Computational stabilization of T cell receptors allows pairing with antibodies to form bispecifics

Karen Froning, Jack Maguire, Arlene Sereno, Flora Huang, Shawn Chang, Kenneth Weichert, Anton J. Frommelt, Jessica Dong, Xiufeng Wu, Heather Austin, Elaine M. Conner, Jonathan R. Fitchett, Aik Roy Heng, Deepa Balasubramaniam, Mark T. Hilgers, Brian Kuhlman () and Stephen J. Demarest ()
Additional contact information
Karen Froning: Eli Lilly Biotechnology Center, 10300 Campus Point Drive
Jack Maguire: Program in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill
Arlene Sereno: Eli Lilly Biotechnology Center, 10300 Campus Point Drive
Flora Huang: Eli Lilly Biotechnology Center, 10300 Campus Point Drive
Shawn Chang: Eli Lilly Biotechnology Center, 10300 Campus Point Drive
Kenneth Weichert: Eli Lilly Biotechnology Center, 10300 Campus Point Drive
Anton J. Frommelt: Eli Lilly Biotechnology Center, 10300 Campus Point Drive
Jessica Dong: Eli Lilly Biotechnology Center, 10300 Campus Point Drive
Xiufeng Wu: Eli Lilly Biotechnology Center, 10300 Campus Point Drive
Heather Austin: Eli Lilly Biotechnology Center, 10300 Campus Point Drive
Elaine M. Conner: Eli Lilly Biotechnology Center, 10300 Campus Point Drive
Jonathan R. Fitchett: Eli Lilly Biotechnology Center, 10300 Campus Point Drive
Aik Roy Heng: Eli Lilly Biotechnology Center, 10300 Campus Point Drive
Deepa Balasubramaniam: Eli Lilly Biotechnology Center, 10300 Campus Point Drive
Mark T. Hilgers: Eli Lilly Biotechnology Center, 10300 Campus Point Drive
Brian Kuhlman: Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
Stephen J. Demarest: Eli Lilly Biotechnology Center, 10300 Campus Point Drive

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract Recombinant T cell receptors (TCRs) can be used to redirect naïve 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 (Cα/Cβ) that increase the unfolding temperature of Cα/Cβ by 20 °C, improve the expression of four separate α/β 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 Cα/Cβ 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.

Date: 2020
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DOI: 10.1038/s41467-020-16231-7

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