| 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. |
| Authors | Gene M Dubowchik, Raymond A Firestone, Linda Padilla, David Willner, Sandra J Hofstead, Kathleen Mosure, Jay O Knipe, Shirley J Lasch, Pamela A Trail
(Affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 5100, Wallingford, Connecticut 06492, USA. Gene.Dubowchik at bms.com)
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| Journal | Bioconjugate chemistry
(Bioconjug Chem)
2002 Jul-Aug
Vol. 13
Issue 4
Pg. 855-69
ISSN: 1043-1802 United States |
| PMID | 12121142
(Publication Type: Journal Article)
|
| Chemical References |
- Antibodies, Monoclonal
- Antigens, Neoplasm
- BR96-doxorubicin immunoconjugate
- Cross-Linking Reagents
- Dipeptides
- Enzymes
- Lewis Blood-Group System
- 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 System
(immunology)
- Lysosomes
(enzymology, metabolism)
- Rats
- Tumor Cells, Cultured
|
