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

TLDR

Despite advances in animal models, progress in altering the natural course of human type 1 diabetes remains limited, as immunosuppressive agents show only short‑term effectiveness without inducing tolerance and require continuous treatment. The study investigated whether a single course of the humanized anti‑CD3 monoclonal antibody hOKT3γ1(Ala‑Ala) could alter the progression of recent‑onset type 1 diabetes in a randomized controlled trial. The trial administered a single course of hOKT3γ1(Ala‑Ala) within six weeks of diagnosis and monitored disease progression through C‑peptide, HbA1c, insulin use, and immune cell counts. A single course of hOKT3γ1(Ala‑Ala) was well tolerated and preserved C‑peptide responses for at least two years, accompanied by lower HbA1c and insulin needs, with early CD8⁺ T‑cell expansion predicting clinical benefit.

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 HbA1c 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 diabetes for at least 2 years in the absence of continued immunosuppressive medications.