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AAVrh.10 immunogenicity in mice and humans. Relevance of antibody cross-reactivity in human gene therapy

Gene Therapy volume 22, pages 196–201 (2015)Cite this article

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Abstract

Simian adeno-associated virus (AAV) serotype rh.10 is a promising gene therapy tool, achieving safe, sustained transgene expression in the nervous system, lung, liver and heart in animal models. To date, preexisting immunity in humans has not been confirmed, though exposure is unexpected. We compared the humoral immune response with serotypes AAVrh.10 and AAV9 in mice, and AAVrh.10, AAV9 and AAV2 in 100 healthy humans. Mice, injected-intravenously, raised significantly more anti-AAV9 than anti-AAVrh.10 IgG (immunoglobulins), and sera demonstrated greater neutralizing capacity, correspondingly. Antibody cross-binding studies in mice showed negligible cross-recognition between AAVrh.10, AAV9 and AAV2. In humans, IgG prevalence against the most common human serotype, AAV2, was 72%; AAV9, 47% and AAVrh.10, a surprising, 59%. Yet, neutralizing-antibody seroprevalences were 71% for AAV2, 18% for AAV9 and 21% for AAVrh.10. Thus, most anti-AAV9 and anti-AAVrh.10 IgG were nonneutralizing. Indeed, sera generally neutralized AAV2 more strongly than AAVrh.10. Further, all samples neutralizing AAVrh.10 or AAV9 also neutralized AAV2, suggesting antibody cross-recognition. This contrasts with the results in mice, and highlights the complexity of tailoring gene therapy to minimize the immune response in humans, when multiple-mixed infections during a lifetime evoke a broad repertoire of preexisting antibodies capable of cross reacting with non-human serotypes.

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Acknowledgements

We thank the Vector Production Unit at CBATEG (Universitat Autònoma de Barcelona) for producing AAV vectors, the LLEB (UAB) for the luminescence measurements, Dr James M. Wilson (University of Pennsylvania) for providing AAV9 and AAVrh.10 RepCap plasmids and Dr Lorena Ariza (CBATEG, UAB) for experimental advice. We are also grateful to the Catalan Banc de Sang i Teixits (BST) for the human samples. GP was recipient of predoctoral fellowship from the Generalitat de Catalunya (2009FI_B00219). This work was supported by the Generalitat de Catalunya (2014 SGR 1354), the Instituto de Salud Carlos III (PS09720) and the Marató TV3 (110432) to AB.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain

    R Thwaite, G Pagès, M Chillón & A Bosch

  2. Institut Català de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

    M Chillón

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  1. R Thwaite
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  2. G Pagès
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Correspondence to A Bosch.

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Thwaite, R., Pagès, G., Chillón, M. et al. AAVrh.10 immunogenicity in mice and humans. Relevance of antibody cross-reactivity in human gene therapy. Gene Ther 22, 196–201 (2015). https://doi.org/10.1038/gt.2014.103

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