Ito Takaaki, Suzuki Tatsuya, Sakai Yusuke, Nishioka Keisuke, Itoh Yumi, Sakamoto Kentarou, Ikemura Nariko, Matoba Satoaki, Kanda Yasunari, Takagi Junichi, Okamoto Toru, Tahara Kohei, Hoshino Atsushi
Laboratory of Pharmaceutical Engineering, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
Department of Microbiology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
Mol Ther Methods Clin Dev. 2025 Mar 31;33(2):101459. doi: 10.1016/j.omtm.2025.101459. eCollection 2025 Jun 12.
The persistent threat of SARS-CoV-2 and the emergence of new variants has prompted the development of a novel, easily administered modality that can overcome viral mutations. The engineered ACE2 decoy shows neutralizing activity comparable to monoclonal antibodies and is broadly effective against SARS-CoV-2 variants and ACE2-utilizing sarbecoviruses. In addition to intravenous administration, this decoy has shown antiviral efficacy through nebulized aerosol inhalation in murine and primate models, offering a dose-sparing advantage. Clinically, dry powder formulation is ideal for convenience and storage but poses challenges for protein biologics. This study developed a freeze-dried spray formulation of the ACE2 decoy for inhalation. The trehalose and leucine-based excipient maintained neutralizing activity and prevented aggregate formation. The dry powder showed aerodynamic distribution from bronchi to alveoli, aiding protection against SARS-CoV-2 infections. Neutralizing activity, structural stability, and powder dispersibility were preserved after 6 months of storage. In a mouse model of SARS-CoV-2 infection, significant reductions in viral replication and lung pathology were observed with intratracheal administration 24 h post-infection. The ACE2 decoy retained activity against recent JN.1 and current KP.3 strains, confirming its robust efficacy against viral mutations. This ACE2 decoy powder inhalant is a self-administered, next-generation treatment addressing the ongoing immune-evading evolution of SARS-CoV-2.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的持续威胁以及新变种的出现，促使人们开发一种新型的、易于给药的方式，以克服病毒突变。工程化的血管紧张素转换酶2（ACE2）诱饵显示出与单克隆抗体相当的中和活性，并且对SARS-CoV-2变种和利用ACE2的沙贝病毒具有广泛的有效性。除静脉给药外，这种诱饵在小鼠和灵长类动物模型中通过雾化气溶胶吸入显示出抗病毒功效，具有节省剂量的优势。在临床上，干粉制剂因其便利性和储存性而理想，但对蛋白质生物制品构成挑战。本研究开发了一种用于吸入的ACE2诱饵冻干喷雾制剂。基于海藻糖和亮氨酸的赋形剂保持了中和活性并防止聚集体形成。干粉显示出从支气管到肺泡的空气动力学分布，有助于预防SARS-CoV-2感染。储存6个月后，中和活性、结构稳定性和粉末分散性得以保留。在SARS-CoV-2感染的小鼠模型中，感染后24小时气管内给药可观察到病毒复制和肺部病理的显著减少。ACE2诱饵对最近的JN.1和当前的KP.3毒株仍保持活性，证实了其对病毒突变具有强大的功效。这种ACE2诱饵粉末吸入剂是一种自我给药的下一代治疗方法，可应对SARS-CoV-2持续的免疫逃逸进化。
