Presented at:
64th Scientific Sessions of the American Diabetes Association, Orlando, FL, June 4-8, 2004
Abstract #271-OR
Treatment with hOKT3γ1(Ala-Ala) improves insulin responses and reduces insulin requirements in patients with new onset Type 1 diabetes (T1DM)
Herold K, Gitelman S, Masharani U, Greenbaum C, Hagopian W, Gottlieb P, Muir A, Ramos E, Tomilin N, Bluestone JA
NY, NY; San Francisco, CA; Seattle, WA; Denver, CO; Augusta, GA; Washington, DC
Previous studies in murine models and patients with T1DM have suggested that treatment with anti-CD3 mAb induces tolerance and prevents the loss of insulin production that characterizes its natural history.
We initiated a new multicenter randomized controlled trial with anti-CD3 mAb hOKT3γ1(Ala-Ala) to test if tx with the mAb prevents loss of insulin production and effects on autoimmune activity. Ten patients within 8 wks of dx were randomized to tx with hOKT3γ1(Ala-Ala) (n=6, 4M, 15.5± 1.6 yrs) or a control group (n=4, 3M, 9.0±0.9yrs) at 3 centers. The mAb was given over 12 days, but at 65% higher dose than used previously (NEJM 346:1692). Circulating lymphocytes decr to 17% of pretx levels with tx but were108% of pretx count 6 weeks after the last dose of mAb. The total area under the curve (AUC) of C-pep response to a mixed meal test was measured at 0, 6, and 12 mos. At entry, AUC was not significantly different in the two groups (drug tx'd:10.5±2.18, controls: 4.88±1.43 ng/ml/240min, p=0.46). After 1 yr, there was significantly greater loss of C-pep in the control group 67.7 ± 16.3% compared to the drug tx'd group 1.4 ± 12.9% (p<0.02) and the AUCs were significantly greater in the drug tx'd patients (10.7 ± 3.0 ng/ml/4hr vs 2.28 ± 1.42 ng/ml/4hr, p<0.02). All pts had CDE contact to ensure that HgbA1c levels were < 7.5%: the differences in the levels were not significant at 1 yr (6.78 ± 0.48% in drug tx'd vs 7.03 ± 0.64% in control, p=0.55). However, the insulin dosage in the drug tx'd group was significantly lower 0.33 ± 0.15U/kg vs 0.68 ± 0.33 U/kg, p<0.01). Drug tx had no sig effect on anti-GAD65, anti-IA2, or IAA antibodies.
We conclude that a single course of mAb hOKT3γ1(Ala-Ala) improves insulin production and reduces insulin requirements for at least 1 year after treatment.