A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity

Published on Aug 1, 2016in Molecular Cancer Therapeutics5.615
· DOI :10.1158/1535-7163.MCT-16-0184
Michael L. Miller17
Estimated H-index: 17
(ImmunoGen, Inc.),
Nathan Fishkin9
Estimated H-index: 9
(ImmunoGen, Inc.)
+ 14 AuthorsRavi V. J. Chari30
Estimated H-index: 30
(ImmunoGen, Inc.)
The promise of tumor-selective delivery of cytotoxic agents in the form of antibody-drug conjugates (ADCs) has now been realized, evidenced by the approval of two ADCs, both of which incorporate highly cytotoxic tubulin-interacting agents, for cancer therapy. An ongoing challenge remains in identifying potent agents with alternative mechanisms of cell killing that can provide ADCs with high therapeutic indices and favorable tolerability. Here we describe the development of a new class of potent DNA alkylating agents that meets these objectives. Through chemical design, we changed the mechanism of action of our novel DNA crosslinking agent to a mono-functional DNA alkylator. This modification, coupled with linker optimization, generated ADCs that were well tolerated in mice and demonstrated robust antitumor activity in multiple tumor models at doses 1.5 - 3.5% of maximally tolerated levels. These properties underscore the considerable potential of these purpose-created, unique DNA-interacting conjugates for broadening the clinical application of ADC technology.
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