Abstract
T-cell engager (TCE) immunotherapy has demonstrated significant clinical activity in multiple cancers by inducing coengagement of T cells and tumor cells, resulting in T-cell activation and T cell-dependent cellular cytotoxicity (TDCC) against tumor cells. Current-generation TCEs are predominantly composed of antibody-based binding domains targeting the cluster of differentiation 3e molecule of the T-cell antigen receptor (TCR)-cluster of differentiation 3 complex on T cells and a tumor-associated antigen on tumor cells. However, limitations of this approach include cytokine release syndrome and a limited therapeutic window. In this study, we report the generation and preclinical evaluation of SAR444200, the first NANOBODY-based TCE clinical candidate binding to TCRαβ and glypican-3 (GPC3) to coengage T cells and GPC3+ tumor cells, causing TDCC. SAR444200 bound with nanomolar to picomolar affinity to TCRαβ and GPC3, respectively, and induced in vitro TDCC against multiple human tumor cell lines with differential GPC3 expression with picomolar potency. In vivo analysis using human cancer cell line-derived xenografts (HuH-7 and HepG2) in immunodeficient mice showed complete tumor regression at doses starting from 0.7 mg/kg. In exploratory non-human primate studies, intravenous administration of SAR444200 was well tolerated up to 8 mg/kg and exhibited greater than dose-proportional clearances and dose-proportional maximum concentrations across the tested dose range. The highly potent and efficacious activity of SAR444200 in diverse models of GPC3+ tumors and the extremely wide tolerated dose range merit further development of this compound. Furthermore, NANOBODY-based TCEs developed using an anti-TCRαβ moiety may have specific advantages for the development of TCEs.