Hepatocellular carcinoma (HCC) is the fastest rising and third leading cause of cancer related deaths worldwide (WHO IARC). Major causes include the hepatitis B and C viruses, alcoholism, Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis. These medical conditions trigger liver fibrosis by damaging the liver and are closely associated with the development of HCC. As a matter of fact, more than 80% of HCC develop in fibrotic or cirrhotic livers. Early stages of liver cancer do not usually produce symptoms, and many challenges are associated with the screening of HCC, leading to late diagnosis. HCC resection is the first curative option as effective drug treatments are absent, with most patients experiencing HCC recurrence within 5 years. While new therapeutic modalities have been recently approved, treatment response and survival in patients remain poor. Within ERC-AdG HEPCIR 671231 we identified a humanized monoclonal antibody (mAb) targeting human tight junction protein Claudin-1 (CLDN1) for the treatment of advanced liver disease and liver cancer. CLDN1 is a cell membrane protein mediating cell-cell adhesion, cell fate and differentiation. While the function of CLDN1 within tight junctions is well characterized, the role of non-junctional CLDN1 in HCC remains unexplored. The ERC PoC HEPCAN program allowed us to investigate the role of CLDN1 as a driver and therapeutic target for HCC using CLDN1 monoclonal antibodies in a series of proof-of-concept studies. We were able to demonstrate tumor growth suppression in a large series of patient-derived model systems, including multicellular tumorspheres and patient-derived xenograft (PDX) mouse. In vivo and ex vivo studies further suggested synergistic efficacy in combination with sorafenib. Mechanistic studies also revealed that CLDN1 mAbs suppressed tumor cell proliferation, invasion and stemness. Our results provide robust pre-clinical proof-of-concept for humanized CLDN1-specific mAbs for the treatment of HCC. The unique and differentiated mechanism of action has the potential to break the plateau of limited response and survival offered by currently approved therapies. Furthermore, this program has significantly contributed to the creation of Alentis Therapeutics, a biotech company based in Basel and Strasbourg with a focus on developing breakthrough treatments for fibrotic diseases and cancer. Alentis was created in 2019 as a spin-off of the University of Strasbourg and successfully completed two financing rounds for the clinical development of CLDN1-targeting therapies of a total of around 68 M€. The future clinical development of CLDN1 mAbs as therapeutics for fibrosis (with first in human Phase I trials beginning in December 2021) and liver cancer, offers an opportunity to develop a completely novel strategy to improve standard-of-care for aggressive cancers affecting more than 85k Europeans every year and rising, and leading cause of cancer deaths with 800k deaths worldwide annually and 78k deaths in Europe alone in 2020.
