Novel Trispecific Neutralizing Antibodies With Enhanced Potency and Breadth Against Pan‐Sarbecoviruses
ABSTRACT The ongoing emergence of new variants of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) underscores the urgent need for developing antivirals targeting both SARS‐CoV‐2 variants and related sarbecoviruses. To this end, we designed novel trispecific antibodies, Tri‐1 and Tri...
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Wiley
2025-05-01
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| Online Access: | https://doi.org/10.1002/mco2.70191 |
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| author | Rui Qiao Yuanchen Liu Qiyu Mao Jiayan Li Yinying Lu Jialu Shi Chen Li Jizhen Yu Jiami Gong Xun Wang Yuchen Shao Lei Sun Wenhong Zhang Hongjie Yu Hin Chu Pengfei Wang Xiaoyu Zhao |
| author_facet | Rui Qiao Yuanchen Liu Qiyu Mao Jiayan Li Yinying Lu Jialu Shi Chen Li Jizhen Yu Jiami Gong Xun Wang Yuchen Shao Lei Sun Wenhong Zhang Hongjie Yu Hin Chu Pengfei Wang Xiaoyu Zhao |
| author_sort | Rui Qiao |
| collection | DOAJ |
| description | ABSTRACT The ongoing emergence of new variants of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) underscores the urgent need for developing antivirals targeting both SARS‐CoV‐2 variants and related sarbecoviruses. To this end, we designed novel trispecific antibodies, Tri‐1 and Tri‐2, engineered by fusing the single‐chain variable fragments (scFvs) of a potent antibody (PW5‐570) to the Fc region of “Knob‐into‐Hole” bispecific antibodies (bsAbs) composed of two distinct broad antibodies (PW5‐5 and PW5‐535). Compared with the parental antibodies, Tri‐1 and Tri‐2 displayed enhanced binding affinities to the receptor‐binding domains of SARS‐CoV, SARS‐CoV‐2 wild type, and Omicron XBB.1.16, with each arm contributed to the overall enhancement. Furthermore, pseudovirus neutralization assays revealed that Tri‐1 and Tri‐2 effectively neutralized all tested SARS‐CoV, SARS‐CoV‐2 variants, and related sarbecoviruses (Pangolin‐GD, RaTG13, WIV1, and SHC014), demonstrating potency and breadth superior to any single parental antibody. Consistently, Tri‐1 and Tri‐2 were found to effectively neutralize authentic SARS‐CoV and SARS‐CoV‐2 variants with IC50 values comparable to or better than those of parental antibodies. Taken together, this study highlights the potential effectiveness of Tri‐1 and Tri‐2 as novel formats for harnessing cross‐neutralizing antibodies in the development of multivalent agents to combat both current and future SARS‐like coronaviruses. |
| format | Article |
| id | doaj-art-9d7d9fb9cdba41278aff41b9765fba80 |
| institution | OA Journals |
| issn | 2688-2663 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | MedComm |
| spelling | doaj-art-9d7d9fb9cdba41278aff41b9765fba802025-08-20T02:32:12ZengWileyMedComm2688-26632025-05-0165n/an/a10.1002/mco2.70191Novel Trispecific Neutralizing Antibodies With Enhanced Potency and Breadth Against Pan‐SarbecovirusesRui Qiao0Yuanchen Liu1Qiyu Mao2Jiayan Li3Yinying Lu4Jialu Shi5Chen Li6Jizhen Yu7Jiami Gong8Xun Wang9Yuchen Shao10Lei Sun11Wenhong Zhang12Hongjie Yu13Hin Chu14Pengfei Wang15Xiaoyu Zhao16Shanghai Sci‐Tech Inno Center for Infection & Immunity National Medical Center for Infectious Diseases Huashan Hospital Institute of Infection and Health Shanghai Key Laboratory of Oncology Target Discovery and Antibody Drug Development Fudan University Shanghai ChinaDepartment of Microbiology School of Clinical Medicine Li Ka Shing Faculty of Medicine The University of Hong Kong Pokfulam Hong Kong Special Administrative Region Hong Kong ChinaShanghai Fifth People's Hospital Shanghai Institute of Infectious Disease and Biosecurity Institutes of Biomedical Sciences Fudan University Shanghai ChinaShanghai Pudong Hospital State Key Laboratory of Genetic Engineering MOE Engineering Research Center of Gene Technology School of Life Sciences Shanghai Institute of Infectious Disease and Biosecurity Fudan University Pudong Medical Center Fudan University Shanghai ChinaShanghai Sci‐Tech Inno Center for Infection & Immunity National Medical Center for Infectious Diseases Huashan Hospital Institute of Infection and Health Shanghai Key Laboratory of Oncology Target Discovery and Antibody Drug Development Fudan University Shanghai ChinaDepartment of Microbiology School of Clinical Medicine Li Ka Shing Faculty of Medicine The University of Hong Kong Pokfulam Hong Kong Special Administrative Region Hong Kong ChinaShanghai Pudong Hospital State Key Laboratory of Genetic Engineering MOE Engineering Research Center of Gene Technology School of Life Sciences Shanghai Institute of Infectious Disease and Biosecurity Fudan University Pudong Medical Center Fudan University Shanghai ChinaShanghai Pudong Hospital State Key Laboratory of Genetic Engineering MOE Engineering Research Center of Gene Technology School of Life Sciences Shanghai Institute of Infectious Disease and Biosecurity Fudan University Pudong Medical Center