Engineering T-cell receptor–like antibodies for biologics and cell therapy

A major prevailing challenge limiting our ability to fully harness the potential of the latest-generation therapeutic antibodies is the scarcity of clinically established disease-specific targets. A major next step forward will therefore be to expand this target space. The recent clinical success of immunotherapies such as adoptive T-cell transfer, immune checkpoint inhibition, and chimeric antigen receptor (CAR) T-cell therapy strongly supports focusing on the immunopeptidome of peptides presented by human leukocyte antigen (pHLA) that are normally surveilled by T-cell receptors (TCRs). Directing novel antibody development toward pHLA targets has given rise to TCR-like antibodies, which reached the clinic in 2020, as both bispecific T-cell engaging antibodies and the CARs of CAR-T cell therapies. In this review, we highlight recent advances in TCR-like antibodies, including therapeutic modalities, engineering strategies, and benchmarks for success.