Anti-KLK5 antibody and method of use

Abstract

This invention provides an anti-KLK5 antibody and a method for using the same. [Solution] An antibody or antibody fragment that binds to KLK5 is provided. In some embodiments, the antibody is a monoclonal antibody, a human antibody, a humanized antibody, or a chimeric antibody. Also provided are an isolated nucleic acid encoding the antibody, a host cell containing the nucleic acid, and a method for producing the antibody, comprising culturing the host cell.

Description

[Technical Field]

[0001] Cross-reference of related applications This application asserts a benefit under § 119(e) of U.S. Patent Act for Provisional Patent Application No. 62 / 643,034, filed on 14 March 2018, which is incorporated herein by reference in its entirety.

[0002] Sequence List This application includes a sequence listing filed via EFS-Web, which is incorporated herein by reference in its entirety. The above ASCII copy, created on March 11, 2019, is named P34707-WO_SL.txt and is 424,525 bytes in size.

[0003] The present invention relates to an anti-KLK5 antibody and a method for using the same. [Background technology]

[0004] Human kallikrein-related peptidases (KLKs) are (chymo)trypsin-like serine proteases expressed in various tissues, including the prostate, ovaries, breasts, testes, brain, and skin. KLKs belong to the S1A subgroup of the chymotrypsin-like serine protease family of clan PA(S). The 15 human KLK genes are located on chromosome 19q13.4 and constitute the largest continuous serine protease cluster in the human genome. These genes generally consist of five coding exons, and in some cases one or two 5' non-coding exons, encoding kallikrein-related peptidases KLK1 to KLK15. All KLK genes encode single-stranded preproproteins containing a 224-237 residue chymotrypsin-like or trypsin-like catalytic domain with approximately 40% amino acid sequence identity between KLK4 and KLK15. KLK1 and its close homologs KLK2 and KLK3 form their own clades, while KLK4, 5, and 7 belong to different subgroups, although KLK6 is more similar to KLK13 and KLK14. See Debela et al., "Biol Chem", Vol. 389, pp. 623-632 (2008).

[0005] KLK5 appears to be most abundantly expressed in human skin, particularly in the upper layers of the skin, the stratum spinosum and stratum granulosum, where keratinocytes undergo terminal differentiation to form the stratum corneum, the outermost epidermis, and a barrier against the external environment, resulting in a flattened, brick-like structure. See Debela et al., "J Mol Biol," Vol. 373, pp. 1017-1031 (2007), and Tan et al., "J Med Chem.", January 22, 2015, Vol. 58, No. 2, pp. 598-612 (2014). KLK5 has been described as playing a pathological role in skin disorders such as Netherton syndrome. See Furio et al., "PLOS Genet," Vol. 11, No. 9, e1005389 (2015). Netherton syndrome is caused by a loss-of-function mutation in the SPINK5 gene, which encodes the Kazal-type serine protease inhibitor 5 (SPINK5). See Descargues et al., "Nat Genet," January 2005, Vol. 37, No. 1, pp. 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," July, Vol. 23, No. 7, pp. 524-526 (2014). SPINK5 deficiency in Netherton syndrome results in unantagonized KLK activity. KLK5 hyperactivity is considered an important element in the pathophysiology of Netherton syndrome because KLK5 is a regulator of proteolysis in the epidermis. Excision of KLK5 and KLK7 rescues the lethality of the Netherton syndrome-like phenotype. See Briot et al., "J Exp Med.", May 11, Vol. 206, No. 5, pp. 1135-1147 (2009), Furio et al., "J Exp Med.", March 10, Vol. 211, No. 3, pp. 499-513 (2014), and Kasparek et al., "PLoS Genet.", January 17, 2017, Vol. 13, No. 1, e1006566 (2017). Netherton syndrome is a complex systemic disease with multiple effects, and there is currently no satisfactory treatment.

[0006] Asthma is a clinically heterogeneous disorder associated with both genetic and environmental risk factors. Estimates of heritability from asthma twin studies range from 35% to 80%, suggesting a significant role of genetic risk. See, for example, Ullemar et al., "Allergy," Vol. 71, pp. 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," Vol. 46, pp. 51-55 (2014). Recent studies have identified SNPs at the KLK4 / 5 locus that protect against risk for low-periostin asthma or type 2 low-inflammatory asthma. In the same study, KLK5 levels were found to increase during bronchoalveolar lavage in patients with severe asthma, supporting the hypothesis that KLK5 plays a role in bronchial obstruction and asthmatic pathogenesis.

[0007] Despite advances in the field of diseases such as Netherton syndrome and asthma, there is a need to identify targets and develop means that can complement or enhance the effectiveness of existing therapies. [Overview of the project]

[0008] This specification provides an anti-KLK5 antibody and a method for using the same.

[0009] This specification further provides isolated antibodies that bind to KLK5, wherein the antibodies include (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 28; (b) HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 38, SEQ ID NO: 45, and SEQ ID NO: 54; (c) HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 65, SEQ ID NO: 69, and SEQ ID NO: 72; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 96; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 109; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 127.

[0010] In some embodiments, the antibody comprises (a) HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 17, SEQ ID NO: 22, and SEQ ID NO: 24; (b) HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, and SEQ ID NO: 53; (c) HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 65, SEQ ID NO: 69, and SEQ ID NO: 72; (d) HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 82, SEQ ID NO: 87, and SEQ ID NO: 91; (e) HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 99, SEQ ID NO: 101, and SEQ ID NO: 105; and (f) HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 115, SEQ ID NO: 119, and SEQ ID NO: 122.

[0011] In some embodiments of the antibody, the antibody is (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 17, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 35, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 65, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 82, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 101, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 115, (ii) HVR-H1 containing the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 42, and (c) the amino acid sequence of SEQ ID NO: 69 (d) HVR-H3 containing the amino acid sequence of SEQ ID NO: 87, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 105, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 119, or (iii) HVR-H1 containing the amino acid sequence of SEQ ID NO: 24, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 52, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 72, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 91, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 99, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 122.

[0012] In some embodiments of the antibody, the antibody comprises (a) the VH sequence of SEQ ID NO: 202 and the VL sequence of SEQ ID NO: 140, (b) the VH sequence of SEQ ID NO: 225 and the VL sequence of SEQ ID NO: 151, or (c) the VH sequence of SEQ ID NO: 257 and the VL sequence of SEQ ID NO: 162.

[0013] In some embodiments of the antibody, the antibody comprises (a) the VH sequence of SEQ ID NO: 201 and the VL sequence of SEQ ID NO: 139, (b) the VH sequence of SEQ ID NO: 221 and the VL sequence of SEQ ID NO: 149, or (c) the VH sequence of SEQ ID NO: 248 or SEQ ID NO: 254 and the VL sequence of SEQ ID NO: 160.

[0014] This specification further provides isolated antibodies that bind to KLK5, wherein the antibodies include (a) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 201 and a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 139, (b) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 221 and a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 149, or (c) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 248 or SEQ ID NO: 254 and a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 160.

[0015] This specification further provides isolated antibodies that bind to KLK5, wherein the antibodies include (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 14, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 32, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 62, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 79, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 99, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 112, and (ii) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 15, and (b) the amino acid sequence of SEQ ID NO: 33 (c) HVR-H2 containing the amino acid sequence of SEQ ID NO: 63, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 80, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 100, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 113, (iii) (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 16, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 34, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 64, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 81, and (e) HVR-L3 containing the amino acid sequence of SEQ ID NO: 99 VR-L2, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 114, (iv) (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 18, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 39, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 66, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 83, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 102, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 116, (v) (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 19, (b) HVR-L3 containing the amino acid sequence of SEQ ID NO: 40 VR-H2, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 67, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 84, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 103, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 117, (vi) (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 20, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 33, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 68, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 85, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 103,(f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 118, (vii) (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 41, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 86, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 104, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 118, (viii) (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 46, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 88, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 105, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 120 (ix)(a) HVR-H1 containing the amino acid sequence of SEQ ID NO. 22, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO. 42, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO. 70, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO. 89, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO. 105, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO. 118, or (x)(a) HVR-H1 containing the amino acid sequence of SEQ ID NO. 23, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO. 47, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO. 71, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO. 90, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO. 106, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO. 121.

[0016] In some embodiments, the antibody comprises a VH sequence selected from the group consisting of SEQ ID NOs: 170, 171, 172, 203, 204, 205, 206, 226, 227, and 228, and a VL sequence selected from the group consisting of SEQ ID NOs: 131, 132, 133, 141, 142, 143, 144, 152, 153, and 154.

[0017] In some embodiments, the antibody includes (a) the VH sequence of SEQ ID NO: 170 and the VL sequence of SEQ ID NO: 131, (b) the VH sequence of SEQ ID NO: 171 and the VL sequence of SEQ ID NO: 132, (c) the VH sequence of SEQ ID NO: 172 and the VL sequence of SEQ ID NO: 133, (d) the VH sequence of SEQ ID NO: 203 and the VL sequence of SEQ ID NO: 141, (e) the VH sequence of SEQ ID NO: 204 and the VL sequence of SEQ ID NO: 142, (f) the VH sequence of SEQ ID NO: 205 and the VL sequence of SEQ ID NO: 143, (g) the VH sequence of SEQ ID NO: 206 and the VL sequence of SEQ ID NO: 144, (h) the VH sequence of SEQ ID NO: 226 and the VL sequence of SEQ ID NO: 152, (i) the VH sequence of SEQ ID NO: 227 and the VL sequence of SEQ ID NO: 153, or (j) the VH sequence of SEQ ID NO: 228 and the VL sequence of SEQ ID NO: 154.

[0018] This specification further provides isolated antibodies that bind to KLK5, wherein the antibodies (a) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 170 and a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 131, (b) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 171 and a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 132, (c) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 172 and a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 133, (d) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 203 and a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 141, and (e) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 204 and at least (f) a VL sequence having 95% sequence identity, (g) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 205 and a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 143, (h) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 206 and a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 144, (h) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 226 and a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 152, (i) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 227 and a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 153, or (j) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 228 and a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 154.

[0019] In some embodiments of the antibody, the antibody is IgG1 or IgG4.

[0020] In some embodiments of the antibody, the antibody inhibits the biological activity of KLK5 by at least 50%, as measured by one or more methods described in the following examples herein. In some embodiments, one or more methods include recombinant KLK5 direct activity assay, conjugated pro-KLK1 fluorescent peptide assay, conjugated pro-KLK7 fluorescent peptide assay, pro-KLK1 LC / MS assay, pro-KLK7 LC / MS assay, and K i(app) The assay is selected from the group consisting of assays. In some embodiments, the biological activity is the serine protease activity of KLK5.

[0021] In some embodiments of the antibody, the antibody is a monoclonal antibody.

[0022] In some embodiments of the antibody, the antibody is a human antibody, a humanized antibody, or a chimeric antibody.

[0023] In some embodiments of the antibody, the antibody is an antibody fragment that binds to KLK5.

[0024] This specification further provides antibodies that form a thermodynamic epitope when bound to KLK5, and which contain one or more sequences selected from the group consisting of SEQ ID NO: 316, SEQ ID NO: 317, SEQ ID NO: 318, and SEQ ID NO: 319, as measured by hydrogen exchange mass spectrometry.

[0025] This specification further provides antibodies that compete for binding with any of the antibodies described herein.

[0026] This specification further provides antibodies that bind to the same epitope as any of the antibodies described herein.

[0027] This specification further provides isolated nucleic acids encoding any of the antibodies described herein.

[0028] This specification further provides host cells containing the nucleic acids described herein.

[0029] This specification further provides a method for producing an antibody, comprising culturing the host cells described herein so that the antibody is produced.

[0030] This specification further provides immunocomplexes containing the antibodies described herein.

[0031] This specification further provides pharmaceutical formulations comprising the antibodies described herein and pharmaceutically acceptable carriers.

[0032] This specification further provides antibodies described herein for use as pharmaceuticals.

[0033] This specification further provides antibodies described herein for use in the treatment of diseases selected from the group consisting of Netherton syndrome, asthma, atopic dermatitis, psoriasis, and rosacea. In some embodiments, the disease is selected from the group consisting of Netherton syndrome, asthma, atopic dermatitis, psoriasis, rosacea, and eosinophilic esophagitis. In some embodiments, the asthma is selected from the group consisting of atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin-sensitive / exacerbating asthma, mild asthma, moderate to severe asthma, corticosteroid-untreated asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, newly diagnosed untreated asthma, smoking-induced asthma, asthma uncontrolled by corticosteroids, T helper lymphocyte type 2 (Th2) asthma or type 2 (Th2) high-level asthma or type 2 (T2)-driven asthma, eosinophilic asthma, hyperperiostin asthma, hypereosinophilic asthma, low Th2 asthma or non-Th2-driven asthma, hypoperiostin asthma, and hypoeosinophilic asthma. In some embodiments, the asthma is low TH2 asthma.

[0034] This specification further provides antibodies described herein for use in inhibiting the biological activity of KLK5.

[0035] This specification further provides the use of the antibodies described herein in the manufacture of pharmaceuticals. In some embodiments, the pharmaceutical is for the treatment of a disease selected from the group consisting of Netherton syndrome, asthma, atopic dermatitis, psoriasis, and rosacea. In some embodiments, the disease is selected from the group consisting of Netherton syndrome, asthma, atopic dermatitis, psoriasis, rosacea, and eosinophilic esophagitis. In some embodiments, the asthma is selected from the group consisting of atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin-sensitive / exacerbating asthma, mild asthma, moderate to severe asthma, corticosteroid-untreated asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, newly diagnosed untreated asthma, smoking-induced asthma, asthma uncontrolled by corticosteroids, T helper lymphocyte type 2 (Th2) asthma or type 2 (Th2) high-level asthma or type 2 (T2)-driven asthma, eosinophilic asthma, hyperperiostin asthma, hypereosinophilic asthma, low Th2 asthma or non-Th2-driven asthma, hypoperiostin asthma, and hypoeosinophilic asthma. In some embodiments, the asthma is low TH2 asthma.

[0036] This specification further provides the use of the antibodies described herein in the manufacture of a pharmacopoeia for inhibiting the biological activity of KLK5.

[0037] This specification further provides a method for treating an individual having a disease, wherein the disease is selected from the group consisting of Netherton syndrome, asthma, atopic dermatitis, psoriasis, and rosacea, and the method comprises administering an effective amount of the antibody described herein to the individual. In some embodiments, the disease is selected from the group consisting of Netherton syndrome, asthma, atopic dermatitis, psoriasis, rosacea, and eosinophilic esophagitis. In some embodiments, the asthma is selected from the group consisting of atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin-sensitive / exacerbating asthma, mild asthma, moderate to severe asthma, corticosteroid-untreated asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, newly diagnosed untreated asthma, smoking-induced asthma, asthma uncontrolled by corticosteroids, T helper lymphocyte type 2 (Th2) asthma or type 2 (Th2) high-level asthma or type 2 (T2)-driven asthma, eosinophilic asthma, hyperperiostin asthma, hypereosinophilic asthma, low Th2 asthma or non-Th2-driven asthma, hypoperiostin asthma, and hypoeosinophilic asthma. In some embodiments, the asthma is low Th2 asthma.

[0038] This specification further provides a method for inhibiting the biological activity of KLK5 in an individual, comprising administering to the individual an effective amount of the antibody described herein for the purpose of inhibiting the biological activity of KLK5.

[0039] This specification further provides antibodies that specifically bind to human KLK5, which bind to epitopes on human KLK5 comprising one or more amino acid residues selected from the group consisting of 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. In some embodiments, the antibody binds to an epitope on human KLK5 containing 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 antibody binds to an epitope on human KLK5 containing one or more amino acid residues selected from the group consisting of 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 antibody binds to an epitope on human KLK5 containing one or more amino acid residues selected from the group consisting of 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.

[0040] This specification further provides antibodies that, upon binding to human KLK5, induce a conformational change in human KLK5, wherein the conformational change allosterically leads to the destruction of the substrate binding site and / or active site of human KLK5. [Brief explanation of the drawing]

[0041] [Figure 1A-F] Figures 1A to 1N show the evaluation of KLK5 inhibitors using fluorescent peptide substrates in direct assays. 5 nM recombinant human KLK5 inhibitors and 0.19–100 nM KLK5 inhibitors were pre-incubated for 30 minutes before the addition of 50 μM Boc-VPR-AMC. Plates were examined every 102 seconds for 30–60 minutes using a PHERAstar® Plus reader with a 340 nm excitation / 460 nm emission module. The results for the KLK5 inhibitors are shown below. Figure 1A: Spink9.SRE.Fc (Spink9), Figure 1B: mAb1108, Figure 1C: 3-3F5, Figure 1D: 10C8, Figure 1E: 9B6, Figure 1F: 9F2, Figure 1G: 9H3, Figure 1H: 9H5, Figure 1I: 8B7, Figure 1J: 2B11, Figure 1K: 8F5, Figure 1L: 10C5, Figure 1M: 10H3, and Figure 1N: 2-3F4. [Figure 1G-L] Figures 1A to 1N show the evaluation of KLK5 inhibitors using fluorescent peptide substrates in direct assays. 5 nM recombinant human KLK5 inhibitors and 0.19–100 nM KLK5 inhibitors were pre-incubated for 30 minutes before the addition of 50 μM Boc-VPR-AMC. Plates were examined every 102 seconds for 30–60 minutes using a PHERAstar® Plus reader with a 340 nm excitation / 460 nm emission module. The results for the KLK5 inhibitors are shown below. Figure 1A: Spink9.SRE.Fc (Spink9), Figure 1B: mAb1108, Figure 1C: 3-3F5, Figure 1D: 10C8, Figure 1E: 9B6, Figure 1F: 9F2, Figure 1G: 9H3, Figure 1H: 9H5, Figure 1I: 8B7, Figure 1J: 2B11, Figure 1K: 8F5, Figure 1L: 10C5, Figure 1M: 10H3, and Figure 1N: 2-3F4. [Figure 1M-N] Figures 1A to 1N show the evaluation of KLK5 inhibitors using fluorescent peptide substrates in direct assays. 5 nM recombinant human KLK5 inhibitors and 0.19–100 nM KLK5 inhibitors were pre-incubated for 30 minutes before the addition of 50 μM Boc-VPR-AMC. Plates were examined every 102 seconds for 30–60 minutes using a PHERAstar® Plus reader with a 340 nm excitation / 460 nm emission module. The results for the KLK5 inhibitors are shown below. Figure 1A: Spink9.SRE.Fc (Spink9), Figure 1B: mAb1108, Figure 1C: 3-3F5, Figure 1D: 10C8, Figure 1E: 9B6, Figure 1F: 9F2, Figure 1G: 9H3, Figure 1H: 9H5, Figure 1I: 8B7, Figure 1J: 2B11, Figure 1K: 8F5, Figure 1L: 10C5, Figure 1M: 10H3, and Figure 1N: 2-3F4.

[0042] [Figure 2A-F] Figures 2A to 2N show the evaluation of KLK5 inhibitors in a pro-KLK7 binding assay. 5 nM recombinant human KLK5 inhibitors and 0.19–100 nM anti-KLK5 inhibitors were pre-incubated for 30 minutes before the addition of 125 nM pro-KLK7 and 100 μM suc-LLVY-AMC. After 24 hours, fluorescence readings were taken every 102 seconds from 30 to 60 minutes, and the RFU endpoint value was calculated by averaging the last 5 readings. The results for KLK5 inhibitors are shown below. Figure 2A: Spink9.SRE.Fc, Figure 2B: mAb1108, Figure 2C: 3-3F5, Figure 2D: 10C8, Figure 2E: 9B6, Figure 2F: 9F2, Figure 2G: 9H3, Figure 2H: 9H5, Figure 2I: 8B7, Figure 2J: 2B11, Figure 2K: 8F5, Figure 2L: 10C5, Figure 2M: 10H3, and Figure 2N: 2-3F4. [Figure 2G-L]Figures 2A to 2N show the evaluation of KLK5 inhibitors in a pro-KLK7 binding assay. 5 nM recombinant human KLK5 inhibitors and 0.19–100 nM anti-KLK5 inhibitors were pre-incubated for 30 minutes before the addition of 125 nM pro-KLK7 and 100 μM suc-LLVY-AMC. After 24 hours, fluorescence readings were taken every 102 seconds from 30 to 60 minutes, and the RFU endpoint value was calculated by averaging the last 5 readings. The results for KLK5 inhibitors are shown below. Figure 2A: Spink9.SRE.Fc, Figure 2B: mAb1108, Figure 2C: 3-3F5, Figure 2D: 10C8, Figure 2E: 9B6, Figure 2F: 9F2, Figure 2G: 9H3, Figure 2H: 9H5, Figure 2I: 8B7, Figure 2J: 2B11, Figure 2K: 8F5, Figure 2L: 10C5, Figure 2M: 10H3, and Figure 2N: 2-3F4. [Figure 2M-N] Figures 2A to 2N show the evaluation of KLK5 inhibitors in a pro-KLK7 binding assay. 5 nM recombinant human KLK5 inhibitors and 0.19–100 nM anti-KLK5 inhibitors were pre-incubated for 30 minutes before the addition of 125 nM pro-KLK7 and 100 μM suc-LLVY-AMC. After 24 hours, fluorescence readings were taken every 102 seconds from 30 to 60 minutes, and the RFU endpoint value was calculated by averaging the last 5 readings. The results for KLK5 inhibitors are shown below. Figure 2A: Spink9.SRE.Fc, Figure 2B: mAb1108, Figure 2C: 3-3F5, Figure 2D: 10C8, Figure 2E: 9B6, Figure 2F: 9F2, Figure 2G: 9H3, Figure 2H: 9H5, Figure 2I: 8B7, Figure 2J: 2B11, Figure 2K: 8F5, Figure 2L: 10C5, Figure 2M: 10H3, and Figure 2N: 2-3F4.

[0043] [Figure 3A-F]Figures 3A to 3N show the evaluation of KLK5 inhibitors in a pro-KLK1 binding assay. 0.5 nM recombinant human KLK5 inhibitors and 0.019–10 nM KLK5 inhibitors were pre-incubated for 30 minutes before the addition of 31.25 nM pro-KLK1 and 50 μM PFR-AMC. Plates were examined every 102 seconds for 120 minutes using a PHERAstar® Plus reader with a 340 nm excitation / 460 nm emission module. The results for KLK5 inhibitors are shown below. Figure 3A: Spink9.SRE.Fc, Figure 3B: mAb1108, Figure 3C: 3-3F5, Figure 3D: 10C8, Figure 3E: 9B6, Figure 3F: 9F2, Figure 3G: 9H3, Figure 3H: 9H5, Figure 3I: 8B7, Figure 3J: 2B11, Figure 3K: 8F5, Figure 3L: 10C5, Figure 3M: 10H3, and Figure 3N: 2-3F4. [Figure 3G-L] Figures 3A to 3N show the evaluation of KLK5 inhibitors in a pro-KLK1 binding assay. 0.5 nM recombinant human KLK5 inhibitors and 0.019–10 nM KLK5 inhibitors were pre-incubated for 30 minutes before the addition of 31.25 nM pro-KLK1 and 50 μM PFR-AMC. Plates were examined every 102 seconds for 120 minutes using a PHERAstar® Plus reader with a 340 nm excitation / 460 nm emission module. The results for KLK5 inhibitors are shown below. Figure 3A: Spink9.SRE.Fc, Figure 3B: mAb1108, Figure 3C: 3-3F5, Figure 3D: 10C8, Figure 3E: 9B6, Figure 3F: 9F2, Figure 3G: 9H3, Figure 3H: 9H5, Figure 3I: 8B7, Figure 3J: 2B11, Figure 3K: 8F5, Figure 3L: 10C5, Figure 3M: 10H3, and Figure 3N: 2-3F4. [Figure 3M-N]Figures 3A to 3N show the evaluation of KLK5 inhibitors in a pro-KLK1 binding assay. 0.5 nM recombinant human KLK5 inhibitors and 0.019–10 nM KLK5 inhibitors were pre-incubated for 30 minutes before the addition of 31.25 nM pro-KLK1 and 50 μM PFR-AMC. Plates were examined every 102 seconds for 120 minutes using a PHERAstar® Plus reader with a 340 nm excitation / 460 nm emission module. The results for KLK5 inhibitors are shown below. Figure 3A: Spink9.SRE.Fc, Figure 3B: mAb1108, Figure 3C: 3-3F5, Figure 3D: 10C8, Figure 3E: 9B6, Figure 3F: 9F2, Figure 3G: 9H3, Figure 3H: 9H5, Figure 3I: 8B7, Figure 3J: 2B11, Figure 3K: 8F5, Figure 3L: 10C5, Figure 3M: 10H3, and Figure 3N: 2-3F4.

[0044] [Figure 4A-F] Figures 4A–4N show the results of LC / MS assays measuring the inhibition of pro-KLK7 proteolysis by recombinant KLK5 by monitoring KLK5-derived cleavage product peptides. Pre-incubation of KLK5 with selected antibodies SPINK9.SRE.Fc, mAb1108, and 12 preceded a 2-hour incubation with 5 nM KLK5 and 15 nM pro-KLK7. The results for KLK5 inhibitors are shown below. Figure 4A: SPINK9.SRE.Fc, Figure 4B: mAb1108, Figure 4C: 10C8, Figure 4D: 9B6, Figure 4E: 2B11, Figure 4F: 9F2, Figure 4G: 2-3F4, Figure 4H: 10H3, Figure 4I: 9H3, Figure 4J: 8B7, Figure 4K: 8F5, Figure 4L: 3-3F5, Figure 4M: 10C5, and Figure 4N: 9H5. [Figure 4G-L]Figures 4A–4N show the results of LC / MS assays measuring the inhibition of pro-KLK7 proteolysis by recombinant KLK5 by monitoring KLK5-derived cleavage product peptides. Pre-incubation of KLK5 with selected antibodies SPINK9.SRE.Fc, mAb1108, and 12 preceded a 2-hour incubation with 5 nM KLK5 and 15 nM pro-KLK7. The results for KLK5 inhibitors are shown below. Figure 4A: SPINK9.SRE.Fc, Figure 4B: mAb1108, Figure 4C: 10C8, Figure 4D: 9B6, Figure 4E: 2B11, Figure 4F: 9F2, Figure 4G: 2-3F4, Figure 4H: 10H3, Figure 4I: 9H3, Figure 4J: 8B7, Figure 4K: 8F5, Figure 4L: 3-3F5, Figure 4M: 10C5, and Figure 4N: 9H5. [Figure 4M-N] Figures 4A–4N show the results of LC / MS assays measuring the inhibition of pro-KLK7 proteolysis by recombinant KLK5 by monitoring KLK5-derived cleavage product peptides. Pre-incubation of KLK5 with selected antibodies SPINK9.SRE.Fc, mAb1108, and 12 preceded a 2-hour incubation with 5 nM KLK5 and 15 nM pro-KLK7. The results for KLK5 inhibitors are shown below. Figure 4A: SPINK9.SRE.Fc, Figure 4B: mAb1108, Figure 4C: 10C8, Figure 4D: 9B6, Figure 4E: 2B11, Figure 4F: 9F2, Figure 4G: 2-3F4, Figure 4H: 10H3, Figure 4I: 9H3, Figure 4J: 8B7, Figure 4K: 8F5, Figure 4L: 3-3F5, Figure 4M: 10C5, and Figure 4N: 9H5.

