Table_1_XAV-19, a Swine Glyco-Humanized Polyclonal Antibody Against SARS-CoV-2 Spike Receptor-Binding Domain, Targets Multiple Epitopes and Broadly Neutralizes Variants.docx

Amino acid substitutions and deletions in the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants can reduce the effectiveness of monoclonal antibodies (mAbs). In contrast, heterologous polyclonal antibodies raised against S protein, through the recognition of multiple target epitopes, have the potential to maintain neutralization capacities. XAV-19 is a swine glyco-humanized polyclonal neutralizing antibody raised against the receptor binding domain (RBD) of the Wuhan-Hu-1 Spike protein of SARS-CoV-2. XAV-19 target epitopes were found distributed all over the RBD and particularly cover the receptor binding motives (RBMs), in direct contact sites with the angiotensin converting enzyme-2 (ACE-2). Therefore, in Spike/ACE-2 interaction assays, XAV-19 showed potent neutralization capacities of the original Wuhan Spike and of the United Kingdom (Alpha/B.1.1.7) and South African (Beta/B.1.351) variants. These results were confirmed by cytopathogenic assays using Vero E6 and live virus variants including the Brazil (Gamma/P.1) and the Indian (Delta/B.1.617.2) variants. In a selective pressure study on Vero E6 cells conducted over 1 month, no mutation was associated with the addition of increasing doses of XAV-19. The potential to reduce viral load in lungs was confirmed in a human ACE-2 transduced mouse model. XAV-19 is currently evaluated in patients hospitalized for COVID-19-induced moderate pneumonia in phase 2a-2b (NCT04453384) where safety was already demonstrated and in an ongoing 2/3 trial (NCT04928430) to evaluate the efficacy and safety of XAV-19 in patients with moderate-to-severe COVID-19. Owing to its polyclonal nature and its glyco-humanization, XAV-19 may provide a novel safe and effective therapeutic tool to mitigate the severity of coronavirus disease 2019 (COVID-19) including the different variants of concern identified so far.

SARS-CoV-2变异株的刺突蛋白中的氨基酸替换和缺失可降低单克隆抗体的有效性。相反，针对S蛋白产生的异源多克隆抗体，通过识别多个靶表位，具有维持中和能力的潜力。XAV-19是一种针对SARS-CoV-2武汉-Hu-1株刺突蛋白受体结合域（RBD）的猪源人源化多克隆中和抗体。XAV-19的靶表位分布在整个RBD上，特别是覆盖了与血管紧张素转换酶-2（ACE-2）直接接触的受体结合位点（RBMs）。因此，在刺突/ACE-2相互作用实验中，XAV-19对原始武汉刺突、英国（Alpha/B.1.1.7）和南非（Beta/B.1.351）变异株均表现出强大的中和能力。这些结果通过使用Vero E6细胞和包括巴西（Gamma/P.1）和印度（Delta/B.1.617.2）变异株在内的活病毒变异株进行的细胞病理学实验得到了证实。在一项为期1个月针对Vero E6细胞的筛选压力研究中，未发现与XAV-19剂量增加相关的突变。在ACE-2转导的人源化小鼠模型中，XAV-19降低肺部病毒载量的潜力得到了证实。XAV-19目前正在评估中，针对因COVID-19引起的轻至中度肺炎住院患者进行2a-2b期（NCT04453384）试验，其中已证实其安全性，并在一项正在进行中的2/3期试验（NCT04928430）中评估XAV-19在轻至重度COVID-19患者中的有效性和安全性。由于其多克隆特性和糖基人源化，XAV-19可能为减轻包括迄今为止已确定的关注变异株在内的冠状病毒病2019（COVID-19）的严重程度提供一种新颖的安全有效的治疗工具。