US20110262385A1 - Use of interleukin-22 in the treatment of fatty liver disease - Google Patents

Use of interleukin-22 in the treatment of fatty liver disease Download PDF

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Publication number
US20110262385A1
US20110262385A1 US12/672,274 US67227408A US2011262385A1 US 20110262385 A1 US20110262385 A1 US 20110262385A1 US 67227408 A US67227408 A US 67227408A US 2011262385 A1 US2011262385 A1 US 2011262385A1
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fatty liver
cells
liver
use according
human
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Yu Liang HUANG
Zhi Hua Huang
Qi Sun
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Generon Shanghai Corp Ltd
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Assigned to GENERON (SHANGHAI) CORPORATION reassignment GENERON (SHANGHAI) CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HUANG, YU LIANG, HUANG, ZHI HUA, SUN, QI
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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
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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

  • Fatty liver is a disease in which excessive amounts of lipids accumulate in the liver cells. Normally lipids account for 3%-4% of the total weight of the liver. If the amount of lipid goes beyond 5%, a fatty liver forms. Lipids may comprise up to 40%-50% of the liver weight in severe fatty liver diseases. Fatty liver mainly comes from the disorder of lipid metabolism of the liver. The main form of lipid in the liver is triglyceride, which is characterized by macrovesicular steatosis. Fatty liver can lead to fibrosis of liver, cirrhosis and hepatocellular carcinoma. In US, around 31% of the adults are indicated to have fatty liver by NMR.
  • available clinical therapeutic strategies include, antioxidant, e.g., vitamin C, vitamin E; compounds in methione metabolism, e.g., betaine; metformin, which can sensitize insulin, other similar medications include: thiazolidinediones (TZD), inhibitors of angiotension II receptor; urodeoxycholic acid, which has the effect of cell protection, anti-apoptosis and regulation of immunity; pentoxifylline, which can act by inhibiting inflammatory factors such as tumor necrosis factor (TNF)- ⁇ ; other medicaments such as troglitazone, rosiglitazone and pioglitazone. All the therapeutic methods are not satisfactory.
  • TNF tumor necrosis factor
  • IL-22 functions by binding to its receptor IL-22R1 and IL-22R2.
  • IL-22R1 is specific receptor for IL-22, which is mainly expressed in skin, kidney, digestive system (pancreas, intestine, liver, large intestine, and colon) and respiratory system (lung, bronchus).
  • IL-22R1 is specific receptor for IL-22, which is mainly expressed in skin, kidney, digestive system (pancreas, intestine, liver, large intestine, and colon) and respiratory system (lung, bronchus).
  • A Oil Red O stained liver section of ob/ob mice (control);
  • FIG. 8A shows that treatment of high fat diet-induced FLD rats reduced body weight
  • FIG. 12 shows electron microscopy imaging of liver sections showing the size of fat droplets in hepatocytes.
  • IL-22 refers to a protein, which has essentially the same amino acid sequence as the human/murine IL-22 as described by Dumoutier in U.S. Pat. No. 6,359,117 and the same biological activity as natural IL-22.
  • IL-22 of the present invention includes but is not limited to human IL-22, recombinant human IL-22, murine IL-22 and recombinant murine IL-22.
  • subject refers to mice, human or other mammal animals.
  • therapeutically effective amount refers to an amount of IL-22 which can achieve the goal of therapy. It is to be understood by one of ordinary skill in the art that, therapeutically effective dose may change, depending on the routes of administration, the types of other ingredients used and the combination with other medicaments.
  • IL-22 of the present invention is expressed by recombinant gene clone technique.
  • the expression system includes prokaryotic cells, yeast or higher eukaryotic cells.
  • Suitable prokaryotic cell includes, but is not limited to G + or G ⁇ bacteria, such as E. coli .
  • Available strains of E. coli includes K12MM294 (ATCC 31,446), X1776 (ATCC 31,537), W3110 (ATCC 27,325) and K5772 (ATCC 53,635) etc.
  • Other suitable prokaryotic expression system includes, but is not limited to Erwinia, Klebsiella, Proteus, Salmonella , such as Salmonella typhimurium, Serratia such as Serratia marcescans, Shigella, B. subtilis, B. licheniformis, Pseudomonas such as P. aeruginosa and Streptomyces.
  • E. coli W3110 is preferred since it is often used as the host cell for
  • Host cells used to express glycosylated IL-22 of the present invention are mainly derived from multicellular organism.
  • invertebrate include insect, such as Drosophila S2 and Spodoptera Sf9, plant cells.
  • Suitable mammalian cells include Chinese Hamster Ovary (CHO), COS cells, in particular, SV40-transformed CV1 cell line (COS-7, ATCC CRL 1651); human embryo kidney cell line 293 (Graham et al., J. Gen Virol., 36:59 (1997)); CHO/-DHFR (Urlaub and Chasin, Proc. Natl. Acad. Sci. USA, 77:4216 (1980)); murine Sertoli cell (TM4, Mather, Biol.
  • nucleic acid micro-injection electroporation
  • bacterial protoplast fusion with intact cells or polycations
  • polycations such as polybrene, polyornithine
  • Keown et al. Methods in Enzymology, 185:527-537 (1990) and Mansour et al., Nature, 336:348-352 (1988).
  • Some other inducible yeast promoter can regulate transcription according to different growing conditions, including promoters for alcohol dehydrogenase 2, isocytochrome c, acid phosphatase, degrading enzymes related to degradation of nitrogen, Metallothionein, Glyceraldehyde-3-Phosphate, degrading enzymes of maltose and galactose.
  • promoters for alcohol dehydrogenase 2, isocytochrome c, acid phosphatase, degrading enzymes related to degradation of nitrogen, Metallothionein, Glyceraldehyde-3-Phosphate, degrading enzymes of maltose and galactose Detailed description of vectors and promoters suitable for yeast expression system can be seen in EP 73,657.
  • Enhancer is a kind of cis-acting element of DNA molecules, usually 10-300 bp, which can enhance the transcription of DNA molecules by acting on the promoters. Numbers of enhancers known enhancers are from mammalian gene, e.g. haptoglobin, elastase, albumin, ⁇ -fetoprotein and insulin.
  • the IL-22 encoding DNA sequence of the present invention can be used in gene therapy.
  • Gene therapy includes traditional therapy, which has long term effects after one time therapy and administration of gene therapy drugs, in which effective DNA or mRNA are administered one or several times.
  • Antisense RNA or DNA may also be used as gene therapy drugs to block the expression of some genes. It has been demonstrated that antisense oligonucleotide can act as inhibitors in cells, although they are only adsorbed by cell membrane to a limited extent and have a low concentration in cells (Zamecnik et al., Proc. Natl. Acad. Sci. USA 83:4143-4146 [1986]).
  • the absorbance of oligonucleotides may be improved by modification, such as substituent of the negative charged phosphodiester by balance charged groups.
  • micro-capsule containing IL-22 of the present invention can be used as sustained release system.
  • Sustained release micro-capsule system of recombinant protein has been successfully applied to rhGH, rhIFN, IL-2 and MNrgp 120 (Johnson et al., Nat. Med., 2:795-799 (1996); Yasuda, Biomed. Ther 27:1221-1223 (1993); WO 97/03692, WO 96/40072, WO 96/07399; U.S. Pat. No. 5,654,010).
  • IL-22 has the effect of treating fatty liver diseases. 2. IL-22 has the effect of decreasing levels of transaminases (especially, aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT).
  • transaminases especially, aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT).
  • Both human IL-22 and murine IL-22 were verified by DNA sequencing, as shown in FIG. 1 and FIG. 2 .
  • 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 0.1 mM 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° C.
  • the recombinant murine IL-22 obtained in example 2 was injected to obese ob/ob mice (8-12 weeks, 35-50 g) at a dose of 300 ⁇ g/kg/d for 14 days. Same amount of vehicle solution (0.1% BSA, PBS) was injected to the mice in control groups. The animals were sacrificed at day 15 and the serum was collected. Levels of serum ALT and AST were determined. The results are shown in FIG. 5 .
  • the recombinant murine IL-22 obtained in example 2 was injected to obese ob/ob mice (8-12 weeks, 35-50 g) at a dose of 300 ⁇ g/kg/d for 14 days. Same amount of vehicle solution (0.1% BSA, PBS) was injected to the mice in control groups. The animals were sacrificed at day 15. The liver was collected and fixed in 10% formalin. Tissue section was stained with Hematoxylin-Eosin. The results were shown in FIG. 6 .

