Antibodies to treat cancer

Abstract

Compositions and methods for the treatment of cancer, particularly melanoma, myeloma, small cell lung cancer, thymic lymphoma, T-cell lymphoma, B-cell lymphoma, osteosarcoma, and acute T-cell leukemia, are disclosed. Illustrative compositions include one or more anti-ganglioside antibodies and polynucleotides that encode such anti-ganglioside antibodies. These antibodies may be for example, hamster antibodies, chimeric human/hamster antibodies, or humanized antibodies. The disclosed compositions are useful, for example, in the treatment of cancer and can be used to induce apoptosis in a cancer cell.

What is claimed is:  
     
         1 . A method of inhibiting proliferation of a myeloma tumor cell expressing a ganglioside antigen, the method comprising contacting the cell with an antibody, wherein the antibody specifically binds to the ganglioside.  
     
     
         2 . The method of  claim 1 , wherein the antigen is selected from the group consisting of monosialo-GM2, asialo-GM2, disialo-GM2, monosialo-GM3, disialo-GD1a, disialo-GD1b, asialo-GM1, monosialo-GM1, lysosialo-GM1, trisialo-GT1b, and disialo-GD3.  
     
     
         3 . The method of  claim 1 , wherein the antigen is monosialo-GM2.  
     
     
         4 . The method of  claim 3 , wherein the antibody specifically binds the monosialo-GM2 antigen.  
     
     
         5 . The method of  claim 4  wherein the antibody is a selected from the group consisting of chimeric antibody, a humanized antibody, a human antibody, and a primatized antibody.  
     
     
         6 . The method of  claim 4 , wherein the antibody is selected from the group consisting of DMF10.167.4, DMF10.62.3, a chimeric antibody having a variable region of DMF10.167.4, a chimeric antibody having a variable region of DMF10.62.3, and a humanized antibody having all complementary determinant regions of DMF10.67.4.  
     
     
         7 . The method of  claim 6 , wherein the chimeric antibody has a light chain amino acid sequence of SEQ ID NO:21 and a heavy chain amino acid sequence of SEQ ID NO:22.  
     
     
         8 . The method of  claim 7 , wherein isoleucine at linear position 52 of the sequence of the light chain variable region of SEQ ID NO:21 is replaced with valine, and threonine at linear position 78 of the sequence of the heavy chain variable region of SEQ ID NO:22 is replaced with lysine.  
     
     
         9 . A method of inhibiting the proliferation of a cancer cell, the method comprising contacting the cell with a chimeric antibody comprising a light chain amino acid sequence of SEQ ID NO:21 and a heavy chain amino acid sequence of SEQ ID NO:22.  
     
     
         10 . The method of  claim 9 , wherein the antibody is administered in vivo to a mammal.  
     
     
         11 . The method of  claim 9 , wherein the cancer cell is selected from the group consisting of thymic lymphoma, T-cell lymphoma, B-cell lymphoma, melanoma, osteosarcoma, acute T-cell leukemia, small cell lung cancer, and myeloma.  
     
     
         12 . The method of  claim 10 , wherein isoleucine at linear position 52 of the sequence of the light chain variable region as defined in SEQ ID NO:21 is replaced with valine.  
     
     
         13 . The method of  claim 10 , wherein threonine at linear position 78 of the sequence of the heavy chain variable region of SEQ ID NO:22 is replaced with lysine.  
     
     
         14 . The method of  claim 10 , wherein isoleucine at linear position 52 of the sequence of the light chain variable region of SEQ ID NO:21 is replaced with valine and threonine at linear position 78 of the sequence of the heavy chain variable region of SEQ ID NO:22 is replaced with lysine.  
     
     
         15 . A purified chimeric antibody, or antigen-binding fragment thereof, wherein the chimeric antibody comprises an amino acid sequence comprising SEQ ID NO:21 or SEQ ID NO:22.  
     
     
         16 . The antibody of  claim 15 , wherein the antibody is effective in inhibiting cell proliferation of a tumor cell to which the antibody specifically binds.  
     
     
         17 . The antibody of  claim 15 , wherein the antibody is effective in inducing apoptosis in a tumor cell to which the antibody specifically binds.  
     
     
         18 . The antibody of  claim 15 , wherein the antibody binds specifically to monosialo-GM2 on the surface of a tumor cell and induces apoptosis in a monolayer, or a single-cell suspension of the tumor cells, or both.  
     
