Eradication of large colon tumor xenografts by targeted delivery of maytansinoids
Department of Quantitative Health Sciences
Animals; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antibodies, Neoplasm; Colorectal Neoplasms; Humans; Immunotoxins; Maytansine; Mice; Mice, SCID; Neoplasm Transplantation; Transplantation, Heterologous; Tumor Cells, Cultured
The maytansinoid drug DM1 is 100- to 1000-fold more cytotoxic than anticancer drugs that are currently in clinical use. The immunoconjugate C242-DM1 was prepared by conjugating DM1 to the monoclonal antibody C242, which recognizes a mucin-type glycoprotein expressed to various extents by human colorectal cancers. C242-DM1 was found to be highly cytotoxic toward cultured colon cancer cells in an antigen-specific manner and showed remarkable antitumor efficacy in vivo. C242-DM1 cured mice bearing subcutaneous COLO 205 human colon tumor xenografts (tumor size at time of treatment 65-130 mm3), at doses that showed very little toxicity and were well below the maximum tolerated dose. C242-DM1 could even effect complete regressions or cures in animals with large (260- to 500-mm3) COLO 205 tumor xenografts. Further, C242-DM1 induced complete regressions of subcutaneous LoVo and HT-29 colon tumor xenografts that express the target antigen in a heterogeneous manner. C242-DM1 represents a new generation of immunoconjugates that may yet fulfill the promise of effective cancer therapy through antibody targeting of cytotoxic agents.
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Citation: Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8618-23.