One of the main mechanisms by which clinically approved anti-cancer antibodies, Herceptin and Rituxan, mediate their anti-tumor effect is by antibody-dependent cell-mediated cytotoxicity (ADCC) 1,2,3. In a xenograft model in mice deficient in the inhibitory Fc-gammaRIIB4, Herceptin demonstrated substantially increased tumor clearance compared to wild-type mice. Furthermore, in a syngeneic Fc-gammaRIIB4-deficient mouse tumor model, an anti-melanoma antibody resulted in 100-fold greater reduction of tumor load than in wild type mice, indicating that engagement of Fc-gammaRIIB by therapeutic antibodies may limit their effectiveness. The observation that deletion of Fc-gammaRIIB increases protection in nude mice implicates involvement of effector cells other than NK cells, which lack Fc-gammaRIIB. Monocytes and macrophages, which express Fc-gammaRIIB, are the likely effector populations whose recruitment and anti-tumor effect may be limited by the engagement of the inhibitory Fc-gammaRIIB. An agent aimed at blocking Fc-gammaRllB can be envisioned to have tremendous value in the elimination of tumor cells by lowering their triggering threshold through the activating Fc receptors and enhancing ADCC activity of tumor-specific antibodies. In this proposal, it is hypothesized that the therapeutic effect, of approved tumor-specific antibodies and those under development, may be enhanced by concomitant administration of a blocking antibody to the inhibitory Fc receptor, Fc-gammaRIIB. MacroGenics, Inc., has selected 2B6, a murine monoclonal antibody specifically directed against the human Fc-gammaRIIB receptor, from a panel of antibodies to evaluate its role in enhancing tumor clearance. Of note, these are the first set of monoclonal antibodies directed specifically against the human inhibitory receptor, Fc-gammaRIIB. It is hypothesized here that blocking the inhibitory pathway with this Fc-gammaRIIB-specific antibody will lower the threshold for the activation signal, augmenting ADCC, and hence enhance tumor clearance. The role of 2B6 will be tested along with an anti-Her2neu antibody, 4D5 (the parent molecule of Herceptin) in xenograft nude mouse models of ovarian and breast cancer with adoptively transferred human monocytes. These studies are proposed as proof-of-concept for the use of anti-Fc-gammaRIIB antibodies in enhancing the effectiveness of anti-tumor therapeutics whose in vivo mechanism of action is mediated by ADCC. A successful study could therefore impact on and benefit a large numbers of cancer patients in the future.
Thesaurus Terms: antibody receptor, antireceptor antibody, breast neoplasm, cell mediated cytotoxicity, drug design /synthesis /production, monoclonal antibody, neoplasm /cancer immunotherapy, ovary neoplasm CD antigen, antitumor antibody, disease /disorder model, macrophage, monocyte, nonhuman therapy evaluation, protooncogene athymic mouse, cell line, clinical research, human genetic material tag, human tissue, immunocytochemistry
