Preclinical characterization of amubarvimab and romlusevimab, a pair of non-competing neutralizing monoclonal antibody cocktail, against SARS-CoV-2
Monoclonal antibodies (mAbs) targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein have demonstrated clinical efficacy in preventing or treating coronavirus disease 2019 (COVID-19), resulting in the emergency use authorization (EUA) for several SARS-CoV-2 targeting...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.980435/full |
| _version_ | 1811261142186590208 |
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| author | Yun Ji Qi Zhang Lin Cheng Jiwan Ge Ruoke Wang Mengqi Fang Eric M. Mucker Peng Chen Ji Ma Rui Zhang Chunming Li Holly Hammond Lauren Baracco Michael Holbrook Matthew Frieman Zheng Zhang Xinquan Wang Jay W. Hooper Linqi Zhang Qing Zhu |
| author_facet | Yun Ji Qi Zhang Lin Cheng Jiwan Ge Ruoke Wang Mengqi Fang Eric M. Mucker Peng Chen Ji Ma Rui Zhang Chunming Li Holly Hammond Lauren Baracco Michael Holbrook Matthew Frieman Zheng Zhang Xinquan Wang Jay W. Hooper Linqi Zhang Qing Zhu |
| author_sort | Yun Ji |
| collection | DOAJ |
| description | Monoclonal antibodies (mAbs) targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein have demonstrated clinical efficacy in preventing or treating coronavirus disease 2019 (COVID-19), resulting in the emergency use authorization (EUA) for several SARS-CoV-2 targeting mAb by regulatory authority. However, the continuous virus evolution requires diverse mAb options to combat variants. Here we describe two fully human mAbs, amubarvimab (BRII-196) and romlusevimab (BRII-198) that bind to non-competing epitopes on the receptor binding domain (RBD) of spike protein and effectively neutralize SARS-CoV-2 variants. A YTE modification was introduced to the fragment crystallizable (Fc) region of both mAbs to prolong serum half-life and reduce effector function. The amubarvimab and romlusevimab combination retained activity against most mutations associated with reduced susceptibility to previously authorized mAbs and against variants containing amino acid substitutions in their epitope regions. Consistently, the combination of amubarvimab and romlusevimab effectively neutralized a wide range of viruses including most variants of concern and interest in vitro. In a Syrian golden hamster model of SARS-CoV-2 infection, animals receiving combination of amubarvimab and romlusevimab either pre- or post-infection demonstrated less weight loss, significantly decreased viral load in the lungs, and reduced lung pathology compared to controls. These preclinical findings support their development as an antibody cocktail therapeutic option against COVID-19 in the clinic. |
| first_indexed | 2024-04-12T18:58:03Z |
| format | Article |
| id | doaj.art-c44757fcc73249619c8e0e342192a10c |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-12T18:58:03Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-c44757fcc73249619c8e0e342192a10c2022-12-22T03:20:15ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-09-011310.3389/fimmu.2022.980435980435Preclinical characterization of amubarvimab and romlusevimab, a pair of non-competing neutralizing monoclonal antibody cocktail, against SARS-CoV-2Yun Ji0Qi Zhang1Lin Cheng2Jiwan Ge3Ruoke Wang4Mengqi Fang5Eric M. Mucker6Peng Chen7Ji Ma8Rui Zhang9Chunming Li10Holly Hammond11Lauren Baracco12Michael Holbrook13Matthew Frieman14Zheng Zhang15Xinquan Wang16Jay W. Hooper17Linqi Zhang18Qing Zhu19Brii Biosciences Inc., Durham, NC, United StatesCenter for Global Health and Infectious Diseases, Comprehensive AIDS Research Center, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, ChinaInstitute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People’s Hospital, Shenzhen, ChinaThe Ministry of Education Key Laboratory of Protein Science, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Collaborative Innovation Center for Biotherapy, School of Life Sciences, Tsinghua University, Beijing, ChinaCenter for Global Health and Infectious Diseases, Comprehensive AIDS Research Center, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, ChinaCenter for Global Health and Infectious Diseases, Comprehensive AIDS Research Center, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, ChinaU.