A broad antibody with enhanced HIV-1 neutralization via bispecific antibody-mediated prepositioning.
| Title: | A broad antibody with enhanced HIV-1 neutralization via bispecific antibody-mediated prepositioning. |
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| Authors: | Kim S; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA.; Sarafan ChEM-H, Stanford University, Stanford, CA, USA.; Radford CE; Molecular and Cellular Biology Graduate Program, University of Washington and Basic Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.; Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Center, Seattle, WA, USA.; Xu D; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA.; Sarafan ChEM-H, Stanford University, Stanford, CA, USA.; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA.; Zhong J; Department of Chemistry, Stanford University, Stanford, CA, USA.; Do J; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA.; Sarafan ChEM-H, Stanford University, Stanford, CA, USA.; Pham DM; Sarafan ChEM-H, Stanford University, Stanford, CA, USA.; Stanford Biophysics Program, Stanford University School of Medicine, Stanford, CA, USA.; Travisano KA; Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA, USA.; Filsinger Interrante MV; Sarafan ChEM-H, Stanford University, Stanford, CA, USA.; Stanford Biophysics Program, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA, USA.; Bruun TUJ; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA.; Sarafan ChEM-H, Stanford University, Stanford, CA, USA.; Stanford Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA, USA.; Rezek V; Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA, USA.; UCLA AIDS Institute and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, David Geffen School of Medicine University of California, Los Angeles (UCLA), Los Angeles, CA, USA.; Wilder B; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.; Palomares M; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.; Seaman MS; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.; Kitchen SG; Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA, USA.; UCLA AIDS Institute and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, David Geffen School of Medicine University of California, Los Angeles (UCLA), Los Angeles, CA, USA.; Bloom JD; Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Center, Seattle, WA, USA.; Howard Hughes Medical Institute, Seattle, WA, USA.; Kim PS; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA. kimpeter@stanford.edu.; Sarafan ChEM-H, Stanford University, Stanford, CA, USA. kimpeter@stanford.edu.; Chan Zuckerberg Biohub, San Francisco, CA, USA. kimpeter@stanford.edu. |
| Source: | Nature communications [Nat Commun] 2025 May 18; Vol. 16 (1), pp. 4617. Date of Electronic Publication: 2025 May 18. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [London] : Nature Pub. Group |
| MeSH Terms: | HIV-1*/immunology ; HIV-1*/genetics ; HIV-1*/drug effects ; Antibodies, Bispecific*/immunology ; Antibodies, Bispecific*/pharmacology ; Antibodies, Bispecific*/genetics ; HIV Infections*/immunology ; HIV Infections*/virology ; Antibodies, Neutralizing*/immunology ; HIV Antibodies*/immunology; HIV Envelope Protein gp41/immunology ; HIV Envelope Protein gp41/genetics ; Viral Load/drug effects ; Receptors, IgG/genetics ; Receptors, IgG/immunology ; Receptors, IgG/metabolism ; CD4 Antigens/immunology ; Broadly Neutralizing Antibodies/immunology ; Humans ; Animals ; Mice ; Male ; HEK293 Cells ; Neutralization Tests |
| 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.; (© 2025. The Author(s).) |
| Competing Interests: | Competing interests: The authors declare no competing interests. |
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| Grant Information: | DP1 AI158125 United States AI NIAID NIH HHS; P30 AI152501 United States AI NIAID NIH HHS; 5DP1AI158125 U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID) |
| Substance Nomenclature: | 0 (Antibodies, Bispecific); 0 (Antibodies, Neutralizing); 0 (HIV Antibodies); 0 (HIV Envelope Protein gp41); 0 (Receptors, IgG); 0 (CD4 Antigens); 0 (Broadly Neutralizing Antibodies) |
| Entry Date(s): | Date Created: 20250518 Date Completed: 20250518 Latest Revision: 20260306 |
| Update Code: | 20260306 |
| PubMed Central ID: | PMC12086220 |
| DOI: | 10.1038/s41467-025-60035-6 |
| PMID: | 40383778 |
| Database: | MEDLINE |
Journal Article