Enhancement of the selectivity and antitumor efficacy of a CC-1065 analogue through immunoconjugate formation
Department of Quantitative Health Sciences
Animals; Antibiotics, Antineoplastic; Antigens, CD; Antigens, CD19; Antigens, CD56; Antigens, Differentiation, B-Lymphocyte; Antigens, Differentiation, T-Lymphocyte; Female; Humans; Immunotoxins; *Indoles; Leucomycins; Lymphoma, B-Cell; Mice; Mice, SCID; Tumor Cells, Cultured
Bis-indolyl-(seco)-1,2,9a-tetrahydrocyclopropa[c]benz[e]indol-4-on e compounds are synthetic analogues of CC-1065 that are highly cytotoxic toward a broad spectrum of tumor cell lines. One of these compounds, called DC1, was conjugated to antibodies via novel cleavable disulfide linkers. Conjugates of DC1 with murine mAbs anti-B4 and N901 directed against tumor-associated antigens CD19 and CD56, respectively, proved to be extremely potent and antigen selective in killing target cells in culture. DC1 conjugates with humanized versions of anti-B4 and N901 antibodies were also constructed and demonstrated to be as cytotoxic and selective as the respective murine antibody conjugates. The anti-B4-DC1 conjugate showed antitumor efficacy in an aggressive metastatic human B-cell lymphoma survival model in SCID mice and completely cured animals hearing large tumors. Anti-B4-DC1 was considerably more effective in this tumor model than doxorubicin, cyclophosphamide, etoposide, or vincristine at their maximum tolerated doses.
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Citation: Cancer Res. 1995 Sep 15;55(18):4079-84.