HRP20211980T1 - Protutijela protiv sortilina i postupci njihove upotrebe - Google Patents
Protutijela protiv sortilina i postupci njihove upotrebe Download PDFInfo
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- HRP20211980T1 HRP20211980T1 HRP20211980TT HRP20211980T HRP20211980T1 HR P20211980 T1 HRP20211980 T1 HR P20211980T1 HR P20211980T T HRP20211980T T HR P20211980TT HR P20211980 T HRP20211980 T HR P20211980T HR P20211980 T1 HRP20211980 T1 HR P20211980T1
- Authority
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- Croatia
- Prior art keywords
- amino acid
- seq
- acid sequence
- hvr
- antibody
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- 238000000034 method Methods 0.000 title claims 4
- 125000003275 alpha amino acid group Chemical group 0.000 claims 42
- 238000006467 substitution reaction Methods 0.000 claims 6
- 102100032889 Sortilin Human genes 0.000 claims 5
- 210000004027 cell Anatomy 0.000 claims 5
- 108010014657 sortilin Proteins 0.000 claims 5
- 239000000427 antigen Substances 0.000 claims 4
- 108091007433 antigens Proteins 0.000 claims 4
- 102000036639 antigens Human genes 0.000 claims 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 4
- 150000007523 nucleic acids Chemical class 0.000 claims 3
- 101000868139 Homo sapiens Sortilin Proteins 0.000 claims 2
- 102000019204 Progranulins Human genes 0.000 claims 2
- 108010012809 Progranulins Proteins 0.000 claims 2
- 102000004584 Somatomedin Receptors Human genes 0.000 claims 2
- 108010017622 Somatomedin Receptors Proteins 0.000 claims 2
- 102000007238 Transferrin Receptors Human genes 0.000 claims 2
- 108010033576 Transferrin Receptors Proteins 0.000 claims 2
- 208000027418 Wounds and injury Diseases 0.000 claims 2
- 230000006378 damage Effects 0.000 claims 2
- 201000010099 disease Diseases 0.000 claims 2
- 208000035475 disorder Diseases 0.000 claims 2
- 238000010494 dissociation reaction Methods 0.000 claims 2
- 230000005593 dissociations Effects 0.000 claims 2
- 239000012634 fragment Substances 0.000 claims 2
- 208000014674 injury Diseases 0.000 claims 2
- 108020004707 nucleic acids Proteins 0.000 claims 2
- 102000039446 nucleic acids Human genes 0.000 claims 2
- 230000000770 proinflammatory effect Effects 0.000 claims 2
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 claims 1
- 208000024827 Alzheimer disease Diseases 0.000 claims 1
- 208000035143 Bacterial infection Diseases 0.000 claims 1
- 102100021943 C-C motif chemokine 2 Human genes 0.000 claims 1
- 102100032367 C-C motif chemokine 5 Human genes 0.000 claims 1
- 108010071134 CRM197 (non-toxic variant of diphtheria toxin) Proteins 0.000 claims 1
- 206010010904 Convulsion Diseases 0.000 claims 1
- 206010012289 Dementia Diseases 0.000 claims 1
- 201000011240 Frontotemporal dementia Diseases 0.000 claims 1
- 208000010412 Glaucoma Diseases 0.000 claims 1
- 102100034221 Growth-regulated alpha protein Human genes 0.000 claims 1
- 102000018710 Heparin-binding EGF-like Growth Factor Human genes 0.000 claims 1
- 101800001649 Heparin-binding EGF-like growth factor Proteins 0.000 claims 1
- 101000897480 Homo sapiens C-C motif chemokine 2 Proteins 0.000 claims 1
- 101000797762 Homo sapiens C-C motif chemokine 5 Proteins 0.000 claims 1
- 101001069921 Homo sapiens Growth-regulated alpha protein Proteins 0.000 claims 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 claims 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 claims 1
- 208000004575 Infectious Arthritis Diseases 0.000 claims 1
- 206010061218 Inflammation Diseases 0.000 claims 1
- 208000032578 Inherited retinal disease Diseases 0.000 claims 1
- 102000003746 Insulin Receptor Human genes 0.000 claims 1
- 108010001127 Insulin Receptor Proteins 0.000 claims 1
- 108090001005 Interleukin-6 Proteins 0.000 claims 1
- 101710172064 Low-density lipoprotein receptor-related protein Proteins 0.000 claims 1
- 101000868164 Mus musculus Sortilin Proteins 0.000 claims 1
- 108091028043 Nucleic acid sequence Proteins 0.000 claims 1
- 208000018737 Parkinson disease Diseases 0.000 claims 1
- 201000007737 Retinal degeneration Diseases 0.000 claims 1
- 208000032430 Retinal dystrophy Diseases 0.000 claims 1
- 206010040070 Septic Shock Diseases 0.000 claims 1
- 208000006011 Stroke Diseases 0.000 claims 1
- -1 TMEM 30(A) Proteins 0.000 claims 1
- 208000030886 Traumatic Brain injury Diseases 0.000 claims 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims 1
- 201000004810 Vascular dementia Diseases 0.000 claims 1
- 230000002159 abnormal effect Effects 0.000 claims 1
