Abstract
The approved recombinant adeno-associated virus (AAV) intravenous drugs are limited by the high prevalence of pre-existing anti-AAV antibodies in the general population, which are known to restrict patients’ ability to receive gene therapy and limit transfection efficacy in vivo. Based on that, we developed a novel and low immunogenicity recombinant human immunoglobulin G degrading enzyme (KJ103), which has clinical value in removing anti- AAV antibodies in vivo gene transfer. Herein, we performed two randomized, blinded, placebo-controlled, single ascending dose phase I studies in China and New Zealand, to evaluate pharmacokinetics, pharmacodynamics, safety and immunogenicity of KJ103 in healthy participants. The results comfirmed that KJ103 rapidly reduced IgG and maintained low levels for 1 week. The 0.01 to 0.40 mg/kg dose range of KJ103 had a favorable safety and tolerability profile in healthy participants of different ethnic and gender groups. KJ103 has low percentage of pre-existing ADAs compared to currently licensed human IgG degrading enzyme (i.e. IdeS), and the induced ADAs mostly return to baseline six months after administration. These characteristics are well suited for the treatment of immune disorders, immune rejection, and immunotherapy where pre-existing antibodies reduce efficacy (e.g. AAV-mediated gene therapy in individuals positive for pre-existing anti-AAV antibodies). The potential of KJ103 warrants further exploration.