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Jak1 pathway inhibitors for the treatment of cytokine-related disorders

A technology of cytokines and inhibitors, applied in the field of JAK1 pathway inhibitors

Pending Publication Date: 2020-11-13
INCYTE CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the mechanism of action of tocilizumab is limited to anti-IL-6R only

Method used

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  • Jak1 pathway inhibitors for the treatment of cytokine-related disorders
  • Jak1 pathway inhibitors for the treatment of cytokine-related disorders
  • Jak1 pathway inhibitors for the treatment of cytokine-related disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment A

[0156] Example A: In Vitro JAK Kinase Assay

[0157] JAK1 pathway inhibitors useful in the treatment of cytokine-related diseases or disorders are tested for their inhibitory activity on JAK targets according to the following in vitro assay described in Park et al., Analytical Biochemistry 1999, 269, 94-104. The catalytic domains of human JAK1 (a.a.837-1142), JAK2 (a.a.828-1132) and JAK3 (a.a.781-1124) with an N-terminal His tag were expressed in insect cells using baculovirus and purified. The catalytic activity of JAK1, JAK2 or JAK3 was determined by measuring the phosphorylation of biotinylated peptides. Phosphorylated peptides were detected by homogeneous time-resolved fluorescence (HTRF). Compound activity against each kinase was measured in 40 microliter reactions containing enzyme, ATP and 500 nM peptide in 50 mM Tris (pH 7.8) buffer with 100 mM NaCl, 5 mM DTT and 0.1 mg / mL (0.01%) BSA. IC 50 . For 1mM IC 50The ATP concentration in the reaction was measured to be 1...

Embodiment B

[0158] Example B: Cytokine Release Syndrome Induced by Anti-CD3 Antibody in BALB / c Mice

[0159] The efficacy of JAK1 pathway inhibitors against CRS can be tested according to the in vivo assay described in Ferran, C. et al. Clin. Exp. Immunol. 1991, 86, 537-543. Specifically, this study tested the ability of compounds to reduce or ameliorate anti-CD3 antibody-induced cytokine release syndrome (CRS) in BALB / c mice. Antibody clone 145-2C11 is an immunoglobulin G (IgG) hamster MoAb specific for the epsilon chain of the CD3 murine molecule (Léo, O. et al., Proc. Natl. Acad. Sci. USA, 1987, 34, 1374 ). Treatment with 145-2C11 induces high-affinity IL-2 receptors on the surface of splenic T cells and elicits e.g. tumor necrosis factor (TNF-α), IL-2, IL-3, IL-6 and interferon-γ (IFN -γ) release of some cytokines (Ferran et al., Eur. J. Immunol. 1990, 20, 509-515 and Algre, M. et al., Eur. J. Immunol., 1990, 707). The release of these cytokines causes behavioral changes in the ani...

Embodiment C

[0183] Example C: Concanavalin A-Induced Cytokine Release Syndrome

[0184] Concanavalin A (Con A) is a selective T lymphocyte mitogen that causes widespread inflammatory cytokine release and proliferation of CD4 and CD8 T cells. Injection of Con-A has been shown in the literature to induce cytokine release syndrome and was used as a model to test the efficacy of cytokine release syndrome therapy (Gantner, F. et al. Hepatology, 1995, 21, 190-198). The mitogen response depends on the expression of T cell receptors. Animals exhibit behavioral changes such as fever, malaise, hypotension, hypoxia, capillary leak, and potential multi-organ toxicity.

[0185] A.Materials and methods

[0186]

[0187] B. Experimental design

[0188] In detail, this study tests the ability of selective JAK1 inhibitors (such as compound 1 of Table 1) to reduce or ameliorate Con A-induced cytokine release syndrome (CRS) in BALB / c mice. A total of forty (40) BALB / c mice were used in this one d...

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Abstract

This disclosure relates to JAK1 pathway inhibitors and the use thereof in treating cytokine-related diseases or disorders such as cytokine release syndrome (CRS), hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndrome (MAS), and CAR-T-cell-related encephalopathy syndrome (CRES).

Description

technical field [0001] The present disclosure relates to JAK1 pathway inhibitors and their use in the treatment of cytokine-related diseases or disorders. Background technique [0002] Cytokine-related diseases or disorders are characterized by excessive immune activation and include cytokine release syndrome (CRS), hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndrome (MAS), and CAR-T cell Related Encephalopathy Syndrome (CRES). [0003] Cytokine release syndrome (CRS) is a direct result of excessive production of inflammatory cytokines caused by supraphysiological levels of immune activation and manifests as a series of clinical symptoms, including fever, nausea, fatigue, myalgia, malaise, low Blood pressure, hypoxia, capillary leak, leading to potential multi-organ toxicity. [0004] CRS is, for example, a deleterious side effect of immune-based therapies for serious diseases such as cancer. Immune-based therapies that can cause CRS include, against ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4155A61K31/437A61K31/519A61P37/00
CPCA61K31/4155A61K31/437A61K31/519A61P37/00C07K16/2866A61K31/573A61K31/506A61K39/395A61K2039/505A61K2300/00A61P37/02
Inventor M·奥尼尔蒙哥马利A·奈玛S·斯诺德格拉斯
Owner INCYTE CORP
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