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

Abstract

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.

Tight junction component protein claudin-1 deficiency in retinal pigment epithelium leads to early and intermediate age-related macular degeneration phenotypes in mice

“…Recently, claudin has been suggested to have roles in non-junctional mechanisms. Claudin-1 promotes epithelial–mesenchymal transition (EMT) in the liver (Roehlen et al, 2022) and claudin-19 is related to degradation of internalized photoreceptor OS in the stem cell-derived RPE (Liu et al, 2021). Our study provided new insights into the possible association of claudin-1 with abnormalities in lipid metabolism and cellular senescence in the RPE.…”

Tight Junction Proteins as Therapeutic Targets to Treat Liver Fibrosis and Hepatocellular Carcinoma

“…A highly specific mAb targeting nonjunctional CLDN1 modulates the plasticity of hepatocytes, progenitor cells, and myofibroblasts, restoring their differentiated and functional cell phenotype that is disrupted by fibrosis and inflammation in chronic liver disease and during the development of HCC. 28 The mAbs act mainly on CLDN1 expressed on hepatocytes and progenitor cells as well as CLDN1 additionally expressed on stellate cells and myofibroblasts. The CLDN1-specific mAbs exhibit a dual effect on liver fibrosis and HCC prevention and thus have potential as a treatment for patients with active chronic liver disease and advanced fibrosis or at a high risk of HCC development.…”

“…53 These changes result in modulation of the plasticity of hepatocytes, progenitor cells, and myofibroblasts, leading to a reversal of their pathological, immature, and profibrotic profile to more differentiated and functionals, thereby reversing fibrosis and reducing HCC development. 28,[54][55][56] The function and intracellular signaling of CLDN1, along with the effects of the nonjunctional CLDN1-specific mAb are presented in ►Fig. 2.…”

“…28,60 The clinical development of an mAb targeting nonjunctional CLDN1 in liver and other organ fibrosis is currently ongoing. A fully humanized anti-human CLDN1 mAb has undergone safely testing in cynomolgus monkeys 28 and healthy volunteers. Moreover, a phase Ib clinical trial is currently ongoing for patients with advanced liver fibrosis or compensated cirrhosis (FEGATO-01, NCT05939947).…”

“…Targeting nonjunctional CLDN1 by a mAb has been shown to suppress tumor initiation and progression in patient-derived ex vivo and in vivo models of HCC. 28 84 Mechanistically, tumor cell suppression was associated with broad inhibitory effects on oncogenic signaling cascades, EMT, as well as cancer stemness. 84 These oncogenic pathways are also modified in other cancers such as head and neck cancer.…”