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 can drive potent and specific T cell killing of diseased cells based on altered or aberrant expression of intracellular proteins, such as viral or tumor-associated antigens. Among pHLA-targeting modalities, soluble T cell receptors (TCRs) are an attractive candidate for clinical development because of their evolutionarily engrained peptide specificities. However, native TCRs require extensive affinity maturation for efficacy in clinically validated T cell engager formats. Furthermore, native TCR repertoires are pruned for self-reactivity by central tolerance, limiting the discovery of TCRs against many attractive therapeutic pHLA targets, and posing an additional barrier to the development of soluble TCR-based therapeutics.

To overcome these barriers, we have developed a novel yeast-based platform for the discovery and engineering of soluble TCRs. We describe the design and selection of the first fully human pre-immune TCR libraries in yeast, facilitating rapid discovery of diverse high-affinity TCRs. We further describe the generation of engineered TCR variants that achieve substantially improved affinities and functional potencies in T cell engager formats relative to their parental TCRs while retaining target specificity. This work provides key insights into optimal strategies for generating high-affinity soluble TCRs to accelerate the pre-clinical development of potent and specific pHLA-targeting therapeutics.

Key Topics:

• Learn about peptide-HLA targeting therapeutics


• Learn about the comparative advantages and disadvantages of soluble TCRs and TCR mimetic antibodies


• Learn about novel technologies for the discovery and engineering of soluble TCRs


• Learn how soluble TCRs are characterized for both affinity and specificity to enable the development of potent and specific pHLA-targeting therapeutics.