Structurally Mapping Antigenic Epitopes of Adeno-associated Virus 9: Development of Antibody Escape Variants
Shanan N. Emmanuel, J. Kennon Smith, Jane Hsi, Yu-Shan Tseng, Matias Kaplan, Mario Mietzsch, Paul Chipman, Aravind Asokan, Robert McKenna, Mavis Agbandje-McKenna
Abstract
The use of recombinant adeno-associated viruses (rAAVs) as delivery vectors for therapeutic genes is becoming increasingly popular, especially following the FDA approval of Luxturna and Zolgensma, based on serotypes AAV2 and AAV9, respectively. However, high-titer anti-AAV neutralizing antibodies in the general population exempt patients from treatment. The goal of this study is to circumvent this issue by creating AAV variant vectors not recognized by preexisting neutralizing antibodies. The mapping of the antigenic epitopes of five different monoclonal antibodies (MAbs) on AAV9, to recapitulate a polyclonal response, enabled the rational design of escape variants with minimal disruption to cell tropism and gene expression. This study, which included four newly developed and now commercially available MAbs, provides a platform for the engineering of rAAV9 vectors that can be used to deliver genes to patients with preexisting AAV antibodies.