1. Structural and mechanistic basis of neutralization by a pan-hantavirus protective antibody.
- Author
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Mittler, Eva, Serris, Alexandra, Esterman, Emma S., Florez, Catalina, Polanco, Laura C., O'Brien, Cecilia M., Slough, Megan M., Tynell, Janne, Gröning, Remigius, Sun, Yan, Abelson, Dafna M., Wec, Anna Z., Haslwanter, Denise, Keller, Markus, Ye, Chunyan, Bakken, Russel R., Jangra, Rohit K., Dye, John M., Ahlm, Clas, and Rappazzo, C. Garrett
- Subjects
MONOCLONAL antibodies ,HANTAVIRUS diseases ,VACCINE approval ,HETERODIMERS ,IMMUNOGLOBULINS ,HANTAVIRUSES ,VIRUS diseases - Abstract
Emerging rodent-borne hantaviruses cause severe diseases in humans with no approved vaccines or therapeutics. We recently isolated a monoclonal broadly neutralizing antibody (nAb) from a Puumala virus–experienced human donor. Here, we report its structure bound to its target, the Gn/Gc glycoprotein heterodimer comprising the viral fusion complex. The structure explains the broad activity of the nAb: It recognizes conserved Gc fusion loop sequences and the main chain of variable Gn sequences, thereby straddling the Gn/Gc heterodimer and locking it in its prefusion conformation. We show that the nAb's accelerated dissociation from the divergent Andes virus Gn/Gc at endosomal acidic pH limits its potency against this highly lethal virus and correct this liability by engineering an optimized variant that sets a benchmark as a candidate pan-hantavirus therapeutic. Editor's summary: Infection with hantaviruses can cause severe disease in humans, and virus-specific therapeutics and vaccines are urgently needed. Neutralizing antibodies represent a promising therapeutic option, but most antibodies fail to neutralize evolutionarily divergent hantaviruses, limiting their utility. To address this, Mittler et al. performed structural analysis on a recently identified broadly neutralizing antibody isolated from an individual who recovered from infection with an Old World hantavirus, Puumala virus. Using structural information and complementary binding, neutralization, and functional studies, the authors engineered an optimized variant of this patient-derived antibody that could protect against infection by Puumala virus and lethal challenge by Andes virus, a New World hantavirus, in rodent models. This broadly neutralizing antibody, ADI-65534, represents a potential therapeutic candidate to treat hantavirus infections. —Courtney Malo [ABSTRACT FROM AUTHOR]
- Published
- 2023
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