WO2000050067A1 - Procede et composition pour la regulation de la production hepatique et extra hepatique du facteur de croissance insulinoide 1 - Google Patents

Procede et composition pour la regulation de la production hepatique et extra hepatique du facteur de croissance insulinoide 1 Download PDF

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Publication number
WO2000050067A1
WO2000050067A1 PCT/SE2000/000391 SE0000391W WO0050067A1 WO 2000050067 A1 WO2000050067 A1 WO 2000050067A1 SE 0000391 W SE0000391 W SE 0000391W WO 0050067 A1 WO0050067 A1 WO 0050067A1
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WIPO (PCT)
Prior art keywords
igf
liver
production
hepatic
growth
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PCT/SE2000/000391
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English (en)
Inventor
John-Olov Jansson
Claes Olsson
Olle Isaksson
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Saltech I Göteborg Ab
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Filing date
Publication date
Priority claimed from SE9900708A external-priority patent/SE9900708L/xx
Priority claimed from SE9903108A external-priority patent/SE9903108D0/xx
Application filed by Saltech I Göteborg Ab filed Critical Saltech I Göteborg Ab
Priority to AU35792/00A priority Critical patent/AU3579200A/en
Publication of WO2000050067A1 publication Critical patent/WO2000050067A1/fr

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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
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a method for separately regulating hepatic and extrahepatic production of insulin- like growth factor- 1 (IGF-1). It also relates to the treatment of obesity; and use of inhibitors of hepatic and circulating IGF-1 for the production of pharmaceuticals for preventing or reducing obesity.
  • the invention further refers to the treatment of retinopathy in diabetic patients and use of inhibitors of hepatic and circulating IGF-1 for the production of pharmaceuticals for preventing or reducing retinopathy.
  • IGF-1 Insulin-like growth factor-1
  • IGF-1 Insulin-like growth factor- 1
  • IGF-1 Insulin-like growth factor-1
  • tyrosine kinase family of cell membrane receptors
  • IGF-1 is present in large quantities in blood circulation.
  • the results obtained by us (Sjogren et al., 1999) as well as others (Froesh et al. 1985) demonstrate that the majority of all circulating IGF-1 is liver derived.
  • the circulating IGF-1 is to a large part bound in a ternary complex to two other proteins, acid labile subunit (ALS) and IGF binding protein-3 (IGFBP-3), which also are produced by the liver (Jones & Clemmons, 1995, Stewart & Rothwein, 1996).
  • ALS acid labile subunit
  • IGFBP-3 IGF binding protein-3
  • GH Growth hormone
  • IGF-1 a major stimulator of body growth released from the pituitary, stimulates the production of IGF-1 in the liver but also locally in peripheral target tissues of the growth promoting effect of GH (Isaksson et al., 1982, D'Ercole et al., 1984, Froesh et al, 1985, Daughaday & Rotwein, 1989).
  • GH is secreted in a more or less pulsatile fashion (Jansson et al., 1985).
  • the degree of pulsatility seems to be affected by several factors such as age and gender (Jansson et al., 1985, Jaffe et al., 1998).
  • continuous GH promotes several effects in the liver (Jansson et al., 1985, Gustafsson et al, 1983).
  • a continuous GH pattern may be more effective than a pulsatile GH secretion in inducing liver growth as well as hepatic IGF-1 production.
  • the latter effect could in turn result in higher levels of liver derived IGF-1 in blood circulation after continuous GH treatment (Clark et al., 1995, Orlowski & Chernausek, 1988).
  • the physiological role of liver derived, circulating IGF-1 versus locally produced IGF-1 has been unclear.
  • estrogens may regulate liver production of IGF-1.
  • Orally administered estrogens which have been reported to inhibit the hepatic IGF-1 production via a so called first passage effect exerted directly on the liver (O'Sullivan et al., 1998).
  • food intake is a stimulator of hepatic IGF-1 production (Stewart & Rothwein, 1996).
  • IGF-1 and IGF-2 are assumed to be of crucial importance for body growth. Experiments in which the IGF-1 and IGF-2 genes have been deleted in mice indicate that both IGF-1 and IGF-2 are of importance for growth before birth (Powel-Braxton et al., 1993, Liu et al., 1993, Baker et al., 1993). These gene knock out experiments as well as studies in which IGF-2 has been expressed in very high levels in transgenic mice indicate that IGF-2 is not important for postnatal growth. Moreover, treatment with IGF-2 does not reverse the growth inhibition in GH deficient rats indicating that IGF-2 is not of major importance for the growth stimulating effect of endogenous GH during adult life (see Stewart & Rothwein, 1996).
  • IGF-1 unlike IGF-2, is of importance for growth after birth (Powel-Braxton et al, 1993, Liu et al., 1993, Baker et al. 1993).
  • a patient with a deletion of the IGF-I gene demonstrated postnatal growth failure in addition to intrauterine growth retardation (Woods et al., 1996).
  • IGF-1 can partly, but not completely, substitute for GH in stimulation of body growth (Daughaday & Rotwein, 1989, Stewart & Rothwein, 1996).
  • systemic administration of IGF-I to GH-deficient/ GH receptor-mutated animals and man stimulates body growth.
  • IGF binding proteins a group of endogenous factors could also be used pharmacologically to inhibit deleterious effects of IGF, as previously claimed (US Pat 5681818, US Pat 5693754, US Pat 5840673).
