Murine single-chain variable fragment regions of the chimeric antigen receptor (Murine scFv)

The murine single-chain variable fragment (scFv) regions of the chimeric antigen receptor (CAR) constitute the extracellular domain responsible for antigen recognition in CAR-T cell therapies. These regions are typically engineered from the variable heavy and light chains of murine monoclonal antibodies, such as the FMC63 clone used in many CD19-targeted therapies (PubMed: 28935460). Their primary biological function is to provide the CAR-T cell with high-affinity binding to specific tumor-associated antigens, bypassing the need for major histocompatibility complex (MHC) presentation (NIH: PMC5541235). However, because these sequences are derived from mice, they are recognized as foreign by the human immune system, potentially leading to the development of human anti-mouse antibodies (HAMA) or anti-idiotypic antibodies (PubMed: 31086117). This immunogenicity is a significant therapeutic challenge, as it can result in the rapid clearance of CAR-T cells, reduced efficacy, or hypersensitivity reactions in patients. Consequently, there is a strong clinical trend toward humanizing these scFv regions to improve the safety and durability of the treatment (Nature: 10.1038/s41408-020-00392-5). In addition to immunogenicity, the stability and affinity of the murine scFv are critical factors that influence the overall potency and tonic signaling of the CAR-T product (PubMed: 25180009).

Other names

Mouse-derived scFvMurine scFv domainFMC63-derived scFvMurine antigen-binding domain

The murine scFv provides the antigen-recognition specificity for Chimeric Antigen Receptor (CAR) T-cells, allowing them to bind to specific tumor-associated antigens independently of MHC restriction.