HRP20182017T4 - Protutijela koja specifično vežu alfa toksin koji stvara staphylococcus aureus i postupci uporabe - Google Patents
Protutijela koja specifično vežu alfa toksin koji stvara staphylococcus aureus i postupci uporabe Download PDFInfo
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- HRP20182017T4 HRP20182017T4 HRP20182017TT HRP20182017T HRP20182017T4 HR P20182017 T4 HRP20182017 T4 HR P20182017T4 HR P20182017T T HRP20182017T T HR P20182017TT HR P20182017 T HRP20182017 T HR P20182017T HR P20182017 T4 HRP20182017 T4 HR P20182017T4
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- antigen
- binding fragment
- antibody
- seq
- alpha toxin
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- 108010092231 staphylococcal alpha-toxin Proteins 0.000 title claims 2
- 239000012634 fragment Substances 0.000 claims 24
- 239000000427 antigen Substances 0.000 claims 21
- 108091007433 antigens Proteins 0.000 claims 21
- 102000036639 antigens Human genes 0.000 claims 21
- 230000027455 binding Effects 0.000 claims 21
- 101710092462 Alpha-hemolysin Proteins 0.000 claims 10
- 101710197219 Alpha-toxin Proteins 0.000 claims 10
- 101710124951 Phospholipase C Proteins 0.000 claims 10
- 239000002776 alpha toxin Substances 0.000 claims 10
- 125000003275 alpha amino acid group Chemical group 0.000 claims 9
- 206010035664 Pneumonia Diseases 0.000 claims 4
- 150000001413 amino acids Chemical class 0.000 claims 4
- 230000015572 biosynthetic process Effects 0.000 claims 4
- 206010040872 skin infection Diseases 0.000 claims 3
- 241000191967 Staphylococcus aureus Species 0.000 claims 2
- 230000003115 biocidal effect Effects 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- 230000002401 inhibitory effect Effects 0.000 claims 2
- 230000002265 prevention Effects 0.000 claims 2
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims 1
- 102000004127 Cytokines Human genes 0.000 claims 1
- 108090000695 Cytokines Proteins 0.000 claims 1
- 206010018910 Haemolysis Diseases 0.000 claims 1
- 238000010171 animal model Methods 0.000 claims 1
- 239000003242 anti bacterial agent Substances 0.000 claims 1
- 238000003556 assay Methods 0.000 claims 1
- 230000006037 cell lysis Effects 0.000 claims 1
- MYPYJXKWCTUITO-KIIOPKALSA-N chembl3301825 Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)C(O)[C@H](C)O1 MYPYJXKWCTUITO-KIIOPKALSA-N 0.000 claims 1
- 230000001461 cytolytic effect Effects 0.000 claims 1
- 230000008588 hemolysis Effects 0.000 claims 1
- 230000008595 infiltration Effects 0.000 claims 1
- 238000001764 infiltration Methods 0.000 claims 1
- 239000000178 monomer Substances 0.000 claims 1
- 229920001184 polypeptide Polymers 0.000 claims 1
- 108090000765 processed proteins & peptides Proteins 0.000 claims 1
- 102000004196 processed proteins & peptides Human genes 0.000 claims 1
- 230000000770 proinflammatory effect Effects 0.000 claims 1
- 230000024033 toxin binding Effects 0.000 claims 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/12—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
-
- 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
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/40—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum bacterial
-
- 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
-
- 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
- A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
-
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/12—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria
- C07K16/1267—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-positive bacteria
- C07K16/1271—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-positive bacteria from Micrococcaceae (F), e.g. Staphylococcus
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
- G01N33/56911—Bacteria
- G01N33/56938—Staphylococcus
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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
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2299/00—Coordinates from 3D structures of peptides, e.g. proteins or enzymes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
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- 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
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- 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
- C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
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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
-
- 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
-
- 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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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/195—Assays involving biological materials from specific organisms or of a specific nature from bacteria
- G01N2333/305—Assays involving biological materials from specific organisms or of a specific nature from bacteria from Micrococcaceae (F)
- G01N2333/31—Assays involving biological materials from specific organisms or of a specific nature from bacteria from Micrococcaceae (F) from Staphylococcus (G)
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/20—Dermatological disorders
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/44—Multiple drug resistance
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- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/70—Mechanisms involved in disease identification
- G01N2800/709—Toxin induced
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Claims (17)
1. Izolirano protutijelo ili njegov ulomak koji veže antigen, naznačeno time što se izolirano protutijelo ili njegov ulomak koji veže antigen imunospecifično veže na polipeptid alfa toksina koji stvara Staphylococcus aureus i sadrži:
(a) VH CDR1 sadrži sekvencu aminokiseline iz SEQ ID NO: 69;
(b) VH CDR2 sadrži sekvencu aminokiseline iz SEQ ID NO: 70;
(c) VH CDR3 sadrži sekvencu aminokiseline iz SEQ ID NO: 71;
(d) VL CDR1 sadrži sekvencu aminokiseline iz SEQ ID NO: 1;
(e) VL CDR2 sadrži sekvencu aminokiseline iz SEQ ID NO: 2, i
(f) VL CDR3 sadrži sekvencu aminokiseline iz SEQ ID NO: 68 .
