Enhancement of the selectivity and antitumor efficacy of a CC-1065 analogue through immunoconjugate formation
Chari, R.V.; Jackel, K.A.; Bourret, L.A.; Derr, S.M.; Tadayoni, B.M.; Mattocks, K.M.; Shah, S.A.; Liu, C.; Blättler, W.A.; Goldmacher, V.S.
Cancer Research 55(18): 4079-4084
1995
ISSN/ISBN: 0008-5472 PMID: 7545085 Document Number: 452115
Bis-indolyl-(seco)-1,2,9,9a-tetrahydrocyclopropa(c)benz(e)indol-4-one 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 bearing large tumors. Anti-B4-DC1 was considerably more effective in this tumor model than doxorubicin, cyclophosphamide, etoposide, or vincristine at their maximum tolerated doses.