Anti-KLK5 antibodies and methods of use

Abstract

To provide anti-KLK5 antibodies, and methods of using the same.SOLUTION: An isolated antibody that binds to KLK5 comprises HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 containing particular amino acid sequences. The antibody is for use in treating a disease selected from the group consisting of Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis, and rosacea.SELECTED DRAWING: Figure 18B

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 62 / 643,034, filed March 14, 2018, the entire contents of which are incorporated herein by reference.

[0002] Sequence Listing This application contains a Sequence Listing that was submitted via EFS-Web and is incorporated herein by reference in its entirety. The 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 anti-KLK5 antibodies and methods of using the same. [Background technology]

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

[0005] KLK5 appears to be most abundantly expressed in human skin, particularly in the upper spinous and granular layers of the skin, where keratinocytes undergo terminal differentiation into flattened, brick-like structures that form the stratum corneum, the outermost epidermal layer and a barrier against the external environment. See Debela et al., J Mol Biol, 373, 1017-1031 (2007), and Tan et al., J Med Chem., 2015, 58, No. 2, 598-612 (2014). It has been described that KLK5 plays a pathological role in skin disorders such as Netherton syndrome. See Furio et al., PLOS Genet, 11, No. 9, e1005389 (2015). Netherton syndrome is caused by loss-of-function mutations in the SPINK5 gene, which encodes Kazal-type serine protease inhibitor 5 (SPINK5). See Descargues et al., Nat Genet., 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 23, No. 7, pp. 524-526 (2014). Lack of SPINK5 in Netherton syndrome results in unopposed KLK activity. KLK5 hyperactivity is thought to be a key factor in the pathophysiology of Netherton syndrome because KLK5 is a regulator of protein degradation in the epidermis. Ablation of KLK5 and KLK7 rescues the lethality of the Netherton syndrome-like phenotype. See Briot et al., J Exp Med., May 11, Vol. 206, No. 5, pp. 1135-47 (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 disorder 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. Heritability estimates from twin studies of asthma range from 35% to 80%, suggesting an important role for genetic risk. See, e.g., Ullemar et al., Allergy 71:230-238 (2016). Several large-scale GWAS have been conducted on asthma and asthma-related phenotypes, and many of the identified loci, such as ORMDL3, IL13, IL1RL1, and genes near the TSLP gene, have been confirmed in multiple study populations. See, e.g., Bonnelykke et al., Nat Genet 46:51-55 (2014). Recent studies have identified SNPs in the KLK4 / 5 locus that are protective for the risk of low periostin asthma or type 2 low-inflammatory asthma. In the same study, KLK5 levels were found to be increased in bronchoalveolar lavage of patients with severe asthma, supporting the hypothesis that KLK5 plays a role in bronchial obstruction and asthma pathogenesis.

[0007] Despite progress in the field of diseases such as Netherton syndrome and asthma, there is a need to identify targets and develop tools that can complement or enhance the effectiveness of existing treatments. Summary of the Invention

[0008] Provided herein are anti-KLK5 antibodies and methods of using same.

[0009] Further provided herein is an isolated antibody that binds to KLK5, wherein the antibody comprises: (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) an 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) an 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) an 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) an 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) an 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) an 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 any of the antibodies, the antibody is selected from the group consisting of: (i) (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; (ii) (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-H3 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, or (iii) (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.

[0012] In some embodiments of any of the antibodies, 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 any of the antibodies, 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] Further provided herein is an isolated antibody that binds to KLK5, wherein the antibody comprises (a) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 201 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 139, (b) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 221 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 149, or (c) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 248 or SEQ ID NO: 254 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 160.

[0015] Further provided herein is an isolated antibody that binds to KLK5, wherein the antibody is selected from the group consisting of (i) (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; (ii) (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: 62. (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; (iii) (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-L3 comprising the amino acid sequence of SEQ ID NO: 99 (iv) (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, (v) (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, (vi) (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, (vii) (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, (viii) (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. (ix) (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, or (x) (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.

[0016] In some embodiments, the antibody comprises a VH sequence selected from the group consisting of SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:226, SEQ ID NO:227, and SEQ ID NO:228, and a VL sequence selected from the group consisting of SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:152, SEQ ID NO:153, and SEQ ID NO:154.

[0017] In some embodiments, 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.

[0018] Further provided herein is an isolated antibody that binds to KLK5, wherein the antibody is selected from the group consisting of: (a) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 170 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 131; (b) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 171 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 132; (c) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 172 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 133; (d) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 203 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 141; and (e) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 204 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 142. (f) 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; (g) 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 any of the antibodies, the antibody is an IgG1 or an IgG4.

[0020] In some embodiments of any of the antibodies, the antibody inhibits the biological activity of KLK5 by at least 50% as measured by one or more of the methods described in the Examples herein below. In some embodiments, the one or more methods include a recombinant KLK5 direct activity assay, a bound pro-KLK1 fluorescent peptide assay, a bound pro-KLK7 fluorescent peptide assay, a pro-KLK1 LC / MS assay, a pro-KLK7 LC / MS assay, and a KLK5 direct activity assay. i(app) In some embodiments, the biological activity is the serine protease activity of KLK5.

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

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

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

[0024] Further provided herein is an antibody that forms a thermodynamic epitope when bound to KLK5, the antibody comprising one or more of the 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] Further provided herein are antibodies that compete for binding with any of the antibodies described herein.

[0026] Further provided herein are antibodies that bind to the same epitope as any of the antibodies described herein.

[0027] Further provided herein is an isolated nucleic acid encoding any of the antibodies described herein.

[0028] Further provided herein is a host cell comprising a nucleic acid described herein.

[0029] Further provided herein is a method of producing an antibody, comprising culturing a host cell described herein such that said antibody is produced.

[0030] Further provided herein is an immunoconjugate comprising the antibody described herein.

[0031] Further provided herein is a pharmaceutical formulation comprising an antibody described herein and a pharmaceutically acceptable carrier.

[0032] Further provided herein is an antibody described herein for use as a medicament.

[0033] Further provided herein is an antibody described herein for use in treating a disease selected from the group consisting of Netherton syndrome, asthma, atopic dermatitis, psoriasis, and rosacea, hi 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 / exacerbated asthma, mild asthma, moderate-to-severe asthma, corticosteroid-naive asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, newly diagnosed untreated asthma, smoking-related asthma, corticosteroid-uncontrolled asthma, T helper lymphocyte type 2 (Th2) asthma or type 2 (Th2)-high or type 2 (T2)-driven asthma, eosinophilic asthma, periostin-high asthma, eosinophilic asthma, Th2-low or non-Th2-driven asthma, periostin-low asthma, and eosinophilic asthma. In some embodiments, the asthma is Th2-low asthma.

[0034] Further provided herein is an antibody as described herein for use in inhibiting the biological activity of KLK5.

[0035] Further provided herein is the use of an antibody described herein in the manufacture of a medicament. In some embodiments, the medicament 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 / exacerbated asthma, mild asthma, moderate-to-severe asthma, corticosteroid-naive asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, newly diagnosed untreated asthma, smoking-related asthma, corticosteroid-uncontrolled asthma, T helper lymphocyte type 2 (Th2) asthma or type 2 (Th2)-high or type 2 (T2)-driven asthma, eosinophilic asthma, periostin-high asthma, eosinophilic asthma, Th2-low or non-Th2-driven asthma, periostin-low asthma, and eosinophilic asthma. In some embodiments, the asthma is Th2-low asthma.

[0036] Further provided herein is the use of an antibody described herein in the manufacture of a medicament for inhibiting the biological activity of KLK5.

[0037] Further provided herein are methods of treating an individual having a disease, wherein the disease is selected from the group consisting of Netherton syndrome, asthma, atopic dermatitis, psoriasis, and rosacea, comprising administering to the individual an effective amount of an antibody described herein, 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 / exacerbated asthma, mild asthma, moderate-to-severe asthma, corticosteroid-naive asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, newly diagnosed untreated asthma, smoking-related asthma, corticosteroid-uncontrolled asthma, T helper lymphocyte type 2 (Th2) asthma or type 2 (Th2)-high or type 2 (T2)-driven asthma, eosinophilic asthma, high periostin asthma, high eosinophilic asthma, low Th2 asthma or non-Th2-driven asthma, low periostin asthma, and low eosinophilic asthma. In some embodiments, the asthma is low Th2 asthma.

[0038] Further provided herein is a method for inhibiting the biological activity of KLK5 in an individual, the method comprising administering to the individual an effective amount of an antibody described herein to inhibit the biological activity of KLK5.

[0039] Further provided herein is 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 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 that includes one or more amino acid residues selected from the group consisting of Pro130, Ser131, Ala132, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Gln174A, Ile176, Asp177, Asp178, Arg224, and Lys233, according to standard protease numbering. In some embodiments, the antibody binds to an epitope on human KLK5 that includes one or more amino acid residues selected from the group consisting of Pro130, Ser131, Ala132, 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 that includes 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] The present specification further provides an antibody that, when bound to human KLK5, causes a conformational change in human KLK5, wherein the conformational change allosterically disrupts the substrate binding site and / or active site of human KLK5. [Brief explanation of the drawings]

