Doxorubicin immunoconjugates containing bivalent, lysosomally-cleavable dipeptide linkages

…, S Radia, H Mastalerz, MA Walker, RA Firestone…

Index: Dubowchik, Gene M; Radia, Shilpa; Mastalerz, Harold; Walker, Michael A.; Firestone, Raymond A.; Dalton King, H.; Hofstead, Sandra J.; Willner, David; Lasch, Shirley J.; Trail, Pamela A. Bioorganic and Medicinal Chemistry Letters, 2002 , vol. 12, # 11 p. 1529 - 1532

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Citation Number: 42

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 (IC50= 0.2 μM) that was equipotent to DOX with a near doubling of drug molecules/MAb. Size exclusion chromatography showed 18b to be ...