Abstract A091: Rapid engineering of soluble T cell receptors for enhanced affinity via a high-throughput yeast-based platform

Abstract T cell receptors (TCRs) enable T cell immunosurveillance of intracellular proteins via recognition of peptide-HLA (pHLA) complexes. Soluble TCR-based CD3 bispecific therapeutics co-opt this recognition and can drive T cell killing of cancerous and infected cells, making them a powerful class of drugs with diverse potential applications. However, native TCRs require substantial affinity maturation against their target pHLAs for use in these therapeutics. Here, we leverage an extensively engineered yeast strain to rapidly generate and characterize TCR variants. Through iterative cycles of affinity maturation, we can identify TCR variants with hundreds-of-thousands-fold improved affinity to their target pHLA, accelerating the pre-clinical development of soluble TCR-based CD3 bispecific therapeutics. Citation Format: Saira Reyes, Vivien Qiao, Elizabeth McGurk, Asparouh Lilov, Elizabeth Champney, Cory Ahonen, Arvind Sivasubramanian, Eric Krauland, James Geoghegan, C. Garrett Rappazzo. Rapid engineering of soluble T cell receptors for enhanced affinity via a high-throughput yeast-based platform [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A091.