P07
Long-lasting antibody delivery by a myotropic Adeno-Associated Virus (AAV) Capsid Variant: high serum levels, favourable glycosylation profile and protection from SARS-CoV-2 challenge
J T Wagner(1) S M Müller-Schmucker(1) W Wang(2) P Arnold(3) N Uhlig(4) L Issmail(4) V Eberlein(4) D Damm(1) K Roshanbinfar(5) A Ensser(1) F Oltmanns(1) A S Peter(1) V Temchura(1) S Schrödel(6) M Salomon(6) F B Engel(5) C Thirion(6) T Grunwald(4) M Wuhrer(2) D Grimm(7) K Überla(1)
1:Institute of Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany; 2:Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, Netherlands; 3:Institute of Functional and Clinical Anatomy, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany; 4:Fraunhofer Institute for Cell Therapy and Immunology IZI, Preclinical Validation, Leipzig, Germany; 5:Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany; 6:Sirion Biotech, Graefeling, Germany; 7:Department of Infectious Diseases/Virology, Section Viral Vector Technologies, Medical Faculty, University of Heidelberg; BioQuant Center, BQ0030, University of Heidelberg; Cluster of Excellence CellNetworks; German Center for Infection Research (DZIF); German Center for Cardiovascular Research (DZHK), partner site Heidelberg, Germany
Delivery of monoclonal antibodies (mAb) by AAV-based vectors is a promising strategy for long-term protection from infectious diseases. Therefore, we designed a monocistronic AAV vector construct coding for TRES6, a neutralizing mAb against SARS-CoV-2. The AAV vector construct was packaged in two different AAV capsids: the hepatotropic AAV8 and the myotropic AAVMYO. Following either intravenous or intramuscular injection, both capsids led to high TRES6 serum concentrations persisting for the entire observation period of up to 52 weeks. TRES6 serum concentrations after AAVMYO delivery were approximately 3.7-fold higher. Despite finding a broad tissue distribution of vector DNA, transcriptionally active sites following AAVMYO transduction appeared to be restricted to skeletal muscle and heart. In AAV8 transduced mice, substantial vector RNA copies were only identified in the liver. The distinct tissue-specific transgene expression coincided with differences in the glycosylation pattern of the encoded antibody's Fc region: AAVMYO delivered TRES6 had a favourable glycosylation pattern, predicted to impact Fc-γ-receptor binding. SARS-CoV-2 challenge experiments in human ACE-2 transgenic mice confirmed efficient protection after delivery of the vector by both capsids.