EP1934249A1 - Antagonistes utilises contre l'interaction de pf4 et de rantes - Google Patents

Antagonistes utilises contre l'interaction de pf4 et de rantes

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Publication number
EP1934249A1
EP1934249A1 EP06806162A EP06806162A EP1934249A1 EP 1934249 A1 EP1934249 A1 EP 1934249A1 EP 06806162 A EP06806162 A EP 06806162A EP 06806162 A EP06806162 A EP 06806162A EP 1934249 A1 EP1934249 A1 EP 1934249A1
Authority
EP
European Patent Office
Prior art keywords
polypeptide
amino acid
group
formula
seq
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP06806162A
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German (de)
English (en)
Inventor
Christian Weber
Philipp Von Hundelshausen
Rory Koenen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Rheinisch Westlische Technische Hochschuke RWTH
Original Assignee
Rheinisch Westlische Technische Hochschuke RWTH
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Application filed by Rheinisch Westlische Technische Hochschuke RWTH filed Critical Rheinisch Westlische Technische Hochschuke RWTH
Priority to EP10181077.8A priority Critical patent/EP2363412B1/fr
Publication of EP1934249A1 publication Critical patent/EP1934249A1/fr
Withdrawn legal-status Critical Current

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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
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/521—Chemokines
    • C07K14/523—Beta-chemokines, e.g. RANTES, I-309/TCA-3, MIP-1alpha, MIP-1beta/ACT-2/LD78/SCIF, MCP-1/MCAF, MCP-2, MCP-3, LDCF-1, LDCF-2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
    • A61K49/0008—Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • 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 invention relates to polypeptides, their pharmacologically acceptable salts, derivatives and / or conjugates, their use for the preparation of a medicament and
  • the polypeptides are useful in the treatment of diseases related to monocyte recruitment.
  • Arteriosclerosis of arterial vessels forms the morphological background of cardiovascular diseases.
  • the initial recruitment of monocytes is of crucial importance for the genesis of the arteriosclerotic early lesion.
  • monocyte arrest is at the onset of the pathogenesis of cardiovascular diseases such as atherosclerosis, stenosis and thrombosis.
  • chemokines such as RANTES (regulated on activation, normal cell expressed and secreted) as signaling molecules are associated with these processes.
  • RANTES peptide antagonists For example, DE 100 14 516 A1 discloses the use of metRANTES as an antagonist against the RANTES receptor CCR1.
  • a disadvantage of the use of this antagonist is that chemokines are involved as signal molecules in a variety of physiological processes, so that the use of such an antagonist an unpredictable number of physiological processes is affected and numerous side effects and sequelae can occur.
  • the object of the present invention was to provide means which overcome at least one of the disadvantages of the prior art.
  • the object of the present invention was to provide agents which have an improved specificity. This object is achieved by a polypeptide, its pharmacologically acceptable salts, derivatives and / or conjugates, wherein the polypeptide has an amino acid sequence SEQ ID NO: 1 according to formula (1) as indicated below:
  • Xi is selected from the group comprising lysine, glutamine, arginine, histidine and / or asparagine, or an amino acid deletion;
  • X 2 v is selected from the group comprising glutamic acid, aspartic acid and / or glutamine, or an amino acid deletion;
  • X 3 is selected from the group comprising glycine, serine, and / or alanine
  • X 4 is selected from the group comprising lysine, leucine, and / or arginine
  • X 5 is selected from the group comprising serine, cysteine, glycine, and / or threonine
  • X 6 is selected from the group comprising serine, glycine, and / or threonine
  • X 7 is selected from the group comprising asparagine and / or glutamine
  • X 8 is selected from the group comprising proline, tyrosine and / or glycine
  • X 9 is selected from the group comprising glycine, alanine and / or serine
  • X 10 is selected from the group comprising isoleucine, valine and / or asparagine
  • Xi 1 is selected from the group comprising valine, isoleucine and / or asparagine
  • tyrosine; X] 5 is selected from the group comprising arginine, lysine, glutamine, histidine and / or
  • polypeptides of the invention are useful as antagonists to the interaction between RANTES and Platelet Factor 4.
  • the term "antagonist against the interaction between RANTES and Platelet Factor 4" means peptides, proteins or other compounds which can act as antagonists to the interaction between the chemokines RANTES and Platelet Factor 4.
  • the polypeptides according to the invention can have a specific effect on the recruitment of monocytes mediated by the interaction of the chemokines RANTES and Platelet Factor 4 (PF4).
  • RANTES chemokines RANTES and Platelet Factor 4
  • PF4 Platelet Factor 4
  • the polypeptides of the invention have little or no effect on the numerous functions of the chemokines.
  • a selective blocking of the recruitment of monocytes, for example, to endothelium can be effected.
  • monocyte recruitment encompasses the significance of migration of monocytes through the endothelium, their attachment and spreading, for example into endothelial clefts.
  • the attachment of the Monocytes are also referred to as monocyte adhesion, or as monocyte arrest if the attachment takes place as under physiological conditions in shear flow, for example in blood capillaries, microvascular or arterial current paths.
