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Antibody-NKG2D Ligand Fusion Protein for Breast Cancer Therapy
Background: NKG2D ligands activate the NKG2D receptor expressed on effector cells belonging to the innate and adaptive immune systems, thereby linking the innate and adaptive immune response. Over-expression of NKG2D ligands on tumor cells leads to tumor regression in murine tumor models. Objectives/Hypothesis: We propose the direct targeting of NKG2D ligands to tumor cells using an antibody-NKG2D ligand (Rae-1©¬) fusion protein targeted against the breast tumor antigen HER2. We hypothesize that antibody homing to HER2-positive tumor cells will deliver the NKG2D ligand to tumor cells. Local delivery of NKG2D ligand will effectively re-target NK cell cytotoxicity to tumor cells, leading to an enhanced innate response and priming of an adaptive response mediated by CD8+ T cells. Specific Aims: I. Investigation of the immune properties of anti-HER2 antibody-Rae-1©¬ fusion proteins in vitro. II. Study ability of the antibody-Rae-1©¬ fusion protein in vivo to inhibit tumor growth in murine tumor models. Study Design: We will characterize activity of Rae-1©¬ fusions in vitro, and identify candidate molecules for in vivo testing. We will investigate the kinetics of NKG2D receptor, perforin, or cytokine (IFN-¥ã, or TNF-¥á) expression in NK cells in response to the anti-HER2 IgG3-Rae-1©¬ fusion proteins. We will then examine whether targeting of the anti-HER2 IgG3-Rae-1©¬ fusion protein to HER2+ tumors will inhibit tumor growth in vivo. Using cytotoxic factor deficient mouse models and/or lymphocyte subset depletion studies, we will explore the mechanisms of anti-tumor activity of the Rae-1©¬ fusion protein. Potential Outcomes and Benefits of the Research: The FDA-approved anti-HER2 antibody Trastuzumab is effective in a subset of HER2+ breast cancer patients. Trastuzumab activity may be mediated through direct effects on signaling and/or through immunologic effects, e.g. antibody dependent cytotoxicity. Antibody-Rae1©¬ fusion may improve Trastuzumab activity by enhancing response through effector cell (NK, CD8+ T cell) activation. If this concept is proved in mouse models, the murine NKG2D ligand in the antibody fusion molecule can be replaced with human NKG2D ligands for testing in man. Antibody-NKG2D ligand fusion protein could also potentially be used to treat other malignancies by substituting other tumor specificities in the antibody domain.
Surgical removal of tumor in combination with radiation and chemotherapy is generally used to eradicate breast cancer. However, micrometastatic residual disease frequently leads to relapse. The objective of the proposal is to develop novel antibody fusion proteins that are designed to target residual disease and activate a specific host anti-tumor immune response. NKG2D ligands activate immune cells via the NKG2D receptor leading to innate and/or adaptive response. Over-expression of NKG2D ligands has led to tumor regression in several mouse tumor models. We propose the direct targeting of NKG2D ligands to tumor cells using an antibody-NKG2D ligand (Rae-1©¬) fusion protein directed against the HER2 antigen, which is expressed on the surface of many aggressive breast cancers. The FDA-approved anti-HER2 antibody (Trastuzumab) is effective only in minority of HER2+ breast cancer patients. Local delivery of Rae-1©¬ will effectively re-target immune cells to tumor cells, leading to an enhanced innate response and facilitate the priming of an adaptive response. Antibody-Rae 1©¬ fusion may therefore improve Trastuzumab activity. Antibody-NKG2D ligand fusion proteins could potentially be used to treat other malignancies, or non-HER2 expressing tumors by substituting other tumor specificities in the antibody domain.