[0045] [Figure 5A-F]Figures 5A–4N show the results of LC / MS assays measuring the inhibition of pro-KLK1 proteolysis by recombinant KLK5 by monitoring KLK5-derived cleavage product peptides. Pre-incubation of KLK5 with selected antibodies SPINK9.SRE.Fc, mAb1108, and 12 preceded a 20-minute incubation with 0.5 nM KLK5 and 300 nM pro-KLK1 (Figures 5A–5N). The results for KLK5 inhibitors are shown below. Figure 5A: SPINK9.SRE.Fc, Figure 5B: mAb1108, Figure 5C: 10C8, Figure 5D: 9B6, Figure 5E: 2B11, Figure 5F: 9F2, Figure 5G: 2-3F4, Figure 5H: 10H3, Figure 5I: 9H3, Figure 5J: 8B7, Figure 5K: 8F5, Figure 5L: 3-3F5, Figure 5M: 10C5, and Figure 5N: 9H5. [Figure 5G-L] Figures 5A–4N show the results of LC / MS assays measuring the inhibition of pro-KLK1 proteolysis by recombinant KLK5 by monitoring KLK5-derived cleavage product peptides. Pre-incubation of KLK5 with selected antibodies SPINK9.SRE.Fc, mAb1108, and 12 preceded a 20-minute incubation with 0.5 nM KLK5 and 300 nM pro-KLK1 (Figures 5A–5N). The results for KLK5 inhibitors are shown below. Figure 5A: SPINK9.SRE.Fc, Figure 5B: mAb1108, Figure 5C: 10C8, Figure 5D: 9B6, Figure 5E: 2B11, Figure 5F: 9F2, Figure 5G: 2-3F4, Figure 5H: 10H3, Figure 5I: 9H3, Figure 5J: 8B7, Figure 5K: 8F5, Figure 5L: 3-3F5, Figure 5M: 10C5, and Figure 5N: 9H5. [Figure 5M-N]Figures 5A–4N show the results of LC / MS assays measuring the inhibition of pro-KLK1 proteolysis by recombinant KLK5 by monitoring KLK5-derived cleavage product peptides. Pre-incubation of KLK5 with selected antibodies SPINK9.SRE.Fc, mAb1108, and 12 preceded a 20-minute incubation with 0.5 nM KLK5 and 300 nM pro-KLK1 (Figures 5A–5N). The results for KLK5 inhibitors are shown below. Figure 5A: SPINK9.SRE.Fc, Figure 5B: mAb1108, Figure 5C: 10C8, Figure 5D: 9B6, Figure 5E: 2B11, Figure 5F: 9F2, Figure 5G: 2-3F4, Figure 5H: 10H3, Figure 5I: 9H3, Figure 5J: 8B7, Figure 5K: 8F5, Figure 5L: 3-3F5, Figure 5M: 10C5, and Figure 5N: 9H5.

[0046] [Figure 6A-F] Figures 6A to 6N show the specificity of KLK5 inhibitors to KLK7 activity. 5 nM recombinant human KLK7 inhibitors and 0.19–100 nM anti-KLK5 inhibitors were pre-incubated for 30 minutes before the addition of 100 μM suc-LLVY-AMC. Plates were examined every 102 seconds for 75 minutes using a PHERAstar® Plus reader with a 340 nm excitation / 460 nm emission module. IC50 values ​​are summarized in Table 6. The results for KLK5 inhibitors are shown below. Figure 6A: Spink9.SRE.Fc, Figure 6B: mAb1108, Figure 6C: 3-3F5, Figure 6D: 10C8, Figure 6E: 9B6, Figure 6F: 9F2, Figure 6G: 9H3, Figure 6H: 9H5, Figure 6I: 2B11, Figure 6J: 8B7, Figure 6K: 8F5, Figure 6L: 10C5, Figure 6M: 10H3, and Figure 6N: 2-3F4. [Figure 6G-L]Figures 6A to 6N show the specificity of KLK5 inhibitors to KLK7 activity. 5 nM recombinant human KLK7 inhibitors and 0.19–100 nM anti-KLK5 inhibitors were pre-incubated for 30 minutes before the addition of 100 μM suc-LLVY-AMC. Plates were examined every 102 seconds for 75 minutes using a PHERAstar® Plus reader with a 340 nm excitation / 460 nm emission module. IC50 values ​​are summarized in Table 6. The results for KLK5 inhibitors are shown below. Figure 6A: Spink9.SRE.Fc, Figure 6B: mAb1108, Figure 6C: 3-3F5, Figure 6D: 10C8, Figure 6E: 9B6, Figure 6F: 9F2, Figure 6G: 9H3, Figure 6H: 9H5, Figure 6I: 2B11, Figure 6J: 8B7, Figure 6K: 8F5, Figure 6L: 10C5, Figure 6M: 10H3, and Figure 6N: 2-3F4. [Figure 6M-N] Figures 6A to 6N show the specificity of KLK5 inhibitors to KLK7 activity. 5 nM recombinant human KLK7 inhibitors and 0.19–100 nM anti-KLK5 inhibitors were pre-incubated for 30 minutes before the addition of 100 μM suc-LLVY-AMC. Plates were examined every 102 seconds for 75 minutes using a PHERAstar® Plus reader with a 340 nm excitation / 460 nm emission module. IC50 values ​​are summarized in Table 6. The results for KLK5 inhibitors are shown below. Figure 6A: Spink9.SRE.Fc, Figure 6B: mAb1108, Figure 6C: 3-3F5, Figure 6D: 10C8, Figure 6E: 9B6, Figure 6F: 9F2, Figure 6G: 9H3, Figure 6H: 9H5, Figure 6I: 2B11, Figure 6J: 8B7, Figure 6K: 8F5, Figure 6L: 10C5, Figure 6M: 10H3, and Figure 6N: 2-3F4.

[0047] [Figure 7A-F]Figures 7A to 7N show the specificity of KLK5 inhibitors to KLK1 activity. 3 nM recombinant human KLK1 inhibitors and 0.19–100 nM anti-KLK5 inhibitors were pre-incubated for 30 minutes before the addition of 100 μM PFR-AMC. Plates were examined every 102 seconds for 60 minutes using a PHERAstar® Plus reader with a 340 nm excitation / 460 nm emission module. IC50 values ​​are summarized in Table 7. The results for KLK5 inhibitors are shown below. Figure 7A: Spink9.SRE.Fc, Figure 7B: mAb1108, Figure 7C: 3-3F5, Figure 7D: 10C8, Figure 7E: 9B6, Figure 7F: 9F2, Figure 7G: 9H3, Figure 7H: 9H5, Figure 7I: 8B7, Figure 7J: 2B11, Figure 7K: 8F5, Figure 7L: 10C5, Figure 7M: 10H3, and Figure 7N: 2-3F4. [Figure 7G-L] Figures 7A to 7N show the specificity of KLK5 inhibitors to KLK1 activity. 3 nM recombinant human KLK1 inhibitors and 0.19–100 nM anti-KLK5 inhibitors were pre-incubated for 30 minutes before the addition of 100 μM PFR-AMC. Plates were examined every 102 seconds for 60 minutes using a PHERAstar® Plus reader with a 340 nm excitation / 460 nm emission module. IC50 values ​​are summarized in Table 7. The results for KLK5 inhibitors are shown below. Figure 7A: Spink9.SRE.Fc, Figure 7B: mAb1108, Figure 7C: 3-3F5, Figure 7D: 10C8, Figure 7E: 9B6, Figure 7F: 9F2, Figure 7G: 9H3, Figure 7H: 9H5, Figure 7I: 8B7, Figure 7J: 2B11, Figure 7K: 8F5, Figure 7L: 10C5, Figure 7M: 10H3, and Figure 7N: 2-3F4. [Figure 7M-N]Figures 7A to 7N show the specificity of KLK5 inhibitors to KLK1 activity. 3 nM recombinant human KLK1 inhibitors and 0.19–100 nM anti-KLK5 inhibitors were pre-incubated for 30 minutes before the addition of 100 μM PFR-AMC. Plates were examined every 102 seconds for 60 minutes using a PHERAstar® Plus reader with a 340 nm excitation / 460 nm emission module. IC50 values ​​are summarized in Table 7. The results for KLK5 inhibitors are shown below. Figure 7A: Spink9.SRE.Fc, Figure 7B: mAb1108, Figure 7C: 3-3F5, Figure 7D: 10C8, Figure 7E: 9B6, Figure 7F: 9F2, Figure 7G: 9H3, Figure 7H: 9H5, Figure 7I: 8B7, Figure 7J: 2B11, Figure 7K: 8F5, Figure 7L: 10C5, Figure 7M: 10H3, and Figure 7N: 2-3F4.

[0048] [Figure 8A-F] Figures 8A to 8N show the specificity of KLK5 inhibitors to KLK4 activity. 2 nM recombinant human KLK4 inhibitors and 0.19–100 nM anti-KLK5 inhibitors were pre-incubated for 30 minutes before the addition of 50 μM Boc-VPR-AMC. Plates were examined every 102 seconds for 60 minutes using a PHERAstar® Plus reader with a 340 nm excitation / 460 nm emission module. IC50 values ​​are summarized in Table 8. The results for KLK5 inhibitors are shown below. Figure 8A: Spink9.SRE.Fc, Figure 8B: mAb1108, Figure 8C: 3-3F5, Figure 8D: 10C8, Figure 8E: 9B6, Figure 8F: 9F2, Figure 8G: 9H3, Figure 8H: 9H5, Figure 8I: 8B7, Figure 8J: 2B11, Figure 8K: 8F5, Figure 8L: 10C5, Figure 8M: 10H3, and Figure 8N: 2-3F4. [Figure 8G-L]Figures 8A to 8N show the specificity of KLK5 inhibitors to KLK4 activity. 2 nM recombinant human KLK4 inhibitors and 0.19–100 nM anti-KLK5 inhibitors were pre-incubated for 30 minutes before the addition of 50 μM Boc-VPR-AMC. Plates were examined every 102 seconds for 60 minutes using a PHERAstar® Plus reader with a 340 nm excitation / 460 nm emission module. IC50 values ​​are summarized in Table 8. The results for KLK5 inhibitors are shown below. Figure 8A: Spink9.SRE.Fc, Figure 8B: mAb1108, Figure 8C: 3-3F5, Figure 8D: 10C8, Figure 8E: 9B6, Figure 8F: 9F2, Figure 8G: 9H3, Figure 8H: 9H5, Figure 8I: 8B7, Figure 8J: 2B11, Figure 8K: 8F5, Figure 8L: 10C5, Figure 8M: 10H3, and Figure 8N: 2-3F4. [Figure 8M-N] Figures 8A to 8N show the specificity of KLK5 inhibitors to KLK4 activity. 2 nM recombinant human KLK4 inhibitors and 0.19–100 nM anti-KLK5 inhibitors were pre-incubated for 30 minutes before the addition of 50 μM Boc-VPR-AMC. Plates were examined every 102 seconds for 60 minutes using a PHERAstar® Plus reader with a 340 nm excitation / 460 nm emission module. IC50 values ​​are summarized in Table 8. The results for KLK5 inhibitors are shown below. Figure 8A: Spink9.SRE.Fc, Figure 8B: mAb1108, Figure 8C: 3-3F5, Figure 8D: 10C8, Figure 8E: 9B6, Figure 8F: 9F2, Figure 8G: 9H3, Figure 8H: 9H5, Figure 8I: 8B7, Figure 8J: 2B11, Figure 8K: 8F5, Figure 8L: 10C5, Figure 8M: 10H3, and Figure 8N: 2-3F4.

[0049] [Figure 9A-F]Figures 9A to 9N show the specificity of KLK5 inhibitors to trypsin activity. 0.25 nM trypsin isolated from bovine pancreas and 0.19–100 nM anti-KLK5 inhibitors were pre-incubated for 30 minutes before the addition of 50 μM Boc-VPR-AMC. Plates were examined every 102 seconds for 60 minutes using a PHERAstar® Plus reader with a 340 nm excitation / 460 nm emission module. The IC50 values ​​of the selected antibodies (Figures 9C to 9N) are summarized in Table 9. The results for KLK5 inhibitors are shown below. Figure 9A: Spink9.SRE.Fc, Figure 9B: mAb1108, Figure 9C: 3-3F5, Figure 9D: 10C8, Figure 9E: 9B6, Figure 9F: 9F2, Figure 9G: 9H3, Figure 9H: 9H5, Figure 9I: 8B7, Figure 9J: 2B11, Figure 9K: 8F5, Figure 9L: 10C5, Figure 9M: 10H3, and Figure 9N: 2-3F4. [Figure 9G-L] Figures 9A to 9N show the specificity of KLK5 inhibitors to trypsin activity. 0.25 nM trypsin isolated from bovine pancreas and 0.19–100 nM anti-KLK5 inhibitors were pre-incubated for 30 minutes before the addition of 50 μM Boc-VPR-AMC. Plates were examined every 102 seconds for 60 minutes using a PHERAstar® Plus reader with a 340 nm excitation / 460 nm emission module. The IC50 values ​​of the selected antibodies (Figures 9C to 9N) are summarized in Table 9. The results for KLK5 inhibitors are shown below. Figure 9A: Spink9.SRE.Fc, Figure 9B: mAb1108, Figure 9C: 3-3F5, Figure 9D: 10C8, Figure 9E: 9B6, Figure 9F: 9F2, Figure 9G: 9H3, Figure 9H: 9H5, Figure 9I: 8B7, Figure 9J: 2B11, Figure 9K: 8F5, Figure 9L: 10C5, Figure 9M: 10H3, and Figure 9N: 2-3F4. [Figure 9M-N]Figures 9A to 9N show the specificity of KLK5 inhibitors to trypsin activity. 0.25 nM trypsin isolated from bovine pancreas and 0.19–100 nM anti-KLK5 inhibitors were pre-incubated for 30 minutes before the addition of 50 μM Boc-VPR-AMC. Plates were examined every 102 seconds for 60 minutes using a PHERAstar® Plus reader with a 340 nm excitation / 460 nm emission module. The IC50 values ​​of the selected antibodies (Figures 9C to 9N) are summarized in Table 9. The results for KLK5 inhibitors are shown below. Figure 9A: Spink9.SRE.Fc, Figure 9B: mAb1108, Figure 9C: 3-3F5, Figure 9D: 10C8, Figure 9E: 9B6, Figure 9F: 9F2, Figure 9G: 9H3, Figure 9H: 9H5, Figure 9I: 8B7, Figure 9J: 2B11, Figure 9K: 8F5, Figure 9L: 10C5, Figure 9M: 10H3, and Figure 9N: 2-3F4.

[0050] [Figure 10A-B]Figures 10A to 10AB show the analysis of the efficacy of KLK5 inhibitors by Kiapp measurement. KLK5 inhibitors at various concentrations (0.5, 0.25, 0.125, and 0.0625 nM) and anti-KLK5 inhibitors at 0.0019–10 nM were pre-incubated for 30 minutes before the addition of 300 μM Z-VPR-pNA. The plates were read using a Versamax tunable microplate reader by 405 nm measurements acquired every 102 seconds over 3 hours. The derived Kiapp values ​​are summarized in Table 10. The results for KLK5 inhibitors are as follows (each left-hand figure shows the IC50 values ​​of the KLK5 inhibitor at various KLK5 concentrations (0.5, 0.25, 0.125, and 0.0625 nM), and each right-hand figure shows the IC50 values ​​determined and plotted as a function of KLK5 concentration): Figures 10A and 10B: Spink9.SRE.Fc, Figures 10C and 10D: mAb1108, Figures 10E and 10F :3-3F5, Figures 10G and 10H:10C8, Figures 10I and 10J:9B6, Figures 10K and 10L:9F2, Figures 10M and 10N:9H3, Figures 10O and 10P:9H5, Figures 10Q and 10R:8B7, Figures 10S and 10T:2B11, Figures 10U and 10V:8F5, Figures 10W and 10X:10C5, Figures 10Y and 10Z:10H3, Figures 10AA and 10AB:2-3F4. [Figure 10C-D]Figures 10A to 10AB show the analysis of the efficacy of KLK5 inhibitors by Kiapp measurement. KLK5 inhibitors at various concentrations (0.5, 0.25, 0.125, and 0.0625 nM) and anti-KLK5 inhibitors at 0.0019–10 nM were pre-incubated for 30 minutes before the addition of 300 μM Z-VPR-pNA. The plates were read using a Versamax tunable microplate reader by 405 nm measurements acquired every 102 seconds over 3 hours. The derived Kiapp values ​​are summarized in Table 10. The results for KLK5 inhibitors are as follows (each left-hand figure shows the IC50 values ​​of the KLK5 inhibitor at various KLK5 concentrations (0.5, 0.25, 0.125, and 0.0625 nM), and each right-hand figure shows the IC50 values ​​determined and plotted as a function of KLK5 concentration): Figures 10A and 10B: Spink9.SRE.Fc, Figures 10C and 10D: mAb1108, Figures 10E and 10F :3-3F5, Figures 10G and 10H:10C8, Figures 10I and 10J:9B6, Figures 10K and 10L:9F2, Figures 10M and 10N:9H3, Figures 10O and 10P:9H5, Figures 10Q and 10R:8B7, Figures 10S and 10T:2B11, Figures 10U and 10V:8F5, Figures 10W and 10X:10C5, Figures 10Y and 10Z:10H3, Figures 10AA and 10AB:2-3F4. [Figure 10E-F]Figures 10A to 10AB show the analysis of the efficacy of KLK5 inhibitors by Kiapp measurement. KLK5 inhibitors at various concentrations (0.5, 0.25, 0.125, and 0.0625 nM) and anti-KLK5 inhibitors at 0.0019–10 nM were pre-incubated for 30 minutes before the addition of 300 μM Z-VPR-pNA. The plates were read using a Versamax tunable microplate reader by 405 nm measurements acquired every 102 seconds over 3 hours. The derived Kiapp values ​​are summarized in Table 10. The results for KLK5 inhibitors are as follows (each left-hand figure shows the IC50 values ​​of the KLK5 inhibitor at various KLK5 concentrations (0.5, 0.25, 0.125, and 0.0625 nM), and each right-hand figure shows the IC50 values ​​determined and plotted as a function of KLK5 concentration): Figures 10A and 10B: Spink9.SRE.Fc, Figures 10C and 10D: mAb1108, Figures 10E and 10F :3-3F5, Figures 10G and 10H:10C8, Figures 10I and 10J:9B6, Figures 10K and 10L:9F2, Figures 10M and 10N:9H3, Figures 10O and 10P:9H5, Figures 10Q and 10R:8B7, Figures 10S and 10T:2B11, Figures 10U and 10V:8F5, Figures 10W and 10X:10C5, Figures 10Y and 10Z:10H3, Figures 10AA and 10AB:2-3F4. [Figure 10G-H]Figures 10A to 10AB show the analysis of the efficacy of KLK5 inhibitors by Kiapp measurement. KLK5 inhibitors at various concentrations (0.5, 0.25, 0.125, and 0.0625 nM) and anti-KLK5 inhibitors at 0.0019–10 nM were pre-incubated for 30 minutes before the addition of 300 μM Z-VPR-pNA. The plates were read using a Versamax tunable microplate reader by 405 nm measurements acquired every 102 seconds over 3 hours. The derived Kiapp values ​​are summarized in Table 10. The results for KLK5 inhibitors are as follows (each left-hand figure shows the IC50 values ​​of the KLK5 inhibitor at various KLK5 concentrations (0.5, 0.25, 0.125, and 0.0625 nM), and each right-hand figure shows the IC50 values ​​determined and plotted as a function of KLK5 concentration): Figures 10A and 10B: Spink9.SRE.Fc, Figures 10C and 10D: mAb1108, Figures 10E and 10F :3-3F5, Figures 10G and 10H:10C8, Figures 10I and 10J:9B6, Figures 10K and 10L:9F2, Figures 10M and 10N:9H3, Figures 10O and 10P:9H5, Figures 10Q and 10R:8B7, Figures 10S and 10T:2B11, Figures 10U and 10V:8F5, Figures 10W and 10X:10C5, Figures 10Y and 10Z:10H3, Figures 10AA and 10AB:2-3F4. [Figure 10I-J]Figures 10A to 10AB show the analysis of the efficacy of KLK5 inhibitors by Kiapp measurement. KLK5 inhibitors at various concentrations (0.5, 0.25, 0.125, and 0.0625 nM) and anti-KLK5 inhibitors at 0.0019–10 nM were pre-incubated for 30 minutes before the addition of 300 μM Z-VPR-pNA. The plates were read using a Versamax tunable microplate reader by 405 nm measurements acquired every 102 seconds over 3 hours. The derived Kiapp values ​​are summarized in Table 10. The results for KLK5 inhibitors are as follows (each left-hand figure shows the IC50 values ​​of the KLK5 inhibitor at various KLK5 concentrations (0.5, 0.25, 0.125, and 0.0625 nM), and each right-hand figure shows the IC50 values ​​determined and plotted as a function of KLK5 concentration): Figures 10A and 10B: Spink9.SRE.Fc, Figures 10C and 10D: mAb1108, Figures 10E and 10F :3-3F5, Figures 10G and 10H:10C8, Figures 10I and 10J:9B6, Figures 10K and 10L:9F2, Figures 10M and 10N:9H3, Figures 10O and 10P:9H5, Figures 10Q and 10R:8B7, Figures 10S and 10T:2B11, Figures 10U and 10V:8F5, Figures 10W and 10X:10C5, Figures 10Y and 10Z:10H3, Figures 10AA and 10AB:2-3F4. [Figure 10K-L]Figures 10A to 10AB show the analysis of the efficacy of KLK5 inhibitors by Kiapp measurement. KLK5 inhibitors at various concentrations (0.5, 0.25, 0.125, and 0.0625 nM) and anti-KLK5 inhibitors at 0.0019–10 nM were pre-incubated for 30 minutes before the addition of 300 μM Z-VPR-pNA. The plates were read using a Versamax tunable microplate reader by 405 nm measurements acquired every 102 seconds over 3 hours. The derived Kiapp values ​​are summarized in Table 10. The results for KLK5 inhibitors are as follows (each left-hand figure shows the IC50 values ​​of the KLK5 inhibitor at various KLK5 concentrations (0.5, 0.25, 0.125, and 0.0625 nM), and each right-hand figure shows the IC50 values ​​determined and plotted as a function of KLK5 concentration): Figures 10A and 10B: Spink9.SRE.Fc, Figures 10C and 10D: mAb1108, Figures 10E and 10F :3-3F5, Figures 10G and 10H:10C8, Figures 10I and 10J:9B6, Figures 10K and 10L:9F2, Figures 10M and 10N:9H3, Figures 10O and 10P:9H5, Figures 10Q and 10R:8B7, Figures 10S and 10T:2B11, Figures 10U and 10V:8F5, Figures 10W and 10X:10C5, Figures 10Y and 10Z:10H3, Figures 10AA and 10AB:2-3F4. [Figure 10M-N]Figures 10A to 10AB show the analysis of the efficacy of KLK5 inhibitors by Kiapp measurement. KLK5 inhibitors at various concentrations (0.5, 0.25, 0.125, and 0.0625 nM) and anti-KLK5 inhibitors at 0.0019–10 nM were pre-incubated for 30 minutes before the addition of 300 μM Z-VPR-pNA. The plates were read using a Versamax tunable microplate reader by 405 nm measurements acquired every 102 seconds over 3 hours. The derived Kiapp values ​​are summarized in Table 10. The results for KLK5 inhibitors are as follows (each left-hand figure shows the IC50 values ​​of the KLK5 inhibitor at various KLK5 concentrations (0.5, 0.25, 0.125, and 0.0625 nM), and each right-hand figure shows the IC50 values ​​determined and plotted as a function of KLK5 concentration): Figures 10A and 10B: Spink9.SRE.Fc, Figures 10C and 10D: mAb1108, Figures 10E and 10F :3-3F5, Figures 10G and 10H:10C8, Figures 10I and 10J:9B6, Figures 10K and 10L:9F2, Figures 10M and 10N:9H3, Figures 10O and 10P:9H5, Figures 10Q and 10R:8B7, Figures 10S and 10T:2B11, Figures 10U and 10V:8F5, Figures 10W and 10X:10C5, Figures 10Y and 10Z:10H3, Figures 10AA and 10AB:2-3F4. [Figure 10O-P]Figures 10A to 10AB show the analysis of the efficacy of KLK5 inhibitors by Kiapp measurement. KLK5 inhibitors at various concentrations (0.5, 0.25, 0.125, and 0.0625 nM) and anti-KLK5 inhibitors at 0.0019–10 nM were pre-incubated for 30 minutes before the addition of 300 μM Z-VPR-pNA. The plates were read using a Versamax tunable microplate reader by 405 nm measurements acquired every 102 seconds over 3 hours. The derived Kiapp values ​​are summarized in Table 10. The results for KLK5 inhibitors are as follows (each left-hand figure shows the IC50 values ​​of the KLK5 inhibitor at various KLK5 concentrations (0.5, 0.25, 0.125, and 0.0625 nM), and each right-hand figure shows the IC50 values ​​determined and plotted as a function of KLK5 concentration): Figures 10A and 10B: Spink9.SRE.Fc, Figures 10C and 10D: mAb1108, Figures 10E and 10F :3-3F5, Figures 10G and 10H:10C8, Figures 10I and 10J:9B6, Figures 10K and 10L:9F2, Figures 10M and 10N:9H3, Figures 10O and 10P:9H5, Figures 10Q and 10R:8B7, Figures 10S and 10T:2B11, Figures 10U and 10V:8F5, Figures 10W and 10X:10C5, Figures 10Y and 10Z:10H3, Figures 10AA and 10AB:2-3F4. [Figure 10Q-R]Figures 10A to 10AB show the analysis of the efficacy of KLK5 inhibitors by Kiapp measurement. KLK5 inhibitors at various concentrations (0.5, 0.25, 0.125, and 0.0625 nM) and anti-KLK5 inhibitors at 0.0019–10 nM were pre-incubated for 30 minutes before the addition of 300 μM Z-VPR-pNA. The plates were read using a Versamax tunable microplate reader by 405 nm measurements acquired every 102 seconds over 3 hours. The derived Kiapp values ​​are summarized in Table 10. The results for KLK5 inhibitors are as follows (each left-hand figure shows the IC50 values ​​of the KLK5 inhibitor at various KLK5 concentrations (0.5, 0.25, 0.125, and 0.0625 nM), and each right-hand figure shows the IC50 values ​​determined and plotted as a function of KLK5 concentration): Figures 10A and 10B: Spink9.SRE.Fc, Figures 10C and 10D: mAb1108, Figures 10E and 10F :3-3F5, Figures 10G and 10H:10C8, Figures 10I and 10J:9B6, Figures 10K and 10L:9F2, Figures 10M and 10N:9H3, Figures 10O and 10P:9H5, Figures 10Q and 10R:8B7, Figures 10S and 10T:2B11, Figures 10U and 10V:8F5, Figures 10W and 10X:10C5, Figures 10Y and 10Z:10H3, Figures 10AA and 10AB:2-3F4. [Figure 10S-T]Figures 10A to 10AB show the analysis of the efficacy of KLK5 inhibitors by Kiapp measurement. KLK5 inhibitors at various concentrations (0.5, 0.25, 0.125, and 0.0625 nM) and anti-KLK5 inhibitors at 0.0019–10 nM were pre-incubated for 30 minutes before the addition of 300 μM Z-VPR-pNA. The plates were read using a Versamax tunable microplate reader by 405 nm measurements acquired every 102 seconds over 3 hours. The derived Kiapp values ​​are summarized in Table 10. The results for KLK5 inhibitors are as follows (each left-hand figure shows the IC50 values ​​of the KLK5 inhibitor at various KLK5 concentrations (0.5, 0.25, 0.125, and 0.0625 nM), and each right-hand figure shows the IC50 values ​​determined and plotted as a function of KLK5 concentration): Figures 10A and 10B: Spink9.SRE.Fc, Figures 10C and 10D: mAb1108, Figures 10E and 10F :3-3F5, Figures 10G and 10H:10C8, Figures 10I and 10J:9B6, Figures 10K and 10L:9F2, Figures 10M and 10N:9H3, Figures 10O and 10P:9H5, Figures 10Q and 10R:8B7, Figures 10S and 10T:2B11, Figures 10U and 10V:8F5, Figures 10W and 10X:10C5, Figures 10Y and 10Z:10H3, Figures 10AA and 10AB:2-3F4. [Figure 10U-V]Figures 10A to 10AB show the analysis of the efficacy of KLK5 inhibitors by Kiapp measurement. KLK5 inhibitors at various concentrations (0.5, 0.25, 0.125, and 0.0625 nM) and anti-KLK5 inhibitors at 0.0019–10 nM were pre-incubated for 30 minutes before the addition of 300 μM Z-VPR-pNA. The plates were read using a Versamax tunable microplate reader by 405 nm measurements acquired every 102 seconds over 3 hours. The derived Kiapp values ​​are summarized in Table 10. The results for KLK5 inhibitors are as follows (each left-hand figure shows the IC50 values ​​of the KLK5 inhibitor at various KLK5 concentrations (0.5, 0.25, 0.125, and 0.0625 nM), and each right-hand figure shows the IC50 values ​​determined and plotted as a function of KLK5 concentration): Figures 10A and 10B: Spink9.SRE.Fc, Figures 10C and 10D: mAb1108, Figures 10E and 10F :3-3F5, Figures 10G and 10H:10C8, Figures 10I and 10J:9B6, Figures 10K and 10L:9F2, Figures 10M and 10N:9H3, Figures 10O and 10P:9H5, Figures 10Q and 10R:8B7, Figures 10S and 10T:2B11, Figures 10U and 10V:8F5, Figures 10W and 10X:10C5, Figures 10Y and 10Z:10H3, Figures 10AA and 10AB:2-3F4. [Figure 10W-X]Figures 10A to 10AB show the analysis of the efficacy of KLK5 inhibitors by Kiapp measurement. KLK5 inhibitors at various concentrations (0.5, 0.25, 0.125, and 0.0625 nM) and anti-KLK5 inhibitors at 0.0019–10 nM were pre-incubated for 30 minutes before the addition of 300 μM Z-VPR-pNA. The plates were read using a Versamax tunable microplate reader by 405 nm measurements acquired every 102 seconds over 3 hours. The derived Kiapp values ​​are summarized in Table 10. The results for KLK5 inhibitors are as follows (each left-hand figure shows the IC50 values ​​of the KLK5 inhibitor at various KLK5 concentrations (0.5, 0.25, 0.125, and 0.0625 nM), and each right-hand figure shows the IC50 values ​​determined and plotted as a function of KLK5 concentration): Figures 10A and 10B: Spink9.SRE.Fc, Figures 10C and 10D: mAb1108, Figures 10E and 10F :3-3F5, Figures 10G and 10H:10C8, Figures 10I and 10J:9B6, Figures 10K and 10L:9F2, Figures 10M and 10N:9H3, Figures 10O and 10P:9H5, Figures 10Q and 10R:8B7, Figures 10S and 10T:2B11, Figures 10U and 10V:8F5, Figures 10W and 10X:10C5, Figures 10Y and 10Z:10H3, Figures 10AA and 10AB:2-3F4. [Figure 10Y-Z]Figures 10A to 10AB show the analysis of the efficacy of KLK5 inhibitors by Kiapp measurement. KLK5 inhibitors at various concentrations (0.5, 0.25, 0.125, and 0.0625 nM) and anti-KLK5 inhibitors at 0.0019–10 nM were pre-incubated for 30 minutes before the addition of 300 μM Z-VPR-pNA. The plates were read using a Versamax tunable microplate reader by 405 nm measurements acquired every 102 seconds over 3 hours. The derived Kiapp values ​​are summarized in Table 10. The results for KLK5 inhibitors are as follows (each left-hand figure shows the IC50 values ​​of the KLK5 inhibitor at various KLK5 concentrations (0.5, 0.25, 0.125, and 0.0625 nM), and each right-hand figure shows the IC50 values ​​determined and plotted as a function of KLK5 concentration): Figures 10A and 10B: Spink9.SRE.Fc, Figures 10C and 10D: mAb1108, Figures 10E and 10F :3-3F5, Figures 10G and 10H:10C8, Figures 10I and 10J:9B6, Figures 10K and 10L:9F2, Figures 10M and 10N:9H3, Figures 10O and 10P:9H5, Figures 10Q and 10R:8B7, Figures 10S and 10T:2B11, Figures 10U and 10V:8F5, Figures 10W and 10X:10C5, Figures 10Y and 10Z:10H3, Figures 10AA and 10AB:2-3F4. [Figure 10AA-AB]Figures 10A to 10AB show the analysis of the efficacy of KLK5 inhibitors by Kiapp measurement. KLK5 inhibitors at various concentrations (0.5, 0.25, 0.125, and 0.0625 nM) and anti-KLK5 inhibitors at 0.0019–10 nM were pre-incubated for 30 minutes before the addition of 300 μM Z-VPR-pNA. The plates were read using a Versamax tunable microplate reader by 405 nm measurements acquired every 102 seconds over 3 hours. The derived Kiapp values ​​are summarized in Table 10. The results for KLK5 inhibitors are as follows (each left-hand figure shows the IC50 values ​​of the KLK5 inhibitor at various KLK5 concentrations (0.5, 0.25, 0.125, and 0.0625 nM), and each right-hand figure shows the IC50 values ​​determined and plotted as a function of KLK5 concentration): Figures 10A and 10B: Spink9.SRE.Fc, Figures 10C and 10D: mAb1108, Figures 10E and 10F :3-3F5, Figures 10G and 10H:10C8, Figures 10I and 10J:9B6, Figures 10K and 10L:9F2, Figures 10M and 10N:9H3, Figures 10O and 10P:9H5, Figures 10Q and 10R:8B7, Figures 10S and 10T:2B11, Figures 10U and 10V:8F5, Figures 10W and 10X:10C5, Figures 10Y and 10Z:10H3, Figures 10AA and 10AB:2-3F4.

