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Cathepsin B-labile dipeptide linkers for lysosomal release of doxorubicin from internalizing immunoconjugates: model studies of enzymatic drug release and antigen-specific in vitro anticancer activity.

Abstract
The anticancer drug doxorubicin (DOX) has been linked to chimeric BR96, an internalizing monoclonal antibody that binds to a Lewis(y)-related, tumor-associated antigen, through two lysosomally cleavable dipeptides, Phe-Lys and Val-Cit, giving immunoconjugates 72 and 73. A self-immolative p-aminobenzyloxycarbonyl (PABC) spacer between the dipeptides and the DOX was required for rapid and quantitative generation of free drug. DOX release from model substrate Z-Phe-Lys-PABC-DOX 49 was 30-fold faster than from Z-Val-Cit-PABC-DOX 42 with the cysteine protease cathepsin B alone, but rates were identical in a rat liver lysosomal preparation suggesting the participation of more than one enzyme. Conjugates 72 and 73 showed rapid and near quantitative drug release with cathepsin B and in a lysosomal preparation, while demonstrating excellent stability in human plasma. Against tumor cell lines with varying levels of BR96 expression, both conjugates showed potent, antigen-specific cytotoxic activity, suggesting that they will be effective in delivering DOX selectively to antigen-expressing carcinomas.
AuthorsGene M Dubowchik, Raymond A Firestone, Linda Padilla, David Willner, Sandra J Hofstead, Kathleen Mosure, Jay O Knipe, Shirley J Lasch, Pamela A Trail
JournalBioconjugate chemistry (Bioconjug Chem) 2002 Jul-Aug Vol. 13 Issue 4 Pg. 855-69 ISSN: 1043-1802 [Print] United States
PMID12121142 (Publication Type: Journal Article)
Chemical References
  • Antibodies, Monoclonal
  • Antigens, Neoplasm
  • BR96-doxorubicin immunoconjugate
  • Cross-Linking Reagents
  • Dipeptides
  • Enzymes
  • Lewis Blood Group Antigens
  • Lewis Y antigen
  • Doxorubicin
  • Cathepsin B
Topics
  • Animals
  • Antibodies, Monoclonal (pharmacokinetics)
  • Antigens, Neoplasm (immunology)
  • Cathepsin B (metabolism)
  • Cell Division (drug effects)
  • Cross-Linking Reagents (chemistry, metabolism)
  • Dipeptides (chemistry, metabolism)
  • Doxorubicin (chemical synthesis, pharmacokinetics)
  • Drug Stability
  • Enzymes (metabolism)
  • Humans
  • Kinetics
  • Lewis Blood Group Antigens (immunology)
  • Lysosomes (enzymology, metabolism)
  • Rats
  • Tumor Cells, Cultured

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