[0041] [Figure 1A-F] Figures 1A-1N show the evaluation of each KLK5 inhibitor using a fluorescent peptide substrate in a direct assay. 5 nM recombinant human KLK5 inhibitor and 0.19-100 nM KLK5 inhibitors were preincubated for 30 minutes before the addition of 50 μM Boc-VPR-AMC. Plates were scanned every 102 seconds for 30-60 minutes using a PHERAstar® Plus reader using 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-1N show the evaluation of each KLK5 inhibitor using a fluorescent peptide substrate in a direct assay. 5 nM recombinant human KLK5 inhibitor and 0.19-100 nM KLK5 inhibitors were preincubated for 30 minutes before the addition of 50 μM Boc-VPR-AMC. Plates were scanned every 102 seconds for 30-60 minutes using a PHERAstar® Plus reader using 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-1N show the evaluation of each KLK5 inhibitor using a fluorescent peptide substrate in a direct assay. 5 nM recombinant human KLK5 inhibitor and 0.19-100 nM KLK5 inhibitors were preincubated for 30 minutes before the addition of 50 μM Boc-VPR-AMC. Plates were scanned every 102 seconds for 30-60 minutes using a PHERAstar® Plus reader using 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-2N show the evaluation of KLK5 inhibitors in the pro-KLK7 binding assay. 5 nM recombinant human KLK5 inhibitor and 0.19-100 nM anti-KLK5 inhibitors were preincubated 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 between 30 and 60 minutes, and RFU endpoint values ​​were calculated by averaging the last five readings. Results for the 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-2N show the evaluation of KLK5 inhibitors in the pro-KLK7 binding assay. 5 nM recombinant human KLK5 inhibitor and 0.19-100 nM anti-KLK5 inhibitors were preincubated 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 between 30 and 60 minutes, and RFU endpoint values ​​were calculated by averaging the last five readings. Results for the 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-2N show the evaluation of KLK5 inhibitors in the pro-KLK7 binding assay. 5 nM recombinant human KLK5 inhibitor and 0.19-100 nM anti-KLK5 inhibitors were preincubated 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 between 30 and 60 minutes, and RFU endpoint values ​​were calculated by averaging the last five readings. Results for the 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-3N show the evaluation of KLK5 inhibitors in a pro-KLK1 binding assay. 0.5 nM recombinant human KLK5 inhibitor and 0.019-10 nM KLK5 inhibitors were preincubated for 30 minutes before the addition of 31.25 nM pro-KLK1 and 50 μM PFR-AMC. Plates were scanned every 102 seconds for 120 minutes using a PHERAstar® Plus reader using a 340 nm excitation / 460 nm emission module. Results for the 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-3N show the evaluation of KLK5 inhibitors in a pro-KLK1 binding assay. 0.5 nM recombinant human KLK5 inhibitor and 0.019-10 nM KLK5 inhibitors were preincubated for 30 minutes before the addition of 31.25 nM pro-KLK1 and 50 μM PFR-AMC. Plates were scanned every 102 seconds for 120 minutes using a PHERAstar® Plus reader using a 340 nm excitation / 460 nm emission module. Results for the 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-3N show the evaluation of KLK5 inhibitors in a pro-KLK1 binding assay. 0.5 nM recombinant human KLK5 inhibitor and 0.019-10 nM KLK5 inhibitors were preincubated for 30 minutes before the addition of 31.25 nM pro-KLK1 and 50 μM PFR-AMC. Plates were scanned every 102 seconds for 120 minutes using a PHERAstar® Plus reader using a 340 nm excitation / 460 nm emission module. Results for the 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 an LC / MS assay measuring the inhibition of proteolysis of pro-KLK7 by recombinant KLK5 by monitoring KLK5-derived cleavage product peptides. Preincubation of KLK5 with SPINK9.SRE.Fc, mAb1108, and 12 selected antibodies preceded a 2-hour incubation with 5 nM KLK5 and 15 nM pro-KLK7. The results for the 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 an LC / MS assay measuring the inhibition of proteolysis of pro-KLK7 by recombinant KLK5 by monitoring KLK5-derived cleavage product peptides. Preincubation of KLK5 with SPINK9.SRE.Fc, mAb1108, and 12 selected antibodies preceded a 2-hour incubation with 5 nM KLK5 and 15 nM pro-KLK7. The results for the 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 an LC / MS assay measuring the inhibition of proteolysis of pro-KLK7 by recombinant KLK5 by monitoring KLK5-derived cleavage product peptides. Preincubation of KLK5 with SPINK9.SRE.Fc, mAb1108, and 12 selected antibodies preceded a 2-hour incubation with 5 nM KLK5 and 15 nM pro-KLK7. The results for the 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-5N show the results of an LC / MS assay measuring the inhibition of proteolysis of pro-KLK1 by recombinant KLK5 by monitoring KLK5-derived cleavage product peptides. Preincubation of KLK5 with SPINK9.SRE.Fc, mAb1108, and 12 selected antibodies preceded a 20-minute incubation with 0.5 nM KLK5 and 300 nM pro-KLK1 (Figures 5A-5N). The results for the 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-5N show the results of an LC / MS assay measuring the inhibition of proteolysis of pro-KLK1 by recombinant KLK5 by monitoring KLK5-derived cleavage product peptides. Preincubation of KLK5 with SPINK9.SRE.Fc, mAb1108, and 12 selected antibodies preceded a 20-minute incubation with 0.5 nM KLK5 and 300 nM pro-KLK1 (Figures 5A-5N). The results for the 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-5N show the results of an LC / MS assay measuring the inhibition of proteolysis of pro-KLK1 by recombinant KLK5 by monitoring KLK5-derived cleavage product peptides. Preincubation of KLK5 with SPINK9.SRE.Fc, mAb1108, and 12 selected antibodies preceded a 20-minute incubation with 0.5 nM KLK5 and 300 nM pro-KLK1 (Figures 5A-5N). The results for the 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-6N show the specificity of KLK5 inhibitors for KLK7 activity. 5 nM recombinant human KLK7 inhibitor and 0.19-100 nM anti-KLK5 inhibitors were preincubated for 30 minutes before the addition of 100 μM suc-LLVY-AMC. Plates were scanned every 102 seconds for 75 minutes using a PHERAstar® Plus reader using a 340 nm excitation / 460 nm emission module. IC50 values ​​are summarized in Table 6. 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-6N show the specificity of KLK5 inhibitors for KLK7 activity. 5 nM recombinant human KLK7 inhibitor and 0.19-100 nM anti-KLK5 inhibitors were preincubated for 30 minutes before the addition of 100 μM suc-LLVY-AMC. Plates were scanned every 102 seconds for 75 minutes using a PHERAstar® Plus reader using a 340 nm excitation / 460 nm emission module. IC50 values ​​are summarized in Table 6. 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-6N show the specificity of KLK5 inhibitors for KLK7 activity. 5 nM recombinant human KLK7 inhibitor and 0.19-100 nM anti-KLK5 inhibitors were preincubated for 30 minutes before the addition of 100 μM suc-LLVY-AMC. Plates were scanned every 102 seconds for 75 minutes using a PHERAstar® Plus reader using a 340 nm excitation / 460 nm emission module. IC50 values ​​are summarized in Table 6. 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-7N show the specificity of KLK5 inhibitors for KLK1 activity. 3 nM recombinant human KLK1 inhibitor and 0.19-100 nM anti-KLK5 inhibitors were preincubated for 30 minutes before the addition of 100 μM PFR-AMC. Plates were scanned every 102 seconds for 60 minutes using a PHERAstar® Plus reader using a 340 nm excitation / 460 nm emission module. IC50 values ​​are summarized in Table 7. 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-7N show the specificity of KLK5 inhibitors for KLK1 activity. 3 nM recombinant human KLK1 inhibitor and 0.19-100 nM anti-KLK5 inhibitors were preincubated for 30 minutes before the addition of 100 μM PFR-AMC. Plates were scanned every 102 seconds for 60 minutes using a PHERAstar® Plus reader using a 340 nm excitation / 460 nm emission module. IC50 values ​​are summarized in Table 7. 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-7N show the specificity of KLK5 inhibitors for KLK1 activity. 3 nM recombinant human KLK1 inhibitor and 0.19-100 nM anti-KLK5 inhibitors were preincubated for 30 minutes before the addition of 100 μM PFR-AMC. Plates were scanned every 102 seconds for 60 minutes using a PHERAstar® Plus reader using a 340 nm excitation / 460 nm emission module. IC50 values ​​are summarized in Table 7. 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-8N show the specificity of KLK5 inhibitors for KLK4 activity. 2 nM recombinant human KLK4 inhibitor and 0.19-100 nM anti-KLK5 inhibitors were preincubated for 30 minutes before the addition of 50 μM Boc-VPR-AMC. Plates were scanned every 102 seconds for 60 minutes using a PHERAstar® Plus reader using a 340 nm excitation / 460 nm emission module. IC50 values ​​are summarized in Table 8. 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-8N show the specificity of KLK5 inhibitors for KLK4 activity. 2 nM recombinant human KLK4 inhibitor and 0.19-100 nM anti-KLK5 inhibitors were preincubated for 30 minutes before the addition of 50 μM Boc-VPR-AMC. Plates were scanned every 102 seconds for 60 minutes using a PHERAstar® Plus reader using a 340 nm excitation / 460 nm emission module. IC50 values ​​are summarized in Table 8. 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-8N show the specificity of KLK5 inhibitors for KLK4 activity. 2 nM recombinant human KLK4 inhibitor and 0.19-100 nM anti-KLK5 inhibitors were preincubated for 30 minutes before the addition of 50 μM Boc-VPR-AMC. Plates were scanned every 102 seconds for 60 minutes using a PHERAstar® Plus reader using a 340 nm excitation / 460 nm emission module. IC50 values ​​are summarized in Table 8. 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-9N show the specificity of KLK5 inhibitors for trypsin activity. 0.25 nM trypsin isolated from bovine pancreas and 0.19-100 nM anti-KLK5 inhibitors were preincubated for 30 minutes before the addition of 50 μM Boc-VPR-AMC. Plates were scanned every 102 seconds for 60 minutes using a PHERAstar® Plus reader using a 340 nm excitation / 460 nm emission module. IC50 values ​​for selected antibodies (Figures 9C-9N) are summarized in Table 9. 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-9N show the specificity of KLK5 inhibitors for trypsin activity. 0.25 nM trypsin isolated from bovine pancreas and 0.19-100 nM anti-KLK5 inhibitors were preincubated for 30 minutes before the addition of 50 μM Boc-VPR-AMC. Plates were scanned every 102 seconds for 60 minutes using a PHERAstar® Plus reader using a 340 nm excitation / 460 nm emission module. IC50 values ​​for selected antibodies (Figures 9C-9N) are summarized in Table 9. 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-9N show the specificity of KLK5 inhibitors for trypsin activity. 0.25 nM trypsin isolated from bovine pancreas and 0.19-100 nM anti-KLK5 inhibitors were preincubated for 30 minutes before the addition of 50 μM Boc-VPR-AMC. Plates were scanned every 102 seconds for 60 minutes using a PHERAstar® Plus reader using a 340 nm excitation / 460 nm emission module. IC50 values ​​for selected antibodies (Figures 9C-9N) are summarized in Table 9. 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-10AB show analysis of KLK5 inhibitor potency by measuring Kiapp. Various concentrations (0.5, 0.25, 0.125, and 0.0625 nM) of KLK5 inhibitors and 0.0019-10 nM of anti-KLK5 inhibitors were preincubated for 30 minutes before the addition of 300 μM Z-VPR-pNA. Plates were read on a Versamax tunable microplate reader with measurements at 405 nm acquired every 102 seconds over a 3-hour period. The derived Kiapp are summarized in Table 10. The results for KLK5 inhibitors are as follows (each left panel shows the IC50 values ​​of the KLK5 inhibitors at various KLK5 concentrations (0.5, 0.25, 0.125, and 0.0625 nM), and each right panel 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-10AB show analysis of KLK5 inhibitor potency by measuring Kiapp. Various concentrations (0.5, 0.25, 0.125, and 0.0625 nM) of KLK5 inhibitors and 0.0019-10 nM of anti-KLK5 inhibitors were preincubated for 30 minutes before the addition of 300 μM Z-VPR-pNA. Plates were read on a Versamax tunable microplate reader with measurements at 405 nm acquired every 102 seconds over a 3-hour period. The derived Kiapp are summarized in Table 10. The results for KLK5 inhibitors are as follows (each left panel shows the IC50 values ​​of the KLK5 inhibitors at various KLK5 concentrations (0.5, 0.25, 0.125, and 0.0625 nM), and each right panel 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-10AB show analysis of KLK5 inhibitor potency by measuring Kiapp. Various concentrations (0.5, 0.25, 0.125, and 0.0625 nM) of KLK5 inhibitors and 0.0019-10 nM of anti-KLK5 inhibitors were preincubated for 30 minutes before the addition of 300 μM Z-VPR-pNA. Plates were read on a Versamax tunable microplate reader with measurements at 405 nm acquired every 102 seconds over a 3-hour period. The derived Kiapp are summarized in Table 10. The results for KLK5 inhibitors are as follows (each left panel shows the IC50 values ​​of the KLK5 inhibitors at various KLK5 concentrations (0.5, 0.25, 0.125, and 0.0625 nM), and each right panel 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-10AB show analysis of KLK5 inhibitor potency by measuring Kiapp. Various concentrations (0.5, 0.25, 0.125, and 0.0625 nM) of KLK5 inhibitors and 0.0019-10 nM of anti-KLK5 inhibitors were preincubated for 30 minutes before the addition of 300 μM Z-VPR-pNA. Plates were read on a Versamax tunable microplate reader with measurements at 405 nm acquired every 102 seconds over a 3-hour period. The derived Kiapp are summarized in Table 10. The results for KLK5 inhibitors are as follows (each left panel shows the IC50 values ​​of the KLK5 inhibitors at various KLK5 concentrations (0.5, 0.25, 0.125, and 0.0625 nM), and each right panel 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-10AB show analysis of KLK5 inhibitor potency by measuring Kiapp. Various concentrations (0.5, 0.25, 0.125, and 0.0625 nM) of KLK5 inhibitors and 0.0019-10 nM of anti-KLK5 inhibitors were preincubated for 30 minutes before the addition of 300 μM Z-VPR-pNA. Plates were read on a Versamax tunable microplate reader with measurements at 405 nm acquired every 102 seconds over a 3-hour period. The derived Kiapp are summarized in Table 10. The results for KLK5 inhibitors are as follows (each left panel shows the IC50 values ​​of the KLK5 inhibitors at various KLK5 concentrations (0.5, 0.25, 0.125, and 0.0625 nM), and each right panel 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-10AB show analysis of KLK5 inhibitor potency by measuring Kiapp. Various concentrations (0.5, 0.25, 0.125, and 0.0625 nM) of KLK5 inhibitors and 0.0019-10 nM of anti-KLK5 inhibitors were preincubated for 30 minutes before the addition of 300 μM Z-VPR-pNA. Plates were read on a Versamax tunable microplate reader with measurements at 405 nm acquired every 102 seconds over a 3-hour period. The derived Kiapp are summarized in Table 10. The results for KLK5 inhibitors are as follows (each left panel shows the IC50 values ​​of the KLK5 inhibitors at various KLK5 concentrations (0.5, 0.25, 0.125, and 0.0625 nM), and each right panel 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-10AB show analysis of KLK5 inhibitor potency by measuring Kiapp. Various concentrations (0.5, 0.25, 0.125, and 0.0625 nM) of KLK5 inhibitors and 0.0019-10 nM of anti-KLK5 inhibitors were preincubated for 30 minutes before the addition of 300 μM Z-VPR-pNA. Plates were read on a Versamax tunable microplate reader with measurements at 405 nm acquired every 102 seconds over a 3-hour period. The derived Kiapp are summarized in Table 10. The results for KLK5 inhibitors are as follows (each left panel shows the IC50 values ​​of the KLK5 inhibitors at various KLK5 concentrations (0.5, 0.25, 0.125, and 0.0625 nM), and each right panel 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-10AB show analysis of KLK5 inhibitor potency by measuring Kiapp. Various concentrations (0.5, 0.25, 0.125, and 0.0625 nM) of KLK5 inhibitors and 0.0019-10 nM of anti-KLK5 inhibitors were preincubated for 30 minutes before the addition of 300 μM Z-VPR-pNA. Plates were read on a Versamax tunable microplate reader with measurements at 405 nm acquired every 102 seconds over a 3-hour period. The derived Kiapp are summarized in Table 10. The results for KLK5 inhibitors are as follows (each left panel shows the IC50 values ​​of the KLK5 inhibitors at various KLK5 concentrations (0.5, 0.25, 0.125, and 0.0625 nM), and each right panel 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-10AB show analysis of KLK5 inhibitor potency by measuring Kiapp. Various concentrations (0.5, 0.25, 0.125, and 0.0625 nM) of KLK5 inhibitors and 0.0019-10 nM of anti-KLK5 inhibitors were preincubated for 30 minutes before the addition of 300 μM Z-VPR-pNA. Plates were read on a Versamax tunable microplate reader with measurements at 405 nm acquired every 102 seconds over a 3-hour period. The derived Kiapp are summarized in Table 10. The results for KLK5 inhibitors are as follows (each left panel shows the IC50 values ​​of the KLK5 inhibitors at various KLK5 concentrations (0.5, 0.25, 0.125, and 0.0625 nM), and each right panel 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-10AB show analysis of KLK5 inhibitor potency by measuring Kiapp. Various concentrations (0.5, 0.25, 0.125, and 0.0625 nM) of KLK5 inhibitors and 0.0019-10 nM of anti-KLK5 inhibitors were preincubated for 30 minutes before the addition of 300 μM Z-VPR-pNA. Plates were read on a Versamax tunable microplate reader with measurements at 405 nm acquired every 102 seconds over a 3-hour period. The derived Kiapp are summarized in Table 10. The results for KLK5 inhibitors are as follows (each left panel shows the IC50 values ​​of the KLK5 inhibitors at various KLK5 concentrations (0.5, 0.25, 0.125, and 0.0625 nM), and each right panel 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-10AB show analysis of KLK5 inhibitor potency by measuring Kiapp. Various concentrations (0.5, 0.25, 0.125, and 0.0625 nM) of KLK5 inhibitors and 0.0019-10 nM of anti-KLK5 inhibitors were preincubated for 30 minutes before the addition of 300 μM Z-VPR-pNA. Plates were read on a Versamax tunable microplate reader with measurements at 405 nm acquired every 102 seconds over a 3-hour period. The derived Kiapp are summarized in Table 10. The results for KLK5 inhibitors are as follows (each left panel shows the IC50 values ​​of the KLK5 inhibitors at various KLK5 concentrations (0.5, 0.25, 0.125, and 0.0625 nM), and each right panel 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-10AB show analysis of KLK5 inhibitor potency by measuring Kiapp. Various concentrations (0.5, 0.25, 0.125, and 0.0625 nM) of KLK5 inhibitors and 0.0019-10 nM of anti-KLK5 inhibitors were preincubated for 30 minutes before the addition of 300 μM Z-VPR-pNA. Plates were read on a Versamax tunable microplate reader with measurements at 405 nm acquired every 102 seconds over a 3-hour period. The derived Kiapp are summarized in Table 10. The results for KLK5 inhibitors are as follows (each left panel shows the IC50 values ​​of the KLK5 inhibitors at various KLK5 concentrations (0.5, 0.25, 0.125, and 0.0625 nM), and each right panel 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-10AB show analysis of KLK5 inhibitor potency by measuring Kiapp. Various concentrations (0.5, 0.25, 0.125, and 0.0625 nM) of KLK5 inhibitors and 0.0019-10 nM of anti-KLK5 inhibitors were preincubated for 30 minutes before the addition of 300 μM Z-VPR-pNA. Plates were read on a Versamax tunable microplate reader with measurements at 405 nm acquired every 102 seconds over a 3-hour period. The derived Kiapp are summarized in Table 10. The results for KLK5 inhibitors are as follows (each left panel shows the IC50 values ​​of the KLK5 inhibitors at various KLK5 concentrations (0.5, 0.25, 0.125, and 0.0625 nM), and each right panel 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-10AB show analysis of KLK5 inhibitor potency by measuring Kiapp. Various concentrations (0.5, 0.25, 0.125, and 0.0625 nM) of KLK5 inhibitors and 0.0019-10 nM of anti-KLK5 inhibitors were preincubated for 30 minutes before the addition of 300 μM Z-VPR-pNA. Plates were read on a Versamax tunable microplate reader with measurements at 405 nm acquired every 102 seconds over a 3-hour period. The derived Kiapp are summarized in Table 10. The results for KLK5 inhibitors are as follows (each left panel shows the IC50 values ​​of the KLK5 inhibitors at various KLK5 concentrations (0.5, 0.25, 0.125, and 0.0625 nM), and each right panel 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] FIG. 11 shows a table summarizing the IC50 values ​​evaluated and shown in FIGS.

