Liver-Directed but Not Muscle-Directed AAV-Antibody Gene Transfer Limits Humoral Immune Responses in Rhesus Monkeys
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UMass Chan Affiliations
Horae Gene Therapy CenterDocument Type
Journal ArticlePublication Date
2020-03-13Keywords
AAV vectorAAV-antibody delivery
AAV1
AAV8
CMV promoter
Desmin promoter
TBG promoter
anti-drug antibody responses
monoclonal antibody
prime-boost immunization
Amino Acids, Peptides, and Proteins
Genetics and Genomics
Immunology and Infectious Disease
Molecular Biology
Therapeutics
Viruses
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Show full item recordAbstract
A number of publications have described the use of adeno-associated virus (AAV) for the delivery of anti-HIV and anti-simian immunodeficiency virus (SIV) monoclonal antibodies (mAbs) to rhesus monkeys. Anti-drug antibodies (ADAs) have been frequently observed, and long-term AAV-mediated delivery has been inconsistent. Here, we investigated different AAV vector strategies and delivery schemes to rhesus monkeys using the rhesus monkey mAb 4L6. We compared 4L6 immunoglobulin G1 (IgG1) delivery using the AAV1 versus the AAV8 serotype with a cytomegalovirus (CMV) promoter and the use of a muscle-specific versus a liver-specific promoter. Long-term expression levels of 4L6 IgG1 following AAV8-mediated gene transfer were comparable to those following AAV1-mediated gene transfer. AAV1-mediated gene transfer, using a muscle-specific promoter, showed robust ADAs and transiently low 4L6 IgG1 levels that ultimately declined to below detectable levels. Intravenous AAV8-mediated gene transfer, using a liver-specific promoter, also resulted in low levels of delivered 4L6 IgG1, but those low levels were maintained in the absence of any detectable ADAs. Booster injections using AAV1-CMV allowed for increased 4L6 IgG1 serum levels in animals that were primed with AAV8 but not with AAV1. Our results suggest that liver-directed expression may help to limit ADAs and that re-administration of AAV of a different serotype can result in successful long-term delivery of an immunogenic antibody.Source
Fuchs SP, Martinez-Navio JM, Rakasz EG, Gao G, Desrosiers RC. Liver-Directed but Not Muscle-Directed AAV-Antibody Gene Transfer Limits Humoral Immune Responses in Rhesus Monkeys. Mol Ther Methods Clin Dev. 2019 Nov 26;16:94-102. doi: 10.1016/j.omtm.2019.11.010. PMID: 31890736; PMCID: PMC6923507. Link to article on publisher's site
DOI
10.1016/j.omtm.2019.11.010Permanent Link to this Item
http://hdl.handle.net/20.500.14038/41413PubMed ID
31890736Related Resources
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Copyright 2019 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)Distribution License
http://creativecommons.org/licenses/by-nc-nd/4.0/ae974a485f413a2113503eed53cd6c53
10.1016/j.omtm.2019.11.010
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Except where otherwise noted, this item's license is described as Copyright 2019 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)