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-1 might only be used therapeutically when the antibody can be targeted specifically to tumor cells. (C) 1994 Wiley-Liss, Inc.