Oral Administration of OKT3 MAb to Patients with NASH, Promotes Regulatory T-cell Induction, and Alleviates Insulin Resistance: Results of a Phase IIa Blinded Placebo-Controlled Trial

ᅟ: Oral administration of anti-CD3 antibodies induced regulatory T cells (Tregs) alleviating the insulin resistance and liver damage in animal models. Objective: To determine the safety and biological effects of oral OKT3 monoclonal antibody (Balashov et al. Neurology 55:192–8, 2000) in patients with NASH. Design: In this Phase-IIa trial, four groups of patients with biopsy-proven NASH (n = 9/group) received placebo (group A) or oral OKT3 (group B: 0.2; C: 1.0; D: 5.0 mg/day) for 30 days. Patients were followed for safety, liver enzymes, glucose, lipid profile, oral glucose tolerance test (OGTT), serum cytokines and Tregs. Results: Oral OKT3 was well tolerated without treatment-related adverse events. OKT3 induced Tregs: with significant increases of CD4⁺LAP⁺ (Latency associated peptide) and CD4⁺CD25⁺LAP⁺ cells in Group D, and a significant increase in TGF-β in Groups C and D. AST decreased significantly in group D and a trend in Groups B and C. Fasting plasma glucose decreased significantly in all treatment groups compared with placebo. OGTT decreased significantly in Group D. Correlations were observed between the changes in several immune-modulatory effects and clinical biomarkers. While serum anti-CD3 levels where undetectable increases in human anti-mouse antibody levels were observed in Groups C and D. Conclusion: Oral administration of anti-CD3 MAb to patients with NASH was safe and well tolerated. Positive biological effects were noted in several hepatic, metabolic and immunologic parameters. These findings provide the basis for future trials to investigate the effect of oral anti-CD3 MAb immunotherapy in patients with NASH.