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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

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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.

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Abbreviations

NASH:

Nonalcoholic steatohepatitis

T2D:

Type 2 diabetes

Tregs:

Regulatory T cells

OGTT:

Oral glucose tolerance test

HAMA:

Human anti-mouse antibody

LAP:

Latency-associated peptide

MAb:

Monoclonal antibody

FACS:

Fluorescence-activated cell sorting

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Acknowledgments

We thank AML (Herzliya, Israel) for clinical chemistry/biochemistry/cytometry analyses and Medistat (Tel Aviv, Israel) for statistical analyses.

Grant Support

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

Disclosure

This clinical trial was funded by NasVax Ltd, Ness-Ziona, Israel; Yaron Ilan is a consultant for NasVax; Nadya Lisovoder, Sarit Samira, and Ronald Ellis are employees and Itamar Shalit is a director of NasVax.

Author information

Author notes

  1. Gadi Lalazar

    Present address: Department of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, 10461, USA

Authors and Affiliations

  1. Liver Unit, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

    Gadi Lalazar, Meir Mizrahi, Ilit Turgeman, Ami Ben Ya’acov, Yehudit Shabat, Nila Hemed, Lidya Zolotarovya, Yoav Lichtenstein & Yaron Ilan

  2. Digestive Diseases Institute, Shaare Zedek Medical Center, Jerusalem, Israel

    Tomer Adar

  3. NasVax Ltd, Ness-Ziona, Israel

    Nadya Lisovoder, Sarit Samira, Itamar Shalit & Ronald Ellis

  4. Department of Liver, Ziv Medical Center, Safed, Israel

    Assy Nimer

  5. Gastroenterology and Liver Units, Department of Medicine, Hadassah Medical Center, POB 12000, Jerusalem, Israel

    Yaron Ilan

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  1. Gadi Lalazar
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Corresponding author

Correspondence to Yaron Ilan.

Additional information

Gadi Lalazarv, Meir Mizrahi and Ilit Turgeman contributed equally to this work.

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Lalazar, G., Mizrahi, M., Turgeman, I. et al. 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. J Clin Immunol 35, 399–407 (2015). https://doi.org/10.1007/s10875-015-0160-6

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  • DOI: https://doi.org/10.1007/s10875-015-0160-6

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