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

[0053] [Figure 13A-1] Figure 13A shows an 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 an 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 regions are also shown according to Kabat numbering. [Figure 13A-2] Figure 13A shows an 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 an 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 regions are also shown according to Kabat numbering. [Figure 13A-3] Figure 13A shows an 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 an 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 regions are also shown according to Kabat numbering. [Figure 13B-1]Figure 13A shows an 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 an 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 regions are also shown according to Kabat numbering. [Figure 13B-2] Figure 13A shows an 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 an 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 regions are also shown according to Kabat numbering. [Figure 13B-3] Figure 13A shows an 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 an 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 regions are also shown according to Kabat numbering. [Figure 13B-4]Figure 13A shows an 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 an 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 regions are also shown according to Kabat numbering.

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

[0055] [Figure 15A] Figure 15A shows an alignment of the light chain variable sequences of anti-KLK5 antibody clone 9H5 and four humanized 9H5 clones. Figure 15B shows an 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. CDR regions according to Kabat numbering are also shown. [Figure 15B-1] Figure 15A shows an alignment of the light chain variable sequences of anti-KLK5 antibody clone 9H5 and four humanized 9H5 clones. Figure 15B shows an 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. CDR regions according to Kabat numbering are also shown. [Figure 15B-2] Figure 15A shows an alignment of the light chain variable sequences of anti-KLK5 antibody clone 9H5 and four humanized 9H5 clones. Figure 15B shows an 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. CDR regions according to Kabat numbering are also shown. [Figure 15B-3] Figure 15A shows an alignment of the light chain variable sequences of anti-KLK5 antibody clone 9H5 and four humanized 9H5 clones. Figure 15B shows an 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. CDR regions according to Kabat numbering are also shown.

[0056] [Figure 16A]Figure 16A shows an alignment of the light chain variable sequences of the anti-KLK5 antibody clone 3-3F5 and five humanized 3-3F5 clones. Figure 16B shows an alignment of the heavy chain variable sequences of the anti-KLK5 antibody clone 3-3F5 and 27 humanized 3-3F5 clones. Amino acid residues highlighted in black are altered residues. The CDR regions according to Kabat numbering are also shown. [Figure 16B-1] Figure 16A shows an alignment of the light chain variable sequences of the anti-KLK5 antibody clone 3-3F5 and five humanized 3-3F5 clones. Figure 16B shows an alignment of the heavy chain variable sequences of the anti-KLK5 antibody clone 3-3F5 and 27 humanized 3-3F5 clones. Amino acid residues highlighted in black are altered residues. The CDR regions according to Kabat numbering are also shown. [Figure 16B-2] Figure 16A shows an alignment of the light chain variable sequences of the anti-KLK5 antibody clone 3-3F5 and five humanized 3-3F5 clones. Figure 16B shows an alignment of the heavy chain variable sequences of the anti-KLK5 antibody clone 3-3F5 and 27 humanized 3-3F5 clones. Amino acid residues highlighted in black are altered residues. The CDR regions according to Kabat numbering are also shown. [Figure 16B-3] Figure 16A shows an alignment of the light chain variable sequences of the anti-KLK5 antibody clone 3-3F5 and five humanized 3-3F5 clones. Figure 16B shows an alignment of the heavy chain variable sequences of the anti-KLK5 antibody clone 3-3F5 and 27 humanized 3-3F5 clones. Amino acid residues highlighted in black are altered residues. The CDR regions according to Kabat numbering are 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% residual, and buffer (starvation media) alone (gray circles) was set to 0% residual. Dose-response curves are shown for Spink5.Fc (black circles and black dotted line), humanized 3.3F5 (black diamonds and black solid line) anti-KLK5 antibody, humanized 9H5 anti-KLK5 antibody (solid gray squares and gray solid line), and humanized 10C5 anti-KLK5 antibody (open black circles and black dotted line). Data shown are the mean ± standard deviation of at least three independent experiments.

[0058] [Figure 18A] Figure 18A shows the overlap of human KLK5 with the KLK5-10C5 Fab complex. Figure 18B shows the interface between human KLK5 and 10C5 Fab. The numbering of amino acid residues in human KLK5 is based on the standard numbering of proteases. See Debela et al., J Mol Biol 373:1017-1031 (2007). The numbering of amino acid residues in the Fab fragment is based on Kabat. [Figure 18B] Figure 18A shows the overlap of human KLK5 with the KLK5-10C5 Fab complex. Figure 18B shows the interface between human KLK5 and 10C5 Fab. The numbering of amino acid residues in human KLK5 is based on the standard numbering of proteases. See Debela et al., J Mol Biol 373:1017-1031 (2007). The numbering of amino acid residues in 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 numbering of amino acid residues in human KLK5 is based on the standard numbering of proteases. The numbering of amino acid residues in 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 numbering of amino acid residues in human KLK5 is based on the standard numbering of proteases. The numbering of amino acid residues in 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 3-3F5 Fab. The numbering of amino acid residues in human KLK5 is based on the standard numbering of proteases. The numbering of amino acid residues in 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 3-3F5 Fab. The numbering of amino acid residues in human KLK5 is based on the standard numbering of proteases. The numbering of amino acid residues in the Fab fragment is based on Kabat. DETAILED DESCRIPTION OF THE INVENTION

[0061] I. Definition The terms "anti-KLK5 antibody" and "antibody that binds to KLK5" refer to an antibody that is capable of binding to KLK5 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting KLK5. In some embodiments, the extent of binding of an 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, as measured, for example, by radioimmunoassay (RIA). In some embodiments, an antibody that binds to KLK5 has an affinity of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM, or ≦0.001 nM (e.g., 10 -8 M or less, e.g. 10 -8 M~10 -13 M, e.g. 10 -9 M~10 -13 In some embodiments, antibodies that bind to KLK5 have 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~10 -13 M, e.g. 10 -9 M~10 -13 M) IC 50 value (the concentration of an inhibitor, such as an antibody or fragment thereof, required to reduce the rate of an enzymatic reaction by 50%). 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 a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired antigen-binding activity.

[0063] The term "isolated" as used with respect to an antibody, binding polypeptide, polynucleotide, or small molecule refers to one that is separated from components of its natural environment. In some embodiments, the antibody, binding polypeptide, polynucleotide, or small molecule is purified to greater than 95% or 99% purity, 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 assessing antibody purity, see, e.g., Flatman et al., J. Chromatogr. B 848:79-87 (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 comprising the population are identical and / or bind to the same binding region (e.g., epitope) except for possible variant antibodies (e.g., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such mutations usually being present in small amounts). In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody in a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and should not be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies described herein may be produced by a variety of techniques, including, but not limited to, hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or portions of human immunoglobulin loci, including, but not limited to, such methods and other exemplary methods for producing monoclonal antibodies.

[0065] A "blocking antibody" or "antagonist antibody" is one that inhibits or reduces the biological activity of the antigen to which it binds. Preferred blocking or antagonist antibodies substantially or completely inhibit the biological activity of the antigen.

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

[0067] The terms "full-length antibody," "intact antibody," and "whole antibody" are used interchangeably herein to refer to an antibody (e.g., an anti-KLK5 antibody) having a structure substantially identical to that of a native antibody or having a heavy chain containing an Fc region.

[0068] A "human antibody" is an antibody having an amino acid sequence that corresponds to that of an antibody produced by a human or human cell, or an antibody derived from a non-human source using the human antibody repertoire or other human antibody-encoding sequences. This definition of human antibody specifically excludes human antibodies that contain non-human antigen-binding residues.

[0069] A "humanized" antibody refers to a chimeric antibody comprising amino acid residues from non-human HVRs and amino acid residues from human FRs. In some embodiments, a humanized antibody comprises substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to those of a non-human antibody and all or substantially all of the FRs correspond to those of a human antibody. A humanized antibody may optionally comprise at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[0070] "Native antibodies" refer to naturally occurring immunoglobulin molecules with various structures. For example, native IgG antibodies are heterotetrameric glycoproteins of approximately 150,000 daltons, consisting of two identical light chains and two identical heavy chains that are disulfide-bonded. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or a 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 a light chain variable domain, followed by a constant light (CL) domain. The light chain of an antibody may be assigned to one of two types, called kappa (κ) or lambda (λ), based on the amino acid sequence of its constant domain.

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

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

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

[0074] The term "thermodynamic epitope," e.g., in the context of epitope mapping using hydrogen exchange mass spectrometry, refers to those portions of a protein whose main-chain conformational dynamics or local free energy of unfolding changes in response to a specific binding event, such as becoming bound to an antibody. A conformational epitope may or may not be partially or completely contained within a thermodynamic epitope.

[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 defined loops ("hypervariable loops") and / or contains residues that contact the antigen ("antigen contacts"). Generally, antibodies contain six HVRs, three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3). Exemplary HVRs herein include: (a) hypervariable loops occurring at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol., 196:901-917 (1987)); (b) CDRs occurring at amino acid residues 24–34 (L1), 50–56 (L2), 89–97 (L3), 31–35b (H1), 50–65 (H2), and 95–102 (H3) (Kabat et al., "Sequences of Proteins of Immunological Interest," 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991)); (c) antigen contacts occurring at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al., J. Mol. Biol., 262:732-745 (1996)); 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 in the variable domain (e.g., FR residues) are numbered herein according to Kabat et al., supra, e.g., as set forth in Figures 13-16 and in the Sequence Listing herein below. Unless otherwise specified, CDRs are determined according to Kabat et al., supra.

[0076] The term "variable region" or "variable domain" refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to an antigen. The heavy and light chain variable domains (VH and VL, respectively) of natural antibodies generally have similar structures, with each domain containing four conserved framework regions (FR) and three hypervariable regions (HVR). (See, e.g., Kindt et al., "Kuby Immunology," 6th ed., W.H. Freeman 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, respectively, using a VH or VL domain from an antibody that binds to that antigen. See, for example, Portolano et al., J. Immunol., 150:880-887 (1993); Clarkson et al., Nature, 352:624-628 (1991).

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

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

[0079] For purposes herein, an "acceptor human framework" is a framework that comprises the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as defined below. An acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence, or may comprise amino acid sequence changes. In some embodiments, the number of amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or the human consensus framework sequence.

[0080] A "human consensus framework" is a framework that represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is made from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as in Kabat et al., "Sequences of Proteins of Immunological Interest," 5th ed., NIH Publication No. 91-3242, Bethesda, MD (1991), vols. 1-3. In one embodiment, for VL, the subgroup is subgroup kappa I in Kabat et al. (supra). In one embodiment, for VH, the subgroup is subgroup III in Kabat et al. (supra).

[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, 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 a 1:1 interaction between members of a binding pair (e.g., an antibody, binding polypeptide, polynucleotide, small molecule, and antigen). The affinity of molecule X for its partner Y can generally be represented by the 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 matured" antibody refers to an antibody that has one or more alterations in one or more hypervariable regions (HVRs) compared to a parent antibody that does not have such alterations, which improve the affinity of the antibody for antigen.

[0083] A "binding region" is a portion of a binding partner (e.g., an antigen) to which a KLK5 antibody selectively binds. In the case of a binding polypeptide binding partner, a linear binding region can be a peptide portion of about 4 to 15 (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) amino acid residues. A non-linear conformational binding region can include residues of a contiguous polypeptide sequence in the three-dimensional (3D) structure of the binding polypeptide binding partner.

[0084] "Effector functions" refer to biological activities attributable to the Fc region of an antibody, which vary depending on the antibody isotype. Examples of antibody effector functions include: C1q binding and complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g., B cell receptors); and B cell activation.

[0085] As used herein, the terms "KLK5" and "kallikrein 5," unless otherwise indicated, refer to any native KLK5 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). The terms encompass "full-length," unprocessed KLK5 and any form of KLK5 resulting from cellular processing. The terms also encompass naturally occurring variants of KLK5, such as splice variants or allelic variants. In some embodiments, the amino acid sequence of an exemplary human KLK5 is UNIPROT Q9Y337. In some embodiments, the amino acid sequence of an exemplary human KLK5 is selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, 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. In some embodiments, the amino acid sequence of an exemplary human KLK5 is amino acid residues 23-293 (minus the signal peptide) of UNIPROT Q9Y337 (G55, D153 variant) set forth in SEQ ID NO: 2. In some embodiments, the amino acid sequence of an exemplary human KLK5 is amino acid residues 23-293 (minus the signal peptide) of the G55, N153 variant set forth in SEQ ID NO: 4. In some embodiments, the amino acid sequence of an exemplary human KLK5 is amino acid residues 23-293 (minus the signal peptide) of the R55, N153 variant set forth in SEQ ID NO: 6. In some embodiments, the amino acid sequence of an exemplary human KLK5 is amino acid residues 23-293 (minus the signal peptide) of the R55, D153 variant set forth in SEQ ID NO: 8.

