WO2023099725A1 - Préparation pharmaceutique contenant un mélange d'un peptide natriurétique (anp) et d'un inhibiteur peptidique du récepteur cxcr4 - Google Patents

Préparation pharmaceutique contenant un mélange d'un peptide natriurétique (anp) et d'un inhibiteur peptidique du récepteur cxcr4 Download PDF

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Publication number
WO2023099725A1
WO2023099725A1 PCT/EP2022/084186 EP2022084186W WO2023099725A1 WO 2023099725 A1 WO2023099725 A1 WO 2023099725A1 EP 2022084186 W EP2022084186 W EP 2022084186W WO 2023099725 A1 WO2023099725 A1 WO 2023099725A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical preparation
diseases
preparation according
group
seq
Prior art date
Application number
PCT/EP2022/084186
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German (de)
English (en)
Inventor
Wolf-Georg Forssmann
Original Assignee
Pharis Biotec Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharis Biotec Gmbh filed Critical Pharis Biotec Gmbh
Publication of WO2023099725A1 publication Critical patent/WO2023099725A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2242—Atrial natriuretic factor complex: Atriopeptins, atrial natriuretic protein [ANP]; Cardionatrin, Cardiodilatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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

Definitions

  • composition containing a mixture of a natriuretic peptide (ANP) and a peptide inhibitor of the CXCR4 receptor
  • the subject matter of the present invention is a pharmaceutical preparation containing a mixture of at least one natriuretic peptide (ANP) with at least one peptide inhibitor of the CXCR4 receptor as effective components for the treatment of diseases.
  • NBP natriuretic peptide
  • the pharmaceutical composition according to the invention enables a surprisingly effective treatment of vascular diseases, organ infarctions, peripheral circulatory disorders, renal insufficiency, muscular degeneration, rheumatic diseases, tumor diseases, degenerative-genetic or acquired diseases, dermatological diseases or inflammatory skin syndromes and bone diseases due to a synergistic effect of its active components.
  • the active components of the pharmaceutical composition according to the invention are at least one natriuretic peptide (ANP) and at least one peptidic inhibitor of the CXCR4 receptor, which are present in a mixture in the pharmaceutical composition according to the invention.
  • vascular diseases selected from the group consisting of acute and chronic heart failure can be treated with the pharmaceutical composition according to the invention.
  • ADHF acute and chronic heart failure
  • organ infarctions selected from the group consisting of infarctions of the heart and/or the brain can be treated with the pharmaceutical composition according to the invention.
  • rheumatic disorders selected from the group consisting of juvenile rheumatoid arthritis can be treated with the pharmaceutical composition according to the invention.
  • the pharmaceutical composition according to the invention can be used to treat tumors selected from the group consisting of CXCR4-dependent cancers and blood cancers.
  • degenerative-genetic or acquired diseases selected from the group consisting of diseases of the nervous system and the sensory organs (AML, MS) can be treated with the pharmaceutical composition according to the invention.
  • dermatological diseases selected from the group consisting of skin tumors can be treated with the pharmaceutical composition according to the invention.
  • inflammatory skin syndromes and bone diseases selected from the group consisting of osteoporosis or tumor metastases can be treated with the pharmaceutical composition according to the invention.
  • the pharmaceutical preparation according to the invention can contain the natriuretic peptide (ANP) in an amount from 2.0 ng/kg/min to 64.0 ng/kg/min or from 0.4 mg/75 kg/d mg to 6.4 mg/75 kg /d mg per dose unit and/or the peptidic inhibitor of the CXCR4 receptor in an amount of 50 mg/75kg/d to 1000 dose units.
  • the ANP and the peptidic inhibitor of the CXCR4 receptor are preferably present in the stated ranges of amounts.
  • the natriuretic peptide (ANP) present in the preparation according to the invention can be selected from the group consisting of ANF, ANP, urodilatin and their variants, mutants and derivatives.
  • natriuretic peptides with the following sequences should be mentioned as natriuretic peptides:
  • ANF 4-23 (SEQ ID No 1):
  • ANP-28 (SEQ ID No 2):
  • the peptide inhibitor of the CXCR4 receptor present in the preparation according to the invention can be selected from the group consisting of peptides with the peptides mentioned in SEQ ID No. 4 to SEQ ID No. 19 and their variants, mutants and derivatives.
  • IVRYTKKVPQVS (SEQ ID No 5)
  • IMRWSRKMPCVS SEQ ID No. 10.
  • the natriuretic peptide (ANP) or peptide inhibitor of the CXCR4 receptor is a therapeutically active fragment, mutant and/or derivative of the natriuretic peptide or peptide inhibitor of the CXCR4 receptor.
  • Variants of the CXCR4 receptor natriuretic peptide or peptide inhibitor also include modified forms of the polypeptide, as well as its mutants or derivatives.
  • Modified natriuretic peptides or peptidic inhibitors of the CXCR4 receptor are polypeptides in which one or more amino acids of the native sequence have been altered such that a non- naturally occurring amino acid residue is present in the polypeptide chain. In principle, such modifications can arise or be undertaken during or after protein translation and include, for example, phosphorylation, glycosylation, sulfonation, crosslinking, acylation or also proteolytic cleavage.
  • fragments of the natriuretic peptide or the peptide inhibitor of the CXCR4 receptor are also suitable as agents for the diseases mentioned, provided they cause an inhibition of the infection with coronavirus that is comparable to the native natriuretic peptide or peptide inhibitor of the CXCR4 receptor .
  • amino acid substitutions can be made in a conservative manner.
  • a conservative replacement is understood to mean a mutation in which one codon is replaced by another. This encodes a different amino acid that is chemically related to the original amino acid, such as glycine with alanine or threonine with serine.
  • a non-conservative exchange occurs when the original codon is replaced by a codon that codes for an amino acid with different chemical properties, for example glycine with lysine.
