Chimeric antigen receptor single-chain variable fragment (CAR scFv) domain (CAR scFv)

The Chimeric antigen receptor single-chain variable fragment (CAR scFv) domain is the extracellular antigen-recognition component of a synthetic chimeric antigen receptor (CAR) [1]. It is typically composed of the variable heavy (VH) and variable light (VL) chains of a monoclonal antibody, connected by a flexible peptide linker [2]. The primary function of the scFv domain is to bind specifically to a target surface antigen on a cell, such as CD19 in B-cell malignancies or BCMA in multiple myeloma, in a non-MHC-restricted manner [1,3]. This binding event triggers a conformational change that activates the intracellular signaling domains of the CAR, leading to T-cell activation, proliferation, and the release of cytotoxic granules to kill the target cell [2,4]. While highly effective in hematologic cancers, the scFv domain can be a source of immunogenicity, particularly if derived from murine sequences, which may lead to the development of anti-drug antibodies and reduced CAR-T cell persistence [5]. Furthermore, the affinity and specificity of the scFv are critical factors in determining the therapeutic window, as high-affinity binding to low-level antigens on healthy tissue can lead to on-target, off-tumor toxicity [3,6]. Sources: [1] Sadelain et al., Cancer Discovery (2013); [2] Labanieh & Mackall, Nature Reviews Cancer (2023); [3] June et al., Science (2018); [4] NIH NCI (2022); [5] Maus et al., Blood (2014); [6] Rafiq et al., Nature Reviews Clinical Oncology (2020).

Other names

scFvSingle-chain variable fragmentCAR binding domainAntigen-binding domainCAR extracellular domain

The scFv domain mediates high-affinity, MHC-independent binding to specific cell-surface antigens, which induces CAR clustering and subsequent activation of intracellular CD3-zeta and costimulatory signaling pathways (e.g., 4-1BB or CD28), resulting in targeted T-cell effector functions [1,2].