A Single Course of Anti-CD3 Monoclonal Antibody hOKT3γ1(Ala-Ala) Results in Improvement in C-Peptide Responses and Clinical Parameters for at Least 2 Years after Onset of Type 1 Diabetes

A Single Course of Anti-CD3 Monoclonal Antibody hOKT3γ1(Ala-Ala) Results in Improvement in C-Peptide Responses and Clinical Parameters for at Least 2 Years after Onset of Type 1 Diabetes Kevan C. Herold 1 , Stephen E. Gitelman 2 , Umesh Masharani 2 , William Hagopian 3 , Brygida Bisikirska 1 , David Donaldson 4 , Kristina Rother 5 , Beverly Diamond 1 , David M. Harlan 5 and Jeffrey A. Bluestone 2 1 Department of Medicine, Division of Endocrinology and the Naomi Berrie Diabetes Center, College of Physicians and Surgeons, Columbia University, New York, New York 2 Diabetes Center, University of California at San Francisco, San Francisco, California 3 Pacific Northwest Research Institute, Seattle, Washington 4 Department of Pediatrics, University of Utah, Salt Lake City, Utah 5 National Institutes of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland Address correspondence and reprint requests to Kevan Herold, MD, Associate Professor of Medicine, Columbia University, PH10-105, 630 W. 168th St., New York, NY 10032. E-mail: kh318{at}columbia.edu 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 hOKT3γ1(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 hOKT3γ1(Ala-Ala) results in improved C-peptide responses and clinical parameters in type 1 di