Autolus Limited, The MediaWorks, London, United Kingdom.
National Institute for Biological Standards and Controlgrid.70909.37, Herts, United Kingdom.
J Virol. 2021 Sep 9;95(19):e0068521. doi: 10.1128/JVI.00685-21.
The human angiotensin-converting enzyme 2 acts as the host cell receptor for SARS-CoV-2 and the other members of the family SARS-CoV-1 and HCoV-NL63. Here, we report the biophysical properties of the SARS-CoV-2 spike variants D614G, B.1.1.7, B.1.351, and P.1 with affinities to the ACE2 receptor and infectivity capacity, revealing weaknesses in the developed neutralizing antibody approaches. Furthermore, we report a preclinical characterization package for a soluble receptor decoy engineered to be catalytically inactive and immunologically inert, with broad neutralization capacity, that represents an attractive therapeutic alternative in light of the mutational landscape of COVID-19. This construct efficiently neutralized four SARS-CoV-2 variants of concern. The decoy also displays antibody-like biophysical properties and manufacturability, strengthening its suitability as a first-line treatment option in prophylaxis or therapeutic regimens for COVID-19 and related viral infections. Mutational drift of SARS-CoV-2 risks rendering both therapeutics and vaccines less effective. Receptor decoy strategies utilizing soluble human ACE2 may overcome the risk of viral mutational escape since mutations disrupting viral interaction with the ACE2 decoy will by necessity decrease virulence, thereby preventing meaningful escape. The solution described here of a soluble ACE2 receptor decoy is significant for the following reasons: while previous ACE2-based therapeutics have been described, ours has novel features, including (i) mutations within ACE2 to remove catalytical activity and systemic interference with the renin/angiotensin system, (ii) abrogated FcγR engagement, reduced risk of antibody-dependent enhancement of infection, and reduced risk of hyperinflammation, and (iii) streamlined antibody-like purification process and scale-up manufacturability indicating that this receptor decoy could be produced quickly and easily at scale. Finally, we demonstrate that ACE2-based therapeutics confer a broad-spectrum neutralization potency for ACE2-tropic viruses, including SARS-CoV-2 variants of concern in contrast to therapeutic MAb.
人类血管紧张素转换酶 2 是 SARS-CoV-2 及 SARS-CoV-1 和 HCoV-NL63 家族其他成员的宿主细胞受体。在这里，我们报告了 SARS-CoV-2 刺突变体 D614G、B.1.1.7、B.1.351 和 P.1 与 ACE2 受体的亲和力和感染能力的生物物理特性，揭示了开发中和抗体方法的弱点。此外，我们报告了一种针对可溶性受体诱饵的临床前特征描述包，该诱饵设计为无催化活性和免疫惰性，但具有广泛的中和能力，鉴于 COVID-19 的突变景观，这代表了一种有吸引力的治疗选择。该构建体有效地中和了四种令人关注的 SARS-CoV-2 变体。诱饵还显示出类似抗体的生物物理特性和可制造性，这增强了其作为 COVID-19 和相关病毒感染的预防或治疗方案中的一线治疗选择的适用性。SARS-CoV-2 的突变漂移有可能降低治疗和疫苗的有效性。利用可溶性人 ACE2 的受体诱饵策略可能会克服病毒突变逃逸的风险，因为破坏病毒与 ACE2 诱饵相互作用的突变将不可避免地降低病毒的毒力，从而防止有意义的逃逸。这里描述的可溶性 ACE2 受体诱饵解决方案具有以下重要意义：虽然已经描述了以前基于 ACE2 的治疗方法，但我们的方法具有新的特点，包括（i）ACE2 内的突变以去除催化活性和对肾素/血管紧张素系统的系统干扰，（ii）阻断 FcγR 结合，降低感染的抗体依赖性增强风险，降低过度炎症风险，以及（iii）简化的类似抗体的纯化过程和可扩展性制造能力，表明这种受体诱饵可以快速、轻松地大规模生产。最后，我们证明基于 ACE2 的治疗方法赋予 ACE2 亲嗜性病毒广谱中和效力，包括与治疗性单克隆抗体相比的 SARS-CoV-2 变体。
