Molecular Therapy: Methods & Clinical Development (05/27/19). Majowicz, Anna; Nijmeijer, Bart; Lampen, Margit H.; et al.
Due to the potential for pre-existing immunity to negatively affect the efficacy of adeno-associated virus (AAV)-based gene therapy, many clinical trials of AAV-based gene therapy exclude patients with pre-existing neutralizing antibodies (NABs) directed against the capsid proteins. Miesbach et al. (Blood, 2018) have previously reported on the safety and efficacy of AMT-060 (AAV5-hFIX) in 10 adult males with hemophilia B. Prior to treatment, all of these men were determined to be negative for anti-AAV5 NABs using a green-fluorescent protein-based assay. In the current study, researchers evaluated the impact of pre-existing anti-AAV5 NABs as measured using a more sensitive (luciferase-based) assay on efficacy outcomes in the AMT-060 study participants, and in nonhuman primates (NHPs) treated with AAV5-hFIX. Using the luciferase-based assay, 3 of 10 patients from the AMT-060 study tested positive for pre-existing anti-AAV NABs (with titers measuring up to 1:340); however no correlation between the presence of pre-existing NABs and hFIX levels following AMT-060 gene transfer was observed. This finding was supported by results from NHPs, in which the presence of pre-existing anti-AAV5 NAB titers did not negatively impact hFIX liver transduction. In the ongoing AMT-061 trial (AAV5-hFIX Padua), patients with anti-AAV5 NABs are not excluded; indeed the authors report that 3 patients with low levels of anti-AAV5 NABs prior to treatment had meaningful hFIX levels following AMT-061 treatment.