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

[0087] The numbering in the following paragraphs is with respect to full-length, unprocessed KLK5. In some embodiments, the nucleic acid sequence of human KLK5 comprises a sequence encoding N at position 153. In some embodiments, the nucleic acid sequence of human KLK5 comprises a sequence encoding D at position 153. In some embodiments, the nucleic acid sequence of human KLK5 comprises a sequence encoding G at position 55. In some embodiments, the nucleic acid sequence of human KLK5 comprises a sequence encoding R at position 55. In some embodiments, the nucleic acid sequence of human KLK5 comprises a sequence encoding G at position 55 and an N at position 153. In some embodiments, the nucleic acid sequence of human KLK5 comprises a sequence encoding G at position 55 and a D at position 153. In some embodiments, the nucleic acid sequence of human KLK5 comprises a sequence encoding R at position 55 and an N at position 153. In some embodiments, the nucleic acid sequence of human KLK5 comprises a sequence encoding R at position 55 and an N at position 153. In some embodiments, the nucleic acid sequence of human KLK5 comprises a sequence encoding R at position 55 and a D at position 153.

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

[0089] As used herein, the term "SPINK fusion polypeptide" refers to a fusion polypeptide in which a SPINK polypeptide or a fragment thereof (e.g., a particular domain of a SPINK polypeptide (e.g., SPINK5 and / or SPINK9)) is linked directly or indirectly 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 particular domain of a SPINK polypeptide (e.g., SPINK5 and / or SPINK9)) is linked directly or indirectly to an Fc region. In some embodiments, the Fc region is selected from the group consisting of an IgG1 Fc region, an IgG2a Fc region, and an IgG4 Fc region. 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 variations, such as insertions, deletions, substitutions, particularly conservative amino acid substitutions, of a SPINK polypeptide, SPINK domain, or Fc that 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 polypeptides provided herein are capable of binding to KLK5, which may result in inhibition of KLK5. 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," unless otherwise specified, refers to any naturally occurring polypeptide of interest (e.g., KLK5 or SPINK5) from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). The term encompasses "full-length," unprocessed polypeptides, as well as any form of the polypeptide that results from processing within a cell. The term also encompasses naturally occurring variants of the polypeptide, such as splice variants or allelic variants.

[0092] "Percent amino acid sequence identity" to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to those in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, without considering any conservative substitutions as part of the sequence identity. Alignment to determine percent amino acid sequence identity can be accomplished in a variety of ways within the skill 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 sequences, including any algorithms necessary to achieve maximum alignment across the entire length of the sequences being compared. However, for purposes herein, percent amino acid sequence identity values ​​are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program is the copyright of Genentech, Inc., and the source code, along with user documentation, has been submitted to the U.S. Copyright Office, Washington, DC 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, CA, or may be compiled from the source code. The ALIGN-2 program should be compiled for use on UNIX operating systems, including Digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary. In situations where ALIGN-2 is used for amino acid sequence comparison, the % amino acid sequence identity of a given amino acid sequence A to, with, or relative to a given amino acid sequence B (alternatively, it can be expressed as a given amino acid sequence A having or containing a certain % amino acid sequence identity to, with, or relative to a given amino acid sequence B) is calculated as follows: Fraction X / Y×100 where X is the number of amino acid residues scored as identity matches by the sequence alignment program ALIGN-2 in this program's alignment of A and B, 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 will not equal the % amino acid sequence identity of B to A. Unless specifically stated otherwise, all % amino acid sequence identity values ​​used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

[0093] As used interchangeably herein, "polynucleotide" or "nucleic acid" refers to a polymer of nucleotides of any length, and includes DNA and RNA. The nucleotides may be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase or by a synthetic reaction. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and their analogs. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after synthesis, such as by conjugation with a label. Other types of modifications include, for example, "caps," substitutions of one or more analogs of naturally occurring nucleotides, internucleotide modifications such as those with uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoamidates, carbamates, etc.) and those with charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.), those containing pendant moieties such as proteins (e.g., nucleases, toxins, antibodies, signal peptides, ply-L-lysine, etc.), those containing intercalators (e.g., acridine, psoralens, etc.), those containing chelators (e.g., metals, radioactive metals, boron, metal oxides, etc.), those containing alkylators, those with modified linkages (e.g., alpha-anomeric nucleic acids, etc.), and unmodified forms of polynucleotide(s). Additionally, any of the hydroxyl groups normally present in the sugar may be replaced by, for example, phosphonate groups, phosphate groups, protected by standard protecting groups, or activated to provide for additional linkage to additional nucleotides, or may be conjugated to a solid or semi-solid support. The 5' and 3' terminal OH can be phosphorylated or substituted with amines or organic capping group moieties of 1 to 20 carbon atoms. Other hydroxyls may also be derivatized to standard protecting groups.Polynucleotides may also contain analogous forms of ribose or deoxyribose sugars commonly known in the art, including, for example, 2'-O-methyl-, 2'-O-allyl, 2'-fluoro-, or 2'-azido-ribose, carbocyclic sugar analogs, α-anomeric sugars, epimeric sugars such as arabinose, xylose, or lyxose, pyranose sugars, furanose sugars, sedoheptulose, acrylic acid analogs, and abasic nucleoside analogs such as methyl riboside. One or more phosphodiester linkages may be replaced by alternative linking groups. These alternative linking groups include, but are not limited to, embodiments in which phosphate is replaced with 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 substituted or unsubstituted alkyl (1-20C) (optionally containing an ether (-O-) linkage), aryl, alkenyl, cycloalkyl, cycloalkenyl, or araldyl. Not all linkages in a polynucleotide need be identical. The foregoing description applies to all polynucleotides referred to herein, including RNA and DNA.

[0094] An "isolated" polynucleotide or nucleic acid refers to a molecule that has been separated from a component of its natural environment. Isolated nucleic acid includes a nucleic acid molecule that is contained in a cell that originally contained the nucleic acid molecule, but where the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.

[0095] An "isolated nucleic acid encoding an anti-KLK5 antibody" refers to one or more nucleic acid molecules encoding the antibody heavy and light chains (or fragments thereof), including such nucleic acid molecule(s) in a single vector or separate vectors, and such nucleic acid molecule(s) present in one or more locations within a host cell.

[0096] As used herein, the term "KLK5 genomic sequence" refers to 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" are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells," which include the primary transformed cell and progeny derived from the primary transformed cell, regardless of the number of passages. The progeny may not be completely identical in nucleic acid content to the parent cell, but may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell are included in the 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. The term includes vectors as autonomously replicating nucleic acid structures and vectors that integrate into the genome of a host cell into which they are introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as "expression vectors."

[0099] As used herein, a "reference sample," "reference cell," "reference tissue," "control sample," "control cell," or "control tissue" refers to a sample, cell, tissue, standard, or level used for comparison purposes. In one embodiment, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and / or non-diseased part (e.g., tissue or cells) of the body of the same subject. For example, a healthy and / or non-diseased cell or tissue adjacent to a diseased cell or tissue (e.g., a cell or tissue adjacent to a tumor). In another embodiment, the reference sample is obtained from untreated tissue and / or cells of the body of the same subject. In yet another embodiment, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and / or non-diseased part (e.g., tissue or cells) of the body of another subject. In yet another embodiment, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from an untreated tissue and / or cells of the body of another subject.

[0100] As used herein, the term "sample" refers to a preparation obtained or derived from a subject of interest that contains cellular and / or other molecular elements to be characterized and / or identified, for example, based on physical, biochemical, chemical, and / or physiological characteristics. For example, the phrase "disease sample" and variations thereof refer to any sample obtained from a subject of interest that is expected to contain or known to contain the cellular and / or molecular entities to be characterized. Samples include, but are not limited to, primary or cultured cells or cell lines, cell supernatants, cell lysates, platelets, serum, plasma, vitreous fluid, lymphatic fluid, 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] A "tissue sample" or "cell sample" refers to a collection of similar cells obtained from a subject's tissue. The source of the tissue or cell sample may be solid tissue, such as from fresh, frozen, and / or preserved organs, tissue samples, biopsies, and / or aspirates; blood or any blood constituents, such as plasma; bodily fluids, such as cerebrospinal fluid, amniotic fluid, peritoneal fluid, or interstitial fluid; or cells from any stage in a subject's pregnancy or development. A tissue sample may also be primary or cultured cells or cell lines. Optionally, a tissue or cell sample is obtained from a diseased tissue / organ. A tissue sample may contain compounds not naturally mixed with natural tissue, such as preservatives, anticoagulants, buffers, fixatives, nutrients, or antibiotics.

[0102] An "effective amount" of an agent, eg, a pharmaceutical formulation, refers to an amount effective, at dosages necessary, for periods of time necessary, to achieve a desired therapeutic result.

[0103] A "subject" is a mammal. Mammals include, but are not limited to, domestic animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In 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.

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

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

[0107] As used herein, the term "Th2-high asthma" refers to asthma that exhibits high levels of one or more Th2 cell-associated cytokines, e.g., IL13, IL4, IL9, IL5, or asthma that exhibits Th2 cytokine-associated inflammation. In some embodiments, the term Th2-high asthma can be used interchangeably with high eosinophilic asthma. In some embodiments, Th2-high asthma is Th2-driven asthma. In some embodiments, the asthma patient has been determined to be Eosinophilic Inflammation Positive (EIP). See, e.g., International Patent Application Publication No. 2015 / 061441, which is incorporated herein by reference in its entirety. In some embodiments, the subject has been determined to have elevated levels of at least one eosinophilic signature gene compared to a control or reference level. See, e.g., International Patent Application Publication No. 2015 / 061441. In some embodiments, Th2-high asthma is high periostin asthma. In some embodiments, the subject has high serum periostin. In some embodiments, the subject is 18 years of age or older. In some embodiments, the subject has been determined to have an elevated serum periostin level compared to a control or reference level. In some embodiments, the control or reference level is the median periostin level in a population. In some embodiments, the subject has been determined to have a serum periostin level of 20 ng / mL or greater. In some embodiments, the subject has been determined to have a serum periostin level of 25 ng / mL or greater. In some embodiments, the subject has been determined to have a serum periostin level of 50 ng / mL or greater. In some embodiments, the control or reference level of 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 has been determined to have an elevated eosinophil count compared to a control or reference level. In some embodiments, the control or reference level is the median level in a population. In some embodiments, the subject has been determined to have an eosinophil count of 150 / μL of blood or greater.In some embodiments, the subject has been determined to have an eosinophil count of 200 / μL blood or greater. In some embodiments, the subject has been determined to have an eosinophil count of 250 / μL blood or greater. In some embodiments, the subject has been determined to have an eosinophil count of 300 / μL blood or greater. In some embodiments, the subject has been determined to have an eosinophil count of 350 / μL blood or greater. In some embodiments, the subject has been determined to have an eosinophil count of 400 / μL blood or greater. In some embodiments, the subject has been determined to have an eosinophil count of 450 / μL blood or greater. In some embodiments, the subject has been determined to have an eosinophil count of 500 / μL blood or greater. In some preferred embodiments, the subject has an eosinophil count of 300 / μL blood or greater. 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 instances, the subject exhibits FeNO levels greater than about any of 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 instances, the subject has an IgE level greater 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 that exhibits low levels of one or more Th2 cell-associated cytokines, e.g., IL13, IL4, IL9, IL5, or asthma that exhibits non-Th2 cytokine-associated inflammation. In some embodiments, the term Th2-low asthma can be used interchangeably with hypoeosinophilic asthma. In some embodiments, the asthma patient has been determined to be eosinophilic inflammation negative (EIN). See, e.g., WO 2015 / 061441. In some embodiments, Th2-low asthma is Th17-driven asthma. In some embodiments, the Th2-low asthma is low-periostin asthma. In some embodiments, the subject is 18 years of age or older. In some embodiments, the subject has been determined to have a decreased serum periostin level compared to a control or reference level. In some embodiments, the control or reference level is the median periostin level in a population. In some embodiments, the subject has been determined to have a serum periostin level of less than 20 ng / mL. In some embodiments, the asthma is hypoeosinophilic asthma. In some embodiments, the subject has been determined to have a decreased eosinophil count compared to a control or reference level. In some embodiments, the control or reference level is the median level in a population. In some embodiments, the subject has been determined to have an eosinophil count of less than 150 / μL of blood. In some embodiments, the subject has been determined to have an eosinophil count of less than 100 / μL of blood. In certain preferred embodiments, the subject has been determined to have an eosinophil count of less than 300 / μL of blood.

[0109] "Treatment" (and variations such as "treat" or "treating") refers to clinical intervention in an attempt to alter the natural history of the subject or cell being treated. Desirable effects of treatment include one or more of: prevention of disease onset or recurrence, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of disease, stable disease (i.e., not worsening), reduced rate of disease progression, amelioration or palliation of disease symptoms, prolongation of survival compared to expected survival if not receiving treatment, and improved prognosis.

[0110] The term "package insert" is used to refer to instructions customarily included in commercial packaging of therapeutic products that contain information about the indications, uses, dosages, administration, concomitant therapies, contraindications, and / or warnings regarding the use of such therapeutic product.

[0111] In the context of the embodiments described herein, use of the terms "a," "an," and "the," and similar terms, should be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" should be construed as open-ended terms (i.e., meaning "including, but not limited to"), unless otherwise indicated. Aspects and embodiments provided herein are understood to include "consisting of" and / or "consisting essentially of" aspects and embodiments.

[0112] As will be understood by one of ordinary skill in the art, reference herein to "about" a value or parameter includes (and describes) embodiments directed to that value or parameter itself. For example, a statement referring to "about X" includes a statement of "X."

[0113] The phrase "substantially different," as used herein, refers to a sufficiently high difference between two numerical values ​​(typically one associated with a molecule and the other associated with a reference / comparator molecule) such that one of skill in the art would consider the difference between the two values ​​to be statistically significant with respect to the biological characteristic measured by such values ​​(e.g., Kd values). The difference between the two values ​​can 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 for the reference / comparator molecule.

