WO2017063657A1 - Antagoniste peptidique dérivé de l'il-1ra - Google Patents

Antagoniste peptidique dérivé de l'il-1ra Download PDF

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Publication number
WO2017063657A1
WO2017063657A1 PCT/DK2016/050331 DK2016050331W WO2017063657A1 WO 2017063657 A1 WO2017063657 A1 WO 2017063657A1 DK 2016050331 W DK2016050331 W DK 2016050331W WO 2017063657 A1 WO2017063657 A1 WO 2017063657A1
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peptide
use according
seq
diabetes mellitus
administered
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PCT/DK2016/050331
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English (en)
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Eva Steiness
Torben Skarsfeldt
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Phlogo Aps
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • C07K14/7155—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for 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

Definitions

  • the present invention relates to a peptide consisting of SEQ ID NO:1 derived from IL1 RA, or a variant thereof which differs from SEQ ID NO:1 at one amino acid position, for use in a method of postponing the onset of diabetes mellitus, increasing beta-cell mass, lowering average blood glucose, and/or increasing plasma insulin.
  • Interleukin 1 is a general name for two distinct pro-inflammatory cytokines proteins, IL-1 alpha and IL-1 beta. IL-1 exerts its effects by binding to specific transmembrane receptors (IL-1 R) on multiple cell types. The effects of IL-1 are counteracted by natural inhibitors such as soluble IL-1 receptors and IL-1 R antagonist protein (IL1 RA). IL1 RA inhibits the effect of IL-1 by blocking its interaction with the cell surface receptors.
  • Therapeutic approaches for targeting IL-1 for anti-inflammatory purposes have been addressed in the art. These include administration of recombinant IL-1 R antagonist protein, IL-1 trap fusion proteins, anti-IL-1 antibodies, anti-IL-1 Rl and soluble IL-1 R I and II in experimental models of arthritis (reviewed in Gabay C et al. 2010).
  • IL-1 has been assigned a key role in type-1 -diabetes mellitus (T1 D) and is known to cause ⁇ -cell dysfunction and death 13 .
  • IL-1 is produced and released by several cell types in response to tissue insult, or in the context of diabetes mellitus, by ⁇ -cells under hyperglycemic conditions 14 . Once present in the pancreatic microenvironment it can act locally to inhibit insulin synthesis and secretion and induce ⁇ -cell apoptosis through activation of proapoptotic JNK, MAPK and NFKB signalling pathways 13 .
  • IL- 1 can drive T1 D pathogenesis by enhancing the recruitment of immune cells and modify the adaptive immune response towards a more proinflammatory cell reper- toire 12,15 .
  • IL-1 antagonism is thus a promising target for therapeutic intervention 13,16 .
  • Anakinra (US5075222) is a recombinantly produced protein that contains the N- terminal, methionylated, nonglycosylated version of human IL-1 RA, which blocks the actions of IL-1 without any detectable agonist activity.
  • Anakinra has been tested for the treatment of rheumatoid arthritis, adult-onset Still's disease, systemic onset juvenile idiopathic arthritis, osteoarthritis and type 2 diabetes mellitus. Anakinra has been approved for treatment of rheumatoid arthritis; it is delivered as an injection concentrate with 100 mg in each dose; it is prepared from genetically modified E. coli using recombinant DNA technology; and it has a high molecular weight.
  • WO 2012/122985 discloses a 10-amino acid peptide derived from of IL1 RA:
  • SGRKSSKMQA (SEQ ID NO:1 ), and its use in treating inflammatory and
  • SEQ ID NO:1 has previously been shown to inhibit interleukin ⁇ ⁇ -induced NF-kB signaling and macrophage secretion of TNFa, and hence is a potent inhibitor of inflammatory responses. Further, SEQ ID NO:1 prevents IL-1 - induced apoptosis in rat pancreatic islets in vitro 17 .
  • Short and potent peptides derived from full-length IL1 RA may be used in a lower concentration, are stable in solution and can be more easily chemically synthesised with a lower associated cost.
  • SEQ ID NO:1 SGRKSSKMQA; also denoted SER140
  • SGRKSSKMQA SEQ ID NO:1
  • SER140 SEQ ID NO:1
  • SEQ ID NO:1 lowers average blood glucose levels in NOD mice, with a higher proportion of SEQ ID NO:1 -treated mice being normoglycemic compared to vehicle throughout the experiment. Further, SEQ ID NO:1 ameliorates the glucose excursions during the onset of diabetes mellitus in the NOD mice.
  • treatment with SEQ ID NO:1 increases total pancreas mass and pancreatic beta-cell mass.
  • the present invention thus provides a peptide consisting of SEQ ID NO:1 , or a variant thereof which differs from SEQ ID NO:1 at one amino acid position, for use in a method of postponing the onset of diabetes mellitus, reducing the risk of developing diabetes mellitus, postponing the development of diabetes mellitus, reducing progression to diabetes mellitus and/or reducing the incidence of diabetes mellitus.
  • peptide consisting of SEQ ID NO:1 , or a variant thereof which differs from SEQ ID NO:1 at one amino acid position, for use in a method of
  • FIG. 1 Schematic illustration of sampling principles for stereoloqical assessment.
  • A Formalin fixed pancreas samples were rolled tightly into strips of gauze, infiltrated in paraffin and cut into 3-4 systematic uniform random tissue slabs with a razor blade fractionator and embedded in one paraffin block with the cut surface down. The blocks were trimmed and four sections for each animal were sampled 300 ⁇ apart and arranged on two glass slides (A), representing a systematic uniform random sample of the whole pancreas.
