Antibodies Counter Diabetes

Transplant surgeon Takashi Maki once put people with diabetes under the knife. Then and now, some diabetic patients get a new pancreas, full of insulin-producing cells, to replace similar cells that their bodies have destroyed. While pancreas transplantation is still used in some cases of type 1 diabetes, it’s neither widely available nor consistently successful, says Maki.

The Harvard Medical School researcher no longer operates on diabetic patients, but he has high expectations for a drug that he previously gave them after transplants. That drug, made up of immune-suppressing antibodies, discourages rejection of transplanted organs. Such antibodies, it turns out, may on their own stall the runaway autoimmunity that is the core cause of type 1 diabetes. That, in turn, could preserve some of a person’s capacity to produce insulin.

Several groups of scientists are now studying whether a few days or weeks of antibody therapy, if given soon after diagnosis of type 1 diabetes, can keep the disease from worsening.

Moreover, a group led by Jay S. Skyler of the University of Miami in Florida is preparing to test antibody therapy for prevention of diabetes in young, outwardly healthy people who show signs that their immune systems are gearing up for an attack on the pancreas.

“The goal is to stop the destructive process [and] to preserve pancreas function,” says Skyler.

Until this year, most evidence that antibody therapy might work came from laboratory studies in animals. Two reports issued in recent months, however, indicate that short-term antibody therapy can preserve some pancreatic function in diabetic patients for at least 18 months.

That doesn’t mean that a cure for type 1 diabetes is at hand. But by impeding progression of the disease, researchers have turned a corner toward that objective. Antibody therapy, in combination with early detection of autoimmunity and use of pancreas-regenerating drugs, might prevent or reverse a lifelong condition that now affects more than 1 million people in the United States.

Insulin insufficient

In healthy people, the pancreas contains clusters of cells, called beta cells, that generate the hormone insulin. The body depends on insulin to control its use of glucose, the carbohydrate that fuels most metabolic processes.

In type 1 diabetes, a person’s immune cells attack and eventually wipe out all the beta cells. Left with no means of producing the hormone, the diabetic person becomes permanently reliant on injected insulin. In contrast, people with type 2 diabetes retain beta cells, but other cells lose sensitivity to insulin. Even with insulin therapy, type 1 diabetes is far from a benign disorder. People must constantly watch what they eat and must time their use of insulin to maintain a stable concentration of glucose in their blood. The annual cost of insulin and various other expenses adds up to more than $10,000 per diabetic person.

Furthermore, these patients face elevated risks of blindness, kidney failure, leg problems that lead to amputation, and severe cardiovascular problems. Life expectancy can be as much as 15 years shorter than that of people without the disease.

The attack on the pancreas builds gradually. A child’s blood often shows signs of autoimmune activity several years before beta cells begin to die. For a year or two after symptoms appear, some beta cells persist. The delay between detectable autoimmune activity and the death of the last beta cells represents an opportunity—but one that’s been difficult to exploit.

For example, studies in rodents and a few people in the 1980s and 1990s suggested that insulin, given before diabetes developed, might desensitize the immune system to the hormone and the beta cells that make it—and thus protect the pancreas. Skyler and other members of a research collaboration screened some 100,000 relatives of people with type 1 diabetes and identified more than 700 children and young adults who appeared to be at high risk of developing the disease. About a quarter of that group was given twice-daily injections of insulin, but that treatment didn’t delay development of diabetes, Skyler’s team reported in 2002.

The researchers had members of another quarter of that group swallow a daily capsule of insulin. Again, the odds of a participant developing diabetes over several years didn’t drop. The collaboration, known as the Type 1 Diabetes TrialNet, reported these disappointing findings in the May Diabetes Care.

In other clinical trials, immune-suppressing agents such as the drug cyclosporine have blunted the autoimmune attack on beleaguered beta cells. But those drugs also disable protective aspects of the immune system, leaving patients vulnerable to infection and cancer. Furthermore, as soon as the drugs’ use is suspended, the immune system again attacks the pancreas.

If they took the drugs indefinitely, “patients wouldn’t get diabetes, but they would die after several years from immune suppression,” says Matthias von Herrath of the La Jolla (Calif.) Institute for Allergy and Immunology. Transplant patients also face increased risk of cancers and fatal infections.

Short-term diabetes treatment that achieves lasting immune suppression could overcome that problem, von Herrath says.

Hit and run

In the 1990s, researchers doing experiments on rodents made strides toward short-term therapies that can combat autoimmunity. Kevan C. Herold of Columbia University and his colleagues found that they could prevent diabetes in mice by administering many copies of a monoclonal antibody.

A monoclonal antibody is a particle that latches on to a specified protein, for example, a receptor on the surface of certain immune cells. Once flagged with the antibody, those cells fall in the crosshairs of other immune cells. That’s how monoclonal antibodies—as well as polyclonal antibodies, which target multiple surface proteins—can knock out some immune cells to prevent rejection of transplanted tissues.

Herold focused on CD3, a surface protein on the immune cells that make trouble in type 1 diabetes. His collaborator Jeffrey Bluestone of the University of California, San Francisco developed one monoclonal antibody, called hOKT3g1 (Ala-Ala), that targets CD3.

