Therapeutic, soluble T cell receptors (TCRs) can access intracellular antigens via peptide–HLA (pHLA) recognition, but natural TCRs often bind weakly and express poorly as TCR-Fc molecules, which consequently presents a key bottleneck for drug development. Adimab scientists address those limitations with a fully human, yeast-displayed synthetic TCR-mimic platform built to discover potent, specific, and manufacturable TCRs at scale. 

Approach and results

• High-frequency human TCR α/β variable domains were paired with large CDR3 α and β diversities to construct synthetic libraries in yeast, followed by selections for pHLA binding and chain-shuffle enrichment under stringent conditions. 
• Compared with antigen-matched natural TCRs, library-derived TCRs showed markedly improved monovalent affinities (e.g., KD 58 nM vs 1.1 µM) and superior mammalian expression titers and quality as TCR-Fc fusion proteins. 
• Sequence analyses indicated that synthetic hits retained repertoire-like features (e.g., TRBV19 prevalence) while exhibiting distinct CDR3β motifs predicted to enhance hydrophobic packing with the peptide. 
• Developability profiling highlighted improved production characteristics for library-derived TCRs relative to natural counterparts, supporting downstream formatting and testing. 
• Proposed next steps include defining peptide specificity using peptide-diversified pHLA libraries in yeast and orthogonal off-target prediction/validation. 

Overall, our data show that a human synthetic TCR library in yeast reproducibly delivers soluble TCRs that surpass natural scaffolds in both affinity and mammalian expression. These molecules also preserve repertoire-like sequence hallmarks. The approach directly addresses long-standing bottlenecks of natural TCRs and enables accelerated discovery for TCR-based therapeutics. 

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