ADC Cytotoxin
English Public
Drug Potency and ADC Activity
Early ADCs used clinically approved chemotherapeutic drugs because of their ready availability, amenability to chemical manipulation and their well known toxicological properties. Much about the strengths and pitfalls of antibody-mediated drug delivery was learned from BR96-doxorubicin, an ADC directed against the LewisY tetra-saccharide antigen on human carcinomas. Doxorubicin was attached to a chimeric version of the BR96 antibody, through an acid-labile hydrazone linker. Upon binding to the antigen, the antibody was internalized and doxorubicin released within acidic endosomal and lysosomal vesicles. Treatment of tumor-bearing mice and rats with BR96-doxorubicin led to immunologically specific tumor cures, albeit at high (>100 mg/kg) doses, reflecting the low potency of the targeted drug. In a phase I clinical trial, the maximum-tolerated dose of BR96-doxorubicin was ~700 mg/m2, with dose-limiting gastrointestinal toxicities. In a subsequent phase II trial, the toxicities were attributed to normal gut expression of LewisY. In both trials, limited antitumor activity was obtained. Thus, the limitations of BR96-doxorubicin include low molar potency of the cytotoxic drug and antigen expression on sensitive normal tissue. Additionally, the hydrazone linker had a half-life of ~43 hours that was ~7-fold lower than the pharmacokinetic terminal half-life of the BR96 antibody. https://www.bocsci.com/tag/adcs-cytotoxin-487.html
Early ADCs used clinically approved chemotherapeutic drugs because of their ready availability, amenability to chemical manipulation and their well known toxicological properties. Much about the strengths and pitfalls of antibody-mediated drug delivery was learned from BR96-doxorubicin, an ADC directed against the LewisY tetra-saccharide antigen on human carcinomas. Doxorubicin was attached to a chimeric version of the BR96 antibody, through an acid-labile hydrazone linker. Upon binding to the antigen, the antibody was internalized and doxorubicin released within acidic endosomal and lysosomal vesicles. Treatment of tumor-bearing mice and rats with BR96-doxorubicin led to immunologically specific tumor cures, albeit at high (>100 mg/kg) doses, reflecting the low potency of the targeted drug. In a phase I clinical trial, the maximum-tolerated dose of BR96-doxorubicin was ~700 mg/m2, with dose-limiting gastrointestinal toxicities. In a subsequent phase II trial, the toxicities were attributed to normal gut expression of LewisY. In both trials, limited antitumor activity was obtained. Thus, the limitations of BR96-doxorubicin include low molar potency of the cytotoxic drug and antigen expression on sensitive normal tissue. Additionally, the hydrazone linker had a half-life of ~43 hours that was ~7-fold lower than the pharmacokinetic terminal half-life of the BR96 antibody. https://www.bocsci.com/tag/adcs-cytotoxin-487.html
by alexded
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