  • the polypeptides according to the invention can provide high specificity and show no or only slight side effects on the numerous chemokine RANTES and PF4-mediated metabolic processes, for example of the immune or coagulation system.
  • the administration of the polypeptides according to the invention avoids the risk of bleeding as in conventional medication for cardiovascular diseases.
  • C corresponds to the common one-letter code of the amino acids for the amino acid cysteine used here, correspondingly "Y” stands for tyrosine, “F” stands for phenylalanine, “T” stands for threonine and "S” for serine.
  • Each polypeptide of the present invention has a cysteine residue at the amino-terminal and carboxy-terminal ends, which can provide cyclization of the polypeptide.
  • a cyclized polypeptide has improved stability.
  • the polypeptide according to the invention may have a longer efficacy and is accordingly usable in a lesser amount.
  • polypeptide is to be understood as meaning synthetic or non-synthetic peptide compounds, as well as purified, modified fragments of natural proteins, native forms or recombinant peptides or proteins.
  • polypeptide for the purposes of the present invention comprises pharmacologically acceptable salts, pharmacologically acceptable derivatives and / or conjugates of the corresponding polypeptide.
  • Preferred pharmacologically acceptable derivatives are, for example, esters, amides, N-acyl and / or O-acyl derivatives, carboxylated, acetylated, phosphorylated and / or glycosylated polypeptides.
  • Preferred conjugates are, for example, sugar or polyethylene glycol conjugates, biotinylated, radioactively or fluorescently labeled polypeptides.
  • the polypeptide has a length of at most 25 amino acids.
  • the polypeptide has a number of amino acids in the range of> 15 to ⁇ 25 amino acids, preferably in the range of> 15 to ⁇ 22 amino acids.
  • the length of the polypeptide can influence its effectiveness. In particular, it is surprising that a
  • Amino acid sequence of this length can cause an inhibition of Monozytenarrestes.
  • the polypeptide has a number of amino acids in the range of> 18 to ⁇ 23 amino acids, more preferably in the range of> 18 to ⁇ 22 amino acids, in particularly preferred embodiments, the polypeptide in the range of> 19 to ⁇ 22 amino acids In further preferred embodiments, the polypeptide is in the range of> 20 to ⁇ 21 amino acids. Most preferably, the polypeptide has 22 amino acids.
  • number of amino acids in the context of the invention also includes, of course, the meaning of the length of the amino acid sequence of the polypeptide.
  • Xi corresponds to lysine or, at the point Xi, the amino acid sequence has a deletion, particularly preferably Xi corresponds to the amino acid lysine.
  • X 2 is or is the amino acid glutamic acid
  • X 2 particularly preferably corresponds to the amino acid glutamic acid.
  • a polypeptide with a deletion at the site Xi and / or X 2 a unfold antagonistic effects. It can be provided that Xi and X 2 correspond to an amino acid deletion.
  • X 3 preferably corresponds to a small, neutral and flexible amino acid.
  • X 3 is selected from the group comprising glycine and / or serine, more preferably X 3 corresponds to the amino acid glycine. It has been found that these amino acids positively influence the stability of the structure of the polypeptide. Such an increase in stability is particularly advantageous because increased stability of the polypeptide can result in prolonging interaction of the polypeptide with the chemokine PF4. Thus, improved stabilization of the peptide may enhance the antagonistic properties of the polypeptide.
  • X 4 corresponds to the amino acid lysine.
  • X 5 is selected from the group comprising serine, glycine, and / or threonine.
  • X 5 corresponds to serine.
  • This embodiment of the polypeptide may advantageously result in improving the solubility of the polypeptide.
  • an increase in the solubility of the polypeptide can lead to an increase in the applicability of the polypeptide in water. This allows for a simplification of the administration of the polypeptide in the usual water-based administration methods.
  • improved solubility of the polypeptide can provide improved dispersibility of the polypeptide in the aqueous systems of the body, particularly in blood.
  • X 6 corresponds to the amino acid serine.
  • X 7 corresponds to the amino acid asparagine.
  • Xg corresponds to an amino acid selected from the group comprising proline and / or tyrosine.
  • X 8 corresponds to the amino acid proline.
  • X 9 corresponds to glycine. It was found that the amino acid glycine at this point of the
  • Amino acid sequence can lead to a surprisingly stable polypeptide compound.
  • Xi 0 and Xj 3 are independently selected from the group comprising valine and / or isoleucine.
  • Xi 0 corresponds to isoleucine.
  • Xi 3 corresponds to isoleucine.
  • Xi 0 and X] 3 correspond to isoleucine. It has been found that isoleucine at sites Xi 0 and Xi 3 of the polypeptide can contribute to increased stability of the conformation of the polypeptide.
  • Xn preferably corresponds to the amino acid valine.
  • Xi 2 is preferably selected from the group comprising phenylalanine and / or tyrosine, more preferably Xj 2 corresponds to the amino acid phenylalanine.
  • Xi 4 preferably corresponds to the amino acid threonine.
