Open AccessHigh‐affinity PD ‐1 molecules deliver improved interaction with PD ‐L1 and PD ‐L2
Author(s) -
Li Yanyan,
Liang Zhaoduan,
Tian Ye,
Cai Wenxuan,
Weng Zhiming,
Chen Lin,
Zhang Huanling,
Bao Yifeng,
Zheng Hongjun,
Zeng Sihai,
Bei Chunhua,
Li Yi
Publication year - 2018
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13666
Subject(s) - pd l1 , chemistry , immune checkpoint , immune system , phage display , antibody , mutant , microbiology and biotechnology , small molecule , cancer immunotherapy , biochemistry , receptor , blockade , biology , immunotherapy , gene , immunology , peptide
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.