Scholarlink

<p>Targeting the stimulatory immune checkpoint glucocorticoid-induced TNFR-related protein (GITR) using agonistic monoclonal antibodies (mAbs) is a promising strategy for cancer immunotherapy that activates effector T cells and eliminates regulatory T cells. The antitumor activity of anti-GITR mAbs depends on the engagement of the fragment crystallizable (Fc) domain to their receptors (FcγRs); however, this has not been comprehensively investigated in human anti-GITR mAbs. Here, we used Fc protein and glycan engineering to modify the FcγR interactions of anti-GITR human mAbs and characterized them in humanized mice. We identified an Fc-optimized human IgG scaffold that enhances antitumor efficacy through multiple FcγR-mediated mechanisms, including regulatory T cell depletion and mutual engagement and activation of CD4<sup>+</sup> T cells and dendritic cells, leading to antitumor cytotoxicity of CD4<sup>+</sup> T cells and enhanced CD8<sup>+</sup> T cell activity. Our findings suggest a strategy to optimize human anti-GITR mAbs, harnessing beneficial immune pathways to improve their therapeutic potential.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Fc-optimized GITR antibody enhances a CD4 T cell–dendritic cell crosstalk to promote antitumor immunity

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年8月5日

查看全文
  • Yahel Avraham,
  • Natasha Barth,
  • Tzlil Yair Bar-On,
  • Barak Toval,
  • Aviya Habshush Menachem,
  • Jasmine Blanga,
  • Ella Herzog,
  • Hagar Rotem,
  • Yuval Shapir Itai,
  • Tali Feferman,
  • Moshe Biton,
  • Rony Dahan

摘要

Targeting the stimulatory immune checkpoint glucocorticoid-induced TNFR-related protein (GITR) using agonistic monoclonal antibodies (mAbs) is a promising strategy for cancer immunotherapy that activates effector T cells and eliminates regulatory T cells. The antitumor activity of anti-GITR mAbs depends on the engagement of the fragment crystallizable (Fc) domain to their receptors (FcγRs); however, this has not been comprehensively investigated in human anti-GITR mAbs. Here, we used Fc protein and glycan engineering to modify the FcγR interactions of anti-GITR human mAbs and characterized them in humanized mice. We identified an Fc-optimized human IgG scaffold that enhances antitumor efficacy through multiple FcγR-mediated mechanisms, including regulatory T cell depletion and mutual engagement and activation of CD4+ T cells and dendritic cells, leading to antitumor cytotoxicity of CD4+ T cells and enhanced CD8+ T cell activity. Our findings suggest a strategy to optimize human anti-GITR mAbs, harnessing beneficial immune pathways to improve their therapeutic potential.