  • IGF-1 receptor specific tyrphostins could inhibit the effects of IGF-1 (Parrizas et al., 1997).
  • IGF does not affect the proliferation of hepatocytes, since these cells have no IGF-1 receptors. However, some tumours cells originating from hepatocytes may get more IGF-1 receptors, a feature that could provide them with a growth advantage (Caro et al., 1988). In vivo, overexpression of IGF-2, which also act via IGF-1 receptors, has been found in pre-neoplastic noduli and hepatic tumours (Stewart & Rothwein 1996). Lung cancer cells that have higher number of IGF-1 receptors and are more responsive to IGF are also more prone to get implanted as metastases in the liver (Long et al., 1994).
  • IGF-1 may play a role also for the development of liver cirrhosis, a condition with accumulation of collagen and connective tissue in the liver.
  • IGF-1 receptors there are very few IGF-1 receptors on normal, non-tumour hepatocytes (Froesh et al., 1985). Instead, the cirrhosis promoting effect of IGF-1 seems to be mediated by receptors on another cell type in the liver, i.e., the so-called stellate cells.
  • these cells begin to proliferate and to produce collagen and other components of connective tissue that cause this illness. This proliferation and collagen production may partly be due to stimulation by IGF-1 (Pinzani et al, 1990).
  • Fig. 1 shows body weight growth curves for male (A) and female (B) mice after inactivation of the IGF-1 gene, compared with controls
  • Fig. 2 shows the liver / body weight ratio for IGF-1 inactivated mice compared to controls.
  • liver IGF-1 production caused a 75-80% decrease of the levels of IGF-1 in blood circulation. There was no substantial effect on body growth, while liver growth was increased in relation to body weight.
  • beneficial effects include, but are not limited to, stimulated liver growth and function.
  • IGF-1 antagonists IGF binding proteins, e.g. IGF binding protein III, or thyraphostins into blood circulation or by blockade of hepatic IGF-1 formation, for instance by oral treatment with estrogenic agents or by local treatment with small nucleotide molecules.
  • hepatic IGF-1 insulin growth factor-1
  • Such stimulation of body growth could be due to direct effects of growth hormone (GH) on extrahepatic tissues and may include stimulation of local IGF-1 in these extrahepatic tissues.
  • GH growth hormone
  • One way to get selective effects of GH on IGF-1 production and growth of extrahepatic target tissues could be by administration of GH in infrequent injections rather than more continuously.
  • IGF-1 could be linked to molecules, including IGF binding proteins, with a high affinity to extrahepatic tissues.
  • IGF-I -/- mice are leaner than control mice. This result indicates that it is possible to influence body composition via a delivery of a substance modulating the effect of circulating liver-derived IGF-I.
  • beneficial effects on body composition include, but are not limited to, treatment of obesity.
  • Inhibition of the biological effects exerted by IGF-I in blood circulation could be obtained by injection of IGF-I antagonists, IGF binding proteins, or thyrohostins into blood circulation or by blockade of hepatic IGF-I formation, for instance by oral treatment with estrogenic agents or by local treatment with small nucleotide molecules.
  • mice with a selective and inducible knock out of the IGF-1 gene in the liver were generated by mating of two mouse strains. These strains were the MxCre31 which were provided by Ralph Kuhn and Claus Rajewsky at the University of Cologne and the IGF-1 loxP mice with exon 4 of the IGF-I gene flanked with loxP sites generated by Derek LeRoith and coworkers at NIH (Liu et al., 1998).
  • the efficiency of recombination was studied by Southern blot. The recombination in the liver was higher than 90 % and a complete recombination was found in purified hepatocytes in LI- IGF-I -/- mice. A less than 20 % recombination was found in all other tissues except the spleen where 65% recombination was found. No recombination was found in Cre mice not induced with INF. IGF-I mRNA levels were decreased more than 90% in liver while no significant effect was seen in other tissues except in the spleen where IGF-1 mRNA was decreased by about 60%.
  • Serum IGF-I levels decreased dramatically in mice with liver specific IGF-1 gene deletion. The effect was seen within one week after INF-induction and was still present 53 days later. Thus, liver-derived IGF-I is the main determinant of serum IGF-I levels. The present results showed that at least 75% of all IGF-I in mouse serum is derived from the liver. This finding is in line with the results of previous indirect calculations based on the IGF-I production rate in isolated rat liver (Froesh et al., 1985).
  • US Patent Publication No US 5,240,961 (Aug 31, 1993): Method of treating reduced insulin like growth factor and bone loss associated with ageing.
  • US Patent Publication No US 5,681,818 (Oct 28, 1997) Therapeutic uses of human somatomedin earner proteins.
  • IGF-BP3 Insulin-like growth factor binding protein 3
  • Intravenous growth hormone growth responses to patterned infusions in hypophysectomized rats. J Endocnnol. 104, 53-61. Clark R.G., Mortensen D., Carlsson L.M S., Carmignac D., Robinson I.C.A.F. (1995). Growth responses to patterned GH delivery. Endocrine 3, 717-723
  • GH growth hormone
  • IGF-I Liver-derived msulm-hke growth factor I

