| Autor: |
Suzuki, Kensuke, Tajima, Masaki, Tokumaru, Yosuke, Oshiro, Yuya, Nagata, Satoshi, Kamada, Haruhiko, Kihara, Miho, Nakano, Kohei, Honjo, Tasuku, Ohta, Akio |
| Zdroj: |
Science Immunology; 2023, Vol. 8 Issue 79, p1-13, 13p |
| Abstrakt: |
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. Inhibitory anti–PD-1 sticks its landing: The PD-1 glycoprotein on T cells is widely appreciated as an immune checkpoint molecule recognized by blocking monoclonal antibodies (mAbs) that can boost the function of antitumor T cells in the setting of cancer. In sharp contrast, a distinct set of anti–PD-1 mAbs has the opposite functional effect, switching on inhibitory signaling in T cells. Using a panel of 81 anti-human PD-1 mAbs with binding sites mapping to eight separate segments on PD-1's surface, Suzuki et al. found that the inhibitory mAbs all bound to the membrane proximal portion of PD-1. Protein engineering that improved binding of this group of mAbs to Fc receptors increased their inhibitory effects. These discoveries provide a blueprint for designing potent inhibitory anti-PD-1 antibodies for treatment of human autoimmune diseases. —IRW [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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