HRP20200370T1 - Biokemijski stabilizirano hiv-1 trimer cjepivo - Google Patents
Biokemijski stabilizirano hiv-1 trimer cjepivo Download PDFInfo
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- HRP20200370T1 HRP20200370T1 HRP20200370TT HRP20200370T HRP20200370T1 HR P20200370 T1 HRP20200370 T1 HR P20200370T1 HR P20200370T T HRP20200370T T HR P20200370TT HR P20200370 T HRP20200370 T HR P20200370T HR P20200370 T1 HRP20200370 T1 HR P20200370T1
- Authority
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- Croatia
- Prior art keywords
- hiv
- trimer
- asn
- thr
- vaccine
- Prior art date
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- 239000013638 trimer Substances 0.000 title claims 21
- 229960005486 vaccine Drugs 0.000 title claims 8
- 241000725303 Human immunodeficiency virus Species 0.000 claims 26
- 108090000765 processed proteins & peptides Proteins 0.000 claims 10
- 150000001875 compounds Chemical class 0.000 claims 6
- 238000000034 method Methods 0.000 claims 6
- 102000004196 processed proteins & peptides Human genes 0.000 claims 6
- 229920001184 polypeptide Polymers 0.000 claims 5
- 230000003472 neutralizing effect Effects 0.000 claims 3
- 238000005829 trimerization reaction Methods 0.000 claims 3
- QIQABBIDHGQXGA-ZPFDUUQYSA-N Glu-Ile-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O QIQABBIDHGQXGA-ZPFDUUQYSA-N 0.000 claims 2
- XBWMTPAIUQIWKA-BYULHYEWSA-N Gly-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CN XBWMTPAIUQIWKA-BYULHYEWSA-N 0.000 claims 2
- 241000713772 Human immunodeficiency virus 1 Species 0.000 claims 2
- 150000001413 amino acids Chemical group 0.000 claims 2
- 150000007523 nucleic acids Chemical group 0.000 claims 2
- FEZJJKXNPSEYEV-CIUDSAMLSA-N Arg-Gln-Ala Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O FEZJJKXNPSEYEV-CIUDSAMLSA-N 0.000 claims 1
- NPAVRDPEFVKELR-DCAQKATOSA-N Arg-Lys-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O NPAVRDPEFVKELR-DCAQKATOSA-N 0.000 claims 1
- OVQJAKFLFTZDNC-GUBZILKMSA-N Arg-Pro-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O OVQJAKFLFTZDNC-GUBZILKMSA-N 0.000 claims 1
- XHFXZQHTLJVZBN-FXQIFTODSA-N Asn-Arg-Asn Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N)CN=C(N)N XHFXZQHTLJVZBN-FXQIFTODSA-N 0.000 claims 1
- QHBMKQWOIYJYMI-BYULHYEWSA-N Asn-Asn-Val Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O QHBMKQWOIYJYMI-BYULHYEWSA-N 0.000 claims 1
- SPIPSJXLZVTXJL-ZLUOBGJFSA-N Asn-Cys-Ser Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(O)=O SPIPSJXLZVTXJL-ZLUOBGJFSA-N 0.000 claims 1
- REQUGIWGOGSOEZ-ZLUOBGJFSA-N Asn-Ser-Asn Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)N)C(=O)O)N)C(=O)N REQUGIWGOGSOEZ-ZLUOBGJFSA-N 0.000 claims 1
- GZXOUBTUAUAVHD-ACZMJKKPSA-N Asn-Ser-Glu Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O GZXOUBTUAUAVHD-ACZMJKKPSA-N 0.000 claims 1
- QNIACYURSSCLRP-GUBZILKMSA-N Asp-Lys-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(O)=O QNIACYURSSCLRP-GUBZILKMSA-N 0.000 claims 1
- RONJIBWTGKVKFY-HTUGSXCWSA-N Gln-Thr-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O RONJIBWTGKVKFY-HTUGSXCWSA-N 0.000 claims 1
- NSVOVKWEKGEOQB-LURJTMIESA-N Gly-Pro-Gly Chemical compound NCC(=O)N1CCC[C@H]1C(=O)NCC(O)=O NSVOVKWEKGEOQB-LURJTMIESA-N 0.000 claims 1
- UIQGJYUEQDOODF-KWQFWETISA-N Gly-Tyr-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)CN)CC1=CC=C(O)C=C1 UIQGJYUEQDOODF-KWQFWETISA-N 0.000 claims 1
- UYODHPPSCXBNCS-XUXIUFHCSA-N Ile-Val-Leu Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC(C)C UYODHPPSCXBNCS-XUXIUFHCSA-N 0.000 claims 1
- HVHRPWQEQHIQJF-AVGNSLFASA-N Leu-Lys-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O HVHRPWQEQHIQJF-AVGNSLFASA-N 0.000 claims 1
- MVVSHHJKJRZVNY-ACRUOGEOSA-N Leu-Phe-Tyr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O MVVSHHJKJRZVNY-ACRUOGEOSA-N 0.000 claims 1
- ZEDVFJPQNNBMST-CYDGBPFRSA-N Met-Arg-Ile Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O ZEDVFJPQNNBMST-CYDGBPFRSA-N 0.000 claims 1
- DRXODWRPPUFIAY-DCAQKATOSA-N Met-Asn-Lys Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(O)=O)CCCCN DRXODWRPPUFIAY-DCAQKATOSA-N 0.000 claims 1
- HTKNPQZCMLBOTQ-XVSYOHENSA-N Phe-Asn-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CC=CC=C1)N)O HTKNPQZCMLBOTQ-XVSYOHENSA-N 0.000 claims 1
- GDUZTEQRAOXYJS-SRVKXCTJSA-N Ser-Phe-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CO)N GDUZTEQRAOXYJS-SRVKXCTJSA-N 0.000 claims 1
- GZYNMZQXFRWDFH-YTWAJWBKSA-N Thr-Arg-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1CCC[C@@H]1C(=O)O)N)O GZYNMZQXFRWDFH-YTWAJWBKSA-N 0.000 claims 1
- SWIKDOUVROTZCW-GCJQMDKQSA-N Thr-Asn-Ala Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](C)C(=O)O)N)O SWIKDOUVROTZCW-GCJQMDKQSA-N 0.000 claims 1
- YLXAMFZYJTZXFH-OLHMAJIHSA-N Thr-Asn-Asp Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N)O YLXAMFZYJTZXFH-OLHMAJIHSA-N 0.000 claims 1