  • FIG. 1 Stereological analyses of NOD mice pancreata.
  • A ⁇ -cell mass (mg)
  • B ⁇ - ⁇ -cell mass (mg)
  • C unstained endocrine cell mass (mg)
  • D immune cell mass (mg) in vehicle and SER140 treated NOD mice.
  • FIG. 5 Immune cell distribution and expression of pro-inflammatory cytokines in NOD mice pancreata. Immunohistochemistry staining of the immune cells in pancreatic islets of vehicle and SER140 treated mice at day 56 of treatment, for (A) CD3, (B) CD20 and (C) F4/80. Arrows indicate F4/80+ cells. In situ hybridization analysis of the expression of genes encoding the pro-inflammatory cytokines IL-6 (D), TNF-a (E) and IFN- ⁇ (F) in and around pancreatic islets (red dots, arrows) in vehicle vs. SER140 treated mice at day 56 of treatment. (D-F). (A-F) Left - vehicle, right - SER140 treated.
  • D pro-inflammatory cytokines IL-6
  • E TNF-a
  • F IFN- ⁇
  • FIG. 6 Stereological analyses of non-diabetic and diabetic NOD mice pancreata.
  • A ⁇ -cell mass (mg)
  • B ⁇ -cell mass vs. blood glucose (BG) (mmol/L)
  • C non- ⁇ -cell mass (mg)
  • D unstained endocrine cell mass (mg)
  • E immune cell mass in diabetic and non-diabetic vehicle and SER140 treated NOD mice.
  • F ⁇ -cell mass vs. immune cell mass.
  • Interleukins are a group of cytokines first seen to be expressed by white blood cells (leukocytes).
  • Interleukin 1 IL1 or IL-1
  • IL1 A IL-1 alpha
  • IL1 B IL-1 beta
  • the interleukin-1 receptor antagonist protein (IL1 RA) is a protein that in humans is encoded by the IL IRN gene (UniProt Accession No.: P18510, IL1 RA HUMAN). It is a member of the IL-1 cytokine family that inhibits the activities of IL1 A and IL1 B, and modulates a variety of IL-1 related immune and inflammatory responses. Four alternatively spliced transcript variants encoding distinct isoforms have been reported. In terms of protein similarities, IL1 B is more closely related to IL1 RA than it is to IL1 A.
  • IL1 has two distinct receptors, IL1 Rl and IL1 Rll (IL-1 receptor type I and II, or 1 and 2, respectively).
  • IL1 RI comprises an extracellular portion with three immunoglobulin-like modules for IL1 binding and a long cytoplasmic domain, whereas IL1 Rll contains the same ectodomain but a shorter cytoplasmic domain.
  • the receptors both exist in transmembrane (TM) and soluble forms: the soluble IL-1 receptors are thought to be post-translationally derived from cleavage of the extracellular portion of the membrane receptors. Both IL-1 receptors (CD121 a/IL1 R1 , CD121 b/IL1 R2 ) appear to be well conserved in evolution, and map to the same chromosomal location. The receptors can both bind all three forms of IL-1 (IL-1 alpha, IL-1 beta and IL-1 R A).
  • IL1 associates with IL1 Rl with low affinity, and the binding of the IL1 R accessory protein (IL1 R-AcP) to the complex results in high-affinity binding that forms an asymmetric tertiary complex composed of IL1 , IL1 Rl, and IL1 R-AcP, resulting in receptor activation and subsequent intracellular signal transduction and cellular responses.
  • IL1 RA binds primarily to IL1 Rl but does not induce signal transduction because it lacks a second binding site.
  • IL1 Rll is a decoy receptor because the binding of IL1 to ILRII is unable to trigger intracellular signals. The naturally occurring IL1 RA and the decoy receptor attenuate the effects of IL1 .
  • SGRKSSKMQA SEQ ID NO:1
  • SEQ ID NO:1 has been shown in vitro to prevent IL-1 -induced apoptosis in rat pancreatic islets 17 .
  • SEQ ID NO:1 is able to postpone the onset of diabetes mellitus with a statistical significant higher incidence of Type 1 diabetes mellitus in vehicle compared to SEQ ID NO:1 -treated NOD mice (non-obese diabetic animal model). It is also shown herein that SEQ ID NO:1 lowers average blood glucose levels in NOD mice, with a higher proportion of SEQ ID NO:1 -treated mice being normoglycemic compared to vehicle throughout the experiment. Further, SEQ ID NO:1 ameliorates the glucose excursions during the onset of diabetes mellitus in the NOD mice and preserves total pancreas mass and beta-cell mass in NOD mice.
  • the NOD animal mouse model exhibits destructive autoimmune pancreatic insulitis from four weeks of age with Type 1 diabetes mellitus development from three months of age. Approximately 60% of all animals have developed T1 D by six months of age 18 . Further, the NOD mouse seems to reflect many crucial aspects of the human disease, including development of islet-specific autoantibodies and inflammation of the pancreatic islets. Diabetes mellitus is characterized by recurrent or persistent hyperglycemia, and is diagnosed by demonstrating any one of the following:
  • hemoglobin A1 C HbA 1c
  • HbA 1c Glycated hemoglobin at or above 48 mmol/mol ( ⁇ 6.5 DCCT %). It is thus an aspect of the invention to provide a peptide consisting of SEQ ID NO:1 SEQ ID NO:1 , or a variant thereof which differs from SEQ ID NO:1 at one amino acid position, for use in a method of postponing the onset of diabetes mellitus.
