Rational design of universal immunotherapy for TfR1-tropic arenaviruses

• Published in: Nature communications Vol. 11; no. 1; pp. 67 - 11
• Main Authors: Cohen-Dvashi, Hadas, Amon, Ron, Agans, Krystle N., Cross, Robert W., Borenstein-Katz, Aliza, Mateo, Mathieu, Baize, Sylvain, Padler-Karavani, Vered, Geisbert, Thomas W., Diskin, Ron
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.01.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 631/154/51; 631/250/251; 631/326/596; 631/326/596/1961; 631/535/1266; 82/1; Antibodies; Antibodies, Neutralizing - chemistry; Antibodies, Neutralizing - genetics; Antibodies, Neutralizing - immunology; Antibodies, Viral - chemistry; Antibodies, Viral - genetics; Antibodies, Viral - immunology; Arenaviridae Infections - immunology; Arenaviridae Infections - therapy; Arenaviridae Infections - virology; Arenavirus - chemistry; Arenavirus - genetics; Arenavirus - immunology; Binding sites; Biological effects; Biological weapons; Countermeasures; Design; Drug Design; Glycoproteins; Hemorrhage; Humanities and Social Sciences; Humans; Immunology; Immunotherapy; Life Sciences; Microbiology and Parasitology; Military technology; multidisciplinary; Pharmaceutical sciences; Pharmacology; Proteins; Receptors, Transferrin - chemistry; Receptors, Transferrin - genetics; Receptors, Transferrin - immunology; Receptors, Virus - genetics; Receptors, Virus - immunology; Science; Science (multidisciplinary); Transferrin; Transferrins; Viral Proteins - chemistry; Viral Proteins - genetics; Viral Proteins - immunology; Virology; Viruses; Zoonoses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-13924-6

Certain arenaviruses that circulate in rodent populations can cause life-threatening hemorrhagic fevers when they infect humans. Due to their efficient transmission, arenaviruses pose a severe risk for outbreaks and might be exploited as biological weapons. Effective countermeasures against these viruses are highly desired. Ideally, a single remedy would be effective against many or even all the pathogenic viruses in this family. However, despite the fact that all pathogenic arenaviruses from South America utilize transferrin receptor 1 (TfR1) as a cellular receptor, their viral glycoproteins are highly diversified, impeding efforts to isolate cross-neutralizing antibodies. Here we address this problem using a rational design approach to target TfR1-tropic arenaviruses with high potency and breadth. The pan-reactive molecule is highly effective against all arenaviruses that were tested, offering a universal therapeutic approach. Our design scheme avoids the shortcomings of previous immunoadhesins and can be used to combat other zoonotic pathogens. New World arenaviruses utilize the cellular transferrin receptor 1 (TfR1) to enter host cells. Here, the authors develop a TfR1-mimetic immunoadhesin, Arenacept, that targets viral spike complexes and exerts effective pan-reactive neutralization against pathogenic mammarenaviruses.