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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/19—Cytokines; Lymphokines; Interferons
  • A61K38/20—Interleukins [IL]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/19—Cytokines; Lymphokines; Interferons
  • A61K38/20—Interleukins [IL]
  • A61K38/2066—IL-10
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• Interleukin-22 for the prevention and/or treatment of multiple organ dysfunction syndrome (MODS)
• This invention relates to the medical use of Interleukin-22 (IL-22).
• MODS Multiple organ dysfunction syndrome
• MOF multiple organ failure
• SIRS Systemic Inflammatory Response Syndrome
• SIRS is an inflammatory state affecting the whole body. It is one of several conditions related to systemic inflammation, organ dysfunction, and organ failure. SIRS is a subset of cytokine storm, in which there is abnormal regulation of various cytokines. The cause of SIRS can be classified as infectious or noninfectious. SIRS is also closely related to sepsis. When SIRS is due to an infection, it is considered as sepsis. Noninfectious causes of SIRS include trauma, burns, pancreatitis, ischemia and hemorrhage. Sepsis is a serious medical condition characterized by a whole-body inflammatory state. Sepsis can lead to septic shock, multiple organ dysfunction syndrome and death. Both SIRS and sepsis could ultimately progress to MODS.
• the present invention in one aspect, provides the use of interleukin- 22 (IL-22) in manufacture of a composition for preventing and/or treating MODS, MOF, sepsis, or liver failure.
• IL-22 interleukin- 22
• the present invention provides a method for the prevention and the treatment of MODS, MOF, sepsis, or liver failure in a subject, the method comprising administering a pharmaceutically effective amount of IL-22.
• the present invention relates to the use of IL-22 in the manufacture of a medicament for preventing and treating MODS, MOF, sepsis, or liver failure.
• MODS, MOF or sepsis may be caused by, among other causes, trauma such as traffic accidents, burns, heart attack, and severe infective diseases.
• IL-22 of the present invention includes but is not limited to mammal IL-22 and recombinant mammal IL-22.
• IL-22 is human IL-22.
• Figure 1 shows the Murine inter leukin-22 cDNA sequence.
• Figure 2 shows the Human interleukin-22 cDNA sequence.
• Figure 3 shows the Murine interleukin-22 amino acid sequence.
• Figure 4 shows the Human interleukin-22 amino acid sequence.
• Figure 5 shows that IL-22 increased animal survival in LPS-induced sepsis shock in mice.
• Figure 6 shows that IL-22 protects LPS-induced multiple organ failure in rats caused by cachexia.
• Figure 7 shows that IL-22 protected animal from death in LPS/GalN-induced acute liver failure in mice.
• Example 1 Human and murine IL-22 gene cloning
• Cloning of human IL-22 gene Human peripheral blood monocytes were stimulated with anti-human CD 3 mAb and cultured for 24 h. Total RNA was extracted by ultracentrifugation, and cDNA was synthesized with the dT primers. Human IL-22 gene was amplified by PCR with the sense primer (5'-GCA GAA TCT TCA GAA CAG GTT C-3') and anti-sense primer (5'-GGC ATC TAA TTG TTA TTT CTA G-3'). The amplified DNA is cloned into E.coli expression vector.
• mouse IL-22 gene Cloning of mouse IL-22 gene: C57BL/6 female mice were injected with LPS (5 mg/kg, sc). The spleen was obtained after 20 hours. Total RNA was extracted and cDNA was synthesized with the dT primers. Mouse IL-22 gene was amplified by PCR with the sense primer (5'-CTC TCA CTT ATC AAC TGT TGA C-3') and anti-sense primer (5'- GAT GAT GGA CGT TAG CTT CTC AC-3'). The amplified cDNA was cloned into E.coli expression vector pET21(+)
• E. coli strain BL21(+) was used to express the recombinant protein.
• the E.coli cells were homogenized under high pressure.
• IL-22 inclusion bodies were obtained by centrifugation and washed with buffers (Tris-HCl 50 mM, NaCl 100 mM, EDTA 1 mM, DTT 1 mM, and sodium deoxycholate 0.5%) completely.
• Inclusion bodies were solubilized in 8M urea, 50 mM Mes, 10 mM EDTA, and 0.1 mM DTT, pH 6.5.
• Inclusion bodies was refolded 4 times for 20 hours in 100 mM Tris-HCl, 2 mM EDTA, 0.5 M L- arginine, 1 mM reduced glutathion, and 0.ImM oxidized glutathion, pH 8. The mixture was then concentrated and purified using a Superdex75 (Amersham) column chromatography. The protein was eluted with 20 mM Tris-HCl, 50 mM NaCl, pH 7. The purity of IL-22 was determined by SDS-PAGE (>95%) as shown in Fig.3 and Fig.4. IL- 22 protein aliquot was stored at -80 0 C.
• mice Female Balb/c mice, at 6 to 8 weeks, were treated with lipopolysacchride (LPS, salmonella abortus-equi (L-5886, Sigma) prepared at 1.0 mg/mL saline. 0.2 mL LPS solution was injected by i.p. to mice at dose of 10 mg/kg. Animals were divided to different treatment groups and survival was monitored for 7 days. Single dose of LPS at >12.0 mg/kg could result in 100% animal death at 48 to 72 hrs. LPS dosed at 10 mg/kg single dose resulted in 20 to 30% animal survival by day 7.
• LPS lipopolysacchride
• L-5886 salmonella abortus-equi
• Example 4 Protective Effect of IL-22 on Endotoxin-induced multiple organ failure in rats.
• Results are shown in Fig 6. Serum levels of total proteins, albumin were decreased in control group, indicating that these rats were suffering from cachexia. Animals treated with rmIL-22 had significantly improved blood chemistry parameters. These data shows that IL-22 was effective in protect multiple organ failure in rats caused by endotoxin- induced cachexia.
• Example 5 Protective Effect of IL-22 on LPS/GalN-induced acute liver failure in mice.
• Lippolysaccharides 100 ng/mL, Sigma, Cat: L2630
• D-galactosamine D-GaIN, 130 mg/mL, Sigma, Cat: G1639
• Female BALB/c mice 6-8 weeks, were injected introperitoneally (i.p.) with 0.2mL solution containing 0.ImL of LPS and 0.1 mL D-GaIN.
• LPS/GalN The injection of LPS/GalN into mice induced acute liver failure evidenced by rapid elevation of liver enzymes (> 20-fold increase compared to control group) including a greater than 20-fold increase of alanine aminotransferase (ALT) and a greater than 40-fold increase of aspartate aminotransferase (AST) in the serum at 8 hrs. Less than 20% mice were viable at 24 hrs after LPS/GalN challenge.

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• 2010
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