  • substantially identical or similar expressions used in connection with two polypeptides refers to two or more sequences or subsequences which have at least a 70%, in particular at least 80%, in particular at least 90%, in particular have at least 95% sequence identity if they are compared for maximum agreement using a sequence comparison algorithm and a-ligned.
  • Substantial identity exists in particular if a sequence region that is at least 40-60 amino acids in length, in particular 60 -80 amino acids, in particular more than 90-100 amino acid residues and in particular is essentially identical over the entire length of the amino acid sequence of the native polypeptide.
  • nucleic or percent “identical” in the context of two or more polypeptides refers to two or more sequences or subsequences that are the same or a specified percentage of amino acids that are identical are exhibited if they are compared for maximum agreement and "aligned" using a sequence comparison algorithm.
  • Optimized alignment for comparing sequences can be carried out, for example, using the following algorithms: local homology alignment by Smith & Waterman, Adv. Appl. Math.
  • Fragments of the polypeptide can typically be obtained by cleaving the polypeptide chain of the natriuretic peptide or peptidic inhibitor of the CXCR4 receptor. Methods for fragmentation by cleaving the polypeptide chain are known to those skilled in the art.
  • proteases can be split by enzymes, so-called proteases.
  • proteases split polypeptides (proteins) within the amino acid chain or at the end, a distinction is made between proteinases (also called endopeptidases). They break down proteins within the amino acid chain. They usually recognize specific sequence sections within a protein that they can attack and cleave there.
  • exoproteases also called exopeptidases
  • Carboxypeptidases which cleave the amino acids from the carboxyl end (C-terminus), and aminopeptidases, which cleave the amino acids from the amino end (N-terminus).
  • proteases cleave the peptide bond between two specific amino acids; in some cases, they also recognize more than one substrate. These proteases are used, for example, to examine the relationship between proteins, to prepare proteins for sequencing or to isolate active domains of a protein. Table 1 below shows some examples of such proteases: Table 1: Specific proteases and their properties
  • non-specific proteases cleave the peptide chain before or after a whole series of amino acids and thus generate much smaller cleavage fragments.
  • Table 2 below shows some examples of such non-specific proteases:
  • Cyanogen bromide (BrCN) is the most important reagent of this type and cleaves proteins on the C-terminal side of methionine residues. This produces peptidyl homoserine lactone. The resulting peptide fragments can then be separated in the polyacrylamide gel and visualized by staining.
  • Tab. 3 Typical reagents for chemical proteolysis and their properties
  • proteolysis A special case of proteolysis is the so-called limited proteolysis.
  • the protein digestion in this method is not complete, but takes place under precisely defined reaction conditions (proteolysis is therefore limited).
  • proteolysis is therefore limited.
  • the peptide bonds are far less exposed than the peptide bonds on the protein's surface. This means that if a protease acts for a short time or if the protease concentration is very low, the individual protein domains may first be separated before the protease also reaches cleavage sites located further inside.
  • the limited proteolysis is thus carried out with a protease dilution and/or suboptimal reaction conditions and stopped after a short time.
  • the protein is proteolytically cleaved in its native form (and not after denaturation); this sometimes has consequences for the choice of protease. For example, if the protein requires EDTA for optimal stability, a metalloprotease cannot be used for digestion.
  • the pharmaceutical preparation according to the invention can be liquid or solid.
  • the pharmaceutical preparation according to the invention can be formulated in such a way that it can be administered intravascularly, lymphatically, intracardially, epicutaneously, intracutaneously and subcutaneously, intranasally, locally and into the liquor space.
  • the natriuretic peptide or the peptidic inhibitor of the CXCR4 receptor can be present in an essentially aqueous solution, in particular in an aqueous solution with pharmaceutical excipients.
  • the excipients can be added individually or in combination not only to the natriuretic peptide or peptidic inhibitor of the CXCR4 receptor but also to a final formulation.
  • the excipients can be added at various points in the pharmaceutical preparation of the medicinal product.
  • a bacteriostatic agent such as benzyl alcohol, a surfactant such as Tween 20, an isotonic agent such as mannitol, one or more stabilizing amino acids such as lysine or arginine, and an antioxidant may also be included in the formulation.
  • the polypeptide is formulated for parenteral, intravenous, intramuscular, intranasal, inhaled, topical, or buccal administration.
  • Infusion solutions, ointments, sprays and other forms of application of polypeptides known to the pharmaceutical chemist are particularly suitable as galenic formulations. It can be useful to administer the polypeptide bound to a suitable carrier or contained in liposomes.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Cardiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Biomedical Technology (AREA)
  • Organic Chemistry (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • Molecular Biology (AREA)
  • Endocrinology (AREA)
  • Zoology (AREA)
  • Hospice & Palliative Care (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une préparation pharmaceutique contenant un mélange d'au moins un peptide natriurétique (ANP) avec au moins un inhibiteur peptidique du récepteur CXCR4 pour le traitement de maladies vasculaires, d'infarctus d'organes, de troubles circulatoires périphériques, de l'insuffisance rénale, de la dégénérescence musculaire, de troubles rhumatismaux, de maladies tumorales, de maladies dégénératives ou acquises, de maladies dermatologiques ou de syndromes cutanés inflammatoires et de maladies osseuses.
PCT/EP2022/084186 2021-12-02 2022-12-02 Préparation pharmaceutique contenant un mélange d'un peptide natriurétique (anp) et d'un inhibiteur peptidique du récepteur cxcr4 WO2023099725A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP21211963.0 2021-12-02
EP21211963 2021-12-02

