Discovery and Engineering of High-Affinity Soluble T Cell Receptors via a High-Throughput Yeast-Based Platform

In this webinar sponsored by KACTUS, join Dr. Garrett Rappazzo, Senior Scientist of Platform Technologies at Adimab, as he presents his team’s research on the discovery and engineering of soluble T cell receptors for use in potent and specific peptide-HLA targeting therapeutics.

Peptide-HLA (pHLA)-targeting therapeutics offer the potential for highly specific and effective destruction of diseased and infected cells by recognizing altered proteins inside cells. Soluble T cell receptors (TCRs) are attractive options for clinical development due to their innate specificity in pHLA binding, yet natural TCRs face significant challenges, such as the need for extensive affinity enhancement. Additionally, the immune system eliminates self-reactive TCRs, limiting the discovery of natural TCRs against many valuable pHLA targets.

To address these issues, we used Adimab’s yeast-based platform to develop a workflow for the discovery and engineering of soluble TCRs. This platform enabled the creation of the first fully human synthetic TCR libraries in yeast, allowing rapid identification of diverse, high-affinity TCRs. Additionally, we engineered TCR variants with both significantly improved affinities and functional capabilities in T cell engager formats while maintaining precise target specificity. This work can accelerate pre-clinical development of potent and specific pHLA-targeting therapeutics across diverse cancers and viral diseases.