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WO2003013583A1 - Agonistes et antagonistes de faxigene dans le traitement de troubles metaboliques - Google Patents

Agonistes et antagonistes de faxigene dans le traitement de troubles metaboliques Download PDF

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Publication number
WO2003013583A1
WO2003013583A1 PCT/IB2002/003528 IB0203528W WO03013583A1 WO 2003013583 A1 WO2003013583 A1 WO 2003013583A1 IB 0203528 W IB0203528 W IB 0203528W WO 03013583 A1 WO03013583 A1 WO 03013583A1
Authority
WO
WIPO (PCT)
Prior art keywords
faxigen
activity
polypeptide
ligand
insulin
Prior art date
Application number
PCT/IB2002/003528
Other languages
English (en)
Inventor
John Lucas
Deno Dialynas
Kristen Briggs
Aaron Scalia
Original Assignee
Genset S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Genset S.A. filed Critical Genset S.A.
Publication of WO2003013583A1 publication Critical patent/WO2003013583A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6863—Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
    • 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
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value

Definitions

  • said AGONIST is able to lower circulating (either blood, serum or plasma) levels (concentration) of: (i) free fatty acids, (ii) glucose, and/or (iii) triglycerides.
  • AGONISTS are those that increase glucose uptake in adipose cells.
  • said soluble fragment of FAXIGEN polypeptide comprises, consists essentially of, or consists of, at least 6 and not more than 136 consecutive amino acids of SEQ ID NOs:2, 4, 6, 8, or 10, more preferably of amino acids comprising the extracellular domain of FAXIGEN.
  • Preferred said soluble fragment of FAXIGEN comprises the extracellular domain of mature FAXIGEN polypeptide.
  • Particularly preferred soluble fragment of FAXIGEN comprises amino acids 1-122, 2-122, 1-126, 2-126, 1-136 or 2-136 of SEQ ID NOs: 2, 4, 6, 8 or 10.
  • Another particularly preferred soluble fragment of FAXIGEN comprises amino acids 1-122, 2-122, 1-126, 2-126, 1-136 or 2-136 of SEQ ID NOs: 12, 14 or 16.
  • the invention is directed to a FAXIGEN ANTAGONIST, wherein said ANTAGONIST is an antibody that specifically binds FAXIGEN. More preferably the invention is directed to said FAXIGEN antibody, wherein said FAXIGEN antibody binds
  • the present invention of said pharmaceutical or physiologically acceptable composition further provides a method for the use as an insulin de- sensitiser, wherein the sensitivity of a cell or tissue to insulin is reduced.
  • said disorder is selected from the group consisting of cachexia, wasting, cancer-related weight loss, AIDS-related weight loss, chronic inflammatory disease-related weight loss, anorexia, and bulimia.
  • said individual is a mammal, preferably a human.
  • the invention provides ANTAGONIST of the twelfth aspect of the invention, or a composition of the thirteenth aspect of the invention, for use in a method of treatment of the human or animal body.
  • isolated requires that the material be removed from its original environment (e. g., the natural environment if the material is naturally occurring).
  • purified does not require absolute purity; rather, it is intended as a relative definition. Purification of starting material or natural material to at least one order of magnitude, preferably two or three orders, and more preferably four or five orders of magnitude is expressly contemplated.
  • recombinant polypeptide is used herein to refer to polypeptides that have been artificially designed and which comprise at least two polypeptide sequences that are not found as contiguous polypeptide sequences in their initial natural environment, or to refer to polypeptides which have been expressed from a recombinant polynucleotide.
  • operably linked refers to a linkage of polynucleotide elements in a functional relationship.
  • the compounds/polypeptides of the invention are capable of modulating the partitioning of dietary lipids between the liver and peripheral tissues, and are thus believed to treat "diseases involving the partitioning of dietary lipids between the liver and peripheral tissues."
  • peripheral tissues is meant to include muscle and adipose tissue.
  • the compounds/polypeptides of the invention partition the dietary lipids toward or away from the muscle.
  • the dietary lipids are partitioned toward or away from the adipose tissue.
