title: A single course of anti-CD3 monoclonal antibody hOKT3gamma1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes.
abstract: Despite advances in understanding autoimmune diabetes in animal models, there has been little progress in altering the natural course of the human disease, which involves progression to insulin deficiency. Studies with immunosuppressive agents have shown short-term effectiveness, but they have not induced tolerance, and continuous treatment is needed. We studied the effects of hOKT3gamma1(Ala-Ala), a humanized Fc mutated anti-CD3 monoclonal antibody, on the progression of type 1 diabetes in patients with recent-onset disease in a randomized controlled trial. In general, the drug was well tolerated. A single course of treatment, within the first 6 weeks after diagnosis, preserved C-peptide responses to a mixed meal for 1 year after diagnosis (97 +/- 9.6% of response at study entry in drug-treated patients vs. 53 +/- 7.6% in control subjects, P < 0.01), with significant improvement in C-peptide responses to a mixed meal even 2 years after treatment (P < 0.02). The improved C-peptide responses were accompanied by reduced HbA(1c) and insulin requirements. Clinical responses to drug treatment were predicted by an increase in the relative number of CD8(+) T-cells in the peripheral blood after the lymphocyte count recovered 2 weeks after the last dose of drug. We conclude that treatment with the anti-CD3 monoclonal antibody hOKT3gamma1(Ala-Ala) results in improved C-peptide responses and clinical parameters in type 1 diabetes for at least 2 years in the absence of continued immunosuppressive medications.
authors.affiliation: Associate Professor of Medicine, Columbia University, PH10-105, 630 W. 168th St., New York, NY 10032, USA. kh318@columbia.edu
authors.forename: Kevan C
authors.initials: KC
authors.lastname: Herold
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Gitelman
authors.forename: Umesh
authors.initials: U
authors.lastname: Masharani
authors.forename: William
authors.initials: W
authors.lastname: Hagopian
authors.forename: Brygida
authors.initials: B
authors.lastname: Bisikirska
authors.forename: David
authors.initials: D
authors.lastname: Donaldson
authors.forename: Kristina
authors.initials: K
authors.lastname: Rother
authors.forename: Beverly
authors.initials: B
authors.lastname: Diamond
authors.forename: David M
authors.initials: DM
authors.lastname: Harlan
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Bluestone
mesh_terms: D000293:Adolescent; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D002096:C-Peptide / Q000097:blood; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000627:therapeutic use; D008297:Male; D016853:Muromonab-CD3 / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D002096:C-Peptide; D007004:Hypoglycemic Agents; D007328:Insulin; D016853:Muromonab-CD3; C502540:teplizumab