Designed proteins assemble antibodies into modular nanocages.
Designed proteins assemble antibodies into modular nanocages.
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DOI：
10.1126/science.abd9994
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发表时间：
2021-04-02
期刊：
影响因子：
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通讯作者：
Baker D
中科院分区：
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作者：
Divine R;Dang HV;Ueda G;Fallas JA;Vulovic I;Sheffler W;Saini S;Zhao YT;Raj IX;Morawski PA;Jennewein MF;Homad LJ;Wan YH;Tooley MR;Seeger F;Etemadi A;Fahning ML;Lazarovits J;Roederer A;Walls AC;Stewart L;Mazloomi M;King NP;Campbell DJ;McGuire AT;Stamatatos L;Ruohola-Baker H;Mathieu J;Veesler D;Baker D
抗体广泛用于生物学和医学中，并且对多价抗体形式以增加结合亲合力和增强信号传导途径激动性存在相当大的兴趣。然而，目前没有用于形成具有受控价态的精确定向的抗体组装体的通用方法。我们描述了双组分纳米笼的计算设计，通过统一形式和功能克服了这一限制。一种结构组分是任何抗体或Fc融合物，第二种是驱动纳米笼组装的设计的Fc结合同源寡聚物。通过电子显微镜确定的8个抗体纳米笼的结构跨越二面体、四面体、八面体和二十面体架构，每个纳米笼具有2、6、12和30个抗体，与相应的计算模型相匹配。与游离抗体或Fc融合体相比，靶向细胞表面受体的抗体纳米笼增强了DR 5介导的细胞凋亡、Tie 2介导的血管生成、CD 40活化和T细胞增殖中的信号传导;纳米笼组装也增加了α-SARS-CoV-2单克隆抗体和Fc-ACE 2融合蛋白对SARS-CoV-2假病毒的中和作用。我们预计，在不需要共价修饰的情况下将任意抗体组装成具有不同几何形状和价态的高度有序组装体的能力将在生物学和医学中产生广泛的影响。计算设计的蛋白质将抗体组装成强大的生物技术工具。
Antibodies are widely used in biology and medicine, and there has been considerable interest in multivalent antibody formats to increase binding avidity and enhance signaling pathway agonism. However, there are currently no general approaches for forming precisely oriented antibody assemblies with controlled valency. We describe the computational design of two-component nanocages that overcome this limitation by uniting form and function. One structural component is any antibody or Fc fusion and the second is a designed Fc-binding homo-oligomer that drives nanocage assembly. Structures of 8 antibody nanocages determined by electron microscopy spanning dihedral, tetrahedral, octahedral, and icosahedral architectures with 2, 6, 12, and 30 antibodies per nanocage match the corresponding computational models. Antibody nanocages targeting cell-surface receptors enhance signaling compared to free antibodies or Fc-fusions in DR5-mediated apoptosis, Tie2-mediated angiogenesis, CD40 activation, and T cell proliferation; nanocage assembly also increases SARS-CoV-2 pseudovirus neutralization by α-SARS-CoV-2 monoclonal antibodies and Fc-ACE2 fusion proteins. We anticipate that the ability to assemble arbitrary antibodies without need for covalent modification into highly ordered assemblies with different geometries and valencies will have broad impact in biology and medicine. Computationally designed proteins assemble antibodies into powerful biotechnological tools.