Unlocking the potential of broadly reactive coronavirus monoclonal antibodies (mAbs) and their derivatives offers a transformative therapeutic avenue against severe COVID-19, especially crucial for safeguarding high-risk populations. Novel mAb-based immunotherapies may help address the reduced efficacy of current vaccines and neutralizing mAbs caused by the emergence of variants of concern (VOCs). Using phage display technology, we discovered a pan-SARS-CoV-2 mAb (C10) that targets a conserved region within the receptor-binding domain (RBD) of the virus. Noteworthy, C10 demonstrates exceptional efficacy in recognizing all assessed VOCs, including recent Omicron variants. While C10 lacks direct neutralization capacity, it efficiently binds to infected lung epithelial cells and induces their lysis via natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC). Building upon this pan-SARS-CoV-2 mAb, we engineered C10-based, Chimeric Antigen Receptor (CAR)-T cells endowed with efficient killing capacity against SARS-CoV-2-infected lung epithelial cells. Notably, NK and CAR-T-cell mediated killing of lung infected cells effectively reduces viral titers. These findings highlight the potential of non-neutralizing mAbs in providing immune protection against emerging infectious diseases. Our work reveals a pan-SARS-CoV-2 mAb effective in targeting infected cells and demonstrates the proof-of-concept for the potential application of CAR-T cell therapy in combating SARS-CoV-2 infections. Furthermore, it holds promise for the development of innovative antibody-based and cell-based therapeutic strategies against severe COVID-19 by expanding the array of therapeutic options available for high-risk populations.Trial registration: ClinicalTrials.gov identifier: NCT04093596.

中文翻译：

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发现一种具有高效感染细胞杀伤能力的泛抗 SARS-CoV-2 单克隆抗体，用于新型免疫治疗方法。


释放广泛反应性冠状病毒单克隆抗体 （mAb） 及其衍生物的潜力为针对严重 COVID-19 提供了一条变革性的治疗途径，对于保护高危人群尤为重要。基于新型 mAb 的免疫疗法可能有助于解决当前疫苗和因关注变异株 （VOC） 的出现而导致的中和 mAb 的疗效降低问题。利用噬菌体展示技术，我们发现了一种 pan-SARS-CoV-2 mAb （C10），它靶向病毒受体结合域 （RBD） 内的保守区域。值得注意的是，C10 在识别所有评估的 VOC 方面表现出非凡的功效，包括最近的 Omicron 变体。虽然 C10 缺乏直接中和能力，但它能有效地与感染的肺上皮细胞结合，并通过自然杀伤 （NK） 细胞介导的抗体依赖性细胞毒性 （ADCC） 诱导其裂解。基于这种 pan-SARS-CoV-2 mAb，我们设计了基于 C10 的嵌合抗原受体 （CAR）-T 细胞，该细胞对 SARS-CoV-2 感染的肺上皮细胞具有有效的杀伤能力。值得注意的是，NK 和 CAR-T 细胞介导的对肺部感染细胞的杀伤可有效降低病毒滴度。这些发现强调了非中和 mAb 在针对新发传染病提供免疫保护方面的潜力。我们的工作揭示了一种有效靶向感染细胞的泛 SARS-CoV-2 mAb，并展示了 CAR-T 细胞疗法在对抗 SARS-CoV-2 感染方面的潜在应用的概念验证。此外，它通过扩大高危人群可用的治疗选择范围，有望开发针对严重 COVID-19 的创新抗体和基于细胞的治疗策略。试验注册：ClinicalTrials。gov 标识符：NCT04093596。