2. Izolirano protutijelo ili ulomak koji veže antigen prema zahtjevu 1, naznačeno time što sadrži varijabilnu domenu teškog lanca koja je barem 90% identična s aminokiselinskom sekvencom iz SEQ ID NO: 57, i varijabilnu domenu laganog lanca koja je barem 90% identična sa aminokiselinskom sekvencom iz SEQ ID NO: 58.
3. Protutijelo ili ulomak koji veže antigen prema zahtjevu 2, naznačeno time što VH i VL odgovaraju sekvencama aminokiselina iz SEQ ID NO: 57 i 58.
4. Protutijelo ili ulomak koji veže antigen prema bilo kojem od zahtjeva 1 do 3, naznačeno time što izolirano protutijelo ili njegov ulomak koji veže antigen ima jednu ili više značajki odabranih iz skupine koju čine:
(a) konstanta afiniteta (KD) za alfa toksin od oko 13 nM ili manje;
(b) veže se na monomere alfa toksina, ali ne inhibira vezanje alfa toksina na receptor alfa toksina;
(c) inhibira stvaranje oligomera alfa toksina za barem 50%, 60%, 70%, 80%, 90%, ili 95%;
(d) smanjuje citolitičku aktivnost alfa toksina za barem 50%, 60%, 70%, 80%, 90%, ili 95% (npr.., određeno pomoću testova lize stanice i hemolize stanice); i
(e) smanjuje infiltraciju stanica i pro-upalno oslobađanje citokina (npr., u modelu životinjske upale pluća).
5. Pripravak naznačen time što sadrži protutijelo ili ulomak koji veže antigen prema bilo kojem od zahtjeva 1 do 4.
6. Pripravak prema zahtjevu 5, naznačen time što pripravak sadrži dodatno sredstvo, pri čemu je dodatno sredstvo antibiotik.
7. Komplet, naznačen time što sadrži
(a) protutijelo ili ulomak koji veže antigen prema bilo kojem od zahtjeva 1 do 4 ili pripravak prema zahtjevu ili 6;
(b) upute za uporabu pripravka ili smjernice za dobivanje uputa za uporabu pripravka.
8. Protutijelo ili ulomak koji veže antigen prema bilo kojem od zahtjeva 1 do 4 ili pripravak prema zahtjevu 5 ili 6, naznačeno time što je za uporabu za prevenciju, liječenje ili upravljanje upalom pluća kod subjekta.
9. Protutijelo ili ulomak koji veže antigen prema bilo kojem od zahtjeva 1 do 4 ili pripravak prema zahtjevu 5 ili 6, naznačeno time što je za uporabu za prevenciju, liječenje ili upravljanje stanjem infekcije kože kod subjekta.
10. Protutijelo ili ulomak koji veže antigen prema bilo kojem od zahtjeva 1 do 4 ili pripravak prema zahtjevu 5 ili 6, naznačeno time što je za uporabu za prevenciju, liječenje ili upravljanje upalom pluća ili stanjem infekcije kože kod subjekta prema zahtjevu 8 ili 9 inhibicijom stvaranja oligomera alfa toksina Staphylococcus aureus za barem 50%, 60%, 70%, 80%, 90% ili 95%.
