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J Virol Methods. 2016 Oct;236:105-110. doi: 10.1016/j.jviromet.2016.07.009. Epub 2016 Jul 14.

Generation and characterization of anti-Adeno-associated virus serotype 8 (AAV8) and anti-AAV9 monoclonal antibodies.

Author information

1
Department of Biochemistry and Molecular Biology, Center for Structural Biology, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA.
2
Department of Genetics and The Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
3
Department Molecular Genetics and Microbiology, and Powell Gene Therapy Center, College of Medicine, University of Florida, Gainesville, FL, USA.
4
Department of Biochemistry and Molecular Biology, Center for Structural Biology, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA. Electronic address: mckenna@ufl.edu.

Abstract

Adeno-associated viruses (AAVs) are promising viral vectors for therapeutic gene delivery, and the approval of an AAV1 vector for the treatment of lipoprotein lipase deficiency has heralded a new and exciting era for this system. However, preclinical and clinical studies show that neutralization from pre-existing antibodies is detrimental for medical application and this hurdle must be overcome before full clinical realization can be achieved. Thus the binding sites for capsid antibodies must be identified and eliminated through capsid engineering. Towards this goal and to recapitulate patient polyclonal responses, a panel of six new mouse monoclonal antibodies (MAbs) has been generated against AAV8 and AAV9 capsids, two vectors being developed for therapeutic application. Native (capsid) dot blot assays confirmed the specificity of these antibodies for their parental serotypes, with the exception of one MAb, HL2372, selected to cross-react against both capsids. Furthermore, in vitro assays showed that these MAbs are capable of neutralizing virus infection. These MAbs will be utilized for structural mapping of antigenic footprints on their respective capsids to inform development of the next generation of rAAV vectors capable of evading antibody neutralization while retaining parental tropism.

KEYWORDS:

AAV8; AAV9; Adeno-associated viruses; Anti-AAV capsid antibodies; Host-immune escape

PMID:
27424005
PMCID:
PMC5011015
DOI:
10.1016/j.jviromet.2016.07.009
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Statement of Conflict: M. Agbandje-McKenna (MAM) is an SAB member for Voyager Therapeutics, Inc., and has a sponsored research agreement with AGTC and Avalanche Biotechnologies. Both companies have interest in the development of AAV for gene delivery applications. MAM, Aravind Asokan (AA), and Barry Byrne (BB) are inventors of AAV patents licensed to various biopharmaceutical companies. MAM and AA are co-founders of Stride Therapeutics, LLC, and BB is a co-founder of AGTC. These are biopharmaceutical companies with interest in developing AAV vectors for gene delivery application.

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