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Biophysical Characterization of TCR Variants with Reengineered Specificity and Affinity
Author(s) -
Singh Nishant,
Pierce Brian,
Weng Zhiping,
Baker Brian
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.571.30
Subject(s) - t cell receptor , in silico , computational biology , major histocompatibility complex , immunogenicity , antigen , biology , cd8 , immunotherapy , cancer immunotherapy , cytotoxic t cell , adoptive cell transfer , microbiology and biotechnology , in vitro , t cell , chemistry , immunology , immune system , biochemistry , gene
Autologous cytotoxic T‐cells, CD8+ T‐cells, recognize and target certain cancer cells through an interaction between T‐cell receptors (TCR) and antigen bound major histocompatibility complex (MHC complex) on the target cells. This phenomenon has led to advent of adoptive immunotherapy for melanoma. In this therapy, T‐cells from the patient are genetically engineered to express TCRs that respond specifically to melanoma associated antigens and then reintroduced into patients. The first set of clinical trials examining this approach in humans utilized DMF4 and DMF5 TCRs, and showed that DMF4 TCR led to 13% tumor regression, whereas DMF5 TCR led to 30% tumor regression. Upon biophysical characterization it was shown that the improvement in immunogenicity from DMF5 is due to its higher affinity towards the cognate melanoma antigen. This made higher affinity TCRs therapeutically relevant. Traditionally higher affinity TCRs have been generated via in vitro selection techniques. However, in vitro selection methods have inherent limitations. Most notably, gaining peptide independent TCR binding. Structure guided design (SGD) provides an alternative technique for developing therapeutically relevant TCRs. It is an in silico method that combines structural and biophysical information with a modeling software to generate high affinity TCR variants, allowing for highly controlled manipulation of affinity and specificity. While SGD of TCRs is promising, it is in early stages of development and requires further optimization. Structural and biophysical characterization of TCR variants that have high affinity or re‐engineered specificity will help improve TCR SGD.