A monoclonal antibody targeting nonjunctional claudin-1 inhibits fibrosis in patient-derived models by modulating cell plasticity

Tissue fibrosis is a key driver of end-stage organ failure and cancer, overall accounting for up to 45% of deaths in developed countries. There is a large unmet medical need for antifibrotic therapies. Claudin-1 (CLDN1) is a member of the tight junction protein family. Although the role of CLDN1 incorporated in tight junctions is well established, the function of nonjunctional CLDN1 (njCLDN1) is largely unknown. Using highly specific monoclonal antibodies targeting a conformation-dependent epitope of exposed njCLDN1, we show in patient-derived liver three-dimensional fibrosis and human liver chimeric mouse models that CLDN1 is a mediator and target for liver fibrosis. Targeting CLDN1 reverted inflammation-induced hepatocyte profibrogenic signaling and cell fate and suppressed the myofibroblast differentiation of hepatic stellate cells. Safety studies of a fully humanized antibody in nonhuman primates did not reveal any serious adverse events even at high steady-state concentrations. Our results provide preclinical proof of concept for CLDN1-specific monoclonal antibodies for the treatment of advanced liver fibrosis and cancer prevention. Antifibrotic effects in lung and kidney fibrosis models further indicate a role of CLDN1 as a therapeutic target for tissue fibrosis across organs. In conclusion, our data pave the way for further therapeutic exploration of CLDN1-targeting therapies for fibrotic diseases in patients. Description Claudin-1 is a mediator of and therapeutic target for organ fibrosis. Profibrotic protein Claudin-1 Profibrotic protein claudin-1Claudin-1 (CLDN1) protein is a well-studied component of tight junctions, but its role outside of such junctions is not as well described. Using patient-derived organoids and human liver chimeric mouse models, Roehlen et al. now show that non-junctional CLDN1 plays a role in the progression of liver fibrosis. Monoclonal antibodies targeting CLDN1 inhibited fibrosis progression in the liver models and in proof-of-principle lung and kidney fibrosis models, suggesting this protein is a potential anti-fibrotic therapeutic target.—CAC