WO1992012724A1 - Procede de prevention et de traitement du diabete sucre insulinodependant - Google Patents

Procede de prevention et de traitement du diabete sucre insulinodependant Download PDF

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Publication number
WO1992012724A1
WO1992012724A1 PCT/US1991/009151 US9109151W WO9212724A1 WO 1992012724 A1 WO1992012724 A1 WO 1992012724A1 US 9109151 W US9109151 W US 9109151W WO 9212724 A1 WO9212724 A1 WO 9212724A1
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Prior art keywords
irap
insulin
cells
iddm
islets
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PCT/US1991/009151
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English (en)
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Décio Laks EIZIRIK
Stellan Wilhem Sandler
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The Upjohn Company
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Publication of WO1992012724A1 publication Critical patent/WO1992012724A1/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

Definitions

  • the present invention relates to the treatment of insulin dependent diabetes mellitus 5 (IDDM) using Interleukin 1 Receptor Antagonist Protein (IRAP).
  • IDDM insulin dependent diabetes mellitus 5
  • IRAP Interleukin 1 Receptor Antagonist Protein
  • Diabetes mellitus is characterized by a broad array of physiologic and anatomic abnormalities, but its most notable feature is disturbed glucose metabolism, resulting in inappropriate hyperglycemia. In fact, diagnosis is usually based on basal, postprandial, or post- 10 glucose load measurements of blood or plasma glucose-levels. Estimates from the National Health Interview Survey indicate that about 2.4 percent of the United States population, or 5.5 million people, consider themselves to be diabetic.
  • DM has no distinct etiology, pathogenesis, invariable set of clinical findings, specific laboratory tests, or definitive and curative therapy, although it is nearly always associated with 15 fasting hyperglycemia and decreased glucose tolerance.
  • the complete clinical syndrome of DM involves hyperglycemia, large-vessel disease, microvascular disease (retina and kidney) and neuropathy.
  • Diabetic conditions are generally divided into two categories: insulin-dependent diabetes mellitus (IDDM or Type I) and non-insulin-dependent diabetes mellitus (NIDDM or Type II).
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM non-insulin-dependent diabetes mellitus
  • 20 Patients who depend on insulin for the prevention of ketoacidosis have IDDM.
  • IDDM most often develops in childhood or adolescence, so this form of the disease was previously termed juvenile-onset diabetes; other names for IDDM are ketosis- or acidosis-prone and Type I diabetes.
  • IDDM patients are literally dependent on exogenous insulin to prevent ketoacidosis and death.
  • This type of diabetes is associated with certain histocompatibility antigens (HLA) on 25 chromosome 6, with autoimmunity directed against the islet, and possibly with a predisposition to viral infections.
  • HLA histocompatibility antigens
  • Viruses of several types are some of the environmental agents
  • DM results in suppressed insulin secretion.
  • the lack of insulin causes elevated blood 30 glucose levels referred to as hyperglycemia.
  • the classification of a patient as IDDM or NIDDM is often based upon the severity of insulin secretion impairment experienced.
  • physiological problems encountered by patients with DM include: large vessel disease such as increased atherosclerosis, a greater risk of cardiovascular death, and peripheral vascular disease; microvascular disease such as abnormality in the thickness of the basal lamina of 35 capillaries, frequently in the retina and retina glomeruli; and, segmental injury to nerve cells.
  • large vessel disease such as increased atherosclerosis, a greater risk of cardiovascular death, and peripheral vascular disease
  • microvascular disease such as abnormality in the thickness of the basal lamina of 35 capillaries, frequently in the retina and retina glomeruli
  • segmental injury to nerve cells include: large vessel disease such as increased atherosclerosis, a greater risk of cardiovascular death, and peripheral vascular disease; microvascular disease such as abnormality in the thickness of the basal lamina of 35 capillaries, frequently in the retina and retina glomeruli; and, segmental injury to nerve cells.
  • IDDM face the life threatening risks of ketoacidosis.
  • IDDM islet cell antibodies
  • the symptoms and signs of large-vessel atherosclerosis in the diabetic are the same as in nondiabetic patients.
