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dc.contributor.authorFuchs, Sebastian P.
dc.contributor.authorMartinez-Navio, Jose M.
dc.contributor.authorRakasz, Eva G.
dc.contributor.authorGao, Guangping
dc.contributor.authorDesrosiers, Ronald C.
dc.date2022-08-11T08:09:55.000
dc.date.accessioned2022-08-23T16:49:12Z
dc.date.available2022-08-23T16:49:12Z
dc.date.issued2020-03-13
dc.date.submitted2020-04-08
dc.identifier.citation<p>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. <a href="https://doi.org/10.1016/j.omtm.2019.11.010">Link to article on publisher's site</a></p>
dc.identifier.issn2329-0501 (Linking)
dc.identifier.doi10.1016/j.omtm.2019.11.010
dc.identifier.pmid31890736
dc.identifier.urihttp://hdl.handle.net/20.500.14038/41413
dc.description.abstractA 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.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=31890736&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsCopyright 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/)
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectAAV vector
dc.subjectAAV-antibody delivery
dc.subjectAAV1
dc.subjectAAV8
dc.subjectCMV promoter
dc.subjectDesmin promoter
dc.subjectTBG promoter
dc.subjectanti-drug antibody responses
dc.subjectmonoclonal antibody
dc.subjectprime-boost immunization
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectGenetics and Genomics
dc.subjectImmunology and Infectious Disease
dc.subjectMolecular Biology
dc.subjectTherapeutics
dc.subjectViruses
dc.titleLiver-Directed but Not Muscle-Directed AAV-Antibody Gene Transfer Limits Humoral Immune Responses in Rhesus Monkeys
dc.typeJournal Article
dc.source.journaltitleMolecular therapy. Methods and clinical development
dc.source.volume16
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=5212&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/4193
dc.identifier.contextkey17314526
refterms.dateFOA2022-08-23T16:49:12Z
html.description.abstract<p>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.</p>
dc.identifier.submissionpathoapubs/4193
dc.contributor.departmentHorae Gene Therapy Center
dc.source.pages94-102


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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/)
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/)