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01.05.2015 | Original Research

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

verfasst von: 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

Erschienen in: Journal of Clinical Immunology | Ausgabe 4/2015

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Abstract

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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.

Friend PJ, Hale G, Chatenoud L, et al. Phase I study of an engineered aglycosylated humanized CD3 antibody in renal transplant rejection. Transplantation. 1999;68:1632–7.CrossRefPubMed

Herold KC, Gitelman SE, Masharani U, et al. A single course of anti-CD3 monoclonal antibody hOKT3 gamma1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes. 2005;54:1763–9.CrossRefPubMed

Herold KC, Hagopian W, Auger JA, et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med. 2002;346:1692–8.CrossRefPubMed

Chatenoud L, Bluestone JA. CD3-specific antibodies: a portal to the treatment of autoimmunity. Nat Rev Immunol. 2007;7:622–32.CrossRefPubMed

Chen Y, Kuchroo VK, Inobe J, et al. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science. 1994;265:1237–40.CrossRefPubMed

Weiner HL. Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. Immunol Rev. 2001;182:207–14.CrossRefPubMed

Zhang X, Izikson L, Liu L, et al. Activation of CD25(+)CD4(+) regulatory T cells by oral antigen administration. J Immunol. 2001;167:4245–53.CrossRefPubMed

Ishikawa H, Ochi H, Chen ML, et al. Inhibition of autoimmune diabetes by oral administration of anti-CD3 monoclonal antibody. Diabetes. 2007;56:2103–9.CrossRefPubMed

Ochi H, Abraham M, Ishikawa H, et al. Oral CD3-specific antibody suppresses autoimmune encephalomyelitis by inducing CD4+ CD25- LAP+ T cells. Nat Med. 2006;12:627–35.CrossRefPubMed

10.

Rav-Acha M, Sassa D, Ilan Y, et al. [Surgical intervention in infective endocarditis: indications and timing]. Harefuah. 2005;144:421–5.PubMed

11.

Wu HY, Quintana FJ, Weiner HL. Nasal anti-CD3 antibody ameliorates lupus by inducing an IL-10-secreting CD4+ CD25- LAP+ regulatory T cell and is associated with down-regulation of IL-17+ CD4+ ICOS+ CXCR5+ follicular helper T cells. J Immunol. 2008;181:6038–50.CrossRefPubMedCentralPubMed

12.

Wu HY, Maron R, Tukpah AM, et al. Mucosal anti-CD3 monoclonal antibody attenuates collagen-induced arthritis that is associated with induction of LAP+ regulatory T cells and is enhanced by administration of an emulsome-based Th2-skewing adjuvant. J Immunol. 2010;185:3401–7.CrossRefPubMedCentralPubMed

13.

Hotamisligil GS. Inflammation and endoplasmic reticulum stress in obesity and diabetes. Int J Obes (Lond). 2008;32 Suppl 7:S52–4.CrossRef

14.

Winer S, Chan Y, Paltser G, et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med. 2009;15:921–9.CrossRefPubMedCentralPubMed

15.

Ilan Y, Maron R, Tukpah AM, et al. Induction of regulatory T cells decreases adipose inflammation and alleviates insulin resistance in ob/ob mice. Proc Natl Acad Sci U S A. 2010;107:9765–70.CrossRefPubMedCentralPubMed

16.

Ilan Y, Zigmond E, Lalazar G, et al. Oral administration of OKT3 monoclonal antibody to human subjects induces a dose-dependent immunologic effect in T cells and dendritic cells. J Clin Immunol. 2010;30:167–77.CrossRefPubMedCentralPubMed

17.

Renders L, Valerius T. Engineered CD3 antibodies for immunosuppression. Clin Exp Immunol. 2003;133:307–9.CrossRefPubMedCentralPubMed

18.

Weiner HL, da Cunha AP, Quintana F, et al. Oral tolerance. Immunol Rev. 2011;241:241–59.CrossRefPubMedCentralPubMed

19.

Meijer RT, Surachno S, Yong SL, et al. Treatment of acute kidney allograft rejection with a non-mitogenic CD3 antibody. Clin Exp Immunol. 2003;133:485–92.CrossRefPubMedCentralPubMed

20.

Saharinen J, Hyytiainen M, Taipale J, et al. Latent transforming growth factor-beta binding proteins (LTBPs)–structural extracellular matrix proteins for targeting TGF-beta action. Cytokine Growth Factor Rev. 1999;10:99–117.CrossRefPubMed

21.

Verma SC, Lan K, Robertson E. Structure and function of latency-associated nuclear antigen. Curr Top Microbiol Immunol. 2007;312:101–36.PubMedCentralPubMed

22.

Oida T, Zhang X, Goto M, et al. CD4 + CD25- T cells that express latency-associated peptide on the surface suppress CD4 + CD45RB high-induced colitis by a TGF-beta-dependent mechanism. J Immunol. 2003;170:2516–22.CrossRefPubMed

23.

Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441:235–8.CrossRefPubMed

24.

Baecher-Allan C, Hafler DA. Human regulatory T cells and their role in autoimmune disease. Immunol Rev. 2006;212:203–16.CrossRefPubMed

25.

Belkaid Y. Regulatory T, cells and infection: a dangerous necessity. Nat Rev Immunol. 2007;7:875–88.CrossRefPubMed

26.

Tang Q, Bluestone JA. Regulatory T-cell physiology and application to treat autoimmunity. Immunol Rev. 2006;212:217–37.CrossRefPubMed

27.

Shalev I, Schmelzle M, Robson SC, et al. Making sense of regulatory T cell suppressive function. Semin Immunol. 2011;23:282–92.CrossRefPubMedCentralPubMed

28.

Bluestone JA, Tang Q. How do CD4 + CD25+ regulatory T cells control autoimmunity? Curr Opin Immunol. 2005;17:638–42.CrossRefPubMed

29.

Chatenoud L, Bach JF. Regulatory T cells in the control of autoimmune diabetes: the case of the NOD mouse. Int Rev Immunol. 2005;24:247–67.CrossRefPubMed

30.

Randolph DA, Fathman CG. Cd4 + Cd25+ regulatory T cells and their therapeutic potential. Annu Rev Med. 2006;57:381–402.CrossRefPubMed

31.

von Herrath M, Sanda S, Herold K. Type 1 diabetes as a relapsing-remitting disease? Nat Rev Immunol. 2007;7:988–94.CrossRef

32.

Yeh SH, Chuang H, Lin LW, et al. Tai chi chuan exercise decreases A1C levels along with increase of regulatory T-cells and decrease of cytotoxic T-cell population in type 2 diabetic patients. Diabetes Care. 2007;30:716–8.CrossRefPubMed

33.

Ma X, Hua J, Mohamood AR, et al. A high-fat diet and regulatory T cells influence susceptibility to endotoxin-induced liver injury. Hepatology. 2007;46:1519–29.CrossRefPubMed

34.

Chatzigeorgiou A, Chung KJ, Garcia-Martin R, et al. Dual role of B7 costimulation in obesity-related nonalcoholic steatohepatitis and metabolic dysregulation. Hepatology. 2014;60:1196–210.CrossRefPubMed

Titel: 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
verfasst von: 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
Publikationsdatum: 01.05.2015
Verlag: Springer US
Erschienen in: Journal of Clinical Immunology / Ausgabe 4/2015
Print ISSN: 0271-9142
Elektronische ISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-015-0160-6

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Abstract

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Objective

Design

Results

Conclusion

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