Monoclonal antibody therapy of human malignancies is infrequently associated with either clinical responses or inflammatory infiltrates in tumor that are composed of tumoricidal effector cells. Antibody-dependent cellular cytotoxicity (APCC), a potent in vitro tumoricidal mechanism, appears to be less important in eradicating tumors in vivo. New strategies that exploit the ability of murine antibodies to target tumor cells and interact with tumoricidal host effector cells are needed. Antibodies that mind to effector cells and trigger cytotoxicity via either 1) the C03 molecule or antigen receptor on T cells, 2) the Fcy receptor for aggregated immunoglobulin expressed by large Sranuler lymphocytes (LGL's) or 3) the high affinity Fcy receptor expressed by mononuclear phagocytes have teen identified. Such antibodies, when chemically linked to anti-tumor antibodies, potentiate in vitro tumor lysis by the relevant effector cells. In contrast to ADCC, these effects are resistant to competition by excess human immunoglobulin. The present proposal provides for the preparation of be specific monoclonal antibodies, derived by cell fusion, that bind tumor-associated antigens and the Fcy receptor (FcyR III) expressed by LGL's, a potent cytotoxic cell population. These antibodies promote high affinity interactions between tumor targets and affecters and trigger effector cell cytotoxicity. Conditions that promote optimal in vitro bispecific antibody-mediated lysis of relevant tumor cells by interleukin-2 activated peripheral blood mononucluar cells and LGL's will be identified. The ability of these antibodies to focus LGL's at tumor sites and mediate tumor regression will bs tested in vivo using a human tumor xenograft model in nude mice. A syngeneic tumor model using bispecific antibodies containing anti-murine FcyR II specificity will also be developed since interpretation of results in a human tumor xenograft model that uses human effector cells may be difficult. These studies will provide insight into those factors that promote bispecific antibody-mediated inflammatory infiltrates in tumor, the relevance of these infiltrates to anti-tumor effects and the potential of this approach in the treatment of human malignancies.
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