[0051] [Figure 11] Figure 11 shows a table summarizing the IC50 values ​​evaluated in Figures 1 to 10 and shown therein.

[0052] [Figure 12] Figure 12A shows the sequence regions identified by hydrogen exchange measurements as being affected when in complex with each antibody. These underlined sequence regions are region 1 (56-68, pHexp 8.0), region 2 (107-124, pHexp 6.0), region 3 (184-195, pHexp 8.0), and region 4 (232-246, pHexp 6.0), with pHref=7.5 used for effective time correction. Figure 12B shows actual hydrogen exchange data for representative peptides for each underlined sequence region in Figure 12A.

[0053] [Figure 13A-1] Figure 13A shows the alignment of the light chain variable sequences of anti-KLK5 antibody clones 14C8, 14E12, 8E11, 8G10, 9B6, 2-3F4, 10C5, 2B11, 10H3, 9H3, 8B7, 9H5, 9F2, 10C8, 8F5, 3-3F5, 9E3, 10D10, 12B3, and 1D10. Figure 13B shows the alignment of the heavy chain variable sequences of anti-KLK5 antibody clones 14C8, 14E12, 8E11, 8G10, 9B6, 2-3F4, 10C5, 2B11, 10H3, 9H3, 8B7, 9H5, 9F2, 10C8, 8F5, 3-3F5, 9E3, 10D10, 12B3, and 1D10. The CDR area is also shown using Kabat numbering. [Figure 13A-2] Figure 13A shows the alignment of the light chain variable sequences of anti-KLK5 antibody clones 14C8, 14E12, 8E11, 8G10, 9B6, 2-3F4, 10C5, 2B11, 10H3, 9H3, 8B7, 9H5, 9F2, 10C8, 8F5, 3-3F5, 9E3, 10D10, 12B3, and 1D10. Figure 13B shows the alignment of the heavy chain variable sequences of anti-KLK5 antibody clones 14C8, 14E12, 8E11, 8G10, 9B6, 2-3F4, 10C5, 2B11, 10H3, 9H3, 8B7, 9H5, 9F2, 10C8, 8F5, 3-3F5, 9E3, 10D10, 12B3, and 1D10. The CDR area is also shown using Kabat numbering. [Figure 13A-3] Figure 13A shows the alignment of the light chain variable sequences of anti-KLK5 antibody clones 14C8, 14E12, 8E11, 8G10, 9B6, 2-3F4, 10C5, 2B11, 10H3, 9H3, 8B7, 9H5, 9F2, 10C8, 8F5, 3-3F5, 9E3, 10D10, 12B3, and 1D10. Figure 13B shows the alignment of the heavy chain variable sequences of anti-KLK5 antibody clones 14C8, 14E12, 8E11, 8G10, 9B6, 2-3F4, 10C5, 2B11, 10H3, 9H3, 8B7, 9H5, 9F2, 10C8, 8F5, 3-3F5, 9E3, 10D10, 12B3, and 1D10. The CDR area is also shown using Kabat numbering. [Figure 13B-1]Figure 13A shows the alignment of the light chain variable sequences of anti-KLK5 antibody clones 14C8, 14E12, 8E11, 8G10, 9B6, 2-3F4, 10C5, 2B11, 10H3, 9H3, 8B7, 9H5, 9F2, 10C8, 8F5, 3-3F5, 9E3, 10D10, 12B3, and 1D10. Figure 13B shows the alignment of the heavy chain variable sequences of anti-KLK5 antibody clones 14C8, 14E12, 8E11, 8G10, 9B6, 2-3F4, 10C5, 2B11, 10H3, 9H3, 8B7, 9H5, 9F2, 10C8, 8F5, 3-3F5, 9E3, 10D10, 12B3, and 1D10. The CDR area is also shown using Kabat numbering. [Figure 13B-2] Figure 13A shows the alignment of the light chain variable sequences of anti-KLK5 antibody clones 14C8, 14E12, 8E11, 8G10, 9B6, 2-3F4, 10C5, 2B11, 10H3, 9H3, 8B7, 9H5, 9F2, 10C8, 8F5, 3-3F5, 9E3, 10D10, 12B3, and 1D10. Figure 13B shows the alignment of the heavy chain variable sequences of anti-KLK5 antibody clones 14C8, 14E12, 8E11, 8G10, 9B6, 2-3F4, 10C5, 2B11, 10H3, 9H3, 8B7, 9H5, 9F2, 10C8, 8F5, 3-3F5, 9E3, 10D10, 12B3, and 1D10. The CDR area is also shown using Kabat numbering. [Figure 13B-3] Figure 13A shows the alignment of the light chain variable sequences of anti-KLK5 antibody clones 14C8, 14E12, 8E11, 8G10, 9B6, 2-3F4, 10C5, 2B11, 10H3, 9H3, 8B7, 9H5, 9F2, 10C8, 8F5, 3-3F5, 9E3, 10D10, 12B3, and 1D10. Figure 13B shows the alignment of the heavy chain variable sequences of anti-KLK5 antibody clones 14C8, 14E12, 8E11, 8G10, 9B6, 2-3F4, 10C5, 2B11, 10H3, 9H3, 8B7, 9H5, 9F2, 10C8, 8F5, 3-3F5, 9E3, 10D10, 12B3, and 1D10. The CDR area is also shown using Kabat numbering. [Figure 13B-4]Figure 13A shows the alignment of the light chain variable sequences of anti-KLK5 antibody clones 14C8, 14E12, 8E11, 8G10, 9B6, 2-3F4, 10C5, 2B11, 10H3, 9H3, 8B7, 9H5, 9F2, 10C8, 8F5, 3-3F5, 9E3, 10D10, 12B3, and 1D10. Figure 13B shows the alignment of the heavy chain variable sequences of anti-KLK5 antibody clones 14C8, 14E12, 8E11, 8G10, 9B6, 2-3F4, 10C5, 2B11, 10H3, 9H3, 8B7, 9H5, 9F2, 10C8, 8F5, 3-3F5, 9E3, 10D10, 12B3, and 1D10. The CDR area is also shown using Kabat numbering.

[0054] [Figure 14A] Figure 14A shows the alignment of the light chain variable sequences of anti-KLK5 antibody clone 10C5 and six humanized 10C5 clones. Figure 14B shows the alignment of the heavy chain variable sequences of anti-KLK5 antibody clone 10C5 and 28 humanized 10C5 clones. Amino acid residues highlighted in black are altered residues. The CDR region according to Kabat numbering is also shown. [Figure 14B-1] Figure 14A shows the alignment of the light chain variable sequences of anti-KLK5 antibody clone 10C5 and six humanized 10C5 clones. Figure 14B shows the alignment of the heavy chain variable sequences of anti-KLK5 antibody clone 10C5 and 28 humanized 10C5 clones. Amino acid residues highlighted in black are altered residues. The CDR region according to Kabat numbering is also shown. [Figure 14B-2] Figure 14A shows the alignment of the light chain variable sequences of anti-KLK5 antibody clone 10C5 and six humanized 10C5 clones. Figure 14B shows the alignment of the heavy chain variable sequences of anti-KLK5 antibody clone 10C5 and 28 humanized 10C5 clones. Amino acid residues highlighted in black are altered residues. The CDR region according to Kabat numbering is also shown. [Figure 14B-3]Figure 14A shows the alignment of the light chain variable sequences of anti-KLK5 antibody clone 10C5 and six humanized 10C5 clones. Figure 14B shows the alignment of the heavy chain variable sequences of anti-KLK5 antibody clone 10C5 and 28 humanized 10C5 clones. Amino acid residues highlighted in black are altered residues. The CDR region according to Kabat numbering is also shown.

[0055] [Figure 15A] Figure 15A shows the alignment of the light chain variable sequences of anti-KLK5 antibody clone 9H5 and four humanized 9H5 clones. Figure 15B shows the alignment of the heavy chain variable sequences of anti-KLK5 antibody clone 9H5 and 17 humanized 9H5 clones. Amino acid residues highlighted in black are altered residues. The CDR region according to Kabat numbering is also shown. [Figure 15B-1] Figure 15A shows the alignment of the light chain variable sequences of anti-KLK5 antibody clone 9H5 and four humanized 9H5 clones. Figure 15B shows the alignment of the heavy chain variable sequences of anti-KLK5 antibody clone 9H5 and 17 humanized 9H5 clones. Amino acid residues highlighted in black are altered residues. The CDR region according to Kabat numbering is also shown. [Figure 15B-2] Figure 15A shows the alignment of the light chain variable sequences of anti-KLK5 antibody clone 9H5 and four humanized 9H5 clones. Figure 15B shows the alignment of the heavy chain variable sequences of anti-KLK5 antibody clone 9H5 and 17 humanized 9H5 clones. Amino acid residues highlighted in black are altered residues. The CDR region according to Kabat numbering is also shown. [Figure 15B-3] Figure 15A shows the alignment of the light chain variable sequences of anti-KLK5 antibody clone 9H5 and four humanized 9H5 clones. Figure 15B shows the alignment of the heavy chain variable sequences of anti-KLK5 antibody clone 9H5 and 17 humanized 9H5 clones. Amino acid residues highlighted in black are altered residues. The CDR region according to Kabat numbering is also shown.

[0056] [Figure 16A]Figure 16A shows the alignment of the light chain variable sequences of anti-KLK5 antibody clone 3-3F5 and five humanized 3-3F5 clones. Figure 16B shows the alignment of the heavy chain variable sequences of anti-KLK5 antibody clone 3-3F5 and 27 humanized 3-3F5 clones. Amino acid residues highlighted in black are altered residues. The CDR region according to Kabat numbering is also shown. [Figure 16B-1] Figure 16A shows the alignment of the light chain variable sequences of anti-KLK5 antibody clone 3-3F5 and five humanized 3-3F5 clones. Figure 16B shows the alignment of the heavy chain variable sequences of anti-KLK5 antibody clone 3-3F5 and 27 humanized 3-3F5 clones. Amino acid residues highlighted in black are altered residues. The CDR region according to Kabat numbering is also shown. [Figure 16B-2] Figure 16A shows the alignment of the light chain variable sequences of anti-KLK5 antibody clone 3-3F5 and five humanized 3-3F5 clones. Figure 16B shows the alignment of the heavy chain variable sequences of anti-KLK5 antibody clone 3-3F5 and 27 humanized 3-3F5 clones. Amino acid residues highlighted in black are altered residues. The CDR region according to Kabat numbering is also shown. [Figure 16B-3] Figure 16A shows the alignment of the light chain variable sequences of anti-KLK5 antibody clone 3-3F5 and five humanized 3-3F5 clones. Figure 16B shows the alignment of the heavy chain variable sequences of anti-KLK5 antibody clone 3-3F5 and 27 humanized 3-3F5 clones. Amino acid residues highlighted in black are altered residues. The CDR region according to Kabat numbering is also shown.

[0057] [Figure 17]Figure 17 shows the evaluation of KLK5 inhibitors in an A549 cell-based IL-8 secretion assay. KLK5-induced IL-8 secretion levels (gray stars) were set to 100% persistence, and buffer (starvation media) only (gray circles) was set to 0% persistence. Dose-response curves are shown for Spink5.Fc (black circles and black dotted lines), humanized 3.3F5 (black diamonds and black solid lines) anti-KLK5 antibodies, humanized 9H5 anti-KLK5 antibodies (solid gray squares and gray solid lines), and humanized 10C5 anti-KLK5 antibodies (white black circles and black dotted lines). The data shown are the mean ± standard deviation of at least three independent experiments.

[0058] [Figure 18A] Figure 18A shows the overlap of human KLK5 containing the KLK5-10C5 Fab complex. Figure 18B shows the interface between human KLK5 and the 10C5 Fab. The amino acid residue numbering of human KLK5 is based on standard protease numbering. See Debela et al., "J Mol Biol", Vol. 373, pp. 1017-1031 (2007). The amino acid residue numbering of the Fab fragment is based on Kabat. [Figure 18B] Figure 18A shows the overlap of human KLK5 containing the KLK5-10C5 Fab complex. Figure 18B shows the interface between human KLK5 and the 10C5 Fab. The amino acid residue numbering of human KLK5 is based on standard protease numbering. See Debela et al., "J Mol Biol", Vol. 373, pp. 1017-1031 (2007). The amino acid residue numbering of the Fab fragment is based on Kabat.

[0059] [Figure 19A]Figure 19A shows the overlap of human KLK5 with the KLK5-9H5 Fab complex. Figure 19B shows the interface between human KLK5 and 9H5 Fab. The amino acid residue numbering of human KLK5 is based on the standard numbering of proteases. The amino acid residue numbering of the Fab fragment is based on Kabat. [Figure 19B] Figure 19A shows the overlap of human KLK5 with the KLK5-9H5 Fab complex. Figure 19B shows the interface between human KLK5 and 9H5 Fab. The amino acid residue numbering of human KLK5 is based on the standard numbering of proteases. The amino acid residue numbering of the Fab fragment is based on Kabat.

[0060] [Figure 20A] Figure 20A shows the overlap of human KLK5 with the KLK5-3-3F5 Fab complex. Figure 20B shows the interface between human KLK5 and the 3-3F5 Fab. The amino acid residue numbering of human KLK5 is based on the standard numbering of proteases. The amino acid residue numbering of the Fab fragment is based on Kabat. [Figure 20B] Figure 20A shows the overlap of human KLK5 with the KLK5-3-3F5 Fab complex. Figure 20B shows the interface between human KLK5 and the 3-3F5 Fab. The amino acid residue numbering of human KLK5 is based on the standard numbering of proteases. The amino acid residue numbering of the Fab fragment is based on Kabat. [Modes for carrying out the invention]

[0061] I. Definition The terms "anti-KLK5 antibody" and "antibody that binds to KLK5" refer to an antibody that has sufficient affinity to be useful as a diagnostic and / or therapeutic agent in the targeting of KLK5 and can bind to KLK5. In some embodiments, the degree of binding of the anti-KLK5 antibody to an unrelated polypeptide (a polypeptide other than KLK5) is less than about 10% of the binding of the antibody to KLK5 when measured, for example, by radioimmunoassay (RIA). In some embodiments, the antibody that binds to KLK5 has a dissociation constant (Kd) of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM (e.g., 10 -8 M or less, e.g., 10 -8 M to 10 -13 M, e.g., 10 -9 M to 10 -13 M). In some embodiments, the antibody that binds to KLK5 has an IC -8 value (the concentration of an inhibitor such as an antibody or a fragment thereof that is required to reduce the rate of an enzymatic reaction by 50%) 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 -13 M to 10 -9 M, e.g., 10 -13 M). In some embodiments, the anti-KLK5 antibody binds to a binding region (e.g., an epitope) of KLK5 that is conserved among KLK polypeptides of different species.

[0062] The term "antibody" is used in the broadest sense and encompasses various antibody structures including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, as long as they exhibit the desired antigen-binding activity.

[0063] ​The term "isolated," as used with respect to antibodies, conjugated polypeptides, polynucleotides, or small molecules, means that they have been separated from components of their natural environment. In some embodiments, antibodies, conjugated polypeptides, polynucleotides, or small molecules are purified to a purity of 95% or greater than 99%, as determined, for example, by electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse-phase HPLC). For a review of methods for evaluating antibody purity, see, for example, Flatman et al., "J. Chromatogr. B", Vol. 848, pp. 79-87 (2007).

[0064] As used herein, the term “monoclonal antibody” refers to an antibody obtained from a substantially homogeneous population of antibodies. That is, the individual antibodies within the population are identical except for a possible variant antibody (e.g., containing naturally occurring mutations or occurring during the production of the monoclonal antibody preparation, and such mutations are usually present in small amounts), and / or bind to the same binding region (e.g., epitopes). Compared to the preparation of polyclonal antibodies, which typically contain different antibodies against different determinants (epitopes), each monoclonal antibody in the preparation of a monoclonal antibody is against a single determinant of the antigen. Therefore, the modifier “monoclonal” indicates the characteristic of an antibody obtained from a substantially homogeneous population of antibodies and should not be interpreted as requiring antibody production by any particular method. For example, the monoclonal antibodies described herein may be prepared 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, e.g., such methods for producing monoclonal antibodies and other exemplary methods.

[0065] A "blocking antibody" or "antagonist antibody" inhibits or reduces the biological activity of the antigen to which it binds. A preferred blocking antibody or antagonist antibody substantially or completely inhibits the biological activity of the antigen.

[0066] The term "chimeric" antibody refers to an antibody in which a portion of the heavy chain and / or light chain originates from a specific source or species, while the remaining heavy chain and / or light chain originates from a different source or species.

[0067] The terms “full-length antibody,” “intact antibody,” and “whole antibody” mean an antibody (e.g., anti-KLK5 antibody) that is interchangeably used herein and has a structure substantially equivalent to that of a natural antibody, or has a heavy chain containing an Fc region.

[0068] A "human antibody" is an antibody produced from a human or human cell, or an antibody that has an amino acid sequence corresponding to the amino acid sequence of an antibody of a non-human source, utilizing the human antibody repertoire or other human antibody-coding sequences. This definition of a human antibody specifically excludes human antibodies that contain non-human antigen-binding residues.

[0069] A “humanized” antibody refers to a chimeric antibody containing amino acid residues derived from non-human HVR and amino acid residues derived from human FR. In some embodiments, a humanized antibody contains at least one, typically two, substantially all of the variable domains, where all or substantially all of the HVR (e.g., CDR) corresponds to that of a non-human antibody, and all or substantially all of the FR corresponds to that of a human antibody. A humanized antibody may also contain at least a portion of the antibody constant region derived from a human antibody. The “humanized form” of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[0070] "Natural antibodies" refer to naturally occurring immunoglobulin molecules with various structures. For example, a natural IgG antibody is a heterotetrameric glycoprotein with approximately 150,000 daltons, consisting of two identical light chains and two identical heavy chains linked by disulfide bonds. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3). Similarly, from the N-terminus to the C-terminus, each light chain has a variable region (VL), also called a variable light domain or light chain variable domain, followed by a constant light (CL) domain. The light chains of an antibody may be assigned to one of two types, called kappa (κ) and lambda (λ), based on the amino acid sequence of their constant domains.

[0071] The "class" of an antibody refers to the type of constant domain or constant region held by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, some of which can be further divided into "subclasses" (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0072] An "antibody fragment" refers to a molecule other than an intact antibody that contains a portion of an intact antibody and binds to an antigen to which an intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2, bispecific antibodies, linear antibodies, single-chain antibody molecules (e.g., scFv), and multispecific antibodies formed from antibody fragments.

[0073] An antibody that "binds to the same epitope" or "binds to the same binding region" as a reference antibody refers to an antibody that blocks 50% or more of the binding of the reference antibody to its binding partner (e.g., antigen) in a competitive assay, and conversely, a reference antibody that blocks 50% or more of the binding of the antibody to its binding partner in a competitive assay.

[0074] The term "thermodynamic epitope" refers to the portion of a protein whose main chain structural dynamics or local free energy of unfolding changes in response to specific binding events, such as binding to an antibody, for example, in the context of epitope mapping using hydrogen exchange mass spectrometry. Structural epitopes may or may not be partially or completely contained within thermodynamic epitopes.

[0075] The term “hypervariable region” or “HVR” as used herein refers to each region of an antibody variable domain that is hypervariable in sequence (“complementarity-determining region” or “CDR”) and / or structurally forms a predetermined loop (“hypervariable loop”) and / or contains residues that contact an antigen (“antigen contact”). Generally, an antibody contains six HVRs, three in the VH region (H1, H2, H3) and three in the VL region (L1, L2, L3). Examples of HVRs as used herein include: (a) Hypervariable loops arising from 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.", Vol. 196, pp. 901-917 (1987)); (b) CDRs produced 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 edition, Public Health Service, National Institutes of Health, Bethesda, Maryland (1991)); (c) Antigen contact 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.", Vol. 262, pp. 732-745 (1996)); and (d) A combination of (a), (b), and / or (c), comprising HVR amino acid residues 46-56(L2), 47-56(L2), 48-56(L2), 49-56(L2), 26-35(H1), 26-35b(H1), 49-65(H2), 93-102(H3), and 94-102(H3). Unless otherwise specified, HVR residues and other residues (e.g., FR residues) in the variable domain are numbered herein according to Kabat et al., as shown in Figures 13-16 and the following sequence listings herein. Unless otherwise specified, CDR is determined according to Kabat et al.

[0076] The term "variable region" or "variable domain" refers to a domain in the heavy or light chain of an antibody that is involved in the binding of the antibody to an antigen. The variable domains of the heavy and light chains of natural antibodies (VH and VL, respectively) generally have similar structures, and each domain contains four conserved framework regions (FRs) and three hypervariable regions (HVRs). (See, for example, Kindt et al., "Kuby Immunology," 6th edition, WHFreeman and Co., p. 91 (2007).) 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 using the VH or VL domain from the antibody that binds to that antigen, respectively. See, for example, Portolano et al., "J.Immunol.", Vol. 150, pp. 880-887 (1993), and Clarkson et al., "Nature", Vol. 352, pp. 624-628 (1991).

[0077] The term “Fc region” is used herein to define the C-terminal region of an immunoglobulin heavy chain that includes at least a portion of the constant region. This term includes native sequence Fc regions and variant Fc regions. In one embodiment, the human IgG heavy chain Fc region extends from Cys226 or Pro230 to the carboxyl terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified herein, the numbering of amino acid residues in the Fc region or constant region follows the EU numbering system (also known as the EU index), as described in Kabat et al., “Sequences of Proteins of Immunological Interest,” 5th edition, Public Health Service, National Institutes of Health, Bethesda, Maryland (1991).

[0078] "Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The variable domain FR generally consists of four FR domains: FR1, FR2, FR3, and FR4. Therefore, the HVR and FR sequences generally appear in the following sequence in VH (or VL): FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0079] For the purposes of this specification, “acceptor human framework” means a framework comprising the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as defined below. An acceptor human framework “derived” from a human immunoglobulin framework or a human consensus framework may contain the same amino acid sequence or may contain a modification of the amino acid sequence. In some embodiments, the number of amino acid modifications 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 embodiments, the VL acceptor human framework is sequence-identical to the VL human immunoglobulin framework sequence or the human consensus framework sequence.

