The research projects proposed are to elucidate - directly or indirectly - the molecular mechanisms of a novel concept of inducing tumor cell killing: the target-specific activation by a potent biological response modifier of one of the body's own cytotoxic mechanism: complement. We synthesized hybrid proteins consisting of the complement-activating cobra venom factor (CVF) and monoclonal antibodies to tumor associated antigens. By themselves non-toxic, the hybrid proteins became a specific and efficient cytolytic agent for human tumor cells in the presence of serum complement in vitro and in vivo. The proposed research projects include: 1) Analysis of the molecular mechanisms of monoclonal antibody-induced and hybrid-induced complement-mediated killing of tumor cells including resistance phenomena and their manipulation by metabolic inhibitors. 2) Synthesis of hybrid proteins with different heterobifunctional crosslinking reagents to select the optimal crosslinker. 3) Studies of the effect of hybrid proteins in normal animals including clearence from the circulation and non-specific localization into tissues. 4) Studies of the effect of hybrid proteins in athymic animals bearing human tumors including localization into the tumors and their tumor-suppressive activity. 5) Studies to elucidate the structural differences between CVF and C3 in order to generate a human C3 derivative with CVF-line activity which migth replace CVF in hybrid proteins. This approach would result in a target-specific, non-toxic and non-immunogenic cytotoxic agent.
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