2. Academic Validation
  3. Doxorubicin immunoconjugates containing bivalent, lysosomally-cleavable dipeptide linkages

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

Affiliation

  • 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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