Doxorubicin immunoconjugates containing bivalent, lysosomally-cleavable dipeptide linkages

  • Bioorg Med Chem Lett. 2002 Jun 3;12(11):1529-32. doi: 10.1016/s0960-894x(02)00194-4.
Gene M Dubowchik  1 ,  Shilpa Radia ,  Harold Mastalerz ,  Michael A Walker ,  Raymond A Firestone ,  H Dalton King ,  Sandra J Hofstead ,  David Willner ,  Shirley J Lasch ,  Pamela A Trail
Affiliations
  • 1. Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5100, Wallingford, CT 06492-7660, USA. [email protected]
PMID: 12031335 DOI: 10.1016/s0960-894x(02)00194-4
Abstract

Bivalent doxorubicin (DOX)-dipeptides (16a-c) were prepared and conjugated to the monoclonal antibody BR96. The dipeptides are cleaved by lysosomal proteases following internalization of the resulting immunoconjugates. Conjugate 18b demonstrated antigen-specific in vitro tumor cell killing activity (IC(50)=0.2 microM) that was equipotent to DOX with a near doubling of drug molecules/MAb. Size exclusion chromatography showed 18b to be a noncovalent dimer that was formed immediately upon conjugation.

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