Anti-CD3 Monoclonal Antibody in New-Onset Type 1 Diabetes Mellitus.
Herold, Kevan C.; Hagopian, William; Auger, Julie A.; Poumian-Ruiz, Ena; Taylor, Lesley; Donaldson, David; Gitelman, Stephen E.; Harlan, David M.; Xu, Danlin; Zivin, Robert A.; Bluestone, Jeffrey A.
[Article]
New England Journal of Medicine.
346(22):1692-1698, May 30, 2002.
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Background: Type 1 diabetes mellitus is a chronic autoimmune disease caused by the pathogenic action of T lymphocytes on insulin-producing beta cells. Previous clinical studies have shown that continuous immune suppression temporarily slows the loss of insulin production. Preclinical studies suggested that a monoclonal antibody against CD3 could reverse hyperglycemia at presentation and induce tolerance to recurrent disease.
Methods: We studied the effects of a nonactivating humanized monoclonal antibody against CD3 - hOKT3(gamma)1(Ala-Ala) - on the loss of insulin production in patients with type 1 diabetes mellitus. Within 6 weeks after diagnosis, 24 patients were randomly assigned to receive either a single 14-day course of treatment with the monoclonal antibody or no antibody and were studied during the first year of disease.
Results: Treatment with the monoclonal antibody maintained or improved insulin production after one year in 9 of the 12 patients in the treatment group, whereas only 2 of the 12 controls had a sustained response (P=0.01). The treatment effect on insulin responses lasted for at least 12 months after diagnosis. Glycosylated hemoglobin levels and insulin doses were also reduced in the monoclonal-antibody group. No severe side effects occurred, and the most common side effects were fever, rash, and anemia. Clinical responses were associated with a change in the ratio of CD4 T cells to CD8 T cells 30 and 90 days after treatment.
Conclusions: Treatment with hOKT3(gamma)1(Ala-Ala) mitigates the deterioration in insulin production and improves metabolic control during the first year of type 1 diabetes mellitus in the majority of patients. The mechanism of action of the anti-CD3 monoclonal antibody may involve direct effects on pathogenic T cells, the induction of populations of regulatory cells, or both. (N Engl J Med 2002;346:1692-8)
Owned, published, and (C) copyrighted, 2002, by the MASSACHUSETTS MEDICAL SOCIETY