Monoclonal Antibody in Development Shows Promise for Minimizing Rejection after Islet Cell Transplantation

Researchers are marking another milestone in the long road toward making islet cell transplantation a reality for people with type 1 diabetes, which has long been pursued as a possible cure.

The monoclonal antibody AT-1501 suppresses immune rejection, a traditional limitation in harvesting islet cells from donors and transplanting them into the pancreas of someone with type 1 diabetes. A new study shows that the antibody can do this and, importantly, get over a major hurdle of the last monoclonal antibody to show such promise: blood clotting.

“It’s really very exciting,” said Norma Sue Kenyon, Ph.D., professor of surgery at the Diabetes Research Institute (DRI), chief innovation officer of the Miller School of Medicine and vice provost for innovation at the University of Miami. “AT-1501, which targets the CD154 costimulatory molecule, is upregulated on T cells activated by the transplant, is also anti-inflammatory and prevents the ultimate development of antibodies against the donated cells. So it’s just really proven to be very impactful.”

Dr. Kenyon and colleagues at the Miller School, along with investigators at Duke University studying the antibody in a kidney transplant model, tested AT-1501 and showed the antibody facilitated islet cell and kidney transplant survival, reduced inflammation and did not cause blood clotting. They published their pilot study online August 30 in the journal Science Translational Medicine.

Years ago, the other antibody, known as Hu5c8, was being assessed in other conditions and transplant settings. “Some patients experienced blood clots, and a couple actually died,” Dr. Kenyon said. “So despite the tremendous promise of intervening in this costimulatory pathway, that really just ― boom ― brought things to a halt.”

A Better Risk-Benefit Ratio?

Fast forward to the present, and AT-1501 appears to offer the beneficial immune effects without thromboembolic adverse effects. In the study, Dr. Kenyon and colleagues found that AT-1501-based regimens led to fewer infectious and metabolic complications, and achieved improved islet function compared to conventional immunosuppression.

The investigators also looked at combinations of AT-1501 with commonly used immunosuppressive agents after islet transplantation. The combinations worked well, suggesting that AT-1501 therapy can maintain islet graft function and, because it’s more targeted, avoid over suppression of the immune system.

“The results were great,” Dr. Kenyon said.

These are still early days. But the antibody could offer another advantage over some existing immune suppressing agents. It appears to offer a more durable effect, for example. This means if studies continue to be successful, after islet cell transplantation people with type 1 diabetes may not have to take lifelong immunosuppression.

It is most likely that AT-1501 will be used in combination with one or more conventional immunosuppressants, the authors note, so different aspects of the immune response can be targeted simultaneously.

The ultimate goal is to develop an agent that promotes long-lasting “immune tolerance.”

Personal Dimension to Quest

“At the DRI, our focus is to identify a biological cure for type 1 diabetes, the autoimmune form of diabetes, where your immune system attacks and destroys your insulin-producing cells,” Dr. Kenyon said. “Even though we have improved ways of monitoring and administering insulin, there are still people who have severe low blood sugar reactions that require assistance and complications of diabetes occur.”

For her, the risk is personal. “My own daughter has experienced that,” she said.

Dr. Kenyon acknowledges that the research has been very collaborative. She specifically wanted to thank Camillo Ricordi, M.D., long-term collaborator and former DRI director, for contacting Steven Perrin, Ph.D., CEO of Anelixis, the startup that produced the antibody (now Eledon Pharmaceuticals); Anelixis supplied the antibody and sponsored the research. Eledon is the firm developing AT-1501 (Tegoprubart).

“I would like to shout out the DRI, my lab partner Dr. Dora Berman and our amazing research team, as well as the collaborative environment of the DRI and the support of the Diabetes Research Institute Foundation,” Dr. Kenyon said. “And of course, I’m a long-standing member of the Miller School of Medicine and very proud to be here.”

AT-1501 is now in clinical trials in kidney transplantation and amyotrophic lateral sclerosis (ALS). Dr. Kenyon hopes the clinical trials of AT-1501 in people with diabetes will begin soon. Clinical trials will be needed to demonstrate AT-1501’s efficacy in humans.

Tags: Diabetes Research Institute, Dr. Norma Sue Kenyon, islet cell transplantation, type 1 diabetes