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The inhibitory checkpoint molecule programmed death ( PD )‐1 plays a vital role in maintaining immune homeostasis upon binding to its ligands,  PD ‐L1 and  PD ‐L2. Several recent studies have demonstrated that soluble  PD ‐1 ( sPD ‐1) can block the interaction between membrane  PD ‐1 and  PD ‐L1 to enhance the antitumor capability of T cells. However, the affinity of natural  sPD ‐1 binding to  PD ‐L1 is too low to permit therapeutic applications. Here, a  PD ‐1 variant with approximately 3000‐fold and 70‐fold affinity increase to bind  PD ‐L1 and  PD ‐L2, respectively, was generated through directed molecular evolution and phage display technology. Structural analysis showed that mutations at amino acid positions 124 and 132 of  PD ‐1 played major roles in enhancing the affinity of  PD ‐1 binding to its ligands. The high‐affinity  PD ‐1 mutant could compete with the binding of antibodies specific to  PD ‐L1 or  PD ‐L2 on cancer cells or dendritic cells, and it could enhance the proliferation and  IFN ‐γ release of activated lymphocytes. These features potentially qualify the high‐affinity  PD ‐1 variant as a unique candidate for the development of a new class of  PD ‐1 immune‐checkpoint blockade therapeutics.

High‐affinity PD ‐1 molecules deliver improved interaction with PD ‐L1 and PD ‐L2