  • Xj 5 arginine, furthermore, at the point Xj 5 of the
  • Amino acid sequence may be provided an amino acid deletion.
  • Preferred ones concern amino acid deletions Xi, X 2 and / or Xj 5 .
  • one of the amino acids Xj, X 2 or Xi 5 can be deleted, but it can also be provided that amino acid deletions are provided at the sites Xi and X 2 .
  • 5 deletions may be provided at locations Xi, X 2 and X].
  • no deletions are provided in the region of the amino acids X 3 to Xi 4 .
  • X 5 correspond to the amino acid serine, X 9 glycine, Xi 0 isoleucine, and / or X] 3 isoleucine.
  • the amino acids X 5 correspond to serine, X 9 glycine, X 10 isoleucine, Xi 3 isoleucine, Xi of an amino acid deletion and / or Xi 5 of an amino acid deletion.
  • the amino acids X 5 correspond to serine, X 9 glycine, Xi 0 isoleucine, Xj 3 isoleucine, Xi of an amino acid deletion and X 15 of an amino acid deletion.
  • This polypeptide may also have a particularly good antagonistic potential.
  • the amino acids X 5 are serine, X 8 tyrosine, X 9 glycine, X 10 isoleucine, Xn isoleucine, Xi an amino acid deletion and / or Xi 5 an amino acid deletion.
  • the amino acids X 5 are serine, X 8 tyrosine, X 9 glycine, Xi 0 isoleucine, Xn isoleucine, Xi an amino acid deletion and Xi 5 an amino acid deletion.
  • the amino acids X 3 are serine, X 5 serine, X 8 tyrosine, X 9 glycine, X 10 isoleucine, X ) 3 isoleucine, X] an amino acid deletion and / or Xi 5 of an amino acid deletion.
  • the amino acids X 3 are serine, X 5 serine, X 8 tyrosine, X 9 glycine, X 10 isoleucine, X ] 3 isoleucine, Xi an amino acid deletion and Xi 5 an amino acid deletion.
  • the amino acids X 3 correspond to serine, X 5 serine, X 8 proline, X 9 glycine, X] 0 isoleucine, Xn isoleucine, Xi one
  • Amino acid deletion X 2 of an amino acid deletion and Xi 5 of an amino acid deletion.
  • the amino acids X 3 correspond to serine, X 5 serine, Xg tyrosine, X 9 glycine, Xi 0 isoleucine, Xj 2 tyrosine, Xj 3 isoleucine, Xi of an amino acid deletion, X 2 of an amino acid deletion and / or Xj 5 an amino acid deletion.
  • the amino acids X 3 correspond to serine, X 5 serine, Xg tyrosine, X 9 glycine, Xi 0 isoleucine, Xi 2 tyrosine, Xi 3 isoleucine, Xi an amino acid deletion, X 2 an amino acid deletion and Xi 5 an amino acid deletion.
  • polypeptide has an amino acid sequence SEQ ID NO: 2 according to the formula (2) as indicated below:
  • polypeptide of SEQ ID NO: 2 according to the formula (2) has at least one or more amino acid deletions, amino acid substitutions and / or amino acid insertions relative to the amino acid sequence SEQ ID NO: 2 according to the formula (2).
  • the amino acid substitutions refer to the sequence region of the ninth to twentieth amino acid of the amino acid sequence SEQ ID NO: 2 according to the formula (2), the Range of amino acids glycine at the point nine to threonine at the position twenty of the amino acid sequence.
  • one or more of the amino acids selected from the group comprising glycine, cysteine, proline, valine, phenylalanine and / or alanine are substituted by amino acids selected from the group comprising serine, tyrosine, isoleucine and / or glycine.
  • An advantage of these amino acid substitutions is that they may enhance the stability of the polypeptide and / or enhance the antagonist activity of the polypeptide.
  • these amino acid substitutions are selected from substitutions including glycine to serine, non-terminal cysteine to serine, proline to tyrosine, valine to isoleucine, phenylalanine to tyrosine and / or alanine to glycine. These amino acid substitutions can be combined with one another as desired.
  • At least the non-terminal cysteine at the site eleven of the amino acid sequence SEQ ID NO: 2 according to the formula (2) is replaced by serine. Such substitution can advantageously lead to an improvement in the solubility of the polypeptide, in particular the solubility in water.
  • the amino acid substitutions preferably selected from the substitutions comprising glycine against serine, cysteine against serine and / or proline against tyrosine the ninth to fourteenth amino acid , the sequence range from glycine to proline, the amino acid sequence SEQ ID NO: 2 according to the formula (2).
  • this region has at least one of these substitutions, preferably at least the cysteine at the site is eleven
  • Amino acid sequence SEQ ID NO: 2 substituted according to the formula (2) by serine.
  • furthermore proline is exchanged for tyrosine and / or glycine for serine.
  • the substitution of cysteine at eleven of the Amino acid sequence can be arbitrarily combined with other substitutions, in particular with an exchange of proline for tyrosine and / or glycine for serine.
