An investigational antibody could reduce the toxicity associated with immune suppression in islet cell transplantation for type 1 diabetes (T1D), according to new preliminary data. 

Six people with T1D who received intravenous infusions of the investigational anti-CD40 ligand antibody tegoprubart every 3 weeks, as part of their immunosuppressive regimen following cadaveric islet transplants, achieved insulin independence. The first three patients have remained off insulin for over a year, including one with an A1c of 4.7% at 15 months. Only one patient required a second transplant and has since maintained an A1c of 5.3% without insulin. None of the patients experienced the severe toxicities often associated with traditional immunosuppressive regimens. 

The findings were presented at the Rachmiel Levine-Arthur Riggs Diabetes Research Symposium in Los Angeles, California.

A Novel Tacrolimus Replacement 

Currently, islet transplantation for T1D — whether using cadaveric donor islets or stem cell-derived islets — is limited to patients with frequent severe hypoglycemia or hypoglycemia unawareness. A major barrier to broader use is the toxicity of standard immunosuppressive regimens used for most organ transplants, which typically include a calcineurin inhibitor (now tacrolimus, previously cyclosporine), an antiproliferative agent (such as mycophenolate mofetil or mycophenolic acid), and a corticosteroid (such as prednisone or methylprednisolone).

Replacing tacrolimus with tegoprubart reduces overall immunosuppressive toxicity, said investigator Piotr Witkowski, MD, PhD, director of the Pancreas and Islet Transplant Program at UChicago Medicine in Chicago.

Tacrolimus is the strongest and best medication to prevent rejection and the standard of care in organ transplantation, Witkowski told Medscape Medical News. “However, at the dose needed to protect organs from rejection, it’s toxic to the kidney and the islets. It causes hand tremors, headaches, high blood pressure, and also diabetes.”

In contrast, none of the six patients receiving tegoprubart experienced severe hypoglycemia, serious infections, thromboembolic events, rejection, or kidney or neurologic toxicity following transplantation.

“We have six patients doing so well,” Witkowski said. “The islets are working better because there is less toxicity from tacrolimus.”

He added that managing patients on tacrolimus requires frequent check-ins and laboratory monitoring, with dose adjustments to balance side effects and islet function. 

“Here, there is nothing to adjust, and patients feel great,” he said. “It’s like night and day.”

Although the current study uses cadaveric donor islets, Witkowski said that tegoprubart could be used in the future with islets derived from stem cells, provided ongoing studies in that area are successful. 

‘An Exciting Step,’ but Will It Hold Up?

Commenting on the findings, Jordan Wright, MD, PhD, assistant professor of medicine in the Division of Diabetes, Endocrinology, and Metabolism at Vanderbilt University Medical Center, Nashville, Tennessee, said broader use of islet transplantation remains constrained by the need for ongoing immunosuppression.

“An ideal regimen would be targeted, have minimal effect on other immune functions, and would not be toxic to the transplanted cells or other cell types,” Wright told Medscape Medical News. “These early results in humans are an exciting step in that direction." 

However, Wright cautioned that the findings are preliminary and based on a small number of patients.

“It will be critical to see whether these results hold up over longer-term follow-up, and whether the encouraging safety and efficacy results are seen in larger, diverse patient populations,” he said.

Another expert, Kevan Herold, MD, C.N.H. Long Professor of Immunobiology and Medicine (Endocrinology) at Yale School of Medicine in New Haven, Connecticut, expressed support for the approach.

“I have been very enthusiastic about anti-CD40L antibodies since the first studies in islet transplantation,” Herold told Medscape Medical News. “I do think it would be a better alternative than tacrolimus, mostly because it’s specific in the immune pathway that is targeted.”

Upcoming Analyses

This ongoing current phase 1/2 study is funded by Breakthrough T1D. Since Witkowski presented the data on the first six patients at the November conference, a seventh patient has undergone transplantation, with the next five additional procedures planned. 

Breakthrough T1D has also funded a second study of tegoprubart at the University of Chicago and the University of Miami. The trial will enroll patients with T1D and severe hypoglycemia or hypoglycemia unawareness who also have kidney dysfunction but not failure. Currently, such patients are ineligible for transplantation due to tacrolimus-related nephrotoxicity.

Wright noted that other innovative approaches, including genetic modification of transplanted cells, are also showing promise.

“It’s a very exciting time in islet transplantation,” he said. “We’re seeing accelerating successes on multiple fronts in these studies.”

Eledon Pharmaceuticals, which manufactures tegoprubart, is currently sponsoring trials in kidney transplantation, but not in islet transplantation. Meanwhile, other companies are developing CD40 ligand inhibitors. Sanofi, for example, is conducting trials of frexalimab in several immune-mediated conditions, including multiple sclerosis (in phase 3) and systemic lupus erythematosus (phase 2), as well as a phase 2 trial in new-onset T1D for islet cell preservation.

Witkowski is a consultant for Dompé, Vertex, Sernova, and Eledon. Wright reported no disclosures. Herold is a consultant for Sanofi. 

Miriam E. Tucker is a freelance journalist based in the Washington DC area. She is a regular contributor to Medscape Medical News, with other work appearing in The Washington Post, NPR’s Shots blog, and Diatribe. She is on X @MiriamETucker and BlueSky @miriametucker.bsky.social.