[0114] II. Compositions and Methods In one aspect, the present invention is based, in part, on the discovery of KLK5 antibodies that inhibit the biological activity of KLK5. In some embodiments, antibodies that bind to KLK5 are provided. In some embodiments, isolated antibodies that bind to KLK5, i.e., anti-KLK5 antibodies, are provided. In some embodiments, the anti-KLK5 antibodies inhibit the biological activity of KLK5. In some embodiments, the anti-KLK5 antibodies substantially or completely inhibit 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 KLK5-promoted proliferation and contraction of human smooth muscle cells. In some embodiments, the biological activity of KLK5 is 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 chemotactic 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 of the anti-KLK5 antibodies, 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 of the anti-KLK5 antibodies, the anti-KLK5 antibody has an IC of less than about 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 In some embodiments, the anti-KLK5 antibody has an IC value of less 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 In some embodiments, the anti-KLK5 antibody has an IC value of about any of 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 example, for the diagnosis or 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 persistent, chronic, severe asthma accompanied by acute events that worsen symptoms (exacerbations or flare-ups), which can be life-threatening. In some embodiments, the asthma is atopic (also known as allergic) asthma, non-allergic asthma (e.g., often caused by infection with a respiratory virus (e.g., influenza, parainfluenza, rhinovirus, human metapneumovirus, and respiratory syncytial virus) or inhaled irritants (air pollutants, smog, diesel particulates, volatile chemicals and gases, indoors or outdoors, or even from cold, dry air). In some embodiments, the 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 asthma due to aspirin or Asthma caused by new ingestion of an associated NSAID. In some embodiments, the 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, the asthma is chronic corticosteroid-resistant asthma, corticosteroid-refractory asthma, asthma uncontrolled with corticosteroids, or asthma uncontrolled with other chronic asthma control medications. In some embodiments, the asthma is moderate to severe asthma. In some embodiments, the asthma is Th2-high asthma. In some embodiments, the asthma is severe asthma.In some embodiments, the asthma is atopic asthma, allergic asthma, non-allergic asthma (e.g., due to infection and / or respiratory syncytial virus (RSV)), exercise-induced asthma, aspirin-sensitive / exacerbated asthma, mild asthma, moderate-to-severe asthma, corticosteroid-naive asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, newly diagnosed untreated asthma, smoking-related asthma, or corticosteroid-uncontrolled asthma. In some embodiments, the asthma is T helper lymphocyte type 2 (Th2) asthma or type 2 (Th2)-high asthma, or type 2 (T2)-driven asthma. In some embodiments, the asthma is eosinophilic asthma. In some embodiments, the asthma is allergic asthma. In some embodiments, the subject has been determined to be eosinophilic inflammation positive (EIP). See WO 2015 / 061441. In some embodiments, the asthma is high-periostin 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, the asthma is high-eosinophil asthma (e.g., having an eosinophil count of at least about 150, 200, 250, 300, 350, or 400 / mL of blood). In some embodiments, the asthma is Th2-low asthma or non-Th2-driven asthma. In some embodiments, the subject has been determined to be eosinophil inflammation negative (EIN). See WO 2015 / 061441. In some embodiments, the asthma is low-periostin asthma (e.g., having a periostin concentration of less than about 20 ng / mL of serum). In some embodiments, the asthma is low-eosinophil asthma (e.g., having an eosinophil count of less than about 150 / μL of blood or less than about 100 / μL of blood).

[0118] A. Exemplary Anti-KLK5 Antibodies An isolated antibody that binds to KLK5 is 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 that is expressed in human skin, particularly in the upper spinous and granular layers of the skin. It is known that KLK5 plays 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 the human KLK5 precursor protein having a signal peptide containing one or both of the 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 certain embodiments, the anti-KLK5 antibody has one or more of the following characteristics, in any combination: a) inhibiting 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 the serine protease activity of KLK5; c) specific binding to human KLK5; d) IC 50 a value of 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 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, 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 aspect, 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 aspect, 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 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. In one embodiment, the antibody comprises HVR-H3 comprising an amino acid sequence selected from any one of SEQ ID NOs: 62-72. In another embodiment, the antibody comprises HVR-H3 comprising an amino acid sequence selected from any one of SEQ ID NOs: 62-72, and HVR-L3 comprising an amino acid sequence selected from any one of SEQ ID NOs: 112-122. In a further embodiment, the antibody comprises an HVR-H3 comprising an amino acid sequence selected from any one of SEQ ID NOs: 62 to 72, an HVR-L3 comprising an amino acid sequence selected from any one of SEQ ID NOs: 112 to 122, and an HVR-H2 comprising an amino acid sequence selected from any one of SEQ ID NOs: 32 to 53. In a further embodiment, the antibody comprises (a) an HVR-H1 comprising an amino acid sequence selected from any one of SEQ ID NOs: 14 to 24, (b) an HVR-H2 comprising an amino acid sequence selected from any one of SEQ ID NOs: 32 to 53, and (c) an HVR-H3 comprising an amino acid sequence selected from any one of SEQ ID NOs: 62 to 72.

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

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

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

[0126] In another aspect, an anti-KLK5 antibody is provided, comprising a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from any one of SEQ ID NOs: 170 to 257. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to an amino acid sequence selected from any one of SEQ ID NOs: 170 to 257 contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising such a 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 any one of SEQ ID NOs: 170 to 257. In certain embodiments, the substitutions, insertions, or deletions occur within regions outside the HVRs (i.e., within the FRs). Optionally, 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 aspect, 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 to an amino acid sequence selected from any one of SEQ ID NOs: 131 to 161. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to an amino acid sequence selected from any one of SEQ ID NOs: 131 to 162 contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the amino acid sequence selected from any one of SEQ ID NOs: 131-162. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., within the FRs). Optionally, the anti-KLK5 antibody comprises a VL sequence of an amino acid sequence selected from any one of SEQ ID NOs: 131-162, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from: (a) HVR-L1 comprising an amino acid sequence selected from any one of SEQ ID NOs: 79-91; (b) HVR-L2 comprising an amino acid sequence selected from any one of SEQ ID NOs: 99-106; and (c) HVR-L3 comprising an amino acid sequence selected from any one of SEQ ID NOs: 112-122.

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

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

[0130] In another aspect, 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 another aspect, 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 comprises the HC and LC sequences of SEQ ID NOs: 288 and 265, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the HC and LC sequences of SEQ ID NOs: 289 and 266, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the HC and LC sequences of SEQ ID NOs: 290 and 267, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the HC and LC sequences of SEQ ID NOs: 292 and 269, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the HC and LC sequences of SEQ ID NOs: 293 and 269, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the HC and LC sequences of SEQ ID NOs: 294 and 270, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the HC and LC sequences of SEQ ID NOs: 295 and 271, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the HC and LC sequences of SEQ ID NOs: 296 and 272, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the HC and LC sequences of SEQ ID NOs: 297 and 273, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the HC and LC sequences of SEQ ID NOs: 299 and 275, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the HC and LC sequences of SEQ ID NOs: 300 and 275, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the HC and LC sequences of SEQ ID NOs: 301 and 276, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the HC and LC sequences of SEQ ID NOs: 302 and 277, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the HC and LC sequences of SEQ ID NOs: 303 and 278, respectively, including post-translational modifications of those sequences.In one embodiment, the antibody comprises the HC and LC sequences of SEQ ID NO: 305 and SEQ ID NO: 280, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the HC and LC sequences of SEQ ID NO: 306 and SEQ ID NO: 280, respectively, including post-translational modifications of those sequences.

[0132] Provided herein are antibodies comprising a light chain variable domain comprising the HVR1-LC, HVR2-LC, and HVR3-LC sequences according to Kabat numbering as depicted in Figure 14A, Figure 15A, and / or Figure 16A, and a heavy chain variable domain comprising the HVR1-HC, HVR2-HC, and HVR3-HC sequences according to Kabat numbering as depicted in Figure 14B, Figure 15B, and / or Figure 16B. In some embodiments, the antibody comprises a light chain variable domain comprising the HVR1-LC, HVR2-LC, and / or HVR3-LC sequences, and the FR1-LC, FR2-LC, FR3-LC, and / or FR4-LC sequences depicted in Figure 14A, Figure 15A, and / or Figure 16A. In some embodiments, the antibody comprises a heavy chain variable domain comprising the HVR1-HC, HVR2-HC, and / or HVR3-HC sequences, and the FR1-HC, FR2-HC, FR3-HC, and / or FR4-HC sequences depicted in Figure 14B, Figure 15B, and / or Figure 16B.

[0133] In a further aspect, anti-KLK5 antibodies are provided that bind to the same epitope as the anti-KLK5 antibodies provided herein.

[0134] In a further aspect, an anti-KLK5 antibody is provided that, when bound to KLK5, yields a thermodynamic epitope comprising one or more of the 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 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 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., an 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 class or isotype as defined herein.

[0136] In further aspects, anti-KLK5 antibodies according to any of the above embodiments may incorporate any of the features described below, either alone or in combination.

[0137] Antibodies 10C5, 9H5, 3-3F5, and other embodiments In one aspect, 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 aspect, an anti-KLK5 antibody is provided that comprises 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 aspect, an anti-KLK5 antibody is provided that comprises 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 comprises an HVR-H3 comprising the amino acid sequence of SEQ ID NO:65, SEQ ID NO:69, or SEQ ID NO:72, an HVR-L3 comprising the amino acid sequence of SEQ ID NO:115, SEQ ID NO:119, or SEQ ID NO:122, and an 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. In further embodiments, the antibody comprises (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO:17, SEQ ID NO:22, or SEQ ID NO:24, (b) an 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) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:65, SEQ ID NO:69, or SEQ ID NO:72.

[0140] In another aspect, 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 aspect, 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 aspect, an anti-KLK5 antibody is provided, comprising: (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.

[0143] In another aspect, 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 aspect, an anti-KLK5 antibody is provided, comprising: (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.

[0145] In another aspect, 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 aspect, an anti-KLK5 antibody is provided, comprising: (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.

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

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

[0149] In another aspect, an anti-KLK5 antibody is provided, comprising a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 201. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising such a 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 a region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody comprises the VH sequence of SEQ ID NO: 201, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three HVRs 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.

[0150] In another aspect, 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 to the amino acid sequence of SEQ ID NO: 139. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 139. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., within the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence of SEQ ID NO: 139, including 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: 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.

[0151] In another aspect, an anti-KLK5 antibody is provided, wherein 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 and VL sequences of SEQ ID NO:201 and SEQ ID NO:139, respectively, including post-translational modifications of those sequences.

[0152] In a further aspect, 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 of the 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 aspect, an anti-KLK5 antibody is provided, comprising a heavy chain variable domain (VH) sequence having SEQ ID NO: 225. In another aspect, an anti-KLK5 antibody is provided, comprising a light chain variable domain (VL) sequence having SEQ ID NO: 151.

[0154] In another aspect, 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 another aspect, 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 aspect, an anti-KLK5 antibody is provided, comprising a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 221. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising such a 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 a region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody comprises the VH sequence of SEQ ID NO: 221, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three 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, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69.

[0156] In another aspect, 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 to the amino acid sequence of SEQ ID NO: 149. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 149. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., within the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence of SEQ ID NO: 149, including 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 aspect, an anti-KLK5 antibody is provided, wherein 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 and VL sequences of SEQ ID NO: 221 and SEQ ID NO: 149, respectively, including post-translational modifications of those sequences.

[0157] In a further aspect, an anti-KLK5 antibody is provided that binds to the same epitope as the anti-KLK5 antibody provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising the VH sequence of SEQ ID NO: 221 and the VL sequence of SEQ ID NO: 149. In certain embodiments, an antibody is provided that, when bound to KLK5, provides a thermodynamic epitope comprising one or more of the 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 aspect, an anti-KLK5 antibody is provided that comprises a heavy chain variable domain (VH) sequence having SEQ ID NO: 257. In another aspect, an anti-KLK5 antibody is provided that comprises a light chain variable domain (VL) sequence having SEQ ID NO: 162.

[0159] In another aspect, 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 another aspect, 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 aspect, an anti-KLK5 antibody is provided, comprising a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 248. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising such a 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 a region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody comprises the VH sequence of SEQ ID NO: 248, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three 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, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 72.

[0161] In another aspect, 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 to the amino acid sequence of SEQ ID NO: 160. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 160. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., within the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence of SEQ ID NO: 160, including 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: 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.

[0162] In another aspect, an anti-KLK5 antibody is provided, wherein 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 and VL sequences of SEQ ID NO:248 and SEQ ID NO:160, respectively, including post-translational modifications of those sequences.

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

[0164] Provided herein are antibodies comprising a light chain variable domain comprising the HVR1-LC, HVR2-LC, and HVR3-LC sequences according to Kabat numbering as depicted in Figure 14A, Figure 15A, and / or Figure 16A, and a heavy chain variable domain comprising the HVR1-HC, HVR2-HC, and HVR3-HC sequences according to Kabat numbering as depicted in Figure 14B, Figure 15B, and / or Figure 16B. In some embodiments, the antibody comprises a light chain variable domain comprising the HVR1-LC, HVR2-LC, and / or HVR3-LC sequences, and the FR1-LC, FR2-LC, FR3-LC, and / or FR4-LC sequences depicted in Figure 14A, Figure 15A, and / or Figure 16A. In some embodiments, the antibody comprises a heavy chain variable domain comprising the HVR1-HC, HVR2-HC, and / or HVR3-HC sequences, and the FR1-HC, FR2-HC, FR3-HC, and / or FR4-HC sequences depicted in Figure 14B, Figure 15B, and / or Figure 16B.

[0165] 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 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 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 other antibody class or isotype as defined herein.

[0167] Further provided herein is 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 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 that includes one or more amino acid residues selected from the group consisting of Pro130, Ser131, Ala132, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Gln174A, Ile176, Asp177, Asp178, Arg224, and Lys233, according to standard protease numbering. In some embodiments, the antibody binds to an epitope on human KLK5 that includes one or more amino acid residues selected from the group consisting of Pro130, Ser131, Ala132, 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 that includes 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] The present specification further provides an antibody that, when bound to human KLK5, causes a conformational change in human KLK5, wherein the conformational change allosterically disrupts the substrate binding site and / or active site of human KLK5.

