Therapeutic hFIX Activity Achieved after Single AAV5-hFIX Treatment in Hemophilia B Patients and NHPs with Pre-existing Anti-AAV5 NABs

• Published in: Molecular therapy. Methods & clinical development Vol. 14; pp. 27 - 36
• Main Authors: Majowicz, Anna, Nijmeijer, Bart, Lampen, Margit H., Spronck, Lisa, de Haan, Martin, Petry, Harald, van Deventer, Sander J., Meyer, Christian, Tangelder, Marco, Ferreira, Valerie
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.09.2019; Elsevier Limited; American Society of Gene & Cell Therapy
• Subjects: AAV; anti-AAV NABs; Bioassays; Clinical trials; Coagulation factors; Factor IX deficiency; FIX; Gene therapy; Hemophilia; hFIX; Immunoglobulins; Laboratories; NABs; Patients; Studies; Vectors (Biology); NABs; hemophilia; FIX; anti-AAV NABs; AAV; gene therapy; hFIX
• ISSN: 2329-0501; 2329-0501
• DOI: 10.1016/j.omtm.2019.05.009

Currently, individuals with pre-existing neutralizing antibodies (NABs) against adeno-associated virus (AAV) above titer of 5 are excluded from systemic AAV-based clinical trials. In this study we explored the impact of pre-existing anti-AAV5 NABs on the efficacy of AAV5-based gene therapy. AMT-060 (AAV5-human FIX) was evaluated in 10 adults with hemophilia B who tested negative for pre-existing anti-AAV5 NABs using a GFP-based assay. In this study, using a more sensitive luciferase-based assay, we show that 3 of those 10 patients tested positive for anti-AAV5 NABs. However, no relationship was observed between the presence of pre-treatment anti-AAV5 NABs and the therapeutic efficacy of AMT-060. Further studies in non-human primates (NHPs) showed that AAV5 transduction efficacy was similar following AMT-060 treatment, irrespective of the pre-existing anti-AAV5 NABs titers. We show that therapeutic efficacy of AAV5-mediated gene therapy was achieved in humans with pre-existing anti-AAV5 NABs titers up to 340. Whereas in NHPs circulating human factor IX (hFIX) protein was achieved, at a level therapeutic in humans, with pre-existing anti-AAV5 NABs up to 1030. Based on those results, no patients were excluded from the AMT-061 (AAV5-hFIX-Padua) phase IIb clinical trial (n = 3). All three subjects presented pre-existing anti-AAV5 NABs, yet had therapeutic hFIX activity after AMT-061 administration.