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.

中文翻译：

---

适应性多表位靶向和亲和力增强的纳米抗体平台，用于超强、持久的抗病毒治疗


病原体不断进化，并可能产生逃避宿主免疫和治疗的突变。解决这些逃逸机制需要针对进化上保守的脆弱性，因为这些区域的突变通常会带来适应成本。我们介绍了具有增强亲和力的适应性多表位靶向 （AMETA），这是一种模块化的多价纳米抗体平台，可将有效的双特异性纳米抗体偶联到人免疫球蛋白 M （IgM） 支架上。AMETA 可以显示 20+ 纳米抗体，能够与多个保守和中和表位实现卓越的亲和力结合。通过利用多表位 SARS-CoV-2 纳米抗体和结构引导设计，AMETA 构建体的抗病毒效力呈指数级增强，比单体纳米抗体高出一百万倍以上。这些构建体对致病性 sarbecovirus（包括 Omicron 亚系）表现出超强、广泛和持久的疗效，并具有稳健的临床前结果。通过冷冻电子显微镜和建模进行的结构分析揭示了单个构建体中的多种抗病毒机制。在皮摩尔至纳摩尔浓度下，AMETA 可有效诱导刺突和病毒间交联，促进融合后刺突和打击病毒解除武装。AMETA 的模块化设计可实现快速、经济高效的生产和适应不断进化的病原体。