Computational design of orthogonal TCR α/β interfaces for dual-TCR therapeutics.

ABSTRACT: T-cell receptors (TCRs) recognize peptides presented by MHC, enabling access to intracellular targets that are largely inaccessible to antibodies and difficult to target with small molecules. Despite this potential, their inherent cross-reactivity limits tumor specificity, while single-antigen targeting provides limited coverage of intratumoral heterogeneity. Dual-TCR therapeutics comprising two distinct TCRs could enhance tumor specificity via combinatorial recognition while broadening coverage across heterogeneous antigens. However, practical development of dual-TCR therapeutics has been limited by α/β subunit mispairing that prevents efficient production and creates undesired binding properties. Here, we develop orthogonal TCR α/β interfaces that prevent subunit mispairing. Using comput

SUBMITTER: Kinjo T 

PROVIDER: S-EPMC12776297 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature