ENHANCEMENT OF THE SELECTIVITY AND ANTITUMOR EFFICACY OF A CC-1065 ANALOG THROUGH IMMUNOCONJUGATE FORMATION

1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one compounds are synth etic analogues of CC-1065 that are highly cytotoxic toward a broad spe ctrum of tumor cell lines. One of these compounds, called DC1, was con jugated to antibodies via novel cleavable disulfide linkers. Conjugate s of DC1 with murine mAbs anti-B4 and N901 directed against tumor-asso ciated antigens CD19 and CD56, respectively, proved to be extremely po tent and antigen selective in killing target cells in culture. DC1 con jugates with humanized versions of anti-B4 and N901 antibodies were al so constructed and demonstrated to be as cytotoxic and selective as th e respective murine antibody conjugates. The anti-B4-DC1 conjugate sho wed antitumor efficacy in an aggressive metastatic human B-cell lympho ma survival model in SCID mice and completely cured animals bearing la rge tumors. Anti-B4-DC1 was considerably more effective in this tumor model than doxorubicin, cyclophosphamide, etoposide, or vincristine at their maximum tolerated doses.