Monoclonal antibody mediated intracellular targeting of tallysomycin S(10b).
The potency of tallysomycin S(10b) (TLM S(10b)) an analogue bleomycin was enhanced by up to 875-fold when it was conjugated to the internalizing antibody BR96. Attachment to the antibody is achieved via a Cathepsin B cleavable linker. The enhancement in potency is believed to be a result of cellular uptake of the conjugate upon antigen binding followed by rapid release of the drug inside the lysosome. This method provides a novel approach for increasing the potency and therapeutic index of nominally moderately-active cytotoxic agents.
Walker
Michael A
MA
Bristol-Myers Squibb Pharmaceutical Research Institute, Medicinal Chemistry, PO Box 5100, 5 Research Parkway, Wallingford, CT 06492, USA. michael.a.walker@bms.com
King
H Dalton
HD
Dalterio
Richard A
RA
Trail
Pamela
P
Firestone
Raymond
R
Dubowchik
Gene M
GM
D000911:Antibodies, Monoclonal / Q000276:immunology*; D001761:Bleomycin / Q000031:analogs & derivatives* / Q000276:immunology*; D002852:Chromatography, Ion Exchange
D000911:Antibodies, Monoclonal; D001761:Bleomycin; C016126:talisomycin