[0080] The "Human Consensus Framework" is a framework representing the most commonly occurring amino acid residues in the selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is performed from subgroups of variable domain sequences. Generally, the sequence subgroups are those described in Kabat et al., "Sequences of Proteins of Immunological Interest," 5th edition, NIH Publication 91-3242, Bethesda, Maryland (1991), Volumes 1-3. In one embodiment, for VL, the subgroup is subgroup Kappa I in Kabat et al. (see above). In one embodiment, for VH, the subgroup is subgroup III in Kabat et al. (see above).

[0081] "Affinity" or "binding affinity" refers to the total strength of non-covalent interactions between a single binding site of a molecule (e.g., an antibody, binding polypeptide, polynucleotide, or small molecule) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects the 1:1 interaction between the members of a binding pair (e.g., any of the antibodies, binding polypeptides, polynucleotides, small molecules, and antigens). The affinity of molecule X for its partner Y can generally be expressed by a dissociation constant (Kd). Affinity can be measured by common methods known in the art, including the methods described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described below.

[0082] An "affinity-mature" antibody refers to an antibody that, compared to an unmodified parent antibody, has one or more modifications in one or more hypervariable regions (HVRs), and in which such modifications improve the antibody's affinity for the antigen.

[0083] The "binding region" is a portion of the binding partner (e.g., antigen) to which the KLK5 antibody selectively binds. In the case of a binding polypeptide partner, the linear binding region may be a peptide portion of approximately 4 to 15 (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) amino acid residues. The non-linear structural binding region may contain residues of adjacent polypeptide sequences in the three-dimensional (3D) structure of the binding polypeptide partner.

[0084] "Effector function" refers to the biological activity that may be caused by the Fc region of an antibody, which differs 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; downregulation of cell surface receptors (e.g., B cell receptors); and B cell activation.

[0085] As used herein, the terms “KLK5” and “kallikrein 5” refer to any natural KLK5 derived from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise specified. The term encompasses “full-length” untreated KLK5 and any form of KLK5 resulting from cell processing. The term also encompasses naturally occurring variants of KLK5, such as splice variants or allele variants. In some embodiments, the amino acid sequence of exemplary human KLK5 is UNIPROT Q9Y337. In some embodiments, the amino acid sequence of exemplary human KLK5 is selected from the group consisting of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, and 8. In some embodiments, the exemplary human KLK5 amino acid sequence is amino acid residues 23-293 (negative signal peptide) of UNIPROT Q9Y337 (G55, D153 variant), as shown in SEQ ID NO: 2. In some embodiments, the exemplary human KLK5 amino acid sequence is amino acid residues 23-293 (negative signal peptide) of the G55, N153 variant shown in SEQ ID NO: 4. In some embodiments, the exemplary human KLK5 amino acid sequence is amino acid residues 23-293 (negative signal peptide) of the R55, N153 variant shown in SEQ ID NO: 6. In some embodiments, the exemplary human KLK5 amino acid sequence is amino acid residues 23-293 (negative signal peptide) of the R55, D153 variant shown in SEQ ID NO: 8.

[0086] The numbering in the following paragraphs refers to full-length untreated KLK5. In some embodiments, the amino acid sequence of human KLK5 includes amino acid N at position 153. In some embodiments, the amino acid sequence of human KLK5 includes amino acid D at position 153. In some embodiments, the amino acid sequence of human KLK5 includes amino acid G at position 55. In some embodiments, the amino acid sequence of human KLK5 includes amino acid R at position 55. In some embodiments, the amino acid sequence of human KLK5 includes amino acid G at position 55 and amino acid N at position 153. In some embodiments, the amino acid sequence of human KLK5 includes amino acid G at position 55 and amino acid D at position 153. In some embodiments, the amino acid sequence of human KLK5 includes amino acid R at position 55 and amino acid N at position 153. In some embodiments, the amino acid sequence of human KLK5 includes amino acid R at position 55 and amino acid D at position 153.

[0087] The numbering in the following paragraphs refers to full-length untreated KLK5. In some embodiments, the nucleic acid sequence of human KLK5 includes a sequence encoding N at position 153. In some embodiments, the nucleic acid sequence of human KLK5 includes a sequence encoding D at position 153. In some embodiments, the nucleic acid sequence of human KLK5 includes a sequence encoding G at position 55. In some embodiments, the nucleic acid sequence of human KLK5 includes a sequence encoding R at position 55. In some embodiments, the nucleic acid sequence of human KLK5 includes sequences encoding G at position 55 and N at position 153. In some embodiments, the nucleic acid sequence of human KLK5 includes sequences encoding G at position 55 and D at position 153. In some embodiments, the nucleic acid sequence of human KLK5 includes sequences encoding R at position 55 and N at position 153. In some embodiments, the nucleic acid sequence of human KLK5 includes sequences encoding R at position 55 and D at position 153.

[0088] As used herein, the terms “SPINK5” and “Kazal-type serine protease inhibitor 5” refer to any natural SPINK5 derived from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. The term encompasses “full-length” untreated SPINK5 and any form of SPINK5 resulting from cell processing. The term also encompasses naturally occurring variants of SPINK5, such as splice variants or allele variants. In some embodiments, the amino acid sequence of exemplary human SPINK5 is UNIPROT Q9NQ38, shown in SEQ ID NO: 9. In some embodiments, the amino acid sequence of exemplary human SPINK5 is amino acid residues 23-1064 (minus signal peptide) of UNIPROT Q9NQ38, shown in SEQ ID NO: 10.

[0089] As used herein, the term “SPINK fusion polypeptide” means a fusion polypeptide in which a SPINK polypeptide or a fragment thereof (e.g., a specific domain of a SPINK polypeptide (e.g., SPINK5 and / or SPINK9)) is directly or indirectly linked to another polypeptide (e.g., a non-SPINK polypeptide).

[0090] As used herein, the term “SPINK-Fc fusion polypeptide” refers to a fusion polypeptide in which a SPINK polypeptide or fragment thereof (e.g., a specific domain of the SPINK polypeptide (e.g., SPINK5 and / or SPINK9)) is directly or indirectly linked to an Fc region. In some embodiments, the Fc region is selected from the group consisting of IgG1 Fc regions, IgG2a Fc regions, and IgG4 Fc regions. In some embodiments, the Fc region is an IgG2a Fc region. In some embodiments, the IgG2a Fc region is a mouse IgG2a Fc region. In some embodiments, the Fc region is an IgG1 Fc region. In some embodiments, the IgG1 Fc region is a human IgG1 Fc region. In some embodiments, the Fc region is an IgG4 Fc region. In some embodiments, the IgG4 Fc region is a human IgG4 Fc region. In some embodiments, the SPINK polypeptide or fragment thereof is a human SPINK polypeptide or fragment thereof. In some embodiments, the SPINK polypeptide or fragment thereof is a mouse SPINK polypeptide or fragment thereof. It will be understood that minor sequence mutations, such as insertions, deletions, substitutions, and especially conserved amino acid substitutions of the SPINK polypeptide, SPINK domain, or SPINK-Fc fusion polypeptide, which do not affect the function and / or activity of the SPINK polypeptide, SPINK domain, or SPINK-Fc fusion polypeptide, are provided herein. In some embodiments, the SPINK-Fc fusion polypeptide provided herein can bind to KLK5, which may result in KLK5 inhibition. In some embodiments, the SPINK polypeptide or fragment thereof is SPINK9. In some embodiments, the SPINK-Fc fusion polypeptide is SPINK9.SRE.Fc (SEQ ID NO: 320).

[0091] As used herein, the term “polypeptide” means any natural polypeptide of interest (e.g., KLK5 or SPINK5) of any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise specified. The term encompasses “full-length” untreated polypeptides as well as any form of polypeptides resulting from intracellular processing. The term also encompasses naturally occurring variants of polypeptides, such as splice variants or allele variants.

[0092] The "amino acid sequence identity percentage (%)" relative 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 sequence identity, without considering any conservative substitutions as part of the sequence identity. Alignment for determining the amino acid sequence identity percentage can be achieved in various ways within the scope of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning the sequences, including any algorithm necessary to achieve the maximum alignment over the full length of the sequences being compared. However, for the purposes of this specification, the amino acid sequence identity (%) value is generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program is copyrighted by Genentech, Inc., and its source code, along with user documentation, has been filed with the U.S. Copyright Office (Washington, DC, 20559) and registered under U.S. Copyright Registration Number TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc. in South San Francisco, California, or may be compiled from the source code. The ALIGN-2 program should be compiled when used with UNIX operating systems, including Digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not change. When ALIGN-2 is used for amino acid sequence comparison, the amino acid sequence identity percentage of a given amino acid sequence A to, with, or against a given amino acid sequence B (or, a given amino acid sequence A that has, or contains, a specific amino acid sequence identity percentage to, with, or against a given amino acid sequence B) is calculated as follows: Fraction X / Y×100 In the formula, X is the number of amino acid residues scored as identity matches by the sequence alignment program ALIGN-2 in the alignment of A and B in this program, and Y is the total number of amino acid residues in B. It will be understood that if the length of amino acid sequence A is not equal to the length of amino acid sequence B, the amino acid sequence identity % of A to B is not equal to the amino acid sequence identity % of B to A. Unless otherwise specifically stated, all amino acid sequence identity % values ​​used herein are obtained as described in the paragraph immediately preceding the use of the ALIGN-2 computer program.

[0093] Where used synonymously in this specification, “polynucleotide” or “nucleic acid” refers to a polymer of nucleotides of any length, including DNA and RNA. The nucleotides may be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or analogs thereof, or any substrate that can be incorporated into the polymer by DNA or RNA polymerase or by a synthetic reaction. Polynucleotides may include modified nucleotides, such as methylated nucleotides and their analogs. Where present, modifications to the nucleotide structure may be imparted before or after the assembly of the polymer. The nucleotide sequence may be blocked by non-nucleotide components. Polynucleotides may be further modified after synthesis, such as by compounding with labels. Other types of modifications include, for example, "caps," substitution with one or more analogues of naturally occurring nucleotides, internucleotide modifications, such as those with uncharged bonds (e.g., methyl phosphonate, phosphotryester, phosphoamidate, carbamate, etc.) and those with charged bonds (e.g., phosphorothioates, phosphorodithioates, etc.), pendant portions, such as those containing proteins (e.g., nucleases, toxins, antibodies, signal peptides, ply-L-lysine, etc.), those containing intercalators (e.g., acridine, psoralen, etc.), those containing chelating agents (e.g., metals, radioactive metals, boron, metal oxides, etc.), those containing alkylating agents, those containing modifying bonds (e.g., alpha-anomeric nucleic acids, etc.), and unmodified forms of polynucleotides. Furthermore, any of the hydroxyl groups normally present in the sugar may be replaced by, for example, a phosphonic acid group or a phosphate group, protected by a standard protecting group, or activated to prepare for additional binding to additional nucleotides, or compounded with a solid or semi-solid support. The 5′ and 3′ terminal OH groups can be phosphorylated or substituted with amines or organic capping groups of 1 to 20 carbon atoms. Other hydroxyls may also be derivatized to standard protecting groups.Polynucleotides may also include analogues of ribose or deoxyribose sugars commonly known in the art, such as 2'-O-methyl-, 2'-O-allyl, 2'-fluoro-, or 2'-azidol-ribose, carbocyclic sugar analogues, α-anomeric sugars, epimeric sugars, epimeric sugars, e.g., arabinose, xylose, or lyxose, pyranose sugars, furanose sugars, cedoheptulose, acrylic acid analogues, and debasalized nucleoside analogues, e.g., methylriboside. One or more phosphodiester bonds may be substituted by alternative linking groups. These alternative linking groups include, but are not limited to, embodiments in which the phosphate is replaced by P(O)S ("thioate"), P(S)S ("dithioate"), ''(O)NR2 ("amidate"), P(O)R, P(O)OR', CO, or CH2 ("formacetal"), where each R or R' is independently H, or a substituted or unsubstituted alkyl (1-20C) (optionally including an ether (-O-) linkage), aryl, alkenyl, cycloalkyl, cycloalkenyl, or aralgyl. Not all links in the polynucleotide need to be identical. The foregoing description applies to all polynucleotides referred to herein, including RNA and DNA.

[0094] "Isolated" polynucleotides or nucleic acids refer to molecules separated from their natural environment. Isolated nucleic acids include nucleic acid molecules that are originally contained in cells but are located outside of chromosomes or at chromosomal locations different from their natural chromosomal locations.

[0095] "Isolated nucleic acid encoding an anti-KLK5 antibody" means one or more nucleic acid molecules encoding the heavy and light chains (or fragments thereof) of an antibody, including such nucleic acid molecules(s) in a single vector or separate vectors, and such nucleic acid molecules(s) are located at one or more locations within a host cell.

[0096] As used herein, the term “KLK5 genome sequence” means either the cDNA and / or genomic form of the KLK5 gene, which may include introns and upstream and downstream regulatory sequences.

[0097] The terms “host cell,” “host cell line,” and “host cell culture” refer to cells that are interchangeably used and into which exogenous nucleic acids have been introduced, and include the offspring of such cells. Host cells include “transformers” and “transformed cells,” which include primary transformed cells and offspring derived from primary transformed cells, regardless of passage number. Offspring may contain mutations, but may not be exactly identical in nucleic acid content to the parent cells. Mutant offspring having the same function or biological activity as those screened or selected from the original transformed cells are included in the present invention.

[0098] The term “vector,” as used herein, refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. This term includes vectors as self-replicating nucleic acid structures, and vectors integrated into the genome of a host cell into which they are introduced. Certain vectors can direct the expression of the nucleic acid to which they are functionally linked. Such vectors are referred to herein as “expression vectors.”

[0099] As used herein, “reference sample,” “reference cell,” “reference tissue,” “control sample,” “control cell,” or “control tissue” refers to a sample, cell, tissue, standard, or level used for comparative purposes. In one embodiment, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from healthy and / or unaffected portions (e.g., tissue or cells) of the same body of the subject. For example, healthy and / or unaffected cells or tissue adjacent to affected cells or tissue (e.g., cells or tissue adjacent to a tumor). In another embodiment, the reference sample is obtained from untreated tissue and / or cells of the same body of the subject. In yet another embodiment, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from healthy and / or unaffected portions (e.g., tissue or cells) of a different body of the subject. In yet another embodiment, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from untreated tissue and / or cells of a different body of the subject.

[0100] As used herein, the term “sample” means a preparation obtained from or derived from the subject of interest, containing cellular and / or other molecular elements that will be characterized and / or identified, for example, based on physical, biochemical, chemical, and / or physiological characteristics. For example, the phrase “disease sample” and its variations mean any sample obtained from the subject of interest that is expected to contain, or is known to contain, the cells and / or molecular entities to be characterized. Examples of samples include, but are not limited to, primary or cultured cells or cell lines, cell supernatants, cell lysates, platelets, serum, plasma, vitreous fluid, lymph, synovial fluid, follicular fluid, semen, amniotic fluid, milk, whole blood, blood-derived cells, urine, cerebrospinal fluid, saliva, sputum, tears, sweat, mucus, tumor lysates, and tissue culture media, tissue extracts (such as homogenized tissue), tumor tissue, cell extracts, and combinations thereof.

[0101] "Tissue sample" or "cell sample" means a collection of similar cells obtained from the tissue of interest. Sources of tissue or cell samples may include solid tissues such as fresh, frozen, and / or preserved organs, tissue samples, biopsies, and / or aspirates; blood or any blood components such as plasma; bodily fluids such as cerebrospinal fluid, amniotic fluid, ascites, or interstitial fluid; or cells from any stage in the pregnancy or development of the subject. Tissue samples may also be primary or cultured cells or cell lines. Optionally, tissue or cell samples may be obtained from diseased tissue / organ. Tissue samples may contain compounds that do not naturally mix with natural tissues, such as preservatives, anticoagulants, buffers, fixatives, nutrients, or antibiotics.

[0102] The "effective dose" of a drug, such as a pharmaceutical preparation, refers to the amount that is effective in achieving the desired therapeutic outcome over the required period of time.

[0103] The "subject" is a mammal. Mammals include, but are not limited to, livestock (e.g., cattle, 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 some embodiments, the subject is a human.

[0104] As used herein, the term “patient” refers to an animal, such as a mammal. In one embodiment, “patient” refers to a human being.

[0105] The term "pharmaceutical preparation" refers to a preparation in which the biological activity of the active ingredient contained in the preparation is effective, and which does not contain any additional components that are unacceptably toxic to the person to whom the preparation is administered.

[0106] A "pharmaceutically acceptable carrier" refers to a component in a pharmaceutical preparation other than the active ingredient that is non-toxic to the target substance. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0107] As used herein, the term “high Th2 asthma” refers to asthma exhibiting high levels of one or more Th2 cell-associated cytokines, e.g., IL13, IL4, IL9, IL5, or Th2 cytokine-associated inflammation. In some embodiments, the term high Th2 asthma may be used interchangeably with high eosinophilic asthma. In some embodiments, high Th2 asthma is Th2-driven asthma. In some embodiments, the asthma patient is determined to be eosinophilic inflammation positive (EIP). See, for example, International Patent Application Publication 2015 / 061441, which is incorporated herein by reference in its entirety. In some embodiments, the subject is determined to have elevated levels of at least one eosinophilic signature gene compared to a control or reference level. See International Publication 2015 / 061441. In some embodiments, high Th2 asthma is high periostin asthma. In some embodiments, the subject has elevated serum periostin levels. In some embodiments, the subject is 18 years of age or older. In some embodiments, the subject is determined to have elevated serum periostin levels compared to a control or reference level. In some embodiments, the control or reference level is the median level of periostin in the population. In some embodiments, the subject is determined to have serum periostin levels of 20 ng / mL or higher. In some embodiments, the subject is determined to have serum periostin levels of 25 ng / mL or higher. In some embodiments, the subject is determined to have serum periostin levels of 50 ng / mL or higher. In some embodiments, the control or reference level for serum periostin is 20 ng / mL, 25 ng / mL, or 50 ng / mL. In some embodiments, the asthma is hypereosinophilic asthma. In some embodiments, the subject is determined to have elevated eosinophil counts compared to a control or reference level. In some embodiments, the control or reference level is the median level in the population. In some embodiments, the subject is determined to have eosinophil counts of 150 / μL or higher in blood.In some embodiments, the subject is determined to have an eosinophil count of 200 / μL or more. In some embodiments, the subject is determined to have an eosinophil count of 250 / μL or more. In some embodiments, the subject is determined to have an eosinophil count of 300 / μL or more. In some embodiments, the subject is determined to have an eosinophil count of 350 / μL or more. In some embodiments, the subject is determined to have an eosinophil count of 400 / μL or more. In some embodiments, the subject is determined to have an eosinophil count of 450 / μL or more. In some embodiments, the subject is determined to have an eosinophil count of 500 / μL or more. In some preferred embodiments, the subject is determined to have an eosinophil count of 300 / μL or more. In some embodiments, the eosinophils are peripheral blood eosinophils. In some embodiments, the eosinophils are sputum eosinophils. In some embodiments, the subject exhibits high levels of FeNO (exhaled nitric oxide) and / or high levels of IgE. For example, in some cases, subjects exhibit FeNO levels higher than approximately 5 ppb (parts per billion), 10 ppb, 15 ppb, 20 ppb, 25 ppb, 30 ppb, 35 ppb, 40 ppb, 45 ppb, 50 ppb, 60 ppb, 70 ppb, 80 ppb, 90 ppb, and 100 ppb. In some cases, subjects have IgE levels higher than 50 IU / mL.

[0108] The terms “Th2 low asthma,” “non-Th2 high asthma,” “type 2-low asthma,” “T2 low asthma,” “non-eosinophilic asthma,” “pauci-granulocytic asthma,” or “pauci-inflammatory asthma,” as used herein, refer to asthma exhibiting low levels of one or more Th2 cell-related cytokines, e.g., IL13, IL4, IL9, IL5, or asthma exhibiting non-Th2 cytokine-related inflammation. In some embodiments, the term Th2 low asthma may be used interchangeably with low eosinophilic asthma. In some embodiments, asthma patients are determined to be eosinophilic inflammation negative (EIN). See, for example, International Publication 2015 / 061441. In some embodiments, Th2 low asthma is Th17-driven asthma. In some embodiments, low Th2 asthma is hypoperiostin asthma. In some embodiments, subjects are 18 years of age or older. In some embodiments, subjects are determined to have reduced serum periostin levels compared to a control or reference level. In some embodiments, the control or reference level is the median level of periostin in the population. In some embodiments, subjects are determined to have serum periostin less than 20 ng / mL. In some embodiments, asthma is hypoeosinophilic asthma. In some embodiments, subjects are determined to have reduced eosinophil counts compared to a control or reference level. In some embodiments, the control or reference level is the intermediate level in the population. In some embodiments, subjects are determined to have eosinophil counts less than 150 / μL of blood. In some embodiments, subjects are determined to have eosinophil counts less than 100 / μL of blood. In certain preferred embodiments, subjects are determined to have eosinophil counts less than 300 / μL of blood.

[0109] "Treatment" (and variations such as "treat" or "treating") refers to a clinical intervention in an attempt to alter the natural course of the subject or cells being treated. Desired effects of treatment include one or more of the following: prevention of disease onset or recurrence; reduction of symptoms; reduction of any direct or indirect pathological consequences of the disease; a stable (i.e., non-worsening) state of the disease; a decrease in the rate of disease progression; recovery or mitigation of symptoms; an extension of survival time compared to the expected survival rate without treatment; and an improvement in prognosis.

[0110] The term “package insert” is used to refer to the instructions typically included in the commercial packaging of a therapeutic product, which contain information about the indications, usage, dosage, administration, combination therapy, contraindications, and / or warnings regarding the use of such therapeutic product.

[0111] In the context of the embodiments described herein, the terms “a,” “an,” and “the,” and similar terms, should be interpreted as encompassing both singular and plural forms unless otherwise indicated herein or unless the context clearly contradicts this interpretation. The terms “comprising,” “having,” “including,” and “containing,” should be interpreted as open-ended terms (i.e., “including but not limited to”) unless otherwise indicated herein. The aspects and embodiments provided herein are understood to include “consisting of” and / or “essentially consisting of” the aspects and embodiments.

[0112] As will be understood by those skilled in the art, any reference to a value or parameter "about" in this specification includes (and describes) embodiments relating to that value or parameter itself. For example, any statement referring to "about X" includes any statement relating to "X".

[0113] When used herein, the phrase “substantially different” means a sufficiently high difference between two numerical values ​​(generally one associated with a molecule and the other with a reference / comparison molecule), and as a result, a person skilled in the art would consider the difference between these two values ​​to be statistically significant with respect to the biological characteristic measured by such value (e.g., the Kd value). The difference between the two values ​​may be, for example, greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, and / or greater than about 50% as a function of the value relative to the reference / comparison molecule.

[0114] II. Compositions and Methods In one embodiment, the present invention is partially based on the discovery of a KLK5 antibody that inhibits the biological activity of KLK5. In some embodiments, an antibody that binds to KLK5 is provided. In some embodiments, an isolated antibody that binds to KLK5, i.e., an anti-KLK5 antibody, is provided. In some embodiments, the anti-KLK5 antibody inhibits the biological activity of KLK5. In some embodiments, the anti-KLK5 antibody substantially or completely inhibits the biological activity of KLK5. In some embodiments, the biological activity of KLK5 is serine protease activity. In some embodiments, the biological activity of KLK5 is trypsin-like serine protease activity. In some embodiments, the biological activity of KLK5 is the proliferation and contraction of human smooth muscle cells that KLK5 promotes. In some embodiments, the biological activity of KLK5 is the KLK5-induced epithelial expression of inflammatory cytokines, chemokines, and adhesion molecules. In some embodiments, the biological activity of KLK5 is KLK5-induced epithelial production of neutrophil-migrating cytokines and neutrophil influx into lung tissue. In some embodiments, the biological activity of KLK5 is inhibited by at least about 40%, 50%, 60%, 70%, 80%, 90%, and / or more. In some embodiments, the biological activity of KLK5 is inhibited by about 40%, 50%, 60%, 70%, 80%, 90%, and / or more. In some embodiments, the biological activity of KLK5 is inhibited by 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, and / or 90-100%.

[0115] In some embodiments of any anti-KLK5 antibody, the anti-KLK5 antibody substantially or completely inhibits the binding of SPINK5 to KLK5. In some embodiments, the binding of SPINK5 to KLK5 is inhibited by at least about 40%, 50%, 60%, 70%, 80%, 90%, and / or more. In some embodiments, the binding of SPINK5 to KLK5 is inhibited by about 40%, 50%, 60%, 70%, 80%, 90%, and / or more. In some embodiments, the binding of SPINK5 to KLK5 is inhibited by about 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, and / or 90-100%.

[0116] In some embodiments of any anti-KLK5 antibody, the anti-KLK5 antibody has an IC50 smaller than any of the following: about 1000 nM, 500 nM, 100 nM, 50 nM, 10 nM, 5 nM, 1 nM, 500 pM, 100 pM, 50 pM, 10 pM, 5 pM, and / or 1 pM. 50 The antibody has a value. In some embodiments, the anti-KLK5 antibody has an IC50 value smaller than any of 1000 nM, 500 nM, 100 nM, 50 nM, 10 nM, 5 nM, 1 nM, 500 pM, 100 pM, 50 pM, 10 pM, 5 pM, and / or 1 pM. 50 The IC50 is approximately 50 μM to 1 μM, 1 μM to 500 nM, 500 nM to 100 nM, 100 nM to 10 nM, 10 nM to 1 nM, 1000 pM to 500 pM, 500 pM to 200 pM, 200 pM to 150 pM, 150 pM to 100 pM, 100 pM to 10 pM, and / or 10 pM to 1 pM. 50 It has a value.

[0117] The antibodies provided herein are useful for the diagnosis or treatment of diseases selected from the group consisting of, for example, Netherton syndrome, asthma, atopic dermatitis, psoriasis, and rosacea. In some embodiments, the disease is selected from the group consisting of Netherton syndrome, asthma, atopic dermatitis, psoriasis, rosacea, and eosinophilic esophagitis. In some embodiments, asthma is persistent chronic severe asthma with acute events that exacerbate (or relapse) symptoms that may be life-threatening. In some embodiments, asthma is caused by atopic (also known as allergic) asthma, non-allergic asthma (e.g., often by respiratory viruses (e.g., influenza, parainfluenza, rhinovirus, human metapneumovirus, and respiratory rash virus) or infection with inhaled irritants (air pollutants, smog, diesel particles, volatile chemicals and gases, indoors or outdoors, or even by cold, dry air). In some embodiments, asthma is intermittent or exercise-induced asthma due to acute or chronic primary or secondary exposure to “smoke” (typically cigarettes, cigars, pipes), inhalation, or smoking (tobacco, marijuana, or other such substances), or aspirin or This is asthma caused by new intake of related NSAIDs. In some embodiments, asthma is mild asthma or corticosteroid-naive asthma, newly diagnosed untreated asthma, or has not previously required chronic use of inhaled topical or systemic steroids to control symptoms (cough, wheezing, dyspnea / shortness of breath, or chest pain). In some embodiments, asthma is chronic corticosteroid-resistant asthma, corticosteroid-refractory asthma, asthma uncontrolled with corticosteroids, or asthma uncontrolled with other chronic asthma control agents. In some embodiments, asthma is moderate to severe asthma. In some embodiments, asthma is high Th2 asthma. In some embodiments, asthma is severe asthma.In some embodiments, asthma is defined as atopic asthma, allergic asthma, non-allergic asthma (e.g., due to infectious and / or respiratory rash virus (RSV)), exercise-induced asthma, aspirin-sensitive / exacerbating asthma, mild asthma, moderate to severe asthma, corticosteroid-untreated asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, newly diagnosed untreated asthma, smoking-induced asthma, or asthma uncontrolled by corticosteroids. In some embodiments, asthma is defined as T helper lymphocyte type 2 (Th2) asthma or type 2 (Th2) high-level asthma, or type 2 (T2)-driven asthma. In some embodiments, asthma is eosinophilic asthma. In some embodiments, asthma is allergic asthma. In some embodiments, the subject is determined to be eosinophilic inflammation-positive (EIP). See International Publication No. 2015 / 061441. In some embodiments, asthma is hyperperiostin asthma (e.g., having a serum periostin concentration of at least about 20 ng / mL, 25 ng / mL, or 50 ng / mL). In some embodiments, asthma is hypereosinophilic asthma (e.g., eosinophil counts of at least about 150, 200, 250, 300, 350, or 400 / mL of blood). In some embodiments, asthma is low Th2 asthma or non-Th2 driven asthma. In some embodiments, subjects are determined to be eosinophilic inflammation negative (EIN). See International Publication No. 2015 / 061441. In some embodiments, asthma is hypoperiostinic asthma (e.g., having a serum periostin concentration of less than about 20 ng / mL of blood). In some embodiments, asthma is hypoeosinophilic asthma (e.g., eosinophil counts of less than about 150 / μL of blood or less than about 100 / μL of blood).

