 and 70, and (c) a CDR-H3 having an amino acid sequence selected from SEQ ID NOs: 71 and 72, and a light chain variable domain (VL) comprising (d) a CDR-L1 having the amino acid sequence of SEQ ID NO: 73, (e) a CDR-L2 having the amino acid sequence of SEQ ID NO: 74, and (f) a CDR-L3 having an amino acid sequence selected from SEQ ID NOs: 76 to 78. Embodiment 35. An antibody described in embodiment 34, comprising a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 39, (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 the amino acid sequence of SEQ ID NO: 43, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 47. Embodiment 36. An antibody described in embodiment 34, 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 the amino acid sequence of SEQ ID NO: 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 the amino acid sequence of SEQ ID NO: 76. Embodiment 37. The antibody of any one of embodiments 34 to 36, which is a monoclonal antibody. Embodiment 38. The antibody of any one of embodiments 34 to 37, which is a humanized or chimeric antibody. Embodiment 39. An antibody according to any one of embodiments 34 to 38, which is an antibody fragment that binds to human KLK5. Embodiment 40. 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 binds to human KLK5 at 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 embodiments 34 to 39, which binds to cynomolgus KLK5 at the sigma level. Embodiment 41. The antibody of any one of embodiments 34 to 40, wherein the heavy chain variable region is: a) FR1 comprising an amino acid sequence selected from SEQ ID NO: 161, FR2 comprising an amino acid sequence of SEQ ID NO: 162 to 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 having the amino acid sequence of SEQ ID NO: 171, FR2 having an amino acid sequence selected from SEQ ID NOs: 172 to 173, FR3 having the amino acid sequence of SEQ ID NO: 174, and / or FR4 having the amino acid sequence of SEQ ID NO: 175. Embodiment 42. The antibody of any one of embodiments 34 to 41, wherein the light chain variable region is: a) FR1 comprising the amino acid sequence of SEQ ID NO: 166, FR2 comprising an amino acid sequence selected from SEQ ID NOs: 167 to 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 having the amino acid sequence of SEQ ID NO: 176, FR2 having an amino acid sequence selected from SEQ ID NOs: 177 to 178, FR3 having the amino acid sequence of SEQ ID NO: 179, and / or FR4 having the amino acid sequence of SEQ ID NO: 180. Embodiment 43. The antibody of any one of embodiments 34 to 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 to 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) VH sequence defined in (d) and VL sequence defined in (e). Embodiment 44. The antibody of any one of embodiments 34 to 43, comprising 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) VH sequence defined in (d) and VL sequence defined in (e). Embodiment 45. The antibody of any one of embodiments 34 to 44, comprising a VH sequence of SEQ ID NO: 52 and a VL sequence of SEQ ID NO: 55. Embodiment 46. The antibody of any one of embodiments 34 to 44, comprising a VH sequence of SEQ ID NO: 53 and a 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. The antibody of any one of embodiments 34 to 44, comprising a VH sequence of SEQ ID NO: 83 and a VL sequence of SEQ ID NO: 88. Embodiment 50. The antibody of any one of embodiments 34 to 44, comprising a VH sequence of SEQ ID NO: 87 and a 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. The antibody of 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 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). Embodiment 54. The antibody of any one of embodiments 34 to 53, which is a full-length IgG1 antibody. Embodiment 55. The antibody of embodiment 54, comprising an N297G substitution (EU numbering). Embodiment 56. The antibody of any one of embodiments 53 to 55, comprising an M428L substitution (EU numbering) and / or an N434S substitution (EU numbering). Embodiment 57. 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 The antibody of any one of embodiments 34 to 56, which binds to human KLK5 at the sigma-positive region. Embodiment 58. The antibody of any one of embodiments 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. Embodiment 59. 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 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 60 The antibody of embodiment 58 or embodiment 59, wherein the inhibition of human KLK5 protease activity is inhibition of human KLK5-mediated cleavage of the substrate Boc-Val-Pro-Arg-AMC. Embodiment 61. The antibody of any one of embodiments 34 to 60, which is a multispecific antibody. Embodiment 62. The antibody of embodiment 61, which is a bispecific antibody. Embodiment 63. An isolated nucleic acid encoding the antibody of any one of embodiments 34 to 62. Embodiment 64. An isolated host cell comprising the nucleic acid of embodiment 63. Embodiment 65. An isolated host cell expressing an 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 of embodiment 64 or 65 under conditions suitable for expression of said antibody. Embodiment 67 The method of embodiment 66, further comprising recovering the antibody from the host cell. Embodiment 68. An antibody produced by the method of 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 and the second binding domain binds to human KLK5, and 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. Embodiment 70. The bispecific antibody of embodiment 69, wherein the first binding domain is humanized. Embodiment 71. The bispecific antibody of 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) VH sequence defined in (a) and VL sequence defined in (b). Embodiment 72. The bispecific antibody of any one of embodiments 69 to 71, wherein the first binding domain comprises a sequence 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) VH sequence defined in (a) and VL sequence defined in (b). Embodiment 73. The bispecific antibody of 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 of 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. The bispecific antibody of any one of embodiments 69 to 74, wherein the second binding domain 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 to 49; or b) A bispecific antibody 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 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 of 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 of 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 of any one of embodiments 69 to 77, wherein the second binding domain is humanized. Embodiment 79. The bispecific antibody of 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: 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 to 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) VH sequence defined in (d) and VL sequence defined in (e). Embodiment 80. The bispecific antibody of 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) VH sequence defined in (d) and VL sequence defined in (e). Embodiment 81. The bispecific antibody of 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) VH sequence defined in (d) and VL sequence defined in (e). Embodiment 82. The bispecific antibody of 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) VH sequence defined in (d) and VL sequence defined in (e). Embodiment 83. The bispecific antibody of 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 of 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 comprises 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 comprises the VH sequence of SEQ ID NO: 53 and the VL amino acid sequence of SEQ ID NO: 62. Embodiment 85. The bispecific antibody of 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 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. Embodiment 87. The bispecific antibody of any one of embodiments 69 to 86, wherein the first binding domain comprises a first heavy chain variable domain and a first light chain variable domain, wherein the first heavy chain variable domain is linked to a first heavy chain constant region, and the first light chain variable domain is linked to a first light chain constant region; and the second binding domain comprises a second heavy chain variable domain and a second light chain variable domain, wherein 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 of embodiment 87, wherein the first heavy chain constant region comprises a knob mutation and the second heavy chain constant region comprises a hole mutation, or wherein the first heavy chain constant region comprises a hole mutation and the second heavy chain constant region comprises a knob mutation. Embodiment 89. The bispecific antibody of embodiment 88, wherein the antibody is an IgG1 antibody and the knob mutation comprises a T366W substitution. Embodiment 90. The bispecific antibody of embodiment 88 or embodiment 89, wherein the antibody is an IgG1 antibody and the hole mutations comprise at least one, at least two, or at least three substitutions selected from T366S, L368A, and Y407V. Embodiment 91. The bispecific antibody of embodiment 90, wherein said antibody is an IgG1 antibody and said hole mutations comprise T366S, L368A and Y407V substitutions. Embodiment 92. The bispecific antibody of any one of embodiments 87 to 91, wherein the first heavy chain constant region and / or the second heavy chain constant region comprises a N297G substitution (EU numbering). Embodiment 93. The bispecific antibody of embodiment 92, wherein the first heavy chain constant region and the second heavy chain constant region each comprise a N297G substitution (EU numbering). Embodiment 94. A bispecific antibody according to any one of embodiments 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 said first heavy chain constant region further comprises a S183E substitution (EU numbering), said first light chain constant region comprises a V133K substitution (EU numbering), and said second heavy chain constant region further comprises a S183K substitution (EU numbering), and said second light chain constant region comprises a V133E substitution (EU numbering). Embodiment 95. The bispecific antibody of 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 of embodiment 95, wherein said first heavy chain constant region and said second heavy chain constant region each further comprise at least one substitution selected from M428L and N434S (EU numbering). Embodiment 97. The bispecific antibody of embodiment 96, wherein the first heavy chain constant region and the second heavy chain constant region further comprise M428L and N434S substitutions (EU numbering), respectively. Embodiment 98. A bispecific antibody according to any one of embodiments 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. Embodiment 99. The bispecific antibody of 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) A bispecific antibody, wherein said second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 120 or 191, said second light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, said first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 119 or 190, and said first light chain constant region comprises the amino acid sequence of SEQ ID NO: 104. Embodiment 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 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 comprising 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. Embodiment 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 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 comprising 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 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 the heavy chain amino acid sequence of SEQ ID NO: 108 and the light chain amino acid sequence of SEQ ID NO: 109, and the second binding domain comprising the heavy chain amino acid sequence of SEQ ID NO: 110 and the 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 and the second binding domain binds to human KLK5, the first binding domain comprising 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 comprising the heavy chain amino acid sequence of SEQ ID NO: 114 and the 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 said first binding domain binds to human KLK7 and said second binding domain binds to human KLK5, and said 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 to 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 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 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 to 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 to 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 (d) a light chain variable domain (VL) comprising: (a) 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 to 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 to 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 to 78; or g) A bispecific 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 to 78. Embodiment 105. The bispecific antibody of embodiment 104, wherein the second binding domain comprises a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 39, (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 the amino acid sequence of SEQ ID NO: 43, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 47. Embodiment 106. The bispecific antibody of embodiment 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. Embodiment 107. The bispecific antibody of any one of embodiments 104 to 106, wherein the second binding domain is humanized. Embodiment 108. The bispecific antibody of 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 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 to 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) VH sequence defined in (d) and VL sequence defined in (e). Embodiment 109. The bispecific antibody of 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 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) VH sequence defined in (d) and VL sequence defined in (e). Embodiment 110. The bispecific antibody of any one of embodiments 104 to 107, 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) VH sequence defined in (d) and VL sequence defined in (e). Embodiment 111. The bispecific antibody of any one of embodiments 104 to 107, 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) VH sequence defined in (d) and VL sequence defined in (e). Embodiment 112. The bispecific antibody of any one of embodiments 104 to 107, wherein the second 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. Embodiment 113. The bispecific antibody of embodiment 112, wherein the second 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. Embodiment 114. The bispecific antibody of any one of embodiments 104 to 113, wherein the first binding domain is humanized. Embodiment 115. The bispecific antibody of 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, wherein the first heavy chain variable domain is linked to a first heavy chain constant region, and the first light chain variable domain is linked to a first light chain constant region; and the second binding domain comprises a second heavy chain variable domain and a second light chain variable domain, wherein 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 of 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 wherein 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 of embodiment 116, wherein the antibody is an IgG1 antibody and the knob mutation comprises a T366W mutation. Embodiment 118. The bispecific antibody of embodiment 116 or 117, wherein the antibody is an IgG1 antibody and the hole mutations comprise at least one, at least two, or at least three mutations selected from T366S, L368A, and Y407V. Embodiment 119. The bispecific antibody of embodiment 118, wherein the antibody is an IgG1 antibody and the hole mutations comprise T366S, L368A and Y407V mutations. Embodiment 120. The bispecific antibody of any one of embodiments 115 to 119, wherein the first heavy chain constant region and / or the second heavy chain constant region comprises a N297G substitution (EU numbering). Embodiment 121. The bispecific antibody of embodiment 120, wherein the first heavy chain constant region and the second heavy chain constant region each comprise a N297G substitution (EU numbering). Embodiment 122. A bispecific antibody according to any one of embodiments 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), and 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). Embodiment 123. The bispecific antibody of 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 of embodiment 123, wherein said first heavy chain constant region and said second heavy chain constant region each further comprise at least one substitution selected from M428L and N434S (EU numbering). Embodiment 125. The bispecific antibody of embodiment 124, wherein said first heavy chain constant region and said second heavy chain constant region further comprise M428L and N434S substitutions (EU numbering), respectively. Embodiment 126. A 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, 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. Embodiment 127. The bispecific antibody of 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) A bispecific antibody, wherein said second heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 120 or 191, said second light chain constant region comprises the amino acid sequence of SEQ ID NO: 103, said first heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 119 or 190, and said first light chain constant region comprises the amino acid sequence of SEQ ID NO: 104. Embodiment 128. 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 128. The bispecific antibody of any one of embodiments 69 to 127, which binds to human KLK5 at Embodiment 129. The bispecific antibody of 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 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. Dand 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 of embodiment 129 or embodiment 130, wherein the inhibition of human KLK5 protease activity is inhibition of human KLK5-mediated cleavage of the substrate Boc-Val-Pro-Arg-AMC. Embodiment 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 embodiments 69 to 131, which binds to human KLK7 at Embodiment 13. The bispecific antibody of any one of embodiments 69 to 132, which inhibits human KLK7 protease activity with an IC50 of less than 3.5 nM, or less than 3 nM, or less than 2 nM, or less than 1 nM. Embodiment 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 134. The bispecific antibody of any one of embodiments 69 to 133, 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. Embodiment 135. The bispecific antibody of embodiment 133 or embodiment 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. 