- VGYVVSQFSSKZRJ-OEAJRASXSA-N Thr-Phe-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)[C@H](O)C)CC1=CC=CC=C1 VGYVVSQFSSKZRJ-OEAJRASXSA-N 0.000 claims 1
- VBMOVTMNHWPZJR-SUSMZKCASA-N Thr-Thr-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O VBMOVTMNHWPZJR-SUSMZKCASA-N 0.000 claims 1
- COYHRQWNJDJCNA-NUJDXYNKSA-N Thr-Thr-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O COYHRQWNJDJCNA-NUJDXYNKSA-N 0.000 claims 1
- NOXKHHXSHQFSGJ-FQPOAREZSA-N Tyr-Ala-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 NOXKHHXSHQFSGJ-FQPOAREZSA-N 0.000 claims 1
- HVPPEXXUDXAPOM-MGHWNKPDSA-N Tyr-Ile-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 HVPPEXXUDXAPOM-MGHWNKPDSA-N 0.000 claims 1
- 230000036436 anti-hiv Effects 0.000 claims 1
- FSXRLASFHBWESK-UHFFFAOYSA-N dipeptide phenylalanyl-tyrosine Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FSXRLASFHBWESK-UHFFFAOYSA-N 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 108010078144 glutaminyl-glycine Proteins 0.000 claims 1
- 108010010147 glycylglutamine Proteins 0.000 claims 1
- 230000003053 immunization Effects 0.000 claims 1
- 238000002347 injection Methods 0.000 claims 1
- 239000007924 injection Substances 0.000 claims 1
- 108010009298 lysylglutamic acid Proteins 0.000 claims 1
- 102000039446 nucleic acids Human genes 0.000 claims 1
- 108020004707 nucleic acids Proteins 0.000 claims 1
- 210000002966 serum Anatomy 0.000 claims 1
- 108010071207 serylmethionine Proteins 0.000 claims 1
- 108010061238 threonyl-glycine Proteins 0.000 claims 1
Classifications
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- 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
- A61K39/12—Viral antigens
- A61K39/21—Retroviridae, e.g. equine infectious anemia virus
-
- 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
- A61K39/12—Viral antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- 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
- A61P37/04—Immunostimulants
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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
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
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- 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
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/53—DNA (RNA) vaccination
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- 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
- A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
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- 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
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- 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
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55566—Emulsions, e.g. Freund's adjuvant, MF59
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- 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
- A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
- A61K2039/575—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 humoral response
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/16011—Human Immunodeficiency Virus, HIV
- C12N2740/16051—Methods of production or purification of viral material
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- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/16011—Human Immunodeficiency Virus, HIV
- C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
- C12N2740/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
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- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/16011—Human Immunodeficiency Virus, HIV
- C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
- C12N2740/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/16011—Human Immunodeficiency Virus, HIV
- C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
- C12N2740/16171—Demonstrated in vivo effect
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- Animal Behavior & Ethology (AREA)
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- Engineering & Computer Science (AREA)
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- Gastroenterology & Hepatology (AREA)
- Hematology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Biomedical Technology (AREA)
- General Engineering & Computer Science (AREA)
- AIDS & HIV (AREA)
- Tropical Medicine & Parasitology (AREA)
- Oncology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Claims (15)
1. HIV gp140 trimer koji obuhvaća HIV gp140 polipeptid koji sadrži sekvencu aminokiselina najmanje 95% identično sekvenci:
[image]
[image]
sadrži trimerizacijsku domenu, i
peptid promjenjive petlje V3;
gdje HIV gp140 trimer trimer može izazvati proizvodnju neutralizacijskih antiseruma protiv HIV - a kada se stabilizirani trimer daje subjektu.