  • 'postpone' is synonymous to 'delay'.
  • Onset of diabetes mellitus may be postponed or delayed as compared to untreated individuals, such as untreated individuals who are also at risk of developing diabetes mellitus.
  • a peptide consisting of SEQ ID NO:1 or a variant thereof which differs from SEQ ID NO:1 at one amino acid position, for use in a method of postponing the onset of Type 1 diabetes mellitus (T1 D).
  • a peptide consisting of SEQ ID NO:1 or a variant thereof which differs from SEQ ID NO:1 at one amino acid position, for use in a method of postponing the onset of Type 2 diabetes mellitus (T12D).
  • Diabetes mellitus type 1 (also known as type 1 diabetes, or T1 D; formerly insulin- dependent diabetes or juvenile diabetes) is a form of diabetes mellitus that results from the autoimmune destruction of the insulin-producing beta cells in the pancreas.
  • T1 D includes also Latent Autoimmune Diabetes of Adults (LADA) (aka. slow onset type 1 diabetes or diabetes type 1 .5, which is a form of diabetes mellitus type 1 that occurs in adults, often with a slower course of onset.
  • LADA Latent Autoimmune Diabetes of Adults
  • Diabetes mellitus type 2 (formerly noninsulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes) is a metabolic disorder that is characterized by hyperglycemia (high blood sugar) in the context of insulin resistance and relative lack of insulin.
  • NIDDM noninsulin-dependent diabetes mellitus
  • said method is for postponing the onset of Type 1 diabetes mellitus (T1 D). In one embodiment said method is for postponing the onset of Type 2 diabetes mellitus (T12D). Also provided is a method of ameliorating the glucose excursions during the onset of diabetes mellitus, lowering average blood glucose and/or increasing plasma insulin, comprising administering to an individual in need thereof an effective amount of SEQ ID NO:1 , or a variant thereof which differs from SEQ ID NO:1 at one amino acid position.
  • said method is for postponing the onset of Type 1 diabetes mellitus (T1 D). In one embodiment said method is for postponing the onset of Type 2 diabetes mellitus (T12D).
  • SEQ ID NO:1 or a variant thereof which differs from SEQ ID NO:1 at one amino acid position, for the manufacture of a medicament for a method of ameliorating the glucose excursions during the onset of diabetes mellitus, lowering average blood glucose and/or increasing plasma insulin.
  • SEQ ID NO:1 is to be administered to an individual having an increased risk of developing diabetes mellitus, such as developing Type 1 diabetes mellitus and/or Type 2 diabetes mellitus.
  • An increased risk of developing diabetes mellitus may be based on an assessment of family history and/or life style factors.
  • SEQ ID NO:1 is to be administered to an individual having a parent and/or a sibling with diabetes mellitus.
  • SEQ ID NO:1 is to be administered to an individual predisposed for developing diabetes mellitus, such as developing Type 1 diabetes mellitus or Type 2 diabetes mellitus.
  • SEQ ID NO:1 is to be administered to an individual who is developing diabetes mellitus, such as developing Type 1 diabetes mellitus and/or developing Type 2 diabetes mellitus.
  • SEQ ID NO:1 is to be administered to an individual with serum islet autoantibodies.
  • SEQ ID NO:1 is to be administered to an individual who is developing Type 1 diabetes mellitus. Diagnostic methods and predictions tools are constantly developed and improved. Thus diagnosis and prediction of development of Type 1 diabetes mellitus may be made using tools known in the art. Such tools may include susceptibility genes (Winkler et al. 2014) and predictive biomarkers (Bonefacio et al 2015). In one embodiment SEQ ID NO:1 , or a variant thereof which differs from SEQ ID NO:1 at one amino acid position, is to be administered to an individual with diabetes mellitus at an asymptomatic stage.
  • SEQ ID NO:1 or a variant thereof which differs from SEQ ID NO:1 at one amino acid position, is to be administered to an individual having pre-diabetes.
  • Prediabetes is the medical stage in which not all of the symptoms required to label a person as diabetic are present, but blood sugar is abnormally high. The progression into diabetes mellitus from prediabetes is approximately 25% over three to five years.
  • Prediabetes typically has no distinct signs or symptoms. Patients should monitor for the following symptoms: Constant hunger, Unexplained weight loss, Weight gain, Flu-like symptoms, including weakness and fatigue, Blurred vision, Slow healing of cuts or bruises, Tingling or loss of feeling in hands or feet, Recurring gum or skin infections and Recurring vaginal or bladder infections.
  • SEQ ID NO:1 or a variant thereof which differs from SEQ ID NO:1 at one amino acid position, is to be administered to an individual having two or more, such as three or more, of the symptoms of pre-diabetes.
  • SEQ ID NO:1 is to be administered to an individual having impaired fasting glycaemia or impaired fasting glucose (IFG).
  • IGF impaired fasting glucose
  • IFG refers to a condition in which the fasting blood glucose is elevated above what is considered normal levels but is not high enough to be classified as diabetes mellitus. It is considered a pre-diabetic state associated with insulin resistance and increased risk of cardiovascular pathology, although of lesser risk than impaired glucose tolerance (IGT).
  • ITT impaired glucose tolerance
  • Fasting blood glucose levels are in a continuum within a given population, with higher fasting glucose levels corresponding to a higher risk for complications caused by the high glucose levels.
