HRP20201528T1 - Biparatopikalni polipeptidi koji antagoniziraju wnt signalizaciju u tumorskim stanicama - Google Patents
Biparatopikalni polipeptidi koji antagoniziraju wnt signalizaciju u tumorskim stanicama Download PDFInfo
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- HRP20201528T1 HRP20201528T1 HRP20201528TT HRP20201528T HRP20201528T1 HR P20201528 T1 HRP20201528 T1 HR P20201528T1 HR P20201528T T HRP20201528T T HR P20201528TT HR P20201528 T HRP20201528 T HR P20201528T HR P20201528 T1 HRP20201528 T1 HR P20201528T1
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- 108090000765 processed proteins & peptides Proteins 0.000 title claims 23
- 229920001184 polypeptide Polymers 0.000 title claims 21
- 102000004196 processed proteins & peptides Human genes 0.000 title claims 21
- 102000013814 Wnt Human genes 0.000 title claims 2
- 230000011664 signaling Effects 0.000 title claims 2
- 230000003042 antagnostic effect Effects 0.000 title 1
- 210000004881 tumor cell Anatomy 0.000 title 1
- 108060003951 Immunoglobulin Proteins 0.000 claims 21
- 102000018358 immunoglobulin Human genes 0.000 claims 21
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 claims 11
- 102100024952 Protein CBFA2T1 Human genes 0.000 claims 8
- 125000003275 alpha amino acid group Chemical group 0.000 claims 6
- 238000000034 method Methods 0.000 claims 3
- 206010028980 Neoplasm Diseases 0.000 claims 2
- 201000011510 cancer Diseases 0.000 claims 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 2
- 239000013604 expression vector Substances 0.000 claims 2
- 102000009027 Albumins Human genes 0.000 claims 1
- 108010088751 Albumins Proteins 0.000 claims 1
- 206010006187 Breast cancer Diseases 0.000 claims 1
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- 206010009944 Colon cancer Diseases 0.000 claims 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims 1
- 101001043594 Homo sapiens Low-density lipoprotein receptor-related protein 5 Proteins 0.000 claims 1
- 101001039199 Homo sapiens Low-density lipoprotein receptor-related protein 6 Proteins 0.000 claims 1
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 claims 1
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 claims 1
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 claims 1
- 102100021926 Low-density lipoprotein receptor-related protein 5 Human genes 0.000 claims 1
- 102100040704 Low-density lipoprotein receptor-related protein 6 Human genes 0.000 claims 1
- 208000019693 Lung disease Diseases 0.000 claims 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims 1
- 206010033128 Ovarian cancer Diseases 0.000 claims 1
- 206010061535 Ovarian neoplasm Diseases 0.000 claims 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims 1
- 208000017442 Retinal disease Diseases 0.000 claims 1
- 206010038923 Retinopathy Diseases 0.000 claims 1
- 206010039491 Sarcoma Diseases 0.000 claims 1
- 230000002159 abnormal effect Effects 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 239000012752 auxiliary agent Substances 0.000 claims 1
- 229940022399 cancer vaccine Drugs 0.000 claims 1
- 238000009566 cancer vaccine Methods 0.000 claims 1
- 238000012258 culturing Methods 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 201000010099 disease Diseases 0.000 claims 1
- 208000035475 disorder Diseases 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims 1
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 claims 1
- 201000005202 lung cancer Diseases 0.000 claims 1
- 208000020816 lung neoplasm Diseases 0.000 claims 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims 1
