Glycan-Controlled Human PD-1 Variants Displaying Broad-Spectrum High Binding to PD-1 Ligands Potentiate T Cell

Ji Yeon Ha, Kwang Jin Chun, Sanghwan Ko, Ho Won Lee, Ok Kyung Hwang, Chung Su Lim, Kyungsoo Ha, Byoung Joon Ko, Sang Taek Jung

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Although therapeutic immunoglobulin G (IgG) antibodies that regulate the activity of immune checkpoints bring innovation to the field of immuno-oncology, they are still limited in their efficiency to infiltrate the tumor microenvironment due to their large molecular size (150 kDa) and the necessity of additional engineering works to ablate effector functions for antibodies targeting immune cells. To address these issues, the human PD-1 (hPD-1) ectodomain, a small protein moiety of 14-17 kDa, has been considered as a therapeutic agent. Here, we used bacterial display-based high-throughput directed evolution to successfully isolate glycan-controlled (aglycosylated or only single-N-linked glycosylated) human PD-1 variants exhibiting over 1000-fold increased hPD-L1 binding affinity compared to that of wild-type hPD-1. The resulting hPD-1 variants, aglycosylated JYQ12 and JYQ12-2 with a single-N-linked glycan chain, showed exceptionally high binding affinity to hPD-L1 and very high affinity to both hPD-L2 and mPD-L1. Moreover, the JYQ12-2 efficiently potentiated the proliferation of human T cells. hPD-1 variants with significantly improved binding affinities for hPD-1 ligands could be used as effective therapeutics or diagnostics that can be differentiated from large-sized IgG antibody-based molecules.

Original languageEnglish
Pages (from-to)2170-2180
Number of pages11
JournalMolecular Pharmaceutics
Volume20
Issue number4
DOIs
Publication statusPublished - 2023 Apr 3

Bibliographical note

Funding Information:
This research was supported by the Korea Drug Development Fund funded by the Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare (HN21C0103, Republic of Korea). The authors are also grateful for support from grants from the Basic Science Research Program (2022R1F1A1073014 and 2022R1A4A2000827) through the National Research Foundation of Korea funded by the Ministry of Science and ICT.

Publisher Copyright:
© 2023 American Chemical Society.

Keywords

  • PD-1
  • PD-L1
  • PD-L2
  • directed evolution
  • protein engineering

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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