Therapy for Argentine hemorrhagic fever in nonhuman primates with a humanized monoclonal antibody.

Abstract

The COVID-19 pandemic has reemphasized the need to identify safe and scalable therapeutics to slow or reverse symptoms of disease caused by newly emerging and reemerging viral pathogens. Recent clinical successes of monoclonal antibodies (mAbs) in therapy for viral infections demonstrate that mAbs offer a solution for these emerging biothreats. We have explored this with respect to Junin virus (JUNV), an arenavirus classified as a category A high-priority agent and the causative agent of Argentine hemorrhagic fever (AHF). There are currently no Food and Drug Administration-approved drugs available for preventing or treating AHF, although immune plasma from convalescent patients is used routinely to treat active infections. However, immune plasma is severely limited in quantity, highly variable in quality, and poses significant safety risks including the transmission of transfusion-borne diseases. mAbs offer a highly specific and consistently potent alternative to immune plasma that can be manufactured at large scale. We previously described a chimeric mAb, cJ199, that provided protection in a guinea pig model of AHF. To adapt this mAb to a format more suitable for clinical use, we humanized the mAb (hu199) and evaluated it in a cynomolgus monkey model of AHF with two JUNV isolates, Romero and Espindola. While untreated control animals experienced 100% lethality, all animals treated with hu199 at 6 d postinoculation (dpi) survived, and 50% of animals treated at 8 dpi survived. mAbs like hu199 may offer a safer, scalable, and more reproducible alternative to immune plasma for rare viral diseases that have epidemic potential.

• Authors: Larry Zeitlin, Robert W Cross, Joan B Geisbert, Viktoriya Borisevich, Krystle N Agans, Abhishek N Prasad, Sven Enterlein, M Javad Aman, Zachary A Bornholdt, Miles B Brennan, Lioudmila Campbell, Do Kim, Neil Mlakar, Crystal L Moyer, Michael H Pauly, William Shestowsky, Kevin J Whaley, Karla A Fenton, Thomas W Geisbert
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 118 Issue 11 (03 16 2021) ISSN: 1091-6490 [Electronic] United States
• PMID: 33836604 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2021 the Author(s). Published by PNAS.

Chemical References

• Antibodies, Monoclonal, Humanized
• Antibodies, Viral

Topics

• Animals
• Antibodies, Monoclonal, Humanized (pharmacology)
• Antibodies, Viral (pharmacology)
• Disease Models, Animal
• Female
• Guinea Pigs
• Hemorrhagic Fever, American (blood, prevention & control)
• Humans
• Junin virus (metabolism)
• Macaca fascicularis