He Changhao, Maniyar Rachana R, Avraham Yahel, Zappasodi Roberta, Rusinova Radda, Newman Walter, Heath Heidi, Wolchok Jedd D, Dahan Rony, Merghoub Taha, Meyerson Joel R
Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, USA.
Ludwig Collaborative and Swim Across America Laboratory, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Sci Adv. 2022 Feb 25;8(8):eabm4552. doi: 10.1126/sciadv.abm4552.
GITR is a TNF receptor, and its activation promotes immune responses and drives antitumor activity. The receptor is activated by the GITR ligand (GITRL), which is believed to cluster receptors into a high-order array. Immunotherapeutic agonist antibodies also activate the receptor, but their mechanisms are not well characterized. We solved the structure of full-length mouse GITR bound to Fabs from the antibody DTA-1. The receptor is a dimer, and each subunit binds one Fab in an orientation suggesting that the antibody clusters receptors. Binding experiments with purified proteins show that DTA-1 IgG and GITRL both drive extensive clustering of GITR. Functional data reveal that DTA-1 and the anti-human GITR antibody TRX518 activate GITR in their IgG forms but not as Fabs. Thus, the divalent character of the IgG agonists confers an ability to mimic GITRL and cluster and activate GITR. These findings will inform the clinical development of this class of antibodies for immuno-oncology.
糖皮质激素诱导肿瘤坏死因子受体（GITR）是一种肿瘤坏死因子受体，其激活可促进免疫反应并驱动抗肿瘤活性。该受体由GITR配体（GITRL）激活，据信GITRL可将受体聚集成高阶阵列。免疫治疗激动剂抗体也可激活该受体，但其作用机制尚未完全明确。我们解析了与抗体DTA-1的Fab片段结合的全长小鼠GITR的结构。该受体为二聚体，每个亚基以一种表明抗体可使受体聚集的方向结合一个Fab片段。用纯化蛋白进行的结合实验表明，DTA-1 IgG和GITRL均可驱动GITR的广泛聚集。功能数据显示，DTA-1和抗人GITR抗体TRX518以其IgG形式而非Fab片段形式激活GITR。因此，IgG激动剂的二价特性赋予了其模拟GITRL并使GITR聚集和激活的能力。这些发现将为这类抗体在免疫肿瘤学中的临床开发提供参考。
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