[0169] In further aspects, anti-KLK5 antibodies according to any of the above embodiments may incorporate any of the features described below, either alone or in combination.

[0170] Antibody 8G10 and Other Embodiments In one aspect, 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 aspect, the 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 aspect, an anti-KLK5 antibody is provided that comprises 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 aspect, 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 aspect, an anti-KLK5 antibody is provided, comprising: (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.

[0174] In another aspect, an anti-KLK5 antibody is provided, comprising a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 170. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising such a 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 a region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody comprises the VH sequence of SEQ ID NO: 170, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three 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, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 62.

[0175] In another aspect, 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 to the amino acid sequence of SEQ ID NO: 131. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising such 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 regions outside the HVRs (i.e., within the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence of SEQ ID NO: 131, including 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: 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.

[0176] In another aspect, an anti-KLK5 antibody is provided, wherein 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 and VL sequences of SEQ ID NO: 170 and SEQ ID NO: 131, respectively, including post-translational modifications of those sequences.

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

[0178] 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 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 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 other antibody class or isotype as defined herein.

[0180] In further aspects, anti-KLK5 antibodies according to any of the above embodiments may incorporate any of the features described below, either alone or in combination.

[0181] Antibody 9B6 and Other Embodiments In one aspect, 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 aspect, the 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 aspect, an anti-KLK5 antibody is provided that comprises 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 aspect, 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 aspect, an anti-KLK5 antibody is provided, comprising: (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.

[0185] In another aspect, an anti-KLK5 antibody is provided, comprising a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 171. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising such a 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 a region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody comprises the VH sequence of SEQ ID NO: 171, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three 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, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63.

[0186] In another aspect, 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 to the amino acid sequence of SEQ ID NO: 132. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 132. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., within the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence of SEQ ID NO: 132, including 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: 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.

[0187] In another aspect, an anti-KLK5 antibody is provided, wherein 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 and VL sequences of SEQ ID NO: 171 and SEQ ID NO: 132, respectively, including post-translational modifications of those sequences.

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

[0189] 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 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 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 other antibody class or isotype as defined herein.

[0191] In further aspects, anti-KLK5 antibodies according to any of the above embodiments may incorporate any of the features described below, either alone or in combination.

[0192] Antibody 2-3F4 and Other Embodiments In one aspect, 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 aspect, the 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 aspect, an anti-KLK5 antibody is provided that comprises 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 aspect, 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 aspect, an anti-KLK5 antibody is provided, comprising: (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.

[0196] In another aspect, an anti-KLK5 antibody is provided, comprising a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 172. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising such a 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 a region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody comprises the VH sequence of SEQ ID NO: 172, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three 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, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 64.

[0197] In another aspect, 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 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 compared to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 133. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside 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 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: 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, wherein 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 and VL sequences 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 antibody provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising the VH 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 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.

[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 other antibody class or isotype as defined herein.

[0202] In further aspects, anti-KLK5 antibodies according to any of the above embodiments may incorporate any of the features described below, either alone or in combination.

[0203] Antibody 10C5 and Other Embodiments In one aspect, 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, (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 aspect, the 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 aspect, an anti-KLK5 antibody is provided that comprises 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 aspect, 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 aspect, an anti-KLK5 antibody is provided, comprising: (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.

[0207] In another aspect, an anti-KLK5 antibody is provided, comprising a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 201. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising such a 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 a region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody comprises the VH sequence of SEQ ID NO: 201, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three HVRs 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.

[0208] In another aspect, 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 to the amino acid sequence of SEQ ID NO: 139. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 139. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., within the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence of SEQ ID NO: 139, including 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: 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.

[0209] In another aspect, an anti-KLK5 antibody is provided, wherein 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 and VL sequences of SEQ ID NO:201 and SEQ ID NO:139, respectively, including post-translational modifications of those sequences.

[0210] In a further aspect, an anti-KLK5 antibody is provided that binds to the same epitope as the anti-KLK5 antibody provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising the VH sequence of SEQ ID NO: 201 and the VL sequence of SEQ ID NO: 139. In certain embodiments, an antibody is provided that, when bound to KLK5, provides a thermodynamic epitope comprising one or more of the 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 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 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 comprises a VH domain comprising one or more heavy chain framework sequences selected from (a) heavy chain framework region 1 (HC-FR1) of SEQ ID NO: 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 comprises a VH domain comprising an HC-FR1 of SEQ ID NO: 333. In one embodiment, the anti-KLK5 antibody comprises a VH domain comprising an HC-FR2 of SEQ ID NO: 334. In one embodiment, the anti-KLK5 antibody comprises a VH domain comprising an HC-FR3 of SEQ ID NO: 335. In one embodiment, the anti-KLK5 antibody comprises a VH domain comprising an HC-FR4 of SEQ ID NO: 336.

[0214] In one embodiment, the anti-KLK5 antibody comprises a VL domain comprising one or more light chain framework sequences selected from (a) light chain framework region 1 (LC-FR1) of SEQ ID NO: 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 comprises a VL domain comprising an LC-FR1 of SEQ ID NO: 329. In one embodiment, the anti-KLK5 antibody comprises a VL domain comprising an LC-FR2 of SEQ ID NO: 330. In one embodiment, the anti-KLK5 antibody comprises a VL domain comprising an LC-FR3 of SEQ ID NO: 331. In one embodiment, the anti-KLK5 antibody comprises a VL domain comprising an LC-FR4 of SEQ ID NO: 332.

[0216] 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 other antibody class or isotype as defined herein.

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

[0218] Further provided herein is an antibody that, upon binding to human KLK5, induces a conformational change in human KLK5, which conformational change allosterically disrupts the substrate-binding site and / or active site of human KLK5. In one embodiment, the antibody comprises (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 17, (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 35, (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 65, (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 82, (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101, and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 115. In one embodiment, the antibody comprises the VH and VL sequences of SEQ ID NO: 201 and SEQ ID NO: 139.

[0219] In further aspects, anti-KLK5 antibodies according to any of the above embodiments may incorporate any of the features described below, either alone or in combination.

[0220] Antibody 2B11 and Other Embodiments In one aspect, 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: 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 one, at least two, or all three 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, an anti-KLK5 antibody is provided that comprises 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: 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 aspect, 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 aspect, an anti-KLK5 antibody is provided, comprising: (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.

[0224] In another aspect, an anti-KLK5 antibody is provided, comprising a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 203. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising such a 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 a region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody comprises the VH sequence of SEQ ID NO: 203, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three 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, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 66.

[0225] In another aspect, 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 to the amino acid sequence of SEQ ID NO: 141. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 141. In certain embodiments, the substitutions, insertions, or deletions occur in a region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody comprises the VL sequence of SEQ ID NO: 141, including 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: 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.

[0226] In another aspect, an anti-KLK5 antibody is provided, wherein 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 and VL sequences of SEQ ID NO:203 and SEQ ID NO:141, respectively, including post-translational modifications of those sequences.

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

[0228] 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 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 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 other antibody class or isotype as defined herein.

[0230] In further aspects, anti-KLK5 antibodies according to any of the above embodiments may incorporate any of the features described below, either alone or in combination.

[0231] Antibody 10H3 and Other Embodiments In one aspect, 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 aspect, the 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 aspect, an anti-KLK5 antibody is provided that comprises 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 aspect, 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 aspect, an anti-KLK5 antibody is provided, comprising: (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.

[0235] In another aspect, an anti-KLK5 antibody is provided, comprising a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 204. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising such a 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 a region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody comprises the VH sequence of SEQ ID NO: 204, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three 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, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 67.

[0236] In another aspect, 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 to the amino acid sequence of SEQ ID NO: 142. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 142. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., within the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence of SEQ ID NO: 142, including 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: 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.

[0237] In another aspect, an anti-KLK5 antibody is provided, wherein 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 and VL sequences of SEQ ID NO:204 and SEQ ID NO:142, respectively, including post-translational modifications of those sequences.

[0238] In a further aspect, an anti-KLK5 antibody is provided that binds to the same epitope as the anti-KLK5 antibody provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising the VH sequence of SEQ ID NO: 204 and the VL sequence of SEQ ID NO: 142. In certain embodiments, an antibody is provided that, when bound to KLK5, provides a thermodynamic epitope comprising one or more of the 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 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 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 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 other antibody class or isotype as defined herein.

[0241] In further aspects, anti-KLK5 antibodies according to any of the above embodiments may incorporate any of the features described below, either alone or in combination.

[0242] Antibody 9H3 and Other Embodiments In one aspect, 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 aspect, the 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 aspect, an anti-KLK5 antibody is provided that comprises 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 aspect, 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 aspect, an anti-KLK5 antibody is provided, comprising: (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.

[0246] In another aspect, an anti-KLK5 antibody is provided, comprising a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 205. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising such a 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 a region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody comprises the VH sequence of SEQ ID NO: 205, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three 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, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 68.

[0247] In another aspect, 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 to the amino acid sequence of SEQ ID NO: 143. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 143. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., within the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence of SEQ ID NO: 143, including 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: 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.

[0248] In another aspect, an anti-KLK5 antibody is provided, wherein 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 and VL sequences of SEQ ID NO: 205 and SEQ ID NO: 143, respectively, including post-translational modifications of those sequences.

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

[0250] 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 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 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 other antibody class or isotype as defined herein.

[0252] In further aspects, anti-KLK5 antibodies according to any of the above embodiments may incorporate any of the features described below, either alone or in combination.

[0253] Antibody 8B7 and Other Embodiments In one aspect, 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 aspect, the 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 aspect, an anti-KLK5 antibody is provided that comprises 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 aspect, 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 aspect, an anti-KLK5 antibody is provided, comprising: (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.

[0257] In another aspect, an anti-KLK5 antibody is provided, comprising a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 206. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising such a 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 a region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody comprises the VH sequence of SEQ ID NO: 206, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three 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, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69.

[0258] In another aspect, 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 to the amino acid sequence of SEQ ID NO: 144. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 144. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., within the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence of SEQ ID NO: 144, including 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: 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.

[0259] In another aspect, an anti-KLK5 antibody is provided, wherein 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 and VL sequences of SEQ ID NO:206 and SEQ ID NO:144, respectively, including post-translational modifications of those sequences.

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

[0261] 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 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 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 other antibody class or isotype as defined herein.

[0263] In further aspects, anti-KLK5 antibodies according to any of the above embodiments may incorporate any of the features described below, either alone or in combination.

[0264] Antibody 9H5 and Other Embodiments In one aspect, 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 aspect, the 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 aspect, an anti-KLK5 antibody is provided that comprises 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 aspect, 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 aspect, an anti-KLK5 antibody is provided, comprising: (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.

[0268] In another aspect, an anti-KLK5 antibody is provided, comprising a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 221. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising such a 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 a region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody comprises the VH sequence of SEQ ID NO: 221, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three 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, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69.

[0269] In another aspect, 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 to the amino acid sequence of SEQ ID NO: 149. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 149. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., within the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence of SEQ ID NO: 149, including 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.

[0270] In another aspect, an anti-KLK5 antibody is provided, wherein 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 and VL sequences of SEQ ID NO: 221 and SEQ ID NO: 149, respectively, including post-translational modifications of those sequences.

[0271] In a further aspect, an anti-KLK5 antibody is provided that binds to the same epitope as the anti-KLK5 antibody provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising the VH sequence of SEQ ID NO: 221 and the VL sequence of SEQ ID NO: 149. In certain embodiments, an antibody is provided that, when bound to KLK5, provides a thermodynamic epitope comprising one or more of the 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 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 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 comprises a VH domain comprising one or more heavy chain framework sequences selected from (a) heavy chain framework region 1 (HC-FR1) of SEQ ID NO: 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 comprises a VH domain comprising an HC-FR1 of SEQ ID NO: 341. In one embodiment, the anti-KLK5 antibody comprises a VH domain comprising an HC-FR2 of SEQ ID NO: 342. In one embodiment, the anti-KLK5 antibody comprises a VH domain comprising an HC-FR3 of SEQ ID NO: 343. In one embodiment, the anti-KLK5 antibody comprises a VH domain comprising an HC-FR4 of SEQ ID NO: 344.

[0275] In one embodiment, the anti-KLK5 antibody comprises a VL domain comprising one or more light chain framework sequences selected from (a) light chain framework region 1 (LC-FR1) of SEQ ID NO: 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 comprises a VL domain comprising an LC-FR1 of SEQ ID NO: 337. In one embodiment, the anti-KLK5 antibody comprises a VL domain comprising an LC-FR2 of SEQ ID NO: 338. In one embodiment, the anti-KLK5 antibody comprises a VL domain comprising an LC-FR3 of SEQ ID NO: 339. In one embodiment, the anti-KLK5 antibody comprises a VL domain comprising an LC-FR4 of SEQ ID NO: 340.

[0277] 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 other antibody class or isotype as defined herein.

[0278] Further provided herein is an antibody that specifically binds to human KLK5, wherein the antibody binds to an epitope on human KLK5 comprising one or more amino acid residues selected from the group consisting of Pro130, Ser131, Ala132, 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) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22, (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 42, (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69, (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 87, (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 105, and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 119. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO: 221 and SEQ ID NO: 149.

[0279] Further provided herein is an antibody that, when bound to human KLK5, causes a conformational change in human KLK5, wherein the conformational change allosterically disrupts the substrate-binding site and / or active site of human KLK5. In one embodiment, the antibody comprises (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22, (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 42, (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69, (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 87, (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 105, and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 119. In one embodiment, the antibody comprises the VH and VL sequences of SEQ ID NO: 221 and SEQ ID NO: 149.

[0280] In further aspects, anti-KLK5 antibodies according to any of the above embodiments may incorporate any of the features described below, either alone or in combination.

[0281] Antibody 9F2 and Other Embodiments In one aspect, 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 aspect, the 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 aspect, an anti-KLK5 antibody is provided that comprises 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 aspect, 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 aspect, an anti-KLK5 antibody is provided, comprising: (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.

[0285] In another aspect, an anti-KLK5 antibody is provided, comprising a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 226. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising such a 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 a region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody comprises the VH sequence of SEQ ID NO: 226, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three 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, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69.