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. Embodiment 137. An isolated nucleic acid encoding a 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 of any one of embodiments 69 to 136. Embodiment 139. An isolated nucleic acid encoding the second binding domain of the bispecific antibody of any one of embodiments 69 to 136. Embodiment 140. An isolated host cell comprising the isolated nucleic acid of embodiment 137. Embodiment 141. An isolated host cell comprising the isolated nucleic acid of embodiment 138. Embodiment 142. An isolated host cell comprising the isolated nucleic acid of embodiment 139. Embodiment 143. An isolated host cell expressing a 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 of any one of embodiments 69 to 136. Embodiment 145. An isolated host cell expressing the second binding domain of the bispecific antibody of 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 a host cell according to embodiment 140 or embodiment 143 under conditions suitable for expression of said antibody. Embodiment 147. The method of 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 a host cell according to embodiment 141 or embodiment 144 under conditions suitable for expression of the first binding domain; and (ii) culturing a host cell according to embodiment 142 or embodiment 145 under conditions suitable for expression of the second binding domain. Embodiment 149. The method of embodiment 148, further comprising recovering the first binding domain and the second binding domain and constructing the bispecific antibody. Embodiment 150. A pharmaceutical composition comprising the antibody of any one of embodiments 1 to 27 and a pharmaceutically acceptable carrier. Embodiment 151. The pharmaceutical composition of embodiment 150, further comprising an additional therapeutic agent. Embodiment 152. The pharmaceutical composition of embodiment 151, wherein the additional therapeutic agent is a KLK5 inhibitor. Embodiment 153. The pharmaceutical composition of embodiment 152, wherein the KLK5 inhibitor is an anti-KLK5 antibody. Embodiment 154. The pharmaceutical composition of embodiment 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 to 49; or b) A pharmaceutical composition comprising a heavy chain variable domain (VH) comprising (a) CDR-H1 having the amino acid sequence of SEQ ID NO: 68, (b) CDR-H2 having an amino acid sequence selected from SEQ ID NOs: 69 and 70, and (c) CDR-H3 having an amino acid sequence selected from SEQ ID NOs: 71 and 72, and a light chain variable domain (VL) comprising (d) CDR-L1 having the amino acid sequence of SEQ ID NO: 73, (e) CDR-L2 having the amino acid sequence of SEQ ID NO: 74, and (f) CDR-L3 having an amino acid sequence selected from SEQ ID NOs: 75 to 78. Embodiment 155. The pharmaceutical composition of 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 of 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 of any one of embodiments 153 to 156, wherein the anti-KLK5 antibody is a monoclonal antibody. Embodiment 158. The pharmaceutical composition of any one of embodiments 153 to 157, wherein the anti-KLK5 antibody is a humanized or chimeric antibody. Embodiment 159. The pharmaceutical composition of 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 of 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 54-67; 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 to 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) VH sequence defined in (d) and VL sequence defined in (e). Embodiment 161. The pharmaceutical composition of 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: 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) VH sequence defined in (d) and VL sequence defined in (e). Embodiment 162. The pharmaceutical composition of 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: 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) VH sequence defined in (d) and VL sequence defined in (e). Embodiment 163. The pharmaceutical composition of 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) VH sequence defined in (d) and VL sequence defined in (e). Embodiment 164. The pharmaceutical composition of embodiment 153, wherein the anti-KLK5 antibody is an antibody of any one of embodiments 34 to 62. Embodiment 165. The pharmaceutical composition of embodiment 153, wherein the anti-KLK5 antibody is an antibody described in any one of embodiments 47, 48, 51, and 52. Embodiment 166. A pharmaceutical composition comprising the antibody of any one of embodiments 34 to 62 and a pharmaceutically acceptable carrier. Embodiment 167. The pharmaceutical composition of embodiment 166, further comprising an additional therapeutic agent. Embodiment 168. The pharmaceutical composition of embodiment 167, wherein the additional therapeutic agent is a KLK7 inhibitor. Embodiment 169. The pharmaceutical composition of embodiment 168, wherein the KLK7 inhibitor is an anti-KLK7 antibody. Embodiment 170. The pharmaceutical composition of embodiment 169, wherein the anti-KLK7 antibody is an antibody described in any one of embodiments 1 to 27. Embodiment 171. A pharmaceutical composition comprising an antibody according to any one of embodiments 1 to 27, an antibody according to any one of embodiments 34 to 62, and a pharmaceutically acceptable carrier. Embodiment 172. A 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 of embodiment 173, further comprising an additional therapeutic agent. Embodiment 175. The pharmaceutical composition of embodiment 174, wherein the additional therapeutic agent is an anti-inflammatory agent. Embodiment 176. A pharmaceutical composition according to any one of embodiments 150 to 175, for topical administration. Embodiment 177. A pharmaceutical composition according to any one of embodiments 150 to 175, for subcutaneous 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 medicament. Embodiment 179. The antibody of any one of embodiments 1 to 27 and 34 to 62, the bispecific antibody of any one of embodiments 69 to 136, or the pharmaceutical composition of any one of embodiments 150 to 177, for use in treating a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis, and rosacea. 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 / 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 high type 2 (Th2) asthma, or type 2 (T2)-driven asthma, eosinophilic asthma, high periostin asthma, high eosinophilic asthma, low Th2 asthma or non-Th2-driven asthma, low periostin asthma, and low eosinophilic asthma. Embodiment 181. The antibody, bispecific antibody, or pharmaceutical composition for use according to embodiment 180, wherein the asthma is hypoeosinophilic asthma. Embodiment 182. A combination of an antibody according to any one of embodiments 1 to 27 with an antibody according to any one of embodiments 34 to 62 for use as a medicament. Embodiment 183. A combination of an antibody according to any one of embodiments 1 to 27 with an 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 rosacea. Embodiment 184. The combination of embodiment 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-related asthma, corticosteroid-uncontrolled asthma, T helper lymphocyte type 2 (Th2) asthma or high type 2 (Th2) asthma, or type 2 (T2)-driven asthma, eosinophilic asthma, high periostin asthma, high eosinophilic asthma, low Th2 asthma or non-Th2-driven asthma, low periostin asthma, and low eosinophilic asthma. Embodiment 185. The combination of embodiment 184, wherein the asthma is hypoeosinophilic asthma. Embodiment 186. Use 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 in the manufacture of a medicament for treating a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis, and rosacea. Embodiment 187. The use of embodiment 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 high type 2 (Th2) asthma, or type 2 (T2)-driven asthma, eosinophilic asthma, high periostin asthma, high eosinophilic asthma, low Th2 asthma or non-Th2-driven asthma, low periostin asthma, and low eosinophilic asthma. Embodiment 188. The use of embodiment 187, wherein the asthma is hypoeosinophilic asthma. Embodiment 189. 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 treating a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis and rosacea. Embodiment 190. The use of embodiment 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 high type 2 (Th2) asthma, or type 2 (T2)-driven asthma, eosinophilic asthma, high periostin asthma, high eosinophilic asthma, low Th2 asthma or non-Th2-driven asthma, low periostin asthma, and low eosinophilic asthma. Embodiment 191. The use of embodiment 190, wherein the asthma is hypoeosinophilic asthma. Embodiment 192. Use 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 in the manufacture of a medicament 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. Embodiment 193. 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 epidermal inflammation, reducing epithelial permeability, reducing transepidermal water loss, reducing skin infiltration, reducing parakeratosis, restoring the epithelial barrier, and / or reducing skin inflammatory cytokines. Embodiment 194. 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 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. Embodiment 195. 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: a) an effective amount of an antibody described in any one of embodiments 1 to 27; and b) an effective amount of an antibody described in any one of embodiments 34 to 62. Embodiment 196. The method of embodiment 195, wherein the antibody of (a) and the antibody of (b) are administered simultaneously. Embodiment 197. The method of embodiment 195, wherein the antibody of (a) and the antibody of (b) are administered sequentially. Embodiment 198. 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 a bispecific antibody according to any one of embodiments 69 to 136, or an effective amount of a pharmaceutical composition according to any one of embodiments 150 to 177. Embodiment 199. The method of 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 / 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 high type 2 (Th2) asthma, or type 2 (T2)-driven asthma, eosinophilic asthma, high periostin asthma, high eosinophilic asthma, low Th2 asthma or non-Th2-driven asthma, low periostin asthma, and low eosinophilic asthma. Embodiment 200. The method of embodiment 199, wherein the asthma is hypoeosinophilic asthma. Embodiment 201. The method of any one of embodiments 194 to 198, wherein the individual has Netherton syndrome. Embodiment 202. The method of any one of embodiments 194 to 198, wherein the individual has rosacea. Embodiment 203. The method of any one of embodiments 194 to 202, further comprising administering to the individual an additional therapeutic agent. Embodiment 204. The method of embodiment 203, wherein the additional therapeutic agent is an anti-inflammatory agent. Embodiment 205. A method for reducing epidermal inflammation, reducing epidermal 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 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, to reduce epidermal inflammation, reduce epidermal permeability, reduce transepidermal water loss, reduce skin infiltration, reduce parakeratinization, and / or restore the epithelial barrier. Embodiment 206. A method for reducing epidermal inflammation, reducing epidermal 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 embodiments 1 to 27; and b) an effective amount of an antibody described in any one of embodiments 34 to 62, to reduce epidermal inflammation, reduce epidermal permeability, reduce transepidermal water loss, reduce skin infiltration, reduce parakeratinization, and / or restore the epithelial barrier. Embodiment 207. The method of embodiment 206, wherein the antibody of (a) and the antibody of (b) are administered simultaneously. Embodiment 208. The method of embodiment 206, wherein the antibody of (a) and the antibody of (b) are administered sequentially. Embodiment 209. A method for reducing epidermal inflammation, reducing epidermal 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 bispecific antibody of any one of embodiments 69 to 136, or an effective amount of the pharmaceutical composition of any one of embodiments 150 to 177, to reduce epidermal inflammation, reduce epidermal permeability, reduce transepidermal water loss, reduce skin infiltration, reduce parakeratinization, and / or restore the epithelial barrier. Embodiment 210. The method of any one of embodiments 194 to 209, wherein the administration is subcutaneous or intravenous. Embodiment 211. The method of any one of embodiments 194 to 209, wherein the administration is topical. Embodiment 212. The method of any one of embodiments 194 to 209, wherein the administration is intravenous. Embodiment 213. An isolated antibody that binds to human KLK7, wherein upon binding to human KLK7, it causes a conformational change in human KLK7, and said conformational change allosterically results in the destruction of the substrate binding site and / or active site of human KLK7. Embodiment 214. The isolated antibody of embodiment 213, which is a bispecific antibody. Embodiment 215. The isolated antibody of embodiment 214, wherein the bispecific antibody binds to human KLK7 and human KLK5. Embodiment 216. An isolated antibody described in embodiment 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. Embodiment 217. An 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. Embodiment 218. An 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. Embodiment 219. An 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. Embodiment 220. An 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. Embodiment 221. An isolated antibody according to any one of embodiments 213 to 220, 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). Embodiment 222. An isolated antibody according to any one of embodiments 213 to 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 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. Embodiment 224. The bispecific antibody of embodiment 223, which, upon binding to human KLK5, causes a conformational change in human KLK5, which conformational change allosterically results in the 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 and the second binding domain binds to human KLK5, and upon binding to human KLK5, causes a conformational change in human KLK5, which allosterically results in the destruction of the substrate binding site and / or active site of human KLK5. Embodiment 226. A 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. Embodiment 227. An 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. Embodiment 228. An 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. Embodiment 229. An 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. Embodiment 230. A bispecific antibody according to any one of embodiments 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). Embodiment 231. A bispecific antibody according to any one of embodiments 223 to 230, which binds to an epitope comprising one or more of the 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 of any one of embodiments 213 to 222 and a pharmaceutically acceptable carrier. Embodiment 233. A pharmaceutical composition comprising the bispecific antibody of 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. The antibody of any one of embodiments 213 to 222, the bispecific antibody of any one of embodiments 223 to 231, or the pharmaceutical composition of embodiment 232 or embodiment 233, for use in treating a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis, and rosacea. Embodiment 236. The antibody, bispecific antibody or pharmaceutical composition of embodiment 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 high type 2 (Th2) asthma, or type 2 (T2)-driven asthma, eosinophilic asthma, high periostin asthma, high eosinophilic asthma, low Th2 asthma or non-Th2-driven asthma, low periostin asthma, and low eosinophilic asthma. Embodiment 237. The antibody of any one of embodiments 213 to 222, the bispecific antibody of any one of embodiments 223 to 231, or the pharmaceutical composition of embodiment 232 or embodiment 233, for use in reducing epidermal inflammation, reducing epidermal permeability, reducing transepidermal water loss, reducing skin infiltration, reducing parakeratinization, restoring the epidermal barrier, and / or reducing skin inflammatory cytokines. Embodiment 238. Use of 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 in the manufacture of a medicament for treating a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis, and rosacea. Embodiment 239. The use of embodiment 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-related asthma, corticosteroid-uncontrolled asthma, T helper lymphocyte type 2 (Th2) asthma or high type 2 (Th2) asthma, or type 2 (T2)-driven asthma, eosinophilic asthma, high periostin asthma, high eosinophilic asthma, low Th2 asthma or non-Th2-driven asthma, low periostin asthma, and low eosinophilic asthma. Embodiment 240. Use of 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 in the manufacture of a medicament for reducing epidermal inflammation, for reducing epithelial permeability, for reducing transepidermal water loss, for reducing skin infiltration, for reducing parakeratosis, for restoring the epithelial barrier, and / or for 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 rosacea, comprising administering to the individual an effective amount of 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. Embodiment 242. The method of embodiment 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-related asthma, corticosteroid-uncontrolled asthma, T helper lymphocyte type 2 (Th2) asthma or high type 2 (Th2) asthma, or type 2 (T2)-driven asthma, eosinophilic asthma, high periostin asthma, high eosinophilic asthma, low Th2 asthma or non-Th2-driven asthma, low periostin asthma, and low eosinophilic asthma. Embodiment 243. A method for reducing epidermal inflammation, reducing epidermal 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 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, to reduce epidermal inflammation, reduce epidermal permeability, reduce transepidermal water loss, reduce skin infiltration, reduce parakeratinization, 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. A 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 of any one of embodiments 192, 193 and 240, wherein the medicament is for reducing epidermal inflammation, reducing epidermal permeability, reducing transepidermal water loss, reducing skin infiltration, reducing parakeratosis, restoring the epidermal barrier, and / or reducing skin inflammatory cytokines in individuals with Netherton syndrome. Embodiment 248. 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, wherein 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 treating Netherton syndrome, comprising: (a) a VH sequence of SEQ ID NO: 52 and a VL sequence of SEQ ID NO: 55; or (b) a VH sequence of SEQ ID NO: 53 and a VL sequence of SEQ ID NO: 62. Embodiment 250. An anti-KLK7 antibody for use in treating Netherton syndrome, comprising: (a) a VH sequence of SEQ ID NO: 29 and a VL sequence of SEQ ID NO: 32; or (b) a VH sequence of SEQ ID NO: 30 and a VL sequence of SEQ ID NO: 38. Embodiment 251. An antibody combination for use in treating 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 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. Embodiment 253. 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 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 254. A method for reducing epidermal inflammation, reducing epidermal permeability, reducing transepidermal water loss, reducing skin infiltration, reducing parakeratinization, restoring the epidermal barrier, and / or reducing skin inflammatory cytokines in an individual, comprising administering to the individual a KLK5 antagonist and a KLK7 antagonist. Embodiment 255. The method of embodiment 254, wherein the KLK5 antagonist is an anti-KLK5 antibody and / or the KLK7 antagonist is an anti-KLK7 antibody. Embodiment 256. A method of reducing epidermal inflammation, reducing epidermal permeability, reducing transepidermal water loss, reducing skin infiltration, reducing parakeratinization, restoring the epidermal barrier, and / or reducing skin inflammatory cytokines in an individual, 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, 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. Embodiment 257. A method for reducing epidermal inflammation, reducing epidermal permeability, reducing transepidermal water loss, reducing skin infiltration, reducing parakeratinization, restoring the epidermal 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. Embodiment 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, 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. Embodiment 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. Embodiment 260. The antibody, bispecific antibody or pharmaceutical composition for use according to any one of embodiments 192, 193, 240 or 247, or the method according to any one of embodiments 205, 206, 209, 243 or 254 to 257, or the 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 and the second binding domain binds to human KLK5, the first binding domain comprising 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 comprising 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 and the second binding domain binds to human KLK5, the first binding domain comprising 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 comprising 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 and the second binding domain binds to human KLK5, the first binding domain comprising 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 comprising the heavy chain amino acid sequence of SEQ ID NO: 114 and the light chain amino acid sequence of SEQ ID NO: 115. [Brief explanation of the drawings]

