A groundbreaking discovery in antibody research could offer hope for those suffering from polycystic kidney disease (PKD), a challenging inherited disorder. PKD causes fluid-filled cysts to form within the kidneys, gradually damaging the surrounding tissue and impairing organ function. Many patients with advanced PKD eventually require dialysis, and currently, there is no cure. However, researchers at UC Santa Barbara are exploring a novel therapeutic approach using carefully designed monoclonal antibodies, which are lab-made proteins commonly employed in immunotherapy.
The race to halt the relentless growth of cysts
"The cysts just keep growing endlessly, and we want to put a stop to it," said UCSB biologist Thomas Weimbs, the senior author of a study published in Cell Reports Medicine. Weimbs and his team are developing a strategy to disrupt the uncontrolled expansion of these cysts, which could potentially slow down the progression of PKD.
While there are small-molecule drugs that show promise in slowing cyst expansion, Weimbs highlights that the only approved drug with some benefit also comes with significant side effects and toxicity to nearby kidney tissue. Therapeutic antibodies grown in the lab offer more selectivity, but the commonly produced immunoglobulin G (IgG) is too large to penetrate the cysts.
"IgG antibodies are highly effective in cancer therapy, but they cannot cross the cell layers and enter the cysts," Weimbs explained. The interior of each cyst, a sealed chamber lined with epithelial cells, is where the disease-driving activity occurs. Many of these cyst-lining cells produce growth factors, which they secrete into the cyst fluid, creating a self-perpetuating cycle of cell activation.
A new antibody with a unique design
Here's where it gets interesting: the researchers have designed a monoclonal antibody called dimeric immunoglobulin A (dIgA), which can cross epithelial membranes. Naturally, dIgA is part of the immune system and is released into tears, saliva, and mucus as an early defense mechanism against pathogens. In a 2015 paper, Weimbs and his colleagues proposed that dIgA, by binding to polymeric immunoglobulin receptors on epithelial cells, could move in a one-way direction through the membrane and into kidney cysts. This would allow it to target specific receptors involved in the growth cycle.
The new study builds on this hypothesis and demonstrates the potential of this strategy by targeting the cell mesenchymal-epithelial transition (cMET) receptor, a key driver of cyst development.
Testing the cyst-penetrating antibody
The research team first modified the antibody by altering the IgG DNA sequence to convert it into a dIgA antibody. They confirmed that the redesigned protein could recognize the intended receptor and then tested it in mouse models. The antibody successfully entered the cysts and remained there, without any noticeable harmful effects on healthy renal tissue.
"The next step was to determine if the antibody could block the growth factor receptor," Weimbs said. Their findings showed a decrease in the activity of the cMET receptor, reducing the signals that encourage cell growth. Additionally, the treatment triggered a significant onset of apoptosis (cell death) in cyst epithelial cells.
Looking towards the future
While the research is still in the preclinical stage, Weimbs emphasizes that there is still a long way to go before this approach can be adapted for human treatment. The researchers face challenges such as finding partners interested in PKD therapies, accessing the technology to generate more antibody variants, and identifying additional biological targets for similar strategies.
"There are numerous growth factors active in cyst fluids, as shown in the literature," Weimbs said. "Comparing the blocking of different growth factors and receptors could help us determine the most effective approach and potentially achieve disease slowing or reversal. We can also explore combining different antibodies against various receptors simultaneously. This is the exciting path we are embarking on."
The research team included Margaret F. Schimmel (lead author), Bryan C. Bourgeois, Alison K. Spindt, Sage A. Patel, Tiffany Chin, Gavin E. Cornick, and Yuqi Lu, all from UCSB.