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  • Gastroenterology & Hepatology (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
US12/672,274 2007-08-06 2008-08-01 Use of interleukin-22 in the treatment of fatty liver disease Abandoned US20110262385A1 (en)

Applications Claiming Priority (3)

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CN2007100445927A CN101361968B (zh) 2007-08-06 2007-08-06 白介素-22在治疗脂肪肝中的应用
CNCN200710044592.7 2007-08-06
PCT/US2008/071859 WO2009020844A1 (en) 2007-08-06 2008-08-01 Use of interleukin-22 in the treatment of fatty liver disease

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US9273108B2 (en) 2010-05-25 2016-03-01 Generon (Shanghai) Corporation Ltd. Recombinant human G-CSF dimer and use thereof for the treatment of neurological diseases
US9352024B2 (en) 2011-12-27 2016-05-31 Generon (Shanghai) Corporation Ltd. Uses of interleukin-22(IL-22) in treating and preventing nerve damage diseases or neurodegenerative diseases
US9629898B2 (en) 2010-08-31 2017-04-25 Generon (Shanghai) Corporation, Ltd. Use of interleukin-22 in treating viral hepatitis
US9642917B2 (en) 2011-07-25 2017-05-09 Generon (Shanghai) Corporation, Ltd. Use of G-CSF dimer in preparation of medicament for treatment of neurodegenerative diseases
US10543169B2 (en) 2013-11-07 2020-01-28 Generon (Shanghai) Corporation Ltd. Use of IL-22 dimer in manufacture of a medicament for intravenous administration
US10695406B2 (en) 2014-05-27 2020-06-30 The University Of Queensland Modulation of cellular stress using a B-cell oxidative and/or endoplasmic reticulum stress inhibitor and a targeting agent
US10786551B2 (en) 2007-08-06 2020-09-29 Generon (Shanghai) Corporation Ltd. Use of interleukin-22 in the treatment of fatty liver disease
US11510966B2 (en) 2016-04-15 2022-11-29 Evive Biotechnology (Shanghai) Ltd Use of IL-22 in treating necrotizing enterocolitis
US12527875B2 (en) 2020-02-19 2026-01-20 Evive Biotechnology (Shanghai) Ltd Methods for treating graft versus host disease

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US11246915B2 (en) 2010-09-15 2022-02-15 Applied Molecular Transport Inc. Cholix toxin-derived fusion molecules for oral delivery of biologically active cargo
WO2014145016A2 (en) 2013-03-15 2014-09-18 Genentech, Inc. Il-22 polypeptides and il-22 fc fusion proteins and methods of use
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WO2009020844A1 (en) 2009-02-12
EP2185202A4 (en) 2013-11-06
CN101361968A (zh) 2009-02-11
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US10786551B2 (en) 2020-09-29
AU2008284116A1 (en) 2009-02-12
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