[0008] [Figure 1A] FIG. 1A shows an alignment of the anti-KLK7 antibody rb.14H11c-LC light chain variable region with certain humanized versions of the light chain variable region. [Figure 1B] Figure 1B shows an alignment of the heavy chain variable region of the anti-KLK7 antibody rb.14H11c-HC with certain humanized versions of the heavy chain variable region. CDRs are indicated by Chothia, Kabat, and contact residues. Differences between the humanized versions and the rabbit parent variable region are indicated in white on a black background.

[0009] [Figure 2A] FIG. 2A shows an alignment of the humanized anti-KLK5 antibody hu.10C5-H28L5 light chain variable region with specific modified humanized versions of the light chain variable region. [Figure 2B] Figure 2B shows an alignment of the humanized anti-KLK5 antibody hu.10C5-H28L5 heavy chain variable region with specific modified humanized versions of the heavy chain variable region. CDRs are indicated by Chothia, Kabat, and contact residues. Differences between the humanized version and the parent variable region are indicated in white on a black background.

[0010] [Figure 3A] FIG. 3A shows an alignment of the humanized anti-KLK5 antibody hu.9H5-H14L4 light chain variable region with specific modified humanized versions of the light chain variable region. [Figure 3B]Figure 3B shows an alignment of the humanized anti-KLK5 antibody hu.9H5-H14L4 heavy chain variable region with specific modified humanized versions of the heavy chain variable region. CDRs are indicated by Chothia, Kabat, and contact residues. Differences between the humanized versions and the parent variable region are indicated in white on a black background.

[0011] [Figure 4] FIG. 4 shows the affinity of heavy and light chain variants of humanized anti-KLK5 antibody hu.10C5.L5H28 to the parent antibody hu.10C5.L5H28.

[0012] [Figure 5] FIG. 5 shows a scatter plot of the on-rates (ka) and off-rates (kd) of heavy and light chain variants of the humanized anti-KLK5 antibody hu.9H5.L4H14.

[0013] [Figure 6A] FIG. 6A shows a surface plasmon resonance trace for the hu.10C5.L5H28 variant shown against human KLK5. [Figure 6B] FIG. 6B shows a surface plasmon resonance trace for the hu.10C5.L5H28 variant displayed against cynomolgus KLK5.

[0014] [Figure 7A] FIG. 7A shows a surface plasmon resonance trace for the hu.9H5.L4H14 variant displayed against human KLK5. [Figure 7B] FIG. 7B shows a surface plasmon resonance trace for the hu.9H5.L4H14 variant displayed against cynomolgus monkey KLK5.

[0015] [Figure 8] FIG. 8 shows representative KLK5 protein expression in human normal skin, atopic dermatitis, and rosacea.

[0016] [Figure 9] FIG. 9 shows representative KLK7 mRNA staining in human normal skin, atopic dermatitis, rosacea, and psoriasis.

[0017] [Figure 10A] FIG. 10A shows the depth of expression of KLK5 in normal human skin, atopic dermatitis, rosacea, and psoriasis. [Figure 10B] FIG. 10B shows the depth of expression of KLK7 in human normal skin, topical dermatitis, rosacea, and psoriasis. [Figure 10C] FIG. 10C shows the depth of SPINK5 expression in normal human skin, topical dermatitis, rosacea, and psoriasis.

[0018] [Figure 11] FIG. 11 shows transepidermal water loss in mice administered saline, KLK5, or KLK7.

[0019] [Figure 12A] FIG. 12A shows the daily clinical scores in SDS / S. [Figure 12B] FIG. 12B shows the total terminal atopic dermatitis score in SDS / S. [Figure 12C] Figure 12C shows the AUC skin score in SDS / S. Mice modeling with Staphylococcus aureus protein A atopic dermatitis were administered an isotype control antibody, an anti-mouse KLK5 antibody, an anti-mouse KLK7 antibody, a combination of anti-KLK5 and anti-KLK7 antibodies, or SPINK5-Fc.

[0020] [Figure 13]Figure 13 shows the total terminal atopic dermatitis score, transepidermal water loss, and histological disease severity score in SDS / S. Mice modeling with Staphylococcus aureus protein A atopic dermatitis were administered an isotype control antibody, an anti-mouse KLK5 antibody, an anti-mouse KLK7 antibody, a combination of anti-KLK5 and anti-KLK7 antibodies, or an anti-IL-13 antibody.

[0021] [Figure 14] Representative hematoxylin and eosin staining of SDS / S-derived skin is shown in Figure 14. Mice model of Staphylococcus aureus protein A atopic dermatitis were administered an isotype control antibody, a combination of anti-KLK5 and anti-KLK7 antibodies, or an anti-IL-13 antibody.

[0022] [Figure 15] 15 shows a schematic diagram of an exemplary bispecific anti-KLK5 / KLK7 antibody provided herein, which includes substitutions to promote proper heavy chain / light chain pairing and / or to reduce effector function. In another format, the knob can be on the anti-KLK5 arm and the hole can be on the anti-KLK7 arm.

[0023] [Figure 16A] FIG. 16A shows that skin rash and scaling were reduced in Spink5-deficient mice treated with anti-mKLK5 / mKLK7 bispecific antibody. [Figure 16B] FIG. 16B shows that skin rash and scaling were reduced in Spink5-deficient mice treated with anti-mKLK5 / mKLK7 bispecific antibody. [Figure 16C] FIG. 16C shows that skin rash and scaling were reduced in Spink5-deficient mice treated with anti-mKLK5 / mKLK7 bispecific antibody. [Figure 16D]Figure 16D shows that skin rash and scaling were reduced in Spink5-deficient mice treated with anti-mKLK5 / mKLK7 bispecific antibody. Spink5 f / f Cre-ERT2 negative control mice were treated with 16 mg / kg tamoxifen (16A), and Spink5 f / f Cre-ERT2+ mice were injected with 16 mg / kg (16B), 8 mg / kg (16C), or 4 mg / kg (16D) tamoxifen and then treated with 2.5 mg of anti-gp120 isotype control antibody or 2.5 mg of anti-mKLK5 / mKLK7 bispecific antibody every other day. Dorsal skin was analyzed 6 days after injection.

[0024] [Figure 17A] FIG. 17A shows that the cytokine IL-8 in lysates prepared from the dorsal skin of Spink5-deficient mice after anti-mKLK5 / mKLK7 bispecific antibody treatment was reduced compared to isotype control antibody treatment. [Figure 17B] FIG. 17B shows that the cytokine TNF-α in lysates prepared from the dorsal skin of Spink5-deficient mice after anti-mKLK5 / mKLK7 bispecific antibody treatment was reduced compared to isotype control antibody treatment. [Figure 17C] FIG. 17C shows that the cytokine IL-6 in lysates prepared from the dorsal skin of Spink5-deficient mice after anti-mKLK5 / mKLK7 bispecific antibody treatment was reduced compared to isotype control antibody treatment. [Figure 17D] FIG. 17D shows that the cytokine IL-4 in lysates prepared from the dorsal skin of Spink5-deficient mice after anti-mKLK5 / mKLK7 bispecific antibody treatment was reduced compared to isotype control antibody treatment. [Figure 17E] FIG. 17E shows that the cytokine G-CSF in lysates prepared from the dorsal skin of Spink5-deficient mice after anti-mKLK5 / mKLK7 bispecific antibody treatment was reduced compared to isotype control antibody treatment.

[0025] [Figure 18]Figure 18 shows representative cross sections of hematoxylin and eosin stained skin from Spink5 f / f Cre-ERT2 negative control mice treated with 16 mg / kg tamoxifen, and Spink5 f / f Cre-ERT2+ mice treated with 16 mg / kg tamoxifen and an isotype control antibody or an anti-mKLK5 / mKLK7 bispecific antibody.

[0026] [Figure 19A] FIG. 19A shows epithelial permeability as measured by transepithelial electrical resistance (TEER) in human epidermal keratinocytes treated with KLK5, KLK7, KLK5+KLK7, and KLK5+KLK7+anti-KLK5 / KLK7 bispecific antibody. [Figure 19B] FIG. 19B shows epithelial permeability as measured by transepithelial electrical resistance (TEER) in human epidermal keratinocytes treated with KLK5, KLK7, KLK5+KLK7, and KLK5+KLK7+anti-KLK5 / KLK7 bispecific antibody.

[0027] [Figure 20A] FIG. 20A shows the crystal structure of anti-rb.14H11c Fab bound to KLK7. [Figure 20B] FIG. 20B shows the crystal structure of anti-rb.14H11c Fab bound to KLK7. [Figure 20C] Figure 20C shows the crystal structure of anti-rb.14H11c Fab bound to KLK7. The intact Fab bound to KLK7 is shown in Figure 20A, with only KLK7 superimposed. Figure 20B shows the KLK7-Fab interface. Figure 20C shows the superimposition of KLK7 in its native conformation (yellow) and KLK7 bound to rb.14H11c Fab (blue). A portion of the rb14H11c heavy chain is shown in dark blue. DETAILED DESCRIPTION OF THE INVENTION

[0028] I. Definition For purposes herein, an "acceptor human framework" is a framework that comprises 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 comprise the same amino acid sequence or may contain amino acid sequence changes. 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 the VL human immunoglobulin framework sequence or the human consensus framework sequence.

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

[0030] An "affinity matured" antibody refers to an antibody that contains one or more alterations in one or more complementarity determining regions (CDRs) compared to a parent antibody that does not possess those alterations, such that the affinity of the antibody for antigen is improved.

[0031] The terms "anti-KLK7 antibody" and "antibody that binds to KLK7" refer to an antibody that can bind to KLK7, such as human KLK7, with sufficient affinity so that the antibody is useful as a diagnostic and / or therapeutic agent in targeting KLK7. In one embodiment, the extent of binding of an anti-KLK7 antibody to an unrelated, non-KLK7 protein is less than about 10% of the binding of the antibody to KLK7, as measured, for example, by surface plasmon resonance (SPR). In certain embodiments, an antibody that binds to KLK7 has 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~10 -13 M, e.g. 10 -9 M~10 -13 Dissociation constant (K D ) The antibody has a K value of 1 μM or less. D An antibody is said to "specifically bind" to KLK7 if it has the following structure: In certain embodiments, an 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 an antibody that can bind to KLK5, such as human KLK5, with sufficient affinity so that the antibody is useful as a diagnostic and / or therapeutic agent in targeting KLK5. In one embodiment, the extent of binding of the anti-KLK5 antibody to an unrelated, non-KLK5 protein is less than about 10% of the binding of the antibody to KLK5, as measured, for example, by surface plasmon resonance (SPR). In certain embodiments, the antibody that binds to KLK5 has 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~10 -13 M, e.g. 10 -9 M~10 -13 Dissociation constant (K D ) The antibody has a K value of 1 μM or less. 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 from different species.

[0033] The terms "anti-KLK5 / KLK7 antibody" and "antibody that binds to KLK5 and KLK7" refer to a multispecific antibody that can bind to 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 to 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, e.g. 10 -9 M~10 -13 Dissociation constant (K D ) The antibody has a K value of 1 μM or less. D An antibody is said to "specifically bind" to a target protein if it has the following structure: 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] An "antibody fragment" refers to a molecule other than an intact antibody that contains a portion of the intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv and scFab); single-domain antibodies (dAbs); and multispecific antibodies formed from antibody fragments. 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 the variable domain sufficient to bind to an antigen. In some embodiments, the binding domain comprises heavy chain (HC) CDR1, CDR2, and CDR3, and light chain (LC) CDR1, CDR2, and CDR3. In some embodiments, the binding domain comprises heavy chain (HC) CDR1, FR2, CDR2, FR3, and CDR3, and light chain (LC) CDR1, FR2, CDR2, FR3, and CDR3.

[0037] The term "epitope" refers to a site on a proteinaceous or non-proteinaceous antigen to which an anti-KLK7 or anti-KLK5 antibody binds. Epitopes can be formed from a contiguous stretch of amino acids (linear epitopes) or can include noncontiguous amino acids (conformational epitopes), formed in close spatial proximity due to, for example, antigen folding (i.e., tertiary folding of a proteinaceous antigen). Linear epitopes are typically still bound by antibodies after exposure of a proteinaceous antigen to a denaturing agent, whereas conformational epitopes are typically disrupted by treatment with a denaturing agent. Epitopes typically contain 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 specific epitope (i.e., antibodies that bind to the same epitope) can be performed using methods routine 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 antigens (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 modification-assisted profiling (MAP), allows for the acquisition of a large number of monoclonal antibodies that specifically bind to KLK7 or KLK5 based on the binding profile of each antibody to a large number of chemically or enzymatically modified antigen surfaces (see, e.g., U.S. Patent Application Publication No. 2004 / 0101920). Each antibody in the group binds to the same epitope, which may be distinct from epitopes represented by other groups or may be a unique epitope that overlaps.

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

[0041] Similarly, competitive binding can be used to easily determine whether an antibody binds to the same KLK5 epitope as an anti-KLK5 antibody or competes for binding with an anti-KLK5 antibody. For example, an "antibody that binds to the same epitope" as a 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 competitive assay; conversely, the reference antibody inhibits the binding of the antibody to the antigen by 50% or more in a competitive assay. Also, for example, to determine whether an antibody binds to the same epitope as a reference anti-KLK5 antibody, the reference antibody is bound to KLK5 under saturating conditions. After removing 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 saturation binding of the reference anti-KLK5 antibody, it can be concluded that the anti-KLK5 antibody in question binds to a different epitope from 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, it is possible that the anti-KLK5 antibody in question binds to the same epitope as the epitope bound by the reference anti-KLK5 antibody.To determine whether this antibody binds to the same epitope or whether binding is simply hindered by steric reasons, conventional experiments can be used (such as peptide mutations and binding analysis using ELISA, RIA, surface plasmon resonance, flow cytometry, or other quantitative or qualitative antibody binding assays available in the art).This assay should be performed in two settings, i.e., when both antibodies are saturating antibodies.In both settings, if only the first (saturating) 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 are considered to bind the same or overlapping epitope if a 1-fold, 5-fold, 10-fold, 20-fold, or 100-fold excess of one antibody inhibits binding of the other 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 the same epitope if essentially all amino acid mutations in the antigen that reduce or eliminate binding of one antibody also reduce or eliminate binding of the other. Two antibodies are considered to have "overlapping epitopes" if only a subset of amino acid mutations that reduce or eliminate binding of one antibody also reduce or eliminate 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, while the remainder 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 major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and some of these can be further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. In certain embodiments, the antibody is an IgG1 isotype. In certain embodiments, the antibody is of the IgG1 isotype with P329G, L234A, and L235A mutations to reduce Fc region effector function. In other embodiments, the antibody is of the IgG2 isotype. In certain embodiments, the antibody is of the IgG4 isotype with an S228P mutation in the hinge region to improve the stability of IgG4 antibodies. The heavy chain constant domains corresponding to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively. The light chain of an antibody may be assigned to one of two types, called κ (kappa) or λ (lambda), based on the amino acid sequence of its constant domain.

[0046] "Effector functions" refer to biological activities attributable to the Fc region of an antibody and vary depending on the antibody isotype. Examples of antibody effector functions include: C1q binding and complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down-regulation of cell surface receptors (e.g., B cell receptors); and B cell activation.

[0047] An "effective amount" of an agent, eg, a pharmaceutical composition, refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic or prophylactic result.

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

[0049] "Framework" or "FR" refers to variable domain residues other than the complementarity-determining regions (CDRs). The FR of a variable domain generally consists of four FR domains: FR1, FR2, FR3, and FR4. Thus, the CDR and FR sequences generally appear in the VH (or VL) in the following order: 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 heavy chain that has a structure substantially similar to a native antibody structure or 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 cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells," which include the primary transformed cell and progeny derived from the host cell regardless of the number of passages. The progeny may not be completely identical in nucleic acid content to the parent cell, but may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell are included herein.

