Apoptotic cell death induced by a mouse-human anti-APO-1 chimeric antibody leads to tumor regression.
The murine anti-APO-1 antibody (gamma 3, kappa) induces programmed cell death (apoptosis) following binding to the APO-1 antigen (m.w., 48 kDa) expressed, e.g., on activated or malignant lymphocytes. APO-1 expression on malignant cell lines and tissues suggested potential clinical utility supported by anti-APO-1-mediated tumor regression in a nude mouse model. A mouse-human anti-APO-1 chimeric antibody (gamma 3, kappa) with an affinity similar to that of the murine antibody was produced. Chimeric anti-APO-1 showed the same potential to inhibit growth of the SKW6.4 B-lymphoblastoid cell line as murine anti-APO-1. In addition, both the chimeric and murine anti-APO-1 antibodies were equally capable of mediating complete macroscopic tumor regression of a SKW6.4 xenotransplant in SCID mice by induction of apoptosis. Induction of apoptosis was the only mechanism for tumor regression because neither murine nor chimeric anti-APO-1 showed anti-tumor activity against solid H53 tumor (APO-1 antigen-positive, anti-APO-1-resistant) xenotransplants. Our results indicate that the chimeric anti-APO-1 antibody effectively induces apoptosis and suggest that chimeric anti-APO-1 should be evaluated for the treatment of malignant cells expressing the APO-1 antigen. However, chimeric anti-APO-I might only be used therapeutically when the antibody can be targeted specifically to tumor cells.
Coney
L R
LR
Centocor, Malvern, PA 19355.
Daniel
P T
PT
Sanborn
D
D
Dhein
J
J
Debatin
K M
KM
Krammer
P H
PH
Zurawski
V R
VR
D000818:Animals; D000911:Antibodies, Monoclonal; D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology*; D017209:Apoptosis; D004249:DNA Damage; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured; D019014:fas Receptor
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D011994:Recombinant Proteins; D019014:fas Receptor