Service of Immunology and Allergy, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
J Infect. 2023 Dec;87(6):524-537. doi: 10.1016/j.jinf.2023.10.008. Epub 2023 Oct 16.
Due to the rapid evolution of SARS-CoV-2 to variants with reduced sensitivity to vaccine-induced humoral immunity and the near complete loss of protective efficacy of licensed therapeutic monoclonal antibodies, we isolated a potent, broad-spectrum neutralizing antibody that could potentially provide prophylactic protection to immunocompromised patient populations.
Spike-specific B-cell clones isolated from a vaccinated post-infected donor were profiled for those producing potent neutralizing antibodies against a panel of SARS-CoV-2 variants. The P4J15 antibody was further characterized to define the structural binding epitope, viral resistance, and in vivo efficacy.
The P4J15 mAb shows <20 ng/ml neutralizing activity against all variants including the latest XBB.2.3 and EG.5.1 sub-lineages. Structural studies of P4J15 in complex with Omicron XBB.1 Spike show that the P4J15 epitope shares ∼93% of its buried surface area with the ACE2 contact region, consistent with an ACE2 mimetic antibody. In vitro selection of SARS-CoV-2 mutants escaping P4J15 neutralization showed reduced infectivity, poor ACE2 binding, and mutations are rare in public sequence databases. Using a SARS-CoV-2 XBB.1.5 monkey challenge model, P4J15-LS confers complete prophylactic protection with an exceptionally long in vivo half-life of 43 days.
The P4J15 mAb has potential as a broad-spectrum anti-SARS-CoV-2 drug for prophylactic protection of at-risk patient populations.
由于 SARS-CoV-2 迅速进化为对疫苗诱导的体液免疫敏感性降低的变体，以及已批准的治疗性单克隆抗体的保护效力几乎完全丧失，我们分离出一种强效、广谱的中和抗体，有可能为免疫功能低下的患者群体提供预防性保护。
从接种后感染的供体中分离出针对 Spike 的 B 细胞克隆，对产生针对 SARS-CoV-2 变体的强效中和抗体的克隆进行分析。进一步表征 P4J15 抗体以确定结构结合表位、病毒耐药性和体内疗效。
P4J15 mAb 对所有变体（包括最新的 XBB.2.3 和 EG.5.1 亚系）的中和活性<20ng/ml。P4J15 与奥密克戎 XBB.1 Spike 复合物的结构研究表明，P4J15 表位与 ACE2 结合区域共享约 93%的埋藏表面积，与 ACE2 模拟抗体一致。体外选择逃避 P4J15 中和的 SARS-CoV-2 突变体显示出感染性降低、ACE2 结合不良，并且突变在公共序列数据库中很少见。在 SARS-CoV-2 XBB.1.5 猴攻毒模型中，P4J15-LS 可提供完全的预防性保护，体内半衰期长达 43 天。
P4J15 mAb 具有作为广谱抗 SARS-CoV-2 药物的潜力，可用于保护高危患者群体。
