2. Academic Validation
  3. Antibody agonists trigger immune receptor signaling through local exclusion of receptor-type protein tyrosine phosphatases

Antibody agonists trigger immune receptor signaling through local exclusion of receptor-type protein tyrosine phosphatases

  • Immunity. 2024 Feb 13;57(2):256-270.e10. doi: 10.1016/j.immuni.2024.01.007.
Anna H Lippert 1,  Christopher Paluch 2,  Meike Gaglioni 3,  Mai T Vuong 3,  James McColl 1,  Edward Jenkins 3,  Martin Fellermeyer 3,  Joseph Clarke 3,  Sumana Sharma 3,  Sara Moreira da Silva 4,  Billur Akkaya 5,  Consuelo Anzilotti 5,  Sara H Morgan 3,  Claire F Jessup 3,  Markus Körbel 1,  Uzi Gileadi 6,  Judith Leitner 7,  Rachel Knox 3,  Mami Chirifu 3,  Jiandong Huo 3,  Susan Yu 3,  Nicole Ashman 3,  Yuan Lui 3,  Ian Wilkinson 8,  Kathrine E Attfield 9,  Lars Fugger 9,  Nathan J Robertson 4,  Christopher J Lynch 4,  Lynne Murray 4,  Peter Steinberger 7,  Ana Mafalda Santos 3,  Steven F Lee 1,  Richard J Cornall 10,  David Klenerman 11,  Simon J Davis 12
Affiliations

Affiliations

  • 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 MiroBio Ltd, Winchester House, Oxford Science Park, Oxford, UK.
  • 5 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.
  • 6 MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK.
  • 7 Division of Immune Receptors and T cell Activation, Institute of Immunology, Medical University of Vienna, Vienna, Austria.
  • 8 Absolute Antibody Ltd, Redcar, Cleveland, UK.
  • 9 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.
  • 10 MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK; Nuffield Department of Medicine, University of Oxford, Oxford, UK. Electronic address: [email protected].
  • 11 Department of Chemistry, University of Cambridge, Cambridge, UK. Electronic address: [email protected].
  • 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. Electronic address: [email protected].
PMID: 38354703 DOI: 10.1016/j.immuni.2024.01.007
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.

Keywords

antibody; autoimmunity; cancer; immune checkpoint; immune receptor; immunotherapy; kinetic-segregation model; receptor agonism.

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