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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A Cytokine-neutralizing Antibody As A Structural Mimetic Of 2 Receptor Interactions
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A Cytokine-neutralizing Antibody As A Structural Mimetic Of 2 Receptor Interactions

机译：细胞因子中和抗体作为2受体相互作用的结构模拟。

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摘要

TGF-β isoforms are key modulators of a broad range of biological pathways and increasingly are exploited as therapeutic targets. Here, we describe the crystal structures of a pan-TGF-β neutralizing antibody, GC-1008, alone and in complex with TGF-β3. The antibody is currently in clinical evaluation for idiopathic pulmonary fibrosis, melanoma, and renal cell cancer. GC-1008 recognizes an asymmetric binding interface across the TGF-β homodimer with high affinity. Whereas both cognate receptors, TGF-β-receptor types I and II, are required to recognize all 3 TGF-β isoforms, GC-1008 has been engineered to bind with high affinity to TGF-β1, 2, and 3 via a single interaction surface. Comparison with existing structures and models of TGF-β interaction with its receptors suggests that the antibody binds to a similar epitope to the 2 receptors together and is therefore a structurally different but functionally identical mimic of the binding mode of both receptors.
机译：TGF-β同工型是广泛的生物学途径的关键调节剂，并越来越多地被用作治疗靶标。在这里，我们描述了泛TGF-β中和抗体GC-1008单独和与TGF-β3结合的晶体结构。该抗体目前正在针对特发性肺纤维化，黑色素瘤和肾细胞癌进行临床评估。 GC-1008以高亲和力识别跨TGF-β同型二聚体的不对称结合界面。识别I和II型TGF-β受体均需要两个同源受体才能识别所有3种TGF-β同工型，而GC-1008已被设计为通过一次相互作用以高亲和力结合TGF-β1、2和3表面。与现有结构和TGF-β与其受体相互作用的模型的比较表明，该抗体与两个受体的相似表位结合在一起，因此是两个受体结合模式的结构不同但功能相同的模拟物。

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