Treatment of human malignancies with unconjugated murine monoclonal antibodies infrequently leads to meaningful clinical responses, possibly because these antibodies do not bind to cytotoxic effector cells in vivo via their Fc domains due to competition from circulating immunoglobulins. This limits the ability of these antibodies to focus a host immune response against tumor. Bispecific monoclonal antibodies (BsMAb) which have dual specificity for tumor antigens and epitopes outside the immunoglobulin Fcc binding domain of Fc-gamma receptor III (Fc-gamma-RIII) trigger tumor antigen-specific cytotoxicity by large granular lymphocytes (LGL) and macrophages in the presence of competing human immunoglobulin or whole blood, and possess activity in human tumor xenograft models in scid mice. One such BsMAb, designated 2B1, has dual specificity for the extracellular domain of c-erbB2 protein and the 3G8 epitope of Fc-gamma- RIII; an ongoing Phase IA trial will identify the Phase II working dose of this BsMAb. This BsMAb is a suitable reagent to test the central hypothesis of this work, which is that BsMAb therapy can promote the accumulation of relevant cytotoxic effector cells at tumor sites, with therapeutic results. The first specific aim of this proposal is to determine the efficacy of 2B1 BsMAb therapy and the ability of 2B1 to induce effector cell infiltration of tumor. To accomplish this objective, a Phase IB/II trial of intravenously administered 2B1 in women with metastatic breast cancer will be conducted. A minimum of 10 patients will have biopsy-accessible disease to address the tumor infiltration question, and a minimum of 14 patients will have measurable disease to answer the efficacy considerations. The second specific aim is to enhance BsMAb- targeted LGL migration to tumor by expanding this effector cell population and modifying capillary endothelial permeability in a Phase IA/lB trial of 2B1 plus interleukin-2 (lL-2) to permit the selective retention of 2B1- directed LGL at tumor sites. The third specific aim is to expand and utilize mononuclear phagocytes and Fc-gamma-RIII-expressing effector cells in a Phase IA/IB trial of 2B1 and macrophage-colony stimulating factor- based treatment. The clinical trial designs permit the retrospective comparisons of the tumor biopsy studies in all three clinical trials, and will yield information about the relative effects of each treatment program on relevant effector cell migration or proliferation at tumor sites. At the conclusion of these studies, the efficacy of 2B1 therapy in breast cancer will be known, and the effects of concomitant therapy with other biologic agents on selected critical endpoints will be better understood. These studies will be performed by a consortium of investigators experienced in the conduct of complex, collaborative, early phase clinical trials of novel biologic agents and strategies. As the involved investigators are key participants in the Biologic Response Modifiers Committee of the Eastern Cooperative Oncology Group (ECOG), subsequent development of 2B1 will occur with the ECOG.
| Borghaei, Hossein; Alpaugh, R Katherine; Bernardo, Patricia et al. (2007) Induction of adaptive Anti-HER2/neu immune responses in a Phase 1B/2 trial of 2B1 bispecific murine monoclonal antibody in metastatic breast cancer (E3194): a trial coordinated by the Eastern Cooperative Oncology Group. J Immunother 30:455-67 |
| Weiner, L M; Alpaugh, R K; von Mehren, M (1997) Redirected cellular cytotoxicity employing bispecific antibodies and other multifunctional binding proteins. Cancer Immunol Immunother 45:190-2 |
| Weiner, L M; Clark, J I; Ring, D B et al. (1995) Clinical development of 2B1, a bispecific murine monoclonal antibody targeting c-erbB-2 and Fc gamma RIII. J Hematother 4:453-6 |