  • Impaired fasting glucose is defined as a fasting glucose that is higher than the upper limit of normal, but not high enough to be classified as diabetes mellitus. Some patients with impaired fasting glucose also may be diagnosed with impaired glucose tolerance, but many have normal responses to a glucose tolerance test.
  • the WHO diabetes diagnostic criteria are:
  • SEQ ID NO:1 is to be administered to an individual having impaired glucose tolerance (IGT).
  • IGT impaired glucose tolerance
  • IGT is a pre-diabetic state of dysglycemia associated with insulin resistance and increased risk of cardiovascular pathology.
  • IGT is defined as two-hour glucose levels of 140 to 199 mg per dl_ (7.8 to 1 1 .0 mmol/l) on the 75-g oral glucose tolerance test.
  • a patient is said to be under the condition of IGT when he/she has an intermediately raised glucose level after 2 hours, but less than would qualify for type 2 diabetes mellitus.
  • the fasting glucose may be either normal or mildly elevated. From 10 to 15 percent of adults in the United States have impaired glucose tolerance or impaired fasting glucose. The risk of progression to diabetes mellitus and development of cardiovascular disease is greater than for IFG.
  • SEQ ID NO:1 or a variant thereof which differs from SEQ ID NO:1 at one amino acid position, is to be administered to an individual having two-hour glucose levels of 140 to 199 mg per dl_ (7.8 to 1 1 .0 mmol/l) on the 75-g oral glucose tolerance test.
  • SEQ ID NO:1 , or a variant thereof which differs from SEQ ID NO:1 at one amino acid position is to be administered to an individual having elevated fasting glucose (hyperglycemia).
  • the World Health Organization (WHO) criteria for impaired fasting glucose differs from the American Diabetes Association (ADA) criteria, because the normal range of glucose is defined differently by each.
  • Fasting plasma glucose levels 100 mg/dL (5.5 mmol/L) and higher have been shown to increase complication rates significantly, however, WHO opted to keep its upper limit of normal at under 1 10 mg/dL for fear of causing too many people to be diagnosed as having impaired fasting glucose, whereas the ADA lowered the upper limit of normal to a fasting plasma glucose under
  • SEQ ID NO:1 or a variant thereof which differs from SEQ ID NO:1 at one amino acid position, is to be administered to an individual having fasting blood glucose levels of
  • SEQ ID NO:1 is to be administered to an individual having a blood glucose level of 140 to 199 mg/dL (7.8 to 1 1 .0 mM) measured by the two hour glucose tolerance test after ingesting the standardized 75 Gm glucose solution.
  • SEQ ID NO:1 is to be administered to an individual having glycated hemoglobin between 5.7 and 6.4 percent.
  • SEQ ID NO:1 or a variant thereof which differs from SEQ ID NO:1 at one amino acid position, is to be administered to an individual having metabolic syndrome.
  • Metabolic syndrome is a clustering of at least three of five of the following medical conditions: abdominal (central) obesity, elevated blood pressure, elevated fasting plasma glucose, high serum triglycerides, and low high-density lipoprotein (HDL) levels. Metabolic syndrome is associated with the risk of developing diabetes mellitus. Some studies have shown the prevalence in the USA to be an estimated 34% of the adult population, and the prevalence increases with age. Metabolic syndrome and prediabetes may be the same disorder, just diagnosed by a different set of biomarkers.
  • SEQ ID NO:1 is to be administered to an individual having one or more, such as two or more, such as three or more, of the following symptoms: obesity, elevated blood pressure, elevated fasting plasma glucose, high serum triglycerides, and low high-density lipoprotein (HDL) levels.
  • obesity is to be administered to an individual having one or more, such as two or more, such as three or more, of the following symptoms: obesity, elevated blood pressure, elevated fasting plasma glucose, high serum triglycerides, and low high-density lipoprotein (HDL) levels.
  • HDL high-density lipoprotein
  • SEQ ID NO:1 is to be administered to an individual having elevated fasting serum triglyceride level, such as elevated fasting serum VLDL triglyceride level.
  • elevated fasting serum triglyceride level is defined as a level of triglycerides > 200.
  • SEQ ID NO:1 is to be administered to an individual having low levels of HDL.
  • elevated fasting serum triglyceride level is defined as a level of HDL ⁇ 35.
  • SEQ ID NO:1 is to be administered to an individual having dyslipidemia, including hyperlipidemias, hypercholesterolemia, hyperglyceridemia,
  • hyperlipoproteinemia such as LDL
  • hyperlipidemia both LDL and triglycerides
  • Dyslipidemia is an abnormal amount of lipids (e.g. cholesterol and/or fat) in the blood.
  • lipids e.g. cholesterol and/or fat
  • most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood. This is often due to diet and lifestyle. Prolonged elevation of insulin levels can also lead to dyslipidemia.
  • increased levels of O-GlcNAc transferase (OGT) may cause dyslipidemia.
  • SEQ ID NO:1 or a variant thereof which differs from SEQ ID NO:1 at one amino acid position, is to be administered to an individual with newly diagnosed diabetes mellitus, such as newly diagnosed Type 1 diabetes mellitus and/or Type 2 diabetes mellitus.
  • SEQ ID NO:1 is to be administered to an individual with newly diagnosed Type 1 diabetes mellitus.
  • a patient with newly diagnosed diabetes mellitus is likely to benefit from the present invention in order to postpone the further development, or deterioration or progression, of diabetes mellitus.
  • SEQ ID NO:1 or a variant thereof which differs from SEQ ID NO:1 at one amino acid position, can postpone the further development, or deterioration or progression, of diabetes mellitus.
