The pandemic of Coronavirus Disease 2019 (COVID-19) caused by SARS-CoV-2 has induced global eagerness to develop vaccines and therapeutics for treating COVID-19, including neutralizing antibodies. To develop effective therapeutic antibodies against SARS-CoV-2, it is critical to understand the interaction between viral and host's proteins. The human ACE2 (_hACE2) protein is the crucial target for the SARS-CoV's Spike protein that allows the virus to adhere to host epithelial cells. X-ray crystal structures and biophysical properties of protein-protein interactions reveal a large interaction surface with high binding-affinity between SARS-CoV-2 and _hACE2 (18 interactions), at least 15-fold stronger than between SARS-CoV-1 and _hACE2 (eight interactions). This suggests that antibodies against CoV-1 infection might not be very efficient against CoV-2. Furthermore, interspecies comparisons indicate that ACE2 proteins of man and cat are far closer than dog, ferret, mouse, and rat with significant differences in binding-affinity between Spike and ACE2 proteins. This strengthens the notion of productive SARS-CoV-2 transmission between felines and humans and that classical animal models are not optimally suited for evaluating therapeutic antibodies. The large interaction surface with strong affinity between SARS-CoV-2 and _hACE2 (dG−12.4) poses a huge challenge to develop reliable antibody therapy that truly blocks SARS-CoV-2 adherence and infection. We gauge that single antibodies against single epitopes might not sufficiently interfere with the strong interaction-synapse between Spike and _hACE2 proteins. Instead, appropriate combinations of high-affinity neutralizing antibodies against different epitopes might be needed, preferably of IgA-class for optimal and prolonged activity at epithelial layers of respiratory and intestine tracts.

由 SARS-CoV-2 引起的 2019 冠状病毒病 (COVID-19) 大流行引发了全球对开发治疗 COVID-19 的疫苗和疗法（包括中和抗体）的渴望。为了开发针对 SARS-CoV-2 的有效治疗抗体，了解病毒和宿主蛋白质之间的相互作用至关重要。人类 ACE2 ( _h ACE2) 蛋白是 SARS-CoV 刺突蛋白的关键靶点，使病毒能够粘附到宿主上皮细胞上。_{蛋白质-蛋白质相互作用的 X 射线晶体结构和生物物理特性揭示了 SARS-CoV-2 和h} ACE2之间具有高结合亲和力的大相互作用表面（18 种相互作用），比 SARS-CoV-1 之间至少强 15 倍和_h ACE2（八种相互作用）。这表明针对 CoV-1 感染的抗体可能对 CoV-2 不是非常有效。此外，种间比较表明，人和猫的 ACE2 蛋白比狗、雪貂、小鼠和大鼠更接近，Spike 和 ACE2 蛋白之间的结合亲和力存在显着差异。这强化了猫科动物和人类之间有效的 SARS-CoV-2 传播的概念，并且经典动物模型并不最适合评估治疗性抗体。_{SARS-CoV-2 和h} ACE2 (dG−12.4)之间具有强亲和力的大相互作用表面，对开发真正阻止 SARS-CoV-2 粘附和感染的可靠抗体疗法提出了巨大的挑战。_{我们估计，针对单一表位的单一抗体可能不足以干扰 Spike 和h} ACE2 蛋白之间的强相互作用突触。相反，可能需要针对不同表位的高亲和力中和抗体的适当组合，最好是 IgA 类抗体，以在呼吸道和肠道上皮层获得最佳且持久的活性。