DK2366399T3 - Ikke-cytotoksiske proteinkonjugater - Google Patents

Ikke-cytotoksiske proteinkonjugater Download PDF

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DK2366399T3
DK2366399T3 DK10166556.0T DK10166556T DK2366399T3 DK 2366399 T3 DK2366399 T3 DK 2366399T3 DK 10166556 T DK10166556 T DK 10166556T DK 2366399 T3 DK2366399 T3 DK 2366399T3
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ser
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DK10166556.0T
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Joseph Francis
Lance Steward
Keith Foster
John Chaddock
Philip Marks
Patrick Stancombe
Roger K Aoki
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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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    • 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)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Wood Science & Technology (AREA)
  • General Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Biotechnology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biophysics (AREA)
  • Toxicology (AREA)
  • Microbiology (AREA)
  • Pain & Pain Management (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Endocrinology (AREA)
  • Immunology (AREA)
  • Physics & Mathematics (AREA)
  • Plant Pathology (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, hvor proteasen eller proteasefragmentet er i stand til at spalte et protein af den exocytiske fusionsindretning af en nociceptiv sensorisk afferent; 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. et protease spaltningssted, ved hvilket sted fusionsproteinet kan spaltes med en protease, hvor proteasespaltningsstedet er lokaliseret mellem den ikke-cytotoksiske protease eller fragmentet deraf og target-enheden; d. et translokationsdomæne, der er i stand til at sikre translokation af proteasen eller proteasefragmentet inde fra et endosom, igennem den endosomale membran og ind i den nociceptive sensoriske afferents cytosol; hvor targetenheden er lokaliseret mellem proteasespaltningsstedet og translokationsdomænet, og hvor proteasen (eller fragment deraf) og translokationsdomænet er indbyrdes adskilt med højst 100 aminosyrerester.
2. Fusionsprotein ifølge krav 1, hvor targetenheden og proteasespaltningsstedet er adskilt med højst 10 aminosyrerester, fortrinsvis med højst 5 aminosyrerester, og mere fortrinsvis med højst nul aminosyrerester.
3. Fusionsprotein ifølge et hvilket som helst af de foregående krav, hvor den ikke-cytotoksiske protease er en clostridium-neurotoxin-L-kæde eller en IgA-protease.
4. Fusionsprotein ifølge et hvilket som helst af de foregående krav, hvor translokationsdomænet er HN domænet afen clostridium-neurotoxin.
5. Fusionsprotein ifølge et hvilket som helst af de foregående krav, hvor targetenheden omfatter højst 50 aminosyrerester, fortrinsvis højst 40 aminosyrerester, og mere fortrinsvis højst 30 aminosyrerester og mest fortrinsvis højst 20 aminosyrerester.
6. Fusionsprotein ifølge et hvilket som helst af kravene 1-5, hvor targetenhe-den: (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 ORLi-receptoren, fortrinsvis hvor targetenheden binder specifikt til ORL1-receptoren, mere foretrukket hvor targetenheden er en agonist af ORLrreceptoren.
7. Fusionsprotein ifølge krav 6, hvor targetenheden har mindst 70% aminosy-resekvensidentitet med SEQ ID Nr. 38 eller et fragment deraf, eller hvor targetenheden har mindst 80% aminosyresekvensidentitet med SEQ ID Nr. 38 eller et fragment deraf, eller hvor targetenheden har mindst 90% aminosyresekvensidentitet med SEQ ID Nr. 38 eller et fragment deraf, eller hvor targetenheden har mindst 95% aminosyresekvensidentitet 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 af SEQ ID Nr: 40, 42, 44, 46, 48 eller 50, eller hvor targetenheden er nociceptin.
8. Fusionsprotein ifølge et hvilket som helst af kravene 1-5, hvor targetenheden er valgt fra gruppen, der består af nociceptin, β-endorphin, endomorphin-1, endomorphin-2, dynorphin, met-enkephalin, leuenkephalin, 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, som er til stede ved N-terminal-og/eller C-terminalenden af fusionsproteinet; mere foretrukket 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 en peptid-spacermolekyle.
11. Nukleinsyresekvens, der koder for polypeptidfusionsproteinet ifølge et hvilket som helst af de foregående krav.
12. DNA vektor, der omfatter en promoter, en nukleinsyresekvens ifølge krav 11, hvor DNA sekvensen er lokaliseret nedstrøms for promoteren, og en terminator er lokaliseret nedstrøms for DNA konstruktet.
13. Fremgangsmåde til fremstilling af et enkeltkædet polypeptidfusionsprote-in 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 kravene 1-10 i kontakt med en protease, der er i stand til at spalte protea-se-spaltningsstedet; b. spalter proteasespaltningsstedet; og derved danner et tokædet fusionsprotein.
15. Ikke-cytotoksisk polypeptid, der kan opnås ved fremgangsmåden ifølge krav 14, hvor polypeptidet er en tokædet polypeptid, og hvor: a. den første kæde omfatter en ikke-cytotoksisk protease eller et fragment deraf, hvor proteasen eller proteasefragmentet er i stand til at spalte et protein af den exocytiske fusionsindretning afen nociceptiv sensorisk afferent; b. den anden kæde omfatter targetenheden og translokationsdomænet, der er i stand til at sikre translokation af proteasen eller proteasefragmentet inde fra et endosom, igennem 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 kravene 1-10 eller et polypeptid ifølge krav 15, til fremstilling af et medikament til behandling, forebyggelse eller lindring af smerte; hvor smerten fortrinsvis er kronisk smerte.
17. Fusionsprotein ifølge et hvilket som helst af kravene 1-10 eller et po-lypeptid ifølge krav 15 til anvendelse til behandling, forebyggelse eller lindring af smerte; hvor smerten fortrinsvis er kronisk smerte.
DK10166556.0T 2004-12-01 2005-12-01 Ikke-cytotoksiske proteinkonjugater DK2366399T3 (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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DK2366399T3 true DK2366399T3 (da) 2015-06-29

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

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DK10157432T DK2204182T3 (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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DK05810711T DK1877073T3 (da) 2004-12-01 2005-12-01 Ikke-cytotoksiske proteinkonjugater
DK10184150.0T DK2335718T3 (da) 2004-12-01 2005-12-01 Ikke-cytotoksiske proteinkonjugater
DK05810103T DK1830872T3 (da) 2004-12-01 2005-12-01 Fusionsproteiner

Country Status (13)

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US (5) US8067200B2 (da)
EP (4) EP2335718B1 (da)
JP (7) JP5174464B2 (da)
AT (1) ATE488245T1 (da)
CY (2) CY1111324T1 (da)
DE (1) DE602005024857D1 (da)
DK (6) DK2204182T3 (da)
ES (6) ES2540111T3 (da)
GB (3) GB0426394D0 (da)
HU (2) HUE027025T2 (da)
PL (3) PL2366399T3 (da)
PT (5) PT2366399E (da)
SI (2) SI1830872T1 (da)

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