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

Hashimoto, Yuichi; Okada, Yoshiaki; Shirakura, Keisuke; Tachibana, Keisuke; Sawada, Makoto; Yagi, Kiyohito; Doi, Takefumi; Kondoh, Masuo

doi:10.1124/jpet.118.252361

Cited by 12 publications

(10 citation statements)

References 111 publications

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“…Claudin is a tetra transmembrane family with more than 20 members. These proteins are important components of the tight junctions (37). In 2008, Claudin18 splice variant 2 was proposed as a pancancer target suit able for therapeutic antibody development (38).…”

Section: Discussionmentioning

confidence: 99%

Targeting tumor lineage plasticity in hepatocellular carcinoma using an anti-CLDN6 antibody-drug conjugate

Kong

Tang

et al. 2021

Sci. Transl. Med.

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Tumor lineage plasticity is emerging as a critical mechanism of therapeutic resistance and tumor relapse. Highly plastic tumor cells can undergo phenotypic switching to a drug-tolerant state to avoid drug toxicity. Here, we investigate the transmembrane tight junction protein Claudin6 (CLDN6) as a therapeutic target related to lineage plasticity for hepatocellular carcinoma (HCC). CLDN6 was highly expressed in embryonic stem cells but markedly decreased in normal tissues. Reactivation of CLDN6 was frequently observed in HCC tumor tissues as well as in premalignant lesions. Functional assays indicated that CLDN6 is not only a tumor-associated antigen but also conferred strong oncogenic effects in HCC. Overexpression of CLDN6 induced phenotypic shift of HCC cells from hepatic lineage to biliary lineage, which was more refractory to sorafenib treatment. The enhanced tumor lineage plasticity and cellular identity change were potentially induced by the CLDN6/TJP2 (tight junction protein 2)/YAP1 (Yes-associated protein 1) interacting axis and further activation of the Hippo signaling pathway. A de novo anti-CLDN6 monoclonal antibody conjugated with cytotoxic agent (Mertansine) DM1 (CLDN6-DM1) was developed. Preclinical data on both HCC cell lines and primary tumors showed the potent antitumor efficiency of CLDN6-DM1 as a single agent or in combination with sorafenib in HCC treatment.

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Section: Discussionmentioning

confidence: 99%

Targeting tumor lineage plasticity in hepatocellular carcinoma using an anti-CLDN6 antibody-drug conjugate

Kong

Tang

et al. 2021

Sci. Transl. Med.

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“…In addition, subtype-specific anti-claudin antibodies or peptidomimetics could be tested. 63,64 In monolayered normal human keratinocytes, a modified His-cCPE variant with a high affinity for Cldn1, -2, -4, and -5 had similar TJmodulating effects as a monoclonal anti-Cldn1 antibody. 49 Furthermore, antibody-type claudin binders have a high production cost, making them less attractive for clinical use than small recombinant proteins.…”

Section: Claudin Targeting In the Epidermis By Gst-ccpe Variants To E...mentioning

confidence: 99%

Claudin targeting as an effective tool for directed barrier modulation of the viable epidermis

Beier

Waldow

Farahani

et al. 2022

Annals of the New York Academy of Sciences

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Tight junction (TJ) formation is vital for epidermal barrier function. We aimed to specifically manipulate TJ barriers in the reconstructed human epidermis (RHE) by claudin‐1 and ‐4 knockdown (KD) and by claudin‐binding fusion proteins of glutathione S‐transferase and modified C‐terminal fragments of Clostridium perfringens enterotoxin (GST‐cCPE). Impedance spectroscopy and tracer permeability imaging were employed for functional barrier assessment and investigation of claudin contribution. KD of claudin‐1, but not claudin‐4, impaired the paracellular barrier in vitro. Similarly, claudin‐binding GST‐cCPE variants weakened the paracellular but not the stratum corneum barrier. Combining both TJ targeting methods, we found that claudin‐1 targeting by GST‐cCPE after claudin‐4 KD led to a marked decrease in paracellular barrier properties. Conversely, after claudin‐1 KD, GST‐cCPE did not further impair the barrier. Comparison of GST‐cCPE variants with different claudin‐1/claudin‐4 affinities, NHS‐fluorescein tracer detection, and immunostaining of RHE paraffin sections showed that GST‐cCPE variants bind to extrajunctional claudin‐1 and ‐4, which are differentially distributed along the stratum basale–stratum granulosum axis. GST‐cCPE binding blocks these claudins, thereby specifically opening the paracellular barrier of RHE. The data indicate a critical role for claudin‐1 in regulating paracellular permeability for ions and small molecules in the viable epidermis. Claudin targeting is presented as a proof‐of‐concept for precise barrier modulation.

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“…Currently, most binders that target TJ proteins are either fragments of bacterial toxins (first-generation binders) or monoclonal antibodies (mAbs; second-generation binders) [32,33,34].…”

Section: Claudin and Angulin Bindersmentioning

confidence: 99%

“…The TJ cavity is estimated to be 0.5 nm under physiological conditions [116,117]. Large binders, such as antibodies, which are unable to access proteins embedded in TJs, are a promising modality for treating cancers and for improving the effectiveness of vaccines because in these conditions the target claudins are exposed on the cell surfaces [34,87,88,96]. TJ components are potent targets for the development of many novel therapies, but targets and drug modalities must be optimized to afford an acceptable risk–benefit balance.…”

Section: Safety Of Claudin- and Angulin-targeted Therapiesmentioning

confidence: 99%

Potential for Tight Junction Protein–Directed Drug Development Using Claudin Binders and Angubindin-1

Hashimoto

Tachibana

Krug

et al. 2019

IJMS

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The tight junction (TJ) is an intercellular sealing component found in epithelial and endothelial tissues that regulates the passage of solutes across the paracellular space. Research examining the biology of TJs has revealed that they are complex biochemical structures constructed from a range of proteins including claudins, occludin, tricellulin, angulins and junctional adhesion molecules. The transient disruption of the barrier function of TJs to open the paracellular space is one means of enhancing mucosal and transdermal drug absorption and to deliver drugs across the blood–brain barrier. However, the disruption of TJs can also open the paracellular space to harmful xenobiotics and pathogens. To address this issue, the strategies targeting TJ proteins have been developed to loosen TJs in a size- or tissue-dependent manner rather than to disrupt them. As several TJ proteins are overexpressed in malignant tumors and in the inflamed intestinal tract, and are present in cells and epithelia conjoined with the mucosa-associated lymphoid immune tissue, these TJ-protein-targeted strategies may also provide platforms for the development of novel therapies and vaccines. Here, this paper reviews two TJ-protein-targeted technologies, claudin binders and an angulin binder, and their applications in drug development.

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

Cited by 12 publications

References 111 publications

Targeting tumor lineage plasticity in hepatocellular carcinoma using an anti-CLDN6 antibody-drug conjugate

Targeting tumor lineage plasticity in hepatocellular carcinoma using an anti-CLDN6 antibody-drug conjugate

Claudin targeting as an effective tool for directed barrier modulation of the viable epidermis

Potential for Tight Junction Protein–Directed Drug Development Using Claudin Binders and Angubindin-1

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