Adimab scientists used yeast-based libraries to discover fully human T cell receptors (TCRs) with high affinity to multiple cancer-related targets for use in soluble T cell engager therapeutics, overcoming the affinity limitations of patient-derived repertoires. By simultaneously targeting multiple tumor-associated peptide-HLA (pHLA) antigens, these high-affinity TCRs can better address tumor heterogeneity and benefit a broader patient population.

Approach and results 

• Soluble TCR-based T cell engagers target otherwise inaccessible intracellular tumor antigens through pHLA recognition, but natural TCRs, including rare, multi-epitope-specific TCRs, bind their targets too weakly for efficacy in clinically validated formats.
• Adimab generated highly diverse fully human synthetic TCR libraries in yeast to overcome limitations in natural repertoires.
• Through iterative selection of yeast-based TCR libraries with three HLA-A2-restricted tumor antigens (MART-1, BST2, IMP2), we isolated rare, fully human TCRs with highly selective, high-affinity binding to all three tumor-associated antigens.

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