Claudin‐targeted drug development using anti‐claudin monoclonal antibodies to treat hepatitis and cancer

Abstract

The 27-member family of tetraspan membrane proteins known as claudins (CLDNs) is a major component of tight junctions. A series of studies elucidating the relationship between CLDNs and various pathological conditions has provided new insights into drug development. For instance, CLDN-1 may be a potent target for epidermal absorption of drugs and for treating hepatitis C virus (HCV) infection. CLDN-4 may be a target for treating cancer. Because CLDNs are also expressed in various normal tissues, safety and efficacy evaluations are critical for translational research. We previously developed several anti-CLDN antibodies and have established proof of concept for CLDN-targeted drug development using these reagents. Here, we provide an overview of CLDN-1 as a target for improving epidermal drug absorption and preventing HCV infection and of CLDN-4 as a target for anticancer therapeutics.

The Late Endosomal Pathway Regulates the Ciliary Targeting of Tetraspanin Protein Peripherin 2

“…The tetraspanins are a family of four-pass transmembrane proteins that have both their N and C termini facing the cytosol. Tetraspanins are known to act as molecular scaffolds and have been implicated in several pathological conditions (e.g., cancer, infectious disease, inflammation, blindness; Hashimoto et al, 2017). Peripherin 2 (PRPH2 or peripherin/rds) is a photoreceptor-specific tetraspanin protein abundantly expressed in the cilium (outer segment) of both rods and cones.…”

β‐Elemene inhibits peritoneal metastasis of gastric cancer cells by modulating FAK/Claudin‐1 signaling

“…Claudin‐1 also stimulates the activation of pro‐matrix metalloproteinase‐2 to enhance invasiveness (Miyamori et al, ). Thus, targeting Claudin‐1 could potentially inhibit tumor metastasis (Hashimoto et al, ). Our study showed that β‐elemene downregulated Claudin‐1 mRNA and protein expression.…”

“…To elucidate the anti-metastasis mechanism of β-elemene in gastric cancer, RNA-seq was used to explore differentially expressed genes after β-elemene treatment. Claudin-1 has previously been identified as a potential target for anti-metastatic treatments (Cherradi et al, 2017;Hashimoto et al, 2017). Claudin-1 is a tight junction protein whose overexpression is seen in several cancers (de Oliveira et al, 2005;Eftang et al, 2013;Leotlela et al, 2007).…”

“…Several studies have indicated that Claudin‐1 is upregulated in colorectal (de Oliveira, de Oliveira, De Souza, & Morgado‐Diaz, ), melanoma (Leotlela et al, ), and gastric cancer (Eftang et al, ) and can promote the epithelial‐mesenchymal transition (EMT; Stebbing, Filipović, & Giamas, ). Efforts to target Claudin‐1 have become a novel strategy to inhibit tumor metastasis (Hashimoto, Fukasawa, Kuniyasu, Yagi, & Kondoh, ). Focal adhesion kinase (FAK) is a nonreceptor protein tyrosine kinase that can promote tumor invasion and metastasis (Kleinschmidt & Schlaepfer, ).…”

“…Efforts to target Claudin-1 have become a novel strategy to inhibit tumor metastasis (Hashimoto, Fukasawa, Kuniyasu, Yagi, & Kondoh, 2017). Focal adhesion kinase (FAK) is a nonreceptor protein tyrosine kinase that can promote tumor invasion and metastasis (Kleinschmidt & Schlaepfer, 2017).…”