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<p>The prevalence of autoimmune diseases such as inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) is increasing. Glucocorticoid-induced TNFR-related protein (GITR), a TNF receptor superfamily (TNFRSF) member, is activated by GITR-ligand (GITRL). GITR signaling is pathogenic in models of RA and IBD, leading to lymphocyte proliferation and secretion of pro-inflammatory cytokines. Despite promising preclinical data, GITR neutralization in autoimmune diseases remains under-explored, due to challenges in avoiding antibody-mediated GITR activation. Therefore, we developed a human GITR-specific antibody that inhibits GITRL-mediated GITR-signaling, while preserving the GITRL epitope on GITR. The antibody strongly inhibited GITR signaling in the in vitro assays via a novel mechanism of disrupting downstream higher-order structures rather than direct blocking of GITR binding. Even though the antibody did not demonstrate efficacy in an NSG human skin graft transplant model, this general mechanism might be a viable therapeutic intervention for other TNFRSF members relying more significantly on soluble ligands.</p>

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Ligand non-competitive GITR antibody prevents formation of the obligatory signal-triggering GITRL: GITR stoichiometry

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月18日

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  • Jing Yan,
  • Jessica Min-DeBartolo,
  • Ching-Shin Huang,
  • M. Nusrat Sharif,
  • Li Li,
  • Susan Fish,
  • Corey Dower,
  • Denise Murphy,
  • Tatyana Andreyeva,
  • Heng Liu,
  • Xinbing Han,
  • Wei Zheng,
  • Jot Hui Ooi,
  • Jason Edmonds,
  • Ting Chen,
  • Zachary Maben,
  • Chad R. Stevens,
  • Polina Goihberg,
  • Malgorzata Nocula-Lugowska,
  • Steven M Evans,
  • Lidia Mosyak,
  • Kerry Kelleher,
  • Caitlyn Dickinson,
  • Martin Hegen,
  • Aaron Winkler,
  • Fridrik Karlsson

摘要

The prevalence of autoimmune diseases such as inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) is increasing. Glucocorticoid-induced TNFR-related protein (GITR), a TNF receptor superfamily (TNFRSF) member, is activated by GITR-ligand (GITRL). GITR signaling is pathogenic in models of RA and IBD, leading to lymphocyte proliferation and secretion of pro-inflammatory cytokines. Despite promising preclinical data, GITR neutralization in autoimmune diseases remains under-explored, due to challenges in avoiding antibody-mediated GITR activation. Therefore, we developed a human GITR-specific antibody that inhibits GITRL-mediated GITR-signaling, while preserving the GITRL epitope on GITR. The antibody strongly inhibited GITR signaling in the in vitro assays via a novel mechanism of disrupting downstream higher-order structures rather than direct blocking of GITR binding. Even though the antibody did not demonstrate efficacy in an NSG human skin graft transplant model, this general mechanism might be a viable therapeutic intervention for other TNFRSF members relying more significantly on soluble ligands.