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Antitumor Activity of Carcinoma-reactive BR96-Doxorubicin Conjugate against Human Carcinomas in Athymic Mice and Rats and Syngeneic Rat Carcinomas in Immunocompetent Rats¹

Unit of Tumor Immunology, Department of Cell and Molecular Biology, Wallenberg Laboratory, University of Lund, 220 07 Lund, Sweden [H. O. S., M. I.]; Bristol-Myers Squibb Pharmaceutical Institute, Wallingford, Connecticut 06492 [D. W.]; and Bristol-Myers Squibb Pharmaceutical Institute, Seattle, Washington 98121 [I. H., K. E. H., P. A. T.]

The internalizing monoclonal antibody BR96 was conjugated to the anticancer drug doxorubicin (DOX) using an acid-labile hydrazone bond to DOX and a thioether bond to the monoclonal antibody. The resulting conjugate, termed BR96-DOX, binds to a tumor-associated Lewis^y antigen that is abundantly expressed on the surface of human carcinoma cells. BR96-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. Unconjugated DOX, given at its maximum tolerated dose, and matching doses of nonbinding IgG-DOX conjugate were not active against RCA or BN7005 carcinomas. An anticonjugate antibody response was produced in BN rats treated with BR96-DOX. However, this could be largely prevented by administering the immuno-suppressive drug deoxyspergualin. These results 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 therapy in a model in which the tumor is syngeneic and the host is immunocompetent.

¹ This work was supported by the Bristol Myers Squibb Pharmaceutical Research Institute and the Swedish Medical Research Council.

² To whom requests for reprints should be addressed, at Unit of Tumor Immunology, Department of Cell and Molecular Biology, Wallenberg Laboratory, Box 7031, 220 07 Lund, Sweden.

Received 2/ 5/97. Accepted 8/ 7/97.

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