Adeno-associated virus mediated expression of monoclonal antibody MR191 protects mice against Marburg virus and provides long-term expression in sheep.

Autor: Rghei AD; Department of Pathobiology, University of Guelph, Guelph, ON, N1G 2W1, Canada., van Lieshout LP; Department of Pathobiology, University of Guelph, Guelph, ON, N1G 2W1, Canada., Cao W; Special Pathogens Program, Public Health Agency of Canada, Winnipeg, MB, R3E 3R2, Canada., He S; Special Pathogens Program, Public Health Agency of Canada, Winnipeg, MB, R3E 3R2, Canada., Tierney K; Special Pathogens Program, Public Health Agency of Canada, Winnipeg, MB, R3E 3R2, Canada., Lopes JA; Department of Pathobiology, University of Guelph, Guelph, ON, N1G 2W1, Canada., Zielinska N; Department of Pathobiology, University of Guelph, Guelph, ON, N1G 2W1, Canada., Baracuhy EM; Department of Pathobiology, University of Guelph, Guelph, ON, N1G 2W1, Canada., Campbell ESB; Department of Pathobiology, University of Guelph, Guelph, ON, N1G 2W1, Canada., Minott JA; Department of Pathobiology, University of Guelph, Guelph, ON, N1G 2W1, Canada., Guilleman MM; Department of Pathobiology, University of Guelph, Guelph, ON, N1G 2W1, Canada., Hasson PC; Department of Pathobiology, University of Guelph, Guelph, ON, N1G 2W1, Canada., Thompson B; Avamab Pharma Inc, Calgary, AB, T2T 2P9, Canada., Karimi K; Department of Pathobiology, University of Guelph, Guelph, ON, N1G 2W1, Canada., Bridle BW; Department of Pathobiology, University of Guelph, Guelph, ON, N1G 2W1, Canada., Susta L; Department of Pathobiology, University of Guelph, Guelph, ON, N1G 2W1, Canada., Qiu X; Special Pathogens Program, Public Health Agency of Canada, Winnipeg, MB, R3E 3R2, Canada., Banadyga L; Special Pathogens Program, Public Health Agency of Canada, Winnipeg, MB, R3E 3R2, Canada., Wootton SK; Department of Pathobiology, University of Guelph, Guelph, ON, N1G 2W1, Canada. kwootton@uoguelph.ca.
Jazyk: angličtina
Zdroj: Gene therapy [Gene Ther] 2022 Sep 01. Date of Electronic Publication: 2022 Sep 01.
DOI: 10.1038/s41434-022-00361-2
Abstrakt: Vectored monoclonal antibody (mAb) expression mediated by adeno-associated virus (AAV) gene delivery leads to sustained therapeutic mAb expression and protection against a wide range of infectious diseases in both small and large animal models, including nonhuman primates. Using our rationally engineered AAV6 triple mutant capsid, termed AAV6.2FF, we demonstrate rapid and robust expression of two potent human antibodies against Marburg virus, MR78 and MR191, following intramuscular (IM) administration. IM injection of mice with 1 × 10 11 vector genomes (vg) of AAV6.2FF-MR78 and AAV6.2FF-MR191 resulted in serum concentrations of approximately 141 μg/mL and 195 μg/mL of human IgG, respectively, within the first four weeks. Mice receiving 1 × 10 11  vg (high) and 1 × 10 10  vg (medium) doses of AAV6.2FF-MR191 were completely protected against lethal Marburg virus challenge. No sex-based differences in serum human IgG concentrations were observed; however, administering the AAV-mAb over multiple injection sites significantly increased serum human IgG concentrations. IM administration of three two-week-old lambs with 5 × 10 12  vg/kg of AAV6.2FF-MR191 resulted in serum human IgG expression that was sustained for more than 460 days, concomitant with low levels of anti-capsid and anti-drug antibodies. AAV-mAb expression is a viable method for prolonging the therapeutic effect of recombinant mAbs and represents a potential alternative "vaccine" strategy for those with compromised immune systems or in possible outbreak response scenarios.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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