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

Gadi Lalazar, Meir Mizrahi, Ilit Turgeman, Tomer Adar, Ami Ben Ya’acov, Yehudit Shabat, Assy Nimer, Nila Hemed, Lidya Zolotarovya, Yoav Lichtenstein, Nadya Lisovoder, Sarit Samira, Itamar Shalit, Ronald Ellis, Yaron Ilan

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)399-407
Number of pages9
JournalJournal of Clinical Immunology
Volume35
Issue number4
DOIs
StatePublished - 26 May 2015
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2015, Springer Science+Business Media New York.

Funding

This work was supported by NasVax Ltd, Ness-Ziona Israel, and by the Roaman-Epstein Liver Research Foundation.

FundersFunder number
NasVax Ltd
Ness-Ziona Israel
Roaman-Epstein Liver Research Foundation

    Keywords

    • NASH
    • anti CD3
    • oral tolerance

    Fingerprint

    Dive into the research topics of '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'. Together they form a unique fingerprint.

    Cite this