US2016326259A1PendingUtilityA1

Frizzled-binding agents and uses thereof

Assignee: ONCOMED PHARM INCPriority: Sep 26, 2008Filed: Jan 21, 2016Published: Nov 10, 2016

Est. expirySep 26, 2028(~2.2 yrs left)· nominal 20-yr term from priority

Inventors:Austin Gurney Aaron Sato Fumiko Takada Axelrod Timothy Chartes Hoey Sanjeev Satyal Satyajit Sujit Kumar Mitra

C07K 2317/30C07K 16/30A61K 39/39558C07K 2317/92C07K 2317/21A61K 31/00A61K 31/7068C07K 16/2863C07K 2319/30C07K 2317/55A61P 35/00G01N 33/5011A61K 2039/505A61P 43/00C07K 2317/76C07K 2299/00A61K 31/337C07K 16/28C07K 16/303C07K 2317/94C07K 2317/34A61K 45/06C07K 16/3015C07K 2317/732A61K 39/3955C07K 2317/565C07K 2317/734C07K 16/3023C07K 2317/24

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References

Claims

Abstract

Novel anti-cancer agents, including, but not limited to, antibodies, that bind to human frizzled receptors are provided. Novel epitopes within the human frizzled receptors which are suitable as targets for anti-cancer agents are also identified. Methods of using the agents or antibodies, such as methods of using the agents or antibodies to inhibit Wnt signaling and/or inhibit tumor growth are further provided.

Claims

exact text as granted — not AI-modified

What we claim is: 
     
         1 - 107 . (canceled) 
     
     
         108 . A method of treating a subject having cancer, the method comprising administering to the subject a therapeutically effective amount of a monoclonal antibody that specifically binds at least one human frizzled receptor selected from the group consisting of FZD1, FZD2, FZD5, FZD7, and FZD8, wherein the antibody binds to at least one of the following amino acid sequences within the frizzled receptor:
 (i) Q(DE/ED)AGLEVHQF(Y/W)PL (SEQ ID NO:24);   (ii) (K/Q)(F/Y)GF(Q/A) (SEQ ID NO:69);   (iii) QDEAGLEVHQFWPL (SEQ ID NO:67), wherein the human frizzled receptor is FZD8;   (iv) GLEVHQ (SEQ ID NO: 25) wherein the human frizzled receptor is FZD8; and   (v) YGFA (SEQ ID NO:74) or QYGFA (SEQ ID NO:66), wherein the human frizzled receptor is FZD8.   
     
     
         109 . The method of  claim 108 , wherein the antibody is present in a pharmaceutical composition. 
     
     
         110 . The method of  claim 108 , wherein the antibody binds to at least the amino acid sequence Q(DE/ED)AGLEVHQF(Y/W)PL (SEQ ID NO:24). 
     
     
         111 . The method of  claim 108 , wherein the antibody binds to at least the amino acid sequence (K/Q)(F/Y)GF(Q/A) (SEQ ID NO:69). 
     
     
         112 . The method of  claim 108 , wherein the antibody binds to at least the amino acid sequence QDEAGLEVHQFWPL (SEQ ID NO:67), wherein the human frizzled receptor is FZD8. 
     
     
         113 . The method of  claim 108 , wherein the antibody binds to at least the amino acid sequence GLEVHQ (SEQ ID NO:25), wherein the human frizzled receptor is FZD8. 
     
     
         114 . The method of  claim 108 , wherein the antibody binds to at least the amino acid sequence YGFA (SEQ ID NO:74) or QYGFA (SEQ ID NO:66), wherein the human frizzled receptor is FZD8. 
     
     
         115 . The method of  claim 108 , wherein the antibody is a chimeric antibody, a human antibody, a humanized antibody, an antibody fragment, a bispecific antibody, a monospecific antibody, a monovalent antibody, an IgG1 antibody, or an IgG2 antibody. 
     
     
         116 . The method of  claim 115 , wherein the antibody is a humanized antibody. 
     
     
         117 . The method of  claim 115 , wherein the antibody is a human antibody. 
     
     
         118 . The method of  claim 115 , wherein the antibody is an IgG1 antibody or an IgG2 antibody. 
     
     
         119 . The method of  claim 115 , wherein the antibody is an antibody fragment. 
     
     
         120 . The method of  claim 108 , wherein the antibody binds to at least human FZD5 and FZD8. 
     
     
         121 . The method of  claim 120 , wherein the antibody binds to human FZD1, FZD2, FZD5, FZD7, and FZD8. 
     
     
         122 . The method of  claim 108 , wherein the antibody binds to QDEAGLEVHQFWPL (SEQ ID NO:67) and binds to YGFA (SEQ ID NO:74), wherein the human frizzled receptor is FZD8. 
     
     
         123 . The method of  claim 108 , wherein the antibody binds to GLEVHQ (SEQ ID NO:25) and binds to YGFA (SEQ ID NO:74), wherein the human frizzled receptor is FZD8. 
     
     
         124 . The method of  claim 108 , wherein the antibody binds to QDEAGLEVHQFWPL (SEQ ID NO:67) and binds to QYGFA (SEQ ID NO:66), wherein the human frizzled receptor is FZD8. 
     
     
         125 . The method of  claim 108 , wherein the antibody binds to GLEVHQ (SEQ ID NO:25) and binds to QYGFA (SEQ ID NO:66), wherein the human frizzled receptor is FZD8. 
     
     
         126 . The method of  claim 108 , wherein the cancer is selected from the group consisting of squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, and head and neck cancer. 
     
     
         127 . The method of  claim 126 , wherein the cancer is breast cancer. 
     
     
         128 . The method of  claim 126 , wherein the cancer is lung cancer. 
     