  • amino acid substitutions refer to the range of the fifteenth to twentieth amino acids, alanine to threonine, of the polypeptide of the amino acid sequence of SEQ ID NO: 2 according to the formula (2).
  • Preferred amino acid substitutions of the amino acids of this range are selected from substitutions comprising alanine to glycine, valine to isoleucine and / or phenylalanine to tyrosine.
  • alanine is substituted for glycine.
  • valine at the position sixteen of the amino acid sequence SEQ ID NO: 2 according to the formula (2) is replaced by isoleucine, preferably at least two of the valine are replaced by isoleucine, preferably valine at the positions sixteen and nineteen are replaced by isoleucine , It may also be preferred that each valine of the amino acid sequence SEQ ID NO: 2 according to the formula (2) is replaced by isoleucine.
  • polypeptide can be provided that phenylalanine is replaced by tyrosine.
  • alanine at position fifteen of the sequence SEQ ID NO: 2 according to the formula (2) is substituted for glycine, valine at the position sixteen for isoleucine and valine at the position nineteen for isoleucine. It has been found that these substitutions lead to a surprisingly stable polypeptide compound.
  • substitutions and / or amino acid deletions can be combined with one another as desired; in particular, the substitutions can be combined with one another as desired.
  • the polypeptide may have deletions of amino acids.
  • Preferred amino acid deletions concern deletions of the amino acids lysine, Glutamine and / or arginine.
  • the deletions preferably relate to the amino acids lysine at the position two of the sequence SEQ ID NO: 2 according to the formula (2) the amino acid glutamine at the position three and / or arginine at the position twenty-one the amino acid sequence SEQ ID NO: 2 according to the formula ( 2).
  • the deletions can be combined with one another as desired.
  • an amino acid is deleted, it may also be contemplated that both lysine at site two and arginine at site twenty-one are deleted.
  • lysine may be deleted at location two, glutamine at location three, and arginine at location twenty-one.
  • no deletions are provided in the region of the fourth to twentieth amino acids of the amino acid sequence SEQ ID NO: 2 according to the formula (2).
  • the amino acids in the region of the fourth to eighth amino acids are affected neither by amino acid deletions nor by amino acid substitutions.
  • an amino acid sequence which has at least two amino acid substitutions in the ninth to twentieth amino acids of the sequence SEQ ID NO: 2 according to the formula (2) preferably three amino acid substitutions, more preferably four amino acid substitutions, even more preferred has five amino acid substitutions in this range, has good antagonistic properties.
  • the number of amino acids of the polypeptide of this embodiment ranges from> 15 to ⁇ 25 amino acids, preferably from> 18 to ⁇ 23 amino acids, more preferably from> 19 to ⁇ 22 amino acids, more preferably from > 20 to ⁇ 21 amino acids, most preferably 22 amino acids.
  • a particularly suitable embodiment of the polypeptide according to the invention, its pharmacologically acceptable salts, derivatives and / or conjugates, has an amino acid sequence SEQ ID NO: 3 according to the following formula (3):
  • polypeptide having an amino acid sequence SEQ ID NO: 3, as shown according to the formula (3) has a particularly high antagonistic potential.
  • polypeptide can have a particularly good antagonistic effect.
  • a polypeptide having an amino acid sequence SEQ ID NO: 3 according to the formula (3) can significantly and reproducibly inhibit the interaction of RANTES and PF4 which causes an enhancement of monocyte arrest.
  • a polypeptide of an amino acid sequence SEQ ID NO: 3, as shown in formula (3) can act specifically against the interaction of RANTES and PF4. Further interference with the function of chemokines can thus be reduced or even prevented. This allows the targeted use of the polypeptide in the treatment of diseases related to monocyte recruitment or RANTES-dependent recruitment of other leukocyte populations, such as eosinophils, particularly cardiovascular disease.
  • polypeptide according to the invention has an amino acid sequence SEQ ID NO: 4 according to formula (4) as indicated below:
  • CEYFYTSGKSSNPGIVFITC (4) (SEQ ID NO: 4).
  • a further preferred embodiment of the polypeptide according to the invention, its pharmacologically acceptable salts, derivatives and / or conjugates, has an amino acid sequence SEQ ID NO: 5 according to the formula (5) as indicated below:
  • CEYFYTSGKSSNYGIVFITC (5) (SEQ ID NO: 5).
  • polypeptide of the invention has an amino acid sequence SEQ ID NO: 6 according to the following formula (6) as indicated below:
  • CEYFYTSSKSSNYGIVFITC (6) (SEQ ID NO: 6).
  • polypeptide of the invention has a pharmacologically acceptable salts, derivatives and / or conjugates.
  • Amino acid sequence SEQ ID NO: 7 according to formula (7) as indicated below:
  • CYFYTSSKSSNPGIVFITC (7) (SEQ ID NO: 7).
  • polypeptide in preferred embodiments are those polypeptides preferably have improved stability. This allows the polypeptides to reach their site of action to a greater extent and to undergo stable interactions with proteins or peptide compounds. In particular, increased stability of the polypeptide allows it to be used in vivo and in vitro.
