Johns Hopkins Medicine scientists have found that a drug called mAb43 may be able to prevent and reverse the onset of clinical type 1 diabetes in mice and even extend their lifespan in some cases. They believe that this experimental monoclonal antibody drug is unique because it directly targets the insulin-producing beta cells in the pancreas and is specifically designed to protect them.The researchers believe that the drug’s ability to target specific cells may allow for long-term use in humans with minimal side effects. Monoclonal antibodies are produced by cloning an animal or human cell line. The discovery, published online and in the May issue of Diabetes, suggests the potential for a new treatment for type 1 diabetes. This autoimmune condition affects approximately 2 million American children and adults and currently has no cure or prevention methods. Unlike type 2 diabetes, where the pancreas produces insufficient insulin, type 1 diabetes is characterized by the immune system attacking the body’s own cells.The pancreas in people with type 1 diabetes does not produce insulin because the immune system attacks the cells responsible for its production. This lack of insulin disrupts the body’s ability to regulate blood sugar levels. Dax Fu, Ph.D., an associate professor of physiology at the Johns Hopkins University School of Medicine, and the research team leader, explains that individuals with type 1 diabetes are required to receive lifelong insulin injections and may experience complications such as stroke and vision problems if the condition is not properly managed. Fu also states that mAb43 targets a specific protein on the surface of beta cells, which are clustered in islets. The drug was specifically designed for this purpose.The researchers have developed a protective shield to hide beta cells from the immune system, which usually attacks them. They used a mouse version of the monoclonal antibody, and plan to create a humanized version for testing in humans.
In their study, the researchers administered a weekly dose of mAb43 through intravenous injection to 64 non-obese mice who were prone to type 1 diabetes. After 35 weeks, all the mice showed no signs of diabetes. Only one mouse developed diabetes temporarily, but it recovered after 35 weeks. This particular mouse already had early signs of diabetes before receiving the antibody.
Researchers delayed giving weekly mAb43 doses to five diabetes-prone mice until they were 14 weeks old, and then continued dosages and monitoring for up to 75 weeks. One of the five mice developed diabetes, but no adverse events were found, according to the researchers.
In the experiments where mAb43 was given early on, the mice lived for the entire 75-week monitoring period, compared to the control group of mice that did not receive the drug and lived approximately 18-40 weeks.
Following this, the researchers, including postdoctoral fellows Devi Kasinathan and Zheng Guo, lUpon further examination of the mice that were administered mAb43, the researchers utilized a biological marker known as Ki67 to determine whether beta cells were undergoing replication in the pancreas. They observed that after treatment with the antibody, immune cells withdrew from the beta cells, leading to a decrease in inflammation in that area. Additionally, the beta cells began to slowly regenerate.
Kasinathan stated, “The combination of mAb43 and insulin therapy has the potential to gradually reduce the need for insulin as beta cells regenerate, ultimately eliminating the necessity for insulin supplementation to control blood sugar levels.”
The study team discovered that mAb43 specifically targeted beta cells, which could potentially have a positive impact on the regeneration process.About 1% to 2% of pancreatic cells are made up of beta cells.
In 2022, the U.S. Food and Drug Administration approved teplizumab, a monoclonal antibody drug. Teplizumab works by binding to T cells, reducing their harmful effects on insulin-producing beta cells. Studies have demonstrated that the drug can delay the onset of stage 3 type 1 diabetes by approximately two years. This delay provides young children diagnosed with the disease with the opportunity to mature and learn how to manage lifelong insulin injections and dietary restrictions.
“It is possible that mAb43 could have a longer duration of use compared to teplizumab and potentially delay the onset of diabetes for a much longer period of time, potentially leading to the prevention of the disease altogether.
“As long as it’s administered, the antibody shows promise,” says Fu.
“We are working on creating a more human-like version of the antibody and conducting clinical trials to test its effectiveness in preventing type 1 diabetes, and to determine if it has any unintended side effects,” says Guo.
Other researchers involved in the study are Dylan Sarver, G. William Wong, and Maria Golson from Johns Hopkins; Shumei Yun from the University of Maryland, Aaron Michels and Liping Yu from the University of Colorado; and Chandan Sona and Matthew Poy from Johns Hopkins All Children’s Hospital.
The research was partially funded by the National Institutes of Health.The following research studies were supported by National Institutes of Health (R01DK125746, P30DK116073, R01DK110183, R01 DK135688 and RO1DK084171).
Journal Reference:
- Devi Kasinathan, Zheng Guo, Dylan C. Sarver, G. William Wong, Shumei Yun, Aaron W. Michels, Liping Yu, Chandan Sona, Matthew N. Poy, Maria L. Golson, Dax Fu. Cell-Surface ZnT8 Antibody Prevents and Reverses Autoimmune Diabetes in Mice. Diabetes, 2024; 73 (5): 806 DOI: 10.2337/db23-0568
