BIOCONJUGATION OF TUMOR-NECROSIS-FACTOR-ALPHA WITH THE COPOLYMER OF DIVINYL ETHER AND MALEIC-ANHYDRIDE INCREASING ITS ANTITUMOR POTENCY

To enhance the therapeutic usefulness of antitumor cytokines in vivo w e synthesized bioconjugated tumor necrosis factor-alpha (TNF-alpha) wi th divinyl ether and maleic anhydride copolymer (DIVEMA), which has in trinsic antitumor activity as a synthetic biological response modifier , The degree of modification could be controlled by the addition of a, 3-dimethylmaleic anhydride (DMMAn), which binds to amino groups of TNF -alpha by changing the pH. In addition, the specific activity of DIVEM A-TNF-alpha was hardly decreased in vitro. DIVEMA-TNF-alpha showed a m arked antitumor effect compared to native TNF-alpha without any side e ffects such as sudden death, body-weight reduction, and decrease in pl atelet count on mice bearing solid tumors. These results suggest that DIVEMA is a useful polymeric modifier for bioconjugation of TNF-alpha in order to increase its antitumor activity, and multifunctionally bio conjugated TNF-alpha may be a potentiated antitumor agent for therapeu tic use. (C) 1997 Academic Press.