[0118] A. Exemplary anti-KLK5 antibody Isolated antibodies that bind to KLK5 are provided herein. In one embodiment, the antibody inhibits the biological activity of KLK5 by at least 50%. KLK5 is a (chymo)trypsin-like serine protease expressed in human skin, particularly in the upper stratum spinosum and stratum granulosum. KLK5 is known to play a pathological role in skin disorders such as Netherton syndrome.

[0119] An exemplary naturally occurring human KLK5 precursor protein sequence having a signal peptide (amino acids 1-22) is provided in SEQ ID NO: 1. The corresponding mature KLK5 protein sequence corresponding to amino acids 23-293 of SEQ ID NO: 1 is provided in SEQ ID NO: 2. Exemplary variants of human KLK5 precursor protein having a signal peptide containing one or both of amino acid exchanges R55 and N153 are provided in SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively.

[0120] In a particular embodiment, the anti-KLK5 antibody has one or more of the following characteristics in any combination: a) Inhibition of the biological activity of KLK5 by at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%; b) Inhibition of KLK5 serine protease activity; c) Specific binding to human KLK5; d) IC 50 The value is less than 10 nM, less than 5 nM, less than 3 nM, less than 2 nM, less than 1 nM, less than 0.5 nM, less than 0.1 nM; and / or e) IC 50 The values ​​are less than 500 pM, less than 200 pM, less than 100 pM, less than 50 pM, less than 25 pM, less than 10 pM, less than 5 pM, and less than 1 pM.

[0121] Antibodies 8G10, 9B6, 2-3F4, 10C5, 2B11, 10H3, 9H3, 8B7, 9H5, 9F2, 10C8, 8F5, 3-3F5, and other embodiments In one embodiment, an anti-KLK5 antibody is provided comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising an amino acid sequence selected from any one of SEQ ID NOs: 14 to 24, (b) HVR-H2 comprising an amino acid sequence selected from any one of SEQ ID NOs: 32 to 53, (c) HVR-H3 comprising an amino acid sequence selected from any one of SEQ ID NOs: 62 to 72, (d) HVR-L1 comprising an amino acid sequence selected from any one of SEQ ID NOs: 79 to 91, (e) HVR-L2 comprising an amino acid sequence selected from any one of SEQ ID NOs: 99 to 106, and (f) HVR-L3 comprising an amino acid sequence selected from any one of SEQ ID NOs: 112 to 122.

[0122] In one embodiment, an anti-KLK5 antibody is provided comprising at least one, at least two, or a total of three VH HVR sequences selected from (a) HVR-H1 comprising an amino acid sequence selected from any one of SEQ ID NOs: 14 to 24, (b) HVR-H2 comprising an amino acid sequence selected from any one of SEQ ID NOs: 32 to 53, and (c) HVR-H3 comprising an amino acid sequence selected from any one of SEQ ID NOs: 62 to 72. In one embodiment, the antibody comprises HVR-H3 comprising an amino acid sequence selected from any one of SEQ ID NOs: 62 to 72. In another embodiment, the antibody comprises HVR-H3 comprising an amino acid sequence selected from any one of SEQ ID NOs: 62 to 72, and HVR-L3 comprising an amino acid sequence selected from any one of SEQ ID NOs: 112 to 122. In further embodiments, the antibody comprises HVR-H3 containing an amino acid sequence selected from any one of SEQ ID NOs: 62-72, HVR-L3 containing an amino acid sequence selected from any one of SEQ ID NOs: 112-122, and HVR-H2 containing an amino acid sequence selected from any one of SEQ ID NOs: 32-53. In further embodiments, the antibody comprises (a) HVR-H1 containing an amino acid sequence selected from any one of SEQ ID NOs: 14-24, (b) HVR-H2 containing an amino acid sequence selected from any one of SEQ ID NOs: 32-53, and (c) HVR-H3 containing an amino acid sequence selected from any one of SEQ ID NOs: 62-72.

[0123] In another embodiment, an anti-KLK5 antibody is provided comprising at least one, at least two, or a total of three VL HVR sequences selected from (a) HVR-L1 comprising an amino acid sequence selected from any one of SEQ ID NOs: 79 to 91, (b) HVR-L2 comprising an amino acid sequence selected from any one of SEQ ID NOs: 99 to 106, and (c) HVR-L3 comprising an amino acid sequence selected from any one of SEQ ID NOs: 112 to 122. In one embodiment, the antibody comprises (a) HVR-L1 comprising an amino acid sequence selected from any one of SEQ ID NOs: 79 to 91, (b) HVR-L2 comprising an amino acid sequence selected from any one of SEQ ID NOs: 99 to 106, and (c) HVR-L3 comprising an amino acid sequence selected from any one of SEQ ID NOs: 112 to 122.

[0124] In another embodiment, an anti-KLK5 antibody is provided comprising (a) a VH domain comprising at least one, at least two, or a total of three VH HVR sequences selected from (i) an amino acid sequence selected from any one of SEQ ID NOs: 14 to 24, (ii) an amino acid sequence selected from any one of SEQ ID NOs: 32 to 53, and (iii) an amino acid sequence selected from any one of SEQ ID NOs: 62 to 72, and (b) a VL domain comprising at least one, at least two, or a total of three VL HVR sequences selected from (i) an amino acid sequence selected from any one of SEQ ID NOs: 79 to 91, (ii) an amino acid sequence selected from any one of SEQ ID NOs: 99 to 106, and (c) an amino acid sequence selected from any one of SEQ ID NOs: 112 to 122. In another embodiment, an anti-KLK5 antibody is provided comprising (a) HVR-H1 comprising an amino acid sequence selected from any one of SEQ ID NOs: 14 to 24, (b) HVR-H2 comprising an amino acid sequence selected from any one of SEQ ID NOs: 32 to 53, (c) HVR-H3 comprising an amino acid sequence selected from any one of SEQ ID NOs: 62 to 72, (d) HVR-L1 comprising an amino acid sequence selected from any one of SEQ ID NOs: 79 to 91, (e) HVR-L2 comprising an amino acid sequence selected from any one of SEQ ID NOs: 99 to 106, and (f) HVR-L3 comprising an amino acid sequence selected from any one of SEQ ID NOs: 112 to 122.

[0125] In any of the embodiments described above, the anti-KLK5 antibody is humanized. In one embodiment, the anti-KLK5 antibody comprises an HVR as described in any of the embodiments described above, and further comprises an acceptor human framework, such as a human immunoglobulin framework or a human consensus framework.

[0126] In another embodiment, an anti-KLK5 antibody is provided comprising an amino acid sequence selected from any one of SEQ ID NOs: 170-257 and a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity. In a particular embodiment, the VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence selected from any one of SEQ ID NOs: 170-257 contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-KLK5 antibody containing the sequence retains the ability to bind to KLK5. In a particular embodiment, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in any one of SEQ ID NOs: 170-257. In certain embodiments, substitutions, insertions, or deletions occur within the outer region of the HVR (i.e., within the FR). In some cases, the anti-KLK5 antibody comprises a VH sequence selected from any one of SEQ ID NOs. 170–257, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three HVRs selected from (a) HVR-H1 comprising an amino acid sequence selected from any one of SEQ ID NOs. 14–24, (b) HVR-H2 comprising an amino acid sequence selected from any one of SEQ ID NOs. 32–53, and (c) HVR-H3 comprising an amino acid sequence selected from any one of SEQ ID NOs. 62–72.

[0127] In another embodiment, an anti-KLK5 antibody is provided, wherein the antibody comprises a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with an amino acid sequence selected from any one of SEQ ID NOs: 131-161. In a particular embodiment, the VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with an amino acid sequence selected from any one of SEQ ID NOs: 131-162 contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-KLK5 antibody containing 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 an amino acid sequence selected from any one of SEQ ID NOs: 131-162. In certain embodiments, the substitution, insertion, or deletion occurs in the outer region of the HVR (i.e., within the FR). In some cases, the anti-KLK5 antibody includes a VL sequence of an amino acid sequence selected from any one of SEQ ID NOs: 131-162, which includes post-translational modifications of that sequence. In certain embodiments, the VL includes one, two, or three HVRs selected from (a) HVR-L1 containing an amino acid sequence selected from any one of SEQ ID NOs: 79-91, (b) HVR-L2 containing an amino acid sequence selected from any one of SEQ ID NOs: 99-106, and (c) HVR-L3 containing an amino acid sequence selected from any one of SEQ ID NOs: 112-122.

[0128] In another embodiment, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH sequence as in any of the embodiments provided above, and a VL sequence as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH sequence and VL sequence of SEQ ID NO: 170 and SEQ ID NO: 131, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH sequence and VL sequence of SEQ ID NO: 171 and SEQ ID NO: 132, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH sequence and VL sequence of SEQ ID NO: 172 and SEQ ID NO: 133, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH sequence and VL sequence of SEQ ID NO: 201 and SEQ ID NO: 139, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH sequence and VL sequence of SEQ ID NO: 203 and SEQ ID NO: 141, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody includes the VH and VL sequences of SEQ ID NO: 204 and SEQ ID NO: 142, respectively, and includes post-translational modifications of those sequences. In one embodiment, the antibody includes the VH and VL sequences of SEQ ID NO: 205 and SEQ ID NO: 143, respectively, and includes post-translational modifications of those sequences. In one embodiment, the antibody includes the VH and VL sequences of SEQ ID NO: 206 and SEQ ID NO: 144, respectively, and includes post-translational modifications of those sequences. In one embodiment, the antibody includes the VH and VL sequences of SEQ ID NO: 221 and SEQ ID NO: 149, respectively, and includes post-translational modifications of those sequences. In one embodiment, the antibody includes the VH and VL sequences of SEQ ID NO: 226 and SEQ ID NO: 152, respectively, and includes post-translational modifications of those sequences. In one embodiment, the antibody includes the VH and VL sequences of SEQ ID NO: 227 and SEQ ID NO: 153, respectively, and includes post-translational modifications of those sequences. In one embodiment, the antibody includes the VH and VL sequences of SEQ ID NO: 228 and SEQ ID NO: 154, respectively, and includes post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH sequence and VL sequence of SEQ ID NO: 248 and SEQ ID NO: 160, respectively, including post-translational modifications of those sequences.

[0129] In further embodiments, anti-KLK5 antibodies are provided that bind to the same epitope as the anti-KLK5 antibodies provided herein. For example, in certain embodiments, antibodies are provided that bind to the same epitope as an anti-KLK5 antibody comprising a VH sequence of an amino acid sequence selected from any one of SEQ ID NOs. 170-257. In certain embodiments, antibodies are provided that, when bound to KLK5, result in a thermodynamic epitope comprising one or more sequences selected from the group consisting of SEQ ID NOs. 316, SEQ ID NOs. 317, SEQ ID NOs. 318, and SEQ ID NOs. 319, as measured by hydrogen exchange mass spectrometry.

[0130] In another embodiment, an anti-KLK5 antibody is provided, wherein the antibody comprises an HC sequence of an amino acid sequence selected from any one of SEQ ID NOs. 288 to 306. In yet another embodiment, an anti-KLK5 antibody is provided, wherein the antibody comprises an LC sequence of an amino acid sequence selected from any one of SEQ ID NOs. 265 to 280.

[0131] In one embodiment, the antibody includes the HC sequence and LC sequence of SEQ ID NO: 288 and SEQ ID NO: 265, respectively, and includes post-translational modifications of those sequences. In one embodiment, the antibody includes the HC sequence and LC sequence of SEQ ID NO: 289 and SEQ ID NO: 266, respectively, and includes post-translational modifications of those sequences. In one embodiment, the antibody includes the HC sequence and LC sequence of SEQ ID NO: 290 and SEQ ID NO: 267, respectively, and includes post-translational modifications of those sequences. In one embodiment, the antibody includes the HC sequence and LC sequence of SEQ ID NO: 292 and SEQ ID NO: 269, respectively, and includes post-translational modifications of those sequences. In one embodiment, the antibody includes the HC sequence and LC sequence of SEQ ID NO: 293 and SEQ ID NO: 269, respectively, and includes post-translational modifications of those sequences. In one embodiment, the antibody includes the HC sequence and LC sequence of SEQ ID NO: 294 and SEQ ID NO: 270, respectively, and includes post-translational modifications of those sequences. In one embodiment, the antibody includes the HC sequence and LC sequence of SEQ ID NO: 295 and SEQ ID NO: 271, respectively, and includes post-translational modifications of those sequences. In one embodiment, the antibody includes the HC sequence and LC sequence of SEQ ID NO: 296 and SEQ ID NO: 272, respectively, and includes post-translational modifications of those sequences. In one embodiment, the antibody includes the HC sequence and LC sequence of SEQ ID NO: 297 and SEQ ID NO: 273, respectively, and includes post-translational modifications of those sequences. In one embodiment, the antibody includes the HC sequence and LC sequence of SEQ ID NO: 299 and SEQ ID NO: 275, respectively, and includes post-translational modifications of those sequences. In one embodiment, the antibody includes the HC sequence and LC sequence of SEQ ID NO: 300 and SEQ ID NO: 275, respectively, and includes post-translational modifications of those sequences. In one embodiment, the antibody includes the HC sequence and LC sequence of SEQ ID NO: 301 and SEQ ID NO: 276, respectively, and includes post-translational modifications of those sequences. In one embodiment, the antibody includes the HC sequence and LC sequence of SEQ ID NO: 302 and SEQ ID NO: 277, respectively, and includes post-translational modifications of those sequences. In one embodiment, the antibody includes the HC sequence and LC sequence of SEQ ID NO: 303 and SEQ ID NO: 278, respectively, and includes post-translational modifications of those sequences.In one embodiment, the antibody comprises the HC sequence and LC sequence of SEQ ID NO: 305 and SEQ ID NO: 280, respectively, and includes post-translational modifications of those sequences. In another embodiment, the antibody comprises the HC sequence and LC sequence of SEQ ID NO: 306 and SEQ ID NO: 280, respectively, and includes post-translational modifications of those sequences.

[0132] This specification provides an antibody comprising a light chain variable domain containing HVR1-LC, HVR2-LC, and HVR3-LC sequences according to Kabat numbering shown in Figure 14A, Figure 15A, and / or Figure 16A, and a heavy chain variable domain containing HVR1-HC, HVR2-HC, and HVR3-HC sequences according to Kabat numbering shown in Figure 14B, Figure 15B, and / or Figure 16B. In some embodiments, the antibody comprises a light chain variable domain containing HVR1-LC, HVR2-LC, and / or HVR3-LC sequences, as shown in Figure 14A, Figure 15A, and / or Figure 16A, and FR1-LC, FR2-LC, FR3-LC, and / or FR4-LC sequences. In some embodiments, the antibody includes heavy chain variable domains comprising HVR1-HC, HVR2-HC, and / or HVR3-HC sequences, as shown in Figure 14B, Figure 15B, and / or Figure 16B, and FR1-HC, FR2-HC, FR3-HC, and / or FR4-HC sequences.

[0133] In a further embodiment, an anti-KLK5 antibody is provided that binds to the same epitope as the anti-KLK5 antibody provided herein.

[0134] In a further embodiment, an anti-KLK5 antibody is provided that, when bound to KLK5, yields a thermodynamic epitope comprising one or more sequences selected from the group consisting of SEQ ID NO: 316, SEQ ID NO: 317, SEQ ID NO: 318, and SEQ ID NO: 319, as measured by hydrogen exchange mass spectrometry.

[0135] In further embodiments, the anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody comprising a chimeric antibody, a humanized antibody, or a human antibody. In one embodiment, the anti-KLK5 antibody is humanized. In one embodiment, the anti-KLK5 antibody comprises an HVR as in any of the above embodiments, and further comprises an acceptor human framework, e.g., a human immunoglobulin framework or a human consensus framework. In one embodiment, the anti-KLK5 antibody is an antibody fragment, e.g., Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In another embodiment, the antibody is a full-length antibody, e.g., an intact IgG1 antibody or an intact IgG4 antibody, or other antibody classes or isotypes as defined herein.

[0136] In further embodiments, an anti-KLK5 antibody according to any of the above embodiments may incorporate any of the following features, either individually or in combination.

[0137] Antibodies 10C5, 9H5, 3-3F5, and other embodiments In one embodiment, an anti-KLK5 antibody is provided comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 28, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 38, SEQ ID NO: 45, or SEQ ID NO: 54, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 65, SEQ ID NO: 69, or SEQ ID NO: 72, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 96, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 109, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 127.

[0138] In one embodiment, an anti-KLK5 antibody is provided comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 22, or SEQ ID NO: 24; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 65, SEQ ID NO: 69, or SEQ ID NO: 72; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 82, SEQ ID NO: 87, or SEQ ID NO: 91; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 99, SEQ ID NO: 101, or SEQ ID NO: 105; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 115, SEQ ID NO: 119, or SEQ ID NO: 122.

[0139] In one embodiment, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 22, or SEQ ID NO: 24, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 65, SEQ ID NO: 69, or SEQ ID NO: 72. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 65, SEQ ID NO: 69, or SEQ ID NO: 72. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 65, SEQ ID NO: 69, or SEQ ID NO: 72, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 115, SEQ ID NO: 119, or SEQ ID NO: 122. In further embodiments, the antibody includes HVR-H3 containing the amino acid sequence of SEQ ID NO: 65, SEQ ID NO: 69, or SEQ ID NO: 72, HVR-L3 containing the amino acid sequence of SEQ ID NO: 115, SEQ ID NO: 119, or SEQ ID NO: 122, and HVR-H2 containing the amino acid sequence of SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53. In further embodiments, the antibody includes (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 22, or SEQ ID NO: 24, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53, and (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 65, SEQ ID NO: 69, or SEQ ID NO: 72.

[0140] In another embodiment, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 82, SEQ ID NO: 87, or SEQ ID NO: 91, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 99, SEQ ID NO: 101, or SEQ ID NO: 105, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 115, SEQ ID NO: 119, or SEQ ID NO: 122.

[0141] In another embodiment, an anti-KLK5 antibody is provided, comprising (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 17, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 35, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 65, and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 82, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 115.

[0142] In another embodiment, an anti-KLK5 antibody is provided comprising (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 17, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 35, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 65, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 82, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 101, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 115.

[0143] In another embodiment, an anti-KLK5 antibody is provided, comprising (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 42, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69, and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 87, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 105, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 119.

[0144] In another embodiment, an anti-KLK5 antibody is provided comprising (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 42, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 87, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 105, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 119.

[0145] In another embodiment, an anti-KLK5 antibody is provided, comprising (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 24, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 52, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 72, and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 91, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 99, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 122.

[0146] In another embodiment, an anti-KLK5 antibody is provided comprising (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 24, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 52, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 72, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 91, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 99, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 122.

[0147] In another embodiment, an anti-KLK5 antibody is provided comprising a heavy chain variable domain (VH) sequence having SEQ ID NO: 202. In yet another embodiment, an anti-KLK5 antibody is provided comprising a light chain variable domain (VL) sequence having SEQ ID NO: 140.

[0148] In another embodiment, an anti-KLK5 antibody is provided comprising a heavy chain variable domain (VH) sequence selected from any one of SEQ ID NOs: 173-201. In yet another embodiment, an anti-KLK5 antibody is provided comprising a light chain variable domain (VL) sequence selected from any one of SEQ ID NOs: 134-139 and SEQ ID NO: 321.

[0149] In another embodiment, an anti-KLK5 antibody is provided comprising the amino acid sequence of SEQ ID NO: 201 and a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 201. In certain embodiments, the substitutions, insertions, or deletions occur within the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody includes the VH sequence of SEQ ID NO: 201, which includes post-translational modifications of that sequence. In certain embodiments, the VH includes one, two, or three HVRs selected from (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 17, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 35, and (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 65.

[0150] In another embodiment, an anti-KLK5 antibody is provided, the antibody comprising a light chain variable domain (VL) 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: 139. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 139. In certain embodiments, the substitutions, insertions, or deletions occur in the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody includes the VL sequence of SEQ ID NO: 139, which includes post-translational modifications of that sequence. In certain embodiments, the VL includes one, two, or three HVRs selected from (a) HVR-L1 containing the amino acid sequence of SEQ ID NO: 82, (b) HVR-L2 containing the amino acid sequence of SEQ ID NO: 101, and (c) HVR-L3 containing the amino acid sequence of SEQ ID NO: 115.

[0151] In another embodiment, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH sequence as in any of the embodiments provided above, and a VL sequence as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH sequence and VL sequence of SEQ ID NO: 201 and SEQ ID NO: 139, respectively, including post-translational modifications of those sequences.

[0152] In further embodiments, anti-KLK5 antibodies are provided that bind to the same epitope as the anti-KLK5 antibodies provided herein. For example, in certain embodiments, antibodies are provided that bind to the same epitope as the anti-KLK5 antibody comprising the VH sequence of SEQ ID NO: 201 and the VL sequence of SEQ ID NO: 139. In certain embodiments, antibodies are provided that, when bound to KLK5, result in a thermodynamic epitope comprising one or more sequences selected from the group consisting of SEQ ID NO: 316, SEQ ID NO: 317, SEQ ID NO: 318, and SEQ ID NO: 319, as measured by hydrogen exchange mass spectrometry.

[0153] In another embodiment, an anti-KLK5 antibody is provided comprising a heavy chain variable domain (VH) sequence having SEQ ID NO: 225. In yet another embodiment, an anti-KLK5 antibody is provided comprising a light chain variable domain (VL) sequence having SEQ ID NO: 151.

[0154] In another embodiment, an anti-KLK5 antibody is provided comprising a heavy chain variable domain (VH) sequence selected from any one of SEQ ID NOs. 207 to 224. In yet another embodiment, an anti-KLK5 antibody is provided comprising a light chain variable domain (VL) sequence selected from any one of SEQ ID NOs. 145 to 150.

[0155] In another embodiment, an anti-KLK5 antibody is provided comprising the amino acid sequence of SEQ ID NO: 221 and a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 221. In certain embodiments, the substitutions, insertions, or deletions occur within the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody includes the VH sequence of SEQ ID NO: 221, which includes post-translational modifications of that sequence. In certain embodiments, the VH includes one, two, or three HVRs selected from (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 42, and (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69.

[0156] In another embodiment, an anti-KLK5 antibody is provided, the antibody comprising a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 149. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 149. In certain embodiments, the substitutions, insertions, or deletions occur in the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody comprises the VL sequence of SEQ ID NO: 149, which includes post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 87, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 105, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 119. In another embodiment, an anti-KLK5 antibody is provided, where the antibody comprises a VH as in any of the embodiments provided above, and a VL as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH sequence and VL sequence of SEQ ID NO: 221 and SEQ ID NO: 149, respectively, which include post-translational modifications of those sequences.

[0157] In further embodiments, anti-KLK5 antibodies are provided that bind to the same epitope as the anti-KLK5 antibodies provided herein. For example, in certain embodiments, antibodies are provided that bind to the same epitope as an anti-KLK5 antibody comprising the VH sequence of SEQ ID NO: 221 and the VL sequence of SEQ ID NO: 149. In certain embodiments, antibodies are provided that, when bound to KLK5, result in a thermodynamic epitope comprising one or more sequences selected from the group consisting of SEQ ID NO: 316, SEQ ID NO: 317, SEQ ID NO: 318, and SEQ ID NO: 319, as measured by hydrogen exchange mass spectrometry.

[0158] In another embodiment, an anti-KLK5 antibody is provided comprising a heavy chain variable domain (VH) sequence having sequence number 257. In yet another embodiment, an anti-KLK5 antibody is provided comprising a light chain variable domain (VL) sequence having sequence number 162.

[0159] In another embodiment, an anti-KLK5 antibody is provided comprising a heavy chain variable domain (VH) sequence selected from any one of SEQ ID NOs. 229 to 256. In yet another embodiment, an anti-KLK5 antibody is provided comprising a light chain variable domain (VL) sequence selected from any one of SEQ ID NOs. 155 to 161.

[0160] In another embodiment, an anti-KLK5 antibody is provided comprising the amino acid sequence of SEQ ID NO: 248 and a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 248. In certain embodiments, the substitutions, insertions, or deletions occur within the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody includes the VH sequence of SEQ ID NO: 248, which includes post-translational modifications of that sequence. In certain embodiments, the VH includes one, two, or three HVRs selected from (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 24, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 52, and (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 72.

[0161] In another embodiment, an anti-KLK5 antibody is provided, the antibody comprising a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 160. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 160. In certain embodiments, the substitutions, insertions, or deletions occur in the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody includes the VL sequence of SEQ ID NO: 160, which includes post-translational modifications of that sequence. In certain embodiments, the VL includes one, two, or three HVRs selected from (a) HVR-L1 containing the amino acid sequence of SEQ ID NO: 91, (b) HVR-L2 containing the amino acid sequence of SEQ ID NO: 99, and (c) HVR-L3 containing the amino acid sequence of SEQ ID NO: 122.

[0162] In another embodiment, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH sequence as in any of the embodiments provided above, and a VL sequence as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH sequence and VL sequence of SEQ ID NO: 248 and SEQ ID NO: 160, respectively, including post-translational modifications of those sequences.

[0163] In further embodiments, an anti-KLK5 antibody is provided that binds to the same epitope as the anti-KLK5 antibody provided herein. For example, in a particular embodiment, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising the VH sequence of SEQ ID NO: 248 and the VL sequence of SEQ ID NO: 160.

[0164] This specification provides an antibody comprising a light chain variable domain containing HVR1-LC, HVR2-LC, and HVR3-LC sequences according to Kabat numbering shown in Figure 14A, Figure 15A, and / or Figure 16A, and a heavy chain variable domain containing HVR1-HC, HVR2-HC, and HVR3-HC sequences according to Kabat numbering shown in Figure 14B, Figure 15B, and / or Figure 16B. In some embodiments, the antibody comprises a light chain variable domain containing HVR1-LC, HVR2-LC, and / or HVR3-LC sequences, as shown in Figure 14A, Figure 15A, and / or Figure 16A, and FR1-LC, FR2-LC, FR3-LC, and / or FR4-LC sequences. In some embodiments, the antibody includes heavy chain variable domains comprising HVR1-HC, HVR2-HC, and / or HVR3-HC sequences, as shown in Figure 14B, Figure 15B, and / or Figure 16B, and FR1-HC, FR2-HC, FR3-HC, and / or FR4-HC sequences.