Fudan University Shanghai ChinaShanghai Pudong Hospital State Key Laboratory of Genetic Engineering MOE Engineering Research Center of Gene Technology School of Life Sciences Shanghai Institute of Infectious Disease and Biosecurity Fudan University Pudong Medical Center Fudan University Shanghai ChinaShanghai Pudong Hospital State Key Laboratory of Genetic Engineering MOE Engineering Research Center of Gene Technology School of Life Sciences Shanghai Institute of Infectious Disease and Biosecurity Fudan University Pudong Medical Center Fudan University Shanghai ChinaShanghai Pudong Hospital State Key Laboratory of Genetic Engineering MOE Engineering Research Center of Gene Technology School of Life Sciences Shanghai Institute of Infectious Disease and Biosecurity Fudan University Pudong Medical Center Fudan University Shanghai ChinaShanghai Fifth People's Hospital Shanghai Institute of Infectious Disease and Biosecurity Institutes of Biomedical Sciences Fudan University Shanghai ChinaDepartment of Infectious Diseases Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response National Medical Center for Infectious Diseases Huashan Hospital Fudan University Shanghai ChinaSchool of Public Health Key Laboratory of Public Health Safety Fudan University Ministry of Education Shanghai ChinaDepartment of Microbiology School of Clinical Medicine Li Ka Shing Faculty of Medicine The University of Hong Kong Pokfulam Hong Kong Special Administrative Region Hong Kong ChinaShanghai Sci‐Tech Inno Center for Infection & Immunity National Medical Center for Infectious Diseases Huashan Hospital Institute of Infection and Health Shanghai Key Laboratory of Oncology Target Discovery and Antibody Drug Development Fudan University Shanghai ChinaShanghai Sci‐Tech Inno Center for Infection & Immunity National Medical Center for Infectious Diseases Huashan Hospital Institute of Infection and Health Shanghai Key Laboratory of Oncology Target Discovery and Antibody Drug Development Fudan University Shanghai ChinaABSTRACT The ongoing emergence of new variants of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) underscores the urgent need for developing antivirals targeting both SARS‐CoV‐2 variants and related sarbecoviruses. To this end, we designed novel trispecific antibodies, Tri‐1 and Tri‐2, engineered by fusing the single‐chain variable fragments (scFvs) of a potent antibody (PW5‐570) to the Fc region of “Knob‐into‐Hole” bispecific antibodies (bsAbs) composed of two distinct broad antibodies (PW5‐5 and PW5‐535). Compared with the parental antibodies, Tri‐1 and Tri‐2 displayed enhanced binding affinities to the receptor‐binding domains of SARS‐CoV, SARS‐CoV‐2 wild type, and Omicron XBB.1.16, with each arm contributed to the overall enhancement. Furthermore, pseudovirus neutralization assays revealed that Tri‐1 and Tri‐2 effectively neutralized all tested SARS‐CoV, SARS‐CoV‐2 variants, and related sarbecoviruses (Pangolin‐GD, RaTG13, WIV1, and SHC014), demonstrating potency and breadth superior to any single parental antibody. Consistently, Tri‐1 and Tri‐2 were found to effectively neutralize authentic SARS‐CoV and SARS‐CoV‐2 variants with IC50 values comparable to or better than those of parental antibodies. Taken together, this study highlights the potential effectiveness of Tri‐1 and Tri‐2 as novel formats for harnessing cross‐neutralizing antibodies in the development of multivalent agents to combat both current and future SARS‐like coronaviruses.https://doi.org/10.1002/mco2.70191coronavirussarbecovirusSARS‐CoV‐2bispecific antibodytrispecific antibodybroadly neutralizing antibody |
| spellingShingle | Rui Qiao Yuanchen Liu Qiyu Mao Jiayan Li Yinying Lu Jialu Shi Chen Li Jizhen Yu Jiami Gong Xun Wang Yuchen Shao Lei Sun Wenhong Zhang Hongjie Yu Hin Chu Pengfei Wang Xiaoyu Zhao Novel Trispecific Neutralizing Antibodies With Enhanced Potency and Breadth Against Pan‐Sarbecoviruses MedComm coronavirus sarbecovirus SARS‐CoV‐2 bispecific antibody trispecific antibody broadly neutralizing antibody |
| title | Novel Trispecific Neutralizing Antibodies With Enhanced Potency and Breadth Against Pan‐Sarbecoviruses |
| title_full | Novel Trispecific Neutralizing Antibodies With Enhanced Potency and Breadth Against Pan‐Sarbecoviruses |
| title_fullStr | Novel Trispecific Neutralizing Antibodies With Enhanced Potency and Breadth Against Pan‐Sarbecoviruses |
| title_full_unstemmed | Novel Trispecific Neutralizing Antibodies With Enhanced Potency and Breadth Against Pan‐Sarbecoviruses |
| title_short | Novel Trispecific Neutralizing Antibodies With Enhanced Potency and Breadth Against Pan‐Sarbecoviruses |
| title_sort | novel trispecific neutralizing antibodies with enhanced potency and breadth against pan sarbecoviruses |
| topic | coronavirus sarbecovirus SARS‐CoV‐2 bispecific antibody trispecific antibody broadly neutralizing antibody |
| url | https://doi.org/10.1002/mco2.70191 |
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