Immunoconjugates containing novel maytansinoids: promising anticancer drugs.
The potential of immunoconjugates of cytotoxic drugs for the treatment of cancer has not yet been realized owing to the difficulty of delivering therapeutic concentrations of these drugs to the target cells. In an effort to overcome this problem we have synthesized maytansinoids that have 100- to 1000-fold higher cytotoxic potency than clinically used anticancer drugs. These maytansinoids are linked to antibodies via disulfide bonds, which ensures the release of fully active drug inside the cells. The conjugates show high antigen-specific cytotoxicity for cultured human cancer cells (50% inhibiting concentration, 10 to 40 pM), low systemic toxicity in mice, and good pharmacokinetic behavior.
Chari
R V
RV
ImmunoGen, Inc., Cambridge, Massachusetts 02139.
Martell
B A
BA
Gross
J L
JL
Cook
S B
SB
Shah
S A
SA
Blättler
W A
WA
McKenzie
S J
SJ
Goldmacher
V S
VS
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000627:therapeutic use; D001667:Binding, Competitive; D004354:Drug Screening Assays, Antitumor; D000922:Immunotoxins / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D008453:Maytansine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D051379:Mice; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D008453:Maytansine