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A lipid-encapsulated mRNA encoding a potently neutralizing human monoclonal antibody protects against chikungunya infection

Kose, Nurgun ; Fox, Julie M ; Sapparapu, Gopal ; Bombardi, Robin ; Tennekoon, Rashika N ; de Silva, A Dharshan ; Elbashir, Sayda M ; Theisen, Matthew A ; Humphris-Narayanan, Elisabeth ; Ciaramella, Giuseppe ; Himansu, Sunny ; Diamond, Michael S ; Crowe, Jr, James E

Science immunology, 2019-05, Vol.4 (35) [Periódico revisado por pares]

United States

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Título:
A lipid-encapsulated mRNA encoding a potently neutralizing human monoclonal antibody protects against chikungunya infection
Autor: Kose, Nurgun ; Fox, Julie M ; Sapparapu, Gopal ; Bombardi, Robin ; Tennekoon, Rashika N ; de Silva, A Dharshan ; Elbashir, Sayda M ; Theisen, Matthew A ; Humphris-Narayanan, Elisabeth ; Ciaramella, Giuseppe ; Himansu, Sunny ; Diamond, Michael S ; Crowe, Jr, James E
Assuntos: Animals ; Antibodies, Monoclonal - immunology ; Antibodies, Monoclonal - therapeutic use ; Antibodies, Neutralizing - immunology ; Antibodies, Neutralizing - therapeutic use ; Antibodies, Viral - immunology ; Antibodies, Viral - therapeutic use ; B-Lymphocytes ; Cell Line ; Chikungunya Fever - immunology ; Chikungunya Fever - therapy ; Chikungunya Fever - virology ; Chikungunya virus - immunology ; Cricetinae ; Disease Models, Animal ; Female ; Humans ; Immunoglobulin G - immunology ; Immunoglobulin G - therapeutic use ; Lipids - chemistry ; Macaca ; Male ; Mice ; Mice, Inbred C57BL ; Nanocapsules - chemistry ; RNA, Messenger - chemistry ; RNA, Messenger - pharmacology ; RNA, Messenger - therapeutic use
É parte de: Science immunology, 2019-05, Vol.4 (35)
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A.D.deS. and R.N.T. obtained approvals and collected/purified PBMCs. N.K. performed initial screening and isolation of antibodies. N.K., R.B. and G.S. isolated hybridomas, purified antibodies, and sequenced mAb clones. J.M.F. and M.S.D. conducted and interpreted neutralization assays and mouse studies. S.M.E., E.H.-N., S.H., and G.C. designed the RNA LNP formulations and devised and oversaw mouse and NHP studies. M.S.D and S.H. contributed to the statistical analysis. N.K., S.H. and J.E.C. prepared the manuscript. All authors revised and approved the final version of the manuscript.
Author contributions
Descrição: Infection with chikungunya virus (CHIKV) 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 substantial 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 after infusion of mRNAs in lipid nanoparticles in mice. We evaluated the protective capacity of CHKV-24 mAb immunoglobulin G protein or mRNA in mouse models of CHIKV infection. Treatment with CHKV-24 mRNA protected mice from arthritis, musculoskeletal tissue infection, and lethality and reduced viremia to undetectable levels at 2 days after inoculation. Infusion of macaques with CHKV-24 mRNA achieved a mean maximal mAb concentration of 10.1 to 35.9 micrograms per milliliter, with a half-life of 23 days, a level well above what is 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 that it might be useful to prevent human disease.
Editor: United States
Idioma: Inglês

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A lipid-encapsulated mRNA encoding a potently neutralizing human monoclonal antibody protects against chikungunya infection

Kose, Nurgun ; Fox, Julie M ; Sapparapu, Gopal ; Bombardi, Robin ; Tennekoon, Rashika N ; de Silva, A Dharshan ; Elbashir, Sayda M ; Theisen, Matthew A ; Humphris-Narayanan, Elisabeth ; Ciaramella, Giuseppe ; Himansu, Sunny ; Diamond, Michael S ; Crowe, Jr, James E

United States

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