[0165] In further embodiments, the anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody comprising a chimeric antibody, a humanized antibody, or a human antibody. In one embodiment, the anti-KLK5 antibody is humanized. In one embodiment, the anti-KLK5 antibody comprises an HVR as in any of the above embodiments, and further comprises an acceptor human framework, such as a human immunoglobulin framework or a human consensus framework.

[0166] In one embodiment, the anti-KLK5 antibody is an antibody fragment, such as Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In another embodiment, the antibody is a full-length antibody, such as an intact IgG1 antibody or an intact IgG4 antibody, or another antibody class or isotype as defined herein.

[0167] This specification further provides antibodies that specifically bind to human KLK5, which bind to epitopes on human KLK5 comprising one or more amino acid residues selected from the group consisting of 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. In some embodiments, the antibody binds to an epitope on human KLK5 containing 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 antibody binds to an epitope on human KLK5 containing one or more amino acid residues selected from the group consisting of 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 antibody binds to an epitope on human KLK5 containing one or more amino acid residues selected from the group consisting of 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.

[0168] This specification further provides antibodies that, upon binding to human KLK5, induce a conformational change in human KLK5, wherein the conformational change allosterically leads to the destruction of the substrate binding site and / or active site of human KLK5.

[0169] In further embodiments, an anti-KLK5 antibody according to any of the above embodiments may incorporate any of the following features, either individually or in combination.

[0170] Antibody 8G10 and other embodiments In one embodiment, an anti-KLK5 antibody is provided comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 14, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 32, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 62, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 79, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 99, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 112.

[0171] In one embodiment, the present invention provides an anti-KLK5 antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 14, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 32, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 62. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 62. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 62 and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 112. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 62, HVR-L3 comprising the amino acid sequence of SEQ ID NO: 112, and HVR-H2 comprising the amino acid sequence of SEQ ID NO: 32. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 14, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 32, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 62.

[0172] In another embodiment, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 79, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 99, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 112. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 79, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 99, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 112.

[0173] In another embodiment, an anti-KLK5 antibody is provided, comprising (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 14, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 32, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 62, and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 79, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 99, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 112. In another embodiment, an anti-KLK5 antibody is provided comprising (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 14, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 32, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 62, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 79, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 99, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 112.

[0174] In another embodiment, an anti-KLK5 antibody is provided comprising the amino acid sequence of SEQ ID NO: 170 and a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 170. In certain embodiments, the substitutions, insertions, or deletions occur within the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody includes the VH sequence of SEQ ID NO: 170, which includes post-translational modifications of that sequence. In certain embodiments, the VH includes one, two, or three HVRs selected from (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 14, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 32, and (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 62.

[0175] In another embodiment, an anti-KLK5 antibody is provided, the antibody comprising a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 131. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 131. In certain embodiments, the substitutions, insertions, or deletions occur in the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody includes the VL sequence of SEQ ID NO: 131, which includes post-translational modifications of that sequence. In certain embodiments, the VL includes one, two, or three HVRs selected from (a) HVR-L1 containing the amino acid sequence of SEQ ID NO: 79, (b) HVR-L2 containing the amino acid sequence of SEQ ID NO: 99, and (c) HVR-L3 containing the amino acid sequence of SEQ ID NO: 112.

[0176] In another embodiment, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH sequence as in any of the embodiments provided above, and a VL sequence as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH sequence and VL sequence of SEQ ID NO: 170 and SEQ ID NO: 131, respectively, including post-translational modifications of those sequences.

[0177] In further embodiments, an anti-KLK5 antibody is provided that binds to the same epitope as the anti-KLK5 antibody provided herein. For example, in a particular embodiment, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising the VH sequence of SEQ ID NO: 170 and the VL sequence of SEQ ID NO: 131.

[0178] In further embodiments, the anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody comprising a chimeric antibody, a humanized antibody, or a human antibody. In one embodiment, the anti-KLK5 antibody is humanized. In one embodiment, the anti-KLK5 antibody comprises an HVR as in any of the above embodiments, and further comprises an acceptor human framework, such as a human immunoglobulin framework or a human consensus framework.

[0179] In one embodiment, the anti-KLK5 antibody is an antibody fragment, such as Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In another embodiment, the antibody is a full-length antibody, such as an intact IgG1 antibody or an intact IgG4 antibody, or another antibody class or isotype as defined herein.

[0180] In further embodiments, an anti-KLK5 antibody according to any of the above embodiments may incorporate any of the following features, either individually or in combination.

[0181] Antibody 9B6 and other embodiments In one embodiment, an anti-KLK5 antibody is provided comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 15, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 33, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 80, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 100, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 113.

[0182] In one embodiment, the present invention provides an anti-KLK5 antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 15, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 33, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63 and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 113. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63, HVR-L3 comprising the amino acid sequence of SEQ ID NO: 113, and HVR-H2 comprising the amino acid sequence of SEQ ID NO: 33. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 15, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 33, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63.

[0183] In another embodiment, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 80, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 100, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 113. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 80, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 100, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 113.

[0184] In another embodiment, an anti-KLK5 antibody is provided, comprising (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 15, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 33, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63, and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 80, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 100, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 113. In another embodiment, an anti-KLK5 antibody is provided comprising (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 15, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 33, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 63, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 80, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 100, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 113.

[0185] In another embodiment, an anti-KLK5 antibody is provided comprising the amino acid sequence of SEQ ID NO: 171 and a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 171. In certain embodiments, the substitutions, insertions, or deletions occur within the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody includes the VH sequence of SEQ ID NO: 171, which includes post-translational modifications of that sequence. In certain embodiments, the VH includes one, two, or three HVRs selected from (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 15, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 33, and (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 63.

[0186] In another embodiment, an anti-KLK5 antibody is provided, the antibody comprising a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 132. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 132. In certain embodiments, the substitutions, insertions, or deletions occur in the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody includes the VL sequence of SEQ ID NO: 132, which includes post-translational modifications of that sequence. In certain embodiments, the VL includes one, two, or three HVRs selected from (a) HVR-L1 containing the amino acid sequence of SEQ ID NO: 80, (b) HVR-L2 containing the amino acid sequence of SEQ ID NO: 100, and (c) HVR-L3 containing the amino acid sequence of SEQ ID NO: 113.

[0187] In another embodiment, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH sequence as in any of the embodiments provided above, and a VL sequence as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH sequence and VL sequence of SEQ ID NO: 171 and SEQ ID NO: 132, respectively, including post-translational modifications of those sequences.

[0188] In further embodiments, an anti-KLK5 antibody is provided that binds to the same epitope as the anti-KLK5 antibody provided herein. For example, in a particular embodiment, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising the VH sequence of SEQ ID NO: 171 and the VL sequence of SEQ ID NO: 132.

[0189] In further embodiments, the anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody comprising a chimeric antibody, a humanized antibody, or a human antibody. In one embodiment, the anti-KLK5 antibody is humanized. In one embodiment, the anti-KLK5 antibody comprises an HVR as in any of the above embodiments, and further comprises an acceptor human framework, such as a human immunoglobulin framework or a human consensus framework.

[0190] In one embodiment, the anti-KLK5 antibody is an antibody fragment, such as Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In another embodiment, the antibody is a full-length antibody, such as an intact IgG1 antibody or an intact IgG4 antibody, or another antibody class or isotype as defined herein.

[0191] In further embodiments, an anti-KLK5 antibody according to any of the above embodiments may incorporate any of the following features, either individually or in combination.

[0192] Antibody 2-3F4 and other embodiments In one embodiment, an anti-KLK5 antibody is provided comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 16, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 34, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 64, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 81, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 99, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 114.

[0193] In one embodiment, the present invention provides an anti-KLK5 antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 16, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 34, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 64. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 64. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 64 and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 114. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 64, HVR-L3 comprising the amino acid sequence of SEQ ID NO: 114, and HVR-H2 comprising the amino acid sequence of SEQ ID NO: 34. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 16, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 34, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 64.

[0194] In another embodiment, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 81, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 99, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 114. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 81, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 99, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 114.

[0195] In another embodiment, an anti-KLK5 antibody is provided, comprising (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 16, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 34, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 64, and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 81, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 99, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 114. In another embodiment, an anti-KLK5 antibody is provided comprising (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 16, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 34, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 64, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 81, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 99, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 114.

[0196] In another embodiment, an anti-KLK5 antibody is provided comprising the amino acid sequence of SEQ ID NO: 172 and a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 172. In certain embodiments, the substitutions, insertions, or deletions occur within the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody includes the VH sequence of SEQ ID NO: 172, which includes post-translational modifications of that sequence. In certain embodiments, the VH includes one, two, or three HVRs selected from (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 16, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 34, and (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 64.

[0197] In another aspect, an anti-KLK5 antibody is provided, where the antibody comprises a light chain variable domain (VL) 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: 133. 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 as compared to the reference sequence, but the anti-KLK5 antibody comprising the 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: 133. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside of the HVRs (i.e., within the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence of SEQ ID NO: 133, including post-translational modifications of the sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 81, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 99, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 114.

[0198] In another aspect, an anti-KLK5 antibody is provided, where the antibody comprises a VH as in any of the embodiments provided above, and a VL as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH sequence and the VL sequence of SEQ ID NO: 172 and SEQ ID NO: 133, respectively, including post-translational modifications of those sequences.

[0199] In a further aspect, an anti-KLK5 antibody is provided that binds to the same epitope as the anti-KLK5 antibodies provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising the VH sequence of SEQ ID NO: 172 and the VL sequence of SEQ ID NO: 133.

[0200] In a further aspect, 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 humanized. In one embodiment, the anti-KLK5 antibody includes HV Rs as in any of the above embodiments and further includes an acceptor human framework, such as a human immunoglobulin framework or a human consensus framework.

[0201] 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 an intact IgG4 antibody, or another antibody class or isotype defined herein.

[0202] In a further aspect, the anti-KLK5 antibody according to any of the above embodiments can incorporate any of the features described below, alone or in combination.

[0203] Antibody 10C5 and other embodiments In one aspect, provided is an anti-KLK5 antibody comprising at least 1, 2, 3, 4, 5, or 6 HV Rs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 17, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 35, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 65, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 82, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 115.

[0204] In one embodiment, the present invention provides an anti-KLK5 antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 17, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 35, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 65. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 65. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 65 and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 115. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 65, HVR-L3 comprising the amino acid sequence of SEQ ID NO: 115, and HVR-H2 comprising the amino acid sequence of SEQ ID NO: 35. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 17, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 35, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 65.

[0205] In another embodiment, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 82, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 115. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 82, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 115.

[0206] In another embodiment, an anti-KLK5 antibody is provided, comprising (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 17, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 35, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 65, and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 82, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 115. In another embodiment, an anti-KLK5 antibody is provided comprising (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 17, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 35, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 65, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 82, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 101, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 115.

[0207] In another embodiment, an anti-KLK5 antibody is provided comprising the amino acid sequence of SEQ ID NO: 201 and a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 201. In certain embodiments, the substitutions, insertions, or deletions occur within the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody includes the VH sequence of SEQ ID NO: 201, which includes post-translational modifications of that sequence. In certain embodiments, the VH includes one, two, or three HVRs selected from (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 17, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 35, and (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 65.

[0208] In another embodiment, an anti-KLK5 antibody is provided, the antibody comprising a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 139. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 139. In certain embodiments, the substitutions, insertions, or deletions occur in the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody includes the VL sequence of SEQ ID NO: 139, which includes post-translational modifications of that sequence. In certain embodiments, the VL includes one, two, or three HVRs selected from (a) HVR-L1 containing the amino acid sequence of SEQ ID NO: 82, (b) HVR-L2 containing the amino acid sequence of SEQ ID NO: 101, and (c) HVR-L3 containing the amino acid sequence of SEQ ID NO: 115.

[0209] In another embodiment, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH sequence as in any of the embodiments provided above, and a VL sequence as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH sequence and VL sequence of SEQ ID NO: 201 and SEQ ID NO: 139, respectively, including post-translational modifications of those sequences.

[0210] In further embodiments, anti-KLK5 antibodies are provided that bind to the same epitope as the anti-KLK5 antibodies provided herein. For example, in certain embodiments, antibodies are provided that bind to the same epitope as an anti-KLK5 antibody comprising the VH sequence of SEQ ID NO: 201 and the VL sequence of SEQ ID NO: 139. In certain embodiments, antibodies are provided that, when bound to KLK5, result in a thermodynamic epitope comprising one or more sequences selected from the group consisting of SEQ ID NO: 316, SEQ ID NO: 317, SEQ ID NO: 318, and SEQ ID NO: 319, as measured by hydrogen exchange mass spectrometry.

[0211] In further embodiments, the anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody comprising a chimeric antibody, a humanized antibody, or a human antibody. In one embodiment, the anti-KLK5 antibody is humanized. In one embodiment, the anti-KLK5 antibody comprises an HVR as in any of the above embodiments, and further comprises an acceptor human framework, such as a human immunoglobulin framework or a human consensus framework.

[0212] In one embodiment, the anti-KLK5 antibody includes 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: 333, (b) heavy chain framework region 2 (HC-FR2) of SEQ ID NO: 334, (c) heavy chain framework region 3 (HC-FR3) of SEQ ID NO: 335, and (d) heavy chain framework region 4 (HC-FR4) of SEQ ID NO: 336.

[0213] In one embodiment, the anti-KLK5 antibody includes a VH domain containing HC-FR1 of SEQ ID NO: 333. In one embodiment, the anti-KLK5 antibody includes a VH domain containing HC-FR2 of SEQ ID NO: 334. In one embodiment, the anti-KLK5 antibody includes a VH domain containing HC-FR3 of SEQ ID NO: 335. In one embodiment, the anti-KLK5 antibody includes a VH domain containing HC-FR4 of SEQ ID NO: 336.

[0214] In one embodiment, the anti-KLK5 antibody includes 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: 329, (b) light chain framework region 2 (LC-FR2) of SEQ ID NO: 330, (c) light chain framework region 3 (LC-FR3) of SEQ ID NO: 331, and (d) light chain framework region 4 (LC-FR4) of SEQ ID NO: 332.

[0215] In one embodiment, the anti-KLK5 antibody includes a VL domain containing LC-FR1 of SEQ ID NO: 329. In one embodiment, the anti-KLK5 antibody includes a VL domain containing LC-FR2 of SEQ ID NO: 330. In one embodiment, the anti-KLK5 antibody includes a VL domain containing LC-FR3 of SEQ ID NO: 331. In one embodiment, the anti-KLK5 antibody includes a VL domain containing LC-FR4 of SEQ ID NO: 332.

[0216] In one embodiment, the anti-KLK5 antibody is an antibody fragment, such as Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In another embodiment, the antibody is a full-length antibody, such as an intact IgG1 antibody or an intact IgG4 antibody, or another antibody class or isotype as defined herein.

[0217] This specification further provides antibodies that specifically bind to human KLK5, which bind to epitopes on human KLK5 comprising one or more amino acid residues selected from the group consisting of Pro130, Ser131, Ala132, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Gln174A, Ile176, Asp177, Asp178, Arg224, and Lys233, according to standard protease numbering. In one embodiment, the antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 17, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 35, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 65, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 82, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 101, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 115. In one embodiment, the antibody comprises the VH sequence and VL sequence of SEQ ID NO: 201 and SEQ ID NO: 139.

[0218] This specification further provides antibodies that, upon binding to human KLK5, induce a conformational change in human KLK5, wherein the conformational change allosterically leads to the destruction of the substrate binding site and / or active site of human KLK5. In one embodiment, the antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 17, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 35, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 65, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 82, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 101, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 115. In one embodiment, the antibody comprises the VH sequence and VL sequence of SEQ ID NO: 201 and SEQ ID NO: 139.

[0219] In further embodiments, an anti-KLK5 antibody according to any of the above embodiments may incorporate any of the following features, either individually or in combination.

[0220] Antibody 2B11 and other embodiments In one aspect, provided is an anti-KLK5 antibody comprising at least 1, 2, 3, 4, 5, or 6 HVRS selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 18, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 39, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 66, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 83, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 102, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 116.

[0221] In one aspect, the invention provides an anti-KLK5 antibody comprising at least 1, at least 2, or all 3 VH HVR sequences selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 18, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 39, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 66. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 66. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 66 and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 116. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 66, HVR-L3 comprising the amino acid sequence of SEQ ID NO: 116, and HVR-H2 comprising the amino acid sequence of SEQ ID NO: 39. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 18, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 39, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 66.

[0222] In another aspect, provided is an anti-KLK5 antibody comprising at least 1, at least 2, or all 3 VL HVR sequences selected from: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 83, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 102, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 116. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 83, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 102, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 116.

[0223] In another embodiment, an anti-KLK5 antibody is provided, comprising (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 18, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 39, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 66, and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 83, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 102, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 116. In another embodiment, an anti-KLK5 antibody is provided comprising (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 18, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 39, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 66, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 83, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 102, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 116.

[0224] In another embodiment, an anti-KLK5 antibody is provided comprising the amino acid sequence of SEQ ID NO: 203 and a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 203. In certain embodiments, the substitutions, insertions, or deletions occur within the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody includes the VH sequence of SEQ ID NO: 203, which includes post-translational modifications of that sequence. In certain embodiments, the VH includes one, two, or three HVRs selected from (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 18, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 39, and (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 66.

[0225] In another embodiment, an anti-KLK5 antibody is provided, the antibody comprising a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 141. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 141. In certain embodiments, the substitutions, insertions, or deletions occur in the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody includes the VL sequence of SEQ ID NO: 141, which includes post-translational modifications of that sequence. In certain embodiments, the VL includes one, two, or three HVRs selected from (a) HVR-L1 containing the amino acid sequence of SEQ ID NO: 83, (b) HVR-L2 containing the amino acid sequence of SEQ ID NO: 102, and (c) HVR-L3 containing the amino acid sequence of SEQ ID NO: 116.

[0226] In another embodiment, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH sequence as in any of the embodiments provided above, and a VL sequence as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH sequence and VL sequence of SEQ ID NO: 203 and SEQ ID NO: 141, respectively, including post-translational modifications of those sequences.

[0227] In further embodiments, an anti-KLK5 antibody is provided that binds to the same epitope as the anti-KLK5 antibody provided herein. For example, in a particular embodiment, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising the VH sequence of SEQ ID NO: 203 and the VL sequence of SEQ ID NO: 141.

[0228] In further embodiments, the anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody comprising a chimeric antibody, a humanized antibody, or a human antibody. In one embodiment, the anti-KLK5 antibody is humanized. In one embodiment, the anti-KLK5 antibody comprises an HVR as in any of the above embodiments, and further comprises an acceptor human framework, such as a human immunoglobulin framework or a human consensus framework.

[0229] In one embodiment, the anti-KLK5 antibody is an antibody fragment, such as Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In another embodiment, the antibody is a full-length antibody, such as an intact IgG1 antibody or an intact IgG4 antibody, or another antibody class or isotype as defined herein.

[0230] In further embodiments, an anti-KLK5 antibody according to any of the above embodiments may incorporate any of the following features, either individually or in combination.

[0231] Antibody 10H3 and other embodiments In one embodiment, an anti-KLK5 antibody is provided comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 19, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 40, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 67, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 84, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 103, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 117.

[0232] In one embodiment, the present invention provides an anti-KLK5 antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 19, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 40, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 67. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 67. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 67 and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 117. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 67, HVR-L3 comprising the amino acid sequence of SEQ ID NO: 117, and HVR-H2 comprising the amino acid sequence of SEQ ID NO: 40. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 40, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 67.

[0233] In another embodiment, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 84, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 103, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 117. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 84, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 103, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 117.

[0234] In another embodiment, an anti-KLK5 antibody is provided, comprising (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 19, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 40, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 67, and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 84, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 103, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 117. In another embodiment, an anti-KLK5 antibody is provided comprising (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 19, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 40, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 67, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 84, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 103, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 117.

[0235] In another embodiment, an anti-KLK5 antibody is provided comprising the amino acid sequence of SEQ ID NO: 204 and a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 204. In certain embodiments, the substitutions, insertions, or deletions occur within the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody includes the VH sequence of SEQ ID NO: 204, which includes post-translational modifications of that sequence. In certain embodiments, the VH includes one, two, or three HVRs selected from (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 19, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 40, and (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 67.

[0236] In another embodiment, an anti-KLK5 antibody is provided, the antibody comprising a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 142. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 142. In certain embodiments, the substitutions, insertions, or deletions occur in the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody includes the VL sequence of SEQ ID NO: 142, which includes post-translational modifications of that sequence. In certain embodiments, the VL includes one, two, or three HVRs selected from (a) HVR-L1 containing the amino acid sequence of SEQ ID NO: 84, (b) HVR-L2 containing the amino acid sequence of SEQ ID NO: 103, and (c) HVR-L3 containing the amino acid sequence of SEQ ID NO: 117.

[0237] In another embodiment, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH sequence as in any of the embodiments provided above, and a VL sequence as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH sequence and VL sequence of SEQ ID NO: 204 and SEQ ID NO: 142, respectively, including post-translational modifications of those sequences.

[0238] In further embodiments, anti-KLK5 antibodies are provided that bind to the same epitope as the anti-KLK5 antibodies provided herein. For example, in certain embodiments, antibodies are provided that bind to the same epitope as an anti-KLK5 antibody comprising the VH sequence of SEQ ID NO: 204 and the VL sequence of SEQ ID NO: 142. In certain embodiments, antibodies are provided that, when bound to KLK5, result in a thermodynamic epitope comprising one or more sequences selected from the group consisting of SEQ ID NO: 316, SEQ ID NO: 317, SEQ ID NO: 318, and SEQ ID NO: 319, as measured by hydrogen exchange mass spectrometry.

[0239] In further embodiments, the anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody comprising a chimeric antibody, a humanized antibody, or a human antibody. In one embodiment, the anti-KLK5 antibody is humanized. In one embodiment, the anti-KLK5 antibody comprises an HVR as in any of the above embodiments, and further comprises an acceptor human framework, such as a human immunoglobulin framework or a human consensus framework.

[0240] In one embodiment, the anti-KLK5 antibody is an antibody fragment, such as Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In another embodiment, the antibody is a full-length antibody, such as an intact IgG1 antibody or an intact IgG4 antibody, or another antibody class or isotype as defined herein.

[0241] In further embodiments, an anti-KLK5 antibody according to any of the above embodiments may incorporate any of the following features, either individually or in combination.

[0242] Antibody 9H3 and other embodiments In one embodiment, an anti-KLK5 antibody is provided comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 20, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 33, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 68, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 85, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 103, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 118.

[0243] In one embodiment, the present invention provides an anti-KLK5 antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 20, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 33, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 68. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 68. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 68 and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 118. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 68, HVR-L3 comprising the amino acid sequence of SEQ ID NO: 118, and HVR-H2 comprising the amino acid sequence of SEQ ID NO: 33. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 20, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 33, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 68.

[0244] In another embodiment, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 85, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 103, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 118. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 85, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 103, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 118.

[0245] In another embodiment, an anti-KLK5 antibody is provided, comprising (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 20, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 33, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 68, and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 85, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 103, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 118. In another embodiment, an anti-KLK5 antibody is provided comprising (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 20, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 33, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 68, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 85, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 103, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 118.

[0246] In another embodiment, an anti-KLK5 antibody is provided comprising the amino acid sequence of SEQ ID NO: 205 and a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 205. In certain embodiments, the substitutions, insertions, or deletions occur within the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody includes the VH sequence of SEQ ID NO: 205, which includes post-translational modifications of that sequence. In certain embodiments, the VH includes one, two, or three HVRs selected from (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 20, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 33, and (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 68.

[0247] In another embodiment, an anti-KLK5 antibody is provided, the antibody comprising a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 143. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 143. In certain embodiments, the substitutions, insertions, or deletions occur in the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody includes the VL sequence of SEQ ID NO: 143, which includes post-translational modifications of that sequence. In certain embodiments, the VL includes one, two, or three HVRs selected from (a) HVR-L1 containing the amino acid sequence of SEQ ID NO: 85, (b) HVR-L2 containing the amino acid sequence of SEQ ID NO: 103, and (c) HVR-L3 containing the amino acid sequence of SEQ ID NO: 118.

[0248] In another embodiment, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH sequence as in any of the embodiments provided above, and a VL sequence as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH sequence and VL sequence of SEQ ID NO: 205 and SEQ ID NO: 143, respectively, including post-translational modifications of those sequences.

[0249] In further embodiments, an anti-KLK5 antibody is provided that binds to the same epitope as the anti-KLK5 antibody provided herein. For example, in a particular embodiment, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising the VH sequence of SEQ ID NO: 205 and the VL sequence of SEQ ID NO: 143.

[0250] In further embodiments, the anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody comprising a chimeric antibody, a humanized antibody, or a human antibody. In one embodiment, the anti-KLK5 antibody is humanized. In one embodiment, the anti-KLK5 antibody comprises an HVR as in any of the above embodiments, and further comprises an acceptor human framework, such as a human immunoglobulin framework or a human consensus framework.

[0251] In one embodiment, the anti-KLK5 antibody is an antibody fragment, such as Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In another embodiment, the antibody is a full-length antibody, such as an intact IgG1 antibody or an intact IgG4 antibody, or another antibody class or isotype as defined herein.

[0252] In further embodiments, an anti-KLK5 antibody according to any of the above embodiments may incorporate any of the following features, either individually or in combination.

[0253] Antibody 8B7 and other embodiments In one embodiment, an anti-KLK5 antibody is provided comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 41, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 86, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 104, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 118.

[0254] In one embodiment, the present invention provides an anti-KLK5 antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 41, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69 and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 118. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 68, HVR-L3 comprising the amino acid sequence of SEQ ID NO: 118, and HVR-H2 comprising the amino acid sequence of SEQ ID NO: 41. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 41, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69.

[0255] In another embodiment, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 86, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 104, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 118. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 86, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 104, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 118.

[0256] In another embodiment, an anti-KLK5 antibody is provided, comprising (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 41, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69, and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 86, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 104, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 118. In another embodiment, an anti-KLK5 antibody is provided comprising (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 41, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 86, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 104, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 118.

[0257] In another embodiment, an anti-KLK5 antibody is provided comprising the amino acid sequence of SEQ ID NO: 206 and a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 206. In certain embodiments, the substitutions, insertions, or deletions occur within the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody includes the VH sequence of SEQ ID NO: 206, which includes post-translational modifications of that sequence. In certain embodiments, the VH includes one, two, or three HVRs selected from (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 41, and (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69.

[0258] In another embodiment, an anti-KLK5 antibody is provided, the antibody comprising a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 144. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 144. In certain embodiments, the substitutions, insertions, or deletions occur in the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody includes the VL sequence of SEQ ID NO: 144, which includes post-translational modifications of that sequence. In certain embodiments, the VL includes one, two, or three HVRs selected from (a) HVR-L1 containing the amino acid sequence of SEQ ID NO: 86, (b) HVR-L2 containing the amino acid sequence of SEQ ID NO: 104, and (c) HVR-L3 containing the amino acid sequence of SEQ ID NO: 118.

[0259] In another embodiment, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH sequence as in any of the embodiments provided above, and a VL sequence as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH sequence and VL sequence of SEQ ID NO: 206 and SEQ ID NO: 144, respectively, including post-translational modifications of those sequences.

[0260] In further embodiments, an anti-KLK5 antibody is provided that binds to the same epitope as the anti-KLK5 antibody provided herein. For example, in a particular embodiment, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising the VH sequence of SEQ ID NO: 206 and the VL sequence of SEQ ID NO: 144.