[0052] A "human antibody" is one that possesses an amino acid sequence that corresponds to that of an antibody produced by a human or human cell, or derived from a non-human source that utilizes the 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] A "human consensus framework" is a framework that represents the most commonly occurring amino acid residues in a 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 as in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda, MD (1991), vols. 1-3. In one embodiment, for VL, the subgroup is subgroup kappa I as in Kabat et al., supra. In one embodiment, for VH, the subgroup is subgroup III as in Kabat et al., supra.

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

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

[0056] Generally, antibodies contain six CDRs, three in the VH (CDR-H1, CDR-H2, CDR-H3) and three in the VL (CDR-L1, CDR-L2, CDR-L3). Exemplary CDRs herein include: (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 located 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., supra. One of skill in the art will understand that CDR designations can be determined according to Chothia, supra, McCallum, supra, or any other scientifically accepted nomenclature system. In one embodiment, the CDR residues include those identified in Figures 1-3 or elsewhere herein.

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

[0059] An "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 human.

[0060] An "isolated" antibody is one that is separated from components of its natural environment. In some embodiments, the antibody is purified to greater than 95% or greater than 99% purity, as determined, for example, by electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse-phase HPLC) methods. For a review of methods for assessing antibody purity, see, e.g., Flatman et al., J. Chromatogr. B 848:79-87 (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. Two linked polypeptides may be separated by additional amino acid sequences; that is, they may not be contiguous with each other or directly linked to each other.

[0062] The terms "nucleic acid molecule" or "polynucleotide" include any compound and / or substance comprising a polymer of nucleotides. Each nucleotide is composed of a base, specifically a purine or 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. Nucleic acid molecules are often described by their base sequence, whereby the bases represent the primary (linear) structure of the nucleic acid molecule. The sequence of bases is typically represented 5' to 3'. As used herein, the term nucleic acid molecule encompasses 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 mixed 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, and both single- and double-stranded forms. Furthermore, the nucleic acid molecules described herein may contain naturally occurring or non-naturally occurring nucleotides. Examples of non-naturally occurring nucleotides include those containing derivatized sugar or phosphate backbone linkages or chemically modified residues, such as modified nucleotide bases. Nucleic acid molecules also encompass DNA and RNA molecules suitable as vectors for direct expression of the antibodies of the present invention in vitro and / or in vivo, for example, in a host or patient. Such DNA (e.g., cDNA) or RNA (e.g., mRNA) vectors may be unmodified or modified. For example, mRNA may be chemically modified to enhance the stability of the RNA vector and / or expression of the encoded molecule, allowing the mRNA to be injected into a subject to produce antibodies 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] An "isolated" nucleic acid refers to a nucleic acid molecule that is separated from a component of its natural environment.

[0064] An isolated nucleic acid includes a nucleic acid molecule that is present extrachromosomally or at a chromosomal location that is different from the natural chromosomal location of the nucleic acid molecule than that contained in a cell that normally contains the nucleic acid molecule. An "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, and includes 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] An "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, and includes 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] An "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, and includes 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., antibodies in which the individual antibodies comprising the population are identical and / or bind the same epitope, except for variant antibodies that may, for example, contain naturally occurring mutations or arise during the manufacture of a monoclonal antibody preparation, in which such variants are generally present in minor amounts. In contrast to polyclonal antibody preparations, which typically contain 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 character 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 produced by a variety of techniques, including, but not limited to, hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci, including, but not limited to, such methods and other exemplary methods for producing monoclonal antibodies described herein.

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

[0069] "Native antibodies" refer to naturally occurring immunoglobulin molecules with various structures. For example, native IgG antibodies are heterotetrameric glycoproteins of approximately 150,000 daltons, comprising two identical light chains and two identical heavy chains disulfide-linked. From the N-terminus to the C-terminus, each heavy chain contains a variable domain (VH), also called a 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 contains a variable domain (VL), also called a 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 instructions typically included in commercial packaging for a therapeutic product, including information regarding the indications, uses, dosage, administration, concomitant therapy, contraindications and / or warnings regarding such therapeutic product.

[0071] "Percent amino acid sequence identity" to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to those in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, without considering any conservative substitutions as part of the sequence identity. Alignment for determining percent amino acid sequence identity can be achieved in a variety of ways within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, Clustal W, Megalign (DNASTAR) software, or the FASTA program package. Those skilled in the art can determine appropriate parameters for sequence alignment, including any algorithms required to achieve maximum alignment across the entire length of the sequences being compared. Alternatively, percent identity values ​​can be generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was written by Genentech, Inc., and the source code is on file in the user documentation of the U.S. Copyright Office, Washington, DC 20559, registered under U.S. Copyright Registration No. TXU510087, and described in WO 2001 / 007611.

[0072] Unless otherwise noted, for purposes herein, percent amino acid sequence identity values ​​are generated using the ggsearch program of the FASTA package version 36.3.8c, followed by 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 at www.fasta.bioch.virginia.edu / fasta_www2 / fasta_down.shtml or www.ebi.ac.uk / Tools / sss / fasta. Alternatively, sequences can be compared using the public server accessible at fasta.bioch.virginia.edu / fasta_www2 / index.cgi using the ggsearch(global protein:protein) program and default options (BLOSUM50; open:-10; ext:-2; Ktup=2), ensuring global rather than local alignment. The percent amino acid identity is given in the output alignment header.

[0073] The term "pharmaceutical composition" or "pharmaceutical formulation" refers to a preparation that is in a form such that the biological activity of the active ingredients contained in the preparation is effective, and that does not contain additional ingredients that are unacceptably toxic to the subject to which 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. The terms encompass "full-length," unprocessed KLK5, as well as any form of KLK5 resulting from processing within a cell. The terms also encompass naturally occurring variants of KLK5, such as splice variants or allelic variants. The amino acid sequence of an exemplary human precursor KLK5 protein is set forth 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 propeptide (amino acids 23-66) is set forth in SEQ ID NO: 2. The amino acid sequence of an exemplary cynomolgus precursor KLK5 protein is set forth in SEQ ID NO: 100 (UniProtKB: A0A2K5W0T6). The amino acid sequence of an exemplary cynomolgus mature KLK5 protein lacking the signal peptide (amino acids 1-22) and propeptide (amino acids 23-64) is set forth 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. The terms encompass "full-length," unprocessed KLK7, as well as any form of KLK7 resulting from processing within a cell. The terms also encompass naturally occurring variants of KLK7, such as splice variants or allelic variants. The amino acid sequence of an exemplary human precursor KLK7 protein is set forth 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 set forth in SEQ ID NO: 4. The amino acid sequence of an exemplary cynomolgus monkey precursor KLK7 protein is set forth in SEQ ID NO: 5 (UniProtKB: G7PYG2). The amino acid sequence of an exemplary mature cynomolgus 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 grammatical variations thereof, e.g., "treat" or "treating") refers to clinical intervention in an attempt to alter the natural course of disease in the individual being treated, and may be performed prophylactically or during the course of clinical pathology. Desired effects of treatment include, but are not limited to, prevention of disease onset or recurrence, alleviation of symptoms, attenuation of any direct or indirect pathological consequences of the disease, prevention of metastasis, slowing the rate of disease progression, remission or palliation of symptoms, and improved or improved prognosis. In some embodiments, the antibodies of the invention are used to delay the onset of disease or to slow the progression of the 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 binding the antibody to an antigen. The variable domains of the heavy and light chains (VH and VL, respectively) of a native antibody generally have a similar structure, and each domain contains four conserved framework regions (FR) and three complementarity-determining regions (CDR). See, for example, Kindt et al., Kuby Immunology, 6 th See, ed. W.H. Freeman and Co., page 91 (2007). The variable domain may comprise heavy chain (HC) CDR1-FR2-CDR2-FR3-CDR3, with or without all or a portion of FR1 and / or FR4; and light chain (LC) CDR1-FR2-CDR2-FR3-CDR3, with or without all or a portion of FR1 and / or FR4. That is, the variable domain may lack a portion of FR1 and / or FR4, so long as it retains antigen-binding activity. A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind to a specific antigen may be isolated by screening a library of complementary VL or VH domains, respectively, using the VH or VL domain of an antibody that binds the antigen. See, e.g., 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 linked. The term includes vectors as self-replicating nucleic acid structures and vectors that integrate into the genome of a host cell into which the vector is introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operably linked. Such vectors are referred to herein as "expression vectors." II. Compositions and Methods

[0080] In one aspect, the present invention is based in part on the discovery that both KLK5 and KLK7 may play a role in epithelial barrier permeability.Therefore, inhibiting both KLK5 and KLK7 may demonstrate improved efficacy in treating conditions associated with excessive epithelial barrier permeability.In certain aspects, an antibody that binds to KLK5 is provided.In certain aspects, an antibody that binds to KLK7 is provided.In certain aspects, a multispecific antibody that binds to KLK5 and KLK7 is provided.The antibody of the present invention is useful for diagnosing or treating, for example, 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, an anti-KLK7 antibody inhibits KLK7 protease activity. In some embodiments, an 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, an 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, as measured by surface plasmon resonance. DIn some embodiments, the anti-KLK7 antibody binds to human KLK7 with 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, as 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 to N82, K152 to S158, and / or Q211 to K222 of KLK7, where 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 to N82, at least one amino acid within amino acids K152 to S158, and at least one amino acid within amino acids Q211 to K222 of KLK7, as numbered according to SEQ ID NO: 4. In some embodiments, the anti-KLK7 antibody binds to an epitope including 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 including 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 including 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 including 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, it causes a conformational change in human KLK7, and this conformational change allosterically disrupts the substrate binding site and / or 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 one, at least two, at least three, at least four, at least five, and / or all six 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 invention provides an antibody comprising at least one, at least two, or all three VH CDR sequences selected from (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. In one aspect, the antibody comprises a CDR-H3 comprising the amino acid sequence of SEQ ID NO:9. In another aspect, the antibody comprises a CDR-H3 comprising the amino acid sequence of SEQ ID NO:9 and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:12. In a further aspect, the antibody comprises a CDR-H3 comprising the amino acid sequence of SEQ ID NO:9, a CDR-L3 comprising the amino acid sequence of SEQ ID NO:12, and a CDR-H2 comprising the amino acid sequence of SEQ ID NO:8. In a further aspect, the antibody 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.

[0087] In another aspect, the 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 embodiment, an antibody of the 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: 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 (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: 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) 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; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (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.

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

[0091] In one embodiment, 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 to 128, (b) heavy chain framework region 2 (HC-FR2) of SEQ ID NOs: 130 to 133, (c) heavy chain framework region 3 (HC-FR3) of SEQ ID NOs: 135 to 143, and (d) heavy chain framework region 4 (HC-FR4) of SEQ ID NOs: 144 to 145.

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

[0093] In another embodiment, the anti-KLK7 antibody comprises a VH domain comprising an HC-FR1 with 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 embodiment, the VH domain comprises an HC-FR1 with at least 95% sequence identity to SEQ ID NOs: 123-128. In another embodiment, the VH domain comprises an HC-FR1 with at least 98% sequence identity to SEQ ID NOs: 123-128.

[0094] In another embodiment, the anti-KLK7 antibody comprises a VH domain comprising an HC-FR2 with 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 embodiment, the VH domain comprises an HC-FR2 with at least 95% sequence identity to SEQ ID NOs: 130-133. In another embodiment, the VH domain comprises an HC-FR2 with at least 98% sequence identity to SEQ ID NOs: 130-133.

[0095] In another embodiment, the anti-KLK7 antibody comprises a VH domain comprising an HC-FR3 with 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 embodiment, the VH domain comprises an HC-FR3 with at least 95% sequence identity to SEQ ID NOs: 135-143. In another embodiment, the VH domain comprises an HC-FR3 with at least 98% sequence identity to SEQ ID NOs: 135-143.

[0096] In another embodiment, the anti-KLK7 antibody comprises a VH domain comprising an HC-FR4 with 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 embodiment, the VH domain comprises an HC-FR4 with at least 95% sequence identity to SEQ ID NOs: 144-145. In another embodiment, the VH domain comprises an HC-FR4 with at least 98% sequence identity to SEQ ID NOs: 144-145.

[0097] In one embodiment, 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 to 150, (b) light chain framework region 2 (LC-FR2) of SEQ ID NOs: 152 to 154, (c) light chain framework region 3 (LC-FR3) of SEQ ID NOs: 156 to 158, and (d) light chain framework region 4 (LC-FR4) of SEQ ID NO: 160.

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

[0099] In another embodiment, the anti-KLK7 antibody comprises a VL domain comprising an LC-FR1 with 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 embodiment, the VL domain comprises an LC-FR1 with at least 95% sequence identity to SEQ ID NOs: 147-150. In another embodiment, the VL domain comprises an LC-FR1 with at least 98% sequence identity to SEQ ID NOs: 147-150.

[0100] In another embodiment, the anti-KLK7 antibody comprises a VL domain comprising an LC-FR2 with 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 embodiment, the VL domain comprises an LC-FR2 with at least 95% sequence identity to SEQ ID NOs: 152-154. In another embodiment, the VL domain comprises an LC-FR2 with at least 98% sequence identity to SEQ ID NOs: 152-154.

[0101] In another embodiment, the anti-KLK7 antibody comprises a VL domain comprising an LC-FR3 with 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 embodiment, the VL domain comprises an LC-FR3 with at least 95% sequence identity to SEQ ID NOs: 156-158. In another embodiment, the VL domain comprises an LC-FR3 with at least 98% sequence identity to SEQ ID NOs: 156-158.

[0102] In another embodiment, the anti-KLK7 antibody comprises a VL domain comprising an LC-FR4 with 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 embodiment, the VL domain comprises an LC-FR1 with at least 95% sequence identity to SEQ ID NO: 160. In another embodiment, the VL domain comprises an LC-FR1 with at least 98% sequence identity to SEQ ID NO: 160.

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

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

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

[0106] In one embodiment, an anti-KLK7 antibody comprises one or more light chain CDR amino acid sequences of a VL selected from SEQ ID NOs: 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 a framework amino acid sequence of a VL selected from SEQ ID NOs: 14 and 31-38. In one embodiment, an anti-KLK7 antibody comprises three light chain CDR amino acid sequences of a VL selected from SEQ ID NOs: 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 a framework amino acid sequence of a VL selected from SEQ ID NOs: 14 and 31-38. In one embodiment, the anti-KLK7 antibody comprises three light chain CDR amino acid sequences of a VL selected from SEQ ID NOs: 14 and 31 to 38, and a framework having at least 95% sequence identity to a VL framework amino acid sequence selected from SEQ ID NOs: 14 and 31 to 38. In another embodiment, the anti-KLK7 antibody comprises three light chain CDR amino acid sequences of a VL selected from SEQ ID NOs: 14 and 31 to 38, and a framework having at least 98% sequence identity, particularly to a VL framework amino acid sequence selected from SEQ ID NOs: 14 and 31 to 38.

