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

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

doi:10.1007/s10875-015-0160-6

Cited by 70 publications

(48 citation statements)

References 33 publications

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“…However, although TGF-β has been described as a pro-fibrogenic cytokine [41], an increase in TGF-β serum levels is associated with improvement in liver function in NASH [42]. Alternatively, the balance between other cytokines and adipokines not measured in this study may explain the noted effect.…”

Section: Discussionmentioning

confidence: 73%

Oral Administration of CardioAid and Lunasin Alleviates Liver Damage in a High-Fat Diet Nonalcoholic Steatohepatitis Model

et al. 2017

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Background: Several of the drugs in development for treatment of nonalcoholic steatohepatitis (NASH) target liver fibrosis or have side effects that prohibit their long-term use in patients with mild to moderate disease. Lunasin is a soy-derived peptide with anti-inflammatory properties. ADM's CardioAid™ is a plant sterol extract that exerts cholesterol- and triacylglycerol-lowering effects. Aim: To determine the immunomodulatory effects of CardioAid and lunasin in a high-fat diet (HFD) animal model of NASH. Methods: C57BL/6 mice on an HFD were orally administered CardioAid or lunasin for 25 weeks. The effects on the immune system, liver function, insulin resistance and lipid profile were studied. Results: Treatment with CardioAid and lunasin was associated with a significant decrease in the CD4/CD8 ratio and an increase in CD4+CD25+ lymphocytes. A decrease in interleukin 1-alpha serum levels and an increase in transforming growth factor beta serum levels were noted. These were associated with alleviation of liver damage as indicated by a significant decrease in liver enzymes and improvement in the histological nonalcoholic fatty liver disease activity score (NAS). Decreases in both serum triglyceride and serum glucose levels were observed in treated mice. A decrease in total body fat measured by EchoMRI was also observed in treated mice. Conclusions: CardioAid and lunasin exerted hepatoprotective and glucose-protective effects in an HFD NASH model. These data and the high-safety profiles of CardioAid and Lunasin support their use in patients in the early stages of NASH to prevent deterioration due to the disease.

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Section: Discussionmentioning

confidence: 73%

Oral Administration of CardioAid and Lunasin Alleviates Liver Damage in a High-Fat Diet Nonalcoholic Steatohepatitis Model

et al. 2017

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“…The drug was well tolerated without any treatment-related adverse reactions [81]. The drug was well tolerated without any treatment-related adverse reactions [81].…”

Section: Immunotherapy For Nash By Oral Administration Of Anti-cd3mentioning

confidence: 92%

Immunotherapy with oral administration of humanized anti-CD3 monoclonal antibody: a novel gut-immune system-based therapy for metaflammation and NASH

Ilan

Shailubhai²,

Sanyal

2018

Clinical and Experimental Immunology

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The immune system plays a role in the pathogenesis of non-alcoholic steatohepatitis (NASH) underlying hepatocyte injury and fibrosis progression at all disease stages. Oral administration of anti-CD3 monoclonal antibody (mAb) has been shown in preclinical studies to be an effective method for systemic immune modulation and alleviates immune-mediated disorders without T cell depletion. In the present review, we summarize the concept of the oral administration of humanized anti-CD3 mAb in patients with NASH and discuss the potential of this treatment to address the current requirements of treatments for NASH. Recently published preclinical and clinical data on oral administration of anti CD3 are discussed. Human trials have shown that the oral administration of anti-CD3 in healthy volunteers, patients with chronic hepatitis C virus (HCV) infection and patients with NASH and type 2 diabetes is safe and well tolerated, as well as biologically active. Oral anti-CD3 induces regulatory T cells, suppresses the chronic inflammatory state associated with NASH and exerts a beneficial effect on clinically relevant parameters. Foralumab is a fully human anti-CD3 mAb that has recently been shown to exert a potent anti-inflammatory effect in humanized mice. It is being developed for treatment of NASH and primary biliary cholangitis (PBC). Oral administration of anti CD3 may provide an effective therapy for patients with NASH.

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“…A treatment regime of five-times 1 mg was considered superior to 0.2 or 5 mg [107]. Two single blind randomized placebo controlled Phase IIa studies in patients with treatment resistant chronic hepatitis C infection (HCV) [108] or nonalcoholic steatohepatitis (NASH) and altered glucose metabolism that included subjects with Type 2 diabetes [109], demonstrated that oral CD3 was safe and well tolerated, as measured by blood hematology, chemistry, immunological safety markers and physical signs [108,109]. Both studies reported positive effects on disease and immunological markers including an increase of Tregs [108,109].…”

Section: Clinical Trials With Oral Anti-cd3 Mabmentioning

confidence: 99%

“…A very promising approach to improve safety is oral or nasal administration of anti-CD3 mAb. Clinical data showed promising results in terms of safety and therapeutic effect [107,109]. Future development in anti-CD3 immunotherapy warrants further clinical studies to explore the potential of mucosal anti-CD3 mAb therapy for treatment of a wide range of autoimmune and inflammatory diseases in humans.…”

Section: Combination Therapies With Anti-cd3 Mab To Improve Safetymentioning

confidence: 99%

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Therapeutic Anti-Cd3 Monoclonal Antibodies: From Bench to Bedside

2016

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The induction of tolerance is a major goal of immunotherapy. Investigations over the last 20 years have shown that anti-CD3 monoclonal antibodies (mAbs) effectively treat autoimmune disease in animal models and have also shown promise in clinical trials. Tolerance induction by anti-CD3 mAbs is related to the induction of Tregs that control pathogenic autoimmune responses. Here, we review preclinical and clinical studies in which intravenous or mucosal administration of anti-CD3 mAbs has been employed and provide an outlook on future developments to enhance the efficacy of this promising therapeutic approach.

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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

Cited by 70 publications

References 33 publications

Oral Administration of CardioAid and Lunasin Alleviates Liver Damage in a High-Fat Diet Nonalcoholic Steatohepatitis Model

Oral Administration of CardioAid and Lunasin Alleviates Liver Damage in a High-Fat Diet Nonalcoholic Steatohepatitis Model

Immunotherapy with oral administration of humanized anti-CD3 monoclonal antibody: a novel gut-immune system-based therapy for metaflammation and NASH

Therapeutic Anti-Cd3 Monoclonal Antibodies: From Bench to Bedside

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