A broad antibody with enhanced HIV-1 neutralization via bispecific antibody-mediated prepositioning

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

doi:10.1038/s41467-025-60035-6

A broad antibody with enhanced HIV-1 neutralization via bispecific antibody-mediated prepositioning

Nat Commun. 2025 May 18;16(1):4617. doi: 10.1038/s41467-025-60035-6.

Authors

Soohyun Kim^{1

2}, Caelan E Radford^{3

4}, Duo Xu^{1

2

5}, Jianing Zhong⁶, Jonathan Do^{1

2}, Dominic M Pham^{2

7}, Katie A Travisano⁸, Maria V Filsinger Interrante^{2

7

9}, Theodora U J Bruun^{1

2

9}, Valerie Rezek^{10

11}, Bailey Wilder¹², Martina Palomares¹², Michael S Seaman¹², Scott G Kitchen^{10

11}, Jesse D Bloom^{4

13}, Peter S Kim^{14

15

16}

Affiliations

¹ Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA.
² Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
³ Molecular and Cellular Biology Graduate Program, University of Washington and Basic Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
⁴ Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Center, Seattle, WA, USA.
⁵ Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA.
⁶ Department of Chemistry, Stanford University, Stanford, CA, USA.
⁷ Stanford Biophysics Program, Stanford University School of Medicine, Stanford, CA, USA.
⁸ Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA, USA.
⁹ Stanford Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA, USA.
¹⁰ Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
¹¹ 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.
¹² Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
¹³ Howard Hughes Medical Institute, Seattle, WA, USA.
¹⁴ Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA. kimpeter@stanford.edu.
¹⁵ Sarafan ChEM-H, Stanford University, Stanford, CA, USA. kimpeter@stanford.edu.
¹⁶ Chan Zuckerberg Biohub, San Francisco, CA, USA. kimpeter@stanford.edu.

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.

MeSH terms

Animals
Antibodies, Bispecific* / genetics
Antibodies, Bispecific* / immunology
Antibodies, Bispecific* / pharmacology
Antibodies, Neutralizing* / immunology
Broadly Neutralizing Antibodies / immunology
CD4 Antigens / immunology
HEK293 Cells
HIV Antibodies* / immunology
HIV Envelope Protein gp41 / genetics
HIV Envelope Protein gp41 / immunology
HIV Infections* / immunology
HIV Infections* / virology
HIV-1* / drug effects
HIV-1* / genetics
HIV-1* / immunology
Humans
Male
Mice
Neutralization Tests
Receptors, IgG / genetics
Receptors, IgG / immunology
Receptors, IgG / metabolism
Viral Load / drug effects

Substances

Antibodies, Bispecific
Antibodies, Neutralizing
HIV Antibodies
HIV Envelope Protein gp41
Receptors, IgG
CD4 Antigens
Broadly Neutralizing Antibodies

Abstract

MeSH terms

Substances

Grants and funding