A clinical research consortium sponsored by NIAID and JDRF
Herold K, Gitelman S, Masharani U, Greenbaum C, Hagopian W, Gottlieb P, Muir A, Ramos E, Bluestone JA, Tomlin N
Columbia University, New York, NY University of California San Francisco, CA Pacific Northwest Research Institute, Seattle, WA University of Colorado, Denver, CO Pediatrics, Medical College of Georgia, Augusta, GA NIAID, Bethesda, MD
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.