- 102000039446 nucleic acids Human genes 0.000 claims 1
- 108020004707 nucleic acids Proteins 0.000 claims 1
- 150000007523 nucleic acids Chemical class 0.000 claims 1
- 201000002528 pancreatic cancer Diseases 0.000 claims 1
- 208000008443 pancreatic carcinoma Diseases 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- 238000011084 recovery Methods 0.000 claims 1
- 239000003381 stabilizer Substances 0.000 claims 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/22—Immunoglobulins specific features characterized by taxonomic origin from camelids, e.g. camel, llama or dromedary
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/40—Immunoglobulins specific features characterized by post-translational modification
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/567—Framework region [FR]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
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- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/31—Fusion polypeptide fusions, other than Fc, for prolonged plasma life, e.g. albumin
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- Chemical Kinetics & Catalysis (AREA)
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- Biophysics (AREA)
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- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Endocrinology (AREA)
- Ophthalmology & Optometry (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Reproductive Health (AREA)
- Pulmonology (AREA)
- Vascular Medicine (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Claims (17)
1. Polipeptid koji se specifično veže na LRP5 i LRP6, naznačen time, da obuhvaća:
- prvu imunoglobulinsku zasebnu varijabilnu domenu koja je odabrana iz skupine imunoglobulinskih zasebnih varijabilnih domena (i) do (iii), koje su definirane prema tome, da sadrže sljedeće CDR slijedove:
(i):
CDR1: TYTVG (= SEQ ID NO:1)
CDR2: AIRRRGSSTYYADSVKG (= SEQ ID NO:2)
CDR3: DTRTVALLQYRYDY (= SEQ ID NO:3)
(ii):
CDR1: SYAMG (= SEQ ID NO:4)
CDR2: AIRRSGRRTYYADSVKG (= SEQ ID NO:5)
CDR3: ARRVRSSTRYNTGTWWWEY (= SEQ ID NO:6)
(iii):
CDR1: RYTMG (= SEQ ID NO:7)
CDR2: AIVRSGGSTYYADSVKG (= SEQ ID NO:8)
CDR3: DRRGRGENYILLYSSGRYEY (= SEQ ID NO:9), i
- drugu imunoglobulinsku zasebnu varijabilnu domenu koja je odabrana iz skupine imunoglobulinskih zasebnih varijabilnih domena (iv) i (v), koje su definirane prema tome, da sadrže sljedeće CDR slijedove:
(iv):
CDR1: SYAMG (= SEQ ID NO:10)
CDR2: AISWSGGSTYYADSVKG (= SEQ ID NO:11)
CDR3: SPIPYGSLLRRRNNYDY (= SEQ ID NO:12)
(v):
CDR1: SYAMG (= SEQ ID NO:13)
CDR2: AISWRSGSTYYADSVKG (= SEQ ID NO:14)
CDR3: DPRGYGVAYVSAYYEY (= SEQ ID NO:15).
2. Polipeptid prema patentnom zahtjevu 1, naznačen time, da:
- navedena prva imunoglobulinska zasebna varijabilna domena sadrži sljedeće CDR slijedove:
CDR1: TYTVG (= SEQ ID NO:1)
CDR2: AIRRRGSSTYYADSVKG (= SEQ ID NO:2)
CDR3: DTRTVALLQYRYDY (= SEQ ID NO:3),
i time, da
- navedena druga imunoglobulinska zasebna varijabilna domena sadrži sljedeće CDR slijedove:
CDR1: SYAMG (= SEQ ID NO:10)
CDR2: AISWSGGSTYYADSVKG (= SEQ ID NO:11)
CDR3: SPIPYGSLLRRRNNYDY (= SEQ ID NO:12).
3. Polipeptid prema patentnom zahtjevu 1, naznačen time, da:
- navedena prva imunoglobulinska zasebna varijabilna domena sadrži sljedeće CDR slijedove:
CDR1: SYAMG (= SEQ ID NO:4)
CDR2: AIRRSGRRTYYADSVKG (= SEQ ID NO:5)
CDR3: ARRVRSSTRYNTGTWWWEY (= SEQ ID NO:6),
i time, da
- navedena druga imunoglobulinska zasebna varijabilna domena sadrži sljedeće CDR slijedove:
CDR1: SYAMG (= SEQ ID NO:13)
CDR2: AISWRSGSTYYADSVKG (= SEQ ID NO:14)
CDR3: DPRGYGVAYVSAYYEY (= SEQ ID NO:15).
