More MS news articles for June 2002

Anti-CD3 Monoclonal Antibody Slows New-Onset Type 1 Diabetes

http://www.medscape.com/viewarticle/434288

May 30, 2002
Laurie Barclay, MD
Reviewed by Gary D. Vogin, MD
Laurie Barclay, is a staff writer with WebMD.
MedscapeWire is edited by Deborah Flapan, an associate editor at Medscape.

When it comes to controlling type 1 diabetes mellitus, there's bad news and good news in the May 30 issue of the New England Journal of Medicine. The bad news is that the long-awaited results of the first part of the Diabetes Prevention Trial (DPT-1) are disappointing: injected insulin does not delay or prevent type 1 diabetes for those at risk, although trials with oral insulin are still ongoing.

But the good news offers hope of a new treatment frontier: attacking the immune origins of the disease to halt progression rather than just control symptoms. Humanized anti-CD3 monoclonal antibody given over 14 days within 6 weeks of diagnosis maintained or improved insulin production for 1 year in 9 of 12 diabetics.

"The most important implication of this research is that we can intervene in type 1 diabetes after onset and still have an impact," senior author Jeffrey Bluestone, director of the UCSF Diabetes Center, tells WebMD. "This opens up the door to a whole host of other approaches, not just this drug."

Bluestone has filed a patent application for this monoclonal antibody and has a commercial agreement regarding its use with Centocor and Johnson & Johnson Pharmaceuticals. "By targeting specific T cells mediating autoimmunity, this drug can modulate the disease by preserving islet cell function," he says. "This brings us one step closer to treating the disease before symptom onset or even before clinical diagnosis, if we can identify those at risk."

In this phase I/II clinical trial, 24 patients, aged 7 to 30 years, were randomized to receive daily injections of the anti-CD3 antibody for 2 weeks or not to receive antibody. There were no severe adverse effects, and the most common adverse effects were fever, rash, and anemia.

During 1 year of follow-up, 9 of 12 treated patients had maintained or improved insulin secretion and improvement in clinical signs and symptoms (P=.01), compared with 2 of 12 controls. Insulin requirements and glycated hemoglobin levels were lower in the treated patients. Patients who responded clinically also had a change in the ratio of CD4+ T cells to CD8+ T cells 30 and 90 days after treatment.

"The significance of the study is that treatment with the anti-CD3 antibody preserved insulin production in patients with new onset type 1 diabetes," lead author Kevan C. Herold, MD, an associate professor of clinical medicine at Columbia University College of Physicians and Surgeons, New York, tells WebMD. "People with type 1 diabetes eventually lose their ability to make insulin entirely, and preservation of any insulin production has a very significant impact on the ability to manage the disease."

In an accompanying editorial, Edwin A. M. Gale, MD, from the University of Bristol, England, notes study limitations including small sample size, short duration of follow-up, nonblinded design, and no standardization of glycemic control. Phase II studies are now underway to address these issues.

Gale tells WebMD that the new treatment is unlikely to avoid the need for insulin, even if all available beta cells are protected. Still, he points out that "practically nothing else" works after onset of diabetes, and that a single course of treatment "seems able to re-educate the immune system permanently."

Despite traditional wisdom that only 10% of pancreatic beta cells are still viable at diagnosis of type 1 diabetes, Gale says that the number of viable cells is difficult to estimate and may vary considerably.

"The rationale is to protect sufficient endogenous beta cells to top up externally administered insulin, and there is very good evidence that the benefits of continued insulin secretion will extend over many years, allowing better control with less hypoglycemia," he says. Strict metabolic control leads to fewer complications such as vascular, eye, and renal disease.

The anti-CD3 antibody, a humanized monoclonal antibody known as hOKT31(Ala-Ala), is a mouse-human hybrid antibody that selectively and rapidly targets beta-cell specific T-lymphocytes. It is less toxic than other OKT3 monoclonal antibodies because it does not activate aggressive inflammatory cytokines causing nausea, headache, hypertension, and even cardiac problems.

"Although broad spectrum immune suppressive agents can also help to preserve insulin production, their toxicity precludes use in children, especially, in which chronic immune suppression would be substituted for insulin," Herold says.

Further testing and development of the new therapy is planned in a multicenter clinical trial of more than 80 patients, using a multiple-dose regimen designed to amplify the effects of the drug in a fashion analogous to the repeated administration of vaccines. Additional trials are under way in conjunction with islet transplantation for type 1 diabetes and for treatment of psoriatic arthritis.

"If we get more conclusive evidence that [the anti-CD3 antibody] can produce lasting benefit after diagnosis, it might be feasible to use it before diagnosis, as attempted in the unsuccessful DPT-1 study," Gale says.

N Engl J Med. 2002;316(22):1692-1698, 1740-1741
 

© 2002 Medscape