| RRC ID |
85421
|
| Author |
Suzuki K, Tajima M, Tokumaru Y, Oshiro Y, Nagata S, Kamada H, Kihara M, Nakano K, Honjo T, Ohta A.
|
| Title |
Anti-PD-1 antibodies recognizing the membrane-proximal region are PD-1 agonists that can down-regulate inflammatory diseases.
|
| Journal |
Sci Immunol
|
| 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.
|
| Volume |
8(79)
|
| Pages |
eadd4947
|
| Published |
2023-1-13
|
| DOI |
10.1126/sciimmunol.add4947
|
| PMID |
36638191
|
| MeSH |
Animals
Antibodies, Blocking / metabolism
Antibodies, Monoclonal* / metabolism
Antibodies, Monoclonal* / pharmacology
Antibodies, Monoclonal* / therapeutic use
Humans
Mice
T-Lymphocytes*
|
| Resource |
| Mice |
RBRC02142 |
