Host receptor-targeted therapeutic approach to counter pathogenic New World mammarenavirus infections

Brady T. Hickerson, Tracy R. Daniels-Wells, Cristian Payes, Lars E. Clark, Pierre V. Candelaria, Kevin W. Bailey, Eric J. Sefing, Samantha Zink, James Ziegenbein, Jonathan Abraham, Gustavo Helguera (), Manuel L. Penichet () and Brian B. Gowen ()
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Brady T. Hickerson: Utah State University
Tracy R. Daniels-Wells: David Geffen School of Medicine at UCLA
Cristian Payes: Instituto de Biología y Medicina Experimental (IBYME CONICET)
Lars E. Clark: Harvard Medical School
Pierre V. Candelaria: David Geffen School of Medicine at UCLA
Kevin W. Bailey: Utah State University
Eric J. Sefing: Utah State University
Samantha Zink: University of California, Los Angeles (UCLA)
James Ziegenbein: University of California, Los Angeles (UCLA)
Jonathan Abraham: Harvard Medical School
Gustavo Helguera: Instituto de Biología y Medicina Experimental (IBYME CONICET)
Manuel L. Penichet: David Geffen School of Medicine at UCLA
Brian B. Gowen: Utah State University

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Five New World mammarenaviruses (NWMs) cause life-threatening hemorrhagic fever (HF). Cellular entry by these viruses is mediated by human transferrin receptor 1 (hTfR1). Here, we demonstrate that an antibody (ch128.1/IgG1) which binds the apical domain of hTfR1, potently inhibits infection of attenuated and pathogenic NWMs in vitro. Computational docking of the antibody Fab crystal structure onto the known structure of hTfR1 shows an overlapping receptor-binding region shared by the Fab and the viral envelope glycoprotein GP1 subunit that binds hTfR1, and we demonstrate competitive inhibition of NWM GP1 binding by ch128.1/IgG1 as the principal mechanism of action. Importantly, ch128.1/IgG1 protects hTfR1-expressing transgenic mice against lethal NWM challenge. Additionally, the antibody is well-tolerated and only partially reduces ferritin uptake. Our findings provide the basis for the development of a novel, host receptor-targeted antibody therapeutic broadly applicable to the treatment of HF of NWM etiology.

Date: 2022
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DOI: 10.1038/s41467-021-27949-3

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