Roadmap to affinity-tuned antibodies for enhanced chimeric antigen receptor T cell function and selectivity

Chimeric antigen receptor (CAR) T cells have revolutionized cancer treatment. CARs use antibody-derived binding domains to redirect T cells to antigens expressed on the surface of cancer cells. However, the high affinity of most currently used CAR-binding domains results in excessive T-cell activation limiting CAR T-cell persistence and the inability to differentiate between antigen-high tumor cells and antigen-low healthy cells. We review recent data on the use of low-affinity CAR-binding domains and evaluate technologies and approaches to engineer and screen low-affinity antibody variants for CAR T-cell development. We propose an ideal workflow for the generation of optimal low-affinity binders derived from existing antibodies to streamline the development of more functional and selective therapeutics.