Agonist anti-trkc antibodies and methods using same

Abstract

The invention concerns agonist anti-trkC antibodies, polypeptides, and polynucleotides encoding the same. The invention further concerns use of such antibodies, polypeptides and/or polynucleotides in the treatment and/or prevention of neuropathies, such as sensory neuropathies, including taxol-induced sensory neuropathy, cisplatin-induced sensory neuropathy, and pyridoxine-induced sensory neuropathy.

1 . A nucleic acid encoding an agonist anti-trkC antibody comprising heavy chain CDRs (CDRHs) comprising:
 (a) a CDRH1 of the formula GYTFTSYXaaXaaH (SEQ ID NO:16), wherein Xaa at position 8 is R or W, and Xaa at position 9 is I, L, R, or M;   (b) a CDRH2 of the formula EIYPSNXaaRTNYNEKFXaaS (SEQ ID NO:17), wherein Xaa at position 7 is A, T, S, or G; and Xaa at position 16 is K or E; and   (c) a CDRH3 of the formula KYYYGNXaaXaaRSWYFDV (SEQ ID NO:18), wherein Xaa at position 7 is T or S; wherein Xaa at position 8 is R, Q, K, S, or Y;   wherein the agonist anti-trkC antibody is not an antibody comprising a heavy chain comprising a CDRH1 region of SEQ ID NO:22, a CDRH2 region of SEQ ID NO:23, and a CDRH3 region of SEQ ID NO:24.   
     
     
         2 . The nucleic acid of  claim 1 , wherein the nucleic acid encodes an agonist anti-trkC antibody which further comprises a light chain variable region. 
     
     
         3 . A nucleic acid encoding an agonist anti-trkC antibody which comprises light chain variable region CDRs (CDRLs) comprising:
 (a) a CDRL1 of the formula RASESXaaDXaaYGISFXaaXaa (SEQ ID NO:19), wherein Xaa at position 6 is I or V; Xaa at position 8 is N or S; Xaa at position 14 is L or M; Xaa at position 15 is A, T, or N;   (b) a CDRL2 of the formula AASNXaaGS (SEQ ID NO:20), wherein Xaa at position 5 is R, L, or Q; and   (c) a CDRL3 of the formula QQSKXaaVPRT (SEQ ID NO:21), wherein Xaa at position 5 is T, A, S, or E;   wherein the agonist anti-trkC antibody is not an antibody comprising a light chain comprising a CDRL1 region of SEQ ID NO:25, a CDRL2 region of SEQ ID NO:26, and a CDRL3 region of SEQ ID NO:27.   
     
     
         4 . The nucleic acid of  claim 3 , wherein the nucleic acid encodes an agonist anti-trkC antibody which further comprises a heavy chain variable region. 
     
     
         5 . A nucleic acid encoding an agonist anti-trkC antibody comprising:
 (a) a heavy chain variable region with CDRHs comprising:
 (i) a CDRH1 of the formula GYTFTSYXaaXaaH (SEQ ID NO:16), wherein Xaa at position 8 is R or W, and Xaa at position 9 is I, L, R, or M; 
 (ii) a CDRH2 of the formula EIYPSNXaaRTNYNEKFXaaS (SEQ ID NO:17), wherein Xaa at position 7 is A, T, S, or G; and Xaa at position 16 is K or E; and 
 (iii) a CDRH3 of the formula KYYYGNXaaXaaRSWYFDV (SEQ ID NO:18), wherein Xaa at position 7 is T or S; wherein Xaa at position 8 is R, Q, K, S, or Y; and 
   (b) a light chain variable region with CDRLs comprising:
 (i) a CDRL1 of the formula RASESXaaDXaaYGISFXaaXaa (SEQ ID NO:19), wherein Xaa at position 6 is I or V; Xaa at position 8 is N or S; Xaa at position 14 is L or M; Xaa at position 15 is A, T, or N; 
 (ii) a CDRL2 of the formula AASNXaaGS (SEQ ID NO:20), wherein Xaa at position 5 is R, L, or Q; and 
 (iii) a CDRL 3 of the formula QQSKXaaVPRT (SEQ ID NO:21), wherein Xaa at position 5 is T, A, S, or E; 
   wherein the agonist anti-trkC antibody is not an antibody comprising (a) CDRHs comprising a CDRH1 region of SEQ ID NO:22, a CDRH2 region of SEQ ID NO:23, and a CDRH3 region of SEQ ID NO:24; and (b) CDRLs comprising a CDRL1 region of SEQ ID NO:25, a CDRL2 region of SEQ ID NO:26, and a CDRL3 region of SEQ ID NO:27.   
     
