Neutralizing monoclonal antibodies protect against human adenovirus type 55 infection in transgenic mice and tree shrews
ABSTRACTRe-emerging human adenovirus type 55 (HAdV55) has become a significant threat to public health due to its widespread circulation and the association with severe pneumonia, but an effective anti-HAdV55 agent remains unavailable. Herein, we report the generation of macaque-derived, human-like...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | Emerging Microbes and Infections |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/22221751.2024.2307513 |
| _version_ | 1797335605976236032 |
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| author | Xinglong Liu Zhengfeng Li Xiao Li Xiaoyan Zhang Yali Zheng Wan Su Ying Feng Yutong Liu Weixuan Wu Xikui Sun Nana Wang Xianmiao Ye Zhichao Zhou Wenkuan Liu Jun He Wei Wang Linbing Qu Rong Zhou Ling Chen Liqiang Feng |
| author_facet | Xinglong Liu Zhengfeng Li Xiao Li Xiaoyan Zhang Yali Zheng Wan Su Ying Feng Yutong Liu Weixuan Wu Xikui Sun Nana Wang Xianmiao Ye Zhichao Zhou Wenkuan Liu Jun He Wei Wang Linbing Qu Rong Zhou Ling Chen Liqiang Feng |
| author_sort | Xinglong Liu |
| collection | DOAJ |
| description | ABSTRACTRe-emerging human adenovirus type 55 (HAdV55) has become a significant threat to public health due to its widespread circulation and the association with severe pneumonia, but an effective anti-HAdV55 agent remains unavailable. Herein, we report the generation of macaque-derived, human-like monoclonal antibodies (mAbs) protecting against HAdV55 infection with high potency. Using fluorophore-labelled HAdV55 virions as probes, we isolated specific memory B cells from rhesus macaques (Macaca mulatta) that were immunized twice with an experimental vaccine based on E1-, E3-deleted, replication-incompetent HAdV55. We cloned a total of 19 neutralizing mAbs, nine of which showed half-maximal inhibitory concentrations below 1.0 ng/ml. These mAbs recognized the hyper-variable-region (HVR) 1, 2, or 7 of viral hexon protein, or the fibre knob. In transgenic mice expressing human desmoglein-2, the major cellular receptor for HAdV55, a single intraperitoneal injection with hexon-targeting mAbs efficiently prevented HAdV55 infection, and mAb 29C12 showed protection at a dose as low as 0.004 mg/kg. Fibre-targeting mAb 28E8, however, showed protection only at a dose up to 12.5 mg/kg. In tree shrews that are permissive for HAdV55 infection and disease, mAb 29C12 effectively prevented HAdV55-caused pneumonia. Further analysis revealed that fibre-targeting mAbs blocked the attachment of HAdV55 to host cells, whereas hexon-targeting mAbs, regardless of their targeting HVRs, mainly functioned at post-attachment stage via inhibiting viral endosomal escape. Our results indicate that hexon-targeting mAbs have great anti-HAdV55 activities and warrant pre-clinical and clinical evaluation. |
| first_indexed | 2024-03-08T08:40:44Z |
| format | Article |
| id | doaj.art-cba41b4de9e84eb091bb05d407a159ad |
| institution | Directory Open Access Journal |
| issn | 2222-1751 |
| language | English |
| last_indexed | 2024-03-08T08:40:44Z |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Emerging Microbes and Infections |
| spelling | doaj.art-cba41b4de9e84eb091bb05d407a159ad2024-02-01T19:58:05ZengTaylor & Francis GroupEmerging Microbes and Infections2222-17512024-12-0113110.1080/22221751.2024.2307513Neutralizing monoclonal antibodies protect against human adenovirus type 55 infection in transgenic mice and tree shrewsXinglong Liu0Zhengfeng Li1Xiao Li2Xiaoyan Zhang3Yali Zheng4Wan Su5Ying Feng6Yutong Liu7Weixuan Wu8Xikui Sun9Nana Wang10Xianmiao Ye11Zhichao Zhou12Wenkuan Liu13Jun He14Wei Wang15Linbing Qu16Rong Zhou17Ling Chen18Liqiang Feng19State Key Laboratory of Respiratory Disease, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, People’s Republic of ChinaState Key Laboratory of Respiratory Disease, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, People’s Republic of ChinaState Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, People’s Republic of ChinaState Key Laboratory of Respiratory Disease, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, People’s Republic of ChinaState Key Laboratory of Respiratory Disease, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, People’s Republic of ChinaState Key Laboratory of Respiratory Disease, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, People’s Republic of ChinaGuangzhou Laboratory & Bioland Laboratory, Guangzhou, People’s Republic of ChinaState Key Laboratory of Respiratory Disease, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, People’s Republic of ChinaState Key Laboratory of Respiratory