11. Protutijelo ili ulomak koji veže antigen prema bilo kojem od zahtjeva 1 do 4 naznačeno time što se imuno specifično veže na ulomak alfa toksina koji stvara Staphylococcus aureus iz SEQ ID NO: 39.
12. Izolirano protutijelo ili ulomak koji veže antigen prema zahtjevu 11, naznačeno time što se protutijelo ili njegov ulomak koji veže antigen veže na ulomak koji sadrži aminokiseline 261-272 iz SEQ ID NO: 39 i/ili aminokiseline 173-201 iz SEQ ID NO: 39.
13. Izolirano protutijelo ili ulomak koji veže antigen prema zahtjevu 12, naznačeno time što se protutijelo ili njegov ulomak koji veže antigen veže se na ulomak koji sadrži aminokiseline 261-272 iz SEQ ID NO: 39 i aminokiseline 173-201 iz SEQ ID NO: 39.
14. Izolirano protutijelo ili ulomak koji veže antigen prema bilo kojem od zahtjeva 1 do 4, naznačeno time što protutijelo ili njegov ulomak koji veže antigen sprječava nastanak heptamera alfa toksina, i pri čemu je navedeno protutijelo ili ulomak koji veže antigen u kontaktu s ostacima na položajima T261, T263, N264, K266, K271, N177, W179, G180, P181, Y182, D183, D185, S186, W187, N188, P189, V190, Y191 i R200 od SEQ ID NO: 39.
15. Pripravak prema zahtjevu 6, naznačen time što je antibiotik vankomicin.
16. Izolirano protutijelo ili ulomak koji veže antigen prema bilo kojem od zahtjeva 11 do 14 naznačeno time što je za uporabu za prevenciju, liječenje ili upravljanje upalom pluća ili stanjem infekcije kože kod subjekta inhibicijom stvaranja oligomera alfa toksina.
17. Izolirano protutijelo ili ulomak koji veže antigen prema bilo kojem od zahtjeva 1-4 i 11-14 koje obuhvaća varijantu Fc regije, naznačeno time što izolirano protutijelo sadrži slijedeće sekvence
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Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161440581P | 2011-02-08 | 2011-02-08 | |
PCT/US2012/024201 WO2012109285A2 (en) | 2011-02-08 | 2012-02-07 | Antibodies that specifically bind staphylococcus aureus alpha toxin and methods of use |
EP12745207.6A EP2673373B3 (en) | 2011-02-08 | 2012-02-07 | Antibodies that specifically bind staphylococcus aureus alpha toxin and methods of use |
Publications (2)
Publication Number | Publication Date |
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HRP20182017T1 HRP20182017T1 (hr) | 2019-02-08 |
HRP20182017T4 true HRP20182017T4 (hr) | 2021-08-20 |
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Application Number | Title | Priority Date | Filing Date |
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HRP20182017TT HRP20182017T4 (hr) | 2011-02-08 | 2018-11-29 | Protutijela koja specifično vežu alfa toksin koji stvara staphylococcus aureus i postupci uporabe |
Country Status (24)
Country | Link |
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US (1) | US9527905B2 (hr) |
EP (2) | EP3470526A3 (hr) |
JP (4) | JP2014508748A (hr) |
KR (1) | KR101993839B1 (hr) |
CN (2) | CN103443285B9 (hr) |
AU (1) | AU2012214531C1 (hr) |
BR (1) | BR112013020086B1 (hr) |
CA (1) | CA2826566C (hr) |
CY (1) | CY1121389T1 (hr) |
DK (1) | DK2673373T6 (hr) |
ES (1) | ES2709065T7 (hr) |
HK (1) | HK1248257A1 (hr) |
HR (1) | HRP20182017T4 (hr) |
HU (1) | HUE040734T2 (hr) |
LT (1) | LT2673373T (hr) |
MX (2) | MX345285B (hr) |
PL (1) | PL2673373T6 (hr) |
PT (1) | PT2673373T (hr) |
RS (1) | RS58190B2 (hr) |
RU (1) | RU2620065C2 (hr) |
SG (3) | SG192212A1 (hr) |
SI (1) | SI2673373T1 (hr) |
TR (1) | TR201817932T4 (hr) |
WO (1) | WO2012109285A2 (hr) |
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