Rapidly evolved PD-1 for enhance receptor and checkpoint inhibitor in immunotherapy.

PD-1 is a crucial molecule indispensable for maintaining immune homeostasis. Disrupting the interaction between PD-1 and its ligands can significantly enhance the immune system's ability to combat tumors. By integrating the PD-1 ligand-binding domain with the CD28 signal fragments (switch molecule) on T cells, we can utilize co-stimulatory signals to boost the function of T cells while removing the inhibition of immune checkpoint molecules. However, the extensive application of anti-PD-1 monoclonal antibodies in clinical settings may neutralize the PD-1 switch molecule, thereby restricting its therapeutic potential. In this study, we used sequential mutation and sorting techniques to rapidly evolve a PD-1 molecule that exhibits high affinity for PD-L1 while avoiding the recognition by five of the six clinically approved anti-PD-1 drugs. Experimental results verify that the Fc fusion protein and switch receptor based on such PD-1 mutant enhance the efficacy of therapeutic T cells.