  • Another advantage of the polypeptide in preferred embodiments is that the polypeptide has improved solubility in water. In particular, increased solubility can lead to the polypeptide being easier and easier to apply.
  • the respective L-amino acids are replaced by D-amino acids. As a result, a further increase in stability can be achieved.
  • polypeptides can be prepared by customary methods of peptide synthesis.
  • polypeptides of the invention are useful as antagonists to the interaction between RANTES and Platelet Factor 4.
  • polypeptides according to the invention can bring about an inhibition of the interaction between RANTES and Platelet Factor 4.
  • polypeptides of the invention are useful as antagonists to the interaction between RANTES and Platelet Factor 4.
  • polypeptides of the invention are suitable for use as medicaments.
  • Another object of the invention relates to the use of the polypeptides according to the invention, in particular of the preferred embodiments, for the preparation of a medicament.
  • polypeptides of the invention can be administered according to conventional methods, preferably parenteral administration is, for example, oral administration, dermal administration, subcutaneous administration and / or intravenous administration.
  • parenteral administration is, for example, oral administration, dermal administration, subcutaneous administration and / or intravenous administration.
  • the polypeptides may be administered by ex vivo applications, for example, prior to implantation of a vascular intronate, or by intra-oral administration, for example, before or after catheter intervention or stenting.
  • intra-oral administration for example, before or after catheter intervention or stenting.
  • a preferably good solubility of the polypeptides in water is of great advantage.
  • polypeptides according to the invention may be administered over a relatively long period of time.
  • the polypeptides of the invention may also be administrable in a prolonged or sustained release form, for example in the form of depot injections or osmotic pumps.
  • the polypeptide of the invention may also be administered in the form of a nucleic acid encoding the respective polypeptide.
  • the nucleic acid molecule can be contained in customary vectors.
  • a DNA sequence coding for the respective polypeptide is administered. It can also be provided to administer the RNA coding for a polypeptide according to the invention.
  • the invention further relates to nucleic acids which comprise nucleic acid sequences which code for polypeptides according to the invention, preferably comprising nucleic acid sequences coding for polypeptides of the amino acid sequences SEQ ID NO: 1 according to formula (1), SEQ ID NO: 2 according to formula (2 SEQ ID NO: 3 according to formula (3), SEQ ID NO: 4 according to formula (4), SEQ ID NO: 5 according to formula (5), SEQ ID NO: 6 according to formula (6), SEQ ID NO: 7 according to formula (7).
  • the nucleic acid which can be used according to the invention is preferably DNA or RNA.
  • the person skilled in the art knows DNA sequences which code for polypeptides according to the above formulas or sequences.
  • Amino acid sequence SEQ ID NO: 3 according to the formula (3) has a DNA sequence SEQ ID NO: 8 according to the formula (8) as indicated below: 5'-TGCAAGGAATATTTCTACACTTCCGGGAAATCCTCCAATCCTGGAATTG TGTTCATCACTAGATGT-S '(8) (SEQ ID NO: 8).
  • nucleic acid molecule encoding a polypeptide of an amino acid sequence SEQ ID NO: 2 according to the formula (2) has a DNA sequence of SEQ ID NO: 9 represented by the formula (9) as shown below:
  • nucleic acid molecule encoding a polypeptide of an amino acid sequence SEQ ID NO: 4 according to the formula (4) has a DNA sequence of SEQ ID NO: 10 according to the formula (10) as indicated below:
  • nucleic acid molecule encoding a polypeptide of an amino acid sequence SEQ ID NO: 5 according to the formula (5) has a DNA sequence SEQ ID NO: 1 1 according to the formula (11) as given below:
  • nucleic acid molecule encoding a polypeptide of an amino acid sequence SEQ ID NO: 6 according to the formula (6) has a DNA sequence of SEQ ID NO: 12 according to the formula (12) as indicated below:
  • nucleic acid molecule encoding a polypeptide of an amino acid sequence SEQ ID NO: 7 according to the formula (7) has a DNA sequence of SEQ ID NO: 13 according to the formula (13) as shown below:
  • RNA sequences which are suitable for polypeptides of an amino acid sequence SEQ ID NO: 1 according to formula (1), SEQ ID NO: 2 according to formula (2), SEQ ID NO: 3 according to formula (3), SEQ ID NO: 4 according to formula (4), SEQ ID NO: 5 according to formula (5), SEQ ID NO: 6 according to formula (6), and SEQ ID NO: 7 according to formula (7).
  • Preferred dosages of the polypeptides of the invention are for administration to humans in the range of> 10 mg / day / 75 kg body weight to ⁇ 1000 mg / day / 75 kg body weight, preferably in the range of> 50 mg / day / 75 kg body weight to ⁇ 200 mg / day / 75 kg body weight, preferably in the range of 150 mg / day / 75 kg body weight.
  • polypeptides of the invention are particularly useful for the therapeutic and / or prophylactic treatment, diagnosis and / or therapy of diseases related to monocyte recruitment.
  • diseases include, for example, cardiovascular and / or inflammatory diseases, in particular arteriosclerosis, stenoses, high blood pressure and / or transplant rejection reactions.
