Eradication of large colon tumor xenografts by targeted delivery of maytansinoids.
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.
Liu
C
C
ImmunoGen, Inc., Cambridge, MA 02139-4239, USA.
Tadayoni
B M
BM
Bourret
L A
LA
Mattocks
K M
KM
Derr
S M
SM
Widdison
W C
WC
Kedersha
N L
NL
Ariniello
P D
PD
Goldmacher
V S
VS
Lambert
J M
JM
Blättler
W A
WA
Chari
R V
RV
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
D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000922:Immunotoxins; D008453:Maytansine; C015682:ansamitocins