Alternative target recognition elements for chimeric antigen receptor (CAR) T cells: beyond standard antibody fragments.

BACKGROUND AIMS: Chimeric antigen receptor T (CAR-T) cells are a remarkably efficacious, highly promising and rapidly evolving strategy in the field of immuno-oncology. The precision of these targeted cellular therapies is driven by the specificity of the antigen recognition element (the "binder") encoded in the CAR. This binder redirects these immune effector cells precisely toward a defined antigen on the surface of cancer cells, leading to T-cell receptor-independent tumor lysis. Currently, for tumor targeting most CAR-T cells are designed using single-chain variable fragments (scFvs) derived from murine or human immunoglobulins. However, there are several emerging alternative binder modalities that are finding increasing utility for improved CAR function beyond scFvs.

METHODS: Here we review the most recent developments in the use of non-canonical protein binding domains in CAR design, including nanobodies, DARPins, natural ligands, and de novo-designed protein elements.

RESULTS: Overall, we describe how new protein binder formats, with their unique structural properties and mechanisms of action, may possess key advantages over traditional scFv CAR designs.

CONCLUSIONS: These alternative binder designs may contribute to enhanced CAR-T therapeutic options and, ultimately, improved outcomes for cancer patients.