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Zoology (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Cette invention se rapporte à un procédé servant à réguler séparément la production hépatique et extra hépatique du facteur de croissance insulinoïde 1 (IGF-1). Les niveaux de l'IGF-1 dans des sérum peuvent être considérablement réduits sans diminuer les actions souhaitées de l'IGF-1, ce que l'on obtient en régulant séparément la distribution systémique et locale de l'IGF-1 sans affecter la croissance corporelle. Cette invention se rapporte également au traitement de l'obésité, ainsi qu'au traitement de la rétinopathie chez les patients diabétiques. L'inhibition des effets biologiques exercés par l'IGF-1 dans la circulation sanguine peut être obtenue par injection d'antagonistes d'IGF-1, de protéine de fixation de l'IGF ou de thyrohostines dans la circulation sanguine ou par blocage de la formation d'IGF-1 hépatique, par exemple par traitement oral avec des agents oestrogènes ou par traitement local avec de petites molécules nucléotides.
PCT/SE2000/000391 1999-02-26 2000-02-28 Procede et composition pour la regulation de la production hepatique et extra hepatique du facteur de croissance insulinoide 1 WO2000050067A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU35792/00A AU3579200A (en) 1999-02-26 2000-02-28 Method and composition for the regulation of hepatic and extrahepatic productionof insulin-like growth factor-1

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
SE9900708A SE9900708L (sv) 1999-02-26 1999-02-26 Föefarande och komposition för reglering av hepatisk och extrahepatisk produktion av insulin-liknande tillväxtfaktor-1
SE9900708-0 1999-02-26
SE9903108-0 1999-09-01
SE9903108A SE9903108D0 (sv) 1999-09-01 1999-09-01 Effect of systemic liver derived IGF-1 for the treatment of obesity

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WO2000050067A1 true WO2000050067A1 (fr) 2000-08-31

