Targeting Phosphatidylserine for Radioimmunotherapy of Breast Cancer Brain Metastasis.

摘要

Brain metastasis occurs in approximately 30% of metastatic breast cancer patients. The prognosis is extremely poor, with a median survival of 4-6 months even with aggressive treatment. Thus, there is an urgent need to develop new treatments that target brain metastases. Radioimmunotherapy (RIT) is a targeted therapy that uses radiolabeled antibodies against tumor-specific antigens to treat lymphoma patients. However, success of RIT in the therapy of solid tumors has generally been limited due to heterogeneous tumor expression of the target antigens and cross-reactivity with normal cells. In preliminary studies, we have demonstrated that phosphatidylserine (PS) is exposed exclusively on tumor vascular endothelium of brain metastases in mouse models. A novel PS-targeting antibody, PGN635, a fully human monoclonal antibody, was used to target exposed PS in the brain metastases. Our data show that PGN635 binds specifically to tumor vascular endothelial cells in multi-focal brain metastases throughout the whole mouse brain. Vascular endothelium in normal brain tissues is negative. Furthermore, pretreatment with 10Gy of whole brain radiation significantly increased PGN635 binding to tumor vascular endothelial cells and tumor cells by increasing their exposure of PS. Vasculature in irradiated normal brain remained negative for exposed PS.