  • polypeptides and / or nucleic acids according to the invention are useful for the treatment of mammals, in particular of humans.
  • the polypeptides according to the invention can positively influence the adhesion of monocytes to the endothelium.
  • particularly preferred embodiments of the polypeptides of the invention can inhibit the enhancement of such monocyte arrest mediated by the heterophilic interaction of RANTES and PF4.
  • particularly preferred embodiments of the polypeptides of the invention may show in experiments an improved inhibition of monocyte arrest enhancement mediated by the heterophilic interaction of RANTES and PF4, as previously known protein or peptide compounds.
  • polypeptides according to the invention can be realized in that the administration of the polypeptides can reduce or prevent the formation of arteriosclerosis, postoperative or postinterventional restenoses, for example after balloon dilatation, atherectomy or bypass operations. It is of particular advantage that the polypeptides of the invention are also useful in advanced or clinical disease or morphological arteriosclerotic changes can prevent or reduce further recruitment of monocytes on the activated endothelium.
  • polypeptides according to the invention can be used in particular for prophylactic treatment, for example in high blood pressure risk patients.
  • a prophylactic use is advantageously made possible in particular by the fact that the polypeptides according to the invention show little or no effect on general chemokine-mediated processes.
  • a further subject of the invention accordingly relates to the use of the polypeptides according to the invention, their pharmacologically acceptable salts, derivatives and / or conjugates, for the preparation of a medicament for the therapeutic and / or prophylactic treatment of diseases selected from the group comprising: - diseases associated with recruitment of monocytes, such as cardiovascular and / or inflammatory diseases, in particular arteriosclerosis, atherosclerosis, unstable plaques, stenoses, restenosis, hypertension, arthritis, myocarditis, autoimmune diseases including encephalomyelitis, inflammatory bowel disease, reperfusion injury after infarcts, for example myocardial or cerebrovascular infarctions,
  • diseases selected from the group comprising: - diseases associated with recruitment of monocytes, such as cardiovascular and / or inflammatory diseases, in particular arteriosclerosis, atherosclerosis, unstable plaques, stenoses, restenosis, hypertension, arthritis, myocarditis, autoimmune diseases including encephalomyelitis, inflammatory
  • Graft rejection and / or skin diseases such as psoriasis, and / or diseases associated with RANTE S-dependent recruitment of other leukocyte populations, such as eosinophils, especially in allergic diseases such as asthma or pneumonitis.
  • an advantageous effect on the course of the disease can be achieved by using the polypeptides according to the invention.
  • a gain of the arteriosclerotic changes are reduced by monocyte arrest.
  • a further advantage of the polypeptides according to the invention can be found in the fact that they can reduce or even prevent rejection reactions after the transplantation of organs and / or tissue.
  • the polypeptides according to the invention preferably cause no or only slight side effects. This allows the polypeptides of the invention to be administered prophylactically. Furthermore, it is of particular advantage that the specificity of the polypeptides according to the invention makes it possible to avoid influencing further metabolic processes so that a prophylactic administration is made possible, for example, in hypertensive risk patients or in the prophylaxis of arteriosclerotic changes.
  • the invention further relates to medicaments comprising polypeptides according to the invention, preferably polypeptides of the sequence SEQ ID NO: 1 according to the formula (1), their pharmacologically acceptable salts, derivatives and / or conjugates.
  • medicaments comprising polypeptides selected from the group comprising polypeptides of the amino acid sequences SEQ ID NO: 3 according to formula (3), SEQ ID NO: 4 according to formula (4), SEQ ID NO: 5 according to formula (5), SEQ ID NO: 6 according to formula (6), and / or SEQ ID NO: 7 according to formula (7).
  • Particularly preferred are drugs comprising polypeptides of
  • the medicament comprises polypeptides according to any one of the above formulas or SEQ ID Nos. It can be provided that the medicament comprises polypeptides according to several formulas or SEQ ID Nos.
  • Medicaments comprising polypeptides according to the invention are particularly useful for the treatment in vivo, for example of humans.
  • a preferred use of the medicaments comprising polypeptides according to the invention are the therapeutic and / or Prophylactic treatment of diseases related to recruitment of monocytes, such as cardiovascular and / or inflammatory diseases, in particular atherosclerosis, atherosclerosis, unstable plaques, stenoses, restenosis, hypertension, arthritis, myocarditis, autoimmune diseases including encephalomyelitis, inflammatory bowel disease, reperfusion damage Infarcts, for example myocardial or cerebrovascular infarctions, transplant rejection and / or skin diseases such as psoriasis, and / or diseases associated with a RANTES-dependent recruitment of other leukocyte populations, such as eosinophils, especially in allergic diseases such as asthma or pneumonitis.
  • diseases related to recruitment of monocytes such as cardiovascular and / or inflammatory diseases, in particular atherosclerosis, atheros
  • medicaments comprising nucleic acids encoding polypeptides according to the invention.
  • the nucleic acid molecule may be contained in conventional vectors.
