A Lipid-encapsulated mRNA Encoding a Potently Neutralizing Human Monoclonal Antibody Protects Against Chikungunya Infection
| Autor: | Michael S. Diamond, Gopal Sapparapu, Sayda Mahgoub Elbashir, Robin G. Bombardi, Elisabeth Humphris-Narayanan, Rashika N. Tennekoon, Nurgun Kose, Giuseppe Ciaramella, Julie M. Fox, James E. Crowe, Sunny Himansu, Matthew A. Theisen, A. Dharshan de Silva |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male medicine.drug_class Immunology Arthritis Viremia Monoclonal antibody medicine.disease_cause Antibodies Viral Virus Immunoglobulin G Article Cell Line 03 medical and health sciences Mice 0302 clinical medicine Nanocapsules Cricetinae medicine Animals Humans Vector (molecular biology) Chikungunya RNA Messenger B-Lymphocytes biology business.industry virus diseases Antibodies Monoclonal General Medicine medicine.disease Virology Antibodies Neutralizing Lipids Mice Inbred C57BL Disease Models Animal 030104 developmental biology biology.protein Chikungunya Fever Macaca Female Antibody business Chikungunya virus 030215 immunology |
| Popis: | Infection with chikungunya virus (CHIKV) typically causes an acute illness characterized by fever, rash, and arthralgia. However, CHIKV infection can sometimes progress to chronic arthritis or even lethal disease. CHIKV continues to cause significant morbidity worldwide as its vector mosquitoes expand and spread. There are currently no approved vaccines or antiviral drugs available for the prevention or treatment of CHIKV. Although antibody therapy has shown promise in the prevention or treatment of CHIKV disease in preclinical models, challenges remain for implementing such therapies. Here, from the B cells of a survivor of natural CHIKV infection, we isolated ultrapotent neutralizing human monoclonal antibodies (mAbs) and encoded their sequences into mRNA molecules delivered by infusion. One human mAb, CHKV-24, was expressed to biologically significant levels in vivo following infusion of mRNAs in lipid nanoparticles in mice. We evaluated the protective capacity of CHKV-24 mAb IgG protein or mRNA in mouse models of CHIKV infection. Treatment with CHKV-24 mRNA protected mice from arthritis, musculoskeletal tissue infection, and lethality in a dose-dependent manner and reduced viremia to undetectable levels at 2 days post-inoculation. Infusion of macaques with CHKV-24 mRNA achieved a mean maximal human mAb concentration of 10.1 to 35.9 μg/mL, with a half-life of 23 days, a level well above that needed for protection in mice. Studies with CHKV-24 mRNA in macaques demonstrated a dose-response effect after the first dose of mRNA and maintained levels after second dose. These preclinical data with CHKV-24 mRNA suggest it might be useful to prevent human disease. |
| Databáze: | OpenAIRE |
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