Polycystic kidney disease (PKD) is an inherited disorder in which clusters of fluid-filled cysts gradually develop within the kidneys. As these cysts enlarge and multiply, they damage the surrounding tissue and limit the organs' ability to function. Many people with advanced PKD eventually require dialysis. There is currently no cure.
Researchers at UC Santa Barbara are exploring a new therapeutic direction that aims to reach and disrupt the uncontrolled expansion of these cysts by using carefully designed monoclonal antibodies -- lab-made proteins commonly used in immunotherapy.
"The cysts just keep growing endlessly," said UCSB biologist Thomas Weimbs, senior author of the study published in Cell Reports Medicine. "And we want to stop them. So we need to get a drug into these cysts that will make them stop."
This work received partial support from the National Institutes of Health and the U.S. Department of Defense.
Why Current Treatments Fall Short
Interrupting a runaway process There are several small-molecule drugs that show potential for slowing cyst expansion. However, according to Weimbs, the only approved drug that offers some benefit also brings significant side effects and toxicity to nearby kidney tissue. Therapeutic antibodies grown in the lab can be more selective, but the form most commonly produced today, immunoglobulin G (IgG), is too large to enter the cysts.
"They're very successful for cancer therapy," Weimbs said. "But IgG antibodies never cross the cell layers and they can never make it inside the cysts." This limitation is crucial, he added, because the interior of each cyst -- essentially a sealed chamber lined with epithelial cells -- is the location where disease-driving activity occurs.
"Many of the cyst-lining cells actually make growth factors and they secrete them into the cyst fluid," he explained. "And these growth factors then bind back to the same cells or to neighboring cells and continue to stimulate themselves and each other. It's like a never-ending scheme in which the cells just keep activating themselves and other cells in there. Our premise was that if you block either the growth factor or the receptor for the growth factor, you should be able to stop this constant activation of the cells."
A New Antibody Designed to Enter Kidney Cysts
Enter dimeric immunoglobulin A (dIgA), a monoclonal antibody that can cross epithelial membranes. In nature, dIgA is produced as part of the immune system and is released into tears, saliva and mucus as an early defense against pathogens. In a 2015 paper, Weimbs and colleagues proposed that by binding to polymeric immunoglobulin receptors on epithelial cells, dIgA could move in a one-way direction through the membrane and into kidney cysts, allowing it to reach specific receptors involved in the growth cycle.
The new study builds on that earlier hypothesis and demonstrates that this strategy can work by targeting a key driver of cyst development, the cell mesenchymal-epithelial transition (cMET) receptor.
Testing a Cyst-Penetrating Antibody
The research team first modified the antibody by altering the IgG DNA sequence to "give it a different backbone" that converted it into a dIgA antibody. They then verified that the redesigned protein could recognize the intended receptor and proceeded to test it in mouse models. The antibody successfully entered the cysts and remained there.
"The next question was, could it actually block that particular growth factor receptor," Weimbs said. Their findings showed that activity of the cMET receptor decreased, which reduced the signals that encourage cell growth. In addition, the paper reports that the treatment triggered a "dramatic onset of apoptosis (cell death) in cyst epithelial cells, but not in healthy renal tissue" without any noticeable harmful effects.
Looking Ahead to Future Applications
Because the work is still in the preclinical stage, Weimbs emphasized that it will be some time before this approach can be adapted for human treatment. The researchers now face several challenges, including finding partners interested in PKD therapies, accessing technology needed to generate more antibody variants, and identifying additional biological targets that may be suitable for similar strategies.
"In the literature there are dozens of growth factors that have been shown to be active in these cyst fluids," Weimbs said. "So it would be a good idea to compare blocking of several different growth factors and several receptors, maybe side-by-side to see which is the most effective, and see if we can achieve slowing or reversal of the disease with any one of them. We can also combine different antibodies against different receptors at the same time. That would be the next step."
Research in this paper was also conducted by Margaret F. Schimmel (lead author), Bryan C. Bourgeois, Alison K. Spindt, Sage A. Patel, Tiffany Chin, Gavin E. Cornick and Yuqi Lu at UCSB.
