An ideal therapeutic anti-SARS-CoV-2 antibody would resist viral escape^1,2,3, have activity against diverse sarbecoviruses^4,5,6,7, and be highly protective through viral neutralization^8,9,10,11 and effector functions^12,13. Understanding how these properties relate to each other and vary across epitopes would aid the development of therapeutic antibodies and guide vaccine design. Here we comprehensively characterize escape, breadth and potency across a panel of SARS-CoV-2 antibodies targeting the receptor-binding domain (RBD). Despite a trade-off between in vitro neutralization potency and breadth of sarbecovirus binding, we identify neutralizing antibodies with exceptional sarbecovirus breadth and a corresponding resistance to SARS-CoV-2 escape. One of these antibodies, S2H97, binds with high affinity across all sarbecovirus clades to a cryptic epitope and prophylactically protects hamsters from viral challenge. Antibodies that target the angiotensin-converting enzyme 2 (ACE2) receptor-binding motif (RBM) typically have poor breadth and are readily escaped by mutations despite high neutralization potency. Nevertheless, we also characterize a potent RBM antibody (S2E12⁸) with breadth across sarbecoviruses related to SARS-CoV-2 and a high barrier to viral escape. These data highlight principles underlying variation in escape, breadth and potency among antibodies that target the RBD, and identify epitopes and features to prioritize for therapeutic development against the current and potential future pandemics.

理想的治疗性抗 SARS-CoV-2 抗体应能抵抗病毒逃逸^1,2,3 ，对多种 sarbecoviruses ^4,5,6,7具有活性，并通过病毒中和^8,9,10,11和效应物提供高度保护功能^12,13 。了解这些特性如何相互关联以及不同表位之间的差异将有助于治疗性抗体的开发并指导疫苗设计。在这里，我们全面描述了一组针对受体结合域 (RBD) 的 SARS-CoV-2 抗体的逃逸性、广度和效力。尽管体外中和效力和 sarbecovirus 结合广度之间存在权衡，但我们发现了具有特殊 sarbecovirus 广度和相应的 SARS-CoV-2 逃逸抵抗力的中和抗体。其中一种抗体 S2H97 以高亲和力与所有 sarbecovirus 进化枝中的隐秘表位结合，并预防性地保护仓鼠免受病毒攻击。靶向血管紧张素转换酶 2 (ACE2) 受体结合基序 (RBM) 的抗体通常具有较差的广度，并且尽管中和效力较高，但很容易通过突变逃脱。尽管如此，我们还表征了一种有效的 RBM 抗体 (S2E12 ⁸ )，其广泛覆盖与 SARS-CoV-2 相关的 sarbecovirus，并且对病毒逃逸具有很高的屏障。这些数据强调了针对 RBD 的抗体之间逃逸、广度和效力差异的基本原理，并确定了针对当前和潜在的未来流行病的治疗开发的优先表位和特征。