  • the dietary lipids are partitioned toward or away from the liver.
  • Preferred diseases believed to involve the partitioning of dietary lipids include obesity- related diseases and disorders such as obesity, insulin resistance, atherosclerosis, atheromatous disease, heart disease, hypertension, stroke, Syndrome X, Noninsulin Dependent Diabetes Mellitus (NIDDM, or Type II diabetes) and Insulin Dependent Diabetes Mellitus (IDDM or Type I diabetes).
  • Diabetes-related complications to be treated by the methods of the invention include microangiopathic lesions, ocular lesions, retinopathy, neuropathy, and renal lesions.
  • Heart disease includes, but is not limited to, cardiac insufficiency, coronary insufficiency, and high blood pressure.
  • Other obesity-related disorders to be treated by compounds of the invention include hyperlipidemia and hyperuricemia.
  • disorders associated with excessive weight loss such as cachexia, wasting, cancer-related weight loss, AJDS-related weight loss, chronic inflammatory disease-related weight loss, anorexia, and bulimia.
  • the expression vector is any of the mammalian, yeast, insect or bacterial expression systems known in the art. Commercially available vectors and expression systems are available from a variety of suppliers including Genetics Institute (Cambridge, MA), Stratagene (La Jolla, California),
  • C2C12 cells are differentiated in the presence or absence of 2 ⁇ g/mL LIGAND for 4 days.
  • oleate oxidation rates are determined by measuring conversion of l- 14 C-oleate (0.2 mM) to 14 C0 2 for 90 min. This experiment can be used to screen for active polypeptides and peptides as well as AGONISTS and ANTAGONISTS or activators and inhibitors of LIGAND receptor.
  • EXAMPLE 3 Effect of LIGAND gain Vitro Glucose Uptake by Muscle Cells
  • L6 Muscle cells are obtained from the European Culture Collection (Porton Down) and are used at passages 7-11. Cells are maintained in standard tissue culture medium DMEM, and glucose uptake is assessed using [ 3 H]-2-deoxyglucose (2DG) with or without LIGAND in the presence or absence of insulin (10 "8 M) as has been previously described (Walker, P.S. et al. (1990) Glucose transport activity in L6 muscle cells is regulated by the coordinate control of subcellular glucose transporter distribution, biosynthesis, and mRNA transcription. JBC 265(3): 1516-1523; and Kilp, A. et al.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Cell Biology (AREA)
  • Hematology (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Urology & Nephrology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pathology (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Analytical Chemistry (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Physics & Mathematics (AREA)
  • Physics & Mathematics (AREA)
  • Food Science & Technology (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne le domaine de la recherche métabolique, en particulier la découverte de composés efficaces pour réduire la masse corporelle et utiles pour traiter des maladies et des troubles liés à l'obésité. Les maladies ou les troubles liés à l'obésité envisagés comme pouvant être traités par les méthodes de l'invention comprennent, de façon non exhaustive, l'hyperlipidémie, l'athérosclérose, la résistance insulinique, le diabète ainsi que l'hypertension. En particulier, l'invention concerne des méthodes d'identification et d'utilisation d'agonistes et d'antagonistes d'activité de faxigène, dans lesquelles ladite activité est choisie dans le groupe comprenant la séparation lipidique, le métabolisme lipidique ainsi que l'activité insulinoïde.
PCT/IB2002/003528 2001-08-10 2002-08-08 Agonistes et antagonistes de faxigene dans le traitement de troubles metaboliques WO2003013583A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US31130401P 2001-08-10 2001-08-10
US60/311,304 2001-08-10
US33712801P 2001-12-04 2001-12-04
US60/337,128 2001-12-04

Publications (1)

Publication Number Publication Date
WO2003013583A1 true WO2003013583A1 (fr) 2003-02-20

Family

ID=26977837

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2002/003528 WO2003013583A1 (fr) 2001-08-10 2002-08-08 Agonistes et antagonistes de faxigene dans le traitement de troubles metaboliques

Country Status (1)

Country Link
WO (1) WO2003013583A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7217790B2 (en) * 1999-10-22 2007-05-15 Zymogenetics, Inc. UMLR polypeptides