  • Newly diagnosed in this respect may be defined as diagnosed within 1 week to 1 month, such as 1 month to 3 months, such as 3 months to 6 months, such as 6 months to 12 months, such as 12 to 24 months, such as 24 to 36 months, such as 36 to 42 months.
  • SGRKSSKMQA or a variant thereof which differs from SEQ ID NO:1 at one amino acid position, for use in a method of postponing the onset of diabetes mellitus, lowering average blood glucose and/or increasing plasma insulin, as specified herein.
  • a peptide consisting of SEQ ID NO:1 When reference is made to "a peptide consisting of SEQ ID NO:1 " the consisting of is confined to the peptide per se. Thus, a peptide consisting of SEQ ID NO:1 does not exclude the presence of additional components, such as linkers, tags, labels, post- translational modifications and the like. Also, the 'consisting of does not exclude the presence of two or more copies of a peptide consisting of SEQ ID NO:1 connected by e.g. a linker.
  • a variant of SEQ ID NO:1 which differs from SEQ ID NO:1 at one amino acid position according to the invention can be defined as follows.
  • a variant of SEQ ID NO:1 which differs from SEQ ID NO:1 at one amino acid position is a functional variant of SEQ ID NO:1 .
  • a functional variant of SEQ ID NO:1 is a variant that preserves the capabilities and activities of the non-variant form of SEQ ID NO:1 .
  • a functional variant of SEQ ID NO:1 is a functional equivalent of SEQ ID NO:1 .
  • SEQ ID NO:1 , as well as a functional variant of SEQ ID NO:1 which differs from SEQ ID NO:1 at one amino acid position is capable of one or more of:
  • a variant which differs from SEQ ID NO:1 at one amino acid position may have an amino acid substitution at any one of positions 1 to 10 of the 10-amino acid long SEQ ID NO:1 .
  • a variant of SEQ ID NO:1 comprise one amino acid substitution. In one embodiment, a variant of SEQ ID NO:1 comprise one conservative amino acid substitution.
  • a conservative substitution is the substitution of amino acids whose side chains have similar biochemical properties and thus do not affect the function of the peptide.
  • Variants thus include sequences wherein an alkyi amino acid is substituted for an alkyi amino acid, wherein an aromatic amino acid is substituted for an aromatic amino acid, wherein a sulfur-containing amino acid is substituted for a sulfur-containing amino acid, wherein a hydroxy-containing amino acid is substituted for a hydroxy-containing amino acid, wherein an acidic amino acid is substituted for an acidic amino acid, wherein a basic amino acid is substituted for a basic amino acid, or wherein a dibasic mono- carboxylic amino acid is substituted for a dibasic monocarboxylic amino acid.
  • a “conservative amino acid substitution” can also be illustrated by a substitution among amino acids within each of the following groups: (1 ) glycine, alanine, valine, leucine, and isoleucine, (2) phenylalanine, tyrosine, and tryptophan, (3) serine and threonine, (4) aspartate and glutamate, (5) glutamine and asparagine, and (6) lysine, arginine and histidine.
  • a variant of SEQ ID NO:1 comprise one non-conservative amino acid substitution.
  • a non-conservative substitution leading to the formation of a variant of the peptide according to the invention would for example differ substantially in polarity, for example a residue with a non-polar side chain (Ala, Leu, Pro, Trp, Val, lie, Leu, Phe or Met) substituted for a residue with a polar side chain such as Gly, Ser, Thr, Cys, Tyr, Asn, or Gin or a charged amino acid such as Asp, Glu, Arg, or Lys, or substituting a charged or a polar residue for a non-polar one; and/or ii) differ substantially in its effect on peptide backbone orientation such as substitution of or for Pro or Gly by another residue; and/or iii) differ substantially in electric charge, for example substitution of a negatively charged residue such as Glu or Asp for a positively charged residue such as Lys, His or Arg (and vice versa); and
  • SEQ ID NO:1 consists of 10 amino acids, referred to as positions 1 to 10.
  • Ser at position 1 of SEQ ID NO:1 is unchanged or substituted with Gly;
  • Gly at position 2 is unchanged or substituted with Ala, Ser or Arg;
  • Arg at position 3 is unchanged or substituted with Lys;
  • Lys at position 4 is unchanged or substituted with Arg, Thr, Gin, Met, Gly or Ser;
  • Ser at position 5 is unchanged or substituted with Pro, Ala, Arg, Leu, Gin, Asn, Gly or Lys;
  • Ser at position 6 is unchanged or substituted with His, Gin, Trp, Asn, Glu, Pro, Ala, Thr, Cys, Gly or Arg;
  • Lys at position 7 is unchanged or substituted with Arg, His, Glu or Ser;
  • Met at position 8 is unchanged or substituted with Leu, Thr or Ser;
  • Gin at position 9 is unchanged or substituted with Glu, His or Lys; and/or Ala at position
  • Any amino acids according to the present invention may be in the L- or D-configuration. If nothing is specified, reference to the L-isomeric form is preferably meant.
  • peptide also embraces post-translational modifications introduced by chemical or enzyme-catalyzed reactions, as are known in the art. These include acetylation, phosphorylation, methylation, glucosylation, glycation, amidation, hydroxylation, deimination, deamidation, carbamylation and sulfation of one or more amino acid residues. Also, functional equivalents may comprise chemical modifications such as ubiquitination, labeling (e.g., with radionuclides, various enzymes, etc.), pegylation (derivatization with polyethylene glycol), or by insertion (or substitution by chemical synthesis) of non-proteinogenic amino acids.