Disease, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, People’s Republic of ChinaState Key Laboratory of Respiratory Disease, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, People’s Republic of ChinaState Key Laboratory of Respiratory Disease, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, People’s Republic of ChinaState Key Laboratory of Respiratory Disease, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, People’s Republic of ChinaState Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, People’s Republic of ChinaState Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, People’s Republic of ChinaState Key Laboratory of Respiratory Disease, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, People’s Republic of ChinaGuangzhou Laboratory & Bioland Laboratory, Guangzhou, People’s Republic of ChinaState Key Laboratory of Respiratory Disease, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, People’s Republic of ChinaGuangzhou Laboratory & Bioland Laboratory, Guangzhou, People’s Republic of ChinaState Key Laboratory of Respiratory Disease, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, People’s Republic of ChinaState Key Laboratory of Respiratory Disease, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, People’s Republic of ChinaABSTRACTRe-emerging human adenovirus type 55 (HAdV55) has become a significant threat to public health due to its widespread circulation and the association with severe pneumonia, but an effective anti-HAdV55 agent remains unavailable. Herein, we report the generation of macaque-derived, human-like monoclonal antibodies (mAbs) protecting against HAdV55 infection with high potency. Using fluorophore-labelled HAdV55 virions as probes, we isolated specific memory B cells from rhesus macaques (Macaca mulatta) that were immunized twice with an experimental vaccine based on E1-, E3-deleted, replication-incompetent HAdV55. We cloned a total of 19 neutralizing mAbs, nine of which showed half-maximal inhibitory concentrations below 1.0 ng/ml. These mAbs recognized the hyper-variable-region (HVR) 1, 2, or 7 of viral hexon protein, or the fibre knob. In transgenic mice expressing human desmoglein-2, the major cellular receptor for HAdV55, a single intraperitoneal injection with hexon-targeting mAbs efficiently prevented HAdV55 infection, and mAb 29C12 showed protection at a dose as low as 0.004 mg/kg. Fibre-targeting mAb 28E8, however, showed protection only at a dose up to 12.5 mg/kg. In tree shrews that are permissive for HAdV55 infection and disease, mAb 29C12 effectively prevented HAdV55-caused pneumonia. Further analysis revealed that fibre-targeting mAbs blocked the attachment of HAdV55 to host cells, whereas hexon-targeting mAbs, regardless of their targeting HVRs, mainly functioned at post-attachment stage via inhibiting viral endosomal escape. Our results indicate that hexon-targeting mAbs have great anti-HAdV55 activities and warrant pre-clinical and clinical evaluation.https://www.tandfonline.com/doi/10.1080/22221751.2024.2307513Human adenovirus type 55; neutralizing monoclonal antibodies; rhesus macaque; targeting sites; mechanism of action |
| spellingShingle | Xinglong Liu Zhengfeng Li Xiao Li Xiaoyan Zhang Yali Zheng Wan Su Ying Feng Yutong Liu Weixuan Wu Xikui Sun Nana Wang Xianmiao Ye Zhichao Zhou Wenkuan Liu Jun He Wei Wang Linbing Qu Rong Zhou Ling Chen Liqiang Feng Neutralizing monoclonal antibodies protect against human adenovirus type 55 infection in transgenic mice and tree shrews Emerging Microbes and Infections Human adenovirus type 55; neutralizing monoclonal antibodies; rhesus macaque; targeting sites; mechanism of action |
| title | Neutralizing monoclonal antibodies protect against human adenovirus type 55 infection in transgenic mice and tree shrews |
| title_full | Neutralizing monoclonal antibodies protect against human adenovirus type 55 infection in transgenic mice and tree shrews |
| title_fullStr | Neutralizing monoclonal antibodies protect against human adenovirus type 55 infection in transgenic mice and tree shrews |
| title_full_unstemmed | Neutralizing monoclonal antibodies protect against human adenovirus type 55 infection in transgenic mice and tree shrews |
| title_short | Neutralizing monoclonal antibodies protect against human adenovirus type 55 infection in transgenic mice and tree shrews |
| title_sort | neutralizing monoclonal antibodies protect against human adenovirus type 55 infection in transgenic mice and tree shrews |
| topic | Human adenovirus type 55; neutralizing monoclonal antibodies; rhesus macaque; targeting sites; mechanism of action |
| url | https://www.tandfonline.com/doi/10.1080/22221751.2024.2307513 |
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