[0261] In further embodiments, the anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody comprising a chimeric antibody, a humanized antibody, or a human antibody. In one embodiment, the anti-KLK5 antibody is humanized. In one embodiment, the anti-KLK5 antibody comprises an HVR as in any of the above embodiments, and further comprises an acceptor human framework, such as a human immunoglobulin framework or a human consensus framework.

[0262] In one embodiment, the anti-KLK5 antibody is an antibody fragment, such as Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In another embodiment, the antibody is a full-length antibody, such as an intact IgG1 antibody or an intact IgG4 antibody, or another antibody class or isotype as defined herein.

[0263] In further embodiments, an anti-KLK5 antibody according to any of the above embodiments may incorporate any of the following features, either individually or in combination.

[0264] Antibody 9H5 and other embodiments In one embodiment, an anti-KLK5 antibody is provided comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 42, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 87, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 105, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 119.

[0265] In one embodiment, the present invention provides an anti-KLK5 antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 42, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69 and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 119. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69, HVR-L3 comprising the amino acid sequence of SEQ ID NO: 119, and HVR-H2 comprising the amino acid sequence of SEQ ID NO: 42. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 42, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69.

[0266] In another embodiment, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 87, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 105, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 119. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 87, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 105, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 119.

[0267] In another embodiment, an anti-KLK5 antibody is provided, comprising (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 42, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69, and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 87, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 105, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 119. In another embodiment, an anti-KLK5 antibody is provided comprising (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 42, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 87, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 105, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 119.

[0268] In another embodiment, an anti-KLK5 antibody is provided comprising the amino acid sequence of SEQ ID NO: 221 and a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 221. In certain embodiments, the substitutions, insertions, or deletions occur within the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody includes the VH sequence of SEQ ID NO: 221, which includes post-translational modifications of that sequence. In certain embodiments, the VH includes one, two, or three HVRs selected from (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 42, and (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69.

[0269] In another embodiment, an anti-KLK5 antibody is provided, the antibody comprising a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 149. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 149. In certain embodiments, the substitutions, insertions, or deletions occur in the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody includes the VL sequence of SEQ ID NO: 149, which includes post-translational modifications of that sequence. In certain embodiments, the VL includes one, two, or three HVRs selected from (a) HVR-L1 containing the amino acid sequence of SEQ ID NO: 87, (b) HVR-L2 containing the amino acid sequence of SEQ ID NO: 105, and (c) HVR-L3 containing the amino acid sequence of SEQ ID NO: 119.

[0270] In another embodiment, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH sequence as in any of the embodiments provided above, and a VL sequence as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH sequence and VL sequence of SEQ ID NO: 221 and SEQ ID NO: 149, respectively, including post-translational modifications of those sequences.

[0271] In further embodiments, anti-KLK5 antibodies are provided that bind to the same epitope as the anti-KLK5 antibodies provided herein. For example, in certain embodiments, antibodies are provided that bind to the same epitope as an anti-KLK5 antibody comprising the VH sequence of SEQ ID NO: 221 and the VL sequence of SEQ ID NO: 149. In certain embodiments, antibodies are provided that, when bound to KLK5, result in a thermodynamic epitope comprising one or more sequences selected from the group consisting of SEQ ID NO: 316, SEQ ID NO: 317, SEQ ID NO: 318, and SEQ ID NO: 319, as measured by hydrogen exchange mass spectrometry.

[0272] In further embodiments, the anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody comprising a chimeric antibody, a humanized antibody, or a human antibody. In one embodiment, the anti-KLK5 antibody is humanized. In one embodiment, the anti-KLK5 antibody comprises an HVR as in any of the above embodiments, and further comprises an acceptor human framework, such as a human immunoglobulin framework or a human consensus framework.

[0273] In one embodiment, the anti-KLK5 antibody includes 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: 341, (b) heavy chain framework region 2 (HC-FR2) of SEQ ID NO: 342, (c) heavy chain framework region 3 (HC-FR3) of SEQ ID NO: 343, and (d) heavy chain framework region 4 (HC-FR4) of SEQ ID NO: 344.

[0274] In one embodiment, the anti-KLK5 antibody includes a VH domain containing HC-FR1 of SEQ ID NO: 341. In one embodiment, the anti-KLK5 antibody includes a VH domain containing HC-FR2 of SEQ ID NO: 342. In one embodiment, the anti-KLK5 antibody includes a VH domain containing HC-FR3 of SEQ ID NO: 343. In one embodiment, the anti-KLK5 antibody includes a VH domain containing HC-FR4 of SEQ ID NO: 344.

[0275] In one embodiment, the anti-KLK5 antibody includes 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: 337, (b) light chain framework region 2 (LC-FR2) of SEQ ID NO: 338, (c) light chain framework region 3 (LC-FR3) of SEQ ID NO: 339, and (d) light chain framework region 4 (LC-FR4) of SEQ ID NO: 340.

[0276] In one embodiment, the anti-KLK5 antibody includes a VL domain containing LC-FR1 of SEQ ID NO: 337. In one embodiment, the anti-KLK5 antibody includes a VL domain containing LC-FR2 of SEQ ID NO: 338. In one embodiment, the anti-KLK5 antibody includes a VL domain containing LC-FR3 of SEQ ID NO: 339. In one embodiment, the anti-KLK5 antibody includes a VL domain containing LC-FR4 of SEQ ID NO: 340.

[0277] In one embodiment, the anti-KLK5 antibody is an antibody fragment, such as Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In another embodiment, the antibody is a full-length antibody, such as an intact IgG1 antibody or an intact IgG4 antibody, or another antibody class or isotype as defined herein.

[0278] This specification further provides antibodies that specifically bind to human KLK5, which bind to epitopes on human KLK5 comprising one or more amino acid residues selected from the group consisting of 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 one embodiment, the antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 42, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 87, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 105, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 119. In one embodiment, the antibody comprises the VH sequence and VL sequence of SEQ ID NO: 221 and SEQ ID NO: 149.

[0279] This specification further provides antibodies that, upon binding to human KLK5, induce a conformational change in human KLK5, wherein the conformational change allosterically leads to the destruction of the substrate binding site and / or active site of human KLK5. In one embodiment, the antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 42, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 87, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 105, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 119. In one embodiment, the antibody comprises the VH sequence and VL sequence of SEQ ID NO: 221 and SEQ ID NO: 149.

[0280] In further embodiments, an anti-KLK5 antibody according to any of the above embodiments may incorporate any of the following features, either individually or in combination.

[0281] Antibody 9F2 and other embodiments In one embodiment, an anti-KLK5 antibody is provided comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 46, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 88, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 105, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120.

[0282] In one embodiment, the present invention provides an anti-KLK5 antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 46, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69 and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69, HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120, and HVR-H2 comprising the amino acid sequence of SEQ ID NO: 46. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 46, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69.

[0283] In another embodiment, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 88, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 105, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 88, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 105, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120.

[0284] In another embodiment, an anti-KLK5 antibody is provided, comprising (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 46, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69, and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 88, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 105, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120. In another embodiment, an anti-KLK5 antibody is provided comprising (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 46, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 88, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 105, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 120.

[0285] In another embodiment, an anti-KLK5 antibody is provided comprising the amino acid sequence of SEQ ID NO: 226 and a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 226. In certain embodiments, the substitutions, insertions, or deletions occur within the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody includes the VH sequence of SEQ ID NO: 226, which includes post-translational modifications of that sequence. In certain embodiments, the VH includes one, two, or three HVRs selected from (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 46, and (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69.

[0286] In another embodiment, an anti-KLK5 antibody is provided, the antibody comprising a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 152. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 152. In certain embodiments, the substitutions, insertions, or deletions occur in the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody includes the VL sequence of SEQ ID NO: 152, which includes post-translational modifications of that sequence. In certain embodiments, the VL includes one, two, or three HVRs selected from (a) HVR-L1 containing the amino acid sequence of SEQ ID NO: 88, (b) HVR-L2 containing the amino acid sequence of SEQ ID NO: 105, and (c) HVR-L3 containing the amino acid sequence of SEQ ID NO: 120.

[0287] In another embodiment, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH sequence as in any of the embodiments provided above, and a VL sequence as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH sequence and VL sequence of SEQ ID NO: 226 and SEQ ID NO: 152, respectively, including post-translational modifications of those sequences.

[0288] In further embodiments, an anti-KLK5 antibody is provided that binds to the same epitope as the anti-KLK5 antibody provided herein. For example, in a particular embodiment, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising the VH sequence of SEQ ID NO: 226 and the VL sequence of SEQ ID NO: 152.

[0289] In further embodiments, the anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody comprising a chimeric antibody, a humanized antibody, or a human antibody. In one embodiment, the anti-KLK5 antibody is humanized. In one embodiment, the anti-KLK5 antibody comprises an HVR as in any of the above embodiments, and further comprises an acceptor human framework, such as a human immunoglobulin framework or a human consensus framework.

[0290] In one embodiment, the anti-KLK5 antibody is an antibody fragment, such as Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In another embodiment, the antibody is a full-length antibody, such as an intact IgG1 antibody or an intact IgG4 antibody, or another antibody class or isotype as defined herein.

[0291] In further embodiments, an anti-KLK5 antibody according to any of the above embodiments may incorporate any of the following features, either individually or in combination.

[0292] Antibody 10C8 and other embodiments In one embodiment, an anti-KLK5 antibody is provided comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 42, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 70, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 89, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 105, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 118.

[0293] In one embodiment, the present invention provides an anti-KLK5 antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 42, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 70. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 70. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 70 and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 118. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 70, HVR-L3 comprising the amino acid sequence of SEQ ID NO: 118, and HVR-H2 comprising the amino acid sequence of SEQ ID NO: 42. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 42, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 70.

[0294] In another embodiment, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 89, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 105, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 118. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 89, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 105, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 118.

[0295] In another embodiment, an anti-KLK5 antibody is provided, comprising (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 42, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 70, and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 89, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 105, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 118. In another embodiment, an anti-KLK5 antibody is provided comprising (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 42, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 70, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 89, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 105, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 118.

[0296] In another embodiment, an anti-KLK5 antibody is provided comprising the amino acid sequence of SEQ ID NO: 227 and a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 227. In certain embodiments, the substitutions, insertions, or deletions occur within the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody includes the VH sequence of SEQ ID NO: 227, which includes post-translational modifications of that sequence. In certain embodiments, the VH includes one, two, or three HVRs selected from (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 42, and (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 70.

[0297] In another embodiment, an anti-KLK5 antibody is provided, the antibody comprising a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 153. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 153. In certain embodiments, the substitutions, insertions, or deletions occur in the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody includes the VL sequence of SEQ ID NO: 153, which includes post-translational modifications of that sequence. In certain embodiments, the VL includes one, two, or three HVRs selected from (a) HVR-L1 containing the amino acid sequence of SEQ ID NO: 89, (b) HVR-L2 containing the amino acid sequence of SEQ ID NO: 105, and (c) HVR-L3 containing the amino acid sequence of SEQ ID NO: 118.

[0298] In another embodiment, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH sequence as in any of the embodiments provided above, and a VL sequence as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH sequence and VL sequence of SEQ ID NO: 227 and SEQ ID NO: 153, respectively, including post-translational modifications of those sequences.

[0299] In further embodiments, an anti-KLK5 antibody is provided that binds to the same epitope as the anti-KLK5 antibody provided herein. For example, in a particular embodiment, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising the VH sequence of SEQ ID NO: 227 and the VL sequence of SEQ ID NO: 153.

[0300] In further embodiments, the anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody comprising a chimeric antibody, a humanized antibody, or a human antibody. In one embodiment, the anti-KLK5 antibody is humanized. In one embodiment, the anti-KLK5 antibody comprises an HVR as in any of the above embodiments, and further comprises an acceptor human framework, such as a human immunoglobulin framework or a human consensus framework.

[0301] In one embodiment, the anti-KLK5 antibody is an antibody fragment, such as Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In another embodiment, the antibody is a full-length antibody, such as an intact IgG1 antibody or an intact IgG4 antibody, or another antibody class or isotype as defined herein.

[0302] In further embodiments, an anti-KLK5 antibody according to any of the above embodiments may incorporate any of the following features, either individually or in combination.

[0303] Antibody 8F5 and other embodiments In one embodiment, an anti-KLK5 antibody is provided comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 47, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 71, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 90, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 106, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 121.

[0304] In one embodiment, the present invention provides an anti-KLK5 antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 47, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 71. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 71. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 71 and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 121. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 70, HVR-L3 comprising the amino acid sequence of SEQ ID NO: 121, and HVR-H2 comprising the amino acid sequence of SEQ ID NO: 47. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 47, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 71.

[0305] In another embodiment, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 90, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 106, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 121. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 90, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 106, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 121.

[0306] In another embodiment, an anti-KLK5 antibody is provided, comprising (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 47, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 71, and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 90, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 106, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 121. In another embodiment, an anti-KLK5 antibody is provided comprising (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 23, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 47, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 71, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 90, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 106, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 121.

[0307] In another embodiment, an anti-KLK5 antibody is provided comprising the amino acid sequence of SEQ ID NO: 228 and a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 228. In certain embodiments, the substitutions, insertions, or deletions occur within the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody includes the VH sequence of SEQ ID NO: 228, which includes post-translational modifications of that sequence. In certain embodiments, the VH includes one, two, or three HVRs selected from (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 23, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 47, and (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 71.

[0308] In another embodiment, an anti-KLK5 antibody is provided, the antibody comprising a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 154. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 154. In certain embodiments, the substitutions, insertions, or deletions occur in the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody includes the VL sequence of SEQ ID NO: 154, which includes post-translational modifications of that sequence. In certain embodiments, the VL includes one, two, or three HVRs selected from (a) HVR-L1 containing the amino acid sequence of SEQ ID NO: 90, (b) HVR-L2 containing the amino acid sequence of SEQ ID NO: 106, and (c) HVR-L3 containing the amino acid sequence of SEQ ID NO: 121.

[0309] In another embodiment, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH sequence as in any of the embodiments provided above, and a VL sequence as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH sequence and VL sequence of SEQ ID NO: 228 and SEQ ID NO: 154, respectively, including post-translational modifications of those sequences.

[0310] In further embodiments, an anti-KLK5 antibody is provided that binds to the same epitope as the anti-KLK5 antibody provided herein. For example, in a particular embodiment, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising the VH sequence of SEQ ID NO: 228 and the VL sequence of SEQ ID NO: 154.

[0311] In further embodiments, the anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody comprising a chimeric antibody, a humanized antibody, or a human antibody. In one embodiment, the anti-KLK5 antibody is humanized. In one embodiment, the anti-KLK5 antibody comprises an HVR as in any of the above embodiments, and further comprises an acceptor human framework, such as a human immunoglobulin framework or a human consensus framework.

[0312] In one embodiment, the anti-KLK5 antibody is an antibody fragment, such as Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In another embodiment, the antibody is a full-length antibody, such as an intact IgG1 antibody or an intact IgG4 antibody, or another antibody class or isotype as defined herein.

[0313] In further embodiments, an anti-KLK5 antibody according to any of the above embodiments may incorporate any of the following features, either individually or in combination.

[0314] Antibody 3-3F5 and other embodiments In one embodiment, an anti-KLK5 antibody is provided comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 24, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 52, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 72, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 91, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 99, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 122.

[0315] In one embodiment, the present invention provides an anti-KLK5 antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 24, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 52, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 72. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 72. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 72 and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 122. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 72, HVR-L3 comprising the amino acid sequence of SEQ ID NO: 122, and HVR-H2 comprising the amino acid sequence of SEQ ID NO: 52. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 24, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 52, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 72.

[0316] In another embodiment, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 91, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 99, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 122. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 91, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 99, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 122.

[0317] In another embodiment, an anti-KLK5 antibody is provided, comprising (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 24, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 52, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 72, and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 91, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 99, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 122. In another embodiment, an anti-KLK5 antibody is provided comprising (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 24, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 52, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 72, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 91, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 99, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 122.

[0318] In another embodiment, an anti-KLK5 antibody is provided comprising the amino acid sequence of SEQ ID NO: 248 and a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 248. In certain embodiments, the substitutions, insertions, or deletions occur within the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody includes the VH sequence of SEQ ID NO: 248, which includes post-translational modifications of that sequence. In certain embodiments, the VH includes one, two, or three HVRs selected from (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 24, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 52, and (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 72.

[0319] In another embodiment, an anti-KLK5 antibody is provided, the antibody comprising a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 160. In certain embodiments, the 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 the anti-KLK5 antibody containing 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: 160. In certain embodiments, the substitutions, insertions, or deletions occur in the region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody includes the VL sequence of SEQ ID NO: 160, which includes post-translational modifications of that sequence. In certain embodiments, the VL includes one, two, or three HVRs selected from (a) HVR-L1 containing the amino acid sequence of SEQ ID NO: 91, (b) HVR-L2 containing the amino acid sequence of SEQ ID NO: 99, and (c) HVR-L3 containing the amino acid sequence of SEQ ID NO: 122.

[0320] In another embodiment, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH sequence as in any of the embodiments provided above, and a VL sequence as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH sequence and VL sequence of SEQ ID NO: 248 and SEQ ID NO: 160, respectively, including post-translational modifications of those sequences.

[0321] In further embodiments, an anti-KLK5 antibody is provided that binds to the same epitope as the anti-KLK5 antibody provided herein. For example, in a particular embodiment, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising the VH sequence of SEQ ID NO: 248 and the VL sequence of SEQ ID NO: 160.

[0322] In further embodiments, the anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody comprising a chimeric antibody, a humanized antibody, or a human antibody. In one embodiment, the anti-KLK5 antibody is humanized. In one embodiment, the anti-KLK5 antibody comprises an HVR as in any of the above embodiments, and further comprises an acceptor human framework, such as a human immunoglobulin framework or a human consensus framework.

[0323] In one embodiment, the anti-KLK5 antibody includes 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: 349, (b) heavy chain framework region 2 (HC-FR2) of SEQ ID NO: 350, (c) heavy chain framework region 3 (HC-FR3) of SEQ ID NO: 351, and (d) heavy chain framework region 4 (HC-FR4) of SEQ ID NO: 352.

[0324] In one embodiment, the anti-KLK5 antibody includes a VH domain containing HC-FR1 of SEQ ID NO: 349. In one embodiment, the anti-KLK5 antibody includes a VH domain containing HC-FR2 of SEQ ID NO: 350. In one embodiment, the anti-KLK5 antibody includes a VH domain containing HC-FR3 of SEQ ID NO: 351. In one embodiment, the anti-KLK5 antibody includes a VH domain containing HC-FR4 of SEQ ID NO: 352.

[0325] In one embodiment, the anti-KLK5 antibody includes 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: 345, (b) light chain framework region 2 (LC-FR2) of SEQ ID NO: 346, (c) light chain framework region 3 (LC-FR3) of SEQ ID NO: 347, and (d) light chain framework region 4 (LC-FR4) of SEQ ID NO: 348.

[0326] In one embodiment, the anti-KLK5 antibody includes a VL domain containing LC-FR1 of SEQ ID NO: 345. In one embodiment, the anti-KLK5 antibody includes a VL domain containing LC-FR2 of SEQ ID NO: 346. In one embodiment, the anti-KLK5 antibody includes a VL domain containing LC-FR3 of SEQ ID NO: 347. In one embodiment, the anti-KLK5 antibody includes a VL domain containing LC-FR4 of SEQ ID NO: 348.

[0327] In one embodiment, the anti-KLK5 antibody is an antibody fragment, such as Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In another embodiment, the antibody is a full-length antibody, such as an intact IgG1 antibody or an intact IgG4 antibody, or another antibody class or isotype as defined herein.

[0328] This specification further provides an antibody that specifically binds to human KLK5, wherein the antibody binds to an epitope on human KLK5 containing one or more amino acid residues selected from the group consisting of 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. In one embodiment, the antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 24, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 52, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 72, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 91, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 99, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 122. In one embodiment, the antibody comprises the VH sequence and VL sequence of SEQ ID NO: 248 and SEQ ID NO: 160.

[0329] This specification further provides antibodies that, upon binding to human KLK5, induce a conformational change in human KLK5, wherein the conformational change allosterically leads to the destruction of the substrate binding site and / or active site of human KLK5. In one embodiment, the antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 24, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 52, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 72, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 91, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 99, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 122. In one embodiment, the antibody comprises the VH sequence and VL sequence of SEQ ID NO: 248 and SEQ ID NO: 160.

[0330] In further embodiments, an anti-KLK5 antibody according to any of the above embodiments may incorporate any of the following features, either individually or in combination.

[0331] 2. Antibody affinity In some embodiments of the anti-KLK5 antibody, the KLK5 antibody has a concentration of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM (e.g., 10 nM) relative to KLK5. -8 M or less, for example, 10 -8 M~10 -13 M, for example 10 -9 M~10 -13 It has binding affinity (dissociation constant Kd) of M.

[0332] In one embodiment, Kd is measured by a radiolabeled antigen-binding assay (RIA). In one embodiment, the RIA is performed using the Fab version of the antibody of interest and its antigen. For example, the solution binding affinity of Fab to the antigen is measured in the presence of a titration system of the unlabeled antigen at a minimum concentration. 125I) Fab is equilibrated with a labeled antigen, and then the bound antigen is captured on a plate coated with anti-Fab antibody for measurement (see, for example, Chen et al., "J.Mol.Biol.", Vol. 293, pp. 865-881 (1999)). To establish the assay conditions, a MICROTITER® multiwell plate (Thermo Scientific) is coated overnight with 5 μg / mL of capture anti-Fab antibody (Cappel Labs) in 50 mM sodium carbonate (pH 9.6), and then blocked with 2% (w / v) bovine serum albumin in PBS for 2-5 hours at room temperature (approximately 23°C). In a non-adsorbent plate (Nunc No. 269620), 100 pM or 26 pM [ 125 Mix the [I]-antigen with serial dilutions of the target Fab (e.g., consistent with the evaluation of the anti-VEGF antibody Fab-12 in Presta et al., "Cancer Res.", Vol. 57, pp. 4593-4599 (1997)). Next, incubate the target Fab overnight, although this incubation may be continued for a longer period (e.g., about 65 hours) to ensure equilibrium is achieved. Then, transfer the mixture to a capture plate for incubation at room temperature (e.g., 1 hour). Next, remove the solution and wash the plate eight times with 0.1% polysorbate 20 (TWEEN-20®) in PBS. Once the plate is dry, add 150 μL / well of scintillant (MICROSCINT-20®, Packard) and count the plate on a TOPCOUNT® gamma counter (Packard) for 10 minutes. Select the concentration of each Fab that yields less than 20% of the maximum binding for use in competitive binding assays.

[0333] In another embodiment, Kd is measured using a BIACORE® surface plasmon resonance assay. For example, an assay using BIACORE®-2000 or BIACORE®-3000 (BIACORE, Inc., Piscataway, NJ) is performed at 25°C using an immobilized antigen CM5 chip to achieve approximately 10 response units (RUs). In one embodiment, a carboxymethylated dextran biosensor chip (CM5, BIACORE, Inc.) is activated with N-ethyl-N'-(3-dimethylaminopropyl)-carbodimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) according to the supplier's instructions. The antigen is diluted to 5 μg / ml (approximately 0.2 μM) with 10 mM sodium acetate at pH 4.8 and injected at a flow rate of 5 μl / min to achieve approximately 10 response units (RUs) of the coupled protein. After antigen injection, 1M ethanolamine is injected to block unreacted groups. For kinetic analysis, 2-fold serial dilutions of Fab (0.78 nM to 500 nM) are injected at a flow rate of approximately 25 μL / min into PBS containing 0.05% polysorbate 20 (TWEEN-20®) surfactant (PBST) at 25°C. The association rate (k オン ) and dissociation rate (k オフ The equality dissociation constant (Kd) is calculated using a simple one-to-one Langmuir coupled model (BIACORE® Evaluation Software version 3.2) by simultaneously fitting the association sensorgram and dissociation sensorgram. オフ / k オン It is calculated as a ratio. For example, see Chen et al., "J.Mol.Biol.", Vol. 293, pp. 865-881 (1999). The ON velocity is 10 by the above surface plasmon resonance assay. 6 M -1 s -1If it exceeds this value, this ON rate can be determined by using a fluorescence quenching technique, which measures the increase or decrease in fluorescence emission intensity (excitation = 295 nm, emission = 340 nm, 16 nm band-passing) of a 20 nM anti-antigen antibody (Fab type) in PBS (pH 7.2) at 25°C in the presence of gradually increasing concentrations of antigen, measured with a spectrometer such as a stopped-flow spectrophotometer (Aviv Instruments) equipped with a stirred cuvette or an 8000 series SLM-AMINCO (Trademark) spectrophotometer (ThermoSpectronic).

[0334] 3. Antibody fragment In some embodiments, the anti-KLK5 antibodies provided herein are antibody fragments. Examples of antibody fragments include, but are not limited to, Fab, Fab', Fab'-SH, F(ab')2, Fv, and scFv fragments, as well as other fragments described below. For a review of specific antibody fragments, see Hudson et al., "Nat Med.", Vol. 9, pp. 129-134 (2003). For a review of scFv fragments, see, for example, Pluckthuen in "The Pharmacology of Monoclonal Antibodies," Vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New York), pp. 269-315 (1994). See also International Publication No. 93 / 16185, and U.S. Patents Nos. 5,571,894 and 5,587,458. For a description of the Fab and F(ab')2 fragments, which contain salvage receptor-binding epitope residues and have a longer in vivo half-life, please refer to U.S. Patent No. 5,869,046.

[0335] A bispecific antibody 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.", Vol. 9, pp. 129-134 (2003), and Hollinger et al., "Proc Natl Acad Sci.USA", Vol. 90, pp. 6444-6448 (1993). Triplespecific and quadruplespecific antibodies are also described in Hudson et al., "Nat. Med.", Vol. 9, pp. 129-134 (2003).

[0336] A single-domain antibody is an antibody fragment that contains all or part of the heavy chain variable domain or all or part of the light chain variable domain of an antibody. In certain embodiments, the single-domain antibody is a human single-domain antibody (see, for example, Domantis, Inc., Waltham, Massachusetts; U.S. Patent No. 6,248,516B1).

[0337] Antibody fragments can be produced by various techniques, including, but not limited to, the proteolysis and production of intact antibodies by recombinant host cells (e.g., E. coli or phages) as described herein.

[0338] 4. Chimeric antibodies and humanized antibodies In some embodiments, the anti-KLK5 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," Vol. 81, pp. 6851-6855 (1984). In one example, a chimeric antibody includes a non-human variable region (e.g., a variable region derived from a non-human primate such as a mouse, rat, hamster, rabbit, or monkey) and a human constant region. In further examples, a chimeric antibody is a "class-switched" antibody in which the class or subclass is changed from those of the parent antibody. A chimeric antibody includes its antigen-binding fragment.

[0339] In certain embodiments, the chimeric antibody is a humanized antibody. Generally, humanizing a non-human antibody reduces its immunogenicity against humans, but maintains the specificity and affinity of the parent non-human antibody. Typically, a humanized antibody contains one or more variable domains derived from a non-human antibody, such as HVR, e.g., CDR (or a portion thereof), and FR (or a portion thereof) derived from a human antibody sequence. The humanized antibody optionally also contains at least a portion of the human constant region. In some embodiments, some FR residues in the humanized antibody are replaced with corresponding residues derived from a non-human antibody (e.g., an antibody from which the HVR residues are derived) to restore or improve antibody specificity or affinity, for example.

