Polycystic Kidney Disease (PKD) is a debilitating genetic disorder in which fluid-filled sacs form and multiply in the kidneys. Over time, these painful, growing cysts impair organ function, and advanced cases often require dialysis. Currently, there is no cure.

However, researchers at the University of California (UC) have developed a cyst-targeted therapy that halts the uncontrolled growth of cysts by leveraging the target specificity of specialized monoclonal antibodies—lab-synthesized immunotherapeutic proteins.

“Cysts keep growing relentlessly,” said Thomas Weimbs, a biologist at the University of California and senior author of the study published in the journal Cell Reports Medicine. “We wanted to stop them. So we needed to deliver the drug directly into the cysts to shut down their growth.”

The research was partially funded by the National Institutes of Health (NIH) and the U.S. Department of Defense.

Several small-molecule drugs show promise for controlling cyst growth. However, the only currently approved drug that effectively slows disease progression comes with numerous side effects and toxicity to the kidneys and surrounding tissues, Weimbs noted. Lab-engineered therapeutic antibodies offer an alternative with superior specificity, but the nearly universally used immunoglobulin G (IgG) antibodies are too large to penetrate cysts.

“They’ve been incredibly successful in cancer treatment,” Weimbs said. “But IgG antibodies can never cross cell layers or enter the interior of cysts.” This is critical, he added, because the cyst interior—a tissue sac lined with epithelial cells—is where the key processes driving growth occur.

“Many cyst-lining cells actually produce growth factors and secrete them into the cyst fluid,” he explained. “These growth factors then bind back to the same cells or neighboring cells, continuing to self-stimulate and cross-stimulate each other. It’s like an endless cycle where cells keep activating themselves and others. Our premise was that if you block the growth factors or their receptors, you should be able to stop this continuous activation.”

This is where dimeric immunoglobulin A (dIgA)—a type of monoclonal antibody capable of crossing epithelial membranes—comes into play. In nature, dIgA is an immune protein that acts as the first line of defense against pathogens by being secreted into tears, saliva, and mucus. By binding to the polymeric immunoglobulin receptor on epithelial cells, Weimbs and his team reasoned in a 2015 paper, the antibody could traverse the membrane in one direction into kidney cysts, where it could target specific receptors and interrupt the cycle fueling uncontrolled cyst growth.

The current study builds on this research direction and demonstrates the therapeutic effectiveness of the strategy by targeting the c-MET receptor—a key driver of cyst progression.

“It’s an endless mechanism where cells keep activating themselves and each other. Our premise was that if you block the growth factors or their receptors, you can halt this continuous cellular activation.”

The researchers first engineered the antibody protein by modifying the DNA sequence of IgG to “give it a different backbone,” converting it into a dIgA antibody. They then tested the resulting protein to confirm its effectiveness against the target receptor before conducting trials in mouse models. They found that the administered antibodies did enter the cysts and remain there.

“The next question was whether it would actually block that specific growth factor receptor,” Weimbs said. Their results showed that c-MET activity was inhibited, which in turn reduced cell growth signaling. Furthermore, the paper notes, the treatment appeared to trigger “a robust induction of apoptosis (cell death) in cyst epithelial cells, with no apparent harmful effects in healthy kidney tissue.”