Safety, efficacy, and immunogenicity of a novel IgG degrading enzyme (KJ103): results from two randomised, blinded, phase 1 clinical trials.

The approved intravenous adeno-associated virus (AAV) therapies are limited by the widespread 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. To address this challenge, we have developed a novel recombinant human immunoglobulin G degrading enzyme KJ103, characterized by low immunogenicity and clinical value for the elimination of anti-AAV antibodies in gene transfer. Herein, we conducted two randomized, blinded, placebo-controlled, single ascending dose Phase I studies in China and New Zealand, to evaluate the pharmacokinetics, pharmacodynamics, safety and immunogenicity of KJ103 in healthy volunteers. The results confirmed that KJ103 rapidly reduced IgG and maintained plasma IgG at low levels for one week. Dose of KJ103 ranging from 0.01 to 0.40 mg/kg had a favorable safety and tolerability profile across diverse ethnic and gender groups. KJ103 demonstrated a lower incidence of pre-existing anti-drug antibodies (ADAs) compared to currently approved human IgG degrading enzyme Imlifidase, with most induced ADAs predominantly reverting to baseline six months after administration. These properties are ideal for the management of immune disorders, rejection responses, and immunotherapies where pre-existing antibodies can reduce efficacy. Furthermore, we tested AAV2 neutralizing antibodies to confirm the potential utility of KJ103 in enhancing gene therapy.