Recent Advances in Claudin-Targeting Technology

Abstract

Most malignant tumors are derived from epithelium, and pathologic microorganisms often invade the body through the mucosal epithelium. Thus epithelial tissues are potent targets for drug delivery. The tight junction (TJ) is the intercellular seal in epithelial cell sheets. Claudins (CLs) are a family of tetratransmembrane proteins with a molecular mass of approximately 23 kDa. CLs are key structural and sealing components of TJs. CLs are often overexpressed in malignant tumors. CL-4 is highly expressed in the epithelial cells covering mucosal immune tissues. Therefore CLs may be potent targets for drug delivery, cancer therapy, and mucosal vaccination. Herein, we overview a series of our studies using the C-terminal fragment of Clostridium perfringens enterotoxin to target and bind CLs; we also discuss the efficacy of CL-targeted drug delivery.

Clinical implications of leukocyte infiltration at the choroid plexus in (neuro)inflammatory disorders

“…Blocking peptides and antibodies against integrins, which are transmembrane receptors for ECM proteins, are used in clinical trials for prostate cancer [113]. Additionally, tumor growth was suppressed in mice by targeting monoclonal cytotoxic antibodies to cells that specifically express CLDN3 and -4, because these TJ components are increased in tumors [115][116][117]. In EAE, therapeutic stabilization of the BBB by a synthetic small molecule inhibitor for protein kinase Cb, which is currently under investigation in clinical trials for cancer treatment, was shown to suppress transmigration of activated T cells across the BBB and was accompanied by the induction of TJ molecules (ZO1, CLDN3, and -5) [111].…”

Efficacy and safety evaluation of claudin‐4‐targeted antitumor therapy using a human and mouse cross‐reactive monoclonal antibody

“…Members of the CLDN family have received much attention as potential therapeutic targets (Cereijido et al 2007;Nagase et al 2013;Runkle and Mu 2013;Haseloff et al 2014). In particular, CLDN-4 is a potential target for antitumor drugs because it is highly expressed in a wide spectrum of cancers, including pancreatic, ovarian, breast, gastric, and colorectal cancers (Facchetti et al 2007;Ding et al 2013).…”

“…; Nagase et al. ; Van Itallie and Anderson ). Tight junctions normally are located on the apical side of the lateral membrane to maintain cell polarity, but various carcinomas display abnormal expression of tight‐junction proteins and resultant disruption of cell polarity (Singh et al.…”

“…Most human cancers are carcinomas, which arise from epithelial cells. In normal epithelial cells, tight junctions between adjacent cells regulate the permeation of small ions, solutes, and large molecules such as proteins (Tsukita et al 2001;Nagase et al 2013;Van Itallie and Anderson 2013). Tight junctions normally are located on the apical side of the lateral membrane to maintain cell polarity, but various carcinomas display abnormal expression of tight-junction proteins and resultant disruption of cell polarity (Singh et al 2010;Beyer et al 2012).…”

Intranasal and oral vaccination with protein-based antigens: advantages, challenges and formulation strategies

“…Claudins are considerably expressed on tumor cells and mucosal epithelium cells, thus they have been explored for targeting delivery in tumor therapy and mucosal vaccination. OVA fused to claudin-4 binding ligands induced both Th1- and Th2-mediated immune response in mice, suggesting clauding-4 targeting as an effective way for intranasal vaccination (Nagase et al, 2013 ). Ad2F, an epithelial cell binding domain, was fused to a botulinum neurotoxin A (BoNT/A) immunogen-Hcbtre (Staats et al, 2011 ).…”