DK2335718T3 - Ikke-cytotoksiske proteinkonjugater - Google Patents

Ikke-cytotoksiske proteinkonjugater Download PDF

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Publication number
DK2335718T3
DK2335718T3 DK10184150.0T DK10184150T DK2335718T3 DK 2335718 T3 DK2335718 T3 DK 2335718T3 DK 10184150 T DK10184150 T DK 10184150T DK 2335718 T3 DK2335718 T3 DK 2335718T3
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Denmark
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protease
seq
fusion protein
fusion
nociceptin
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DK10184150.0T
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English (en)
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Keith Foster
John Chaddock
Philip Marks
Patrick Stancombe
Roger K Aoki
Joseph Francis
Lance Steward
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Sec Dep For Health
Allergan Inc
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Priority claimed from EP05810103A external-priority patent/EP1830872B1/en
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Publication of DK2335718T3 publication Critical patent/DK2335718T3/da

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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
    • C07K14/575—Hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/711—Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
    • 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
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase
    • A61K38/4893—Botulinum neurotoxin (3.4.24.69)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/6415—Toxins or lectins, e.g. clostridial toxins or Pseudomonas exotoxins
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C07K14/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Clostridium (G)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/62—DNA sequences coding for fusion proteins
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6489—Metalloendopeptidases (3.4.24)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/24—Metalloendopeptidases (3.4.24)
    • C12Y304/24069—Bontoxilysin (3.4.24.69), i.e. botulinum neurotoxin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Zoology (AREA)
  • Biomedical Technology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Wood Science & Technology (AREA)
  • General Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biophysics (AREA)
  • Biotechnology (AREA)
  • Toxicology (AREA)
  • Microbiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Immunology (AREA)
  • Plant Pathology (AREA)
  • Physics & Mathematics (AREA)
  • Endocrinology (AREA)
  • Rheumatology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Enzymes And Modification Thereof (AREA)

Claims (17)

1. Enkeltkædet polypeptidfusionsprotein, der omfatter: a. en ikke-cytotoksisk protease eller et fragment deraf, hvilken protease eller hvilket proteasefragment er i stand til at spalte et protein af en nociceptiv sensorisk afferents exocytiske fusionsapparat; b. en targetenhed, der er i stand til at binde til et bindingssted på den nociceptive sensoriske afferent, hvilket bindingssted er i stand til at undergå endocytose til inkorporering i et endosom i den nociceptive sensoriske afferent; c. proteasespaltningssted, ved hvilket sted fusionsproteinet kan spaltes med en protease, hvor proteasespaltningsstedet er lokaliseret mellem den ikke-cytotoksiske protease eller fragmentet deraf og targeten-heden; d. et translokationsdomæne, der er i stand til at sikre translokation af proteasen eller proteasefragmentet inde fra et endosom, over den endosomale membran og ind i den nociceptive sensoriske afferents cytosol; hvor targetenheden er lokaliseret mellem proteasespaltningsstedet og translokationsdomænet, og hvor targetenheden og proteasespaltningsstedet er adskilt af nul aminosyrerester, og hvor targetenheden og proteasespaltningsstedet ikke er adskilt af nul aminosyrerester.
2. Fusionsprotein ifølge krav 1, hvor targetenheden og proteasespaltningsstedet er adskilt af mindst 5 aminosyrerester.
3. Fusionsprotein ifølge et hvilket som helst af de foregående krav, hvor den ikke-cytotoksiske protease er en clostridien-neurotoxin-L-kæde eller en IgA-protease.
4. Fusionsprotein ifølge et hvilket som helst af de foregående krav, hvor translokationsdomænet er et clostridien-neurotoxins FlN-domæne.
5. Fusionsprotein ifølge et hvilket som helst af de foregående krav, hvor targetenheden omfatter højst 50 aminosyrerester, fortrinsvis højst 40 aminosyrerester, mere fortrinsvis mindst 30 aminosyrerester og mest fortrinsvis højst 20 aminosyrerester.
6. Fusionsprotein ifølge et hvilket som helst af krav 1-5, hvor targetenheden: (i) er et opioid; (ii) er en agonist af en receptor, der er til stede på en nociceptiv sensorisk afferent, fortrinsvis hvor targetenheden er en agonist af en receptor, der er til stede på en primær nociceptiv sensorisk afferent; (iii) binder til ORLrreceptoren, fortrinsvis hvor targetenheden binder specifikt til ORLrreceptoren, mere fortrinsvis hvor targetenheden er en agonist af ORLrreceptoren.
7. Fusionsprotein ifølge krav 6, hvor targetenheden har mindst 70 % homologi med SEQ ID Nr. 38 eller et fragment deraf, eller hvor targetenheden har mindst 80 % homologi med SEQ ID Nr. 38 eller et fragment deraf, eller hvor targetenheden har mindst 90 % homologi med SEQ ID Nr. 38 eller et fragment deraf, eller hvor targetenheden har mindst 95 % homologi med SEQ ID Nr. 38 eller et fragment deraf, eller hvor targetenheden er SEQ ID Nr. 38 eller et fragment deraf, eller hvor targetenheden er én SEQ ID Nr. 40, 42, 44, 46, 48 eller 50, eller hvor targetenheden er nociceptin.
8. Fusionsprotein ifølge et hvilket som helst af krav 1-5, hvor targetenheden er valgt fra gruppen, der består af nociceptin, β-endorphin, endomorphin-1, endomorphin-2, dynorphin, met-enkephalin, leu-enkephalin, galanin og PAR-2 peptid.
9. Fusionsprotein ifølge et hvilket som helst af de foregående krav, hvor fusionsproteinet omfatter en oprensnings-tag; fortrinsvis hvor fusionsproteinet omfatter en oprensnings-tag, der er til stede ved fusionsproteinets N-terminale og/eller C-terminale ende; mere fortrinsvis hvor oprensnings-taggen er bundet til fusionsproteinet med et peptid-spacermolekyle.
10. Fusionsprotein ifølge et hvilket som helst af de foregående krav, hvor translokationsdomænet er afskilt fra targetenheden med et peptid-spacermolekyle.
11. Nukleinsyresekvens, der koder for polypeptidfusionsproteinet ifølge et hvilket som helst af de foregående krav.
12. DNA vektor, der omfatter en promotor, en nukleinsyresekvens ifølge krav 11, hvor DNA sekvensen er lokaliseret nedstrøms for promotoren, og en terminator er lokaliseret nedstrøms for DNA konstruktet.
13. Fremgangsmåde til fremstilling af et enkeltkædet polypeptid-fusionsprotein ifølge et hvilket som helst af krav 1-10, der omfatter eksprimering af en nukleinsyresekvens ifølge krav 11 eller en DNA vektor ifølge krav 12, i en værtscelle.
14. Fremgangsmåde til fremstilling af et ikke-cytotoksisk middel, hvilken fremgangsmåde omfatter, at man a) bringer et enkeltkædet polypeptidfusionsprotein ifølge et hvilket som helst af krav 1-10 i kontakt med en protease, der er i stand til at spalte proteasespaltningsstedet; b) spalter proteasespaltningsstedet; og derved danner et tokædet fusionsprotein.
15. Ikke-cytotoksisk polypeptid, der kan opnås ved fremgangsmåden ifølge krav 14, hvor polypeptidet er et tokædet polypeptid, og hvor: a. den første kæde omfatter den ikke-cytotoksiske protease eller et fragment deraf; hvilken protease eller hvilket proteasefragment er i stand til at spalte et protein af en nociceptiv sensorisk afferents exocytiske fusionsapparat; b. den anden kæde omfatter targetenheden og translokationsdomænet, der er i stand til at sikre translokation af proteasen eller proteasef rag mentet inde fra et endosom, over den endosomale membran og ind i den nociceptive sensoriske afferents cytosol; og hvor den første og den anden kæde er bundet sammen ved disulfidbinding.
16. Anvendelse af et fusionsprotein ifølge et hvilket som helst af krav 1-10 eller et polypeptid ifølge krav 15 til fremstilling af et medikament til behandling eller forebyggelse eller lindring af smerte; hvor smerten fortrinsvis er kronisk smerte.
17. Fusionsprotein ifølge et hvilket som helst af krav 1-10 eller et polypeptid ifølge krav 15 til anvendelse til behandling, forebyggelse eller lindring af smerte; hvor smerten fortrinsvis er kronisk smerte.
DK10184150.0T 2004-12-01 2005-12-01 Ikke-cytotoksiske proteinkonjugater DK2335718T3 (da)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB0426394A GB0426394D0 (en) 2004-12-01 2004-12-01 Fusion proteins
GB0504964A GB0504964D0 (en) 2004-12-01 2005-03-10 Fusion proteins
EP05810103A EP1830872B1 (en) 2004-12-01 2005-12-01 Fusion proteins