  • the symptoms and signs of microvascular disease are those of renal failure if the glomerular capillaries are involved, or visual loss if the retinal capillaries are affected.
  • Proteinuria usually is the first indication of nephropathy, and it may reach nephrotic levels. The greater the proteinuria, the more rapid is the development of renal failure. Renal failure is seen in 50% of IDDM patients after 20 to 30 yr of diabetes. Diabetic retinopathy is usually first detected 5 yr or more after the diagnosis of DM is made and is present to some degree by 10 yr in 50% of patients.
  • the primary objective is to achieve the patient's optimal health and nutrition.
  • An integrated index of long-term blood glucose control is now available through the use of stable glucosylated Hb determinations. Normally about 7% of HbA molecules are modified during erythrocyte synthesis. Since the half-life of this cell and its Hb is 60 days, the percent of stable glucosylated Hb reflects the mean blood glucose concentration over the preceding 2 mo. With the removal of the labile glucosylated Hb fraction prior to assay, the final result is not significantly influenced by glucose fluctuations. Determinations of glucosylated Hb are helpful in judging the degree of chronic glucose control in both IDDM and NIDDM patients and in judging efficacy of changes in therapy.
  • the objectives of the treatment of diabetes are (1) to avoid ketoacidosis, (2) to control symptoms resulting from hyperglycemia and glucosuria, and (3) to prevent the micro and macrovascular complications of diabetes. Through the use of self blood glucose monitoring
  • SBGM serum glucose lowering meter
  • sulfonylureas that can lower the blood glucose level when given orally may be used to treat selected patients.
  • exogenous insulin must be administered to maintain proper blood glucose levels.
  • the present invention provides a method of treating IDDM comprising administration of an effective amount of Interleukin-1 Receptor Antagonist Protein (IRAP).
  • IL-1 Interleukin-1 Receptor Antagonist Protein
  • the cytokine interleukin-1 (IL-1) may have an important role in the autoimmune mediated damage of pancreatic B-cells found in patients suffering from IDDM.
  • IRAP a specific blocker of the IL-1 receptor, prevents the deleterious actions of recombinant IL-1 on insulin-producing cells. It is believed that by preventing the suppressive actions of IL-1, the administration of IRAP will protect the pancreatic B-cells from being damaged and, therefore, prevent the onset of pathophysiology associated with IDDM.
  • patients susceptible to IDDM will not require exogenous insulin since they will not experience impaired insulin secretion. They will likewise be spared of all other debilitations related to IDDM.
  • PCT International Application Number PCT/US89/02275 published 30 November 1989 discloses an Interleukin-1 inhibitor purified from cultures human monocytes. Furthermore, an inhibitor gene is disclosed and a recombinant inhibitor described.
  • Liao et al. J. Exp. Med. 159:126-136 (1984) teach the identification of an IL-1 inhibitor found in urine from febrile patients.
  • the IL-1 inhibitor disclosed by Liao et al. has a molecular mass of between 20-40 kdal.
  • Liao et al. note that the evidence suggests that the molecule is a protein or a glycoprotein but that the evidence is insufficient to support such a statement without additional information.
  • a 95 kdal molecule derived from human monocytes stimulated by cytomegalovirus is also disclosed. Additionally, an IL-1 inhibitor with a molecular mass of about 95 kdal derived from human macrophages exposed to influenza and syncytial virus and from human virus-infected B cells is reported.
  • IL-1 induced inhibition of insulin secretion in rat pancreatic islet cells is not related to mechanisms by which alloxan or streptozotocin impair B-cell function.
  • Eizirik D. L., and Sandier, S., Diabetologia, 32:769-773 (1989) disclose that stimulation of insulin-release from pancreatic islet cells induced by acute exposure to human interleukin-1 is accompanied by an increase in mitochondrial oxidative events. It is disclosed that the suggested interleukin-induced inhibition of islet function mediated through impairment of oxidative metabolism is related to the same changes in substrate metabolism responsible for acute stimulatory effects of ⁇ L-l ⁇ on islet functions.
  • Eizirik D.L., et al., Endocrinology, 126:1611-1616 (1991) disclose that IL-1 induced inhibition of insulin secretion in rat pancreatic islets is mediated by activation of gene transcription and protein translation. Similar findings are reported by Eizirik, Autoimmunity, 10:107-113 (1991) in mouse pancreatic islets.
