Bispecific antibodies (Bsab) that bind to human Fc gamma receptor III (Fc-gamma RIII) promote the lysis of targeted tumor cells by human natural killer cells and macrophages. In a Phase I clinical trail, treatment with the murine Bsab 2B1, which binds to the human receptors c-erbB-2 and Fc-gamma RIII, induced potent immunologic activation, reflected by the systemic release of cytokines such as TNF-alpha, with preliminary evidence of clinical activity and the prolonged production of host antibodies reactive with c-erbB-2. The specificity of the antibody responses was directed against intracellular epitopes more frequently than to extracellular epitopes of c-erbB-2, with reactivity to multiple epitopes noted in several patients. These observations can be explained by Bsab-promoted cytolysis, leading to antigen presentation and subsequent induction of adaptive immune responses. The applicant aims to build on this unique observation by testing the hypotheses that: (i) treatment with 2B1 leads to host T cell responses which can be manipulated to clinical advantage; (ii) the Fc domain of 2B1, which directly interacts with a distinct Fc-gamma receptor, Fc-gamma RII, contributes to the ability of 2B1 to induce adaptive immune responses; and (iii) the anti-tumor properties of Bsab can be enhanced by improving the selective tumor targeting of these molecules by increasing the affinity of these molecules for tumor antigens. To test these hypotheses, the applicant will: 1) Characterize antibody and T cell immune responses in patients treated with single agent 2B1 in a Phase II trial in metastatic breast cancer, and in a Phase I trial of 2B1 plus GM-CSF and IL-2; 2) Develop further immunodeficient and immunocompetent human Fc-gamma RIII transgenic mouse models for 2B1 and other Bsab therapy; 3) Test the properties of 2B1 and related Bsab in these murine models to identify the Bsab structural features that are associated with optimal anti-tumor effects.
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