Lippert et al. demonstrated that antibody-mediated immune receptor signaling relies on local receptor-type protein tyrosine phosphatases (RPTP) exclusion. The steric effects of anti-CD28 antibody–receptor complexes on RPTPs governed the signaling intensity of anti-CD28 antibodies, with strong agonists being better at excluding RPTPs. An engineered anti-PD-1 “agonist” (enhancing the inhibitory activity) excluded CD45, triggered Src homology 2 domain-containing phosphatase 2 recruitment, and suppressed systemic lupus erythematosus and delayed-type hypersensitivity in experimental models.
Contributed by Shishir Pant
ABSTRACT: Antibodies can block immune receptor engagement or trigger the receptor machinery to initiate signaling. We hypothesized that antibody agonists trigger signaling by sterically excluding large receptor-type protein tyrosine phosphatases (RPTPs) such as CD45 from sites of receptor engagement. An agonist targeting the costimulatory receptor CD28 produced signals that depended on antibody immobilization and were sensitive to the sizes of the receptor, the RPTPs, and the antibody itself. Although both the agonist and a non-agonistic anti-CD28 antibody locally excluded CD45, the agonistic antibody was more effective. An anti-PD-1 antibody that bound membrane proximally excluded CD45, triggered Src homology 2 domain-containing phosphatase 2 recruitment, and suppressed systemic lupus erythematosus and delayed-type hypersensitivity in experimental models. Paradoxically, nivolumab and pembrolizumab, anti-PD-1-blocking antibodies used clinically, also excluded CD45 and were agonistic in certain settings. Reducing these agonistic effects using antibody engineering improved PD-1 blockade. These findings establish a framework for developing new and improved therapies for autoimmunity and cancer.
Author Info: (1) Department of Chemistry, University of Cambridge, Cambridge, UK. (2) MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK; Radcliffe Department
Author Info: (1) Department of Chemistry, University of Cambridge, Cambridge, UK. (2) MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK; Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK; Nuffield Department of Medicine, University of Oxford, Oxford, UK; MiroBio Ltd, Winchester House, Oxford Science Park, Oxford, UK. (3) MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK; Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK. (4) MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK; Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK. (5) Department of Chemistry, University of Cambridge, Cambridge, UK. (6) MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK; Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK. (7) MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK; Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK. (8) MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK; Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK. (9) MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK; Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK. (10) MiroBio Ltd, Winchester House, Oxford Science Park, Oxford, UK. (11) MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK; Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK; Nuffield Department of Medicine, University of Oxford, Oxford, UK. (12) MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK; Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK; Nuffield Department of Medicine, University of Oxford, Oxford, UK. (13) MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK; Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK. (14) MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK; Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK. (15) Department of Chemistry, University of Cambridge, Cambridge, UK. (16) MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK. (17) Division of Immune Receptors and T cell Activation, Institute of Immunology, Medical University of Vienna, Vienna, Austria. (18) MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK; Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK. (19) MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK; Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK. (20) MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK; Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK. (21) MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK; Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK. (22) MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK; Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK. (23) MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK; Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK. (24) Absolute Antibody Ltd, Redcar, Cleveland, UK. (25) MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK; Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, UK. (26) MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK; Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, UK. (27) MiroBio Ltd, Winchester House, Oxford Science Park, Oxford, UK. (28) MiroBio Ltd, Winchester House, Oxford Science Park, Oxford, UK. (29) MiroBio Ltd, Winchester House, Oxford Science Park, Oxford, UK. (30) Division of Immune Receptors and T cell Activation, Institute of Immunology, Medical University of Vienna, Vienna, Austria. (31) MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK; Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK. (32) Department of Chemistry, University of Cambridge, Cambridge, UK. (33) MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK; Nuffield Department of Medicine, University of Oxford, Oxford, UK. Electronic address: richard.cornall@ndm.ox.ac.uk. (34) Department of Chemistry, University of Cambridge, Cambridge, UK. Electronic address: dk10012@cam.ac.uk. (35) MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK; Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK. Electronic address: simon.davis@imm.ox.ac.uk.
