Abstract
Cell therapy using T cell receptors (TCRs) and chimeric antigen receptors (CARs) represents a new wave of immunotherapies garnering considerable attention and investment. Further progress in this area of medicine depends in part on improving the functional capabilities of the engineered components, while maintaining the overall size of recombinant constructs to ensure their compatibility with existing gene delivery vehicles. We describe a single-variable-domain TCR (svd TCR) that utilizes only the variable domain of the β chain (Vβ). This Vβ module not only works in TCR and CAR formats, but also can be used to create single-chain bispecific CARs and TCRs. Comparison of individual ligand-binding Vβ domains in different formats suggests that the lone Vβ sequence controls the sensitivity and a major part of the specificity of the CAR or TCR construct, regardless of signaling format, in Jurkat and primary T cells.
Highlights
Cell therapy promises to revolutionize certain aspects of medicine, and has recently achieved a significant milestone with approval of the first engineered chimeric antigen receptor T cells (CAR-Ts)[1,2]
Over 100 million T cell receptors (TCRs)-expressing cells were sorted for TCRs specific to the HLA-A*02-01 allele in complex with NY-ESO-1 9 V variant peptide (SLLMWITQV) or MAGE-A3 peptide (FLWGPRALV) using peptide-MHC complexes (pMHCs) multivalent tetramers
Α chain expression was inadvertently lost and β chains that endow specific epitope-binding in the absence of a second TCR variable domain were recovered
Summary
Cell therapy promises to revolutionize certain aspects of medicine, and has recently achieved a significant milestone with approval of the first engineered chimeric antigen receptor T cells (CAR-Ts)[1,2] This therapeutic modality depends on receptor molecules, typically engineered antibody single-chain variable fragment (scFv) domains, to redirect T cell activity to specific cell surface target antigens expressed on the cancer cell. Some aspects of TCRs may limit their utility as modular www.nature.com/scientificreports components of large-molecule and cell-therapy applications, constraints potentially rooted in their basic structure and function Such structural complexity and increased size may hamper the practical development of next-generation bifunctional therapeutics. If such a simplified TCR variable domain that retains specificity and functional activity against particular pMHCs were possible, it could open a path to engineering smaller, more complex binding capabilities with svd TCRs
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