2. HIV gp140 trimer, sukladno patentnom zahtjevu 1, koji sadrži peptid promjenjive petlje V3 koji se sastoji od sekvence Thr Arg Pro Asn Asn Thn Arg Lys Ser Met Arg Ile Gly Pro Gly Gln Thr Phe Tyr Ala Thr Gly Asp Ile Gly Asp Ile Arg Gln Ala Tyr (SEQ ID N0: 8);
3. HIV gp 140 trimer sukladno zahtjevima 1 ili 2, gdje je trimerizacijska domena T4-fibritin fold trimerizacijska domena.
4. HIV gp 140 trimer, sukladno bilo kojem od prethodno navedenih zahtjeva 1 do 3, gdje
HIV gp140 polipeptid uključujuje promjenjive petlje peptida V1 i V2,
navedena V1 petlja peptid sastavljena od sekvenci Thr Asn Ala Thr Phe Lys Asn Asn Val Thr Asn Asp Met Asn Lys Glu Ile Arg Asn Cys Ser Phe Asn Thr Thr Thr Glu Ile Arg (SEQ ID NO: 4); i
navedena V2 petlja peptid sastavljena od sekvenci Ser Phe Asn Thr Thr Thr Glu Ile Arg Asp Lys Gln Gln Gly Tyr Ala Leu Phe Tyr Arg Pro Asp Ile Val Leu Leu Lys Glu Asn Arg Asn Asn Ser Asn Asn Ser Glu Tyr Ile Leu Ile Asn (SEQ ID NO: 6).
5. HIV gp 140 trimer, sukladno bilo kojem od prethodno navedenih zahtjeva 1 do 4, gdje HIV gp140 polipeptid obuhvaća sekvencu aminokiselina
[image]
[image]
6. HIV gp 140 trimer, sukladno bilo kojem od prethodno navedenih zahtjeva 1 do 5, gdje HIV je HIV-1
7. HIV gp 140 trimer sukladno zahtjevim 1 – 6, gdje neutralizirajući anti-HIV antiserum neutralizira HIV-1, odabranu izmedju jednog ili više Clade A, Clade B ili Clade C.
8. Farmaceutski spoj sadrži HIV gp 140 trimer, kao što je naznačenu u zahtjevima 1 - 7.
9. HIV gp 140 trimer, sukladno zahtjevima 1 – 7, ili farmaceutski spoj, sukladno zahtjevu 8. za korištenje kao cjepiva.
10. Cjepivo sadrži HIV gp 140 trimer sukladno patentnim zahtjevima 1 – 7.
11. Cjepivo sadrži sekvence nukleinske kiseline koja kodira HIV gp 140 trimer sukladno zahtjevima 1 – 7.
12. HIV gp 140 trimer sukladno patentnim zahtjevima 1 – 7 ili farmaceutski spoj sukladno patentnom zahtjevu 8, ili cjepivo sukladno patentnim zahtjevima 10 ili 11, naznačeni time, što se koristi kao postupak za proizvodnju neutralizirajućih seruma protiv HIV-a nakon injektiranja u subjekta.
13. HIV gp 140 trimer, sukladno patentnim zahtjevima 1- 7, ili farmaceuski spoj sukladno zahtjevu 8, ili cjepivo sukladno patentnim zahtjevima 10 ili 11, za uporabu za imunizaciju subjekta protiv HIV-a.
14. Postupak dobivanja HIV gp 140 trimera sukladno bilo kojem od zahtjeva 1 – 7, gdje postupak uključuje ekspresiju u eukariotskoj stanici domaćina vektora koji sadrži polipeptid i sadrži nukleinsku kiselinu koja enkodira sekvencu odgovarajućeg HIV gp 140 polipeptida.
15. Postupak dobivanja farmaceutskog spoja ili cjepiva koje sadrže HIV gp 140 trimer, spomenuti postupak sadrži postupak proizvodnje spomenutog HIV gp 140 trimera sukladno patentnom zahtjevu 14, i uključuje dobiveni HIV gp 140 trimer u farmaceutski spoj ili cjepivo sastavljeno od farmacutski prihvatljivog nossča.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10444908P | 2008-10-10 | 2008-10-10 | |
| EP18150843.3A EP3335728B8 (en) | 2008-10-10 | 2009-10-13 | Biochemically stabilized hiv-1 env trimer vaccine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20200370T1 true HRP20200370T1 (hr) | 2020-06-12 |
Family
ID=42101262
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP20180281TT HRP20180281T1 (hr) | 2008-10-10 | 2018-02-15 | Biokemijski stabilizirano hiv-1 env trimer cjepivo |
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