Xenothera, Nantes, France.
Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM) 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié Salpêtrière Hospital, Department of Virology, Paris, France.
Front Immunol. 2021 Nov 15;12:761250. doi: 10.3389/fimmu.2021.761250. eCollection 2021.
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.
严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 变体的 Spike 蛋白中的氨基酸替换和缺失会降低单克隆抗体 (mAb) 的有效性。相比之下，针对 S 蛋白产生的异源多克隆抗体通过识别多个靶标表位，有可能保持中和能力。XAV-19 是一种针对 SARS-CoV-2 的武汉-Hu-1 Spike 蛋白受体结合域 (RBD) 产生的猪源糖基化人源多克隆中和抗体。XAV-19 的靶标表位分布在整个 RBD 上，特别是覆盖受体结合基序 (RBM)，与血管紧张素转化酶-2 (ACE-2) 直接接触。因此，在 Spike/ACE-2 相互作用测定中，XAV-19 对原始武汉 Spike 以及英国 (Alpha/B.1.1.7) 和南非 (Beta/B.1.351) 变体均显示出强大的中和能力。这些结果通过使用 Vero E6 和包括巴西 (Gamma/P.1) 和印度 (Delta/B.1.617.2) 变体在内的活病毒变体进行细胞病变效应测定得到了证实。在对 Vero E6 细胞进行的为期一个月的选择性压力研究中，没有发现与 XAV-19 剂量增加相关的突变。在人 ACE-2 转导的小鼠模型中，证实了降低肺部病毒载量的潜力。XAV-19 目前正在接受评估，用于 COVID-19 引起的中度肺炎住院患者的 2a-2b 期试验（NCT04453384），其中已证实安全性，以及一项正在进行的 2/3 期试验（NCT04928430），以评估 XAV-19 在中重度 COVID-19 患者中的疗效和安全性。由于其多克隆性质及其糖基化人源化，XAV-19 可能为减轻包括迄今为止确定的不同关切变体在内的 2019 年冠状病毒病 (COVID-19) 的严重程度提供一种新型安全有效的治疗工具。
