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Long-Term Growth Suppression of Human Glioma Xenografts by Chemoimmunoconjugates of 4-Desacetylvinblastine-3-carboxyhydrazide and Monoclonal Antibody 9.2.27¹

Department of Pediatric Oncology, Zentrum Kinderheilkunde, Medizinische Hochschule Hannover, D-3000 Hannover 61, Germany [M. S.]; Lilly Research Laboratories, Indianapolis, Indiana 46285 [T. F. B., L. D. A., S. L. B., G. A. K.]; and The Scripps Research Institute, La Jolla, California 92037 [D. D. M., B. M. M., R. A. R.]

A conjugate of 4-desacetylvinblastine-3-carboxyhydrazide (DAVLBHY) and the glioma-reactive monoclonal antibody (mAb) 9.2.27 induced long-term suppression of tumor growth in athymic nude mice engrafted with U87MG human glioma cells. In vitro, DAVLBHY had the strongest antiproliferative activity (inhibitory concentration at which incorporation of [³H]thymidine is at 50% of untreated control is 2.0 x 10^-9 M) of seven cytotoxic drugs tested and so was chosen for conjugation to mAb 9.2.27, which reacts specifically with the core protein of chondroitin sulfate proteoglycans found in human glioblastomas. After conjugation of DAVLBHY to the carbohydrate residues of mAb 9.2.27 it retained its full binding capacity. For in vivo studies, DAVLBHY and several conjugate derivatives were evaluated by using two dosages of i.v. injections, each starting 2 days after s.c. tumor inoculation. The control tumors reached a volume of nearly 3000 mm³ within 30 days. Tumor growth was delayed by about 20 days with four i.v. injections of 0.5 mg/kg 9.2.27-DAVLBHY, which was slightly superior to the unconjugated drug. Moreover, 9.2.27-DAVLBHY produced a highly significant suppression of growth so that the average tumor volume was only 3% of that observed in untreated controls after 28 days. Four injections of this conjugate at a larger dose, 2.0 mg/kg, prevented recurrence of the tumors for 130 days in all animals tested, thus demonstrating a significant increase in the therapeutic index, since the unconjugated drug provided limited inhibition of tumor growth for only 40 days. The specificity of the antitumor effect was demonstrated in a comparison with the control conjugate, KS1/4-DAVLBHY, which despite partial tumor suppression had only a transient effect. The specific antitumor effect of 9.2.27-DAVLBHY was unexpected, since the target antigen is expressed at a relatively low density (40,000 sites/cell) on U87MG glioma cells.

¹ Supported in part by the Preuss Foundation for Brain Tumor Research, and by National Cancer Institute Outstanding Investigator Award 1R35CA42508.

² Recipient of a postdoctoral fellowship of the Deutsche Forschungsgemeinschaft, Germany.

³ To whom requests for reprints should be addressed, at The Scripps Research Institute, Department of Immunology, IMM13, 10666 N. Torrey Pines Road, La Jolla, CA 92037.

Received 8/23/91. Accepted 5/ 6/92.

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