     
         6 . The nucleic acid of  claim 5 , wherein the nucleic acid encodes an agonist anti-trkC antibody which binds human trkC. 
     
     
         7 . The nucleic acid of  claim 6 , wherein the nucleic acid encodes an agonist anti-trkC antibody which binds to human trkC with a K D  less than about 5 nM. 
     
     
         8 . The nucleic acid of  claim 6 , wherein the nucleic acid encodes an agonist anti-trkC antibody which further binds rodent trkC. 
     
     
         9 . The nucleic acid of  claim 5 , wherein the nucleic acid encodes an agonist anti-trkC antibody which comprises a heavy chain variable region comprising:
 (a) a CDRH1 region of SEQ ID NO:4;   (b) a CDRH2 region of SEQ ID NO:5; and   (c) a CDRH3 region of SEQ ID NO:6.   
     
     
         10 . The nucleic acid of  claim 9 , wherein the nucleic acid encodes an agonist anti-TrkC antibody which comprises a heavy chain variable region comprising the sequence of SEQ ID NO:1. 
     
     
         11 . The nucleic acid of  claim 5 , wherein the nucleic acid encodes an agonist anti-trkC antibody which comprises a light chain variable region comprising:
 (a) a CDRL1 region of SEQ ID NO:7;   (b) a CDRL2 region of SEQ ID NO:8; and   (c) a CDRL3 region of SEQ ID NO:9.   
     
     
         12 . The nucleic acid of  claim 11 , wherein the nucleic acid encodes an agonist anti-TrkC antibody which comprises a light chain variable region comprising the sequence of SEQ ID NO:2. 
     
     
         13 . The agonist anti-trkC antibody of  claim 5 , wherein the nucleic acid encodes an agonist anti-trkC antibody comprising
 (a) a heavy chain variable region comprising:
 (i) a CDRH1 region of SEQ ID NO:4; 
 (ii) a CDRH2 region of SEQ ID NO:5; and 
 (iii) a CDRH3 region of SEQ ID NO:6; and 
   (b) a light chain variable region comprising:
 (i) a CDRL1 region of SEQ ID NO:7; 
 (b) a CDRL2 region of SEQ ID NO:8; and 
 (c) a CDRL3 region of SEQ ID NO:9. 
   
     
     
         14 . The nucleic acid of  claim 13 , wherein the nucleic acid encodes an agonist anti-TrkC antibody comprising a heavy chain variable region comprising SEQ ID NO:1, and the light chain variable region comprising the sequence of SEQ ID NO:2. 
     
     
         15 . The nucleic acid of  claim 14 , wherein the nucleic acid encodes an agonist anti-trkC antibody comprising a heavy chain comprising the sequence of SEQ ID NO:28, and the light chain comprising the sequence of SEQ ID NO:29. 
     
     
         16 . The nucleic acid of  claim 14 , wherein the nucleic acid comprises the sequence of
 SEQ ID NO:12 encoding the heavy chain variable region of the agonist anti-trkC antibody, and the sequence of SEQ ID NO:10 encoding the light chain variable region of the agonist anti-trkC antibody.   
     
     
         17 . The nucleic acid of  claim 15 , wherein the nucleic acid comprises the sequence of SEQ ID NO:13 encoding the heavy chain of the agonist anti-trkC antibody, and the sequence of SEQ ID NO:11 encoding the light chain variable region of the agonist anti-trkC antibody. 
     
     
         18 . A vector comprising the nucleic acid of  claim 1 . 
     
     
         19 . A host cell comprising the nucleic acid of  claim 1 .