- 230000004913 activation Effects 0.000 claims 1
- 208000002552 acute disseminated encephalomyelitis Diseases 0.000 claims 1
- 206010064930 age-related macular degeneration Diseases 0.000 claims 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims 1
- 210000003050 axon Anatomy 0.000 claims 1
- 230000007845 axonopathy Effects 0.000 claims 1
- 208000025255 bacterial arthritis Diseases 0.000 claims 1
- 208000022362 bacterial infectious disease Diseases 0.000 claims 1
- 230000008499 blood brain barrier function Effects 0.000 claims 1
- 210000001218 blood-brain barrier Anatomy 0.000 claims 1
- GBVKRUOMSUTVPW-AHNVSIPUSA-N chembl1089636 Chemical compound N([C@H]([C@@H](OC(=O)CCC(=O)N[C@@H](C(O)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)NCC(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCCNC(=O)CCC(=O)O[C@H]([C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)C(=O)O[C@@H]1C(=C2[C@@H](OC(C)=O)C(=O)[C@]3(C)[C@@H](O)C[C@H]4OC[C@]4([C@H]3[C@H](OC(=O)C=3C=CC=CC=3)[C@](C2(C)C)(O)C1)OC(C)=O)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCCNC(=O)CCC(=O)O[C@H]([C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)C(=O)O[C@@H]1C(=C2[C@@H](OC(C)=O)C(=O)[C@]3(C)[C@@H](O)C[C@H]4OC[C@]4([C@H]3[C@H](OC(=O)C=3C=CC=CC=3)[C@](C2(C)C)(O)C1)OC(C)=O)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C(=O)O[C@@H]1C(=C2[C@@H](OC(C)=O)C(=O)[C@]3(C)[C@@H](O)C[C@H]4OC[C@]4([C@H]3[C@H](OC(=O)C=3C=CC=CC=3)[C@](C2(C)C)(O)C1)OC(C)=O)C)C=1C=CC=CC=1)C(=O)C1=CC=CC=C1 GBVKRUOMSUTVPW-AHNVSIPUSA-N 0.000 claims 1
- 230000007423 decrease Effects 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 201000006321 fundus dystrophy Diseases 0.000 claims 1
- 238000000338 in vitro Methods 0.000 claims 1
- 230000004054 inflammatory process Effects 0.000 claims 1
- 230000028709 inflammatory response Effects 0.000 claims 1
- 208000017532 inherited retinal dystrophy Diseases 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 claims 1
- 208000002780 macular degeneration Diseases 0.000 claims 1
- 210000000274 microglia Anatomy 0.000 claims 1
- 201000006417 multiple sclerosis Diseases 0.000 claims 1
- 210000000944 nerve tissue Anatomy 0.000 claims 1
- 201000008482 osteoarthritis Diseases 0.000 claims 1
- 108010046239 paclitaxel-Angiopep-2 conjugate Proteins 0.000 claims 1
- 108010043655 penetratin Proteins 0.000 claims 1
- MCYTYTUNNNZWOK-LCLOTLQISA-N penetratin Chemical compound C([C@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CCCNC(N)=N)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(N)=O)C1=CC=CC=C1 MCYTYTUNNNZWOK-LCLOTLQISA-N 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 108010011110 polyarginine Proteins 0.000 claims 1
- 230000008569 process Effects 0.000 claims 1
- 108090000765 processed proteins & peptides Proteins 0.000 claims 1
- 201000002212 progressive supranuclear palsy Diseases 0.000 claims 1
- 102000004169 proteins and genes Human genes 0.000 claims 1
- 108090000623 proteins and genes Proteins 0.000 claims 1
- 230000004258 retinal degeneration Effects 0.000 claims 1
- 230000036303 septic shock Effects 0.000 claims 1
- 208000020431 spinal cord injury Diseases 0.000 claims 1
- 230000000638 stimulation Effects 0.000 claims 1
- 230000026683 transduction Effects 0.000 claims 1
- 238000010361 transduction Methods 0.000 claims 1
- 230000009529 traumatic brain injury Effects 0.000 claims 1
- 230000029663 wound healing Effects 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
-
- 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
- C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/16—Anti-Parkinson drugs
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
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- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
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- 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]
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- A—HUMAN NECESSITIES
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- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
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- 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
- 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
- C07K16/286—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against neuromediator receptors, e.g. serotonin receptor, dopamine receptor
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/10—Immunoglobulins specific features characterized by their source of isolation or production
