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Use of IL-18 inhibitors

1. The technology of IL-18 and inhibitors, applied in the fields of treatment and/or prevention of arthritis, treatment and/or prevention of inflammatory bowel disease, treatment and/or prevention of liver diseases, can solve problems such as effect doubts

Inactive Publication Date: 2007-10-31
YEDA RES & DEV CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This bidirectional effect of IL-18 raises questions about the efficacy of IL-18 inhibitors in inflammatory diseases
Furthermore, due to the interplay of many different cytokines and chemokines in the regulation of inflammation, it is unpredictable to treat or prevent inflammatory diseases by blocking only one of them

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0168] Example 1: Production of IL-18BP-His tag

[0169] Purified recombinant human IL-18BP containing a histidine tail (r-hIL-18BP-His tag) was produced in CHO cells. Those skilled in the art know that recombinant proteins can be produced in eukaryotic cells. Well-known methods can be used to construct appropriate vectors carrying DNA encoding IL-18BP, which are suitable for transfection of eukaryotic cells to produce recombinant IL-18BP. For cellular expression, the DNA encoding IL-18BP (see Novick et al., 1999) was excised and inserted into an expression vector suitable for transfected cells. Alternatively, this DNA can be prepared by PCR with appropriate sense and antisense primers. The resulting cDNA construct is then inserted into an appropriately constructed eukaryotic expression vector using techniques well known in the art (Manaitis, 1982). The recombinant protein is purified to a purity of more than 95%, and it is found that it has biological activity in vivo and ...

Embodiment 2

[0170] Example 2: Protective effect of IL-18BP on endotoxin-induced death mouse model

[0171] A mouse model was used to examine whether IL-18BP (IL-18 inhibitor) could protect mice against high doses of lipopolysaccharide (LPS). Mice died rapidly after LPS-induced acute liver injury.

[0172] C57BL / 6 mice were injected intraperitoneally (ip) with his-tailed recombinant human IL-18BP (rhIL18BPhis, obtained from recombinant production of the protein) at 4 mg / kg, 1 hour later, with 60 mg / kg of LPS (lethal dose) , Survival rate of mice was compared with the group of animals receiving LPS only (no IL-18BP).

[0173] Five out of seven mice injected with rhIL-18BP-his survived LPS injection compared with control mice, while all mice in the control group died within three days.

[0174] In the absence or presence of increasing doses of rhIL-18BP-his, blood samples were collected 5 hours after LPS injection for ELISA analysis of circulating IFN-γ (Fig. 1). 0.4 and 4 mg / kg rhIL-18BP...

Embodiment 3

[0175] Example 3: IL-18BP has a protective effect against liver injury in a mouse pathological model

[0176] A mouse model of fulminant hepatitis was used to test the effect of IL-18BP. When sequentially administered Proplioni-bacterium acnes (P.acnas) and lipopolysaccharide (LPS), mice developed liver injury.

[0177] P.acnas-sensitized C57BL / 6 mice were injected with increasing doses of rhIL-18BP-his (4, 0.4, 0.04, 0 mg / kg) at different times (1 hour, 20 minutes, simultaneously) before LPS injection. No mice survived and circulating IFN-γ and TNF-α levels were unaffected when rhIL-18BP-his was administered ip concurrently with LPS. Surprisingly, rhIL-18BP (4 and 0.4 mg / kg) resulted in a 70% reduction in circulating alanine aminotransferase, a marker of liver damage, as shown in FIG. 2 .

[0178] In addition, mouse survival was monitored (Fig. 3), when rhIL-18BP was administered ip 20 minutes before LPS, compared with control mice (receiving NaCl instead of IL-18BP), the t...

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Abstract

The invention relates to the use of inhibitors of IL-18 in the preparation of a medicament for treatment and / or prevention of liver injury. The invention further relates to the use of IL-18 inhibitors in the preparation of a medicament for treatment and / or prevention of arthritis, in particular rheumatoid arthritis. In addition to this, the invention relates to the use of inhibitors of IL-18 in the preparation of a medicament for treatment and / or prevention of inflammatory bowel diseases, in particular of Crohn's disease and ulcerative colitis.

Description

[0001] This application is a branch of an invention patent application with the international application number PCT / EP 01 / 01867, the international application date is February 20, 2001, the Chinese national phase application number is 01805293.2, and the name is "Application of IL-18 Inhibitors". case application. field of invention [0002] The present invention relates to the therapeutic use of IL-18 inhibitors in several pathological conditions. More specifically, the present invention relates to the treatment and / or prevention of arthritis, the treatment and / or prevention of liver disease, and the treatment and / or prevention of inflammatory bowel disorders (IBD). Background of the invention [0003] An endotoxin-induced serum activity of gamma interferon (IFN-γ) from mouse splenocytes was described in 1989 (MicaIlef et al., 1996). This serum activity acts not as a direct inducer of IFN-γ, but as a co-stimulator with IL-2 or mitogens. Attempts to purify this activity f...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61K38/20C12N15/63A61P1/04A61P1/16A61P19/02A61P37/02A61K48/00A61K35/12A61K38/21A61K31/00A61KA61K38/17A61K39/35A61PC12N
Inventor Y·奇韦提克C·迪纳埃罗C·普拉特尔－齐贝克S·冯德文特M·鲁宾斯坦D·诺维克S·H·金
Owner YEDA RES & DEV CO LTD
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