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Use of Il-18 inhibitors for treatment and/or prevention of heart disease

A 1. IL-18, heart disease technology, applied in the direction of drug combination, gene therapy, cardiovascular system diseases, etc., can solve the problem that the role of IL-18 in heart disease is not described.

Inactive Publication Date: 2007-07-18
MERCK SERONO SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0030] However, to date, the role of IL-18 in heart disease has not been described

Method used

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  • Use of Il-18 inhibitors for treatment and/or prevention of heart disease
  • Use of Il-18 inhibitors for treatment and/or prevention of heart disease
  • Use of Il-18 inhibitors for treatment and/or prevention of heart disease

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0091] A fully human antibody production method involves "humanization" of the mouse humoral immune system by introducing human immunoglobulin (Ig) loci into mice in which endogenous Ig genes have been inactivated, producing A mouse strain capable of producing human Ig (xenomouse). The Ig locus is complex in its physical structure and gene rearrangements, and the expression process is required to ultimately generate a broad immune response. Antibody diversity arises primarily from combinatorial rearrangements between the different V, D and J genes in the Ig locus. These loci also contain interspersed regulatory elements that control antibody expression, allelic exclusion, class switching, and affinity maturation. Introduction of non-rearranged human Ig transgenes into mice demonstrates that the mouse recombination machinery is compatible with the human gene. In addition, hybridomas secreting various isotype antigen-specific human-mouse antibodies can be obtained from heterog...

Embodiment 1

[0136] Example 1 Inhibition of IL-18 in vitro reduces myocardial ischemic dysfunction

[0137] Materials and methods

[0138] Reagent

[0139] In Chinese hamster ovary cells expressed with terminal (His) 6 The tailed IL-18BPa isoform was purified to homogeneity. It has been described that IL-18BPa-(His) 6 Ability to neutralize IL-18 (Kim et al., 2000). The ICE inhibitor (ICEi) Ac-Try-Val-Ala-Asp-chloromethanone (YVAD) was purchased from Alexis Biochemicals (San Diego) and dissolved in DMSO at a concentration of 10 mg / ml. ICE inhibitors were diluted with Tyrode's solution before use. ICEi reduced endotoxin-induced secretion of mature IL-1β from human peripheral blood mononuclear cells by 92%, as determined by ELISA (Cistron Biotechnology, Pine Brook, NJ).

[0140] isolated atrial trabeculae

[0141] Patients undergoing elective coronary artery bypass surgery with a pump oxygenator require a catheter to be inserted into the right atrium. At that time, a small segment of ...

Embodiment 3

[0173] method

[0174] In vivo intramuscular electrotransfer of mouse IL-18BP expression plasmid

[0175] C57BL / 6 mice were injected with an expression plasmid containing IL-18BP cDNA (called pcDNA3-IL18BP as described in WO01 / 85201) three times every three weeks. Control mice were injected with a control empty plasmid. The cDNA of mouse IL-18BP isoform d was isolated as described (accession number is #Q9ZOM9) (Kim et al., 2000) and subcloned into mammalian cells under the control of the cytomegalovirus promoter (Invitrogen). In the EcoR1 / Not1 site of the expression plasmid pcDNA3 in animal cells. The control plasmid is a similar construct without the therapeutic cDNA. There were 31 mice in the control group, and 27 mice in the experimental group receiving IL-18BP injection.

[0176] IL-18BP or a control expression plasmid (60 micrograms) was injected intramuscularly into the cranial tibiae of both sides of the anesthetized mice as previously described (Mallat et al., 1999...

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Abstract

The invention relates to the use of an inhibitor of IL-18 in the preparation of a medicament for treatment and / or prevention of a heart disease, in particular ischemic heart disease. Combinations of an IL-18 inhibitor and / or a TNF antagonist are also considered for the treatment and / or prevention of a heart disease.

Description

technical field [0001] The present invention relates to the field of cardiovascular diseases. More specifically, the present invention relates to the use of IL-8 inhibitors in the treatment and / or prevention of heart disease, especially ischemic heart disease. Background of the invention [0002] The cytokine interleukin 18 (IL-18) was originally known as interferon-gamma (IFN-gamma) inducible factor (Nakamura et al., 1989). It is an early signal for T lymphocyte helper type 1 (TH 1) responses. IL-18 acts with IL-12, IL-2, antigens, mitogens, and possibly other factors to induce IFN-γ production. IL-18 also increases GM-CSF and IL-2 production, enhances anti-CD3-induced T cell proliferation, and increases Fas-mediated killing of natural killer cells. [0003] Mature IL-18 is produced from its precursor through the action of IL-1β converting enzyme (ICE, caspase-1). [0004] The IL-18 receptor consists of at least two components that function cooperatively in ligand bindi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K38/17A61P9/10A61K45/00A61K38/00A61K39/395A61K45/06A61K48/00A61P9/00A61P9/04A61P43/00C07K14/47C07K14/54C07K14/715
CPCC07K14/54C07K14/7155C07K2319/00C07K14/47A61K48/00A61K38/00A61K2039/505C07K2317/41A61P43/00A61P9/00A61P9/04A61P9/10A61K39/395
Inventor C·迪纳洛B·波梅兰茨L·列兹尼科夫A·哈肯Y·奇韦提克
Owner MERCK SERONO SA
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