Eric Wang, Senior Photographer

Teplizumab, a drug that delays type 1 diabetes, recently became the first drug to delay an autoimmune disease approved by the FDA. A Yale professor played a crucial role in its development. 

Kevan Herold, C.N.H. Long Professor of Immunobiology and of Medicine at the Yale School of Medicine, led the clinical trials for the drug’s development over the past thirty years. Teplizumab’s approval provides a new frontier regarding the diagnosis and treatment of diabetes and paves the way for future work in disease prevention.

The drug was found to delay the development of type 1 diabetes for a median of 2 years. 

“If you’re 8 years old and you are not going to get diabetes for two years [because of teplizumab treatment], that’s a big deal, because now you are going to be 10 years old when you develop diabetes, and hopefully a ten-year-old is a little more mature than an 8-year-old,” Herold said. “Same thing if you are about to go into middle school, you are not going to get diabetes until you are in high school, or even after high school … [diabetes’] absence, even for a day, is a gift.”

Type 1 diabetes is an autoimmune disease where your body destroys the cells of the pancreas that secrete insulin. Insulin is a hormone that signals cells to uptake sugar that can be used for energy. When the insulin-secreting cells are destroyed, the sugar in the bloodstream cannot be absorbed. Approximately 1.9 million Americans have type 1 diabetes according to the American Diabetes Association. The treatment is insulin injections, which can be extremely costly.

Teplizumab, sold under the brand name Tzield, is a monoclonal antibody, a type of antibody manufactured by cloning a white blood cell that was exposed to a target protein. Teplizumab targets the epsilon chain, which is part of the CD3 receptor protein complex. The CD3 complex is a component of the T-cell membrane responsible for recognizing the respective targets of that T-cell, which is a type of immune cell. 

The exact mechanism of the reaction between teplizumab and the epsilоn chain is not certain, but Herоld and his colleagues expect that teplizumab sends a signal to the T-cell by binding to the eрsilon chain. This signal is thought to partially or wholly deactivate the T-cells responsible for destroying the pancreatic cells that produce insulin in patients with type 1 diabetes.

Even after teplizumab treatment, the effectiveness of the immune system will not be impeded, Herold explained. The signal created when the CD3 complex encounters a viral antigen is much stronger than the signal from teplizumab reception. 

“If you look at the long-term safety profile of people [in trials] who have been treated with the drug, there is no evidence of an infectious disease risk,” Herold said.

Herold predicts that the strength of the signal given by teplizumab lies somewhere between that of the antigen signal and the autoimmune signal. This prevents the T-cells from destroying beneficial tissues while allowing them to retain their efficacy in combating viruses. 

While the development and approval of teplizumab have been a long process, Herold has been“very interested in using immunotherapies to change the course of autoimmune disease, specifically diabetes” since the beginning.

The median age of participants in the teplizumab trials is 13 to 14; however, many different ages were included in the trials. Participants were not yet diagnosed with diabetes before their participation in the trial and were identified by their familial relationship to someone with type 1 diabetes, Herold explained. They were then screened for typical immune markers of type 1 diabetes, and if it was determined they were at risk for the disease’s development, they were administered teplizumab over the course of two weeks and the progression of the disease was monitored in the years after.

The clinical trials found that, compared to a placebo group, the development of type 1 diabetes was delayed a median of 2 years in participants who received teplizumab. However, some patients had delays significantly longer than that. One patient even experienced an 11-year delay of type 1 diabetes development.

“We are very keen to understand what’s the difference between those [patients] that have long responses and those that have these short responses, and how we convert those short responses to long responses,” Herold said, explaining that this will be a primary focus of future research.

Herold explained that while two years may not seem like a significant delay, this extra time disease-free is valuable.

For example, there would be more time for research in the field of type 1 diabetes treatment to advance. Herold explained that the way we treat and diagnose diabetes now is different compared to how it was just three years ago. 

“Dr. Herold and his colleagues have spent years working to understand how a person’s own immune system can destroy the beta (or insulin-producing) cells in the pancreas, leading to type 1 diabetes. That work led to trials of teplizumab, ” Nancy Brown, Dean of the Yale School of Medicine, told the News. “To make discoveries that transform lives and health, that is what faculty at YSM aspire to do.”

On Nov. 17, the FDA approved teplizumab for use as a treatment to delay type 1 diabetes in those aged 8 and older. This approval means that it is appropriate to start screening patients for type 1 diabetes with the intent of administering the teplizumab treatment. 

Herold explained that the patients identified to undergo the treatment should eventually extend to the general public, not just those identified on the basis of having relatives with type 1 diabetes. This is especially important, given that most people who develop type 1 diabetes do not have a familial history of the disease, according to Herold.

“That’s a new frontier, screening even in the general population for a disease that you can prevent, not just coming in afterward,” Herold said. “I think that that is a new exciting area of medical investigation.”

Trialnet is an international network of scientists dedicated to type 1 diabetes research. Yale is one of twenty-two Type 1 Diabetes TrialNet International Clinical Centers at the forefront of type 1 diabetes research. Jennifer Sherr, principal investigator of the TrialNet site at Yale and professor of pediatrics at the Yale School of Medicine, talked about the importance of teplizumab’s development.

“[The development of teplizumab] opens the door to prioritize development of new therapies for slowing and stopping T1D and moves us one step closer to TrialNet’s ultimate goal: a future without T1D,” Sherr wrote. “While TrialNet does not have any studies of teplizumab currently underway, we will build on the success of the Teplizumab Prevention Study by continuing to find new ways to slow and eventually stop T1D.”

Herold was the third person to hold the position of TrialNet Chair.