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.

FIG. 1.

Absolute lymphocyte counts in patients with type 1 diabetes treated with hOKT3γ1(Ala-Ala). Twelve and nine patients received a 14-day (A) or 12-day (B) treatment protocol as described. The absolute lymphocyte counts in the peripheral blood are shown (means ± SE) expressed as a percentage of the absolute lymphocyte count before treatment.

FIG. 2.

C-peptide responses to a MMTT in the control and drug-treated groups. The total AUC of the C-peptide during a 4-h MMTT is shown for the drug-treated and control groups (means ± SE). ▪, drug treated; ▪, control. **P < 0.02.

FIG. 3.

HbA_1c levels in the control and drug-treated groups. The means ± SE for each group is shown. ○, control; •, drug treated. *P < 0.05, ***P < 0.01.

FIG. 4.

Insulin use in the control and drug-treated groups. The mean ± SE of the daily insulin dosage (units/kilogram) is shown. ○, control; •, drug treated. There was a significant effect of drug treatment on reduction in insulin usage. *P < 0.05, **P < 0.02, ***P < 0.01.

FIG. 5.

Relationship between the C-peptide response (AUC) to a MMTT and HbA_1c. The values from each subject at 6 (A) and 12 (B) months are shown. There was an inverse relationship between the C-peptide response and the HbA_1c levels at each time point: 6 months, r = −0.52, P < 0.001; 12 months, r = −0.52, P < 0.001. ○, control; •, drug treated.

FIG. 6.

CD4-to-CD8 T-cell ratios in clinical responders and nonresponders to drug treatment. Patients who received anti-CD3 mAb were classified as clinical responders or nonresponders based on the changes in the C-peptide response to a MMTT at 12 months compared with the response at study entry. The ratios of the number of CD4 to CD8 T-cells were calculated from measurements before treatment and at 30 and 90 days after drug administration. Clinical responders showed a reduction in the CD4-to-CD8 T-cell ratio (P < 0.02). ○, nonresponder (n = 6); •, responder (n = 15). *P < 0.05.