[0340] Humanized antibodies and methods for producing them are described, for example, in Almagro and Fransson, "Front. Biosci.", Vol. 13, pp. 1619-1633 (2008), and further, for example, in Riechmann et al., "Nature", Vol. 332, pp. 323-329 (1988); and Queen et al., "Proc. Nat'l Acad.Sci.USA, Vol. 86, pp. 10029-10033 (1989); U.S. Patent Nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al., "Methods," Vol. 36, pp. 25-34 (2005) (describes graft junction of specificity-determining regions (SDRs)); Padlan, "Mol.Immunol.", Vol. 28, pp. 489-498 (1991) ) ("Resurfacing" is described); Dall'Acqua et al., "Methods", Vol. 36, pp. 43-60 (2005) ("FR shuffling" is described); and Osbourn et al., "Methods", Vol. 36, pp. 61-68 (2005) and Klimka et al., "Br.J.Cancer", Vol. 83, pp. 252-260 (2000) ("Guided selection" method for FR shuffling is described).

[0341] Human framework regions usable for humanization are not limited to, but include framework regions selected using the "best fit" method (see, e.g., Sims et al., "J.Immunol.", Vol. 151, p. 2296 (1993)); and framework regions derived from consensus sequences of human antibodies of specific subgroups of light chain or heavy chain variable regions (see, e.g., Carter et al., "Proc.Natl.Acad.Sci.USA", Vol. 89, p. 4285 (1992); and Presta et al., "J.Immunol.", Vol. 151, p. 2623 (1993)). References include human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, "Front. Biosci.", Vol. 13, pp. 1619-1633 (2008)); and framework regions derived from screening of FR libraries (see, e.g., Baca et al., "J. Biol. Chem.", Vol. 272, pp. 10678-10684 (1997) and Rosok et al., "J. Biol. Chem.", Vol. 271, pp. 22611-22618 (1996)).

[0342] 5. Human antibodies In some embodiments, the anti-KLK5 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.", Vol. 5, pp. 368-374 (2001) and Lonberg, "Curr Opin Immunol.", Vol. 20, pp. 450-459 (2008).

[0343] Human antibodies can be prepared by administering immunogens to transgenic animals modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigen loading. Such animals typically contain all or part of the human immunoglobulin locus, with the endogenous immunoglobulin locus replaced, or with the presence or random integration of external chromosomes on the animal's chromosomes. In such transgenic mice, the endogenous immunoglobulin locus is generally inactivated. For a review of methods for obtaining human antibodies from transgenic animals, see Lonberg, "Nat. Biotech," Vol. 23, pp. 1117–1125 (2005). See also, for example, U.S. Patent Nos. 6,075,181 and 6,150,584 describing XENOMOUSE® technology, U.S. Patent No. 5,770,429 describing HUMAB® technology, U.S. Patent No. 7,041,870 describing KM MOUSE® technology, and U.S. Patent Application Publication 2007 / 0061900 describing VELOCIMOUSE® technology. The human variable region of intact antibodies produced by such animals may be further modified, for example, by combining different human constant regions.

[0344] Human antibodies can also be produced by hybridoma-based methods. Human myeloma and mouse-human xenomyeloma cell lines for producing human monoclonal antibodies have been described. (See, for example, Kozbor, "J.Immunol.", Vol. 133, p. 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.", Vol. 147, p. 86 (1991).) Human antibodies produced via human B-cell hybridoma technology are also described in Li et al., "Proc.Natl.Acad.Sci.USA", Vol. 103, pp. 3557-3562 (2006). Further methods include, for example, U.S. Patent No. 7,189,826 (describes the production of monoclonal human IgM antibodies derived from hybridoma cell lines), and Ni, "Xiandai Mianyixue", Vol. 26, No. 4, pp. 265-268 (2006) (describes human-human hybridomas). Human hybridoma technology (trioma technology) is also described in Vollmers and Brandlein, "Histology and Histopathology", Vol. 20, No. 3, pp. 927-937 (2005), and Vollmers and Brandlein, "Methods and Findings in Experimental and Clinical Pharmacology", Vol. 27, No. 3, pp. 185-191 (2005).

[0345] Human antibodies can also be generated by isolating Fv clone variable domain sequences selected from human-derived phage display libraries. Such variable domain sequences may then be combined with desired human constant domains. Techniques for selecting human antibodies from antibody libraries are described below.

[0346] 6. Library-derived antibodies Anti-KLK5 antibodies can be isolated by screening a combinatorial library for antibodies with desired activity(s). For example, various methods are known in the art for generating phage display libraries and screening such libraries for antibodies possessing desired binding properties. Such methods have been reviewed, for example, in Hoogenboom et al., "Methods in Molecular Biology," Vol. 178, pp. 1-37 (edited by O'Brien et al., Human Press, Totowa, New Jersey, 2001); for example, McCafferty et al., "Nature," Vol. 348, pp. 552-554; Clackson et al., "Nature," Vol. 352, pp. 624-628 (1991); Marks et al., "J.Mol.Biol.", Vol. 222, pp. 581-597 (1992); Marks and Bradbury, "Methods in Molecular Biology," Vol. 248, pp. 161-175 (edited by Lo, Human Press) Press, Totowa, New Jersey, 2003; Sidhu et al., "J.Mol.Biol.", Vol. 338, No. 2, pp. 299-310 (2004); Lee et al., "J.Mol.Biol.", Vol. 340, No. 5, pp. 1073-1093 (2004); Fellouse, "Proc.Natl.Acad.Sci.USA", Vol. 101, No. 34, pp. 12467-12472 (2004); and Lee et al., "J.Immunol.Methods", Vol. 284, Nos. 1-2, pp. 119-132 (2004).

[0347] In certain phage display methods, the VH and VL gene repertoires are cloned separately by polymerase chain reaction (PCR), randomly recombined within a phage library, and then screened against antigen-binding phages as described by Winter et al., "Ann. Rev. Immunol.", Vol. 12, pp. 433-455 (1994). The phages typically display antibody fragments as either single-stranded Fv (scFv) fragments or Fab fragments. Libraries from immunization sources provide high-affinity antibodies against immunogens without the need to construct hybridomas. Alternatively, natural repertoires (e.g., from humans) can be cloned to provide single-source antibodies against a wide range of non-self and autoantigens without the need for arbitrary immunization as described by Griffiths et al., "EMBO J", Vol. 12, pp. 725-734 (1993). Finally, natural libraries can also be synthetically constructed by cloning an unrearranged V gene segment from stem cells, encoding the highly variable CDR3 region using PCR primers containing random sequences, and performing rearrangement in vitro, as described in Hoogenboom and Winter, "J.Mol.Biol.", Vol. 227, pp. 381-388 (1992). Examples of patent publications describing human antibody phage libraries include U.S. Patent No. 5,750,373, and U.S. Patent Application Publications 2005 / 0079574, 2005 / 0119455, 2005 / 0266000, 2007 / 0117126, 2007 / 0160598, 2007 / 0237764, 2007 / 0292936, and 2009 / 0002360.

[0348] Antibodies or antibody fragments isolated from a human antibody library are considered human antibodies or human antibody fragments as defined herein.

[0349] 6. Multispecific antibodies In some embodiments, the anti-KLK5 antibodies provided herein are multispecific antibodies, for example, bispecific antibodies. A multispecific antibody is a monoclonal antibody having binding specificity to at least two different sites. In certain embodiments, one binding specificity is for KLK5 and the other is for any other antigen. In certain embodiments, a bispecific antibody may bind to two different epitopes of KLK5. Bispecific antibodies can also be used to localize cytotoxic agents to cells expressing KLK5. Bispecific antibodies may be prepared as full-length antibodies or antibody fragments.

[0350] Techniques for producing multispecific antibodies include, but are not limited to, the recombinant co-expression of two immunoglobulin heavy-light chain pairs with different specificities (see Milstein and Cuello, "Nature," Vol. 305, p. 537 (1983), International Publication No. 93 / 08829, and Traunecker et al., "EMBO J.", Vol. 10, p. 3655 (1991)), and the "knob-in-hole" operation (see, for example, U.S. Patent No. 5,731,168). Multispecific antibodies can also be produced by manipulating the electrostatic steering effect to create antibody Fc-heterodimer molecules (International Publication No. 2009 / 089004A1); by crosslinking two or more antibodies or fragments (see, e.g., U.S. Patent No. 4,676,980 and Brennan et al., "Science," Vol. 229, p. 81 (1985)); by producing bispecific antibodies using leucine zippers (see, e.g., Kostelny et al., "J.Immunol.", Vol. 148, No. 5, pp. 1547-1553 (1992)); and "diabody" They may also be prepared by using techniques to produce bispecific antibody fragments (see, for example, Hollinger et al., "Proc. Natl. Acad. Sci. USA", Vol. 90, pp. 6444-6448 (1993)); using single-stranded Fv(sFv) dimers (see, for example, Gruber et al., "J. Immunol.", Vol. 152, pp. 5368 (1994)); or by preparing tripspecific antibodies as described, for example, Tutt et al., "J. Immunol.", Vol. 147, pp. 60 (1991).

[0351] Modified antibodies having three or more functional antigen-binding sites, including "octopus antibodies," are also included herein (see, for example, U.S. Patent Application Publication 2006 / 0025576A1).

[0352] The antibodies or fragments described herein also include "Dual Acting FAbs" or "DAFs" that contain antigen-binding sites that bind to KLK5 and another different antigen (see, for example, U.S. Patent Application Publication 2008 / 0069820).

[0353] 7. Antibody Variants In some embodiments, amino acid sequence variants of anti-KLK5 antibodies provided herein are intended. For example, it may be desirable to improve the binding affinity and / or other biological properties of the antibody. The amino acid sequence variants of the antibody may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions, and / or insertions, and / or substitutions of residues in the amino acid sequence of the antibody. Any combination of deletions, insertions, and substitutions can be performed so as to arrive at the final construct, insofar as the final construct has the desired characteristics (e.g., antigen binding).

[0354] a) Substitution, insertion, and deletion variants In some embodiments, anti-KLK5 antibody variants having one or more amino acid substitutions are provided. Target sites for mutagenesis by substitution include HVR and FR. Conservative substitutions are shown in Table 1 under the heading "Preferred Substitutions." More substantial changes are presented in Table 1 under the heading "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 product can be screened for desired activity, such as retained / improved antigen binding, reduced immunogenicity, or improved ADCC or CDC. [Table 1]

[0355] Amino acids may be grouped according to their common side-chain properties. (1) Hydrophobic: norleucine, Met, Ala, Val, Leu, Ile; (2) Neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) Acidic: Asp, Glu; (4) Basicity: His, Lys, Arg; (5) Residues that affect chain orientation: Gly, Pro; (6) Aromatic: Trp, Tyr, Phe.

[0356] Non-conservative substitution involves swapping one member of one of these classes with one of another.

[0357] Certain types of substitutional variants involve substituting one or more hypervariable region residues of a parent antibody (e.g., a humanized antibody or a human antibody). Generally, the resulting variant(s) selected for further study will have modifications (e.g., improvements) (e.g., increased affinity, reduced immunogenicity) in certain biological properties compared to the parent antibody, and / or substantially retain certain biological properties of the parent antibody. Exemplary substitutional variants are affinity-mature antibodies that can be conveniently generated using phage display-based affinity maturation techniques, such as those described herein. In short, one or more HVR residues are mutated, the variant antibody is displayed to a phage, and it is screened for specific biological activity (e.g., binding affinity).

[0358] Modifications (e.g., substitutions) may be made in HVRs, for example, to improve antibody affinity. Such modifications may be made in HVR "hot spots," i.e., residues encoded by codons that are frequently mutated during the somatic cell maturation process (see, e.g., Chowdhury, "Methods Mol. Biol.", Vol. 207, pp. 179-196 (2008)), and / or residues that come into contact with the antigen, and the resulting variant VH or VL is tested for binding affinity. Affinity maturation by constructing a secondary library and then reselecting from it is described, e.g., Hoogenboom et al., "Methods in Molecular Biology," Vol. 178, pp. 1-37 (O'Brien et al., Human Press, Totowa, New Jersey, (2001)). In some embodiments of affinity maturation, diversity is introduced into the variable genes selected for maturation by any of the following diverse methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis). Next, a secondary library is created. This library is then screened to identify any antibody variant with the desired affinity. Another method for introducing diversity involves an HVR-targeted approach, which randomizes several HVR residues (e.g., 4-6 residues at a time). HVR residues involved in antigen binding may be specifically identified, for example, using alanine scanning mutagenesis or modeling. In particular, CDR-H3 and CDR-L3 are often targeted.

[0359] In certain embodiments, substitutions, insertions, or deletions may occur in one or more HVRs, provided that such modifications do not substantially reduce the antibody's ability to bind to the antigen. For example, conservative modifications that do not substantially reduce binding affinity (e.g., conservative substitutions as provided herein) may be made in an HVR. Such modifications may be, for example, outside the antigen-contact residue within the HVR. In certain embodiments of the variant VH and VL sequences provided above, each HVR is either unmodified or contains one, two, or three or fewer amino acid substitutions.

[0360] A useful method for identifying antibody residues or regions that can be targeted for mutations is called "alanine scanning mutagenesis," as described by Cunningham and Wells (1989), "Science," Vol. 244, pp. 1081-1085. In this method, one or a group of target residues (e.g., charged residues such as Arg, Asp, His, Lys, and Glu) are identified and replaced with neutral or negatively charged amino acids (e.g., alanine or polyalanine) to determine whether the antibody's interaction with the antigen is affected. Further substitutions may be introduced at amino acid positions that exhibit functional sensitivity to the initial substitution. Alternatively, or in addition, the crystal structure of the antigen-antibody complex may be used to identify the contact points between the antibody and the antigen. Such contact residues and adjacent residues may be targeted as candidates for substitution or removed. Variants may be screened to determine whether they possess the desired properties.

[0361] Amino acid sequence insertions include the fusion of amino and / or carboxyl terminals in polypeptides ranging in length from one residue to 100 or more residues, as well as intrasequence insertions of one or more amino acid residues. An example of terminal insertion is an antibody with an N-terminal methionyl residue. Other insertion variants of antibody molecules include the fusion of the N-terminus or C-terminus of an antibody to an enzyme (e.g., for ADEPT) or polypeptide, which increases the serum half-life of the antibody.

[0362] b) Glycosylated variants In certain embodiments, the anti-KLK5 antibodies provided herein are modified to increase or decrease the degree to which the antibody is glycosylated. The addition or deletion of glycosylation sites to an antibody can be conveniently achieved by modifying the amino acid sequence so that one or more glycosylation sites are created or removed.

[0363] If an antibody contains an Fc region, the carbohydrate bound to it may be modified. Natural antibodies produced by mammalian cells typically contain branched oligosaccharides, commonly bound to Asn297 of the CH2 domain of the Fc region by an N-bond. See, for example, Wright et al., "TIBTECH," Vol. 15, pp. 26-32 (1997). Oligosaccharides may include various carbohydrates, such as mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, as well as fucose bound to GlcNAc in the "stem" of a branched oligosaccharide structure. In some embodiments, oligosaccharide modification may be performed in the antibodies of the present invention to produce antibody variants with specific improved properties.

[0364] In some embodiments, anti-KLK5 antibody variants are provided that have carbohydrate structures lacking fucose (directly or indirectly) bound to the Fc region. For example, the amount of fucose in such antibodies may be 1%–80%, 1%–65%, 5%–65%, or 20%–40%. The amount of fucose is determined by calculating the average amount of fucose in the glycans at Asn297 relative to the total of all sugar structures (e.g., complexes, hybrids, and high-mannose structures) bound to Asn297, measured by MALDI-TOF mass spectrometry as described in International Publication No. 2008 / 077546. Asn297 refers to the asparagine residue located at approximately position 297 (EU numbering of Fc region residues) within the Fc region. However, Asn297 may also be located approximately ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in the antibody. Such fucosylated variants may possess improved ADCC functionality. See, for example, U.S. Patent Application Publication No. 2003 / 0157108 (Presta, L.); and U.S. Patent Application Publication No. 2004 / 0093621 (Kyowa Hakko Kogyo Co., Ltd.). Examples of publications relating to "defucosylated" or "fucose-deficient" antibody variants include: U.S. Patent Application Publication No. 2003 / 0157108; International Publication No. 2000 / 61739; International Publication No. 2001 / 29246; U.S. Patent Application Publication No. 2003 / 0115614; International Publication No. 2002 / 0164328; International Publication No. 2004 / 0093621; International Publication No. 2004 / 0132140; International Publication No. 2004 / 0110704; International Publication No. 2004 / 0110282; International Publication No. 2004 / 0 Publications include No. 109865; International Publica...

Claims

1. An isolated antibody that binds to KLK5, wherein the antibody is An antibody comprising: (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 28; (b) HVR-H2 containing an amino acid sequence selected from the group consisting of SEQ ID NO: 38, SEQ ID NO: 45, and SEQ ID NO: 54; (c) HVR-H3 containing an amino acid sequence selected from the group consisting of SEQ ID NO: 65, SEQ ID NO: 69, and SEQ ID NO: 72; (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 96; (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 109; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO:

127.

2. The aforementioned antibody The antibody according to claim 1, comprising: (a) HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 17, SEQ ID NO: 22, and SEQ ID NO: 24; (b) HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, and SEQ ID NO: 53; (c) HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 65, SEQ ID NO: 69, and SEQ ID NO: 72; (d) HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 82, SEQ ID NO: 87, and SEQ ID NO: 91; (e) HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 99, SEQ ID NO: 101, and SEQ ID NO: 105; and (f) HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 115, SEQ ID NO: 119, and SEQ ID NO:

122.

3. The aforementioned antibody (i) (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 17, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 35, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 65, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 82, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 101, (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 115 (ii) (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 42, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 87, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 105, (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 119, or (iii) The antibody according to any one of claims 1 or 2, comprising: (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 24; (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 52; (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 72; (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 91; (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 99; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO:

122.

4. The antibody according to any one of claims 1 to 3, wherein the antibody comprises (a) the VH sequence of SEQ ID NO: 202 and the VL sequence of SEQ ID NO: 140, (b) the VH sequence of SEQ ID NO: 225 and the VL sequence of SEQ ID NO: 151, or (c) the VH sequence of SEQ ID NO: 257 and the VL sequence of SEQ ID NO:

162.

5. The antibody according to any one of claims 1 to 4, wherein the antibody comprises (a) the VH sequence of SEQ ID NO: 201 and the VL sequence of SEQ ID NO: 139, (b) the VH sequence of SEQ ID NO: 221 and the VL sequence of SEQ ID NO: 149, or (c) the VH sequence of SEQ ID NO: 248 or SEQ ID NO: 254 and the VL sequence of SEQ ID NO:

160.

6. An isolated antibody that binds to KLK5, wherein the antibody comprises (a) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 201 and a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 139, (b) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 221 and a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 149, or (c) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 248 or SEQ ID NO: 254 and a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:

160.

7. An isolated antibody that binds to KLK5, wherein the antibody is (i) (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 14, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 32, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 62, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 79, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 99, (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 112 (ii) (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 15, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 33, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 63, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 80, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 100, (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 113, (iii) (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 16, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 34, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 64, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 81, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 99, (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 114, (iv) (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 18, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 39, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 66, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 83, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 102, (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 116, (v) (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 19, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 40, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 67, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 84, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 103, (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 117 (vi) (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 20, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 33, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 68, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 85, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 103, (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 118, (vii) (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 41, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 86, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 104, (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 118 (viiii) (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 46, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 88, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 105, (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 120, (ix) (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 42, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 70, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 89, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 105, (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 118, or (x) An antibody comprising (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 23, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 47, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 71, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 90, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 106, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO:

121.

8. The antibody according to claim 7, wherein the antibody comprises a VH sequence selected from the group consisting of SEQ ID NOs: 170, 171, 172, 203, 204, 205, 206, 226, 227, and 228, and a VL sequence selected from the group consisting of SEQ ID NOs: 131, 132, 133, 141, 142, 143, 144, 152, 153, and 154.

9. The antibody according to any one of claims 7 or 8, wherein the antibody comprises (a) the VH sequence of SEQ ID NO: 170 and the VL sequence of SEQ ID NO: 131, (b) the VH sequence of SEQ ID NO: 171 and the VL sequence of SEQ ID NO: 132, (c) the VH sequence of SEQ ID NO: 172 and the VL sequence of SEQ ID NO: 133, (d) the VH sequence of SEQ ID NO: 203 and the VL sequence of SEQ ID NO: 141, (e) the VH sequence of SEQ ID NO: 204 and the VL sequence of SEQ ID NO: 142, (f) the VH sequence of SEQ ID NO: 205 and the VL sequence of SEQ ID NO: 143, (g) the VH sequence of SEQ ID NO: 206 and the VL sequence of SEQ ID NO: 144, (h) the VH sequence of SEQ ID NO: 226 and the VL sequence of SEQ ID NO: 152, (i) the VH sequence of SEQ ID NO: 227 and the VL sequence of SEQ ID NO: 153, or (j) the VH sequence of SEQ ID NO: 228 and the VL sequence of SEQ ID NO:

154.

10. An isolated antibody that binds to KLK5, wherein the antibody comprises: (a) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 170 and a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 131; (b) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 171 and a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 132; (c) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 172 and a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 133; (d) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 203 and a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 141; and (e) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 204 and at least 95% sequence identity with the amino acid sequence of SEQ ID NO:

142. An antibody comprising: (f) a VL sequence having a specific property; (g) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 205 and a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 143; (h) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 206 and a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 144; (i) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 226 and a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 152; or (j) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 227 and a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 153; or (j) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 228 and a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:

154.

11. The antibody according to any one of claims 1 to 10, wherein the antibody is IgG1 or IgG4.

12. The antibody according to any one of claims 1 to 11, wherein the antibody inhibits the biological activity of KLK5 by at least 50% so that it can be measured by one or more methods selected from the group consisting of recombinant KLK5 direct activity assay, conjugated pro-KLK1 fluorescent peptide assay, conjugated pro-KLK7 fluorescent peptide assay, pro-KLK1 LC / MS assay, pro-KLK7 LC / MS assay, and Ki(app) assay.

13. The antibody according to any one of claims 1 to 12, wherein the biological activity is the serine protease activity of KLK5.

14. The antibody according to any one of claims 1 to 13, wherein the antibody is a monoclonal antibody.

15. The antibody according to any one of claims 1 to 14, wherein the antibody is a human antibody, a humanized antibody, or a chimeric antibody.

16. The antibody according to any one of claims 1 to 15, wherein the antibody is an antibody fragment that binds to KLK5.

17. An antibody that forms a thermodynamic epitope when bound to KLK5, and which contains one or more sequences selected from the group consisting of SEQ ID NO: 316, SEQ ID NO: 317, SEQ ID NO: 318, and SEQ ID NO: 319, as measured by hydrogen exchange mass spectrometry.

18. An antibody that competes for binding with the antibody described in any one of claims 1 to 16.

19. An antibody that binds to the same epitope as the antibody described in any one of claims 1 to 16.

20. An isolated nucleic acid encoding the antibody according to any one of claims 1 to 16.

21. A host cell comprising the nucleic acid described in claim 20.

22. A method for producing an antibody, comprising culturing the host cells described in claim 21 so that the antibody is produced.

23. An immune complex comprising the antibody described in any one of claims 1 to 16.

24. A pharmaceutical preparation comprising an antibody according to any one of claims 1 to 16 and a pharmaceutically acceptable carrier.

25. An antibody according to any one of claims 1 to 16, for use as a pharmaceutical.

26. An antibody according to any one of claims 1 to 16, for use in the treatment of a disease selected from the group consisting of Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis, and rosacea.

27. The aforementioned asthma includes atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, and aspirin-sensitive / exacerbated asthma. The antibody according to claim 26, selected from the group consisting of asthma), mild asthma, moderate to severe asthma, corticosteroid-untreated asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, corticosteroid-resistant asthma, newly diagnosed untreated asthma, smoking-induced asthma, asthma uncontrolled by corticosteroids, T helper lymphocyte type 2 (Th2) asthma or type 2 (Th2) high-level asthma or type 2 (T2)-driven asthma, eosinophilic asthma, hyperperiostin asthma, hypereosinophilic asthma, low-Th2 asthma or non-Th2-driven asthma, hypoperiostin asthma, and hypoeosinophilic asthma.

28. The antibody according to claim 27, wherein the asthma is low-TH2 asthma.

29. An antibody according to any one of claims 1 to 16, for use in inhibiting the biological activity of KLK5.

30. Use of an antibody according to any one of claims 1 to 16 in the manufacture of a pharmaceutical product.

31. The use according to claim 30, wherein the pharmaceutical agent is for the treatment of a disease selected from the group consisting of Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis, and rosacea.

32. The use according to claim 31, wherein the asthma is selected from the group consisting of atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin-sensitive / exacerbating asthma, mild asthma, moderate to severe asthma, corticosteroid-untreated asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, corticosteroid-resistant asthma, newly diagnosed untreated asthma, smoking-induced asthma, asthma uncontrolled by corticosteroids, T helper lymphocyte type 2 (Th2) asthma or type 2 (Th2) high-level asthma or type 2 (T2)-driven asthma, eosinophilic asthma, hyperperiostin asthma, hypereosinophilic asthma, low-Th2 asthma or non-Th2-driven asthma, hypoperiostin asthma, and hypoeosinophilic asthma.

33. The use according to claim 32, wherein the asthma is low-TH2 asthma.

34. Use of an antibody according to any one of claims 1 to 16 in the manufacture of a pharmaceutical product for inhibiting the biological activity of KLK5.

35. A method for treating an individual having a disease, comprising administering to the individual an effective amount of an antibody according to any one of claims 1 to 16, wherein the disease is selected from the group consisting of Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis, and rosacea.

36. The method according to claim 35, wherein the asthma is selected from the group consisting of atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin-sensitive / exacerbating asthma, mild asthma, moderate to severe asthma, corticosteroid-untreated asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, corticosteroid-resistant asthma, newly diagnosed untreated asthma, smoking-induced asthma, asthma uncontrolled by corticosteroids, T helper lymphocyte type 2 (Th2) asthma or type 2 (Th2) high-level asthma or type 2 (T2)-driven asthma, eosinophilic asthma, hyperperiostin asthma, hypereosinophilic asthma, low-Th2 asthma or non-Th2-driven asthma, hypoperiostin asthma, and hypoeosinophilic asthma.

37. The method according to claim 36, wherein the asthma is Th2 low-level asthma.

38. A method for inhibiting the biological activity of KLK5 in an individual, comprising administering to the individual an effective amount of the antibody described in any one of claims 1 to 16 in order to inhibit the biological activity of KLK5.

39. An antibody that specifically binds to human KLK5, wherein the antibody is classified by standard protease numbering as Pro130, Ser131, Ala132, Gly133, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro17 3. An antibody that binds to an epitope on human KLK5 containing one or more amino acid residues selected from the group consisting of Arg174, Gln174A, Ile176, Asp177, Asp178, Gly184, Asp185, Lys186, Ala186A, Arg188, Asn223, Arg224, Pro225, and Lys233.

40. The antibody according to claim 39, wherein the antibody binds to an epitope on human KLK5 containing one or more amino acid residues selected from the group consisting of Pro130, Ser131, Ala132, Val162, Leu163, Ser164, Glun165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Glun174A, Ile176, Asp177, Asp178, Arg224, and Lys233, as determined by standard protease numbering.

41. The antibody according to claim 39, wherein the antibody binds to an epitope on human KLK5 containing one or more amino acid residues selected from the group consisting of Pro130, Ser131, Ala132, Gly133, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Gln174A, Ile176, Asp177, and Lys233, as determined by standard protease numbering.

42. The antibody according to claim 39, wherein the antibody binds to an epitope on human KLK5 comprising one or more amino acid residues selected from the group consisting of Ser131, Ala132, Gly133, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Pro173, Arg174, Gly184, Asp185, Lys186, Ala186A, Arg188, Asn223, Arg224, and Pro225, as determined by standard protease numbering.

43. An antibody that, upon binding to human KLK5, causes a conformational change in human KLK5, wherein the conformational change allosterically leads to the destruction of the substrate binding site and / or active site of human KLK5.

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