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EP-3641802-B1 - METHODS AND PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF FIBROSIS WITH AGENTS CAPABLE OF INHIBITING THE ACTIVATION OF MUCOSAL-ASSOCIATED INVARIANT T (MAIT) CELLS

EP3641802B1EP 3641802 B1EP3641802 B1EP 3641802B1EP-3641802-B1

Inventors

  • LOTERSZTAJN, SOPHIE
  • WAN, Jinghong
  • PARADIS, Valérie
  • LEHUEN, Agnès
  • HEGDE, Pushpa
  • WEISS, Emmanuel

Dates

Publication Date
20260513
Application Date
20170622

Claims (5)

  1. An agent capable of inhibiting the activation of Mucosal-Associated Invariant T (MAIT) cells for use in a curative method of treating liver fibrosis in a patient in need thereof, wherein the agent is: - An anti-MHC-related molecule 1 (MR1) neutralizing antibody or - A small organic molecule selected from the group consisting of 6-formyl pterin and acetyl-6-formylpterin (Ac-6-FP).
  2. The agent capable of inhibiting the activation of MAIT cells for use according to claim 1 wherein the liver fibrosis results from chronic alcohol consumption, overfeeding, insulin resistance, type 2 diabetes, non-alcoholic fatty liver disease, NASH, steatosis, idiopathic portal hypertension, autoimmune hepatitis, primary sclerosing cholangitis, or primary biliary cirrhosis.
  3. The agent capable of inhibiting the activation of MAIT cells for use according to claim 1 wherein the liver fibrosis is associated with liver steatosis.
  4. The agent capable of inhibiting the activation of MAIT cells for use according to claim 1 wherein the agent is an antibody that blocks the interaction between MR1 and Vα7.2-Jα33 receptors.
  5. The agent capable of inhibiting the activation of MAIT cells for use according to claim 1 wherein the neutralizing antibody does not mediate antibody-dependent cell-mediated cytotoxicity and thus does not comprise an Fc portion that induces antibody dependent cellular cytotoxicity (ADCC).

Description

FIELD OF THE INVENTION: The present invention relates to methods and pharmaceutical compositions for the treatment of fibrosis with agents capable of inhibiting the activation of mucosal-associated invariant T (MAIT) cells. BACKGROUND OF THE INVENTION: Hepatic fibrosis, the common response to chronic liver injury, ultimately leads to cirrhosis, a major public health problem worldwide 1,2. In western countries, the prevailing causes of fibrosis and cirrhosis include chronic alcohol consumption and non-alcoholic fatty liver disease associated with obesity and type-2 diabetes 4. Cirrhosis lacks definitive treatment, and liver transplantation is considered as the only option for end-stage liver disease. Recent advances in the understanding of liver fibrosis pathogenesis have revealed that sustained inflammation originating from resident and infiltrating immune cells drives the fibrogenic process via direct effects on fibrogenic cell proinflammatory and profibrogenic functions, and also contributes to its regression 1,2. In recent years, monocytes/macrophages have received the most interest, but much less is known about the contribution and functions of T cell subsets in the fibrogenic process, in particular regarding the possible impact of innate-like lymphoid cells. Mucosal-associated invariant T (MAIT) cells are non-conventional T cells that express an evolutionarily conserved semi-invariant T cell antigen receptor (TCR) repertoire (made of an invariant Vα7.2-Jα33 in humans and Vα19-Jα33 in mice) and are restricted by the non-classical MHC-related molecule 1 (MR1) 3. They are abundant in human blood, gut and liver, and secrete cytokines such as IL-17, granzyme B, IFN-γ and TNF-α. In healthy individuals, MAIT cells play a defensive role against pathogens, by protecting epithelial and mucosal layer integrity against bacterial invasion and viral infections, in particular in the liver 3,5,6,7. However, their role in inflammatory diseases has only recently emerged 8, with consistent data reporting altered MAIT cells functions during acute and chronic inflammatory injury 9-11. Kurioka, Ayako et al. explores the role of MAIT cells in human liver and their involvement in various liver diseases (Kurioka, Ayako et al. "MAIT cells: new guardians of the liver." Clinical & translational immunology vol. 5,8 e98. 19 Aug. 2016). Toubal, Amine, and Agnès Lehuen reviews the potential role of MAIT cells in diseases, in particular in liver diseases (Toubal, Amine, and Agnès Lehuen. "Lights on MAIT cells, a new immune player in liver diseases." Journal of hepatology vol. 64,5 (2016): 1008-1010). WO2014/005194 discloses ligands which binds to Major histocompatibility complex-related protein 1 (MR1), wherein said binding results in binding of the MR1 to MAIT cells. Pushpa Hedge et al. discloses that chronic liver injury is associated with dysregulation of MAIT cell functions (Pushpa Hedge et al. : 189: Profibrogenic functions of mucosal-associated invariant T (MAIT) cells during chronic liver injury", Hepatology, vol.64, no. 1, supplement 1, 189, 11 November 2016, pages 99A-100A). SUMMARY OF THE INVENTION: The present invention relates to an agent capable of inhibiting the activation of Mucosal-Associated Invariant T (MAIT) cells for use in a curative method of treating liver fibrosis in a patient in need thereof, wherein the agent is: An anti-MHC-related molecule 1 (MR1) neutralizing antibody orA small organic molecule selected from the group consisting of 6-formyl pterin and acetyl-6-formylpterin (Ac-6-FP). In particular, the present invention is defined by the claims. The references to methods of treatment in this description are to be interpreted as references to the compounds, pharmaceutical compositions and medicaments of the present invention for use in a method for the treatment of the human body by therapy. DETAILED DESCRIPTION OF THE INVENTION: Persistent inflammation is a driving force of liver fibrosis progression. Mucosal-Associated Invariant T (MAIT) cells are non-conventional T cells that display altered functions during chronic inflammatory diseases. Here, the inventors hypothesized that MAIT cells may contribute to the fibrogenic process. They report a loss of circulating MAIT cells in cirrhotic patients and their hepatic accumulation in an activated phenotype within the fibrotic septa. Using two models of chronic liver injury, the inventors demonstrate that mice enriched in MAIT cells (Vα19TCRTg) show exacerbated liver fibrosis and higher number of hepatic fibrogenic cells than wild type counterparts, whereas MAIT cell-deficient mice (MR1-/-mice) are resistant. Co-culture experiments indicate that profibrogenic properties of activated human MAIT cells are related to both mitogenic effects on human hepatic myofibroblasts, in an MR1-dependent manner, and pro-inflammatory features, as a result of TNF-α production. The results highlight the profibrogenic functions of MAIT cells and suggest that targeting MAIT cells ma