Anti-klk5 antibodies and methods of use

Abstract

The invention provides anti-KLK5 antibodies and methods of using the same.

1 . 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 the 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 the 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.   
     
     
         2 . The antibody of  claim 1 , wherein the antibody comprises:
 (a) HVR-H1 comprising the amino acid sequence selected from the group consisting of SEQ ID NO:17, SEQ ID NO:22, and SEQ ID NO:24; (b) HVR-H2 comprising the amino acid sequence selected from the group consisting of SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, and SEQ ID NO:53; (c) HVR-H3 comprising the 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 selected from the group consisting of SEQ ID NO:82, SEQ ID NO:87, and SEQ ID NO:91; (e) HVR-L2 comprising the amino acid sequence selected from the group consisting of SEQ ID NO:99, SEQ ID NO:101, and SEQ ID NO:105; and (f) HVR-L3 comprising the amino acid sequence selected from the group consisting of SEQ ID NO:115, SEQ ID NO:119, and SEQ ID NO:122.   
     
     
         3 . The antibody of  claim 1 , wherein the antibody comprises:
 (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-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; 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.   
     
     
         4 . The antibody of  claim 1 , wherein the antibody comprises a) a VH sequence of SEQ ID NO:202 and a VL sequence of SEQ ID NO:140; b) a VH sequence of SEQ ID NO:225 and a VL sequence of SEQ ID NO:151; or c) a VH sequence of SEQ ID NO:257 and a VL sequence of SEQ ID NO:162. 
     
     
         5 . The antibody of  claim 1 , wherein the antibody comprises a) a VH sequence of SEQ ID NO:201 and a VL sequence of SEQ ID NO:139; b) a VH sequence of SEQ ID NO:221 and a VL sequence of SEQ ID NO:149; or c) a VH sequence of SEQ ID NO:248 or SEQ ID NO:254, and a VL sequence of SEQ ID NO:160. 
     
     
         6 . An isolated antibody that binds to KLK5, wherein the antibody comprises a) a VH sequence having at least 95% sequence identity 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. 
     
     
         7 . An isolated antibody that binds to KLK5, wherein the antibody comprises:
 (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; (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-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;   (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.   
     
     
         8 . The antibody of  claim 7 , wherein 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. 
     
     
         9 . The antibody of  claim 7 , wherein the antibody comprises (a) a VH sequence of SEQ ID NO:170 and a VL sequence of SEQ ID NO:131; (b) a VH sequence of SEQ ID NO:171 and a VL sequence of SEQ ID NO:132; (c) a VH sequence of SEQ ID NO:172 and a VL sequence of SEQ ID NO:133; (d) a VH sequence of SEQ ID NO:203 and a VL sequence of SEQ ID NO:141; (e) a VH sequence of SEQ ID NO:204 and a VL sequence of SEQ ID NO:142; (f) a VH sequence of SEQ ID NO:205 and a VL sequence of SEQ ID NO:143; (g) a VH sequence of SEQ ID NO:206 and a VL sequence of SEQ ID NO:144; (h) a VH sequence of SEQ ID NO:226 and a VL sequence of SEQ ID NO:152; (i) a VH sequence of SEQ ID NO:227 and a VL sequence of SEQ ID NO:153; or (j) a VH sequence of SEQ ID NO:228 and a VL sequence of SEQ ID NO:154. 
     
     
         10 . An isolated antibody that binds to KLK5, wherein the antibody comprises (a) a VH sequence having at least 95% sequence identity 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; (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 to the amino acid sequence of SEQ ID NO:205 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:143; (g) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:206 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:144; (h) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:226 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:152; (i) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:227 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:153; or (j) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:228 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:154. 
     
     
         11 . The antibody of  claim 1 , wherein the antibody is an IgG1 or IgG4. 
     
     
         12 . The antibody of  claim 1 , 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, coupled pro-KLK1 fluorescent peptide assay, a coupled pro-KLK7 fluorescent peptide assay, a pro-KLK1 LC/MS assay, a pro-KLK7 LC/MS assay, and a K i(app)  assay. 
     
     
         13 . The antibody of  claim 1 , wherein the biological activity is the serine protease activity of KLK5. 
     
     
         14 . The antibody of  claim 1 , wherein the antibody is a monoclonal antibody. 
     
     
         15 . The antibody of  claim 1 , wherein the antibody is a human, humanized, or chimeric antibody. 
     
     
         16 . The antibody of  claim 1 , wherein the antibody is an antibody fragment that binds KLK5. 
     
     
         17 . An antibody that forms a thermodynamic epitope when bound to KLK5 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. 
     
     
         18 . An antibody that competes for binding with the antibody of  claim 1 . 
     
     
         19 . An antibody that binds to the same epitope as the antibody of  claim 1 . 
     
     
         20 . An isolated nucleic acid encoding the antibody of  claim 1 . 
     
     
         21 . A host cell comprising the nucleic acid of  claim 20 . 
     
     
         22 . A method of producing an antibody comprising culturing the host cell of  claim 21  so that the antibody is produced. 
     
     
         23 . An immunoconjugate comprising the antibody of  claim 1 . 
     
     
         24 . A pharmaceutical formulation comprising the antibody of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         25 - 34 . (canceled) 
     
     
         35 . A method of treating an individual having a disease, wherein the disease is selected from the group consisting of Netherton Syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis and rosacea comprising administering to the individual an effective amount of the antibody of  claim 1 . 
     
     
         36 . The method of  claim 35 , 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 naïve asthma, chronic asthma, corticosteroid resistant asthma, corticosteroid refractory asthma, newly diagnosed and untreated asthma, asthma due to smoking, asthma uncontrolled on corticosteroids, T helper lymphocyte type 2 (Th2) or type 2 (Th2) high, or Type 2 (T2)-driven asthma, eosinophilic asthma, periostin-high asthma, eosinophil-high asthma, Th2-low asthma or nonTh2-driven asthma, periostin-low asthma, and eosinophil-low asthma. 
     
     
         37 . The method of  claim 36 , wherein the asthma is Th2-low asthma. 
     
     
         38 . A method of inhibiting the biological activity of KLK5 in an individual comprising administering to the individual an effective amount of the antibody of  claim 1  to inhibit the biological activity of KLK5. 
     
     
         39 . 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, Asp178, Gly184, Asp185, Lys186, Ala186A, Arg188, Asn223, Arg224, Pro225, and Lys233 according to standard protease numbering. 
     
     
         40 . The antibody of  claim 39 , wherein the antibody binds to an epitope on human KLK5 comprising one or more amino acid residues selected from the group consisting of 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. 
     
     
         41 . The antibody of  claim 39 , wherein the antibody binds to an epitope on human KLK5 comprising one or more amino acid residues selected from the group consisting of 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. 
     
     
         42 . The antibody of  claim 39 , wherein the antibody binds to an epitope on human KLK5 comprising one or more amino acid residues selected from the group consisting of Ser131, Ala132, Gly133, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Pro173, Arg174, Gly184, Asp185, Lys186, Ala186A, Arg188, Asn223, Arg224, and Pro225 according to standard protease numbering. 
     
     
         43 . An antibody when bound to human KLK5 results in a conformational change of human KLK5, wherein the conformational change allosterically results in the disruption of the substrate binding site and/or the active site of human KLK5.