  • labeling e.g., with radionuclides, various enzymes, etc.
  • pegylation derivatization with polyethylene glycol
  • insertion or substitution by chemical synthesis
  • the C-terminal amino acid of a peptide according to the invention exists as the free carboxylic acid, this may also be specified as "-OH".
  • the C-terminal amino acid of a peptide for use according to the invention may in another embodiment be the amidated derivative, which is indicated as "-NH 2 ".
  • the N-terminal amino acid of the peptide comprises a free amino-group, this may also be specified as "H-”.
  • the N-terminal amino acid of a peptide according to the invention may in another embodiment be the acetylated derivative, which is indicated as "-Acetyl" or "COCH 3 ".
  • SEQ ID NO:1 with N-terminal alkylations and C-terminal esterifications are also encompassed within the present invention.
  • Functional equivalents also comprise glycosylated and covalent or aggregative conjugates formed with the same molecules, including dimers or unrelated chemical moieties. Such functional equivalents are prepared by linkage of functionalities to groups which are found in a fragment including at any one or both of the N- and C-termini, by means known in the art.
  • the peptide according to the invention is an isolated peptide. Multimeric compound
  • a peptide of the present invention may be connected to another peptide of the present invention by a chemical bond or through a linker group.
  • a peptide of the invention may be formulated as an oligomer or multimer of monomers, wherein each monomer is as a peptide as defined herein above.
  • a multimeric compound is a multimer comprising two or more peptides selected from SEQ ID NO:1 and a variant thereof which differs from SEQ ID NO:1 at one amino acid position, as specified herein.
  • the multimeric compound is a dimer comprising two peptides selected from SEQ ID NO:1 and a variant thereof which differs from SEQ ID NO:1 at one amino acid position. In one embodiment said two peptides are identical. In one embodiment the multimeric compound is a dimer comprising two copies of SEQ ID NO:1 . In another embodiment said two peptides are non-identical. Preferably the peptides are identical.
  • the multimeric compound is a trimer comprising three peptides according to the present invention.
  • the multimeric compound is a tetramer comprising four peptides selected from SEQ ID NO:1 and a variant thereof which differs from SEQ ID NO:1 at one amino acid position. In one embodiment said four peptides are identical. In one embodiment the multimeric compound is a tetramer comprising four copies of SEQ ID NO:1 . In another embodiment said two peptides are non-identical. Preferably the peptides are identical.
  • the multimeric compound is a dendrimer, such as a tetrameric dendrimer.
  • Dendrimers are repeatedly branched, roughly spherical large molecules, typically symmetric around the core, and often adopts a spherical three-dimensional morphology.
  • Dendrimers according to the present invention may comprise 4 peptides, 8 peptides, 16 peptides, or 32 peptides; preferably four peptides (i.e. a tetrameric dendrimer).
  • the multimeric compound comprises two identical peptides of the present invention (dimer) or the compound comprises four identical copies of a peptide of the present invention (tetramer).
  • the multimers according to the invention may be made by linking the two or more peptide monomers via a peptide bond or a linker group.
  • the individual peptides of the multimer are linked to a lysine backbone, comprising one or more lysine residues.
  • Said linker group in one embodiment comprises a plurality of lysine residues, such as a core moiety having a plurality of lysine residues.
  • any other linking of peptide monomers known to the skilled person may be envisioned.
  • the individual peptides of the multimer are coupled to a polymer carrier, for example a protein carrier.
  • the linking in one embodiment occurs at the N-terminal or C-terminal end of the peptide monomers.
  • linking of said two or more peptide monomers does not occur through a peptide bond.
  • Peptides according to the invention may be synthesized as monomers, dimers or tetramers. Dimers and tetramers consist of two and four chains, respectively, in one embodiment coupled to a lysine backbone.
  • the peptide sequences of the invention are produced synthetically, in particular, by the Sequence Assisted Peptide Synthesis (SAPS) method or Solid- phase peptide synthesis (SPPS). These are well-known to the skilled person. Peptides may be synthesised either batch wise on a fully automated peptide synthesiser using 9-fluorenylmethyloxycarbonyl (Fmoc) or tert-Butyloxycarbonyl (Boc) as N-a- amino protecting group and suitable common protection groups for side-chain functionalities.
  • SAPS Sequence Assisted Peptide Synthesis
  • SPPS Solid- phase peptide synthesis
  • peptides may be further processed to obtain for example cyclic or C- or N-terminal modified isoforms.
  • the methods for cyclization and terminal modification are well-known in the art.
  • the cytokine IL-1 is known to stimulate pro-inflammatory immune responses and impair ⁇ -cell function and viability, all critical events in the pathogenesis of type 1 diabetes (T1 D).
  • T1 D type 1 diabetes
  • SER140 a small peptide IL-1 receptor antagonist
  • Eight weeks of treatment with SER140 reduced the incidence of diabetes by more than 50% compared with vehicle, decreased blood glucose and increased plasma insulin.
  • SER140 changed the endocrine and immune cells dynamics in the NOD mouse pancreas.
  • SER140 treatment postpones the onset of diabetes in female NOD mice by interfering with IL-1 activated pathways involved in the NOD-mouse that ultimately leads to ⁇ -cell death.
  • T1 D is characterized by progressive autoimmune/autoinflammatory destruction of pancreatic ⁇ -cells over a period of years, resulting in absolute insulin deficiency and the need for lifelong dependence on exogenous insulin administration.
