ANTITUMOR-ACTIVITY OF CARCINOMA-REACTIVE BR96-DOXORUBICIN CONJUGATE AGAINST HUMAN CARCINOMAS IN ATHYMIC MICE AND RATS AND SYNGENEIC RAT CARCINOMAS IN IMMUNOCOMPETENT RATS

The internalizing monoclonal antibody BR96 was conjugated to the antic ancer drug doxorubicin (DOX) using an acid-labile hydrazone bond to DO X and a thioether bond to the monoclonal antibody, The resulting conju gate, termed BR96-DOX, binds to a tumor-associated Lewis(y) antigen th at is abundantly expressed on the surface of human carcinoma cells, BR 96-DOX binds to RCA, a human colon carcinoma cell line, and BN7005, a transplantable colon carcinoma induced in a Brown Norway (BN) rat by 1 ,2-dimethyl-hydrazine. BR96-DOX produces cures of established s.c. RCA human colon carcinomas in athymic mice and rats, BR96-DOX also cured both s.c. and intrahepatic BN7005 tumors in immunocompetent BN rats. U nconjugated DOX, given at its maximum tolerated dose, and matching dos es of nonbinding IgG-DOX conjugate were not active against RCA or BN70 05 carcinomas, An anticonjugate antibody response was produced in BN r ats treated with BR96-DOX, However, this could be largely prevented by administering the immunosuppressive drug deoxyspergualin. These resul ts confirm the concept of antibody-directed therapy in models in which the targeted antigen is expressed both in normal tissues and tumors, The findings in BN7005 further demonstrate efficacy of BR96-DOX therap y in a model in which the tumor is syngeneic and the host is immunocom petent.