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Article

Development of a Bispecific Antibody-Based Platform for Retargeting of Capsid Modified AAV Vectors

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Division of Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharma GmbH & Co. KG, 88387 Biberach an der Riss, Germany
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Division of Research Beyond Borders, Boehringer Ingelheim Pharma GmbH & Co. KG, 88387 Biberach an der Riss, Germany
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Division of Biotherapeutics Discovery, Boehringer Ingelheim Pharma GmbH & Co. KG, 88387 Biberach an der Riss, Germany
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Boehringer Ingelheim Venture Fund GmbH, 55216 Ingelheim am Rhein, Germany
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Division of Drug Discovery Sciences Biberach, Boehringer Ingelheim Pharma GmbH & Co. KG, 88387 Biberach an der Riss, Germany
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Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Mauro Vaccarezza
Int. J. Mol. Sci. 2021, 22(15), 8355; https://doi.org/10.3390/ijms22158355
Received: 9 June 2021 / Revised: 23 July 2021 / Accepted: 26 July 2021 / Published: 3 August 2021
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
A major limiting factor for systemically delivered gene therapies is the lack of novel tissue specific AAV (Adeno-associated virus) derived vectors. Bispecific antibodies can be used to redirect AAVs to specific target receptors. Here, we demonstrate that the insertion of a short linear epitope “2E3” derived from human proprotein-convertase subtilisin/kexin type 9 (PCSK9) into different surface loops of the VP capsid proteins can be used for AAV de-targeting from its natural receptor(s), combined with a bispecific antibody-mediated retargeting. We chose to target a set of distinct disease relevant membrane proteins—fibroblast activation protein (FAP), which is upregulated on activated fibroblasts within the tumor stroma and in fibrotic tissues, as well as programmed death-ligand 1 (PD-L1), which is strongly upregulated in many cancers. Upon incubation with a bispecific antibody recognizing the 2E3 epitope and FAP or PD-L1, the bispecific antibody/rAAV complex was able to selectively transduce receptor positive cells. In summary, we developed a novel, rationally designed vector retargeting platform that can target AAVs to a new set of cellular receptors in a modular fashion. This versatile platform may serve as a valuable tool to investigate the role of disease relevant cell types and basis for novel gene therapy approaches. View Full-Text
Keywords: adeno-associated viral vectors; AAV; protein engineering; retargeting; bispecific antibody; capsid modification; FAP; PD-L1 adeno-associated viral vectors; AAV; protein engineering; retargeting; bispecific antibody; capsid modification; FAP; PD-L1
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MDPI and ACS Style

Kuklik, J.; Michelfelder, S.; Schiele, F.; Kreuz, S.; Lamla, T.; Müller, P.; Park, J.E. Development of a Bispecific Antibody-Based Platform for Retargeting of Capsid Modified AAV Vectors. Int. J. Mol. Sci. 2021, 22, 8355. https://doi.org/10.3390/ijms22158355

AMA Style

Kuklik J, Michelfelder S, Schiele F, Kreuz S, Lamla T, Müller P, Park JE. Development of a Bispecific Antibody-Based Platform for Retargeting of Capsid Modified AAV Vectors. International Journal of Molecular Sciences. 2021; 22(15):8355. https://doi.org/10.3390/ijms22158355

Chicago/Turabian Style

Kuklik, Juliane, Stefan Michelfelder, Felix Schiele, Sebastian Kreuz, Thorsten Lamla, Philipp Müller, and John E. Park 2021. "Development of a Bispecific Antibody-Based Platform for Retargeting of Capsid Modified AAV Vectors" International Journal of Molecular Sciences 22, no. 15: 8355. https://doi.org/10.3390/ijms22158355

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