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 HuoSusan 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 Cornall, David Klenerman, Simon J. Davis

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)
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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.
Original languageEnglish
Pages (from-to)256-270, e1-e10
Number of pages25
JournalImmunity
Volume57
Issue number2
DOIs
Publication statusPublished - 13 Feb 2024
Externally publishedYes

Keywords

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

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