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Engineering soluble T‐cell receptors for therapy
Author(s) -
Robinson Ross A.,
McMurran Catriona,
McCully Michelle L.,
Cole David K.
Publication year - 2021
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.15780
Subject(s) - t cell receptor , receptor , limiting , peptide , antigen , protein engineering , ligand (biochemistry) , drug development , immunotherapy , human leukocyte antigen , chemistry , cell , microbiology and biotechnology , computational biology , t cell , drug , immune system , immunology , biology , biochemistry , pharmacology , engineering , mechanical engineering , enzyme
Immunotherapy approaches that target peptide–human leukocyte antigen (pHLA) complexes are becoming highly attractive because of their potential to access virtually all foreign and cellular proteins. For this reason, there has been considerable interest in the development of the natural ligand for pHLA, the T‐cell receptor (TCR), as a soluble drug to target disease‐associated pHLA presented at the cell surface. However, native TCR stability is suboptimal for soluble drug development, and natural TCRs generally have weak affinities for pHLAs, limiting their potential to reach efficacious receptor occupancy levels as soluble drugs. To overcome these limitations and make full use of the TCR as a soluble drug platform, several protein engineering solutions have been applied to TCRs to enhance both their stability and affinity, with a focus on retaining target specificity and selectivity. Here, we review these advances and look to the future for the next generation of soluble TCR‐based therapies that can target monomorphic HLA‐like proteins presenting both peptide and nonpeptide antigens.