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A Pathway Lies In The Bridge Between Cells

Most of us remember from high school biology that cells are the basic building blocks of all living things. Cells join together to form tissues and organs such as hearts, lungs, and livers, which work together to create a functioning human. An adult human body contains trillions of cells, and these cells must coordinate to form a cohesive whole.

One of the ways in which cells work together is through cell junctions, or “intercellular bridges.” These junctions consist of multiprotein complexes that anchor cells to each other — and in some cases enable communication between them. In this WEEKLY, we’ll zoom in on one specific type of cell junction known as a tight junction, and examine its role in health and disease.

Tight Junctions Unraveled

Tight junctions are found in epithelial cells, or the cells that line the cavities and surfaces of blood vessels and organs. In addition to holding cells together, tight junctions form a barrier between adjacent cells, preventing the passage of various molecules into tissues between cells. Anything entering a tissue must actually enter the cells themselves rather than going through any “spaces” around them. Tight junctions enable tighter control over what gets in and out of the tissue by creating barriers between cells.

The tight junction itself is composed of proteins from two neighboring cells that pass through each cell membrane and interact with each other outside of the cells, bridging the two cells:

The tight junction visualized.

The tight junction visualized.

The Gap In Celiac

In patients with celiac disease, consuming the wheat protein gluten disrupts the barrier function of tight junctions within the intestinal epithelium. This disruption occurs when gliadin, a component of gluten, binds to a receptor protein on the surface of intestinal epithelial cells, initiating a signaling pathway resulting in tight junction disassembly. This, in turn, leads to increased intestinal permeability and the activation of inflammatory pathways that cause serious damage to intestinal cells.

Innovate Biopharmaceuticals (Raleigh, NC) is developing a peptide (short sequence of amino acids) drug that appears to reverse the opening of tight junctions in celiac patients. It does this by inhibiting the signaling pathways initiated by gliadin binding. Dubbed larazotide acetate, the drug has successfully completed Phase II clinical studies and is preparing to enter Phase III.

The Gap In Gastrointestinal & Pancreatic Cancer

One of the key protein components of tight junctions is a family of proteins called claudins. Ganymed Pharmaceuticals (Mainz, Germany) is developing a monoclonal antibody (mAb) therapeutic (IMAB362) that targets claudin 18.2, a subtype of claudin that is only expressed in mature stomach cells and is overexpressed in 80% of gastrointestinal adenocarcinomas and 60% of pancreatic tumors. The tumor growth disrupts the tight junction function in these cases. Because the protein is so specific to gastrointestinal cells, it makes a good drug target—the mAb ideally should not impact other tissues in the body, reducing the potential for toxicity. IMAB362 showed very promising results in a Phase II clinical trial for gastroesophageal cancer and is preparing to enter Phase III trials. The drug has also shown promise in preclinical studies of pancreatic cancer.

In order to ensure optimal efficacy, IMAB362 should be given to patients who over express claudin 18. To meet this need, Ganymed is also developing Claudetect 18.2, a companion diagnostic for IMAB362. Claudetect determines expression levels of claudin 18.2 to find out which patients are most likely to respond to treatment. It is currently being used to identify patients for Ganymed’s IMAB362 clinical trials.

Critical Barrier: Blood-Brain Barrier

A great example of a tight junction barrier function is the blood-brain barrier (BBB). This barrier is formed by tight junctions between cells lining the capillaries surrounding the brain. Although this barrier can present a challenge to scientists trying to deliver medicines to the brain, the BBB plays the critical function of preventing most harmful substances from entering the brain. In patients with multiple sclerosis, inflammation disrupts the BBB, allowing white blood cells to enter the brain and attack neurons. Brain tumors also disrupt the BBB, resulting in potentially fatal brain swelling due to excess fluid entering the brain.

We often think in terms of what our tissues need, but a closer look at tight junctions reminds us that sometimes what cells and tissues keep out can be just as important as what is allowed inside.

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