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

ABSTRACT: 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-? 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.

SUBMITTER: Li Y

PROVIDER: S-EPMC6113430 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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

Li Yanyan Y Liang Zhaoduan Z Tian Ye Y Cai Wenxuan W Weng Zhiming Z Chen Lin L Zhang Huanling H Bao Yifeng Y Zheng Hongjun H Zeng Sihai S Bei Chunhua C Li Yi Y

Cancer science 20180807 8

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 affi ...[more]

PMID: 29890018

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Dataset Information

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

Publications

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

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