In 2002, Herold and his colleagues issued a preliminary report on 12 people, ages 7 to 30, who had received hOKT3g1(Ala-Ala). Shortly after being diagnosed with type 1 diabetes, the volunteers got daily injections of the antibody for about 2 weeks. At that time, all the study participants still had some cells that produced insulin.

A year after treatment, nine of the patients produced insulin at least as readily as they had at the beginning of the study. In people not getting the therapy, only 2 of 12 patients had maintained or increased insulin production (SN: 6/1/02, p. 339: Revised Immunity: Drug slows diabetes in young patients).

Herold’s team ultimately treated 42 people, half of whom received monoclonal antibodies. During the second half of the 2-year study, most participants lost at least some insulin-making capability, indicating that the treatment didn’t provide a permanent fix.

Nevertheless, recipients of the antibodies fared better than the other people in the study, Herold and his colleagues reported in the June Diabetes. At the end of the second year, members of the former group produced more natural insulin and used about 30 percent less synthetic insulin than did those who received no antibodies.

Anti-CD3 therapy, Herold says, “seems to diminish the loss of insulin secretion that occurs after the onset of type 1 diabetes.” Most important, he says, is that because the monoclonal antibody was given to the patients for only about 2 weeks, they weren’t exposed to the risks of long-term immune suppression.

A separate study bolsters researchers’ optimism. A team led by Lucienne Chatenoud of Hôpital Necker in Paris developed a different CD3-targeting monoclonal antibody that prevented diabetes in mice. The agent even reversed the disease in mice after the pancreas came under attack.

The researchers subsequently modified that monoclonal antibody into the experimental drug ChAglyCD3, which is safer for people.

In the June 23 New England Journal of Medicine, Chatenoud, her French colleagues, and her collaborators in Belgium, England, and Germany reported success with ChAglyCD3 in a study of 80 volunteers who had recently been diagnosed with type 1 diabetes. The European researchers gave half of the patients a daily intravenous infusion of the monoclonal antibody for 6 days. To the rest, they gave sham infusions.

For at least the 18 months of the study, the volunteers who had received the antibody treatment maintained their insulin production more effectively than did those who received the placebo.

Anti-CD3 therapy “looks like an extremely promising approach,” says Skyler, who wasn’t involved in either the U.S. or the European trial. “These are very early days,” he cautions, but if larger studies confirm the recent findings, anti-CD3 antibodies could become important drugs for people who have just developed type 1 diabetes.

The same therapy might also ambush diabetes before it starts. The TrialNet group plans to test anti-CD3 therapy in people with early signs of autoimmune activity. Says Skyler, “The anti-CD3 trial in prevention is one of our highest priorities.”

Headaches ahead

The recent findings, while encouraging, highlight several challenges in store for researchers. For one thing, most trial volunteers who received monoclonal antibodies experienced unpleasant side effects. In the European study, nearly all such patients developed headaches, joint and muscle pain, fever, and gastrointestinal symptoms during or shortly after the 6 days of treatment. Soon afterward, three-quarters of the patients developed rashes, and a similar fraction got sore throats.

“It’s like they had mono,” comments Herold. Mononucleosis can result when Epstein-Barr virus becomes active in a person. Most people carry the virus, but it typically remains dormant. Immune suppression can reactivate it. Immunological data indicate that, unsurprisingly, latent Epstein-Barr infections reactivated in many of the participants.

In the U.S. study, most volunteers developed headaches and a rash within the first week of antibody treatment, and some experienced fever, muscle aches, and other symptoms. Overall, however, fewer side effects cropped up in that trial, where the antibody doses were lower than in the European one, Herold says.

The impermanence of the antibodies’ effects is another problem. “We’re now recruiting for a trial where we’re going to give the drug twice, to prolong the clinical effect,” says Herold.

But immunologist von Herrath suspects that subsequent rounds of an antibody won’t be as effective as the first one. To overcome the pitfalls, a monoclonal antibody might need to be administered along with other drugs with various effects, von Herrath and David M. Harlan of the National Institutes of Health in Bethesda, Md., suggest in the July Nature Medicine.

“No one knows the right dose” of the monoclonal antibodies, says Herold. He and other researchers are planning a separate trial to test a polyclonal antibody that is commonly used for immune suppression in organ transplantation. Antithymocyte globulin targets CD3 and other cellular proteins, and tests of diabetic mice have suggested that it reverses the disease. Widespread experience with the agent has enabled physicians to calibrate the dose for patients and reduce toxicity.

Regeneration

Other approaches could also complement antibody therapy. Maki and his colleagues recently found that an animal form of antithymocyte globulin reversed diabetes in mice more effectively when they added the drug exendin-4 to the treatment. A short course of both drugs cured 23 of 26 animals, the researchers reported in the July 2004 Diabetes.

While a mono- or polyclonal antibody holds the immune system at bay, Maki proposes, exendin-4 “has the ability to augment or enhance beta-cell regeneration.” Maki and his colleagues propose that exendin-4 sustains dormant and immature beta cells, enabling them to proliferate once the autoimmune process is halted.

For patients who’ve lost all their beta cells, however, there’s nothing for antibodies to salvage, he says. Those patients will continue to depend on insulin—or on Maki’s original calling, transplant surgery.