  • the present invention provides a method for the treatment or prevention of insulin dependent diabetes melitis (IDDM) in mammals.
  • This method comprises administering to a mammal, who is suffering from or is particularly susceptible to said IDDM, an amount of Interleukin-1 receptor antagonist protein (IRAP) effective to cure or prevent said IDDM.
  • IDM insulin dependent diabetes melitis
  • the cytokine interleukin-1 / S may have an important role in the autoimmune mediated damage of pancreatic B-cells in insulin-dependent diabetes mellitus.
  • IL-l/S cytokine interleukin-1 / S
  • IRAP a specific blocker of the type 1 IL-l S receptor
  • rIL-ljS recombinant IL-l S
  • rIL-l/S 5 ng/ml
  • IRAP 500 ng/ml
  • rIL-1 induced impairment in insulin release and decrease in islet insulin and DNA content 5 ng/ml
  • IRAP also counteracted the inhibitory effects of rIL-lS on the growth of the rat insulinoma cell line RINm5F.
  • IL-1 cytokine interleukin-1
  • rIL-l/S recombinant IL-l / S
  • IRAP interleukin-1 receptor antagonist protein
  • Insulin release experiments evaluated the effect of IRAP exposure on the suppression of insulin releasing activity caused in cells by short- and long-term exposure to IL-1.
  • Rat pancreatic islet cells were exposed to IL-1 for one hour, two hours or 48 hours; glucose stimulated insulin release or insulin accumulation in culture medium was then measured.
  • IRAP was added to the cells 15 minutes before one hour exposure to IL-1.
  • IRAP was added after the first hour of IL-1 exposure in cells exposed to E -1 for two hours.
  • IRAP was added at the same time as IL-1 in the 48 hour exposure experiments, and the medium changed every 12 hrs with the addition of fresh IRAP and IL-1.
  • cytokine containing medium was replaced after the allotted time of exposure.
  • Glucose stimulated insulin release 12 hours after exposure to cytokine was measured in the first two time experiments. In the 48 hour experiments, the glucose stimulated insulin release was measured immediately after exposure to IL-1 and/or IRAP. In the 48 hour group, DNA and insulin content was also measured, which is discussed below. Similar insulin release experiments were performed on mouse pancreatic islet cells to evaluate the effect of IRAP exposure on the suppression of insulin releasing activity caused in cells by exposure to IL-1 for one hour.
  • IL-l/S The biological activity of human recombinant IL-l/S that was used was 5 U/ng, as compared with an interim international standard rIL-l/S preparation (NIBSC, London, UK).
  • concentrations of rIL-l/S that were used (5 or 10 ng//ml) have been found to functionally suppress pancreatic islets and arrest the growth of the rat insulinoma cell line RINm5F without inducing widespread cell killing.
  • Recombinant IRAP was prepared as described in Carter, D.B. et al., Nature, 344:633-638 (1990).
  • Pancreatic islets were isolated by collagenase digestion from adult male Sprague- Dawley rats bred in a local colony (Uppsala, Sweden) or from adult male NMRI mice
  • the rat insulinoma cell line used was RINm5F.
  • the rat and mouse islets were cultured free-floating in medium RPMI 1640 containing 11.1 mM glucose and supplemented with 10% (vol/vol) of donor calf serum.
  • Growing RINm5F cells were trypsinized and subcultured in RPMI 1640 supplemented with 10% (vol/vol) fetal calf serum.
  • Exposure of rat and mouse islets to rIL-l/S was performed for 60-120 min. in culture medium, as described above. When cells were to be exposed to IL-1 for 60 min., IRAP was always added 15-20 min. before rIL-l/S.
  • IRAP was added after the first 60 min. of IL-1 exposure. After exposure to rlL- 1/8 and/or IRAP, the islets were washed in RPMI 1640, transferred to new culture dishes and maintained in culture medium for 12 hr without any further additions before functionally studied. In some experiments, rat islets or RINm5F cells were cultured for 48 hr in the presence of both rIL-l/S and IRAP before functional studies.
  • Insulin release insulin accumulation into the medium, DNA and insulin contents was determined as described in Sandier S., et al., Endocrinology 121:1424-1431 (1987). Briefly, insulin release was studied in triplicate groups of 10 islets by a first hour incubation at 1.7 mM glucose. The incubation medium, Krebs-Ringer bicarbonate buffer was supplemented with 2 mg/ml BSA and 10 mM Hepes (KRBH). After the first hour, the medium was gently removed and replaced by KRBH containing 16.7 mM glucose and the incubation continued for a second 60 min. period.
  • IRAP can protect insulin-producing cells against both forms of IL-1 (IL-l/S and IL-l ⁇ ).
