Human monoclonal antibodies to fucosyl-gm1 and methods for using anti-fucosyl-gm1 antibodies

Abstract

The present disclosure provides isolated monoclonal antibodies, particularly human monoclonal antibodies that specifically bind to Fucosyl-GM1 with high affinity. Nucleic acid molecules encoding the antibodies of this disclosure, expression vectors, host cells and methods for expressing the antibodies of this disclosure are also provided. Immunoconjugates, bispecific molecules and pharmaceutical compositions comprising the antibodies of this disclosure are also provided. This disclosure also provides methods for detecting Fucosyl-GM1, as well as methods for treating various diseases, including cancer, using anti-Fucosyl-GM1 antibodies.

We claim: 
     
         1 . An isolated human monoclonal antibody, or an antigen-binding portion thereof, wherein the antibody:
 (a) specifically binds to Fucosyl-GM1; and   (b) binds to the human small cell lung cancer cell line DMS-79 (Human SCLC ATCC #CRL-2049).   
     
     
         2 . An isolated human monoclonal antibody, or an antigen-binding portion thereof, wherein the antibody cross-competes for binding to Fucosyl-GM1 with a reference antibody comprising:
 (a) a human heavy chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:1, 2, 3, 4, 5 and 6; and   (b) a human light chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:7, 8, 9, 10, 11 and 12.   
     
     
         3 . The antibody of  claim 2 , wherein the human heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 1 and the human light chain variable 
       region comprises the amino acid sequence of SEQ ID NO:7. 
     
     
         4 . The antibody of  claim 2 , wherein the human heavy chain variable region comprises the amino acid sequence of SEQ ID NO:2 and the human light chain variable 
       region comprises the amino acid sequence of SEQ ID NO:8. 
     
     
         5 . The antibody of  claim 2 , wherein the human heavy chain variable region comprises the amino acid sequence of SEQ ID NO:3 and the human light chain variable 
       region comprises the amino acid sequence of SEQ ID NO:9. 
     
     
         6 . The antibody of  claim 2 , wherein the human heavy chain variable 
       region comprises the amino acid sequence of SEQ ID NO:5 and the human light chain variable 
       region comprises the amino acid sequence of SEQ ID NO: 11. 
     
     
         7 . The antibody of  claim 2 , wherein the human heavy chain variable 
       region comprises the amino acid sequence of SEQ ID NO:6 and the human light chain variable 
       region comprises the amino acid sequence of SEQ ID NO:12. 
     
     
         8 . An isolated monoclonal antibody, or an antigen-binding 
       portion thereof, comprising a heavy chain variable region that is derived from a human V H  3-48 gene or a human V H  3-48 gene, or a light chain variable region that is derived from a human VK L15 gene, wherein the antibody specifically binds to Fucosyl-GM1. 
     
     
         9 . The antibody of  claim 1 , which comprises:
 (a) a heavy chain variable region CDR1 comprising SEQ ID NO: 13;   (b) a heavy chain variable region CDR2 comprising SEQ ID NO: 19;   (c) a heavy chain variable region CDR3 comprising SEQ ID NO:25;   (d) a light chain variable region CDR1 comprising SEQ ID NO:31;   (e) a light chain variable region CDR2 comprising SEQ ID NO:37; and   (f) a light chain variable region CDR3 comprising SEQ ID NO:43.   
     
     
         10 . The antibody of  claim 1 , which comprises:
 (a) a heavy chain variable region CDR1 comprising SEQ ID NO: 14;   (b) a heavy chain variable region CDR2 comprising SEQ ID NO:20;   (c) a heavy chain variable region CDR3 comprising SEQ ID NO:26;   (d) a light chain variable region CDR1 comprising SEQ ID NO:32;   (e) a light chain variable region CDR2 comprising SEQ ID NO:38; and   (f) a light chain variable region CDR3 comprising SEQ ID NO:4.   
     
     
         11 . The antibody of  claim 1 , which comprises:
 (a) a heavy chain variable region CDR1 comprising SEQ ID NO:15;   (b) a heavy chain variable region CDR2 comprising SEQ ID NO:21;   (c) a heavy chain variable region CDR3 comprising SEQ ID NO:27;   (d) a light chain variable region CDR1 comprising SEQ ID NO:33;   (e) a light chain variable region CDR2 comprising SEQ ID NO:39; and   (f) a light chain variable region CDR3 comprising SEQ ID NO:45.   
     
     
         12 . The antibody of  claim 1 , which comprises:
 (a) a heavy chain variable region CDR1 comprising SEQ ID NO:17;   (b) a heavy chain variable region CDR2 comprising SEQ ID NO:23;   (c) a heavy chain variable region CDR3 comprising SEQ ID NO:29;   (d) a light chain variable region CDR1 comprising SEQ ID NO:35;   (e) a light chain variable region CDR2 comprising SEQ ID NO:41; and   (f) a light chain variable region CDR3 comprising SEQ ID NO:47.   
     
     
         13 . The antibody of  claim 1 , which comprises:
 (a) a heavy chain variable region CDR1 comprising SEQ ID NO:18;   (b) a heavy chain variable region CDR2 comprising SEQ ID NO:24;   (c) a heavy chain variable region CDR3 comprising SEQ ID NO:30;   (d) a light chain variable region CDR1 comprising SEQ ID NO:36;   (e) a light chain variable region CDR2 comprising SEQ ID NO:42; and   (f) a light chain variable region CDR3 comprising SEQ ID NO:48.   
     
     
         14 . An isolated monoclonal antibody or antigen binding portion thereof of  claim 8  comprising:
 (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:1; and a light chain variable region comprising the amino acid sequence of SEQ ID NO:7; or 
 (b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:2; and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8; or 
 (c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:3; and a light chain variable region comprising the amino acid sequence of SEQ ID NO:9; or 
 (d) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:5; and a light chain variable region comprising the amino acid sequence of SEQ ID NO:11; or 
 (e) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:6; and a light chain variable region comprising the amino acid sequence of SEQ ID NO:12. 
 
     
     
         15 . An immunoconjugate comprising the antibody or antigen-binding portion thereof, of  claim 1 , linked to a therapeutic agent. 
     
     
         16 . The immunoconjugate of  claim 15 , wherein the 
       therapeutic agent is a cytotoxin or a radioactive agent. 
     
     
         17 . An isolated nucleic acid molecule encoding the antibody or antigen-binding portion thereof, of  claim 1 . 
     
     
         18 . An expression vector comprising the nucleic acid molecule of  claim 17 . 
     
     
         19 . A host cell comprising the expression vector of  claim 18 . 
     
     
         20 . A method for preparing an anti-Fucosyl-GM1 antibody which 
       comprises expressing the antibody in the host cell of  claim 19  and isolating the antibody from the 
       host cell. 
     
     
         21 . A method of treating or preventing a disease characterized by 
       growth of tumor cells expressing Fucosyl-GM1, comprising administering to a subject the antibody or antigen-binding portion thereof, of  claim 1  in an amount effective to treat or prevent 
       the disease. 
     
     
         22 . The method of  claim 21 , wherein the disease is lung cancer.