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD, United StatesCenter for Global Health and Infectious Diseases, Comprehensive AIDS Research Center, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, ChinaBrii Biosciences Inc., Durham, NC, United StatesCenter for Global Health and Infectious Diseases, Comprehensive AIDS Research Center, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, ChinaBrii Biosciences Inc., Beijing, ChinaCenter for Pathogen Research, Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, United StatesCenter for Pathogen Research, Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, United StatesIntegrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases (NIAID), Fort Detrick, MD, United StatesCenter for Pathogen Research, Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, United StatesInstitute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People’s Hospital, Shenzhen, ChinaThe Ministry of Education Key Laboratory of Protein Science, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Collaborative Innovation Center for Biotherapy, School of Life Sciences, Tsinghua University, Beijing, ChinaU.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD, United StatesCenter for Global Health and Infectious Diseases, Comprehensive AIDS Research Center, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, ChinaBrii Biosciences Inc., Durham, NC, United StatesMonoclonal antibodies (mAbs) targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein have demonstrated clinical efficacy in preventing or treating coronavirus disease 2019 (COVID-19), resulting in the emergency use authorization (EUA) for several SARS-CoV-2 targeting mAb by regulatory authority. However, the continuous virus evolution requires diverse mAb options to combat variants. Here we describe two fully human mAbs, amubarvimab (BRII-196) and romlusevimab (BRII-198) that bind to non-competing epitopes on the receptor binding domain (RBD) of spike protein and effectively neutralize SARS-CoV-2 variants. A YTE modification was introduced to the fragment crystallizable (Fc) region of both mAbs to prolong serum half-life and reduce effector function. The amubarvimab and romlusevimab combination retained activity against most mutations associated with reduced susceptibility to previously authorized mAbs and against variants containing amino acid substitutions in their epitope regions. Consistently, the combination of amubarvimab and romlusevimab effectively neutralized a wide range of viruses including most variants of concern and interest in vitro. In a Syrian golden hamster model of SARS-CoV-2 infection, animals receiving combination of amubarvimab and romlusevimab either pre- or post-infection demonstrated less weight loss, significantly decreased viral load in the lungs, and reduced lung pathology compared to controls. These preclinical findings support their development as an antibody cocktail therapeutic option against COVID-19 in the clinic.https://www.frontiersin.org/articles/10.3389/fimmu.2022.980435/fullmonoclonal antibody (mAb)severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)receptor binding domain (RBD)M252Y/S254T/T256E (YTE)amubarvimab (BRII-196)romlusevimab (BRII-198) |
| spellingShingle | Yun Ji Qi Zhang Lin Cheng Jiwan Ge Ruoke Wang Mengqi Fang Eric M. Mucker Peng Chen Ji Ma Rui Zhang Chunming Li Holly Hammond Lauren Baracco Michael Holbrook Matthew Frieman Zheng Zhang Xinquan Wang Jay W. Hooper Linqi Zhang Qing Zhu Preclinical characterization of amubarvimab and romlusevimab, a pair of non-competing neutralizing monoclonal antibody cocktail, against SARS-CoV-2 Frontiers in Immunology monoclonal antibody (mAb) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain (RBD) M252Y/S254T/T256E (YTE) amubarvimab (BRII-196) romlusevimab (BRII-198) |
| title | Preclinical characterization of amubarvimab and romlusevimab, a pair of non-competing neutralizing monoclonal antibody cocktail, against SARS-CoV-2 |
| title_full | Preclinical characterization of amubarvimab and romlusevimab, a pair of non-competing neutralizing monoclonal antibody cocktail, against SARS-CoV-2 |
| title_fullStr | Preclinical characterization of amubarvimab and romlusevimab, a pair of non-competing neutralizing monoclonal antibody cocktail, against SARS-CoV-2 |
| title_full_unstemmed | Preclinical characterization of amubarvimab and romlusevimab, a pair of non-competing neutralizing monoclonal antibody cocktail, against SARS-CoV-2 |
| title_short | Preclinical characterization of amubarvimab and romlusevimab, a pair of non-competing neutralizing monoclonal antibody cocktail, against SARS-CoV-2 |
| title_sort | preclinical characterization of amubarvimab and romlusevimab a pair of non competing neutralizing monoclonal antibody cocktail against sars cov 2 |
| topic | monoclonal antibody (mAb) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain (RBD) M252Y/S254T/T256E (YTE) amubarvimab (BRII-196) romlusevimab (BRII-198) |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.980435/full |
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