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Recommendations for the Development of Cell-Based Anti-Viral Vector Neutralizing Antibody Assays

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A Correction to this article was published on 04 February 2020

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Abstract

Viral vector–based gene therapies (GTx) have received significant attention in the recent years and the number of ongoing GTx clinical trials is increasing. A platform of choice for many of these studies is adeno-associated virus (AAV). All humans may be exposed to natural AAV infections and could mount an immune response against the virus. Consequently, there can be a high prevalence of pre-existing anti-AAV immunity. This presents a potential limitation for AAV-based GTx due to the potential for AAV-specific antibodies to reduce the efficacy of the GTx. Therefore, appropriate assessment of potential subjects enrolled in these studies should include evaluation for the presence and degree of anti-AAV immunity, including anti-AAV neutralizing antibodies (NAb). Recommendations for the development and validation of cell-based anti-AAV NAb detection methods, including considerations related to selection of appropriate cell line, surrogate vector/reporter gene, assay matrix and controls, and methodologies for calculating assay cut-point are discussed herein. General recommendations for the key assay validation parameters are provided as well as considerations for the development of NAb diagnostic tests. This manuscript is produced by a group of scientists involved in GTx therapeutic development representing various companies. It is our intent to provide recommendations and guidance to industrial and academic laboratories working on viral vector based GTx modalities with the goal of achieving a more consistent approach to anti-AAV NAb assessment.

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  • 04 February 2020

    The first author’s name was published incorrectly as “Gorovits Boris”. The correct name is “Boris Gorovits”.

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Acknowledgments

Manuscript authors worked as part of the American Association of Pharmaceutical Scientists community and are sincerely grateful to the entire AAPS organization for the support and opportunities provided.

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  1. All authors contributed equally to writing of this manuscript.

Authors and Affiliations

  1. Pfizer Inc., 1 Burtt Rd., Andover, MA, USA

    Boris Gorovits

  2. REGENXBIO Inc., 9600 Blackwell Rd #210, Rockville, MD, USA

    Michele Fiscella

  3. bluebird bio, 60 Binney St, Cambridge, MA, USA

    Mike Havert

  4. Precision for Medicine, Inc., 2686 Middlefield Rd d, Redwood City, CA, USA

    Eugen Koren

  5. BioMarin Pharmaceutical Inc., 300 Bel Marin Keys Blvd, Novato, CA, USA

    Brian Long

  6. Novartis Institutes for BioMedical Research, Inc., 250 Massachusetts Ave, Cambridge, MA, USA

    Mark Milton

  7. Alzheimer’s Drug Discovery Foundation, 57 W 57th St #904, New York, USA

    Shobha Purushothama

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Correspondence to Boris Gorovits.

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AAV adeno-associated virus

AAV binding (total) antibodies (TAb) immunoglobulins able to specifically bind to AAV capsid protein epitopes. These antibodies may be neutralizing or non-neutralizing

AAV neutralizing antibodies (NAb) immunoglobulins able to specifically bind to AAV capsid protein epitopes and inhibit one or more critical steps involved in AAV infectivity and cell transduction

Companion diagnostic (CDx) an in vitro test method which provides information that is essential for the safe and effective use of a corresponding drug or biologic product

Gene therapy (GTx) a technique that uses genes, or genetic modification, to treat or prevent disease

Transgenea gene that is transferred due to GTx treatment

Transgene expression of mRNA or protein

Viral vector viral based tools used to deliver genetical material to cells

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The original version of this article was revised: The first author’s name was published incorrectly as “Gorovits Boris”. The correct name is “Boris Gorovits”.

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Gorovits, B., Fiscella, M., Havert, M. et al. Recommendations for the Development of Cell-Based Anti-Viral Vector Neutralizing Antibody Assays. AAPS J 22, 24 (2020). https://doi.org/10.1208/s12248-019-0403-1

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