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1546389A2 (fr) * 2002-09-06 2005-06-29 Elixir Pharmaceuticals, Inc. Regulation de l'axe hormone de croissance/igf-1
US7217796B2 (en) 2002-05-24 2007-05-15 Schering Corporation Neutralizing human anti-IGFR antibody
US7326567B2 (en) 2003-11-12 2008-02-05 Schering Corporation Plasmid system for multigene expression
US7811562B2 (en) 2004-12-03 2010-10-12 Schering Corporation Biomarkers for pre-selection of patients for anti-IGF1R therapy
WO2010146059A2 (fr) 2009-06-16 2010-12-23 F. Hoffmann-La Roche Ag Biomarqueurs pour une thérapie par inhibiteur d'igf-1r
US8017735B2 (en) 2003-11-21 2011-09-13 Schering Corporation Anti-IGFR1 antibody therapeutic combinations
US9234041B2 (en) 2001-01-05 2016-01-12 Pfizer Inc. Antibodies to insulin-like growth factor I receptor

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994022466A1 (fr) * 1993-04-07 1994-10-13 Synergen, Inc. Procedes d'utilisation de proteines de liaison de facteurs de croissance semblables a l'insuline
US5473054A (en) * 1992-05-08 1995-12-05 Thomas Jefferson University IGF-1 analogs
US5661143A (en) * 1993-08-06 1997-08-26 The Children's Medical Center Corp. Estrogenic compounds as anti-mitotic agents
US5798348A (en) * 1995-10-30 1998-08-25 Laboratorios S.A.L.V.A.T., S.A. Fatty-acid monoesters of estrogens for the treatment of obesity and/or overweight
US5840673A (en) * 1995-09-14 1998-11-24 Bristol-Myers Squibb Company Insulin-like growth factor binding protein 3 (IGF-BP3) in treatment of p53-related tumors

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5473054A (en) * 1992-05-08 1995-12-05 Thomas Jefferson University IGF-1 analogs
WO1994022466A1 (fr) * 1993-04-07 1994-10-13 Synergen, Inc. Procedes d'utilisation de proteines de liaison de facteurs de croissance semblables a l'insuline
US5661143A (en) * 1993-08-06 1997-08-26 The Children's Medical Center Corp. Estrogenic compounds as anti-mitotic agents
US5840673A (en) * 1995-09-14 1998-11-24 Bristol-Myers Squibb Company Insulin-like growth factor binding protein 3 (IGF-BP3) in treatment of p53-related tumors
US5798348A (en) * 1995-10-30 1998-08-25 Laboratorios S.A.L.V.A.T., S.A. Fatty-acid monoesters of estrogens for the treatment of obesity and/or overweight

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9234041B2 (en) 2001-01-05 2016-01-12 Pfizer Inc. Antibodies to insulin-like growth factor I receptor
US7217796B2 (en) 2002-05-24 2007-05-15 Schering Corporation Neutralizing human anti-IGFR antibody
US7851181B2 (en) 2002-05-24 2010-12-14 Schering Corporation Neutralizing human anti-IGFR antibody
EP1546389A2 (fr) * 2002-09-06 2005-06-29 Elixir Pharmaceuticals, Inc. Regulation de l'axe hormone de croissance/igf-1
EP1546389A4 (fr) * 2002-09-06 2006-07-26 Elixir Pharmaceuticals Inc Regulation de l'axe hormone de croissance/igf-1
US7326567B2 (en) 2003-11-12 2008-02-05 Schering Corporation Plasmid system for multigene expression
US8062886B2 (en) 2003-11-12 2011-11-22 Schering Corporation Plasmid system for multigene expression
US8017735B2 (en) 2003-11-21 2011-09-13 Schering Corporation Anti-IGFR1 antibody therapeutic combinations
US7811562B2 (en) 2004-12-03 2010-10-12 Schering Corporation Biomarkers for pre-selection of patients for anti-IGF1R therapy
WO2010146059A2 (fr) 2009-06-16 2010-12-23 F. Hoffmann-La Roche Ag Biomarqueurs pour une thérapie par inhibiteur d'igf-1r

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Publication number Publication date
AU3579200A (en) 2000-09-14

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