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[Cancer Research 59, 2917-2923, June 1, 1999]
© 1999 American Association for Cancer Research
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[Cancer Research 59, 2917-2923, June 15, 1999]
© 1999 American Association for Cancer Research

Experimental Therapeutics

Tumor Pretargeting with Avidin Improves the Therapeutic Index of Biotinylated Tumor Necrosis Factor {alpha} in Mouse Models1

Anna Gasparri, Monica Moro, Flavio Curnis, Angelina Sacchi, Stefano Pagano, Fabrizio Veglia, Giulia Casorati, Antonio G. Siccardi, Paolo Dellabona and Angelo Corti2

Department of Biological and Technological Research [A. G., M. M., F. C., A. S., S. P., G. C., P. D., A. C.] and Unit of Biostatistics [F. V.], San Raffaele H Scientific Institute, and Department of Biology and Genetics for Medical Sciences, University of Milan [A. G. S.], 20132 Milan, Italy

The clinical use of tumor necrosis factor {alpha} (TNF) as an anticancer drug is limited to local or locoregional administration because of dose-limiting systemic toxicity. We investigated in animal models whether the therapeutic index of systemically administered human or murine TNF can be increased by tumor pretargeting strategies based on the biotin-avidin system. Pretargeting of s.c. mouse WEHI-164 fibrosarcoma and RMA lymphoma genetically engineered to express the Thy 1.1 antigen on the cell membrane was achieved by i.p. injection of a biotinylated anti-Thy 1.1 antibody and avidin. This pretreatment increased the antitumor activity of systemically administered biotin-TNF conjugates by at least 5-fold. In contrast, pretargeting did not increase the toxicity of biotin-TNF, as judged by animal survival and weight loss after treatment. Ex vivo analysis of tumor cells 24 h after treatment showed that biotin-TNF persisted for several hours on the surface of pretargeted tumors, but not when avidin was omitted. The potentiation of the antitumor effects was related primarily to indirect mechanisms, involving a host-mediated response. The results indicate that tumor pretargeting improves the antitumor activity of TNF. Tumor pretargeting with avidin, which is currently used to increase the uptake of radioactive-labeled biotin in patients, could represent a new strategy for improving the therapeutic index of TNF.




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Copyright © 1999 by the American Association for Cancer Research.