Abstract 6244: A T cell engaging bispecific antibody utilizing a bivalent tumor-selective folate receptor alpha binding arm for the treatment of ovarian cancer

Abstract The use of T cell engagers (TCEs) to treat solid tumors in humans is challenging, and several have been limited by narrow therapeutic windows due to substantial toxicity. Dose-limiting toxicities of TCEs include cytokine release syndrome (CRS) and on-target, off-tumor toxicities since many solid tumor target antigens are also expressed in healthy tissues, albeit at lower levels. While there have been improvements in the clinical management of immune-mediated toxicities such as CRS, on-target, off-tumor effects remain one of the primary challenges of using TCEs for treatment of solid tumors. Here, we describe TNB-928B, a novel fully human TCE that is bivalent for folate receptor alpha (FRα) that selectively targets FRα overexpressing tumor cells yet avoids targeting cells that express low levels of FRα found in normal human cells. Selectivity is conferred by an avidity effect of the FRα targeting arm in combination with a unique low-affinity CD3 arm and is anticipated to reduce the risk of adverse events in normal cells expressing low levels of FRα. TNB-928B induces preferential effector T cell activation, proliferation, and cytotoxic activity with minimal cytokine release, compared to a positive control containing OKT3, thereby improving the therapeutic index. Moreover, TNB-928B exhibits substantial ex vivo tumor cell lysis using endogenous T cells and is effective in vivo promoting T cell infiltration and tumor regression in mouse models of ovarian cancer. Together, these results demonstrate TNB-928B represents a novel next generation immunotherapy modality with enhanced safety and specificity for the treatment of ovarian cancer. Citation Format: Brian C. Avanzino, Kirthana Prabhakar, Pranjali Dalvi, Sharon Hartstein, Hannes Kehm, Aarti Balasubramani, Andrew A. Boudreau, Ben Buelow, Karen Chang, Laura M. Davison, Suhasini Iyer, Vidyut Kalwit, Harbani Malik-Chaudhry, Will Pierson, Geovanni Pineda, Udaya S. Rangaswamy, Sowmya Saiganesh, Ute Schellenberger, Harshad S. Ugamraj, Roland Buelow, Jocelyn Chapman, Nathan D. Trinklein, Katherine E. Harris. A T cell engaging bispecific antibody utilizing a bivalent tumor-selective folate receptor alpha binding arm for the treatment of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6244.