AAV-monoclonal antibody expression protects mice from Ebola virus without impeding the endogenous antibody response to heterologous challenge.
AAV6.2FF
Ebola
adeno-associated virus (AAV)
filovirus
immunotherapy
monoclonal antibody
vectored immunoprophylaxis
Journal
Molecular therapy. Methods & clinical development
ISSN: 2329-0501
Titre abrégé: Mol Ther Methods Clin Dev
Pays: United States
ID NLM: 101624857
Informations de publication
Date de publication:
08 Sep 2022
08 Sep 2022
Historique:
received:
26
01
2022
accepted:
09
08
2022
entrez:
12
9
2022
pubmed:
13
9
2022
medline:
13
9
2022
Statut:
epublish
Résumé
Filoviruses cause severe hemorrhagic fever with case fatality rates as high as 90%. Filovirus-specific monoclonal antibodies (mAbs) confer protection in nonhuman primates as late as 5 days after challenge, and FDA-approved mAbs REGN-EB3 and mAb114 have demonstrated efficacy against Ebola virus (EBOV) infection in humans. Vectorized antibody expression mediated by adeno-associated virus (AAV) can generate protective and sustained concentrations of therapeutic mAbs in animal models for a variety of infectious diseases, including EBOV. Here we demonstrate that AAV6.2FF-mediated expression of murine IgG2a EBOV mAbs, 2G4 and 5D2, protects from mouse-adapted (MA)-EBOV infection with none of the surviving mice developing anti-VP40 antibodies above background. Protective serum concentrations of AAV6.2FF-2G4/AAV6.2FF-5D2 did not alter endogenous antibody responses to heterologous virus infection. AAV-mediated expression of EBOV mAbs 100 and 114, and pan-ebolavirus mAbs, FVM04, ADI-15878, and CA45, as human IgG1 antibodies conferred protection against MA-EBOV at low serum concentrations, with minimum protective serum levels as low as 2 μg/mL. Vectorized expression of murine IgG2a or human IgG1 mAbs led to sustained expression in the serum of mice for >400 days or for the lifetime of the animal, respectively. AAV6.2FF-mediated mAb expression offers an alternative to recombinant antibody administration in scenarios where long-term protection is preferable to passive immunization.
Identifiants
pubmed: 36092367
doi: 10.1016/j.omtm.2022.08.003
pii: S2329-0501(22)00113-9
pmc: PMC9436706
doi:
Types de publication
Journal Article
Langues
eng
Pagination
505-518Informations de copyright
© 2022 The Author(s).
Déclaration de conflit d'intérêts
L.P.L. and S.K.W. are inventors on a US patent for the AAV6.2FF capsid. This patent (US20190216949) is licensed to Avamab Pharma Inc., where B.T., L.P.L., and S.K.W. are co-founders and B.T. serves as an executive. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; nor in the decision to publish the results.
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