4. Polipeptid prema patentnom zahtjevu 1, naznačen time, da:
- navedena prva imunoglobulinska zasebna varijabilna domena sadrži sljedeće CDR slijedove:
CDR1: RYTMG (= SEQ ID NO:7)
CDR2: AIVRSGGSTYYADSVKG (= SEQ ID NO:8)
CDR3: DRRGRGENYILLYSSGRYEY (= SEQ ID NO:9), i
time, da
- navedena druga imunoglobulinska zasebna varijabilna domena sadrži sljedeće CDR slijedove:
CDR1: SYAMG (= SEQ ID NO:13)
CDR2: AISWRSGSTYYADSVKG (= SEQ ID NO:14)
CDR3: DPRGYGVAYVSAYYEY (= SEQ ID NO:15).
5. Polipeptid prema bilo kojem od patentnih zahtjeva 1 do 4, naznačen time, da
navedene imunoglobulinske zasebne varijabilne domene su VHH domene, i poželjno su one humanizirane VHH domene.
6. Polipeptid prema patentnom zahtjevu 1 ili zahtjevu 2, naznačen time, da:
- navedena prva imunoglobulinska zasebna varijabilna domena ima aminokiselinski slijed kako je prikazan u SEQ ID NO:19, i
- navedena druga imunoglobulinska zasebna varijabilna domena ima aminokiselinski slijed kako je prikazan u SEQ ID NO:22.
7. Polipeptid prema patentnom zahtjevu 1 ili zahtjevu 3, naznačen time, da:
- navedena prva imunoglobulinska zasebna varijabilna domena ima aminokiselinski slijed kako je prikazan u SEQ ID NO:20, i
- navedena druga imunoglobulinska zasebna varijabilna domena ima aminokiselinski slijed kako je prikazan u SEQ ID NO:23.
8. Polipeptid prema patentnom zahtjevu 1 ili zahtjevu 4, naznačen time, da:
- navedena prva imunoglobulinska zasebna varijabilna domena ima aminokiselinski slijed kako je prikazan u SEQ ID NO:21, i
- navedena druga imunoglobulinska zasebna varijabilna domena ima aminokiselinski slijed kako je prikazan u SEQ ID NO:23.
9. Polipeptid prema bilo kojem od patentnih zahtjeva 1 do 8, naznačen time, da
su navedene prva i druga imunoglobulinske zasebne varijabilne domene kovalentno povezane pomoću peptidnog povezivača, pri čemu navedeni peptidni povezivač opcionalno sadrži ili je sastavljen od treće imunoglobulinske zasebne varijabilne domene.
10. Polipeptid prema patentnom zahtjevu 9, naznačen time, da navedena treća imunoglobulinska zasebna varijabilna domena je albumin koji se veže na imunoglobulinsku zasebnu varijabilnu domenu, i poželjno je to domena Alb11 koja je definirana prema SEQ ID NO:24.
11. Polipeptid, naznačen time, da je polipeptid odabran iz polipeptidne skupine koja obuhvaća ili koja se sastoji od sljedećih: SEQ ID NO:25, SEQ ID NO:26 i SEQ ID NO:27.
12. Vektor ekspresije, naznačen time, da obuhvaća nukleinsku kiselinu koja kodira polipeptid u skladu s bilo kojim od patentnih zahtjeva 1 do 11.
13. Stanica domaćina, naznačena time, da nosi vektor ekspresije u skladu s patentnim zahtjevom 12.
14. Postupak proizvodnje polipeptida prema bilo kojem od patentnih zahtjeva 1 do 11, naznačen time, da obuhvaća sljedeće korake:
- kultiviranje stanice domaćina u skladu s patentnim zahtjevom 13, pod uvjetima koji dopuštaju ekspresiju polipeptida u skladu s bilo kojim od patentnih zahtjeva 1 do 11; i
- ponovno dobivanje i prema potrebi pročišćavanje navedenog polipeptida.
