Doxorubicin: monoclonal antibody conjugate for therapy of human cervical carcinoma

Abstract

Doxorubicin (Dox) was conjugated via a dextran linker to the F(ab′)₂ fragment of monoclonal antibody (MAb) IH10 which recognizes an antigen expressed on the surface of human cervical carcinoma cells and tissues. Drug‐antibody conjugates (IH10‐Dox) with a molar ratio of Dox to MAb ranging from 40:1 to 60:1 retained antigen‐binding and pharmacological activities. Anti‐tumor activity of the conjugate in vitro was evaluated by measuring inhibition of [5‐³H]‐uridine incorporation into cellular RNA. IH10‐Dox was found to be 30 times more toxic to cervical tumor cells than a control MAb‐Dox conjugate and 150 times more potent than Dox coupled to dextran. In addition, IH10‐Dox was less toxic to antigen‐negative cells in vitro, suggesting that IH10‐Dox killing of cervical carcinoma cells was antibody‐mediated. ¹²⁵I‐labeled IH10‐Dox preferentially localized in solid human cervical carcinoma xenografts in athymic mice with tumor‐to‐blood ratios of IH10‐Dox reaching 17.9 after 24 hr and 32.8 after 48 hr. Treatment of athymic mice bearing human cervical tumors with IH10‐Dox resulted in a dose‐dependent inhibition of tumor growth. Multiple administrations of IH10‐Dox at a dose corresponding to 20 μg doxorubicin significantly suppressed the growth of human cervical tumors in nude mice without significant side effects (weight loss), and this suppression was antibody specific. Both i.p. and i.v. administration of IH10‐Dox were found to be equally effective. Our results suggest that IH10‐Dox may be useful for the treatment of human cervical carcinoma.