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

Anna H Lippert; Christopher Paluch; Meike Gaglioni; Mai T Vuong; James McColl; Edward Jenkins; Martin Fellermeyer; Joseph Clarke; Sumana Sharma; Sara Moreira da Silva; Billur Akkaya; Consuelo Anzilotti; Sara H Morgan; Claire F Jessup; Markus Körbel; Uzi Gileadi; Judith Leitner; Rachel Knox; Mami Chirifu; Jiandong Huo; Susan Yu; Nicole Ashman; Yuan Lui; Ian Wilkinson; Kathrine E Attfield; Lars Fugger; Nathan J Robertson; Christopher J Lynch; Lynne Murray; Peter Steinberger; Ana Mafalda Santos; Steven F Lee; Richard J Cornall; David Klenerman; Simon J Davis

doi:10.1016/j.immuni.2024.01.007

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.

Authors

Anna H Lippert¹, Christopher Paluch², Meike Gaglioni³, Mai T Vuong³, James McColl¹, Edward Jenkins³, Martin Fellermeyer³, Joseph Clarke³, Sumana Sharma³, Sara Moreira da Silva⁴, Billur Akkaya⁵, Consuelo Anzilotti⁵, Sara H Morgan³, Claire F Jessup³, Markus Körbel¹, Uzi Gileadi⁶, Judith Leitner⁷, Rachel Knox³, Mami Chirifu³, Jiandong Huo³, Susan Yu³, Nicole Ashman³, Yuan Lui³, Ian Wilkinson⁸, Kathrine E Attfield⁹, Lars Fugger⁹, Nathan J Robertson⁴, Christopher J Lynch⁴, Lynne Murray⁴, Peter Steinberger⁷, Ana Mafalda Santos³, Steven F Lee¹, Richard J Cornall¹⁰, David Klenerman¹¹, Simon J Davis¹²

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.

MeSH terms

CD28 Antigens
Protein Tyrosine Phosphatases* / metabolism
Receptors, Immunologic
Signal Transduction*

Substances

Protein Tyrosine Phosphatases
CD28 Antigens
Receptors, Immunologic