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Scientists at the Johns Hopkins School of Medicine say an experimental monoclonal antibody drug called mAb43 appears to prevent and reverse the onset of clinical type 1 diabetes in mice and, in some cases, extend the animals' lifespans. There is.
Researchers say the drug is unique because it is designed to directly target insulin-producing beta cells in the pancreas, protecting them from attack by the body's own immune system cells. The drug's specificity for these cells could allow long-term use in humans with few side effects, the researchers said. Monoclonal antibodies are created by cloning or creating identical replicas of animal (including human) cell lines.
The findings were recently reported online and in the May issue of the journal. Diabetesraises the possibility of a new drug for type 1 diabetes, an autoimmune disease that affects approximately. 2 million Americans It affects children and adults alike, and there is no cure or preventive measure. Unlike type 2 diabetes, where the pancreas produces too little insulin, in type 1 diabetes, the pancreas does not produce insulin because the immune system attacks the pancreatic cells that produce insulin.
A lack of insulin interferes with the body's ability to regulate blood sugar levels.
“In addition to lifelong insulin injections, people with type 1 diabetes face many complications, including stroke and vision loss, if not properly managed,” said Dr. Dax Fu, associate professor of physiology at Johns Hopkins University School of Medicine. says. and the research team leader.
Fu said mAb43 binds to a small protein on the surface of beta cells in clusters called pancreatic islets. The drug was designed to provide a kind of shield or cloak to hide beta cells from immune system cells that attack them as “invaders.” The researchers used a mouse version of the monoclonal antibody, but human studies will require developing a humanized version.
In the current study, the researchers administered mAb43 intravenously once a week at 10 weeks of age to 64 non-obese mice that had been bred to develop type 1 diabetes. After 35 weeks, all mice were no longer diabetic. One of the mice briefly developed diabetes, but recovered by week 35, and the mouse had early signs of diabetes before the antibody was administered.
The researchers withheld weekly doses of mAb43 from five mice susceptible to the same type of diabetes until they were 14 weeks old, then continued treatment and monitoring for up to 75 weeks. Researchers said one in five people in the group developed diabetes, but no adverse events were found.
In experiments in which mAb43 was administered early, mice survived the 75-week monitoring period, whereas mice in the control group, which did not receive the drug, survived for approximately 18 to 40 weeks.
The researchers, including postdoctoral fellows Devi Kasinathan and Zheng Guo, then looked more closely at the mice given mAb43 and used a biological marker called Ki67 to detect beta cell proliferation in the pancreas. I checked to see if it was. They said that after treatment with the antibody, immune cells retreated from the beta cells and the amount of inflammation in the area decreased. In addition, beta cells slowly began to regenerate.
“Combining mAb43 with insulin therapy has the potential to gradually reduce insulin use while beta cells regenerate, ultimately eliminating the need to use insulin replacement for blood sugar control,” Kasinathan said. says.
The research team found that mAb43 specifically binds to beta cells, which make up about 1% or 2% of pancreatic cells.
Teplizumab, another monoclonal antibody drug, was approved by the U.S. Food and Drug Administration in 2022. Teplizumab binds to her T cells and reduces the harm of her T cells to insulin-producing beta cells. The drug has been shown to delay the onset of clinical (stage 3) type 1 diabetes by about two years, allowing young children with the disease to grow up and manage lifelong insulin injections and dietary restrictions. It gives you time to learn.
“mAb43 can be used for a longer period of time than teplizumab and may delay the onset of diabetes for a longer period of time, and in some cases for as long as it is administered,” Fu said.
“As a continuing effort, we aim to develop a humanized version of the antibody and conduct clinical trials to test its ability to prevent type 1 diabetes and to learn if there are off-target side effects. ,” Guo said.
Other scientists who contributed to the study include Dylan Thurber, G. William Wong, and Maria Golson of Johns Hopkins. Shumei Yun from the University of Maryland, and Aaron Michels and Liping Yu from the University of Colorado. Chandan Sona and Matthew Poi of Johns Hopkins All Children's Hospital;
Research funding was provided in part by the National Institutes of Health (R01DK125746, P30DK116073, R01DK110183, R01 DK135688, and RO1DK084171).
DOI: doi.org/10.2337/db23-0568
