Neutralizing monoclonal antibodies (NAbs) with prophylactic and therapeutic efficacy have demonstrated fundamental importance in the control of SARS-CoV-2 transmission. However, their wide application has been largely limited by high cost and inconvenience in administration. Here, we developed an intranasal spray containing two synergetic human NAbs that could broadly neutralize the emerging Omicron variants in vitro. A unique synergetic neutralizing mechanism was identified that the two NAbs bound to exclusive epitopes on the RBD and structurally compensate each other in blocking the Spike-ACE2 interaction. Importantly, when given at low dosages for three consecutive days through the intranasal mucosal route, this cocktail showed significant improvement in the emergency preventive and therapeutic effects in hamsters challenged with authentic Omicron BA.1. Further, we performed an investigator-initiated trail in healthy volunteers (ChiCTR2200066525) to study the safety and pharmacokinetics of the antibody cocktail administrated as nasal spray. The nasal spray is generally safe and well tolerated without treatment related severe abnormal effects. The antibody cocktail nasal spray demonstrated nasal concentrations higher than the IC90 of neutralization activity against Omicron BA.4/5 even at 24 hours post dosing. Furthermore, nasal samples from the study subjects demonstrated potent neutralization activity against Omicron BA.4/5 in an ex vivo pseudovirus neutralization assay. Together, we provide a novel approach for NAb regimens, a potentially highly effective product with broad applicable perspective in depressing the infection risk of new epidemic variant and ameliorating the heavy medical burden of hospital.

中文翻译：

---

含有两种协同抗体的鸡尾酒鼻内喷雾的首次人体临床研究可中和 Omicron BA.4/5

具有预防和治疗功效的中和单克隆抗体 (NAb) 已证明在控制 SARS-CoV-2 传播方面具有根本重要性。然而，它们的广泛应用在很大程度上受到成本高和管理不便的限制。在这里，我们开发了一种鼻内喷雾剂，其中包含两种协同作用的人类 NAb，可以在体外广泛中和新兴的 Omicron 变体。确定了一种独特的协同中和机制，即两种 NAb 与 RBD 上的排他表位结合，并在结构上相互补偿以阻断 Spike-ACE2 相互作用。重要的是，当通过鼻粘膜途径连续三天低剂量给药时，这种鸡尾酒在受到正宗 Omicron BA.1 挑战的仓鼠中显示出紧急预防和治疗效果的显着改善。此外，我们在健康志愿者 (ChiCTR2200066525) 中进行了一项研究者发起的试验，以研究作为鼻喷雾剂给药的抗体混合物的安全性和药代动力学。鼻腔喷雾剂通常安全且耐受性良好，没有治疗相关的严重异常反应。即使在给药后 24 小时，抗体混合物鼻腔喷雾剂的鼻腔浓度也高于针对 Omicron BA.4/5 的中和活性的 IC90。此外，来自研究对象的鼻腔样本在离体假病毒中和试验中显示出对 Omicron BA.4/5 的有效中和活性。我们一起为 NAb 方案提供了一种新方法，