[0286] In another aspect, 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 to the amino acid sequence of SEQ ID NO: 152. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 152. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., within the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence of SEQ ID NO: 152, including 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: 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.

[0287] In another aspect, an anti-KLK5 antibody is provided, wherein 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 and VL sequences of SEQ ID NO: 226 and SEQ ID NO: 152, respectively, including post-translational modifications of those sequences.

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

[0289] 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 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 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 other antibody class or isotype as defined herein.

[0291] In further aspects, anti-KLK5 antibodies according to any of the above embodiments may incorporate any of the features described below, either alone or in combination.

[0292] Antibody 10C8 and Other Embodiments In one aspect, 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 aspect, the 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 aspect, an anti-KLK5 antibody is provided that comprises 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 aspect, 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 aspect, an anti-KLK5 antibody is provided, comprising: (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.

[0296] In another aspect, an anti-KLK5 antibody is provided, comprising a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 227. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising such a 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 a region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody comprises the VH sequence of SEQ ID NO: 227, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three 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, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 70.

[0297] In another aspect, 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 to the amino acid sequence of SEQ ID NO: 153. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 153. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., within the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence of SEQ ID NO: 153, including 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: 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.

[0298] In another aspect, an anti-KLK5 antibody is provided, wherein 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 and VL sequences of SEQ ID NO: 227 and SEQ ID NO: 153, respectively, including post-translational modifications of those sequences.

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

[0300] 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 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 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 other antibody class or isotype as defined herein.

[0302] In further aspects, anti-KLK5 antibodies according to any of the above embodiments may incorporate any of the features described below, either alone or in combination.

[0303] Antibody 8F5 and Other Embodiments In one aspect, 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 aspect, the 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 aspect, an anti-KLK5 antibody is provided that comprises 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 aspect, 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 aspect, an anti-KLK5 antibody is provided, comprising: (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.

[0307] In another aspect, an anti-KLK5 antibody is provided, comprising a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 228. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising such a 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 a region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody comprises the VH sequence of SEQ ID NO: 228, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three 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, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 71.

[0308] In another aspect, 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 to the amino acid sequence of SEQ ID NO: 154. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 154. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., within the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence of SEQ ID NO: 154, including 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: 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.

[0309] In another aspect, an anti-KLK5 antibody is provided, wherein 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 and VL sequences of SEQ ID NO: 228 and SEQ ID NO: 154, respectively, including post-translational modifications of those sequences.

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

[0311] 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 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 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 other antibody class or isotype as defined herein.

[0313] In further aspects, anti-KLK5 antibodies according to any of the above embodiments may incorporate any of the features described below, either alone or in combination.

[0314] Antibody 3-3F5 and Other Embodiments In one aspect, 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 aspect, the 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 aspect, an anti-KLK5 antibody is provided that comprises 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 aspect, 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 aspect, an anti-KLK5 antibody is provided, comprising: (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.

[0318] In another aspect, an anti-KLK5 antibody is provided, comprising a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 248. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising such a 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 a region outside the HVR (i.e., within the FR). Optionally, the anti-KLK5 antibody comprises the VH sequence of SEQ ID NO: 248, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three 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, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 72.

[0319] In another aspect, 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 to the amino acid sequence of SEQ ID NO: 160. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 160. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., within the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence of SEQ ID NO: 160, including 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: 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.

[0320] In another aspect, an anti-KLK5 antibody is provided, wherein 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 and VL sequences of SEQ ID NO:248 and SEQ ID NO:160, respectively, including post-translational modifications of those sequences.

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

[0322] 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 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 comprises a VH domain comprising one or more heavy chain framework sequences selected from (a) heavy chain framework region 1 (HC-FR1) of SEQ ID NO: 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 comprises a VH domain comprising an HC-FR1 of SEQ ID NO: 349. In one embodiment, the anti-KLK5 antibody comprises a VH domain comprising an HC-FR2 of SEQ ID NO: 350. In one embodiment, the anti-KLK5 antibody comprises a VH domain comprising an HC-FR3 of SEQ ID NO: 351. In one embodiment, the anti-KLK5 antibody comprises a VH domain comprising an HC-FR4 of SEQ ID NO: 352.

[0325] In one embodiment, the anti-KLK5 antibody comprises a VL domain comprising one or more light chain framework sequences selected from (a) light chain framework region 1 (LC-FR1) of SEQ ID NO: 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 comprises a VL domain comprising an LC-FR1 of SEQ ID NO: 345. In one embodiment, the anti-KLK5 antibody comprises a VL domain comprising an LC-FR2 of SEQ ID NO: 346. In one embodiment, the anti-KLK5 antibody comprises a VL domain comprising an LC-FR3 of SEQ ID NO: 347. In one embodiment, the anti-KLK5 antibody comprises a VL domain comprising an LC-FR4 of SEQ ID NO: 348.

[0327] 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 other antibody class or isotype as defined herein.

[0328] Further provided herein are antibodies that specifically bind to human KLK5, wherein the antibodies bind to an epitope on human KLK5 that includes 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) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 24, (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 52, (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 72, (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 91, (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 99, and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 122. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO: 248 and SEQ ID NO: 160.

[0329] Further provided herein is an antibody that, when bound to human KLK5, causes a conformational change in human KLK5, wherein the conformational change allosterically disrupts the substrate-binding site and / or active site of human KLK5. In one embodiment, the antibody comprises (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 24, (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 52, (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 72, (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 91, (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 99, and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 122. In one embodiment, the antibody comprises the VH and VL sequences of SEQ ID NO: 248 and SEQ ID NO: 160.

[0330] In further aspects, anti-KLK5 antibodies according to any of the above embodiments may incorporate any of the features described below, either alone or in combination.

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

[0332] In one embodiment, Kd is measured by a radiolabeled antigen binding assay (RIA). In one embodiment, the RIA is performed using a Fab version of the antibody of interest and its antigen. For example, the solution binding affinity of the Fab for the antigen is measured in the presence of a titration series of unlabeled antigen at a minimum concentration of ( 125I) Fab is equilibrated with labeled antigen, followed by measurement by capturing the bound antigen on a plate coated with an anti-Fab antibody (see, e.g., Chen et al., J. Mol. Biol., vol. 293, pp. 865-881 (1999)). To establish assay conditions, MICROTITER® multiwell plates (Thermo Scientific) are coated overnight with 5 μg / mL of capture anti-Fab antibody (Cappel Labs) in 50 mM sodium carbonate (pH 9.6), followed by blocking with 2% (w / v) bovine serum albumin in PBS for 2-5 hours at room temperature (approximately 23°C). In non-adsorbent plates (Nunc #269620), 100 pM or 26 pM [ 125 [I]-antigen is mixed with serial dilutions of the Fab of interest (e.g., consistent with the evaluation of anti-VEGF antibody Fab-12 in Presta et al., Cancer Res., 57:4593-4599 (1997)). The Fab of interest is then incubated overnight, although this incubation can be continued for a longer period (e.g., approximately 65 hours) to ensure equilibrium is reached. The mixture is then transferred to a capture plate for incubation (e.g., 1 hour) at room temperature. The solution is then removed, and the plate is washed eight times with 0.1% polysorbate 20 (TWEEN-20®) in PBS. Once the plate has dried, 150 μL / well of scintillant (MICROSCINT-20™, Packard) is added, and the plate is counted for 10 minutes on a TOPCOUNT™ gamma counter (Packard). Concentrations of each Fab that result in 20% or less of maximal binding are selected for use in competitive binding assays.

[0333] According to another embodiment, Kd is measured using a BIACORE® surface plasmon resonance assay. For example, assays using a BIACORE®-2000 or BIACORE®-3000 (BIAcore, Inc., Piscataway, NJ) are performed at 25°C using an immobilized antigen CM5 chip with approximately 10 response units (RU). In one embodiment, a carboxymethylated dextran biosensor chip (CM5, BIACORE, Inc.) is activated with N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide 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, pH 4.8, and then injected at a flow rate of 5 μl / min, achieving approximately 10 response units (RU) of the coupled protein. After injection of the antigen, 1 M ethanolamine is injected to block unreacted groups. For kinetic measurements, two-fold serial dilutions of Fab (0.78 nM to 500 nM) are injected in PBS with 0.05% polysorbate 20 (TWEEN-20™) surfactant (PBST) at 25°C at a flow rate of approximately 25 μL / min. The association rate (k オン ) and dissociation rate (k オフ ) is calculated using a simple one-to-one Langmuir binding model (BIACORE® Evaluation Software version 3.2) by simultaneously fitting the association and dissociation sensorgrams. The equilibrium dissociation constant (Kd) is calculated as k オフ / k オン See, for example, Chen et al., J. Mol. Biol., 293, 865-881 (1999). If the on-rate is 10 6 M -1 s -1If greater than , this on-rate can be determined by using a fluorescence quenching technique to measure the increase or decrease in fluorescence emission intensity (excitation = 295 nm, emission = 340 nm, 16 nm bandpass) of 20 nM anti-antigen antibody (Fab form) in PBS (pH 7.2) at 25°C in the presence of increasing concentrations of antigen, as measured in a spectrometer such as a stopped-flow fitted spectrophotometer with a stirred cuvette (Aviv Instruments) or an 8000 series SLM-AMINCO™ spectrophotometer (ThermoSpectronic).

[0334] 3. Antibody fragment In some embodiments, the anti-KLK5 antibodies provided herein are antibody fragments. 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., 9:129-134 (2003). For a review of scFv fragments, see, e.g., Pluckthuen in The Pharmacology of Monoclonal Antibodies, 113, Rosenburg and Moore eds. (Springer-Verlag, New York), 269-315 (1994). See also WO 93 / 16185 and U.S. Pat. Nos. 5,571,894 and 5,587,458. See US Pat. No. 5,869,046 for a description of Fab and F(ab')2 fragments that contain salvage receptor binding epitope residues and have increased half-lives in vivo.

[0335] Bispecific antibodies are antibody fragments having two antigen-binding sites, which may be bivalent or bispecific. See, e.g., EP 404,097, WO 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). Trispecific and tetraspecific antibodies are also described in Hudson et al., Nat. Med., Vol. 9, pp. 129-134 (2003).

[0336] Single-domain antibodies are antibody fragments that contain 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, single-domain antibodies are human single-domain antibodies (Domantis, Inc., Waltham, Massachusetts; see, e.g., U.S. Patent No. 6,248,516 B1).

[0337] Antibody fragments can be produced by a variety of techniques, including, but not limited to, proteolytic digestion of intact antibodies and production by recombinant host cells (e.g., E. coli or phage), as described herein.

[0338] 4. Chimeric and Humanized Antibodies In some embodiments, the anti-KLK5 antibody provided herein is a chimeric antibody. 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 comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate such as a monkey) and a human constant region. In a further example, a chimeric antibody is a "class-switched" antibody whose class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.

[0339] In certain embodiments, a chimeric antibody is a humanized antibody. Generally, humanizing a non-human antibody reduces its immunogenicity to humans while maintaining the specificity and affinity of the parent non-human antibody. Typically, a humanized antibody contains one or more variable domains in which the HVRs, e.g., CDRs (or portions thereof), are derived from a non-human antibody, and the FRs (or portions thereof) are derived from human antibody sequences. Optionally, a humanized antibody also contains at least a portion of a human constant region. In some embodiments, some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived), e.g., to restore or improve antibody specificity or affinity.

[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); 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) (describing grafting of specificity-determining regions (SDRs)); Padlan, Mol. Immunol., vol. 28, pp. 489-498 (1991) ) (describing "resurfacing"); Dall'Acqua et al., Methods, 36:43-60 (2005) (describing "FR shuffling"); and Osbourn et al., Methods, 36:61-68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (describing a "guided selection" approach to FR shuffling).

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

[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., 5, 368-74 (2001) and Lonberg, Curr Opin Immunol., 20, 450-459 (2008).

[0343] Human antibodies can be prepared by administering immunogens to transgenic animals that have been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigen challenge. Such animals typically contain all or part of the human immunoglobulin loci, with endogenous immunoglobulin loci either replaced or present or randomly integrated into the animal's chromosomes as exogenous chromosomes. In such transgenic mice, the endogenous immunoglobulin loci are generally inactivated. For a review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech., 23:1117-1125 (2005). See also, e.g., U.S. Patent Nos. 6,075,181 and 6,150,584, which describe XENOMOUSE™ technology, U.S. Patent No. 5,770,429, which describes HUMAB® technology, U.S. Patent No. 7,041,870, which describes KM MOUSE® technology, and U.S. Patent Application Publication No. 2007 / 0061900, which describes VELOCIMOUSE® technology. The human variable regions 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 heteromyeloma cell lines for producing human monoclonal antibodies have been described. (See, e.g., Kozbor, J. Immunol. 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J. Immunol. 147:86 (1991).) Human antibodies generated via human B cell hybridoma technology are also described in Li et al., Proc. Natl. Acad. Sci. USA 103:3557-3562 (2006). Further methods include, for example, U.S. Patent No. 7,189,826 (describing the production of monoclonal human IgM antibodies from hybridoma cell lines) and Ni, "Xiandai Mianyixue," Vol. 26, No. 4, pp. 265-268 (2006) (describing 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. 185-91 (2005).

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

[0346] 6. Library-derived antibodies Anti-KLK5 antibodies can be isolated by screening combinatorial libraries for antibodies with the desired activity(ies). For example, various methods are known in the art for generating phage display libraries and screening such libraries for antibodies possessing the desired binding properties. Such methods are reviewed, for example, in Hoogenboom et al., Methods in Molecular Biology, vol. 178, pp. 1-37 (O'Brien et al., eds., Human Press, Totowa, NJ, 2001), and are described, for example, in 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 (Lo, eds., Human Press, Totowa, NJ, 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, No. 1-2, pp. 119-132 (2004).