  • Another object of the invention relates to agents against monocyte arrest, comprising polypeptides according to the invention, the pharmacologically acceptable salts, derivatives and / or conjugates preferably comprising polypeptides of the amino acid sequence SEQ ID NO: 3 according to formula (3).
  • the term "agent against monocyte arrest” has the meaning that the agent can have a positive influence on diseases which are associated with a monocyte arrest, the attachment of monocytes, for example, to endothelium.
  • the formation of arteriosclerotic plaques can be reduced or even prevented.
  • the use of the polypeptides according to the invention can lead to the fact that the recruitment of monocytes and / or their attachment to activated endothelium, in particular on arteriosclerotic plaques or neointima, can be reduced and / or completely or almost completely avoided. Examples which serve to illustrate the present invention are given below.
  • Endothelial cells from the human umbilical cord (HUVEC, human umbilical vein endothelial cells, PromoCell, Heidelberg) were cultured in Endothelial Cell Growth Medium (PromoCell, Heidelberg) and used after 2 to 4 passages.
  • Monocytic Mono Mac 6 cells were in RPMI 1640 medium (PAA Laboratories, Pasching, Austria) with the addition of 10% fetal calf serum, 2 mM L-glutamine (Biowhittaker), 1 mM sodium pyruvate, 50 ug / ml gentamycin and 9 ⁇ g / ml insulin (MM6 medium).
  • the cells were seeded at a density of 2 x 10 5 / ml in 2 ml of MM6 medium in 24 well plates and cultured at 37 ° C in a humidified atmosphere with 5% CO 2 for 3 to 4 days before being used for experiments were used.
  • Polypeptides of the sequence SEQ ID NO: 3 according to the formula (3) whose mouse orthologue according to the sequence SEQ ID NO: 15 according to the formula (15) and a control peptide of the sequence SEQ ID NO: 14 according to the formula (14) chemically synthesized by t-Boc-based solid-phase peptide synthesis using 4-methylbenzhydrylamine resin, purified by reverse phase HPLC, and optionally cyclized in 6 M guanidine-HCl / Tris pH 8. Molecular mass was determined by electrospray mass spectrometry (Dawson PE, Kent SB. (2000) Annu Rev Biochem. 69: 923- 960, Ralpheng TM, Griffin JH, Dawson PE. (1999) Proc Natl Acad. See US A., Vol. 96, pp. 10068-10073).
  • Example 1 Plasmon resonance studies to analyze the inhibitory effect of the polypeptide of the sequence SEQ ID NO: 3 according to the formula (3) on the formation of heteroaggregates of RANTES and PF4
  • HBS-EP buffer (10mM HEPES, 150mM NaCl, 0.005% Tween 20, pH 7.4).
  • bPF4 N-terminus biotinylated human PF4 (bPF4) was chemically synthesized by t-Boc-based solid-phase peptide synthesis and native chemical ligation of PF4 (Dawson
  • the bPF4 was immobilized on the dextran surface of a Cl sensor chip by injecting 200 ⁇ g / ml of bPF4 in HBS-EP through one of the flow chambers and taking up 240 resonance units (RU). The second flow chamber was not treated with bPF4 and served as a reference.
  • RANTES 0.5 ⁇ M, recombinant human RANTES, Peprotech, Rocky Hill, NJ, USA
  • RANTES 0.5 ⁇ M
  • concentrations 0 ⁇ M, 10 ⁇ M, 50 ⁇ M and 100 ⁇ M, of the polypeptide of the sequence SEQ ID NO: 3 according to the formula (3) in HBS-EP buffer overnight at room temperature
  • bPF4 15 ⁇ l of the respective peptide / RANTES mixture and Observation of the bond determined for 180 seconds.
  • the coupling procedure and measurements were performed in a Biacore 2000 (Biacore AB) apparatus at a flow rate of 5 ⁇ l / min.
  • Sensorgrams of the RANTE S binding were corrected for unspecific background signals using the software BIAevaluation 3.0 (Biacore AB) and equilibrium resonance units (RU) were determined for each injection.
  • polypeptide of the sequence SEQ ID NO: 3 could cause a concentration-dependent inhibition of the interaction of RANTES and PF4, wherein the binding of RANTES to immobilized PF4 up to 35% in the presence of the peptide of the sequence SEQ ID NO: 3 was reduced according to the formula (3) at a concentration of 100 ⁇ M.
  • KEYFYTSGK (14) (SEQ ID NO: 14) was preincubated, examined.
  • Petri dishes with confluent HUVEC cell layers activated with IL-1 ⁇ (Interleukin I ⁇ , Peprotech, 10 ng / ml, 12 hours) were installed in a flow chamber.
  • Mono Mac 6 cells (0.5 x 10 6 cells / ml) were resuspended in balanced Hank's solution (HBSS with 10mM Hepes (Gibco BRL), pH 7.3, 0.5% bovine serum albumin (Serva)) and resuspended Kept ice.
