Engineering high-affinity ociperlimab mutants through structure-based antibody optimization

TIGIT acts as a pivotal inhibitory receptor mediating T-cell dysfunction and immune evasion. Using structure-guided saturation mutagenesis of Ociperlimab, we identified several variants, most notably the pentamutant Ociperlimab MP5 and the single-point mutant Ociperlimab SP16, which exhibited significantly improved binding free energies. Beyond affinity enhancement, these mutants demonstrated optimized developability profiles, including reduced aggregation propensity and a marked increase in heavy-chain humanization. Mechanistic analyses revealed that these optimized variants strengthen key interface interactions, enhancing T-cell activation and effector functions. In vitro and in vivo studies demonstrated improved immune responses, including increased T-cell proliferation and functional cytokine secretion. These results provide a mechanistic framework for rational antibody optimization, offering a pathway to more effective TIGIT-targeted immunotherapies.