A comprehensive engineering strategy improves potency and manufacturability of a near pan-neutralizing antibody against HIV

Anti-HIV envelope broadly neutralizing antibodies (bnAbs) are alternatives to conventional antiretrovirals with the potential to prevent and treat infection, reduce latent reservoirs, and/or mediate a functional cure. Clinical trials with "first-generation" bnAbs used alone or in combination show promising antiviral effects but also highlight that additional engineering of "enhanced" antibodies will be required for optimal clinical utility, while preserving or enhancing Current Good Manufacturing Practices (cGMP) manufacturing capability. Here, we report the engineering of an anti-CD4-binding site (CD4bs) bnAb, N49P9.3. Through a series of rational modifications, we produced a variant, N49P9.6-FR-LS, that demonstrates enhanced potency, superior antiviral activity in combination with other bnAbs, low polyreactivity, and longer circulating half-life. Additional engineering for manufacturing produced a final variant, eN49P9, with properties conducive to cGMP production. Overall, these efforts demonstrate the feasibility of developing enhanced anti-CD4bs bnAbs with greatly improved antiviral properties as well as potential translational value.

Authors

Institutions

Publication Details

Journal
Structure
Published
2025-05-14
DOI
https://doi.org/10.1016/j.str.2025.04.016
Citations
2
Primary Topic
HIV Research and Treatment
Type
article
Field-Weighted Citation Impact
2.07

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

A comprehensive engineering strategy improves potency and manufacturability of a near pan-neutralizing antibody against HIV

Alonso Heredia, Hegang Chen, Megan Sprague, David C. Montefiori et al.
2 citations
Structure
HIV Research and Treatment
2.07
article

A comprehensive engineering strategy improves potency and manufacturability of a near pan-neutralizing antibody against HIV

Alonso Heredia, Hegang Chen, Megan Sprague, David C. Montefiori, Ben Atkinson, Zahra Rikhtegaran Tehrani, Bette Korber, Johnathan D. Guest, Mahsa Hojabri, Derrick Deming, Rui Yin, Christine C. Siska, Anthony L. DeVico, Edwin Pozharski, Scott Foulke, George K. Lewis, Joseph G. Jardine, Marzena Pazgier, Brian G. Pierce, Mohammad M. Sajadi, Guido Ferrari, Paolo Lusso, Kshitij Wagh, Mateusz Kędzior, D. Ferrer, Dieter Mielke, Saman Saadat, Randal R. Ketchem, William D. Tolbert, Abdolrahim Abbasi, Parham Habibzadeh, Bryan T. Mayer, Alicia Sato, Michael S. Seaman, Arash Aslanabadi, Andrew Asakawa, Qingbo Liu, Xin Ouyang, Maryam Karimi, Dung N. Nguyen, Rutilio H. Clark, Woo Chi, Taylor Jumpa, Yasmin Dunn, Sarah Calvillo, Roza Zareidoodeji
article en
2 citations

Abstract

Anti-HIV envelope broadly neutralizing antibodies (bnAbs) are alternatives to conventional antiretrovirals with the potential to prevent and treat infection, reduce latent reservoirs, and/or mediate a functional cure. Clinical trials with "first-generation" bnAbs used alone or in combination show promising antiviral effects but also highlight that additional engineering of "enhanced" antibodies will be required for optimal clinical utility, while preserving or enhancing Current Good Manufacturing Practices (cGMP) manufacturing capability. Here, we report the engineering of an anti-CD4-binding site (CD4bs) bnAb, N49P9.3. Through a series of rational modifications, we produced a variant, N49P9.6-FR-LS, that demonstrates enhanced potency, superior antiviral activity in combination with other bnAbs, low polyreactivity, and longer circulating half-life. Additional engineering for manufacturing produced a final variant, eN49P9, with properties conducive to cGMP production. Overall, these efforts demonstrate the feasibility of developing enhanced anti-CD4bs bnAbs with greatly improved antiviral properties as well as potential translational value.

StructureVol. 33(7)
Scripps Research Institute (US), University of Maryland, Baltimore (US), International AIDS Vaccine Initiative (US), Beth Israel Deaconess Medical Center (US), Los Alamos National Laboratory (US), Uniformed Services University of the Health Sciences (US), Duke University (US), Fred Hutch Cancer Center (US), National Institute of Allergy and Infectious Diseases (US), VA Maryland Health Care System (US), University of Maryland, College Park (US), Southeast University (CN), Evotec (United States) (US)
U.S. Department of Defense, U.S. Department of Energy, U.S. Department of Veterans Affairs, Bill and Melinda Gates Foundation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, University of Maryland, National Institutes of Health, National Institute of Standards and Technology, Office of Science, Uniformed Services University of the Health Sciences, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, Basic Energy Sciences, Biological and Environmental Research, SLAC National Accelerator Laboratory, NHLBI Division of Intramural Research
Openalex Percentile: Top 14%
HIV Research and Treatment
2.07
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.