[0107] In one embodiment, the anti-KLK7 antibody 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; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (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, as well as 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 embodiment, the VH domain has at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 13 and 15 to 30. In one embodiment, the VL domain has at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 14 and 31 to 38.

[0108] In one embodiment, 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 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 antibody specifically binds to KLK7. In one embodiment, 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 embodiment, 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 embodiment, the antibody has a dissociation constant (K) 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, as measured by surface plasmon resonance. D In one embodiment, the antibody binds to KLK7 with a dissociation constant (K) 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, as measured by surface plasmon resonance. D ) binds to KLK7.

[0109] In another embodiment, 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 to 30. In one embodiment, 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 to 30. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK7 antibody comprising that sequence retains the ability to bind to KLK7. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in an amino acid sequence selected from SEQ ID NOs: 13 and 15-30. In some embodiments, the substitutions, insertions, or deletions occur in regions outside 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, including post-translational modifications of that sequence. Optionally, the anti-KLK7 antibody comprises a VH sequence of SEQ ID NO: 29 or 30, including post-translational modifications of that sequence. In certain embodiments, 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, an anti-KLK7 antibody is provided that comprises 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 to 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 to 38.In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK7 antibody comprising that sequence retains the ability to bind to KLK7. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in an amino acid sequence selected from SEQ ID NOs: 14 and 31-38. 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 NOs: 14 and 31-38, including post-translational modifications of that sequence. Optionally, the anti-KLK7 antibody comprises a VL sequence of SEQ ID NO: 32 or 38, including post-translational modifications of that 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 aspect, an anti-KLK7 antibody is provided, comprising a VH sequence as in any of the aspects provided above and a VL sequence as in any of the aspects provided above. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO:29 and SEQ ID NO:32, respectively, including post-translational modifications of said sequences. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO:30 and SEQ ID NO:38, respectively, including post-translational modifications of said sequences.

[0111] In a further aspect, the present invention provides antibodies that bind to the same epitope as the anti-KLK7 antibodies provided herein. For example, in a specific aspect, 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 aspect, the present invention provides antibodies that compete with the anti-KLK7 antibodies provided herein for binding to KLK7.

[0113] In a further embodiment of the present invention, the anti-KLK7 antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric antibody, a humanized antibody, or a human antibody. In one embodiment, the anti-KLK7 antibody is an antibody fragment, such as an 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 other antibody classes or isotypes as defined herein.

[0114] In further embodiments, anti-KLK7 antibodies according to any of the above embodiments 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 present invention provides an antibody that binds to KLK5. In one aspect, an isolated antibody that binds to KLK5 is provided. In one aspect, the present invention provides an antibody that specifically binds to KLK5. In certain aspects, an anti-KLK5 antibody inhibits KLK5 protease activity. In some embodiments, an anti-KLK5 antibody inhibits human KLK5-mediated cleavage of the substrate Boc-Val-Pro-Arg-AMC. In some embodiments, an 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, an 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 has 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 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. D It binds to KLK5.

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

[0117] In some embodiments, the anti-KLK5 antibody comprises Pro130, Ser131, Ala132 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). , 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. See, for example, PCT Publication No. WO 2019 / 178316A1. In some embodiments, the anti-KLK5 antibody binds to an epitope on human KLK5 that includes 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 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.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 one, at least two, at least three, at least four, at least five, and / or all six 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 to 49.

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

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

[0122] In one aspect, the 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, an 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 (c) 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) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 39; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 41; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 43; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 47.

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

[0127] In one embodiment, 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 region 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 embodiment, the anti-KLK5 antibody comprises a VH domain comprising an HC-FR1 of SEQ ID NO: 161. In another embodiment, the anti-KLK5 antibody comprises a VH domain comprising an HC-FR2 of SEQ ID NOs: 162-163. In another embodiment, the anti-KLK5 antibody comprises a VH domain comprising an HC-FR3 of SEQ ID NO: 164. In another embodiment, the anti-KLK5 antibody comprises a VH domain comprising an HC-FR4 of SEQ ID NO: 165.

[0129] In another embodiment, the anti-KLK5 antibody comprises a VH domain comprising an HC-FR1 with 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 embodiment, the VH domain comprises an HC-FR1 with at least 95% sequence identity to SEQ ID NO: 161.

[0130] In another embodiment, the VH domain comprises an HC-FR1 with at least 98% sequence identity to SEQ ID NO:161. In another embodiment, the anti-KLK5 antibody comprises a VH domain comprising an HC-FR2 with 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 embodiment, the VH domain comprises an HC-FR2 with at least 95% sequence identity to SEQ ID NOs: 162-163. In another embodiment, the VH domain comprises an HC-FR2 with at least 98% sequence identity to SEQ ID NOs: 162-163.

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

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

[0133] In one embodiment, the anti-KLK5 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 NO: 166, (b) light chain framework region 2 (LC-FR2) of SEQ ID NO: 167-168, (c) light chain framework region 3 (LC-FR3) of SEQ ID NO: 169, and (d) light chain framework region 4 (LC-FR4) of SEQ ID NO: 170.

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

[0135] In another embodiment, the anti-KLK5 antibody comprises a VL domain comprising an LC-FR1 with 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 embodiment, the VL domain comprises an LC-FR1 with at least 95% sequence identity to SEQ ID NO: 166. In another embodiment, the VL domain comprises an LC-FR1 with at least 98% sequence identity to SEQ ID NO: 166.

[0136] In another embodiment, the anti-KLK5 antibody comprises a VL domain comprising an LC-FR2 with 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 embodiment, the VL domain comprises an LC-FR2 with at least 95% sequence identity to SEQ ID NOs: 167-168. In another embodiment, the VL domain comprises an LC-FR2 with at least 98% sequence identity to SEQ ID NOs: 167-168.

[0137] In another embodiment, the anti-KLK5 antibody comprises a VL domain comprising an LC-FR3 with 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 embodiment, the VL domain comprises an LC-FR3 with at least 95% sequence identity to SEQ ID NO: 169. In another embodiment, the VL domain comprises an LC-FR3 with at least 98% sequence identity to SEQ ID NO: 169.

[0138] In another embodiment, the anti-KLK5 antibody comprises a VL domain comprising an LC-FR4 with 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 embodiment, the VL domain comprises an LC-FR4 with at least 95% sequence identity to SEQ ID NO: 170. In another embodiment, the VL domain comprises an LC-FR4 with at least 98% sequence identity to SEQ ID NO: 170.

[0139] In another aspect, the anti-KLK5 antibody comprises one or more of the VH CDR sequences of SEQ ID NO: 50, 52, 53, 105, or 106. In another embodiment, the anti-KLK5 antibody comprises one or more VL CDR sequences of SEQ ID NO: 51 or 54-57. In another embodiment, the anti-KLK5 antibody comprises the VH CDR sequences of SEQ ID NO: 50, 52, 53, 105, or 106 and the VL CDR sequences 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 embodiment, 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 of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 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 embodiment, an anti-KLK5 antibody comprises three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 50, 52, 53, 105, or 106 and a framework of 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 embodiment, an anti-KLK5 antibody comprises three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 50, 52, 53, 105, or 106 and a framework of 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 embodiment, the anti-KLK5 antibody comprises 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 embodiment, an anti-KLK5 antibody comprises one or more light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 51 or 54-57 and a framework of 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 embodiment, an anti-KLK5 antibody comprises three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 51 or 54-57 and a framework of 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 embodiment, the anti-KLK5 antibody comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 51 or 54 to 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 to 57. In another embodiment, the anti-KLK5 antibody comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 51 or 54 to 57 and a framework having at least 98% sequence identity, particularly to the framework amino acid sequence of the VH domain of SEQ ID NO: 50, 52, 53, 105, and 106.

[0143] In one embodiment, 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 to 49, and CDR-L4 comprising the amino acid sequences of SEQ ID NOs: 47 to 49. The present invention also includes 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 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 sequence of SEQ ID NOs: 51 and 54-67. In one embodiment, the VH domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NOs: 50, 52, 53, 105, and 106. In one embodiment, the VL domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NOs: 51 and 54-67.

[0144] In one embodiment, the anti-KLK5 antibody comprises (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 39 or 107; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 40 or 41; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42; (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 the amino acid sequence of SEQ ID NO: 46 to 49, and a CDR-L4 comprising the amino acid sequence of SEQ ID NO: 50, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 1 and a CDR-L3 comprising 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 NOs: 51 and 54-67; and specifically binds to KLK5. In one embodiment, the VH domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NOs: 50, 52, 53, 105, and 106. In one embodiment, the VL domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NOs: 51 and 54-67. In one embodiment, the antibody has a dissociation constant (K D ) compared to the dissociation constants (K D ) binds to KLK5.

[0145] In another embodiment, 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 NOs: 50, 52, 53, 105, and 106. In one embodiment, 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 NOs: 50, 52, 53, 105, and 106. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, 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 embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises a VH sequence of SEQ ID NOs: 50, 52, 53, 105, and 106, including post-translational modifications of that sequence. In certain embodiments, the VH comprises at least one, at least two, or all three CDRs selected from (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 39 or 107, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 40 or 41, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42. In another embodiment, an anti-KLK5 antibody is provided that comprises 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 NOs: 51 and 54 to 67. In one embodiment, 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 NOs: 51 and 54 to 67.In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NOs: 51 and 54-67. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence of SEQ ID NOs: 51 and 54-67, including post-translational modifications of that sequence. In certain embodiments, the VL comprises at least one, at least two, and / or all three 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 to 49.

[0146] In another aspect, an anti-KLK5 antibody is provided comprising a VH sequence as in any of the aspects provided above, and a VL sequence as in any of the aspects provided above. In one aspect, 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, respectively, including post-translational modifications of the sequences.

[0147] In a further aspect, the present invention provides antibodies that bind to the same epitope as the anti-KLK5 antibodies provided herein. For example, in a specific aspect, antibodies are provided that bind to the same epitope as the anti-KLK5 antibodies 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 present invention, the anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric antibody, a humanized antibody, or a human antibody. In one embodiment, the anti-KLK5 antibody is an antibody fragment, such as an 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 other antibody classes or isotypes as defined herein.

[0149] In further embodiments, anti-KLK5 antibodies according to any of the above embodiments 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 one, at least two, at least three, at least four, at least five, and / or all six 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 NOs: 69 and 70; (c) CDR-H3 comprising the amino acid sequences of 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 the amino acid sequences of SEQ ID NOs: 75 to 78.

[0151] In one aspect, the invention provides an antibody comprising at least one, at least two, or all three VH CDR sequences selected from: (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 the amino acid sequence of SEQ ID NO: 72. In a further aspect, the antibody comprises: (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 the amino acid sequence of SEQ ID NO: 72.

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

[0153] In another aspect, an 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 to 78.

[0154] In another aspect, the present invention provides an antibody 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; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 72; (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 the amino acid sequence of SEQ ID NO: 76.

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

[0156] In one embodiment, 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 embodiment, the anti-KLK5 antibody comprises a VH domain comprising an HC-FR1 of SEQ ID NO: 171. In another embodiment, the anti-KLK5 antibody comprises a VH domain comprising an HC-FR2 of SEQ ID NO: 172 or 173. In another embodiment, the anti-KLK5 antibody comprises a VH domain comprising an HC-FR3 of SEQ ID NO: 174. In another embodiment, the anti-KLK5 antibody comprises a VH domain comprising an HC-FR4 of SEQ ID NO: 175.

[0158] In another embodiment, the anti-KLK5 antibody comprises a VH domain comprising an HC-FR1 with 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 embodiment, the VH domain comprises an HC-FR1 with at least 95% sequence identity to SEQ ID NO: 171. In another embodiment, the VH domain comprises an HC-FR1 with at least 98% sequence identity to SEQ ID NO: 171.

[0159] In another embodiment, the anti-KLK5 antibody comprises a VH domain comprising an HC-FR2 with 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 embodiment, the VH domain comprises an HC-FR2 with at least 95% sequence identity to SEQ ID NO: 172 or 173. In another embodiment, the VH domain comprises an HC-FR2 with at least 98% sequence identity to SEQ ID NO: 172 or 173.

[0160] In another embodiment, the anti-KLK5 antibody comprises a VH domain comprising an HC-FR3 with 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 embodiment, the VH domain comprises an HC-FR3 with at least 95% sequence identity to SEQ ID NO: 174. In another embodiment, the VH domain comprises an HC-FR3 with at least 98% sequence identity to SEQ ID NO: 174.

[0161] In another embodiment, the anti-KLK5 antibody comprises a VH domain comprising an HC-FR4 with 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 embodiment, the VH domain comprises an HC-FR4 with at least 95% sequence identity to SEQ ID NO: 175. In another embodiment, the VH domain comprises an HC-FR4 with at least 98% sequence identity to SEQ ID NO: 175.

[0162] In one embodiment, the anti-KLK5 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 NO: 176, (b) light chain framework region 2 (LC-FR2) of SEQ ID NO: 177-178, (c) light chain framework region 3 (LC-FR3) of SEQ ID NO: 179, and (d) light chain framework region 4 (LC-FR4) of SEQ ID NO: 180.

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

[0164] In another embodiment, the anti-KLK5 antibody comprises a VL domain comprising an LC-FR1 with 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 embodiment, the VL domain comprises an LC-FR1 with at least 95% sequence identity to SEQ ID NO: 176. In another embodiment, the VL domain comprises an LC-FR1 with at least 98% sequence identity to SEQ ID NO: 176.

[0165] In another embodiment, the anti-KLK5 antibody comprises a VL domain comprising an LC-FR2 with 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 embodiment, the VL domain comprises an LC-FR2 with at least 95% sequence identity to SEQ ID NO: 177 or 178. In another embodiment, the VL domain comprises an LC-FR2 with at least 98% sequence identity to SEQ ID NO: 177 or 178.

[0166] In another embodiment, the anti-KLK5 antibody comprises a VL domain comprising an LC-FR3 with 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 embodiment, the VL domain comprises an LC-FR3 with at least 95% sequence identity to SEQ ID NO: 179. In another embodiment, the VL domain comprises an LC-FR3 with at least 98% sequence identity to SEQ ID NO: 179.

[0167] In another embodiment, the anti-KLK5 antibody comprises a VL domain comprising an LC-FR4 with 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 embodiment, the VL domain comprises an LC-FR1 with at least 95% sequence identity to SEQ ID NO: 180. In another embodiment, the VL domain comprises an LC-FR1 with at least 98% sequence identity to SEQ ID NO: 180.

[0168] In another aspect, the anti-KLK5 antibody comprises one or more of the VH CDR sequences of SEQ ID NO: 79 or 81 to 87. In another embodiment, the anti-KLK5 antibody comprises one or more VL CDR sequences of SEQ ID NO: 80 or 88 to 94. In another embodiment, the anti-KLK5 antibody comprises the VH CDR sequences of SEQ ID NO: 79 or 81 to 87 and the VL CDR sequences of SEQ ID NO: 80 or 88 to 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 embodiment, an anti-KLK5 antibody comprises one or more heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 79 or 81-87 and a framework of 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 embodiment, an anti-KLK5 antibody comprises three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 79 or 81-87 and a framework of 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 embodiment, the anti-KLK5 antibody comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 79 or 81 to 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 to 87. In another embodiment, the anti-KLK5 antibody comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 79 or 81 to 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 to 87.

