The effective treatment of human malignancies with unconjugated monoclonal antibodies which mediate antibody-dependent cellular cytotoxicity (ADCC) may be limited by inadequate interactions between antibody Fc domains and effector cell Fcgamma receptors which are already occupied by host immunoglobulin. Bispecific monoclonal antibodies (BsMAbs) which bind to tumor antigens and defined effector cell cytotoxicity trigger molecules via their Fab domains have been found to surmount this obstacle, improving conjugation of effector cells and tumor targets and potentiating lysis of relevant tumor. We have developed and tested BsMAbs which bind to tumor antigens and the 3G8 epitope of the human Fcgamma receptor FcgammaRIII, which is the low affinity Fcgamma receptor for aggregated immunoglobulin, expressed by large granular lymphocytes (LGLs) and macrophages. these BsMAbs efficiently promote relevant tumor lysis by these effectors in the presence of competing human immunoglobulins, and possess substantial anti-tumor effects against in vitro organized tumor and in xenograft animal models. These findings allow testing of the central hypothesis of this proposal: i.e. Therapy with a BsMAb targeting tumor and the low affinity Fcgamma receptor will promote in vivo effector cell:tumor conjugation, leading to tumor infiltration by relevant, cytotoxic effector cells. In the new Specific Aim 1, this will be accomplished by optimizing and determining the relevant mechanisms of anti-tumor effects in the existing xenograft models. The development of new syngeneic models of BsMAb therapy will permit direct examination of the relative contributions of LGLs and macrophages to tumor infiltration and therapeutic efficacy.
Specific Aim 2 proposes to further characterize the cytotoxic phenotype of FcgammaRIII-expressing effectors by examining the contributions of defined cell adhesion molecule interactions to cytotoxicity, employing selected cytokines to induce proliferation and differentiation of optimally cytotoxic phenotypes. for improved conjugation and cytotoxicity promoted by BsMAbs to be of clinical significance, relevant effectors or their precursors must be able to traffic to tumor.
Specific Aim 3 proposes in vitro examination of factors regulating migration of FcgammaRIII-expressing cells through vascular endothelium to tumor with the goal of selectively promoting this migration. Verification of in vitro results in the syngeneic animal models will clarify the relevance of the proposed in vitro models, and permit direct comparison of cytotoxic and migratory effector cell phenotypes. Such information will provide future directions for the targeted cellular therapy of cancer.
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