title: Eradication of large colon tumor xenografts by targeted delivery of maytansinoids.
abstract: 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.
authors.affiliation: ImmunoGen, Inc., Cambridge, MA 02139-4239, USA.
authors.forename: C
authors.initials: C
authors.lastname: Liu
authors.forename: B M
authors.initials: BM
authors.lastname: Tadayoni
authors.forename: L A
authors.initials: LA
authors.lastname: Bourret
authors.forename: K M
authors.initials: KM
authors.lastname: Mattocks
authors.forename: S M
authors.initials: SM
authors.lastname: Derr
authors.forename: W C
authors.initials: WC
authors.lastname: Widdison
authors.forename: N L
authors.initials: NL
authors.lastname: Kedersha
authors.forename: P D
authors.initials: PD
authors.lastname: Ariniello
authors.forename: V S
authors.initials: VS
authors.lastname: Goldmacher
authors.forename: J M
authors.initials: JM
authors.lastname: Lambert
authors.forename: W A
authors.initials: WA
authors.lastname: Blättler
authors.forename: R V
authors.initials: RV
authors.lastname: Chari
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000912:Antibodies, Neoplasm / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000628:therapy*; D006801:Humans; D000922:Immunotoxins / Q000633:toxicity*; D008453:Maytansine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000922:Immunotoxins; D008453:Maytansine; C015682:ansamitocins