Advanced liver disease and cancer is the only major cause of death still increasing each year. Major causes include hepatitis B and C viruses, alcohol and non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH). A major contributing factor to the increasing incidence and mortality of liver disease is the staggering rise in obesity. The absence of effective therapeutic options for NAFLD/NASH, advanced liver disease and cancer contribute to the poor prognosis and the high cost associated with patient care. Within ERC-AdG HEPCIR 671231 we identified a humanized monoclonal antibody (mAb) targeting human tight junction protein Claudin-1 (CLDN1) for treatment of NASH. In a mouse model pilot study, the mAb reverted liver disease and steatosis in vivo. The ERC-PoC-PRELICAN grant allowed us to evaluate the anti-CLDN1 mAb for future clinical development and its potential commercialization. For this, we performed proof-of-concept studies in state-of-the-art mouse models for NASH and hepatocarcinogenesis. The therapeutic effect of CLDN1 mAb was robustly demonstrated for treatment of liver inflammation, steatosis, fibrosis and HCC development, without showing any adverse effects. We could gain insights into the CLDN1 mAb mechanism of action, involving the regulation of pathways attenuating fibrogenesis, carcinogenesis, inflammation and restoring the metabolic function of the hepatocytes. As planned, we obtained a robust proof-of-concept data package for the commercialization of the mAb as a first- or best-in-class compound for treatment of NASH, fibrosis and prevention of HCC. Future plans include the creation of a spin-off company in Strasbourg/Basel to develop the compound until proof-of-concept in man (randomized clinical trial Phase IIa).
