MODIFIED TNF-ALPHA: AN ANTI CANCER THERAPY

DESCRIPTION (PROVIDED BY APPLICANT): The long-term goal of the proposed research is the development of effective anti-cancer agents, modified human tumor necrosis factor-alphas (hTNFas). TNFa is a potent anti-neoplastic agent but its therapeutic application has been limited by its significant side effects. However, TNFa can be modified so that it retains its anti-tumor activities while its deleterious effects are reduced. This has been accomplished by mutation of TNFa and derivitization of TNFa with polyethylene glycol (PEG). This proposal focuses on the characterization and comparison of mutant and wild hTNFas modified with 20 kDa PEGs. The specific aims are to: 1) pharmacologically characterize the PEG-hTNFas, toxicity analyses after a single high dose of PEG-TNFa and a prolonged PEG-TNFa treatment; 2) define TNFa anti-cancer features, analyses of: a)anti-tumor efficacies in syngeneic and athymic mice with B16 melanomas, b)affinities of the PEG- hTNFas for hTNF receptors I and II (prerequisite for clinical trials); and 3) determine the anti-human tumor efficacies of these PEG-hTNFas, treatment of athymic mice bearing human colon carcinomas. PROPOSED COMMERCIAL APPLICATION: This proposal focuses on the development of new therapeutic agents, PEG-hNTFas effective against a wide range of solid tumors. Novel geatures of modified hTNFas include the likelihood of a marked synergy with cytotoxic chemotherapeutic agents and the potential to target the tumor vasculature and the host immune system.