Folic acid receptor 1 (FOLR1, FRα) is highly expressed in 80% of ovarian tumors and has a low nanomolar affinity for folic acid. Although ovarian tumors are intrinsically immunogenic, immune reactions to them are inhibited by a suppressive environment. We are developing a bispecific anti-CD3-folate to redirect T cells to engage with and kill tumor cells. Folic acid was site-specifically conjugated to a FAb fragment of an anti-CD3 antibody through an engineered linkable non-natural amino acid. Anti-CD3-folate bispecific FAb is able to engage T cells and exert cytotoxicity in a variety of tumor cell lines including ovarian; OV-90, OVCAR3, and breast cancer; SKOV-3. Cytotoxicity assays generated EC50 in the femtomolar range. This cytotoxicity could be modulated by varying folic acid concentrations in the assay medium. T-cell activation was confirmed by appearance of activation markers on the cell surface and secretion of pro-inflammatory cytokines after treatment of tumor cells in combination with human PBMC's. T cell activation and subsequent cytokine release is dependent on simultaneous binding of tumor and T cell to anti-CD3-Folate. In a xenograft mouse model of ovarian cancer, anti-CD3-folate significantly inhibited tumor growth, and increased life span (ILS)of 30% and 50% for SKOV-3 and OV-90, respectively when compared to control treated animals. These data suggest that anti-CD3-folate bispecifc FAb- mediated T cell engagement could be a powerful tool for immune-ablation of ovarian cancer.
Citation Format: Jinming Xia, Kristine deDios, Evelyn Rodrigo, Robin Humphreys, Alan Wahl, Marco Gymnopoulos. Bispecific anti-CD3-folate for the treatment of ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A58.