6u07

Publication Abstract from PubMed

Recombinant T cell receptors (TCRs) can be used to redirect naive T cells to eliminate virally infected or cancerous cells; however, they are plagued by low stability and uneven expression. Here, we use molecular modeling to identify mutations in the TCR constant domains (Calpha/Cbeta) that increase the unfolding temperature of Calpha/Cbeta by 20 degrees C, improve the expression of four separate alpha/beta TCRs by 3- to 10-fold, and improve the assembly and stability of TCRs with poor intrinsic stability. The stabilizing mutations rescue the expression of TCRs destabilized through variable domain mutation. The improved stability and folding of the TCRs reduces glycosylation, perhaps through conformational stabilization that restricts access to N-linked glycosylation enzymes. The Calpha/Cbeta mutations enables antibody-like expression and assembly of well-behaved bispecific molecules that combine an anti-CD3 antibody with the stabilized TCR. These TCR/CD3 bispecifics can redirect T cells to kill tumor cells with target HLA/peptide on their surfaces in vitro.

Computational stabilization of T cell receptors allows pairing with antibodies to form bispecifics.,Froning K, Maguire J, Sereno A, Huang F, Chang S, Weichert K, Frommelt AJ, Dong J, Wu X, Austin H, Conner EM, Fitchett JR, Heng AR, Balasubramaniam D, Hilgers MT, Kuhlman B, Demarest SJ Nat Commun. 2020 May 11;11(1):2330. doi: 10.1038/s41467-020-16231-7. PMID:32393818^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.