  • T1 D increases the high risk of one or more acute and late disease-associated- complications, e.g. neuropathy, hypoglycemia, cardiovascular disease, and
  • retinopathy 1"2 retinopathy 1"2 .
  • Initial diagnosis have been coupled to a substantial decrease (-90% loss) in ⁇ -cell mass 3 , subsequently leading to a complete loss of insulin production.
  • interventions that prevent or halt the predestined decline of ⁇ -cell function are needed.
  • IL-1 has been assigned a key role in T1 D and has long been known to cause ⁇ -cell dysfunction and death 13 .
  • IL-1 is produced and released by several cell types in response to tissue insult, or in the context of diabetes, by ⁇ -cells under hyperglycemic conditions 14 . Once present in the pancreatic microenvironment it can act locally to inhibit insulin synthesis and secretion and induce ⁇ -cell apoptosis through activation of proapoptotic JNK, MAPK and NFKB signaling pathways 13 . Additionally, IL-1 can drive T1 D pathogenesis by enhancing the recruitment of immune cells and modify the adaptive immune response towards a more proinflammatory cell repertoire 12, 15 . Thus IL-1 antagonism has become a promising target for therapeutic intervention of diabetes 13, 16 .
  • SER140 is a 10-amino acid peptide IL-1 receptor antagonist that has previously been shown to inhibit interleukin ⁇ ⁇ -induced NF-kB signaling and macrophage secretion of TNFa, and hence a potent inhibitor of inflammatory responses 17 . Further, SER140 exceeded the maximal effect of Anakinra in averting IL-1 -induced apoptosis in rat pancreatic islets 17 and is currently being evaluated for treatment of T2D. The many shared features between both major diabetes mellitus types, justify for similar efforts of interfering with IL-1 signaling in T1 D. In this report, we took advantage of the NOD mouse model that spontaneously develops T1 D 18 . The NOD mouse model seems to reflect several crucial aspects of the human disease including pancreatic
  • IL-1 R deficiency have been shown to reduce progression to diabetes in NOD mice 20 making this the ideal model to examine the potential beneficial effects of SER140 in T1 D.
  • Non-fasted blood glucose was monitored bi-weekly before the experiment start.
  • the compound was administered subcutaneously once daily.
  • SER140 was provided by Phlogo ApS, Copenhagen, Denmark (5 mg/mL in water) and diluted in PBS at the required concentration for injection (10 mg/kg, S.C). Throughout the study, animals had ad libitum access to food and water. Bodyweight, food and water intake were recorded bi-weekly from arrival and throughout the study period. Samples for measuring non- fasted BG were collected bi-weekly from the tail vein. Animals were terminated on day 56 and BG was measured using a BIOSEN c-Line glucose meter (EKF-diagnostics, Germany), HbA1 c using autoanalyzer Cobas C-1 1 1 with commercial kit (Roche).
  • pancreas was removed, immersion fixed in 4% formaldehyde at 4°C degrees for 24 hrs and processed as described previously 21 . Briefly, the pancreas was rolled into a cylinder, infiltrated with paraffin overnight using an automated Miles Scientific Tissue- TEK VIP Tissue Processor (Sakura) and cut into three to four systematic uniform random tissue slabs with a razor blade fractionator. The slabs were embedded on their cut surface in one paraffin block. The blocks were trimmed and three series of 4 ⁇ sections were sampled providing a total of twelve to fifteen levels in total for
  • ISH in situ hybridization
  • Antibodies and concentrations used are listed in Supplemental Table 1 . All stainings were performed on an AutostainerLink 48 (Dako) and finally digitized under a 20X objective in an Aperio Scanscope AT slide scanner for qualitative image analysis. ⁇ -/ ⁇ - ⁇ - ⁇ . After deparaffinization in a series of ethanol and xylene and antigen retrieval in citrate buffer (10 mM, pH 6) sections were quenched with 1 % H 2 0 2 in KPBS and blocked with SA-biotin kit (X0590, Dako) and 5% swine serum in TBS-T + 1 % BSA, followed by incubation with the primary non- ⁇ antibody-cocktail .
  • SA-biotin kit X0590, Dako
  • Sections were then incubated with the secondary biotinylated antibody (Fab2) fragment followed by SA-Peroxidase (HRP) and visualized with diaminobenzidine and NiS04.
  • Fab2 secondary biotinylated antibody
  • HRP SA-Peroxidase
  • ⁇ -cells sections were blocked in 10% rabbit serum (X0902, Dako), stained with anti-Insulin and HRP-secondary antibody. Finally, the sections were developed in NovaRed (SK4800, Vector Laboratories), stained in a Mayer solution, dehydrated and mounted in Pertex. See Table 1 .
  • T cells/B-cells and macrophages T cells/B-cells and macrophages. Deparaffinization was performed as previously followed by antigen retrieval in TRIS-EGTA buffer (pH 9) or by proteinase K treatment (F4/80). Endogenous peroxidase activity was quenched in 1 % H 2 0 2 and blocked 5% swine serum, 1 % BSA, and 0.2% Tween20. Sections were then incubated with primary antibodies (CD3, CD20, F4/80) followed by corresponding secondary antibodies. Signal was amplified using Vectastain ABC amplification system (Vectorlabs) (CD20) and Envision+ HRP-coupled polymer system (Dako) and visualized in a DAB solution. Stereological assessment of cell mass
  • the stereological estimation of cell mass was performed by an observer blinded to the experimental groups.
