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

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 an...

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Autores principales: Li, Yanyan, Liang, Zhaoduan, Tian, Ye, Cai, Wenxuan, Weng, Zhiming, Chen, Lin, Zhang, Huanling, Bao, Yifeng, Zheng, Hongjun, Zeng, Sihai, Bei, Chunhua, Li, Yi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113430/
https://www.ncbi.nlm.nih.gov/pubmed/29890018
http://dx.doi.org/10.1111/cas.13666
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author Li, Yanyan
Liang, Zhaoduan
Tian, Ye
Cai, Wenxuan
Weng, Zhiming
Chen, Lin
Zhang, Huanling
Bao, Yifeng
Zheng, Hongjun
Zeng, Sihai
Bei, Chunhua
Li, Yi
author_facet Li, Yanyan
Liang, Zhaoduan
Tian, Ye
Cai, Wenxuan
Weng, Zhiming
Chen, Lin
Zhang, Huanling
Bao, Yifeng
Zheng, Hongjun
Zeng, Sihai
Bei, Chunhua
Li, Yi
author_sort Li, Yanyan
collection PubMed
description 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.
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spelling pubmed-61134302018-09-04 High‐affinity PD‐1 molecules deliver improved interaction with PD‐L1 and PD‐L2 Li, Yanyan Liang, Zhaoduan Tian, Ye Cai, Wenxuan Weng, Zhiming Chen, Lin Zhang, Huanling Bao, Yifeng Zheng, Hongjun Zeng, Sihai Bei, Chunhua Li, Yi Cancer Sci Original Articles 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. John Wiley and Sons Inc. 2018-08-07 2018-08 /pmc/articles/PMC6113430/ /pubmed/29890018 http://dx.doi.org/10.1111/cas.13666 Text en © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Li, Yanyan
Liang, Zhaoduan
Tian, Ye
Cai, Wenxuan
Weng, Zhiming
Chen, Lin
Zhang, Huanling
Bao, Yifeng
Zheng, Hongjun
Zeng, Sihai
Bei, Chunhua
Li, Yi
High‐affinity PD‐1 molecules deliver improved interaction with PD‐L1 and PD‐L2
title High‐affinity PD‐1 molecules deliver improved interaction with PD‐L1 and PD‐L2
title_full High‐affinity PD‐1 molecules deliver improved interaction with PD‐L1 and PD‐L2
title_fullStr High‐affinity PD‐1 molecules deliver improved interaction with PD‐L1 and PD‐L2
title_full_unstemmed High‐affinity PD‐1 molecules deliver improved interaction with PD‐L1 and PD‐L2
title_short High‐affinity PD‐1 molecules deliver improved interaction with PD‐L1 and PD‐L2
title_sort high‐affinity pd‐1 molecules deliver improved interaction with pd‐l1 and pd‐l2
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113430/
https://www.ncbi.nlm.nih.gov/pubmed/29890018
http://dx.doi.org/10.1111/cas.13666
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