UCB Pharma, 208 Bath Road, Slough, SL1 3WE, UK.
UCB Pharma, 7869 NE Day Road W, Bainbridge Island, WA, 98110, USA.
Nat Commun. 2021 Jan 25;12(1):583. doi: 10.1038/s41467-020-20825-6.
We have recently described the development of a series of small-molecule inhibitors of human tumour necrosis factor (TNF) that stabilise an open, asymmetric, signalling-deficient form of the soluble TNF trimer. Here, we describe the generation, characterisation, and utility of a monoclonal antibody that selectively binds with high affinity to the asymmetric TNF trimer-small molecule complex. The antibody helps to define the molecular dynamics of the apo TNF trimer, reveals the mode of action and specificity of the small molecule inhibitors, acts as a chaperone in solving the human TNF-TNFR1 complex crystal structure, and facilitates the measurement of small molecule target occupancy in complex biological samples. We believe this work defines a role for monoclonal antibodies as tools to facilitate the discovery and development of small-molecule inhibitors of protein-protein interactions.
我们最近描述了一系列小分子抑制剂的开发，这些抑制剂稳定了人肿瘤坏死因子 (TNF) 的开放、不对称、信号缺陷形式的可溶性 TNF 三聚体。在这里，我们描述了一种单克隆抗体的产生、特性和用途，该抗体选择性地以高亲和力结合不对称 TNF 三聚体-小分子复合物。该抗体有助于定义apo TNF 三聚体的分子动力学，揭示小分子抑制剂的作用模式和特异性，作为伴侣在解决人 TNF-TNFR1 复合物晶体结构中发挥作用，并促进小分子靶标在复杂生物样品中的占有率的测量。我们相信这项工作定义了单克隆抗体作为工具的作用，以促进蛋白质-蛋白质相互作用的小分子抑制剂的发现和开发。
