AN ANTIMELANOMA IMMUNOTOXIN CONTAINING RECOMBINANT HUMAN TUMOR-NECROSIS-FACTOR - TISSUE DISPOSITION, PHARMACOKINETIC, AND THERAPEUTIC STUDIES IN XENOGRAFT MODELS

The ability of monoclonal antibody conjugates to re-direct plant or ba cterial toxins, chemotherapeutic agents and radionuclides to selected target cells has been well-documented. Recombinant human tumor necrosi s factor (TNF) is a macrophage-derived, non-glycosylated (17 kDa) pept ide with a broad range of biological and immunological effects includi ng antiviral activity, cytotoxic and cytostatic effects. A conjugate o f the antimelanoma antibody ZME-018 and TNF in previous studies has sh own melanoma-selective cytotoxic effects in vitro. Pharmacokinetic stu dies of the ZME-TNF immunotoxin showed that the agent cleared from pla sma biphasically with alpha- and beta-phase half-lives similar to that of ZME itself (72 min and 36 h compared to 84 min and 41 h respective ly). In contrast, TNF itself was cleared rapidly from plasma with a te rminal-phase half-life of only 2.7 h. The clearance rate of ZME-TNF fr om plasma (Cl-p) was almost tenfold more rapid than for ZME (1.1 versu s 0.16 ml/kg x min) but was threefold slower than the clearance for TN F itself (3.4 ml/kg x min). Tissue distribution studies in nude mice b earing human melanoma xenografts showed similar tumor localization of the immunotoxin compared to the free antibody and slightly higher conc entrations in liver and kidney compared to ZME itself. Treatment of nu de mice bearing well-developed A375 tumors with the immunotoxin result ed in a statistically significant (P <0.002) suppression in tumor grow th rate (fivefold increase) compared to saline-treated controls, which increased 20-fold over the same period. These studies demonstrate the feasibility of this approach and suggest that TNF may represent a non -antigenic alternative to immunotoxins containing plant and bacterial toxins.