[0347] In one type of phage display method, repertoires of VH and VL genes can be separately cloned by polymerase chain reaction (PCR), randomly recombined into phage libraries, and then screened for antigen-binding phage, as described in Winter et al., Ann. Rev. Immunol., 12:433-455 (1994). Phages typically display antibody fragments, either as single-chain Fv (scFv) fragments or as Fab fragments. Libraries from immunized sources provide high-affinity antibodies to immunogens without the need for hybridoma construction. Alternatively, natural repertoires (e.g., from humans) can be cloned to generate a single source of antibodies against a wide range of non-self and self antigens without any immunization, as described in Griffiths et al., EMBO J, 12:725-734 (1993). Finally, natural libraries can also be generated synthetically by cloning unrearranged V gene segments from stem cells, using PCR primers containing random sequences to encode hypervariable CDR3 regions, and performing rearrangement in vitro, as described by Hoogenboom and Winter, J. Mol. Biol. 227:381-388 (1992). Patent publications describing human antibody phage libraries include, for example: U.S. Pat. No. 5,750,373, and U.S. Patent Application Publication Nos. 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 herein.

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

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

[0351] Engineered antibodies with three or more functional antigen binding sites, including "octopus antibodies," are also included herein (see, eg, US Patent Application Publication No. 2006 / 0025576A1).

[0352] The antibodies or fragments herein also include "dual acting FAbs" or "DAFs" that contain antigen binding sites that bind to KLK5 and another different antigen (see, e.g., U.S. Patent Application Publication No. 2008 / 0069820).

[0353] 7. Antibody Variants In some embodiments, amino acid sequence variants of the anti-KLK5 antibodies provided herein are contemplated. For example, it may be desirable to improve the binding affinity and / or other biological properties of the antibody. Amino acid sequence variants of antibodies may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody or by peptide synthesis. Such modifications include, for example, deletion, and / or insertion, and / or substitution of residues within the amino acid sequence of the antibody. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, so long as the final construct possesses the desired characteristics (e.g., antigen binding).

[0354] a) Substitution, insertion, and deletion variants In some embodiments, anti-KLK5 antibody variants are provided that have one or more amino acid substitutions. Sites of interest for substitutional mutagenesis include HVRs and FRs. 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 as further described below with reference to amino acid side chain classes. Amino acid substitutions can be introduced into the antibody of interest, and the products screened for a 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 common side chain properties. (1) Hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile; (2) Neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) Acidic: Asp, Glu; (4) Basic: His, Lys, Arg; (5) Residues affecting chain orientation: Gly, Pro; (6) Aromatic: Trp, Tyr, Phe.

[0356] Non-conservative substitutions will involve exchanging a member of one of these classes for another class.

[0357] One type of substitutional variant involves substituting one or more hypervariable region residues of a parent antibody (e.g., a humanized or human antibody). Generally, the resulting variant(s) selected for further study will have a modification (e.g., an improvement) in a certain biological property (e.g., increased affinity, reduced immunogenicity) compared to the parent antibody and / or will have substantially retained a certain biological property of the parent antibody. An exemplary substitutional variant is an affinity-matured antibody, which can be conveniently generated using, for example, phage-display-based affinity maturation techniques such as those described herein. Briefly, one or more HVR residues are mutated, and the variant antibodies are displayed on phage and screened for a particular 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 within HVR "hotspots," i.e., residues encoded by codons that undergo frequent mutation during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and / or residues that contact the antigen, and the resulting variant VH or VL are tested for binding affinity. Affinity maturation by constructing and reselecting from secondary libraries is described, for example, in Hoogenboom et al., Methods in Molecular Biology 178:1-37 (O'Brien et al., eds., Human Press, Totowa, NJ (2001)). In some embodiments of affinity maturation, diversity is introduced into the variable genes selected for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis). A secondary library is then created. This library is then screened to identify any antibody variants with the desired affinity. Another method for introducing diversity involves an HVR-directed approach, in which several HVR residues (e.g., 4-6 residues at a time) are randomized. 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 be made in one or more HVRs so long as such modifications do not substantially reduce the ability of the antibody to bind to the antigen. For example, conservative modifications (e.g., conservative substitutions as provided herein) that do not substantially reduce binding affinity may be made in the HVRs. Such modifications may, for example, be outside of the antigen-contact residues within the HVRs. In certain embodiments of the variant VH and VL sequences provided above, each HVR is either unaltered or contains no more than one, two, or three amino acid substitutions.

[0360] A useful method for identifying antibody residues or regions that can be targeted for mutation is called "alanine scanning mutagenesis," as described by Cunningham and Wells (1989), Science 244:1081-1085. In this method, a residue or group of target residues (e.g., charged residues such as Arg, Asp, His, Lys, and Glu) is 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 demonstrate functional sensitivity to the initial substitution. Alternatively, or in addition, a crystal structure of the antigen-antibody complex may be used to identify contact points between the antibody and antigen. Such contact and neighboring residues may be targeted as candidates for substitution or removed. Variants may be screened to determine whether they possess desired properties.

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

[0362] b) Glycosylation variants In certain embodiments, the anti-KLK5 antibodies provided herein are altered to increase or decrease the extent to which the antibody is glycosylated. Addition or deletion of glycosylation sites to an antibody can be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites are created or removed.

[0363] If the antibody contains an Fc region, the carbohydrate attached thereto can be modified. Natural antibodies produced by mammalian cells typically contain branched, biantennary oligosaccharides, which are commonly attached to Asn297 in the CH2 domain of the Fc region via an N-linkage. See, e.g., Wright et al., TIBTECH, vol. 15, pp. 26-32 (1997). The oligosaccharides can include various carbohydrates, such as mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, as well as fucose attached to the GlcNAc in the "stem" of the biantennary oligosaccharide structure. In some embodiments, oligosaccharide modifications can be made to the antibodies of the invention to generate antibody variants with specific, improved properties.

[0364] In some embodiments, anti-KLK5 antibody variants are provided that have carbohydrate structures lacking fucose attached (directly or indirectly) to the Fc region. For example, the amount of fucose in such antibodies may be 1% to 80%, 1% to 65%, 5% to 65%, or 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose in the glycan at Asn297 relative to the sum of all glycans (e.g., complex, hybrid, and high-mannose structures) attached to Asn297, as measured, for example, by MALDI-TOF mass spectrometry as described in WO 2008 / 077546. Asn297 refers to an 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 from position 297, i.e., between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylation variants may have improved ADCC function. See, for example, U.S. Patent Application Publication Nos. 2003 / 0157108 (Presta, L.); 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; WO 2000 / 61739; WO 2001 / 29246; U.S. Patent Application Publication No. 2003 / 0115614; WO 2002 / 0164328; WO 2004 / 0093621; WO 2004 / 0132140; WO 2004 / 0110704; WO 2004 / 0110282; WO 2004 / 0110614; 109865; WO 2003 / 085119; WO 2003 / 084570; WO 2005 / 035586; WO 2005 / 035778; WO 2005 / 053742; WO 2002 / 031140; Okazaki et al., J. Mol. Biol., Vol. 336, pp. 1239-1249 (2004); Yamane-Ohnuki et al., Biotech. Bioeng., Vol. 87, p. 614 (2004).An example of a cell line capable of producing defucosylated antibodies is Lec13, which is deficient in protein fucosylation. Examples include CHO cells (Ripka et al., Arch. Biochem. Biophys., Vol. 249, pp. 533-545 (1986); U.S. Patent Application Publication No. 2003 / 0157108A1, Presta, L; and WO 2004 / 056312A1, Adams et al., particularly in Example 11), and knockout cell lines such as α-1,6-fucosyltransferase gene, FUT8, knockout CHO cells (see, e.g., Yamane-Ohnuki et al., Biotech. Bioeng., Vol. 87, p. 614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., Vol. 94, No. 4, pp. 680-688 (2006); and WO 2003 / 085107).

[0365] Further provided are anti-KLK5 antibody variants having bisected oligosaccharides, for example, where the biantennary oligosaccharide attached to the Fc region of the antibody is bisected by GlcNAc. Such antibody variants may have reduced fucosylation and / or improved ADCC function. Examples of such antibody variants are described, for example, in WO 2003 / 011878 (Jean-Mairet et al.); U.S. Patent No. 6,602,684 (Umana et al.); and U.S. Patent No. 2005 / 0123546 (Umana et al.). Antibody variants having at least one galactose residue in the oligosaccharide attached to the Fc region are also provided. Such antibody variants may have improved CDC function. Such antibody variants are described, for example, in WO 1997 / 30087 (Patel et al.), WO 1998 / 58964 (Raju, S.), and WO 1999 / 22764 (Raju, S.).

[0366] c) Fc region variants In some embodiments, one or more amino acid modifications can be introduced into the Fc region of an anti-KLK5 antibody provided herein, thereby generating an Fc region variant. The Fc region variant can comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3, or IgG4 Fc region) containing an amino acid modification (e.g., substitution) at one or more amino acid positions.

[0367] In some embodiments, the present invention contemplates antibody variants that possess some, but not all, effector functions, making them desirable candidates for uses in which in vivo antibody half-life is important, but certain effector functions (such as complement and ADCC) are unnecessary or deleterious. In vitro and / or in vivo cytotoxicity assays may be performed to confirm reduced / lack of CDC and / or ADCC activity. For example, Fc receptor (FcR) binding assays may be performed to ensure that the antibody lacks FcγR binding (and thus is likely to lack ADCC activity) but retains FcRn binding ability. NK cells, the primary cells for mediating...

Claims

1. An isolated antibody that binds to KLK5, the antibody comprising: (i) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 13; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 31; (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. (ii) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 60; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 77; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 97; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 110; or (iii) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 12; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 61; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 78; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 98; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:

111. an antibody,

2. An antibody described in claim 1, comprising: a) a VH sequence of SEQ ID NO: 169 and a VL sequence of SEQ ID NO: 130; b) a VH sequence of SEQ ID NO: 167 and a VL sequence of SEQ ID NO: 128; or c) a VH sequence of SEQ ID NO: 168 and a VL sequence of SEQ ID NO:

129.

3. An antibody described in claim 1, comprising: a) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 169 and a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 130; b) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 167 and a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 128; or c) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 168 or SEQ ID NO: 254 and a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:

129.

4. An antibody described in any one of claims 1 to 3, which is IgG1 or IgG4.

5. The antibody of any one of claims 1 to 4, wherein the antibody inhibits the biological activity of KLK5 by at least 50% as measured by one or more methods selected from the group consisting of a recombinant KLK5 direct activity assay, a bound pro-KLK1 fluorescent peptide assay, a bound pro-KLK7 fluorescent peptide assay, a pro-KLK1 LC / MS assay, a pro-KLK7 LC / MS assay, and a K i(app) assay.

6. The antibody described in claim 5, wherein the biological activity is the serine protease activity of KLK5.

7. An antibody described in any one of claims 1 to 6, which is a monoclonal antibody.

8. An antibody described in any one of claims 1 to 7, which is a human antibody, a humanized antibody, or a chimeric antibody.

9. An antibody described in any one of claims 1 to 8, wherein the antibody is an antibody fragment that binds to KLK5.

10. An isolated nucleic acid encoding an antibody described in any one of claims 1 to 9.

11. A host cell comprising the nucleic acid described in claim 10.

12. A method for producing an antibody, comprising culturing the host cell described in claim 11 so that the antibody is produced.

13. An immune complex comprising an antibody described in any one of claims 1 to 9.

14. A pharmaceutical formulation comprising an antibody described in any one of claims 1 to 9 and a pharmaceutically acceptable carrier.

15. An antibody described in any one of claims 1 to 9 for use as a pharmaceutical.

16. An antibody described in any one of claims 1 to 9 for use in treating a disease selected from the group consisting of Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis, and rosacea.

17. The antibody of claim 16, wherein the asthma is selected from the group consisting of atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin sensitive / exacerbated asthma, mild asthma, moderate to severe asthma, corticosteroid-naive asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, newly diagnosed untreated asthma, smoking-induced asthma, asthma uncontrolled with corticosteroids, T helper lymphocyte type 2 (Th2) asthma or type 2 (Th2)-high or type 2 (T2)-driven asthma, eosinophilic asthma, high periostin asthma, high eosinophilic asthma, low Th2 asthma or non-Th2-driven asthma, low periostin asthma, and low eosinophilic asthma.

18. The antibody described in claim 17, wherein the asthma is low TH2 asthma.

19. An antibody described in any one of claims 1 to 9 for use in inhibiting the biological activity of KLK5.

20. Use of an antibody described in any one of claims 1 to 9 in the manufacture of a pharmaceutical.

21. The use described in claim 20, wherein the medicament is for the treatment of a disease selected from the group consisting of Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis, and rosacea.

22. The use of claim 21, wherein the asthma is selected from the group consisting of atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin-sensitive / exacerbated asthma, mild asthma, moderate to severe asthma, corticosteroid-naive asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, newly diagnosed untreated asthma, smoking-induced asthma, asthma uncontrolled with corticosteroids, T helper lymphocyte type 2 (Th2) asthma or high type 2 (Th2) asthma or type 2 (T2)-driven asthma, eosinophilic asthma, high periostin asthma, high eosinophilic asthma, low Th2 asthma or non-Th2-driven asthma, low periostin asthma, and low eosinophilic asthma.

23. The use described in claim 22, wherein the asthma is low Th2 asthma.

24. Use of an antibody described in any one of claims 1 to 9 in the manufacture of a pharmaceutical for inhibiting the biological activity of KLK5.

25. A pharmaceutical for treating an individual having a disease, comprising an effective amount of an antibody described in any one of claims 1 to 9, wherein the disease is selected from the group consisting of Netherton syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis, and rosacea.

26. The pharmaceutical composition of claim 25, wherein the asthma is selected from the group consisting of atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin-sensitive / exacerbated asthma, mild asthma, moderate to severe asthma, corticosteroid-naive asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, newly diagnosed untreated asthma, smoking-induced asthma, asthma uncontrolled with corticosteroids, T helper lymphocyte type 2 (Th2) asthma or high type 2 (Th2) asthma or type 2 (T2)-driven asthma, eosinophilic asthma, high periostin asthma, high eosinophilic asthma, low Th2 asthma or non-Th2-driven asthma, low periostin asthma, and low eosinophilic asthma.

27. ​​The pharmaceutical composition described in claim 26, wherein the asthma is low Th2 asthma.

28. A pharmaceutical for inhibiting the biological activity of KLK5 in an individual, comprising an effective amount of the antibody of any one of claims 1 to 9, The biological activity is the serine protease activity of KLK5.

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