Anti–PD-1 antibodies recognizing the membrane-proximal region are PD-1 agonists that can down-regulate inflammatory diseases

Author:

Suzuki Kensuke12ORCID,Tajima Masaki13ORCID,Tokumaru Yosuke12ORCID,Oshiro Yuya12ORCID,Nagata Satoshi4ORCID,Kamada Haruhiko4ORCID,Kihara Miho5ORCID,Nakano Kohei5ORCID,Honjo Tasuku6ORCID,Ohta Akio1ORCID

Affiliation:

1. Department of Immunology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe 650-0047, Japan.

2. Pharmaceutical R&D Division, Meiji Seika Pharma Co. Ltd., Tokyo 104-8002, Japan.

3. Division of Integrated High-Order Regulatory Systems, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.

4. Laboratory of Antibody Design, Center for Drug Design Research, National Institutes of Biomedical Innovation, Health, and Nutrition, Ibaraki 567-0085, Japan.

5. Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan.

6. Department of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.

Abstract

The PD-1 receptor triggers a negative immunoregulatory mechanism that prevents overactivation of immune cells and subsequent inflammatory diseases. Because of its biological significance, PD-1 has been a drug target for modulating immune responses. Immunoenhancing anti–PD-1 blocking antibodies have become a widely used cancer treatment; however, little is known about the required characteristics for anti–PD-1 antibodies to be capable of stimulating immunosuppressive activity. Here, we show that PD-1 agonists exist in the group of anti–PD-1 antibodies recognizing the membrane-proximal extracellular region in sharp contrast to the binding of the membrane-distal region by blocking antibodies. This trend was consistent in an analysis of 81 anti-human PD-1 monoclonal antibodies. Because PD-1 agonist antibodies trigger immunosuppressive signaling by cross-linking PD-1 molecules, Fc engineering to enhance FcγRIIB binding of PD-1 agonist antibodies notably improved human T cell inhibition. A PD-1 agonist antibody suppressed inflammation in murine disease models, indicating its clinical potential for treatment of various inflammatory disorders, including autoimmune diseases.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

General Medicine,Immunology

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