     
         129 . The method of  claim 128 , wherein the cancer is non-small cell lung cancer. 
     
     
         130 . The method of  claim 126 , wherein the cancer is pancreatic cancer. 
     
     
         131 . A method for treating breast cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of an antibody comprising:
 (a) a heavy chain CDR1 comprising GFTFSHYTLS (SEQ ID NO:1), a heavy chain CDR2 comprising VISGDGSYTYYADSVKG (SEQ ID NO:2), and a heavy chain CDR3 comprising NFIKYVFAN (SEQ ID NO:3), and   b) a light chain CDR1 comprising SGDKLGKKYAS (SEQ ID NO:4) or SGDNIGSFYVH (SEQ ID NO:7), a light chain CDR2 comprising EKDNRPSG (SEQ ID NO:5) or DKSNRPSG (SEQ ID NO:8), and a light chain CDR3 comprising SSFAGNSLE (SEQ ID NO:6) or QSYANTLSL (SEQ ID NO:9).   
     
     
         132 . The method of  claim 131 , wherein the light chain CDR1 comprises SGDNIGSFYVH (SEQ ID NO:7), the light chain CDR2 comprises DKSNRPSG (SEQ ID NO:8), and the light chain CDR3 comprises QSYANTLSL (SEQ ID NO:9). 
     
     
         133 . The method of  claim 132 , wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO:10, and a light chain variable region having the amino acid sequence of SEQ ID NO:14. 
     
     
         134 . The method of  claim 132 , wherein the antibody is administered in combination with a second anti-cancer agent. 
     
     
         135 . The method of  claim 134 , wherein the second anti-cancer agent is an antimitotic agent. 
     
     
         136 . The method of  claim 135 , wherein the antimitotic agent is a taxane. 
     
     
         137 . The method of  claim 136 , wherein the taxane is paclitaxel. 
     
     
         138 . The method of  claim 137 , wherein the breast cancer is HER2-negative breast cancer. 
     
     
         139 . A method for treating lung cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of an antibody comprising:
 (a) a heavy chain CDR1 comprising GFTFSHYTLS (SEQ ID NO:1), a heavy chain CDR2 comprising VISGDGSYTYYADSVKG (SEQ ID NO:2), and a heavy chain CDR3 comprising NFIKYVFAN (SEQ ID NO:3), and   b) a light chain CDR1 comprising SGDKLGKKYAS (SEQ ID NO:4) or SGDNIGSFYVH (SEQ ID NO:7), a light chain CDR2 comprising EKDNRPSG (SEQ ID NO:5) or DKSNRPSG (SEQ ID NO:8), and a light chain CDR3 comprising SSFAGNSLE (SEQ ID NO:6) or QSYANTLSL (SEQ ID NO:9).   
     
     
         140 . The method of  claim 139 , wherein the light chain CDR1 comprises SGDNIGSFYVH (SEQ ID NO:7), the light chain CDR2 comprises DKSNRPSG (SEQ ID NO:8), and the light chain CDR3 comprises QSYANTLSL (SEQ ID NO:9). 
     
     
         141 . The method of  claim 140 , wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO:10, and a light chain variable region having the amino acid sequence of SEQ ID NO:14. 
     
     
         142 . The method of  claim 140 , wherein the antibody is administered in combination with a second anti-cancer agent. 
     
     
         143 . The method of  claim 142 , wherein the second anti-cancer agent is an antimitotic agent. 
     
     
         144 . The method of  claim 143 , wherein the antimitotic agent is a taxane. 
     
     
         145 . The method of  claim 144 , wherein the taxane is docetaxel. 
     
     
         146 . A method for treating pancreatic cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of an antibody comprising:
 (a) a heavy chain CDR1 comprising GFTFSHYTLS (SEQ ID NO:1), a heavy chain CDR2 comprising VISGDGSYTYYADSVKG (SEQ ID NO:2), and a heavy chain CDR3 comprising NFIKYVFAN (SEQ ID NO:3), and   b) a light chain CDR1 comprising SGDKLGKKYAS (SEQ ID NO:4) or SGDNIGSFYVH (SEQ ID NO:7), a light chain CDR2 comprising EKDNRPSG (SEQ ID NO:5) or DKSNRPSG (SEQ ID NO:8), and a light chain CDR3 comprising SSFAGNSLE (SEQ ID NO:6) or QSYANTLSL (SEQ ID NO:9).   
     
     
         147 . The method of  claim 146 , wherein the light chain CDR1 comprises SGDNIGSFYVH (SEQ ID NO:7), the light chain CDR2 comprises DKSNRPSG (SEQ ID NO:8), and the light chain CDR3 comprises QSYANTLSL (SEQ ID NO:9). 
     
     
         148 . The method of  claim 147 , wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO:10, and a light chain variable region having the amino acid sequence of SEQ ID NO:14. 
     
     
         149 . The method of  claim 146 , wherein the antibody is administered in combination with a second anti-cancer agent. 
     
     
         150 . The method of  claim 149 , wherein the second anti-cancer agent is an antimitotic agent. 
     
     
         151 . The method of  claim 150 , wherein the antimitotic agent is a taxane. 
     
     
         152 . The method of  claim 151 , wherein the taxane is nab-paclitaxel. 
     
     
         153 . The method of  claim 149 , wherein the second anti-cancer agent is anti-metabolite. 
     
     
         154 . The method of  claim 153 , wherein the anti-metabolite is gemcitabine. 
     
     
         155 . The method of  claim 154 , wherein the antibody and gemcitabine are administered in combination with a further anti-cancer agent. 
     
     
         156 . The method of  claim 155 , wherein the further anticancer agent is a taxane. 
     
     
         157 . The method of  claim 156 , wherein the taxane is nab-paclitaxel.

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