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  Structural study of AAVrh.10 receptor and antibody interactions.

Mietzsch, M., Yu, J. C., Hsi, J., Chipman, P., Bröcker, F., Fuming, Z., et al. (2021). Structural study of AAVrh.10 receptor and antibody interactions. Journal of Virology, 95(23): e01249-21. doi:10.1128/JVI.01249-21.

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 Creators:
Mietzsch, Mario, Author
Yu, Jennifer C, Author
Hsi, Jane, Author
Chipman, Paul, Author
Bröcker, Felix1, Author           
Fuming, Zhang, Author
Linhardt, Robert J, Author
Seeberger, Peter H.1, Author           
Heilbronn, Regine, Author
McKenna, Robert, Author
Agbandje-McKenna, Mavis, Author
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1Peter H. Seeberger - Vaccine Development, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society, ou_1863308              

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 Abstract: Recombinant Adeno-associated virus (rAAV) vectors are one of the leading tools for the delivery of therapeutic genes in human gene therapy applications. For a successful transfer of their payload, the AAV vectors have to circumvent potential pre-existing neutralizing host antibodies and bind to the receptor of the target cells. Both these aspects have not been structurally analyzed for AAVrh.10. Here, cryo-electron microscopy (cryo-EM) and three-dimensional image reconstruction were used to map the binding site of sulfated N-Acetyllactosamine (LacNAc, previously shown to bind AAVrh.10) and a series of four monoclonal antibodies (MAbs). LacNAc was found to bind to a pocket located on the side of the 3-fold capsid protrusion, that is mostly conserved to AAV9 and equivalent to its galactose-binding site. As a result, AAVrh.10 was also shown to be able to bind to cell surface glycans with terminal galactose. For the antigenic characterization, it was observed that several anti-AAV8 MAbs cross-react with AAVrh.10. The binding sites of these antibodies were mapped to the 3-fold capsid protrusions. Based on these observations, the AAVrh.10 capsid surface was engineered to create variant capsids that escape these antibodies while maintaining infectivity. Importance Gene therapy vectors based on Adeno-associated virus rhesus isolate 10 (AAVrh.10) have been used in several clinical trials to treat monogenetic diseases. However, compared to other AAV serotypes little is known about receptor binding and antigenicity of the AAVrh.10 capsid. Particularly, pre-existing neutralizing antibodies against capsids are an important challenge that can hamper treatment efficiency. This study addresses both topics and identifies critical regions of the AAVrh.10 capsid for receptor and antibody binding. The insights gained were utilized to generate AAVrh.10 variants capable of evading known neutralizing antibodies. The findings of this study could further aid the utilization of AAVrh.10 vectors in clinical trials and help the approval of the subsequent biologics.

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Language(s): eng - English
 Dates: 2021-09-222021
 Publication Status: Published in print
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 Identifiers: DOI: 10.1128/JVI.01249-21
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Title: Journal of Virology
Source Genre: Journal
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Publ. Info: American Society for Microbiology (ASM)
Pages: - Volume / Issue: 95 (23) Sequence Number: e01249-21 Start / End Page: - Identifier: ISSN: 0022-538X