[0171] In one embodiment, an anti-KLK5 antibody comprises one or more light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 80 or 88-94 and a framework of 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 embodiment, an anti-KLK5 antibody comprises three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 80 or 88-94 and a framework of 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 embodiment, the anti-KLK5 antibody comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 80 or 88 to 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 to 94. In another embodiment, the anti-KLK5 antibody comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 80 or 88 to 94 and a framework having at least 98% sequence identity, particularly to the framework amino acid sequence of the VH domain of SEQ ID NO: 80 or 88 to 94.

[0172] In one embodiment, 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 NOs: 69 to 70; (c) CDR-H3 comprising the amino acid sequences of SEQ ID NOs: 71 to 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 to 78, and CDR-L4 comprising the amino acid sequences of SEQ ID NOs: 79 to 80. The present invention also includes 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 embodiment, the VH domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 79 or 81-87. In one embodiment, 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 embodiment, 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 NOs: 69 to 70; (c) CDR-H3 comprising the amino acid sequences of SEQ ID NOs: 71 to 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 to 78, and CDR-L4 comprising the amino acid sequences of SEQ ID NOs: 79 or 8. The present invention relates to a method for specifically binding to KLK5, comprising 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: 1-87, 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 embodiment, the VH domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 79 or 81-87. In one embodiment, the VL domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 80 or 88-94. In one embodiment, the antibody has a dissociation constant (K D ) compared to the dissociation constants (K D ) binds to KLK5.

[0174] In another embodiment, 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 embodiment, 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 embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 79 or 81-87. In some embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises a VH sequence of SEQ ID NO: 79 or 81-87, including post-translational modifications of that sequence. In certain embodiments, 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 embodiment, an anti-KLK5 antibody is provided that comprises 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 to 94. In one embodiment, 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 to 94. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5.In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 80 or 88-94. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., FRs). Optionally, the anti-KLK5 antibody comprises a VL sequence of SEQ ID NO: 80 or 88-94, including post-translational modifications of that 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: 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: 75-78.

[0175] In another aspect, an anti-KLK5 antibody is provided comprising a VH sequence as in any of the aspects provided above, and a VL sequence as in any of the aspects provided above. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NOs: 79 or 81-87 and 80 or 88-94, respectively, including post-translational modifications of those sequences.

[0176] In a further aspect, the present invention provides antibodies that bind to the same epitope as the anti-KLK5 antibodies provided herein. For example, in a specific aspect, there is provided an antibody that binds to the same epitope as an anti-KLK5 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.

[0177] In a further embodiment of the present invention, the anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric antibody, a humanized antibody, or a human antibody. In one embodiment, the anti-KLK5 antibody is an antibody fragment, such as an 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 other antibody classes or isotypes as defined herein.

[0178] In further embodiments, anti-KLK5 antibodies 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 Multispecific Antibodies

[0179] In one aspect, the present invention provides multispecific antibodies that bind to both KLK5 and KLK7. In some embodiments, bispecific antibodies that bind to both KLK5 and KLK7 are provided. In some embodiments, the multispecific (e.g., bispecific) antibodies inhibit both KLK5 protease activity and KLK7 protease activity. In some embodiments, the multispecific (e.g., bispecific) antibodies have 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 multispecific (e.g., bispecific) antibody binds to KLK5 with 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, as measured by surface plasmon resonance. D In some embodiments, the multispecific (e.g., bispecific) antibody binds to KLK7 with a K 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. D In some embodiments, the multispecific (e.g., bispecific) antibody binds to KLK5 with 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, as measured by surface plasmon resonance. D It binds to KLK7.

[0180] In some embodiments, the anti-KLK5 / KLK7 multispecific antibody inhibits human KLK7 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 (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 (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 K50 of the multispecific antibody against human KLK5 D and K of antibodies 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.

[0181] In some embodiments, a 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, upon binding to human KLK5, causes a conformational change in human KLK5, which allosterically results in the 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, upon binding to human KLK7, causes a conformational change in human KLK7, which allosterically results in the 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 described herein. For example, in some such embodiments, 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; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO:9; (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. As a further non-limiting example, in some embodiments, 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; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO:9; (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 CDR-L3 comprising the amino acid sequence of SEQ ID NO:13. 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: 14 and 31-38, 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 those 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 those sequences.

[0184] In some embodiments, the second binding domain comprises an anti-KLK5 antibody binding domain described herein. For example, in some such embodiments, the second binding domain comprises (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. As a further non-limiting example, in some embodiments, the second binding domain comprises (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, (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) an amino acid sequence selected from SEQ ID NOs: 46-49. The second binding domain comprises a light chain variable domain (VL) comprising a CDR-L3, 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 those 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 those sequences.

[0185] In some embodiments, the second binding domain comprises (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 to 78. As a further non-limiting example, in some embodiments, the second binding domain comprises (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, (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 to 78. The second binding domain comprises a light chain variable domain (VL) comprising DR-L3, 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 those 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 those sequences.

[0186] In some embodiments, a multispecific antibody (e.g., a bispecific antibody) is provided, wherein a first binding domain binds to KLK7 and a second binding domain binds to KLK5, the first binding domain being an anti-KLK7 antibody binding domain provided herein, and the second binding domain being 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) 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; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (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 the second binding domain comprises a light chain variable domain (VL) 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, (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. In some embodiments, 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; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (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 the second binding domain comprises (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 to 78.

[0188] In some embodiments, 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; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (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 an amino acid sequence selected from SEQ ID NOs: 13 and 15-30. the second binding domain comprises (a) 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: 14 and 31-38, 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: 39 and 107; a light chain variable domain (VL) comprising (a) a CDR-H1 comprising an amino acid sequence selected from SEQ ID NOs: 40 and 41, (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, (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 to 49; 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) 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; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (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 an amino acid 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) 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: 14 and 31-38; a light chain variable domain (VL) comprising: (a) a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 69; (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; (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 to 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.

[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 and the second binding domain binds to human KLK5, and 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; (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) a light chain variable domain (VL) comprising a 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) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 39, (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 the amino acid sequence of SEQ ID NO: 43, (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (f) a 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 and the second binding domain binds to human KLK5, and 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; (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) a light chain variable domain (VL) comprising a 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) 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 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 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 and the second binding domain binds to human KLK5, and 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 comprises 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 comprises 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 and the second binding domain binds to human KLK5, and 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 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) and 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) and 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 mispairing of the heavy and light chains 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 a S183K substitution (EU numbering), the first light chain constant region comprises a V133E substitution (EU numbering), the second heavy chain constant region comprises a 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 a S183E substitution (EU numbering), the first light chain constant region comprises a V133K substitution (EU numbering), the second heavy chain constant region comprises a 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 mispairing of the heavy and light chains of the bispecific antibody.

[0196] In some embodiments, the bispecific anti-KLK5 / KLK7 antibody comprises Q39E / Q38K and Q39K / Q38E substitutions in the binding domain and S183K / V133E and S183E / V133K substitutions in the constant region. See, for example, WO 2016 / 172485, which is incorporated herein by reference in its entirety for any purpose. A non-limiting exemplary schematic diagram of a bispecific antibody is shown in Figure 15.

[0197] In some embodiments, a bispecific anti-KLK5 / KLK7 antibody is provided, 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. In some embodiments, a bispecific anti-KLK5 / KLK7 antibody is provided, 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.

[0198] In some embodiments, a bispecific anti-KLK5 / KLK7 antibody is provided, 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: 114 or 195 and a light chain amino acid sequence of SEQ ID NO: 111. In some embodiments, a bispecific anti-KLK5 / KLK7 antibody is provided, 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: 110 or 193 and a light chain amino acid sequence of SEQ ID NO: 115.

[0199] In some embodiments, a bispecific anti-KLK5 / KLK7 antibody is provided, 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: 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: 195 and a light chain amino acid sequence of SEQ ID NO: 115.

[0200] In some embodiments, a bispecific anti-KLK5 / KLK7 antibody is provided, 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: 195 and a light chain amino acid sequence of SEQ ID NO: 115.

[0201] In some embodiments, a bispecific anti-KLK5 / KLK7 antibody is provided, 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: 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 and a light chain amino acid sequence of SEQ ID NO: 115.

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

[0203] In certain embodiments, the antibodies provided herein have a cytotoxicity 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, e.g. 10 -9M~10 -13 Dissociation constant (K D )

[0204] In one embodiment, K D is measured using surface plasmon resonance. D is used with a BIAcore™ T200 or BIAcore™ 8K assay. 登録商標 ) is measured using a surface plasmon resonance assay. For example, an assay using a BIAcore™ 8K (BIAcore, Inc., Piscataway, NJ) is performed at 25°C or 37°C with immobilized antibodies on a protein A chip at approximately 300 response units (RU). Ten-fold serial dilutions of 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, ten-fold serial dilutions of antigen are injected into HBS-P buffer at 25°C at a flow rate of 30 μL / min. The binding rate (ka) and dissociation rate (kd) were calculated using a 1:1 Langmuir binding model (BIAcore™ T200 Evaluation Software Version 2.0). The equilibrium dissociation constant (KD) was calculated as the ratio kd / ka.

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

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

[0207] In one embodiment, the antibody fragment is a Fab, Fab', Fab'-SH, or F(ab')2 fragment, particularly a Fab fragment. Papain digestion of an intact antibody yields two identical antigen-binding fragments (so-called "Fab" fragments), each containing the heavy and light chain variable domains (VH and VL, respectively) as well as the light chain constant domain (CL) and the first heavy chain constant domain (CH1). 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 the addition of residues at the carboxy terminus of the CH1 domain, including one or more cysteines from the antibody hinge region. Fab'-SH is a Fab' fragment in which the cysteine ​​residues (multivalent) in the constant domains retain a free thiol group. Pepsin treatment yields a F(ab')2 fragment containing two antigen-binding sites (two Fab fragments) and part of the Fc region. See US Pat. No. 5,869,046 for a description of Fab and F(ab')2 fragments that contain salvage receptor binding epitope residues and have increased half-lives in vivo.

[0208] In another embodiment, the antibody fragment is a diabody, triabody, or tetrabody. A "diabody" is an antibody fragment having two antigen-binding sites, which may 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 tetrabodies are also described in Hudson et al., Nat. Med. 9:129-134 (2003).

[0209] In a further embodiment, 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, where the antibody domains and linker are arranged in one of the following orders from N- to 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 32-50 amino acids. The single-chain Fab fragment is stabilized by a native disulfide bond between the CL and CH1 domains. In addition, these single-chain Fab fragments can be further stabilized by the creation of interchain disulfide bonds through the insertion of cysteine ​​residues (e.g., at position 44 in the variable heavy chain and position 100 in the variable light chain according to the Kabat numbering).

[0210] In another embodiment, 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 an antibody's heavy chain (VH) and light chain (VL) 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, which can connect the N-terminus of the VH to the C-terminus of the VL, or vice versa. This protein can retain the specificity of the original antibody despite the removal of the constant regions and the introduction of the linker. For a review of scFv fragments, see, for example, Plückthun, The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994). See also WO 93 / 16185 and U.S. Patent Nos. 5,571,894 and 5,587,458.

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

[0212] Antibody fragments can be produced by a variety of techniques, including but not limited to, proteolytic digestion of intact antibodies and recombinant production in recombinant host cells (eg, E. coli), as described herein. 3. Chimeric and humanized antibodies

[0213] In certain embodiments, 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 comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate such as a monkey) and a human constant region. In a further example, a chimeric antibody is a "class-switched" antibody whose class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.

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

[0215] Humanized antibodies and methods for their production are reviewed in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and further described in Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat'l Acad. Sci. USA 86:10029-10033 (1989); U.S. Patent 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) (describing resurfacing); Dall'Acqua et al., Methods 36:43-60 (2005) (describing FR shuffling); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (describing a "guided selection" approach to FR shuffling).

[0216] Human framework regions that can be used for humanization include, but are not limited to, framework regions selected using the "best-fit" method (see, e.g., Sims et al., J. Immunol. 151:2296 (1993)); framework regions derived from the consensus sequence of human antibodies of a particular subgroup of 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 (somatically 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 produced using various 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 immunogens to transgenic animals that have been engineered to produce intact human antibodies or intact antibodies with human variable regions in response to antigen challenge. Such animals typically contain all or part of the human immunoglobulin loci that replace the endogenous immunoglobulin loci, or that are extrachromosomally present or randomly integrated into the animal's chromosomes. In such transgenic mice, the endogenous immunoglobulin loci are 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, XENOMOUSE. (商標) See also U.S. Patent Nos. 6,075,181 and 6,150,584, which describe HuMab® technology; U.S. Patent No. 5,770,429, which describes HuMab® technology; U.S. Patent No. 7,041,870, which describes KM MOUSE® technology; and U.S. Patent Application Publication No. 2007 / 0061900, which describes VelociMouse® technology. The human variable regions from intact antibodies produced by such animals may be further modified, for example, by combining with different human constant regions.

[0219] Human antibodies can also be produced using hybridoma methods. 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 produced 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 (which describes the production of monoclonal human IgM antibodies from hybridoma cell lines), and Ni, Xiandai Mianyixue, 26(4):265-268 (2006), which describes 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 human-derived phage display libraries. These variable domain sequences can then be combined with desired human constant domains. Techniques for selecting human antibodies from antibody libraries are described below. 5. Library-derived antibodies

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

[0222] In one particular phage display method, repertoires of VH and VL genes are individually cloned by polymerase chain reaction (PCR) and randomly recombined into phage libraries, which can then be screened for antigen-binding phage, as described by Winter et al. in Annual Review of Immunology 12:433-455 (1994). Phages typically display antibody fragments as either single-chain Fv (scFv) fragments or Fab fragments. Libraries from immune sources provide high-affinity antibodies to immunogens 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 of antigens, from non-self to self, without immunization, as described by Griffiths et al., EMBO Journal 12:725-734 (1993). Finally, naive libraries can also be synthetically generated by cloning unrearranged V gene segments from stem cells and using PCR primers containing random sequences to encode highly variable CDR3 regions and achieve in vitro reordering, 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 the method known in the art for screening combinatorial libraries for antibodies with desired activity(ies) include ribosome and mRNA display, and antibody display and selection methods in bacteria, mammalian cells, insect cells or yeast cells.Methods for yeast surface display are, for example, outlined in Scholler et al., Methods in Molecular Biology 503:135-56 (2012), Cherf et al., Methods in Molecular biology 1319:155-175 (2015), and Zhao et al., Methods in Molecular Biology 889:73-84 (2012).Methods for ribosome display are, for example, described 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 human antibodies or human antibody fragments herein. 6. Multispecific antibodies

[0225] In certain embodiments, the antibodies provided herein are multispecific antibodies, for example, bispecific antibodies. A multispecific antibody is a monoclonal antibody that has 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, a multispecific antibody has three or more binding specificities. In certain embodiments, one of the binding specificities is for KLK7, and the other specificity is 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, a bispecific antibody can bind to two (or more) different epitopes of an antigen. A multispecific antibody can be prepared as a full-length antibody or an antibody fragment.