  • HBSS balanced Hank's solution
  • Serva bovine serum albumin
  • mononuclear MM6 cells were exposed to Ca 2+ and Mg 2+ to a final concentration of 1 mM and 60 nM chemokines RANTES, respectively
  • the enhancement of monocyte arrest could be significantly, for example up to 80%, inhibited by the heterophilic interaction of RANTES and PF4 by the polypeptide of the sequence SEQ ID NO: 3 according to the formula (3), while the inhibition by the polypeptide of the sequence SEQ ID NO: 2 according to the formula (2) was weaker.
  • the control peptide of the sequence SEQ ID NO: 14 according to the formula (14) showed no significant inhibition.
  • mice 9 to 12 week old female ApoE / littermate mice were used as model of atherosclerosis (The Jackson Lab, Bar Harbor, Maine, USA). These were fed high fat (21% fat, Altromin® C 1061) for 12 weeks. During this time, two groups of the mice were given intraperitoneal injections of 50 ⁇ g of the polypeptide of the sequence SEQ ID NO: 15 according to the formula (15) three times a week as indicated below:
  • mice 7 mice
  • mice 8 mice
  • mice 12 mice
  • the mice were sacrificed for histological examination. During the experiment, the mice were healthy and showed no signs of disease. Blood samples were taken at the beginning and at the end of the experimental diet. The leucocyte count was determined haemocytometrically, and the sera were collected and the
  • the extent of atherosclerosis was determined on aortic and thoracoabdominal aortae by staining lipid deposits by oil red O staining (Veillard NR, Kwak B, Pelli G, Mulhaupt F, James RW, Proudfoot AE, Mach F. Antagonism of RANTES receptors reducing atherosclerotic plaque formation in mice, Circ Res. 2004; 94: 253-61) and quantified by means of computerized image analysis (Diskus Software, Hilgers, Aachen). Areas of atherosclerotic lesions were determined in 5 ⁇ m transverse sections through the heart and aortic root.

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Abstract

L'invention concerne un polypeptide de la séquence d'acides aminés SEQ ID NO : 1 de formule (I), ainsi que leur utilisation dans la production d'un médicament et des médicaments destinés à traiter des maladies, qui sont en relation avec un recrutement de monocytes.
EP06806162A 2005-10-14 2006-10-11 Antagonistes utilises contre l'interaction de pf4 et de rantes Withdrawn EP1934249A1 (fr)

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CA2737924A1 (fr) * 2008-10-06 2010-04-15 Joshua Robert Schultz Procedes de traitement de l'inflammation
WO2011116245A2 (fr) * 2010-03-19 2011-09-22 Carolus Therapeutics, Inc. Méthodes de traitement d'une inflammation
US11629196B2 (en) 2020-04-27 2023-04-18 Incelldx, Inc. Method of treating SARS-CoV-2-associated hypercytokinemia by administering a human monoclonal antibody (PRO-140) that inhibits CCR5/CCL5 binding interactions
US11402391B2 (en) 2020-12-21 2022-08-02 Incelldx, Inc. Methods of treating a long-hauler subject for chronic COVID-19 by administering a CCR5 or CCL5 antagonist

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DE10014516A1 (de) * 2000-03-23 2001-09-27 Weber Christian Antagonisten des RANTES Rezeptors CCR1 zur Prävention und Therapie der Atherosklerose und Restenose

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WO1998006751A1 (fr) * 1996-08-16 1998-02-19 Research Corporation Technologies, Inc. Antagonistes des recepteurs de mcp-3, rantes et mip-1alpha
US6168784B1 (en) * 1997-09-03 2001-01-02 Gryphon Sciences N-terminal modifications of RANTES and methods of use
EP0906954A1 (fr) * 1997-09-29 1999-04-07 Applied Research Systems ARS Holding N.V. C-C chémokine tronquée à l'aminoterminus comme antagoniste de chémokines
AU1616499A (en) * 1997-12-01 1999-06-16 Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services, The Chemokine variants and methods of use
IT1303736B1 (it) * 1998-11-11 2001-02-23 San Raffaele Centro Fond Peptidi derivati da rantes con attivita' anti-hiv.
ITMI20030107A1 (it) * 2003-01-24 2004-07-25 Primm Srl Peptidi derivati da rantes.
DE102005049637A1 (de) 2005-10-14 2007-04-26 Rheinisch-Westfälische Technische Hochschule Aachen Antagonisten gegen die Interaktion von PF4 und RANTES
CA2737924A1 (fr) * 2008-10-06 2010-04-15 Joshua Robert Schultz Procedes de traitement de l'inflammation

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DE10014516A1 (de) * 2000-03-23 2001-09-27 Weber Christian Antagonisten des RANTES Rezeptors CCR1 zur Prävention und Therapie der Atherosklerose und Restenose

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Title
KOENEN RORY R ET AL: "Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice", NATURE MEDICINE, NATURE PUBLISHING GROUP, NEW YORK, NY, US, vol. 15, no. 1, 1 January 2009 (2009-01-01), pages 97 - 103, XP009144429, ISSN: 1078-8956, DOI: 10.1038/NM.1898 *
See also references of WO2007042263A1 *

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