  • rat islets were incubated in the presence of rIL-l/S (5 ng/ml) and IRAP for 48 hours and the medium changed every 12 hrs with the addition of fresh IRAP and tTL-l ⁇ .
  • Culture in the presence of high concentrations of IRAP did not affect islet function, as evaluated by acute glucose-stimulated insulin release, DNA and insulin content (Table 2).
  • rIL-lS inhibited insulin release by 90% and also induced a 35% decrease in islet insulin content and a 30% decrease in islet DNA content (P ⁇ 0.02 or less).
  • rBL-1/S-treated islets rBL-1/S-treated islets.
  • IRAP by itself did not interfere with the insulin release of NMRI islets (IRAP-treated islets, 45 ⁇ 3 ng insulin/10 islets x 60).
  • mouse islet cells seem to possess similar IL-1 receptors as the rat islet cells.
  • the islets of Langerhans contain an heterogeneous cell population. Even considering that the prolonged preculture (5-7 days) before exposure to rIL-l/S possibly eliminated most of the non-endocrine cells in the islets, it cannot be excluded that rIL-l/S acted through generation of a secondary signal from non-B cells. If this is the case, the protective action of IRAP could be due to blocking the IL-1 receptor on non-B-cells. To address this issue, the effects of rlL- 1/S and IRAP on a insulinoma cell line, RINm5F were investigated.
  • cytokines as therapeutics are well known.
  • Formulation, handling and administration of cytokines are well known to those having ordinary skill in the art.
  • the method of determining the effective dosage of IRAP for a particular patient is a matter that is within an ordinary level of skill in the art.
  • the Specification enables one having ordinary skill in the art to use the present invention without undue experimentation.
  • the autoimmune mediated damage of pancreatic B-cells caused IL-1 can be averted.
  • the onset or progress of IDDM can be arrested and normal function of insulin producing cells can be maintained.
  • IRAP As a prophylactic or therapeutic in the prevention or treatment of IDDM, an effective amount of IRAP sufficient to block IL-1 receptors on insulin producing cells is administered to a patient.
  • the amount of IRAP present must be equal to or, more preferably, exceed the amount of IL-1 present.
  • the presence of IRAP must be sustained continually at levels sufficient to effectively compete with the endogenous IL-1. The presence of IRAP will prevent the damage and death of insulin-producing cells associated with IDDM.
  • Contemplated equivalents of the present invention include a method of preventing or treating IDDM comprising administration of an effective amount of an IRAP equivalent; an IRAP equivalent being defined as a molecule which is functionally similar and structurally related to IRAP.
  • IRAP equivalents can include: IRAP fragments; molecules with similar amino acids as IRAP but which have some amino acid insertions, deletions or substitutions; and, chimeric proteins containing functional regions of IRAP.
  • Example 1 Use of IRAP in the Treatment of IDDM can include: IRAP fragments; molecules with similar amino acids as IRAP but which have some amino acid insertions, deletions or substitutions; and, chimeric proteins containing functional regions of IRAP.
  • IRAP is formulated either as a solution in saline or buffer at physiological pH, or as an emulsion similar to that used for administration of antibiotics. The purpose of such emulsions is to retard the absorption and the degradation of IRAP. It can also be mixed with adjuvants for the same purpose. IRAP can also be formulated complexed with a human non-neutralizing anti-IRAP antibody to retard degradation and act as a slow release dosage form.
  • IRAP is used to treat humans shortly or immediately after the diagnosis of IDDM. IRAP is administered at doses ranging from 1 ⁇ g/kg to 1000 ⁇ g/kg per treatment, and the frequency of treatments varies from once a day to four times a day.
  • the routes of administration include subcutaneous and intramuscular injection intravenous infusion or oral enteric coated preparations. When given several times a day it is preferentially administered orally before meals. In the preferred embodiment of the present invention, 150 ⁇ g/kg/day are administered by intravenous infusion.
  • IRAP can also be used in humans at high risk of developing IDDM.
  • first degree relatives of diabetic patients with high titers of ICA and a first phase insulin release below the 5th percentile of the normal population will be treated with IRAP, as described above.
  • Results are means ⁇ . SEM of 5-6 separate experiments. * P ⁇ 0.001 vs. control (untreated) group, using ANOVA.
  • Results are means +. SEM of 6 separate experiments. * P ⁇ 0.015 vs. control (untreated) group, using ANOVA.