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DK2335718T3 true DK2335718T3 (da) 2015-09-14

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Family Applications (6)

Application Number Title Priority Date Filing Date
DK10166556.0T DK2366399T3 (da) 2004-12-01 2005-12-01 Ikke-cytotoksiske proteinkonjugater
DK05810711T DK1877073T3 (da) 2004-12-01 2005-12-01 Ikke-cytotoksiske proteinkonjugater
DK10184114.6T DK2292249T3 (da) 2004-12-01 2005-12-01 Ikke-cytotoksiske proteinkonjugater
DK10184150.0T DK2335718T3 (da) 2004-12-01 2005-12-01 Ikke-cytotoksiske proteinkonjugater
DK10157432T DK2204182T3 (da) 2004-12-01 2005-12-01 Ikke-cytotoksiske proteinkonjugater
DK05810103T DK1830872T3 (da) 2004-12-01 2005-12-01 Fusionsproteiner

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DK10166556.0T DK2366399T3 (da) 2004-12-01 2005-12-01 Ikke-cytotoksiske proteinkonjugater
DK05810711T DK1877073T3 (da) 2004-12-01 2005-12-01 Ikke-cytotoksiske proteinkonjugater
DK10184114.6T DK2292249T3 (da) 2004-12-01 2005-12-01 Ikke-cytotoksiske proteinkonjugater

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DK10157432T DK2204182T3 (da) 2004-12-01 2005-12-01 Ikke-cytotoksiske proteinkonjugater
DK05810103T DK1830872T3 (da) 2004-12-01 2005-12-01 Fusionsproteiner

Country Status (13)

Country Link
US (5) US8067200B2 (da)
EP (4) EP2204182B1 (da)
JP (7) JP5174463B2 (da)
AT (1) ATE488245T1 (da)
CY (2) CY1111324T1 (da)
DE (1) DE602005024857D1 (da)
DK (6) DK2366399T3 (da)
ES (6) ES2356179T3 (da)
GB (3) GB0426394D0 (da)
HU (2) HUE027025T2 (da)
PL (3) PL2292249T3 (da)
PT (5) PT1877073E (da)
SI (2) SI1830872T1 (da)

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