     
         19 . The antibody of  claim 15 , further comprising a light chain having the amino acid sequence of SEQ ID NO:21 and a heavy chain having the amino acid sequence of SEQ ID NO:22.  
     
     
         20 . The chimeric antibody of  claim 19 , wherein isoleucine at linear position 52 of the light chain of SEQ ID NO:21 is replaced with valine.  
     
     
         21 . The chimeric antibody of  claim 19 , wherein threonine at linear position 78 of the heavy chain of SEQ ID NO:22 is replaced with lysine.  
     
     
         22 . The chimeric antibody of  claim 19 , wherein isoleucine at linear position 52 of the light chain of SEQ ID NO:21 is replaced with valine and threonine at linear position 78 of the heavy chain variable region of SEQ ID NO:22 is replaced with lysine.  
     
     
         23 . The antibody of  claim 19 , wherein the antibody binds specifically to monosialo-GM2 on the surface of a tumor cell and induces apoptosis in a monolayer, a single-cell suspension of tumor cells, or both.  
     
     
         24 . An purified antibody light chain comprising the sequence of SEQ ID NO:21.  
     
     
         25 . An isolated nucleic acid molecule comprising a nucleotide sequence that encodes for the antibody light chain of  claim 24 .  
     
     
         26 . The isolated nucleic acid molecule of  claim 25 , wherein the nucleotide sequence comprises SEQ ID NO:8.  
     
     
         27 . The purified antibody light chain of  claim 24 , wherein isoleucine at linear position 52 of the light chain consisting of SEQ ID NO:21 is replaced with valine.  
     
     
         28 . An isolated nucleic acid molecule comprising a nucleotide sequence that encode for the antibody light chain of  claim 27 .  
     
     
         29 . A purified antibody comprising the light chain of  claim 24  and a heavy chain.  
     
     
         30 . A purified antibody heavy chain having the amino acid sequence of SEQ ID NO:22.  
     
     
         31 . The purified antibody heavy chain of  claim 30 , wherein a threonine at linear position 78 of the heavy chain that consists of SEQ ID NO:22 is replaced with a lysine.  
     
     
         32 . An isolated nucleic acid molecule, the nucleic acid molecule comprising a nucleic acid sequence that encodes the antibody heavy chain of  claim 31 .  
     
     
         33 . An isolated nucleic acid molecule, the nucleic acid molecule comprising a nucleic acid sequence that encodes the antibody heavy chain of  claim 30 .  
     
     
         34 . The isolated nucleic acid molecule of  claim 33 , wherein the nucleotide sequence comprises the nucleic acid sequence of SEQ ID NO:7.  
     
     
         35 . A purified antibody comprising the heavy chain of  claim 30 .  
     
     
         36 . A purified antibody, or antigen-binding fragment thereof, wherein the antibody comprises a complementary determinant region (CDR) with an amino acid sequence of SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, or SEQ ID NO:18.  
     
     
         37 . The antibody of  claim 36 , wherein the antibody is effective in inhibiting cell proliferation of a tumor cell to which the antibody specifically binds.  
     
     
         38 . The antibody of  claim 36 , wherein the antibody is effective in inducing apoptosis in a tumor cell to which the antibody specifically binds.  
     
     
         39 . The antibody of  claim 36 , wherein the antibody binds specifically to monosialo-GM2 on the surface of a tumor cell and induces apoptosis in a monolayer, a single-cell suspension of the tumor cells, or both.  
     
     
         40 . A method of inhibiting growth of a tumor cell, the method comprising contacting the tumor cell with a chimeric antibody having a light chain amino acid sequence of SEQ ID NO:21 and a heavy chain amino acid sequence of SEQ ID NO:22.  
     
     
         41 . The method of  claim 40 , wherein the growth of the tumor cell is inhibited by inhibiting proliferation of the cell.  
     
     
         42 . The method of  claim 40 , wherein the growth of the tumor cell is inhibited by inducing apoptosis of the cell.  
     
     
         43 . An isolated nucleic acid comprising the nucleic acid sequence of SEQ ID NO:5, 6,9, 10, 11, or 12.  
     
     
         44 . A polypeptide comprising the amino acid sequence of SEQ ID NO:19, 20, 23, 24, 25, or 26.  
     
     
         45 . A purified monoclonal antibody, or antigen-binding fragment thereof, wherein the monoclonal antibody comprises an amino acid sequence of SEQ ID NO:19, 20, 23, 24, 25, or 26.