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Abstract

Cette invention concerne un procédé permettant de traiter le diabète sucré insulinodépendant. Ledit procédé comprend l'administration à un patient souffrant de diabète sucré insulinodépendant, d'une quantité d'une protéine d'antagoniste de récepteur d'interleukine-1 efficace pour réduire la gravité dudit diabète sucré insulinodépendant.
PCT/US1991/009151 1991-01-17 1991-12-12 Procede de prevention et de traitement du diabete sucre insulinodependant WO1992012724A1 (fr)

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US642,327 1991-01-17

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994006457A1 (fr) * 1992-09-17 1994-03-31 Synergen, Inc. Compositions pharmaceutiques a base d'inhibiteurs de l'interleukine-1
EP0734395A1 (fr) * 1993-12-15 1996-10-02 University Of South Florida Antagoniste d'un recepteur de l'interleukine-1 attenuant la gravite de la pancreatite aigue
US6159460A (en) * 1988-05-27 2000-12-12 Amgen Inc. Method for treating interleukin-1 mediated diseases
WO2001011031A2 (fr) * 1999-05-27 2001-02-15 University Of Pittsburgh Of The Commonwealth System Of Higher Education TRANSFERT DE GENES DANS DES CELLULES β PANCREATIQUES POUR PREVENIR LE DYSFONCTIONNEMENT DE CES CELLULES REGROUPEES EN ILOTS
US6599873B1 (en) 1988-05-27 2003-07-29 Amgen Inc. Interleukin-1 inhibitors, compositions, and methods of treatment
US6733753B2 (en) 1997-02-10 2004-05-11 Amgen Inc. Composition and method for treating inflammatory diseases
US6858409B1 (en) 1988-05-27 2005-02-22 Amgen Inc. Nucleic acids encoding interleukin-1 inhibitors and processes for preparing interleukin-1 inhibitors
EP2241328A1 (fr) * 2000-05-12 2010-10-20 Immunex Corporation Inhibiteurs d'interleukine 1 dans le traitement de maladies

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Diabetologia, vol. 34, no. 6, June 1991, (Berlin, DE), D.L. EIZIRIK et al.: "An interleukin-1 receptor antagonist protein protects insulin-producing beta cells against suppressive effects of interleukin-1beta", pages 445-448, see the whole document (cited in the application) *
FEBS Letters, vol. 261, no. 1, February 1990, (Amsterdam, NL), P. HAMMONDS et al.: "Insulin-secreting beta-cells possess specific receptors for interleukin-1beta", pages 97-100, see the abstract; page 99, right-hand column, line 34 - page 100, left-hand column, line 2 (cited in the application) *
Nature, vol. 344, 12 April 1990, (London, GB), D.B. CARTER et al.: "Purification, cloning, expression and biological characterization of an interleukin-1 receptor antagonist protein", pages 341-346, see the abstract; page 637, right-hand column, lines 26-44 (cited in the application) *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6159460A (en) * 1988-05-27 2000-12-12 Amgen Inc. Method for treating interleukin-1 mediated diseases
US6599873B1 (en) 1988-05-27 2003-07-29 Amgen Inc. Interleukin-1 inhibitors, compositions, and methods of treatment
US6858409B1 (en) 1988-05-27 2005-02-22 Amgen Inc. Nucleic acids encoding interleukin-1 inhibitors and processes for preparing interleukin-1 inhibitors
WO1994006457A1 (fr) * 1992-09-17 1994-03-31 Synergen, Inc. Compositions pharmaceutiques a base d'inhibiteurs de l'interleukine-1
AU675969B2 (en) * 1992-09-17 1997-02-27 Amgen, Inc. Pharmaceutical formulations of interleukin-1 inhibitors
EP0734395A1 (fr) * 1993-12-15 1996-10-02 University Of South Florida Antagoniste d'un recepteur de l'interleukine-1 attenuant la gravite de la pancreatite aigue
EP0734395A4 (fr) * 1993-12-15 1997-03-19 Univ South Florida Antagoniste d'un recepteur de l'interleukine-1 attenuant la gravite de la pancreatite aigue
US5919444A (en) * 1993-12-15 1999-07-06 University Of South Florida Method for decreasing severity of acute and chronic pancreatitis
US6733753B2 (en) 1997-02-10 2004-05-11 Amgen Inc. Composition and method for treating inflammatory diseases
WO2001011031A2 (fr) * 1999-05-27 2001-02-15 University Of Pittsburgh Of The Commonwealth System Of Higher Education TRANSFERT DE GENES DANS DES CELLULES β PANCREATIQUES POUR PREVENIR LE DYSFONCTIONNEMENT DE CES CELLULES REGROUPEES EN ILOTS
WO2001011031A3 (fr) * 1999-05-27 2001-08-23 Univ Pittsburgh TRANSFERT DE GENES DANS DES CELLULES β PANCREATIQUES POUR PREVENIR LE DYSFONCTIONNEMENT DE CES CELLULES REGROUPEES EN ILOTS
EP2241328A1 (fr) * 2000-05-12 2010-10-20 Immunex Corporation Inhibiteurs d'interleukine 1 dans le traitement de maladies

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