A broad antibody with enhanced HIV-1 neutralization via bispecific antibody-mediated prepositioning
Abstract Antibodies targeting the highly conserved prehairpin intermediate (PHI) of class I viral membrane-fusion proteins are generally weakly neutralizing and are not considered viable therapeutic agents. We previously demonstrated that antibodies targeting the gp41 N-heptad repeat (NHR), which is...
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60035-6 |
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| author | Soohyun Kim Caelan E. Radford Duo Xu Jianing Zhong Jonathan Do Dominic M. Pham Katie A. Travisano Maria V. Filsinger Interrante Theodora U. J. Bruun Valerie Rezek Bailey Wilder Martina Palomares Michael S. Seaman Scott G. Kitchen Jesse D. Bloom Peter S. Kim |
| author_facet | Soohyun Kim Caelan E. Radford Duo Xu Jianing Zhong Jonathan Do Dominic M. Pham Katie A. Travisano Maria V. Filsinger Interrante Theodora U. J. Bruun Valerie Rezek Bailey Wilder Martina Palomares Michael S. Seaman Scott G. Kitchen Jesse D. Bloom Peter S. Kim |
| author_sort | Soohyun Kim |
| collection | DOAJ |
| description | Abstract Antibodies targeting the highly conserved prehairpin intermediate (PHI) of class I viral membrane-fusion proteins are generally weakly neutralizing and are not considered viable therapeutic agents. We previously demonstrated that antibodies targeting the gp41 N-heptad repeat (NHR), which is transiently exposed in the HIV-1 PHI, exhibit enhanced broad neutralization in cells expressing the Fc receptor, FcγRI. To enhance neutralization in cells lacking FcγRI, we here develop a bispecific antibody (bsAb) by fusing an NHR-targeting antibody to an antibody against CD4, the HIV-1 receptor on T cells. The bsAb provides a 5000-fold neutralization enhancement and shows unprecedented neutralization breadth compared to existing broadly neutralizing antibodies. Importantly, the bsAb reduces viral load in HIV-1-infected humanized male mice, and viral envelope sequencing under bsAb pressure revealed an NHR mutation that potentially impairs viral fitness. These findings validate the NHR as a potential HIV-1 therapeutic target, setting the stage for a new class of broadly neutralizing antibodies. |
| format | Article |
| id | doaj-art-42690c827ba64d56b04488cfc6be4c1b |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-42690c827ba64d56b04488cfc6be4c1b2025-08-20T02:25:13ZengNature PortfolioNature Communications2041-17232025-05-0116111410.1038/s41467-025-60035-6A broad antibody with enhanced HIV-1 neutralization via bispecific antibody-mediated prepositioningSoohyun Kim0Caelan E. Radford1Duo Xu2Jianing Zhong3Jonathan Do4Dominic M. Pham5Katie A. Travisano6Maria V. Filsinger Interrante7Theodora U. J. Bruun8Valerie Rezek9Bailey Wilder10Martina Palomares11Michael S. Seaman12Scott G. Kitchen13Jesse D. Bloom14Peter S. Kim15Department of Biochemistry, Stanford University School of MedicineMolecular and Cellular Biology Graduate Program, University of Washington and Basic Sciences Division, Fred Hutchinson Cancer CenterDepartment of Biochemistry, Stanford University School of MedicineDepartment of Chemistry, Stanford UniversityDepartment of Biochemistry, Stanford University School of MedicineSarafan ChEM-H, Stanford UniversityDepartment of Microbiology & Immunology, Stanford University School of MedicineSarafan ChEM-H, Stanford UniversityDepartment of Biochemistry, Stanford University School of MedicineDepartment of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine at University of California, Los Angeles (UCLA)Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical SchoolCenter for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical SchoolCenter for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical SchoolDepartment of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine at University of California, Los Angeles (UCLA)Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer CenterDepartment of Biochemistry, Stanford University School of MedicineAbstract Antibodies targeting the highly conserved prehairpin intermediate (PHI) of class I viral membrane-fusion proteins are generally weakly neutralizing and are not considered viable therapeutic agents. We previously demonstrated that antibodies targeting the gp41 N-heptad repeat (NHR), which is transiently exposed in the HIV-1 PHI, exhibit enhanced broad neutralization in cells expressing the Fc receptor, FcγRI. To enhance neutralization in cells lacking FcγRI, we here develop a bispecific antibody (bsAb) by fusing an NHR-targeting antibody to an antibody against CD4, the HIV-1 receptor on T cells. The bsAb provides a 5000-fold neutralization enhancement and shows unprecedented neutralization breadth compared to existing broadly neutralizing antibodies. Importantly, the bsAb reduces viral load in HIV-1-infected humanized male mice, and viral envelope sequencing under bsAb pressure revealed an NHR mutation that potentially impairs viral fitness. These findings validate the NHR as a potential HIV-1 therapeutic target, setting the stage for a new class of broadly neutralizing antibodies.https://doi.org/10.1038/s41467-025-60035-6 |
| spellingShingle | Soohyun Kim Caelan E. Radford Duo Xu Jianing Zhong Jonathan Do Dominic M. Pham Katie A. Travisano Maria V. Filsinger Interrante Theodora U. J. Bruun Valerie Rezek Bailey Wilder Martina Palomares Michael S. Seaman Scott G. Kitchen Jesse D. Bloom Peter S. Kim A broad antibody with enhanced HIV-1 neutralization via bispecific antibody-mediated prepositioning Nature Communications |
| title | A broad antibody with enhanced HIV-1 neutralization via bispecific antibody-mediated prepositioning |
| title_full | A broad antibody with enhanced HIV-1 neutralization via bispecific antibody-mediated prepositioning |
| title_fullStr | A broad antibody with enhanced HIV-1 neutralization via bispecific antibody-mediated prepositioning |
| title_full_unstemmed | A broad antibody with enhanced HIV-1 neutralization via bispecific antibody-mediated prepositioning |
| title_short | A broad antibody with enhanced HIV-1 neutralization via bispecific antibody-mediated prepositioning |
| title_sort | broad antibody with enhanced hiv 1 neutralization via bispecific antibody mediated prepositioning |
| url | https://doi.org/10.1038/s41467-025-60035-6 |
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