The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs^1,2,3 and revealed how quickly viral escape can curtail effective options^4,5. When the SARS-CoV-2 Omicron variant emerged in 2021, many antibody drug products lost potency, including Evusheld and its constituent, cilgavimab^4,5,6. Cilgavimab, like its progenitor COV2-2130, is a class 3 antibody that is compatible with other antibodies in combination⁴ and is challenging to replace with existing approaches. Rapidly modifying such high-value antibodies to restore efficacy against emerging variants is a compelling mitigation strategy. We sought to redesign and renew the efficacy of COV2-2130 against Omicron BA.1 and BA.1.1 strains while maintaining efficacy against the dominant Delta variant. Here we show that our computationally redesigned antibody, 2130-1-0114-112, achieves this objective, simultaneously increases neutralization potency against Delta and subsequent variants of concern, and provides protection in vivo against the strains tested: WA1/2020, BA.1.1 and BA.5. Deep mutational scanning of tens of thousands of pseudovirus variants reveals that 2130-1-0114-112 improves broad potency without increasing escape liabilities. Our results suggest that computational approaches can optimize an antibody to target multiple escape variants, while simultaneously enriching potency. Our computational approach does not require experimental iterations or pre-existing binding data, thus enabling rapid response strategies to address escape variants or lessen escape vulnerabilities.

COVID-19 大流行凸显了基于单克隆抗体的预防和治疗药物的前景^1,2,3，并揭示了病毒逃逸可以多快地限制有效选择^4,5。当 2021 年 SARS-CoV-2 Omicron 变种出现时，许多抗体药物产品失去了效力，包括 Evusheld 及其成分 cilgavimab ^4,5,6。 Cilgavimab 与其前身 COV2-2130 一样，是一种 3 类抗体，与组合⁴中的其他抗体兼容，并且很难用现有方法替代。快速修改此类高价值抗体以恢复针对新出现变异的功效是一种引人注目的缓解策略。我们试图重新设计和更新 COV2-2130 针对 Omicron BA.1 和 BA.1.1 菌株的功效，同时保持针对主要 Delta 变种的功效。在这里，我们展示了我们经过计算重新设计的抗体 2130-1-0114-112 实现了这一目标，同时增加了针对 Delta 和后续相关变体的中和效力，并提供了针对测试菌株的体内保护：WA1/2020、BA.1.1和BA.5。对数以万计的假病毒变体的深度突变扫描表明，2130-1-0114-112 在不增加逃逸倾向的情况下提高了广泛的效力。我们的结果表明，计算方法可以优化抗体以靶向多种逃逸变体，同时丰富效力。我们的计算方法不需要实验迭代或预先存在的绑定数据，从而实现快速响应策略来解决逃逸变体或减少逃逸漏洞。