  • the cell mass was estimated by point counting with all points hitting the structure of interest being counted. Sections were scanned in a random systematic way using the newCAST system (Visiopharm, Horsholm, Denmark) to control the stage and collection of data.
  • a single-point grid per frame was used to estimate pancreas mass and a denser grid were used to estimate ⁇ - ⁇ / ⁇ - ⁇ - ⁇ and immune cell mass.
  • the grid system was used to correct the presence of nonpancreatic elements in the dissected sample.
  • the point grid is used to estimate the area fraction of counted cell types. The number of points hitting the structure of interest is then converted into mass by taking the grid ratio into
  • ISH was performed using the RNAscope 2.0 High Definition - RED Assay (Advanced Cell Diagnostics) with IL-6 (NM_031 168.1 ), TNF-a (NM_013693) and IFN- ⁇
  • SER140 was able to postpone the development of diabetes in NOD mice (Fig 2).
  • the first incidence of diabetes (BG>10 mmol/L) was observed in both treatment groups at experimental week one.
  • week two a total of three incidences were observed in the vehicle group with no diabetic cases in the SER140 treated group (Fig 2a).
  • the proportion of normoglycemic SER140 treated mice compared to vehicle became even more evident over time leading to a significantly lower proportion of diabetic mice in the SER140 group at termination (Fig 2a, b).
  • No significant difference was observed in overall body-weight (Fig 3a) whereas both food and water intake (measured as average per cage) decreased in the SER140 treated group (Fig. 3b, c), most likely related to the increased number of diabetic animals in this group.
  • One normoglycemic SER140 treated animal was excluded from the study at experimental day 28 due to general misbehavior unrelated to treatment and was excluded from all measurements.
  • one vehicle and one SER140 treated mice died before study end, probably as a consequence early onset of diabetes, and were not included in the histological analyses due to rapid tissue decay.
  • Immune cell infiltrates as identified by dense haematoxylin staining, were observed around islets in both groups (Figs 1 c,d) but being significantly higher in SER140 treated mice (Fig 4d).
  • the qualitative analysis of specific immune cell subsets revealed that immune cell infiltrates mainly consisted of B-cells (CD20 + ), T-cells (CD3 + ) and only few macrophages (F4/80 + ) but with no noticeable changes in immune cell subtypes with treatment (Fig 5a-c).
  • pro-inflammatory cytokines were observed around and within the islets (Fig 5d-f) in both groups.
  • BG ⁇ 10 mmol/L and diabetic (BG>10 mmol/L) animals revealed a higher ⁇ -cells mass in normoglycemic mice versus diabetic mice irrespective of treatment (Fig 6a; Table 2).
  • further analyses of BG levels as a function of beta cells mass revealed that even a minute mass of enduring ⁇ -cells is able to compensate and maintain normal BG levels (Fi. 6b).
  • ⁇ - ⁇ -cell mass was also significantly lower in the diabetic animals as compared to normoglycemic mice irrespective of treatment demonstrating a progressive loss of ⁇ - ⁇ -cells in the NOD model with diabetes onset (Fig 6c).
  • the NOD mouse presents early signs of insulitis, spontaneously develops autoimmune diabetes and is generally regarded as a suitable animal model of human T1 D.
  • the novel IL-1 R antagonist SER140 is able to postpone the onset of diabetes in female NOD mice coupled to an overall decrease in BG levels and increased insulin levels upon treatment.
  • IL-1 orchestrates several immunological and cellular pathways, hence proposing several mechanistic explanations for pro-diabetic effect, either due to a modulatory role on the local immune system, or a direct role on pancreatic ⁇ -cell function and/or survival 13 .
  • heterogeneity of disease penetrance in the NOD mice could be the explanation for the lack of statistical significance in the effect on ⁇ -cell mass upon SER140 treatment.
  • the apparent higher immune cell mass in SER140 treated mice can simple be explained by a SER140 induced postponement of diabetes onset. More studies are however needed to accurately depict the endocrine and immune cell dynamics in the female NOD mouse model. Speculatively, the apparent higher immune cell mass could be explained by a reduced function of Treg cells within inflamed islets after disease onset in NOD mice 27 and that SER140 blockade of IL-1 signaling might have a preservative function on these cells 28" 29 .
  • Treg cell function might also explain the significant increase in the plasma levels of the anti-inflammatory cytokine IL-10 that has been reported after SER140 treatment 17 .
  • cytokine IL-10 The delayed reduction of Treg cell function might also explain the significant increase in the plasma levels of the anti-inflammatory cytokine IL-10 that has been reported after SER140 treatment 17 .
  • 30"31 we observed a substantial immune cell infiltration into the pancreatic islets being mainly composed of lymphocytes as indicative of insulitis. Consistent with an inflamed pancreas, a substantial proinflammatory cytokine expression were observed around and within the islets. We did, however, not observe any apparent changes in the number of specific immune cell subsets or apparent difference in cytokine expression with treatment.
  • New-Onset Type 1 Diabetes Pilot randomized, placebo-controlled, double-blind study. Diabetes Care. July 1 , 2009 2009;32(7):1244-1249.

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Abstract

La présente invention concerne un peptide constitué de SEQ ID NO : 1 et dérivé de l'IL-1RA, ou un variant de celui-ci qui diffère de SEQ ID NO : 1 au niveau d'une position d'acide aminé, pour utilisation dans un procédé visant à retarder l'installation du diabète sucré, à abaisser la glycémie sanguine moyenne et/ou à renforcer le niveau plasmatique d'insuline.
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