Polycystic kidney disease (PKD) is an inherited disorder in which clusters of fluid-filled cysts gradually develop within the kidneys. As these cysts enlarge and multiply, they damage the surrounding tissue and limit the organs' ability to function. Many people with advanced PKD eventually require dialysis. There is currently no cure.
Researchers at UC Santa Barbara are exploring a new therapeutic direction that aims to reach and disrupt the uncontrolled expansion of these cysts by using carefully designed monoclonal antibodies -- lab-made proteins commonly used in immunotherapy.
"The cysts just keep growing endlessly," said UCSB biologist Thomas Weimbs, senior author of the study published in Cell Reports Medicine. "And we want to stop them. So we need to get a drug into these cysts that will make them stop."
This work received partial support from the National Institutes of Health and the U.S. Department of Defense.
Why Current Treatments Fall Short
Interrupting a runaway process There are several small-molecule drugs that show potential for slowing cyst expansion. However, according to Weimbs, the only approved drug that offers some benefit also brings significant side effects and toxicity to nearby kidney tissue. Therapeutic antibodies grown in the lab can be more selective, but the form most commonly produced today, immunoglobulin G (IgG), is too large to enter the cysts.
"They're very successful for cancer therapy," Weimbs said. "But IgG antibodies never cross the cell layers and they can never make it inside the cysts." This limitation is crucial, he added, because the interior of each cyst -- essentially a sealed chamber lined with epithelial cells -- is the location where disease-driving activity occurs.
"Many of the cyst-lining cells actually make growth factors and they secrete them into the cyst fluid," he explained. "And these growth factors then bind back to the same cells or to neighboring cells and continue to stimulate themselves and each other. It's like a never-ending scheme in which the cells just keep activating themselves and other cells in there. Our premise was that if you block either the growth factor or the receptor for the growth factor, you should be able to stop this constant activation of the cells."
A New Antibody Designed to Enter Kidney Cysts
Enter dimeric immunoglobulin A (dIgA), a monoclonal antibody that can cross epithelial membranes. In nature, dIgA is produced as part of the immune system and is released into tears, saliva and mucus as an early defense against pathogens. In a 2015 paper, Weimbs and colleagues proposed that by binding to polymeric immunoglobulin receptors on epithelial cells, dIgA could move in a one-way direction through the membrane and into kidney cysts, allowing it to reach specific receptors involved in the growth cycle.
The new study builds on that earlier hypothesis and demonstrates that this strategy can work by targeting a key driver of cyst development, the cell mesenchymal-epithelial transition (cMET) receptor.
Testing a Cyst-Penetrating Antibody
The research team first modified the antibody by altering the IgG DNA sequence to "give it a different backbone" that converted it into a dIgA antibody. They then verified that the redesigned protein could recognize the intended receptor and proceeded to test it in mouse models. The antibody successfully entered the cysts and remained there.
"The next question was, could it actually block that particular growth factor receptor," Weimbs said. Their findings showed that activity of the cMET receptor decreased, which reduced the signals that encourage cell growth. In addition, the paper reports that the treatment triggered a "dramatic onset of apoptosis (cell death) in cyst epithelial cells, but not in healthy renal tissue" without any noticeable harmful effects.
Looking Ahead to Future Applications
Because the work is still in the preclinical stage, Weimbs emphasized that it will be some time before this approach can be adapted for human treatment. The researchers now face several challenges, including finding partners interested in PKD therapies, accessing technology needed to generate more antibody variants, and identifying additional biological targets that may be suitable for similar strategies.
"In the literature there are dozens of growth factors that have been shown to be active in these cyst fluids," Weimbs said. "So it would be a good idea to compare blocking of several different growth factors and several receptors, maybe side-by-side to see which is the most effective, and see if we can achieve slowing or reversal of the disease with any one of them. We can also combine different antibodies against different receptors at the same time. That would be the next step."
Research in this paper was also conducted by Margaret F. Schimmel (lead author), Bryan C. Bourgeois, Alison K. Spindt, Sage A. Patel, Tiffany Chin, Gavin E. Cornick and Yuqi Lu at UCSB.
Read more https://www.sciencedaily.com/releases/2025/11/251118220046.htm