Neuronal ceroid-lipofuscinosis type 2 (CLN2) disease is a neurodegenerative lysosomal storage disorder caused by mutations in the TPP1 gene, encoding the lysosomal enzyme tripeptidyl peptidase 1 (TPP1). Affected children show first clinical symptoms between 1.5 and 4 years of age, including seizures, psychomotor decline, and loss of vision. Currently, intraventricular enzyme replacement therapy (ICV-ERT) with recombinant human TPP1 (rhTPP1, Cerliponase alfa) is the only approved treatment. It was shown to slow down the loss of motor and language function. Like in other ERT, immune reaction to the recombinant enzyme is a common adverse event and increases the risk of production of anti-drug antibodies (ADA) and subsequently loss of treatment efficacy. Aim of this study was to analyze drug-specific antibody response in biofluids of CLN2 patients receiving ICV-ERT as standard of care.
Therefore, we developed a two-step assay consisting of a HEK293TGPI-TPP1-cell-based, flow-cytometry assay for highly sensitive screening purposes followed by serial-diluted ELISA for reliable titer-quantification. We prospectively observed a cohort of 10 CLN2 patients before and during ICV-ERT with Cerliponase alfa for a follow-up time of 18 to up to 36 months of therapy duration. ADA response was analyzed in paired serum and CSF samples obtained before and every six months during treatment. These data were complemented by immunophenotyping, clinical disease progression parameters, like Hamburg LiNCL and Weill-Cornell Score, as well as assessment of drug-related adverse events.
Results from this study will help to improve understanding of the humoral immunological response to the recombinant enzyme and the potential influence on treatment efficacy. This will be crucial for the prediction, treatment and prevention of immune reactions to ICV-ERT with Cerliponase alfa. In addition, it will help to improve individual patient risk assessments for future gene therapy approaches.