Abstract 5446: Development of a novel TCR based bispecific platform for cancer therapy

Abstract TCR-T therapies emerged as a new generation of therapeutics targeting solid tumors with high specificity but are not “off-the-shelf”. TCR based T-cell engagers follow the same concept, however it remains challenging to generate such molecules containing TCRs, which usually requires extensive engineering and optimization to achieve good solubility and functionality. To solve this problem, we developed a “plug-n-play” technology, namely TCR-Fab in tandem (T-FIT) fusion protein, for generating off-the-shelf TCR based therapeutics. The design of T-FIT was optimized by comparing recombinant production yield and purity in various formats with different spacers, binding valencies and TCR-Fab geometries. The selected T-FIT format showed IgG like production properties across different TCRs and Fabs. Based on the T-FIT format and our proprietary CD3 antibody, we generated 3 TCR based T-cell engagers, targeting NY-ESO-1, MAGE-A3 and Survivin respectively, and validated the T-FIT platform in preclinical functional assays. All three T-FIT molecules demonstrated potent redirected T-cell lysis activity against target positive cells in vitro. The MAGE-A3 and Survivin targeting T-FIT molecules also showed complete tumor inhibition in xenografted models. Citation Format: Danqing Wu, Li Hu, Lini Huang, Beilei Shi, Lijun Wang, Xuan Wu, Shiyong Gong, Chengbin Wu. Development of a novel TCR based bispecific platform for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5446.