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999059618A1 (fr) * 1998-05-21 1999-11-25 Smithkline Beecham Corporation Acrp30r1l, homologue de acrp30 (proteine associee a un complement de l'adipocyte 30 kd)
WO2000001817A2 (fr) * 1998-07-06 2000-01-13 Schering Corporation Genes mammiferes ; transporteur du type prostaglandine de cellules dendritiques (dc-pgt), hdtea84, hsljd37r et rankl, chimiokine hcc5, proteines de desubiquitination 11 et 12 (dub11, dub12), md-1, md-2 et cycline e2, reactifs apparentes et procedes associes
WO2000039284A1 (fr) * 1998-12-30 2000-07-06 Millennium Pharmaceuticals, Inc. Proteines secretees et acides nucleiques codant ces proteines
EP1033134A1 (fr) * 1997-10-29 2000-09-06 Otsuka Pharmaceutical Co., Ltd. Compositions inhibant la proliferation des muscles lisses, procede de diagnostic de l'arteriosclerose et trousses correspondantes
WO2000053758A2 (fr) * 1999-03-08 2000-09-14 Genentech, Inc. Compositions et methodes de traitement des maladies immunitaires
WO2000061757A1 (fr) * 1999-04-12 2000-10-19 Genentech, Inc. Homologues de facteur de necrose tumorale et acides nucleiques les codant
WO2000068380A2 (fr) * 1999-05-11 2000-11-16 Incyte Genomics, Inc. Proteines de matrice extracellulaire associees a l'adhesion
WO2000073448A1 (fr) * 1999-05-27 2000-12-07 Zymogenetics, Inc. Homologue zacrp7 de proteine lie a un complement adipocyte
WO2001030850A1 (fr) * 1999-10-22 2001-05-03 Zymogenetics, Inc. Polypeptides umlr
WO2001051645A1 (fr) * 2000-01-14 2001-07-19 Genset Tete globulaire obg3 et ses utilisations pour reduire la masse corporelle

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1033134A1 (fr) * 1997-10-29 2000-09-06 Otsuka Pharmaceutical Co., Ltd. Compositions inhibant la proliferation des muscles lisses, procede de diagnostic de l'arteriosclerose et trousses correspondantes
WO1999059618A1 (fr) * 1998-05-21 1999-11-25 Smithkline Beecham Corporation Acrp30r1l, homologue de acrp30 (proteine associee a un complement de l'adipocyte 30 kd)
WO2000001817A2 (fr) * 1998-07-06 2000-01-13 Schering Corporation Genes mammiferes ; transporteur du type prostaglandine de cellules dendritiques (dc-pgt), hdtea84, hsljd37r et rankl, chimiokine hcc5, proteines de desubiquitination 11 et 12 (dub11, dub12), md-1, md-2 et cycline e2, reactifs apparentes et procedes associes
WO2000039284A1 (fr) * 1998-12-30 2000-07-06 Millennium Pharmaceuticals, Inc. Proteines secretees et acides nucleiques codant ces proteines
WO2000053758A2 (fr) * 1999-03-08 2000-09-14 Genentech, Inc. Compositions et methodes de traitement des maladies immunitaires
WO2000061757A1 (fr) * 1999-04-12 2000-10-19 Genentech, Inc. Homologues de facteur de necrose tumorale et acides nucleiques les codant
WO2000068380A2 (fr) * 1999-05-11 2000-11-16 Incyte Genomics, Inc. Proteines de matrice extracellulaire associees a l'adhesion
WO2000073448A1 (fr) * 1999-05-27 2000-12-07 Zymogenetics, Inc. Homologue zacrp7 de proteine lie a un complement adipocyte
WO2001030850A1 (fr) * 1999-10-22 2001-05-03 Zymogenetics, Inc. Polypeptides umlr
WO2001051645A1 (fr) * 2000-01-14 2001-07-19 Genset Tete globulaire obg3 et ses utilisations pour reduire la masse corporelle

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7217790B2 (en) * 1999-10-22 2007-05-15 Zymogenetics, Inc. UMLR polypeptides

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