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

[0227] Multispecific antibodies can also be created by manipulating electrostatic steering effects to create antibody Fc-heterodimeric molecules. See, for example, 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 comprise a Q39E substitution (Kabat numbering), and the first light chain variable region can comprise a Q38K substitution (Kabat numbering). The second heavy chain variable region can comprise a Q39K substitution (Kabat numbering), and the second light chain variable region can comprise a Q38E substitution (Kabat numbering). In some embodiments, the Q39E / Q38K and Q39K / Q38E substitutions reduce mispairing of the heavy and light chains of the bispecific antibody. Similarly, the first heavy chain constant region may comprise a S183K substitution (EU numbering), the first light chain constant region may comprise a V133E substitution (EU numbering), the second heavy chain constant region may comprise a S183E substitution (EU numbering), and the second light chain constant region may comprise a V133K substitution (EU numbering). In some embodiments, the S183K / V133E and S183E / V133K substitutions reduce mispairing of the heavy and light chains 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, bispecific antibodies contain both knob-in-hole and electrostatic substitutions. See, e.g., WO 2016 / 172485, which is incorporated herein by reference in its entirety for any purpose. A non-limiting, exemplary schematic diagram of a bispecific antibody is shown in Figure 15.

[0229] Thus, in some embodiments, a multispecific antibody comprises: a) a first heavy chain / light chain pair that binds to a first antigen, the first heavy chain polypeptide (H1) and the first light chain polypeptide (L1); and b) a second heavy chain / light chain pair that binds to a second antigen, the second heavy chain polypeptide (H2) and the 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) and 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 a S183K mutation, the CL of L1 comprises a V133E mutation, the CH1 of H2 comprises a S183E mutation, and the CL domain of L2 comprises a V133K mutation. In some embodiments, the VH domain of H1 comprises a Q39E mutation, the VL domain of L1 comprises a Q38K mutation, the VH domain of H2 comprises a Q39K mutation, and the VL domain of L2 comprises a 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. Pat. No. 4,676,980, and Brennan et al., Science, 229:81 (1985)); using leucine zippers to produce bispecific antibodies (see, e.g., Kostelny et al., J. Immunol., 148(5):1547-1553 (1992), and WO 2011 / 034605); using conventional light chain technology to circumvent the light chain mispairing problem (see, e.g., WO 98 / 50431); using "diabody" technology to generate bispecific antibody fragments (see, e.g., Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993)); as well as by the use of single-chain Fv (sFv) dimers (see, e.g., Gruber et al., J. Immunol., 152:5368 (1994)); and by the preparation of trispecific antibodies, for example, as described in Tutt et al., J. Immunol. 147:60 (1991).

[0231] Also included herein are engineered antibodies with three or more antigen-binding sites, including, for example, "Octopus antibodies," or DVD-Igs (see, e.g., WO 2001 / 77342 and WO 2008 / 024715). Other examples of multispecific antibodies with three or more antigen-binding sites can be found in WO 2010 / 115589, WO 2010 / 112193, WO 2010 / 136172, WO 2010 / 145792, and WO 2013 / 026831. Bispecific antibodies or antigen-binding fragments thereof also include "dual-acting FAbs" or "DAFs" that contain antigen-binding sites that bind to KLK7 and another different antigen, such as KLK5 (see, e.g., U.S. Patent Application Publication No. 2008 / 0069820 and WO 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, e.g., WO 2009 / 080253), or complete Fab arms (see, e.g., WO 2009 / 080251, WO 2016 / 016299; see also Schaefer et al., PNAS, 108 (2011) 1187-1191, and Klein at al., MAbs 8 (2016) 1010-20). In one embodiment, the multispecific antibody comprises a cross-Fab fragment. The terms "cross-Fab fragment" or "xFab fragment" or "crossover 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 contains 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). 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, for example, WO 2016 / 172485.

[0233] A variety of additional molecular formats of multispecific antibodies are known in the art and are included herein (see, for example, Spiess et al., Mol Immunol 67 (2015) 95-106).

[0234] Examples of bispecific antibody formats that may be useful for this purpose include so-called "BiTE" (bispecific T cell engager) molecules, in which two scFv molecules are fused by a flexible linker (see, e.g., WO 2004 / 106381, WO 2005 / 061547, WO 2007 / 042261 and WO 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 ("TandAbs"; Kipriyanov et al., J Mol Biol 293, 41-56 (1999); "DART" (dual affinity retargeting) molecules, which are based on the diabody format but feature a C-terminal disulfide bridge for stabilizing attachment (Johnson et al., J Mol Biol 399, 436-449 (2010)), and so-called triomabs, which are all-hybrid mouse / rat IgG molecules (reviewed in Seimetz et al., Cancer Treat Rev 36, 458-467 (2010)). Specific T cell bispecific antibody formats included herein are described in WO 2013 / 026833, WO 2013 / 026839, WO 2016 / 020309; Bacac et al., Oncoimmunology 5(8) (2016) e1203498. 7. Antibody Variants

[0235] In certain embodiments, amino acid sequence variants of the antibodies provided herein are contemplated. For example, it may be desirable to change the binding affinity and / or other biological properties of the antibody. Amino acid sequence variants of antibodies 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, as 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 with one or more amino acid substitutions are provided. Sites of interest for substitution mutagenesis include CDRs and FRs. Conservative substitutions are shown in Table 1 under the heading of "preferred substitutions." More substantial changes are provided in Table 1 under the heading of "exemplary substitutions," and are further described below with reference to amino acid side chain classes. Amino acid substitutions can be introduced into the antibody of interest, and the products are screened for desired activity, such as retained / improved antigen binding, reduced immunogenicity, or improved ADCC or CDC. JPEG0007807367000001.jpg129170

[0237] Amino acids can be classified according to general 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 affecting chain orientation: Gly, Pro; (6) Aromatic: Trp, Tyr, Phe.

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

[0239] Certain substitutional variants involve substituting 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 modifications (e.g., improvements) in certain biological properties (e.g., increased affinity, decreased immunogenicity) compared to the parent antibody and / or will substantially retain certain biological properties of the parent antibody. An exemplary substitutional variant is an affinity-matured antibody, which can be conveniently generated using, for example, phage-display-based affinity maturation techniques as described herein. Briefly, one or more CDR residues are mutated, and the variant antibodies are displayed on phage and screened for a particular biological activity (e.g., binding affinity).

[0240] To improve antibody affinity, modifications (e.g., substitutions) may be made, for example, in CDRs. Such modifications may be made in CDR "hot spots," i.e., residues encoded by codons that undergo frequent mutation during the somatic maturation process (e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and / or 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, Methods in Molecular Biology 178:1-37 (O'Brien et al., eds., Human Press, Totowa, NJ, (2001)). In some embodiments 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 generated. This library is then screened to identify antibody variants with the desired affinity. Another method for 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 embodiments, substitutions, insertions, or deletions can occur within one or more CDRs, as long as such modifications do not substantially reduce the antibody's ability to bind to the antigen. For example, conservative changes (e.g., conservative substitutions provided herein) that do not substantially reduce binding affinity can be made in the CDRs. Such modifications can be, for example, outside the antigen-contacting residues in the CDRs. In the above-mentioned specific variant VH and VL sequences, each CDR is either unmodified or has one, two, or three or fewer amino acid substitutions.

[0242] A useful method for identifying antibody residues or regions that can be targeted for mutagenesis is called "alanine scanning mutagenesis," as described by Cunningham and Wells (1989) Science, 244:1081-1085. In this method, residues or groups 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 antigen is affected. Further substitutions can be introduced at amino acid positions that demonstrate functional sensitivity to the initial substitution. Alternatively, or in addition, a crystal structure of an antigen-antibody complex can be used to identify contact points between the antibody and antigen. Such contact residues and adjacent residues can be targeted as candidates for substitution or removed. Variants can be screened to determine whether they possess desired properties.

[0243] Amino acid sequence insertions include amino- and / or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing 100 or more residues, as well as intrasequence insertions of single or multiple amino acid residues. An example of a terminal insertion is an antibody with an N-terminal methionyl residue. Other insertional variants of antibody molecules include the N- or C-terminal fusion 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 extent of glycosylation of the antibody. Addition or deletion of glycosylation sites to an antibody can be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites are created or removed.

[0245] If the antibody contains an Fc region, the oligosaccharides attached thereto can be altered. Natural antibodies produced by mammalian cells typically contain branched, biantennary oligosaccharides that are commonly attached to Asn297 in the CH2 domain of the Fc region via an N-linkage. See, for example, 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 attached to the GlcNAc in the "stem" of the biantennary oligosaccharide structure. In some embodiments, modifications of the oligosaccharides in the antibodies of the present invention can be made to generate antibody variants with specific improved properties.

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

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

[0248] In a further embodiment, antibody variants are provided with bisected oligosaccharides, e.g., biantennary oligosaccharides attached to the Fc region of the antibody are bisected by GlcNAc. Such antibody variants may 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); WO 99 / 54342, WO 2004 / 065540, and WO 2003 / 011878.

[0249] Antibody variants are also provided that have at least one galactose residue in the oligosaccharide attached to the Fc region. Such antibody variants may have improved CDC function. Such antibody variants are described, for example, in WO 1997 / 30087, WO 1998 / 58964, and WO 1999 / 22764. c) Fc region variants

[0250] In certain embodiments, one or more amino acid modifications may be introduced into the Fc region of an antibody presented herein, thereby creating an Fc region variant. The Fc region variant may comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3, or IgG4 Fc region) containing an amino acid modification (e.g., substitution) at one or more amino acid positions.

[0251] In certain embodiments, the present invention contemplates antibody variants that retain some, but not all, effector functions, making them desirable candidates for uses in which in vivo antibody half-life is important but certain effector functions (such as complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC)) are unnecessary or deleterious. In vitro and / or in vivo cytotoxicity assays may be performed to confirm reduced / absent CDC and / or ADCC activity. For example, Fc receptor (FcR) binding assays may be performed to confirm that the antibody lacks FcR binding (and thus likely lacks ADCC activity) but retains FcRn binding ability. NK cells, the primary cells for mediating ADCC, express only FcRIII, whereas monocytes express FcRI, FcRII, and FcRIII. Expression of FcRs on 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 assessing ADCC activity of a molecule of interest are described in U.S. Pat. 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 (see, Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)). Alternatively, non-radioactive assay methods may be employed (e.g., ACTI™ Non-Radioactive Cytotoxicity Assay for Flow Cytometry (CellTechnology, Inc. Mountain View, CA) and CytoTox96 (登録商標)(See Non-Radioactive Cytotoxicity Test Methods (Promega, Madison, WI). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and natural killer (NK) cells. Alternatively, or additionally, ADCC activity of a molecule of interest can be assessed in vivo, e.g., in an animal model, as described in Clynes et al., Proc. Nat'l Acad. Sci. USA 95:652-656 (1998). C1q binding assays may also be performed to confirm that the antibody is unable to bind C1q and lacks CDC activity. See, e.g., the C1q and C3c binding ELISAs in WO 2006 / 029879 and WO 2005 / 100402. To assess complement activation, a CDC assay can be performed (see, e.g., Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996); Cragg, MS et al., Blood 101:1045-1052 (2003); and Cragg, MS and MJ 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, e.g., Petkova, SB et al., Int'l. Immunol. 18(12):1759-1769 (2006); WO 2013 / 120929).

[0252] Antibodies with reduced effector function include antibodies with 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 with 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 have been described with improved or diminished binding to FcRs (see, e.g., U.S. Pat. No. 6,737,056; WO 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 with one or more amino acid substitutions that improve ADCC, for example, 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 with one or more amino acid substitutions that reduce FcγR binding, e.g., at positions 234 and 235 (EU numbering of residues) of the Fc region. In one embodiment, the substitutions are L234A and L235A (LALA). In certain embodiments, the antibody variant further comprises D265A and / or P329G in an Fc region derived from a human IgG1 Fc region.

[0256] In one embodiment, the substitutions are L234A, L235A, and P329G (LALA-PG) in the Fc region derived from a human IgG1 Fc region. (See, e.g., WO 2012 / 130831.) In another embodiment, the substitutions are L234A, L235A, and D265A (LALA-DA) in the Fc region derived from a human IgG1 Fc region. In some embodiments, changes are made within the Fc region that result in altered (i.e., either improved or decreased) C1q binding and / or complement dependent cytotoxicity (CDC), e.g., as described in U.S. Pat. No. 6,194,551, WO 99 / 51642, and Idusogie et al., J. Immunol. 164:4178-4184 (2000).

[0257] Antibodies with increased half-lives and improved binding to fetal Fc receptors (FcRn) that are responsible for transferring maternal IgG to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)) are described in U.S. Patent Application Publication No. 2005 / 0014934 (Hinton et al.). These antibodies comprise an Fc region with one or more substitutions therein that improve binding of the Fc region to FcRn. Such Fc variants include those having a substitution at one or more of the following 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, e.g., a substitution at Fc region residue 434 (see, e.g., U.S. Patent No. 7,371,826; Dall'Acqua, WF, 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, e.g., Dall'Acqua, WF 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, JK et al., Eur. J. Immunol. 24 (1994) 542). Residues I253, H310, and H435 were found to be critical for the interaction between human Fc and mouse FcRn (Kim, JK 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 critical for the interaction (Firan, M. et al., Int. Immunol. 13 (2001) 993; Shields, R.L. et al., J. Biol. Chem. 276 (2001) 6591-6604). Yeung, YA, et al. (J. Immunol. 182 (2009) 7667-7671) reported and investigated various mutations at residues 248-259, 301-317, 376-382, and 424-437.

[0259] In certain embodiments, the antibody variant comprises an Fc region with one or more amino acid substitutions that reduce FcRn binding, e.g., 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 with amino acid substitutions at positions 253, 310, and 435. In one embodiment, the substitutions are I253A, H310A, and H435A in the Fc region derived from a human IgG1 Fc region. See, e.g., Grevys, A. et al., J. Immunol. 194 (2015) 5497-5508.

[0260] The antibody variants comprise an Fc region having one or more amino acid substitutions that reduce FcRn binding, e.g., mutations at Fc region positions 310, and / or 433, and / or 436 (EU numbering of residues). In certain embodiments, the antibody variants comprise 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, which are derived from a human IgG1 Fc region. See, e.g., WO 2014 / 177460.

