Antibody targeting of claudin-1 as a potential colorectal cancer therapy

Abstract

BackgroundMetastatic colorectal cancer (mCRC) is one of the major causes of cancer-related death. Despite the substantial progress in mCRC management, it remains important to identify new therapeutic options and biological markers for personalized medicine. Here, we investigated the expression of claudin-1 (CLDN1), a major tight junction transmembrane protein, in the different colorectal cancer (CRC) molecular subtypes and then assessed the anti-tumor effect of a new anti-CLDN1 monoclonal antibody (mAb).MethodsGene expression profiling and immunochemistry analysis of normal and tumor tissue samples from patients with stage IV CRC were used to determine CLDN1 gene expression. Then, the 6F6 mAb against CLDN1 extracellular part was generated. Its effect on CRC cell cycle, proliferation, survival and migration was assessed in vitro, using a 3D cell culture system, flow cytometry, clonogenic and migration assays. In vivo, 6 F6 mAb efficacy was evaluated in nude mice after subcutaneous xenografts or intrasplenic injection of CRC cells.ResultsCompared with normal mucosa where it was almost exclusively cytoplasmic, in CRC samples CLDN1 was overexpressed (p < 0.001) and mainly localized at the membrane. Moreover, it was differentially expressed in the various CRC molecular subtypes. The strongest expressions were found in the consensus molecular subtype CMS2 (p < 0.001), the transit-ampliflying (p < 0.001) and the C5 subtypes (p < 0.001). Lower CLDN1 expression predicted a better outcome in the molecular subtypes C3 and C5 (p = 0.012 and p = 0.004, respectively). CLDN1 targeting with the 6 F6 mAb led to reduction of survival, growth and migration of CLDN1-positive cells. In preclinical mouse models, the 6F6 mAb decreased tumor growth and liver metastasis formation.ConclusionOur data indicate that CLDN1 targeting with an anti-CLDN1 mAb results in decreased growth and survival of CRC cells. This suggests that CLDN1 could be a new potential therapeutic target.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-017-0558-5) contains supplementary material, which is available to authorized users.

Anti-Claudin Antibodies as a Concept for Development of Claudin-Directed Drugs

“…Similar to the association of CLDN-3 and -4 and various cancers, CLDN-1 and -2 are frequently overexpressed in colorectal cancers (Miwa et al, 2001;Kinugasa et al, 2007), where CLDN-1 and -2 promoted tumor proliferation and invasiveness (Dhawan et al, 2005(Dhawan et al, , 2011. In contrast, treatment with an anti-CLDN-1 mAb (6F6) suppressed tumor growth in colorectal cancer xenograft mice (Cherradi et al, 2017). In addition, anti-CLDN-2 mAb (1A2) attenuated tumor growth in xenograft mice (Hashimoto et al, 2018a).…”

Characterisation of endogenous Claudin‐1 expression, motility and susceptibility to hepatitis C virus in CRISPR knock‐in cells

“…CLDN1 expression has been proposed for cancer prognosis [Fritzsche et al., 2008] and our work provides a novel approach to quantitatively assess it in live cells. Moreover, anti‐CLDN1 antibodies have been proposed for colorectal cancer therapy and antiviral HCV treatment [Mailly et al., 2015; Cherradi et al., 2017], but their mode of action remains only partially understood. Here, the TagRFP‐CLDN1 edited cells provide a powerful platform to study small molecule inhibitors and could also be used to evaluate the anti‐cancerous and antiviral properties of CLDN1‐targeting compounds.…”

“…Given its important role in HCV entry, CLDN1 has been shown to be a target for antiviral therapy [Mailly et al., 2015; Colpitts et al., 2018]. Furthermore, given the overexpression of CLDN1 in various cancers [Kwon, 2013; Zeisel et al., 2018], CLDN1 has been proposed as target for anti‐cancer therapies [Cherradi et al., 2017]. The molecular mechanisms involved in the tight regulation of the expression and distribution of Claudins have been well studied [Anderson and Van Itallie, 2009; Tsukita et al., 2019] but strategies to modulate them are still scarce.…”

FBXW4 Acts as a Protector of FOLFOX-Based Chemotherapy in Metastatic Colorectal Cancer Identified by Co-Expression Network Analysis

“…To date, reliable molecular markers for the FOLFOX/CapeOX regimen resistance in CRC patients are still unavailable, especially for the primary resistance Moreover, we analyzed the data in the GEO dataset, and found eight datasets, GSE19860, GSE52735, GSE104645, GSE14095, GSE83889, GSE72968, GSE110785, and GSE69657 were contained CRC patients who received FOLFOX chemotherapy (Watanabe et al, 2011;Li et al, 2013;Estevez-Garcia et al, 2015;Tong et al, 2015;Del et al, 2017;Cherradi et al, 2017;Kwon et al, 2017;Okita et al, 2018;Cherradi et al, 2019). We further analyzed the above datasets, the results demonstrated that the datasets, GSE104645, GSE110785, GSE19860, GSE52735, and GSE14095, including the information about acquired resistance and lacked the primary resistance.…”