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

Abstract

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.

Adaptive immunity: an emerging player in the progression of NAFLD

“…Accordingly, oral administration of the murine anti-CD3 monoclonal antibodies OKT3 plus β-glucosylceramide to obese leptin-deficient ob/ob mice induces LAP + T reg cells and decreases adipose tissue inflammation along with liver steatosis and transaminase release 120 . In humans, OKT3 antibodies effectively downmodulate T H 1-T H 17 cell responses with a concomitant increase in the expression of T reg cell markers 121 . Furthermore, a single-blind randomized placebo-controlled phase II clinical trial has shown that oral OKT3 administration to patients with biopsy-proven NASH and type 2 diabetes mellitus ameliorates alanine aminotransferase release, and improves blood glucose and insulin levels 121 .…”

“…In humans, OKT3 antibodies effectively downmodulate T H 1-T H 17 cell responses with a concomitant increase in the expression of T reg cell markers 121 . Furthermore, a single-blind randomized placebo-controlled phase II clinical trial has shown that oral OKT3 administration to patients with biopsy-proven NASH and type 2 diabetes mellitus ameliorates alanine aminotransferase release, and improves blood glucose and insulin levels 121 . T reg cell stimulation can also be achieved by the oral administration of hyperimmune cow colostrum (Imm124-E), which improves insulin resistance and liver injury in ob/ob mice 122 .…”

Immune rebalancing by oral immunotherapy: A novel method for getting the immune system back on track

“…111 In a recent review, the potential use of the fully human mAb foralumab in patients with type 2 DM and NASH has been comprehensively assessed. 112 This suggested that foralumab might be suitable for NASH treatment due to a relatively high safety profile, the potential to target all stages of the disease, and an ability to be combined with other NASH therapeutics. Supporting the role that oral administration of foralumab could have in controlling immune responses, the drug has been shown to prevent skin xenograft rejection in mice with human immune systems, without depletion of peripheral T cells.…”

“…These effects associated with a decrease in AST levels, fasting plasma glucose levels, and improved oral glucose tolerance test scores . In a recent review, the potential use of the fully human mAb foralumab in patients with type 2 DM and NASH has been comprehensively assessed . This suggested that foralumab might be suitable for NASH treatment due to a relatively high safety profile, the potential to target all stages of the disease, and an ability to be combined with other NASH therapeutics.…”

Limited expression of TLR9 on T cells and its functional consequences in patients with nonalcoholic fatty liver disease

“…12 We have previously identified the alteration of different T cell subsets in NASH patients 13 and other authors confirmed a key role for T cells in NASH. 14 A low intrahepatic expression of TLR9 mRNA was reported in SS. 15 though it may probably come from the liver parenchyma than from T cells.…”