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

Gene Therapy (2022)Cite this article

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Abstract

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 × 1011 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 × 1011 vg (high) and 1 × 1010 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 × 1012 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.

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Fig. 1: In vitro analysis of AAV6.2FF vectors expressing mAbs MR78, MR82, and MR191.
Fig. 2: In vivo expression kinetics of vectorized MR78 and MR191 and confirmation of MARV GP binding.
Fig. 3: AAV6.2FF-MR191 is highly protective against MA-MARV challenge.
Fig. 4: Comparison of AAV6.2FF-MR78 serum human IgG concentration when administered to male versus female mice and one injection versus four injections.
Fig. 5: Findings of the ovine AAV6.2FF-MR191 long-term monitoring study.

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Data generated or analyzed during this study can be found within the published article and its supplementary files.

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Acknowledgements

We would like to thank all those who were involved in the care of the animals used these studies.

Funding

This work was supported by an OMAFRA Alliance grant (UG-T2-2020-101105) and MITACS Accelerate grant (IT18741) to SKW. ADR was the recipient of an OVC PhD Scholarship and an Ontario Graduate Scholarship. This work was also supported, in part, by the Public Health Agency of Canada (PHAC).

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  1. These authors jointly supervised this work: Logan Banadyga, Sarah K. Wootton.

Authors and Affiliations

  1. Department of Pathobiology, University of Guelph, Guelph, ON, N1G 2W1, Canada

    Amira D. Rghei, Laura P. van Lieshout, Jordyn A. Lopes, Nicole Zielinska, Enzo M. Baracuhy, Elena S. B. Campbell, Jessica A. Minott, Matthew M. Guilleman, Pamela C. Hasson, Khalil Karimi, Byram W. Bridle, Leonardo Susta & Sarah K. Wootton

  2. Special Pathogens Program, Public Health Agency of Canada, Winnipeg, MB, R3E 3R2, Canada

    Wenguang Cao, Shihua He, Kevin Tierney, Xiangguo Qiu & Logan Banadyga

  3. Avamab Pharma Inc, Calgary, AB, T2T 2P9, Canada

    Brad Thompson

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Contributions

Conceptualization: ADR, LPvL, XQ, LB and SKW; methodology: ADR, LPvL, WC, SH, KT, JAL, NZ, EMB, ESBC, JAM, MMG, PCH, LS; writing—original draft preparation: ADR and LPvL; review and editing: JL, WC, BT, BWB, LB, and SKW; supervision: LB and SKW; funding acquisition: LB and SKW. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Sarah K. Wootton.

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Competing interests

LPvL and SKW are inventors on a US patent for the AAV6.2FF capsid. This patent (US20190216949) is licensed to Avamab Pharma Inc., where BT, LPvL and SKW are co-founders and BT 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, or in the decision to publish the results.

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Experiments involving animals were approved by the University of Guelph Animal Care Committee (AUP# 3827) or the Canadian Science Centre for Human and Animal Health Animal Care Committee (H-16-011) according to the guidelines set forth by the Canadian Council on Animal Care.

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Rghei, A.D., van Lieshout, L.P., Cao, W. et al. Adeno-associated virus mediated expression of monoclonal antibody MR191 protects mice against Marburg virus and provides long-term expression in sheep. Gene Ther (2022). https://doi.org/10.1038/s41434-022-00361-2

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