美国西奈山伊坎医学院Yi Shi课等研究人员合作发现，自适应多表位靶向和亲和力增强的纳米抗体平台可用于超强、持久的抗病毒治疗。2024年10月23日，国际知名学术期刊《细胞》在线发表了这一成果。
研究人员介绍了自适应多表位靶向与增强亲和力（AMETA），这是一种模块化的多价纳米抗体平台，通过将强效的双特异性纳米抗体连接到人类免疫球蛋白M（IgM）骨架上。AMETA能够展示20个以上的纳米抗体，从而对多个保守且具有中和能力的表位实现超强的亲和力结合。通过利用针对SARS-CoV-2的多表位纳米抗体和结构引导设计，AMETA构建体显著增强了抗病毒效力，超过单体纳米抗体100万倍以上。
这些构建体在针对包括奥密克戎（Omicron）亚系在内的病原性Sarbecovirus的超强、广泛和持久效力中展现了强大的临床前效果。通过冷冻电子显微镜和建模的结构分析揭示了单一构建体中包含的多种抗病毒机制。在皮摩尔到纳摩尔浓度下，AMETA能够有效诱导刺突蛋白和病毒之间的交联，促进刺突蛋白的后融合状态并显著削弱病毒的功能。AMETA的模块化设计能够实现快速、低成本的生产，并适应不断演化的病原体。
据了解，病原体不断演化，并可能产生突变来逃避宿主的免疫系统和治疗。应对这些逃逸机制需要靶向演化上保守的弱点，因为这些区域的突变通常会带来适应性成本。
附：英文原文
Title: Adaptive multi-epitope targeting and avidity-enhanced nanobody platform for ultrapotent, durable antiviral therapy
Author: Yufei Xiang, Jialu Xu, Briana L. McGovern, Anna Ranzenigo, Wei Huang, Zhe Sang, Juan Shen, Randy Diaz-tapia, Ngoc Dung Pham, Abraham J.P. Teunissen, M. Luis Rodriguez, Jared Benjamin, Derek J. Taylor, Mandy M.T. van Leent, Kris M. White, Adolfo García-Sastre, Peijun Zhang, Yi Shi
Issue&Volume: 2024-10-23
Abstract: Pathogens constantly evolve and can develop mutations that evade host immunity and treatment. Addressing these escape mechanisms requires targeting evolutionarily conserved vulnerabilities, as mutations in these regions often impose fitness costs. We introduce adaptive multi-epitope targeting with enhanced avidity (AMETA), a modular and multivalent nanobody platform that conjugates potent bispecific nanobodies to a human immunoglobulin M (IgM) scaffold. AMETA can display 20+ nanobodies, enabling superior avidity binding to multiple conserved and neutralizing epitopes. By leveraging multi-epitope SARS-CoV-2 nanobodies and structure-guided design, AMETA constructs exponentially enhance antiviral potency, surpassing monomeric nanobodies by over a million-fold. These constructs demonstrate ultrapotent, broad, and durable efficacy against pathogenic sarbecoviruses, including Omicron sublineages, with robust preclinical results. Structural analysis through cryoelectron microscopy and modeling has uncovered multiple antiviral mechanisms within a single construct. At picomolar to nanomolar concentrations, AMETA efficiently induces inter-spike and inter-virus cross-linking, promoting spike post-fusion and striking viral disarmament. AMETA’s modularity enables rapid, cost-effective production and adaptation to evolving pathogens.
DOI: 10.1016/j.cell.2024.09.043
Source: https://www.cell.com/cell/abstract/S0092-8674(24)01143-7