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Preclinical Trials with Combinations and Conjugates of T101 Monoclonal Antibody and Doxorubicin¹

San Diego Veterans Administration Medical Center [R. O. D.], University of California San Diego School of Medicine and Cancer Center [R. O. D., D. L. S., D. E. J.], Hybritech, Inc. [D. L. M., J. M. F.], and Scripps Clinic and Research Foundation [J. A. K.], La Jolla, California 92161

We investigated the potential for additive therapy for malignancy using an anti-human T-cell monoclonal antibody, T101, and the chemotherapy agent doxorubicin (DOX). We compared the efficacy of T101 alone, DOX alone, T101 and DOX covalently linked to dextran to form an immunoconjugate, T101 plus DOX mixed together and injected, T101 and DOX injected separately, and nonspecific murine IgG_2A plus DOX mixed together. Inhibition of [³H]thymidine was examined in vitro, and the clinical efficacy of each treatment was tested on human T-cell tumors growing in athymic mice. In vitro experiments confirmed retention of immunoreactivity and cytotoxicity by the immunoconjugate, but it was not superior to DOX alone. In efficacy experiments, all therapeutic arms were superior to placebo treatment (P < 0.05). However, the best results in the animal tumor model were obtained with T101 mixed with DOX, perhaps because of formation of weak complexes via hydrophobic bonds. This mixture was superior to all other treatments, both by growth curve analysis (P < 0.05) and by analysis of complete regression of tumor (P < 0.01). T101 mixed with DOX was superior to a mixture of nonspecific mouse immunoglobulin and DOX and superior to a combination of T101 injected i.v. and DOX injected i.p. The antitumor effect of T101 mixed with DOX was blocked by premodulating the target antigen with T101. These data suggest that further exploration into monoclonal antibody-anthracycline complexes is warranted.

¹ This work was supported by National Cancer Institute contracts NO1-CM-47672 and NO1-CM-26010, National Cancer Institute grants KO4-CA01091 and RO1-CA41582, the Veterans Administration, Hybritech, Inc., and the University of California, San Diego, Cancer Center.

² To whom requests for reprints should be addressed, at VAMC (V-111-E), 3350 La Jolla Village Drive, San Diego, CA 92161.

Received 12/11/85. Revised 6/ 9/86. Accepted 6/27/86.