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 and Peter S. Kim ()
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Soohyun Kim: Stanford University School of Medicine
Caelan E. Radford: Fred Hutchinson Cancer Center
Duo Xu: Stanford University School of Medicine
Jianing Zhong: Stanford University
Jonathan Do: Stanford University School of Medicine
Dominic M. Pham: Stanford University
Katie A. Travisano: Stanford University School of Medicine
Maria V. Filsinger Interrante: Stanford University
Theodora U. J. Bruun: Stanford University School of Medicine
Valerie Rezek: Los Angeles (UCLA)
Bailey Wilder: Harvard Medical School
Martina Palomares: Harvard Medical School
Michael S. Seaman: Harvard Medical School
Scott G. Kitchen: Los Angeles (UCLA)
Jesse D. Bloom: Fred Hutchinson Cancer Center
Peter S. Kim: Stanford University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60035-6

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