Galectin-9 controls the therapeutic activity of 4-1BB-targeting antibodies.
Galectin-9 controls the therapeutic activity of 4-1BB-targeting antibodies.
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DOI：
10.1084/jem.20132687
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发表时间：
2014-06-30
期刊：
影响因子：
--
通讯作者：
Croft M
中科院分区：
文献类型：
--
作者：
Madireddi S;Eun SY;Lee SW;Nemčovičová I;Mehta AK;Zajonc DM;Nishi N;Niki T;Hirashima M;Croft M
激动型抗4-1BB通过与Galectin-9结合来抑制自身免疫和过敏性炎症，Galectin-9促进4-1BB的聚集、信号和功能活性。针对肿瘤坏死因子家族受体的生物制品是治疗免疫性疾病的首选药物。虽然最近的研究强调了Fcγ受体在与抗体结合时激活CD40、TRAILR和GITR的需要，但其他TnFR分子可能受到其他机制的控制。针对4-1BB(CD137)的抗体目前正在进行临床试验，既可以增强癌症的免疫力，又可以促进抑制自身免疫性疾病的调节性T细胞。我们发现激动剂抗4-1BB抑制自身免疫和变态反应性炎症的作用完全依赖Galectin-9(Galectin-9)。Gal-9直接与4-1BB结合，与抗体的结合部位和4-1BB的天然配体不同，Gal-9促进4-1BB在T细胞、树突状细胞和自然杀伤细胞中的聚集、信号传递和功能活性。人类Gal-9相互作用的保守对于有效的临床靶向4-1BB和可能的其他TNFR超家族分子具有重要的意义。
Agonistic anti–4-1BB suppresses autoimmune and allergic inflammation via binding to Galectin-9, which facilitates 4-1BB aggregation, signaling, and functional activity. Biologics to TNF family receptors are prime candidates for therapy of immune disease. Whereas recent studies have highlighted a requirement for Fcγ receptors in enabling the activity of CD40, TRAILR, and GITR when engaged by antibodies, other TNFR molecules may be controlled by additional mechanisms. Antibodies to 4-1BB (CD137) are currently in clinical trials and can both augment immunity in cancer and promote regulatory T cells that inhibit autoimmune disease. We found that the action of agonist anti–4-1BB in suppressing autoimmune and allergic inflammation was completely dependent on Galectin-9 (Gal-9). Gal-9 directly bound to 4-1BB, in a site distinct from the binding site of antibodies and the natural ligand of 4-1BB, and Gal-9 facilitated 4-1BB aggregation, signaling, and functional activity in T cells, dendritic cells, and natural killer cells. Conservation of the Gal-9 interaction in humans has important implications for effective clinical targeting of 4-1BB and possibly other TNFR superfamily molecules.
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影响因子：
4.8
作者：
Nagae, Masamichi;Nishi, Nozomu;Kato, Ryuichi
通讯作者：
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1038/nrd3930
发表时间：
2013-02
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1073/pnas.0709264104
发表时间：
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影响因子：
11.1
作者：
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通讯作者：
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影响因子：
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作者：
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