Characterization of a proapoptotic antiganglioside GM2 monoclonal antibody and evaluation of its therapeutic effect on melanoma and small cell lung carcinoma xenografts.
Monoclonal antibodies have begun to show great clinical promise for the treatment of cancer. Antibodies that can directly affect a tumor cell's growth and/or survival are of particular interest for immunotherapy. Previously, we described monoclonal antibody DMF10.62.3 that had antiproliferative and proapoptotic effects when it bound an antigen of unknown identity on tumor cells in vitro. In this report, we determined that DMF10.62.3 and a clonally related antibody DMF10.167.4 recognize the ganglioside GM2. These antibodies react with a GM2 epitope that is expressed on a large number of tumor cell lines, including human melanoma and small cell lung carcinoma, but not on normal primary lines or most normal tissues. Interestingly, this pattern of cellular reactivity is distinct from that reported for other previously described GM2 antibodies, a difference that is presumably due to DMF10.167.4's binding to a unique GM2-associated epitope. Additional characterization of DMF10.167.4 revealed that this antibody was able to induce apoptosis and/or block cellular proliferation when cultured in vitro with the human Jurkat T lymphoma, CHL-1 melanoma, and SBC-3 small cell lung carcinoma lines. In vivo, DMF10.167.4 antibody was well tolerated in mice and did not detectably bind to or damage normal tissues. However, this antibody was able to prevent murine E710.2.3 lymphoma, human CHL-1 melanoma, and SBC-3 small cell lung carcinoma lines from establishing tumors in vivo and blocked progression of established CHL-1 and SBC-3 tumors in vivo. Therefore, monoclonal antibody DMF10.167.4 has immunotherapeutic potential.
Retter
Marc W
MW
Antigen Discovery and Preclinical Biology, Corixa Corporation, Seattle, Washington, USA.
Johnson
Jeffrey C
JC
Peckham
David W
DW
Bannink
Jeannette E
JE
Bangur
Chaitanya S
CS
Dresser
Karen
K
Cai
Feng
F
Foy
Teresa M
TM
Fanger
Neil A
NA
Fanger
Gary R
GR
Woda
Bruce
B
Rock
Kenneth L
KL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology; D000918:Antibody Specificity; D017209:Apoptosis / Q000276:immunology; D018288:Carcinoma, Small Cell / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D006224:Cricetinae; D000939:Epitopes / Q000276:immunology; D005260:Female; D005678:G(M2) Ganglioside / Q000276:immunology*; D006801:Humans; D007116:Immunization, Passive / Q000379:methods*; D019169:Jurkat Cells; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008806:Mice, Inbred AKR; D016513:Mice, SCID
D000911:Antibodies, Monoclonal; D000939:Epitopes; D005678:G(M2) Ganglioside