Doxorubicin immunoconjugates containing bivalent, lysosomally-Cleavable dipeptide linkages
- Resource Type
- Article
- Authors
- 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.
- Source
- Bioorganic & Medicinal Chemistry Letters. Jun2002, Vol. 12 Issue 11, p1529. 4p.
- Subject
- *DOXORUBICIN
*PROTEOLYTIC enzymes
- Language
- ISSN
- 0960-894X
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 a noncovalent dimer that was formed immediately upon conjugation. [Copyright &y& Elsevier]