A Therapeutic Non-self-reactive SARS-CoV-2 Antibody Protects from Lung Pathology in a COVID-19 Hamster Model,Cell

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A Therapeutic Non-self-reactive SARS-CoV-2 Antibody Protects from Lung Pathology in a COVID-19 Hamster Model
Cell ( IF 64.5 ) Pub Date : 2020-09-23 , DOI: 10.1016/j.cell.2020.09.049
Jakob Kreye ₁ , S Momsen Reincke ₂ , Hans-Christian Kornau ₃ , Elisa Sánchez-Sendin ₄ , Victor Max Corman ₅ , Hejun Liu ₆ , Meng Yuan ₆ , Nicholas C Wu ₆ , Xueyong Zhu ₆ , Chang-Chun D Lee ₆ , Jakob Trimpert ₇ , Markus Höltje ₈ , Kristina Dietert ₉ , Laura Stöffler ₁₀ , Niels von Wardenburg ₁₀ , Scott van Hoof ₄ , Marie A Homeyer ₁₁ , Julius Hoffmann ₁₀ , Azza Abdelgawad ₇ , Achim D Gruber ₁₂ , Luca D Bertzbach ₇ , Daria Vladimirova ₇ , Lucie Y Li ₁₃ , Paula Charlotte Barthel ₈ , Karl Skriner ₁₄ , Andreas C Hocke ₁₅ , Stefan Hippenstiel ₁₅ , Martin Witzenrath ₁₅ , Norbert Suttorp ₁₅ , Florian Kurth ₁₆ , Christiana Franke ₁₇ , Matthias Endres ₁₈ , Dietmar Schmitz ₃ , Lara Maria Jeworowski ₅ , Anja Richter ₅ , Marie Luisa Schmidt ₅ , Tatjana Schwarz ₅ , Marcel Alexander Müller ₅ , Christian Drosten ₅ , Daniel Wendisch ₁₅ , Leif E Sander ₁₅ , Nikolaus Osterrieder ₁₉ , Ian A Wilson ₂₀ , Harald Prüss ₄

Affiliation

German Center for Neurodegenerative Diseases (DZNE) Berlin, 10117 Berlin, Germany; Helmholtz Innovation Lab BaoBab (Brain Antibody-omics and B-cell Lab), 10117 Berlin, Germany; Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; Department of Pediatric Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
German Center for Neurodegenerative Diseases (DZNE) Berlin, 10117 Berlin, Germany; Helmholtz Innovation Lab BaoBab (Brain Antibody-omics and B-cell Lab), 10117 Berlin, Germany; Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; Berlin Institute of Health (BIH), 10178 Berlin, Germany.
German Center for Neurodegenerative Diseases (DZNE) Berlin, 10117 Berlin, Germany; Neuroscience Research Center (NWFZ), Cluster NeuroCure, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
German Center for Neurodegenerative Diseases (DZNE) Berlin, 10117 Berlin, Germany; Helmholtz Innovation Lab BaoBab (Brain Antibody-omics and B-cell Lab), 10117 Berlin, Germany; Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
Institute of Virology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany, and German Centre for Infection Research (DZIF), 10117 Berlin, Germany.
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Institute of Virology, Freie Universität Berlin, 14163 Berlin, Germany.
Institute of Integrative Neuroanatomy Berlin, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
Institute of Veterinary Pathology, Freie Universität Berlin, 14163 Berlin, Germany; Veterinary Centre for Resistance Research, Freie Universität Berlin, 14163 Berlin, Germany.
German Center for Neurodegenerative Diseases (DZNE) Berlin, 10117 Berlin, Germany; Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
German Center for Neurodegenerative Diseases (DZNE) Berlin, 10117 Berlin, Germany; Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; Berlin Institute of Health (BIH), 10178 Berlin, Germany.
Institute of Veterinary Pathology, Freie Universität Berlin, 14163 Berlin, Germany.
Helmholtz Innovation Lab BaoBab (Brain Antibody-omics and B-cell Lab), 10117 Berlin, Germany; Institute of Integrative Neuroanatomy Berlin, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
Department of Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
Department of Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; Department of Tropical Medicine, Bernhard Nocht Institute for Tropical Medicine and I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20359 Hamburg, Germany.
Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
German Center for Neurodegenerative Diseases (DZNE) Berlin, 10117 Berlin, Germany; Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; Center for Stroke Research Berlin, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; Excellence Cluster NeuroCure Berlin, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, 10785 Berlin, Germany.
Institute of Virology, Freie Universität Berlin, 14163 Berlin, Germany; Department of Infectious Diseases and Public Health, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Hong Kong.
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.

The emergence of SARS-CoV-2 led to pandemic spread of coronavirus disease 2019 (COVID-19), manifesting with respiratory symptoms and multi-organ dysfunction. Detailed characterization of virus-neutralizing antibodies and target epitopes is needed to understand COVID-19 pathophysiology and guide immunization strategies. Among 598 human monoclonal antibodies (mAbs) from 10 COVID-19 patients, we identified 40 strongly neutralizing mAbs. The most potent mAb, CV07-209, neutralized authentic SARS-CoV-2 with an IC₅₀ value of 3.1 ng/mL. Crystal structures of two mAbs in complex with the SARS-CoV-2 receptor-binding domain at 2.55 and 2.70 Å revealed a direct block of ACE2 attachment. Interestingly, some of the near-germline SARS-CoV-2-neutralizing mAbs reacted with mammalian self-antigens. Prophylactic and therapeutic application of CV07-209 protected hamsters from SARS-CoV-2 infection, weight loss, and lung pathology. Our results show that non-self-reactive virus-neutralizing mAbs elicited during SARS-CoV-2 infection are a promising therapeutic strategy.

中文翻译：

一种治疗性非自身反应性 SARS-CoV-2 抗体可保护 COVID-19 仓鼠模型免受肺部病变

SARS-CoV-2 的出现导致 2019 冠状病毒病（COVID-19）大流行，表现为呼吸道症状和多器官功能障碍。需要对病毒中和抗体和目标表位进行详细表征，以了解 COVID-19 病理生理学和指导免疫策略。在来自 10 名 COVID-19 患者的 598 种人单克隆抗体 (mAb) 中，我们鉴定了 40 种强中和性 mAb。最有效的 mAb CV07-209 中和了真正的 SARS-CoV-2，IC 为₅₀值为 3.1 纳克/毫升。与 2.55 和 2.70 Å 的 SARS-CoV-2 受体结合域复合的两种 mAb 的晶体结构揭示了 ACE2 附着的直接阻断。有趣的是，一些近胚系 SARS-CoV-2 中和 mAb 与哺乳动物自身抗原发生反应。CV07-209 的预防和治疗应用可保护仓鼠免受 SARS-CoV-2 感染、体重减轻和肺部病变。我们的研究结果表明，在 SARS-CoV-2 感染期间引发的非自身反应性病毒中和 mAb 是一种有前途的治疗策略。

更新日期：2020-11-12

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