15. Farmaceutski pripravak, naznačen time, da obuhvaća (i) kao djelatni sastojak, polipeptid u skladu s bilo kojim od patentnih zahtjeva 1 do 11, i (ii) farmaceutski prihvatljiv nosač, te prema potrebi (iii) razrjeđivač, ekscipijent, pomoćno sredstvo i/ili stabilizator.
16. Polipeptid prema bilo kojem od patentnih zahtjeva 1 do 11, naznačen time, da se upotrebljava kao lijek u postupku liječenja, prevencije ili ublažavanja bolesti, poremećaja ili stanja kod ljudskog bića ili kod životinje, a poželjno se upotrebljava u postupku (a) za liječenje raka, kao što je rak dojke, rak pluća, rak gušterače, kolorektalni rak, sarkom, rak jajnika ili hepatocelularni karcinom, ili (b) za liječenje idiopatske plućne bolesti, ili (c) za liječenje retinopatije uzrokovane putem abnormalne Wnt signalizacije.
17. Polipeptid prema bilo kojem od patentnih zahtjeva 1 do 11, naznačen time, da se upotrebljava u liječenju raka u kombinaciji s inhibitorom imunološke kontrolne točke, koji je odabran iz skupine koju čine anti-PD1-protutijela, anti-PDL1-protutijela, anti-CTLA4-protutijela, anti-BTLA-protutijela, anti-LAG3-protutijela, i anti-TIM3-protutijela, ili u kombinaciji sa cjepivom protiv raka.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP15197999 | 2015-12-04 | ||
EP16808971.2A EP3383425B1 (en) | 2015-12-04 | 2016-12-02 | Biparatopic polypeptides antagonizing wnt signaling in tumor cells |
PCT/EP2016/079575 WO2017093478A1 (en) | 2015-12-04 | 2016-12-02 | Biparatopic polypeptides antagonizing wnt signaling in tumor cells |
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Publication Number | Publication Date |
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HRP20201528T1 true HRP20201528T1 (hr) | 2020-12-11 |
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Application Number | Title | Priority Date | Filing Date |
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HRP20201528TT HRP20201528T1 (hr) | 2015-12-04 | 2020-09-24 | Biparatopikalni polipeptidi koji antagoniziraju wnt signalizaciju u tumorskim stanicama |
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Country | Link |
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US (2) | US10597449B2 (hr) |
EP (2) | EP3383425B1 (hr) |
JP (2) | JP6728355B2 (hr) |
KR (1) | KR20180081825A (hr) |
CN (1) | CN108289943B (hr) |
AR (1) | AR106949A1 (hr) |
AU (1) | AU2016363787B2 (hr) |
BR (1) | BR112018010537A2 (hr) |
CA (1) | CA3006235A1 (hr) |
CL (1) | CL2018001384A1 (hr) |
CO (1) | CO2018005680A2 (hr) |
CY (1) | CY1123454T1 (hr) |
DK (1) | DK3383425T3 (hr) |
EA (1) | EA201891331A1 (hr) |
ES (1) | ES2821099T3 (hr) |
HK (1) | HK1255725A1 (hr) |
HR (1) | HRP20201528T1 (hr) |
HU (1) | HUE051777T2 (hr) |
IL (1) | IL259119B (hr) |
LT (1) | LT3383425T (hr) |
MA (2) | MA54648A (hr) |
MX (1) | MX2018006760A (hr) |
MY (1) | MY200933A (hr) |
PE (1) | PE20181515A1 (hr) |
PH (1) | PH12018501155A1 (hr) |
PL (1) | PL3383425T3 (hr) |
PT (1) | PT3383425T (hr) |
RS (1) | RS60823B1 (hr) |
SA (1) | SA518391728B1 (hr) |
SG (1) | SG11201804510PA (hr) |
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TW (1) | TWI734719B (hr) |
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TWI794171B (zh) | 2016-05-11 | 2023-03-01 | 美商滬亞生物國際有限公司 | Hdac抑制劑與pd-l1抑制劑之組合治療 |
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