Publications (1)

Publication Number Publication Date
WO2023099725A1 true WO2023099725A1 (fr) 2023-06-08

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PCT/EP2022/084186 WO2023099725A1 (fr) 2021-12-02 2022-12-02 Préparation pharmaceutique contenant un mélange d'un peptide natriurétique (anp) et d'un inhibiteur peptidique du récepteur cxcr4

Country Status (1)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100204446A1 (en) * 2007-09-11 2010-08-12 Wolf-Georg Forssmann Use of natriuretic peptides for treating angioedema syndromes
US20130029902A1 (en) * 2007-07-03 2013-01-31 Wolf-Georg Forssmann Cxc chemokine receptor 4 (cxcr4) antagonistic polypeptide
US20160122389A1 (en) * 2013-06-12 2016-05-05 Pharis Biotech Gmbh Peptides with antagonistic activities against natural cxcr4

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130029902A1 (en) * 2007-07-03 2013-01-31 Wolf-Georg Forssmann Cxc chemokine receptor 4 (cxcr4) antagonistic polypeptide
US20100204446A1 (en) * 2007-09-11 2010-08-12 Wolf-Georg Forssmann Use of natriuretic peptides for treating angioedema syndromes
US20160122389A1 (en) * 2013-06-12 2016-05-05 Pharis Biotech Gmbh Peptides with antagonistic activities against natural cxcr4

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
"Current Protocols in Molecular Biology", 1987, JOHN WILEY & SONS, INC
PEARSONLIPMAN, PROC. NAT'L. ACAD.SCI. USA, vol. 85, 1988, pages 2444
SCIENCE DR: "Wisconsin Genetics Software Package", GENETICS COMPUTER GROUP, vol. 575
SMITHWATERMAN, ADV. APPL. MATH, vol. 2, 1981, pages 482
VON NEEDLEMANWUNSCH, J. MOL. BIOL., vol. 48, 1970, pages 443

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