Anti-CD3 clinical trials in type 1 diabetes mellitus

• Anti-CD3 therapy preserves stimulated C-peptide/insulin across trials and molecules.
• A brief treatment has > 2 year effect on β cells without ongoing immune suppression.
• Subjects with greater benefit include younger patients and those with earlier disease.
• Anti-CD3 therapy has transient adverse events limited to the infusion period.
• Future anti-CD3 studies should recruit younger patients promptly after diagnosis.

Two humanized, anti-CD3 mAbs with reduced FcR binding, teplizumab and otelixizumab, have been evaluated in over 1500 subjects, ages 7–45, with new and recently diagnosed T1D with a range of intravenous doses (3–48 mg) and regimens (6–14 days, single or repeat courses). In general, studies that used adequate dosing demonstrated improvement in stimulated C-peptide responses and reduced need for exogenous insulin for two years and even longer after diagnosis. Drug treatment causes a transient reduction in circulating T cells, but the available data suggest that the mechanism of action may involve induction of regulatory mechanisms. The adverse effects of anti-CD3 treatment are infusion-related and transient. The studies have identified significant differences in efficacy among patient groups suggesting that a key aspect for development of this immune therapy is identification of the demographic, metabolic, and immunologic features that distinguish subjects who are most likely to show beneficial clinical responses.