[0261] In certain embodiments, the antibody variant comprises an Fc region with one or more amino acid substitutions that increase FcRn binding, e.g., 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 with 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 IgG1 Fc region. For other examples of Fc region variants, 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 in amino acid residue PGK. The C-terminus of the heavy chain may also be a shortened C-terminus in which one or two of the C-terminal amino acid residues are removed. In one preferred embodiment, the C-terminus of the heavy chain is a truncated C-terminus PG. In one embodiment of all embodiments reported herein, an antibody comprising a heavy chain comprising a C-terminal CH3 domain as specified herein comprises a C-terminal glycine-lysine dipeptide (G446 and K447, amino acid positions according to EU index numbering). In one embodiment of all embodiments reported herein, an antibody comprising a heavy chain comprising a C-terminal CH3 domain as specified herein comprises a C-terminal glycine residue (G446, amino acid position according to EU index numbering). d) Cysteine ​​Engineered Antibody Variants

[0263] In certain embodiments, cysteine ​​engineered antibodies, e.g., THIOMAB, in which one or more residues of the antibody are substituted with a cysteine ​​residue are used. (商標) In certain embodiments, the substituted residues occur at accessible sites on the antibody. By replacing these residues with cysteine, a reactive thiol group is thereby placed at an accessible site on the antibody, which can be used to conjugate the antibody to other moieties, such as drug moieties or linker-drug moieties, to create immunoconjugates, 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 WO2016040856. e) Antibody derivative

[0264] In certain embodiments, the antibodies provided herein may be further modified to contain additional nonproteinaceous moieties known in the art and readily available. Suitable sites for derivatization of antibodies 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), ethylene glycol / propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene / maleic anhydride copolymers, polyamino acids (either homopolymers or random copolymers), and dextran or poly(n-vinylpyrrolidone), polyethylene glycol, polypropylene glycol homopolymer, polypropylene oxide / ethylene oxide copolymer, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may be advantageous during manufacturing due to its stability in water. The polymer may be of any molecular weight and may be branched or unbranched. The number of polymers attached to an antibody can vary, and when more than one polymer is attached, the polymers can be the same molecule or different molecules. Generally, the number and / or type of polymers used for derivatization can be determined based on considerations such as, but not limited to, the particular property or function of the antibody to be improved, whether the antibody derivative will be used therapeutically under defined conditions, etc. 8. Immunoconjugates

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

[0266] In one embodiment, 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, drugs, and linkers, is described in Pharmacol Review 68:3-19 (2016).

[0267] In another embodiment, the immunoconjugate comprises an antibody, as described herein, conjugated to an enzymatically active toxin or fragment thereof, including, but not limited to, diphtheria A chain, nonbinding active fragment of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Jatropha curcas proteins, dianthin proteins, pokeweed proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, soapwort inhibitor, gelonin, mitogelin, restrictocin, phenomycin, enomycin, and the trichothecenes.

[0268] In another embodiment, the immunoconjugate comprises an antibody described herein conjugated to a radioactive atom to form a radioconjugate. A variety of radioisotopes are available for the production of radioactive materials. 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 comprise a radioactive atom, such as tc99m or I123, for scintigraphy studies, or a spin label, such as iodine-123 again, iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese, or iron, for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, MRI).

[0269] Conjugates of antibodies and cytotoxic agents can be prepared using, for example, a variety of 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 (such as dimethyl adipimidate HCl), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bisazide compounds (such as bis(p-azidobenzoyl)hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and biactive fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). For example, ricin immunotoxins can be prepared as described in Vitetta et al., Science 238:1098 (1987). Carbon-14 labeled 1-isothiocyanatobenzyl-3-methyldiethylenetriaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugating radionucleotides to antibodies. See International Publication No. WO 94 / 11026. The linker may also be a "cleavable linker" that facilitates release of the cytotoxic drug within the cell. For example, acid-labile linkers, peptidase-sensitive linkers, photolabile linkers, dimethyl linkers, or disulfide-containing linkers (Chari et al., Cancer Res. 52:127-131 (1992); U.S. Patent No. 5,208,020) can be used.

[0270] The immunoconjugates or ADCs herein expressly contemplate, but are not limited to, such conjugates prepared with crosslinker reagents including, but not limited to, 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), which are commercially available (e.g., from Pierce Biotechnology, Inc., Rockford, IL, USA). D. Recombinant Methods and Compositions

[0271] Antibodies can be produced using recombinant methods and compositions, for example, as described 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 a native antibody or native antibody fragment, two nucleic acids are required: one for the light chain or fragment thereof and one for the heavy chain or fragment thereof. Such nucleic acids encode an amino acid sequence comprising the VL and / or an amino acid sequence comprising the VH of the antibody (e.g., the light and / or heavy chains of the antibody). These nucleic acids may be on the same expression vector or on different expression vectors.

[0273] For bispecific antibodies having heterodimeric heavy chains, four nucleic acids are required: one for the first light chain, one for the first heavy chain comprising the first heteromonomeric Fc-region polypeptide, one for the second light chain, and one for the second heavy chain comprising the second heteromonomeric Fc-region polypeptide. The four nucleic acids may be contained in one or more nucleic acid molecules or expression vectors. Such nucleic acids encode an amino acid sequence comprising a first VL and / or an amino acid sequence comprising a first VH comprising the first heteromonomeric Fc region and / or an amino acid sequence comprising a second VL and / or an amino acid sequence comprising a second VH comprising the second heteromonomeric Fc region of the antibody (e.g., the first and / or second light chains and / or the first and / or second heavy chains of the antibody). These nucleic acids may be on the same or different expression vectors, and usually these nucleic acids are located on two or three expression vectors, i.e., one vector may contain more than one of these nucleic acids. An example of such a bispecific antibody is CrossMab (see, for example, Schaefer, W. et al., PNAS, 108 (2011) 11187-1191). For example, according to the EU index numbering, one of the heteromonomer heavy chains contains a so-called "knob mutation" (T366W and optionally one of S354C or Y349C), and the other contains a so-called "hole mutation" (T366S, L368A, and Y407V, and optionally Y349C or S354C) (e.g., Carter, P. et al., Immunotechnol. 2 (1996) 73).

[0274] In one aspect, an isolated nucleic acid encoding an antibody for use in the methods described herein is provided.

[0275] In one aspect, a method of making an antibody is provided, com...

Claims

1. 1. An isolated antibody that binds to human KLK7, An antibody 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.

2. 1. An isolated antibody that binds to human kallikrein-related peptidase 7 (KLK7), 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; 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 and / or binds to human KLK7 at 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) 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); antibody.

3. 3. The antibody of claim 1 or 2, 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).

4. (a) 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 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; or (b) The antibody described in any one of claims 1 to 3, wherein in (a), 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.

5. An isolated 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 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 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 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) 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: 76 to 78.

6. The antibody of claim 5, 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) a VH sequence defined in (a) and a 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).

7. (a) 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 and / or inhibit 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; or (b) The antibody according to claim 5 or 6, wherein in (a), the inhibition of human KLK5 protease activity is inhibition of human KLK5-mediated cleavage of the substrate Boc-Val-Pro-Arg-AMC.

8. (a) the antibody is a multispecific antibody, or (b) The antibody of any one of claims 1 to 7, wherein the antibody is a bispecific antibody.

9. An isolated nucleic acid encoding the antibody of any one of claims 1 to 8.

10. 10. An isolated host cell comprising the nucleic acid of claim 9.

11. An isolated host cell expressing the antibody of any one of claims 1 to 7.

12. 1. A method for producing an antibody, comprising: (a) culturing the host cell of claim 10 or 11 under conditions suitable for expression of the antibody, or (b) culturing the host cell of claim 10 or 11 under conditions suitable for expression of the antibody, and recovering the antibody from the host cell.

13. 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 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.

14. 14. The bispecific antibody of claim 13, wherein the first binding domain comprises a sequence selected from the following: (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).

15. 15. The bispecific antibody of claim 13 or 14, 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 bispecific antibody 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 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.

16. The bispecific antibody of any one of claims 13 to 15, 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) a VH sequence defined in (a) and a 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).

17. 17. The bispecific antibody of any one of claims 13 to 16, 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.

18. 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; 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) the bispecific antibody of any one of claims 13 to 17, 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.

19. 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 wherein (i) the first binding domain comprises 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 comprises 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, or (ii) 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 (iii) the first binding domain comprises the heavy chain amino acid sequence of SEQ ID NO: 108 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 and the light chain amino acid sequence of SEQ ID NO: 111; or (iv) 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: 114 and the light chain amino acid sequence of SEQ ID NO:

115.

20. 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 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 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 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) A bispecific antibody 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 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: 76-78.

21. 21. The bispecific antibody of claim 20, 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 54-67; and c) a VH sequence defined in (a) and a 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).

22. (a) the first binding domain comprises a first heavy chain variable domain and a first light chain variable domain, wherein the first heavy chain variable domain is linked to a first heavy chain constant region and 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, wherein 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; or (b) The bispecific antibody of claim 20 or 21, wherein in (a), 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.

23. 23. The bispecific antibody of claim 22, 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), and 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).

24. 24. The bispecific antibody of claim 22 or 23, 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).

25. The bispecific antibody according to any one of claims 22 to 24, 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.

26. (a) the antibody has 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 and / or the antibody 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; or (b) The bispecific antibody according to any one of claims 13 to 25, wherein in (a), the inhibition of human KLK5 protease activity is inhibition of human KLK5-mediated cleavage of the substrate Boc-Val-Pro-Arg-AMC.

27. (a) the antibody has 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 / or the antibody 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; or (b) The bispecific antibody of any one of claims 13 to 26, wherein in (a), 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.

28. An isolated nucleic acid encoding the bispecific antibody of any one of claims 13 to 27.

29. An isolated nucleic acid encoding the first binding domain and the second binding domain of the bispecific antibody of any one of claims 13 to 27.

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

31. An isolated host cell expressing the bispecific antibody of any one of claims 13 to 27.

32. An isolated host cell expressing the first binding domain and the second binding domain of the bispecific antibody of any one of claims 13 to 27.

33. 1. A method for producing a bispecific antibody that binds to human KLK5 and human KLK7, comprising: (a) culturing the host cell of claim 31 or claim 32 under conditions suitable for expression of the antibody; or (b) culturing the host cell of claim 31 or claim 32 under conditions suitable for expression of the antibody, and recovering the antibody from the host cell.

34. 1. A pharmaceutical composition comprising: (a) a pharmaceutical composition comprising the antibody of any one of claims 1 to 4 and a pharmaceutically acceptable carrier; (b) a pharmaceutical composition comprising the antibody of any one of claims 1 to 4, a pharmaceutically acceptable carrier, and an additional therapeutic agent; (c) the additional therapeutic agent in (b) is a KLK5 inhibitor; or (d) The pharmaceutical composition of (c), wherein the KLK5 inhibitor is an anti-KLK5 antibody.

35. 35. The pharmaceutical composition of claim 34, wherein the anti-KLK5 antibody: 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) 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.

36. The pharmaceutical composition according to claim 34, wherein the anti-KLK5 antibody is an antibody according to any one of claims 5 to 7.

37. 1. A pharmaceutical composition comprising: (a) a pharmaceutical composition comprising the antibody of any one of claims 5 to 7 and a pharmaceutically acceptable carrier; (b) a pharmaceutical composition comprising the antibody of any one of claims 5 to 7, a pharmaceutically acceptable carrier, and an additional therapeutic agent; (c) the additional therapeutic agent in (b) is a KLK7 inhibitor; (d) the KLK7 inhibitor in (c) is an anti-KLK7 antibody; or (e) A pharmaceutical composition in which the anti-KLK7 antibody in (d) is an antibody according to any one of claims 1 to 4.

38. An isolated antibody according to any one of claims 1 to 4, which binds to human KLK7, and which, 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.

39. (a) the isolated antibody is a bispecific antibody; (b) the isolated antibody is a bispecific antibody, and the bispecific antibody binds to human KLK7 and human KLK5; or (c) In (b), the isolated antibody of claim 38, which, 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.

40. The antibody may be 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. or the 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. or the antibody 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. or the antibody 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.

41. (a) the antibody binds to an epitope within amino acids R71 to N82, K152 to S158, and / or Q211 to K222 of KLK7 (SEQ ID NO: 4); or (b) In (a), the 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 (SEQ ID NO: 4).

42. 9. The bispecific antibody of claim 8, 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 wherein upon binding to human KLK7, the first binding domain causes a conformational change in human KLK7, which conformational change allosterically results in the disruption of the substrate binding site and / or the active site of human KLK7, and / or wherein upon binding to human KLK5, the second binding domain causes a conformational change in human KLK5, which conformational change allosterically results in the disruption of the substrate binding site and / or the active site of human KLK5.

43. A pharmaceutical composition comprising an antibody or bispecific antibody according to any one of claims 38 to 42.

44. An antibody according to any one of claims 1 to 7 and 38 to 41, a bispecific antibody according to any one of claims 13 to 27 and 42, or a pharmaceutical composition according to any one of claims 34 to 37 and 43 for use as a medicament.

45. An antibody according to any one of claims 1 to 7 and 38 to 41, a bispecific antibody according to any one of claims 13 to 27 and 42, or a pharmaceutical composition according to any one of claims 34 to 37 and 43, for use in the treatment of a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis and rosacea.

46. Use of an antibody according to any one of claims 1 to 7 and 38 to 41, a bispecific antibody according to any one of claims 13 to 27 and 42, or a pharmaceutical composition according to any one of claims 34 to 37 and 43 in the manufacture of a medicament for treating a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis and rosacea.

47. 46. ​​The antibody, bispecific antibody, or pharmaceutical composition of claim 45, 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.

48. 47. The use of claim 46, 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, high periostin asthma, high eosinophilic asthma, Th2-low or non-Th2-driven asthma, low periostin asthma, and low eosinophilic asthma.

49. A combination of an antibody according to any one of claims 1 to 4 and an antibody according to any one of claims 5 to 7 for use as a medicament.

50. A combination of an antibody according to any one of claims 1 to 4 and an antibody according to any one of claims 5 to 7 for use in the treatment of a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis and rosacea.

51. Use of a combination of an antibody according to any one of claims 1 to 4 and an antibody according to any one of claims 5 to 7 in the manufacture of a medicament for treating a disease selected from Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis and rosacea.

52. 51. The combination of claim 50, 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-related asthma, corticosteroid-uncontrolled asthma, T helper lymphocyte type 2 (Th2) asthma or type 2 (Th2)-high 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.

53. 52. The use of claim 51, 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, high periostin asthma, high eosinophilic asthma, Th2-low or non-Th2-driven asthma, low periostin asthma, and low eosinophilic asthma.

54. Use of an antibody according to any one of claims 1 to 7 and 38 to 41, a bispecific antibody according to any one of claims 13 to 27 and 42, or a pharmaceutical composition according to any one of claims 34 to 37 and 43 in the manufacture of a medicament for reducing epidermal inflammation, reducing epidermal permeability, reducing transepidermal water loss, reducing skin infiltration, reducing parakeratinization, restoring the epithelial barrier and / or reducing skin inflammatory cytokines.

55. Use of a combination of an antibody according to any one of claims 1 to 4 and an antibody according to any one of claims 5 to 7 in the manufacture of a medicament for reducing epidermal inflammation, reducing epidermal permeability, reducing transepidermal water loss, reducing skin infiltration, reducing parakeratosis, restoring the epithelial barrier and / or reducing skin inflammatory cytokines.

56. 1. A pharmaceutical composition for ameliorating skin rash and / or scaling in an individual with Netherton syndrome, comprising: (a) a bispecific antibody of any one of claims 13 to 27; or (b) an anti-KLK5 antibody of any one of claims 5 to 7 and an anti-KLK7 antibody of any one of claims 1 to 4, wherein the bispecific antibody comprises a first binding domain and a second binding domain.

Images