- C07K2317/14—Specific host cells or culture conditions, e.g. components, pH or temperature
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- 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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- 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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- 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
- C07K2317/55—Fab or Fab'
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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
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/32—Fusion polypeptide fusions with soluble part of a cell surface receptor, "decoy receptors"
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- Animal Behavior & Ethology (AREA)
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- Genetics & Genomics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
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Claims (17)
1. Izolirano protutijelo protiv sortilina koje se veže na ljudski sortilin, pri čemu protutijelo protiv sortilina povisuje izvanstanične razine progranulina i snižava razine sortilina na staničnoj površini, pri čemu protutijelo protiv sortilina sadrži varijabilnu domenu lakog lanca i varijabilnu domenu teškog lanca, te pri čemu:
a) varijabilna domena lakog lanca sadrži: HVR-L1, koji sadrži aminokiselinski slijed SEQ ID NO: 508, HVR-L2, koji sadrži aminokiselinski slijed SEQ ID NO: 29, te HVR-L3, koji sadrži aminokiselinski slijed SEQ ID NO: 55, a varijabilna domena teškog lanca sadrži: HVR-H1, koji sadrži aminokiselinski slijed SEQ ID NO: 509, HVR-H2, koji sadrži aminokiselinski slijed SEQ ID NO: 510, te HVR-H3, koji sadrži aminokiselinski slijed SEQ ID NO: 511; ili
b) varijabilna domena lakog lanca sadrži: HVR-L1, koji sadrži aminokiselinski slijed SEQ ID NO: 580, HVR-L2, koji sadrži aminokiselinski slijed SEQ ID NO: 581, te HVR-L3, koji sadrži aminokiselinski slijed SEQ ID NO: 100, a varijabilna domena teškog lanca sadrži: HVR-H1, koji sadrži aminokiselinski slijed SEQ ID NO: 582, HVR-H2, koji sadrži aminokiselinski slijed SEQ ID NO: 583, te HVR-H3, koji sadrži aminokiselinski slijed SEQ ID NO: 233.
2. Protutijelo protiv sortilina u skladu s patentnim zahtjevom 1, pri čemu se protutijelo protiv sortilina veže s konstantom disocijacije (KD) za ljudski sortilin koja se kreće u rasponu od 100 nM do 0,005 nM, ili manje od 0,005 nM i/ili pri čemu se protutijelo protiv sortilina veže s konstantom disocijacije (KD) za mišji sortilin koja se kreće u rasponu od 100 nM do 0,005 nM, ili manje od 0,005 nM.
3. Protutijelo protiv sortilina u skladu s patentnim zahtjevom 1 ili 2, pri čemu je protutijelo protiv sortilina ljudsko protutijelo, humanizirano protutijelo, bispecifično protutijelo, monoklonsko protutijelo, viševalentno protutijelo, konjugirano protutijelo ili kimerno protutijelo, ili pri čemu je protutijelo protiv sortilina protutijelo fragment, te pri čemu fragment može biti fragment Fab, Fab’, Fab’-SH, F(ab’)2, Fv ili scFv fragment.
4. Protutijelo protiv sortilina u skladu s bilo kojim od patentnih zahtjeva 1-3, pri čemu je protutijelo protiv sortilina bispecifično protutijelo koje prepoznaje drugi antigen, pri čemu drugi antigen može biti antigen koji olakšava transport kroz krvno-moždanu barijeru, pri čemu se drugi antigen može birati iz skupine koju čine transferinski receptor (TR), inzulinski receptor (HIR), receptor inzulinu sličnog čimbenika rasta (IGFR), proteini 1 i 2 srodni receptoru lipoproteina niske gustoće (LPR-1 i 2), receptor difterijskog toksina, CRM197, TMEM 30(A), domena proteinske transdukcije, TAT, Syn-B, penetratin, poliargininski peptid, peptid angiopep, te ANG1005.
5. Protutijelo protiv sortilina u skladu s bilo kojim od patentnih zahtjeva 1-4, pri čemu:
(a) varijabilna domena lakog lanca sadrži: HVR-L1, koji sadrži aminokiselinski slijed SEQ ID NO: 10, HVR-L2, koji sadrži aminokiselinski slijed SEQ ID NO: 30, te HVR-L3, koji sadrži aminokiselinski slijed SEQ ID NO: 100, a varijabilna domena teškog lanca sadrži: HVR-H1, koji sadrži aminokiselinski slijed SEQ ID NO: 142, HVR-H2, koji sadrži aminokiselinski slijed SEQ ID NO: 170, te HVR-H3, koji sadrži aminokiselinski slijed SEQ ID NO: 233; ili
(b) varijabilna domena lakog lanca sadrži aminokiselinski slijed SEQ ID NO: 430, a varijabilna domena teškog lanca sadrži aminokiselinski slijed SEQ ID NO: 431.
6. Protutijelo protiv sortilina u skladu s bilo kojim od patentnih zahtjeva 1-4, pri čemu:
(a) varijabilna domena lakog lanca sadrži: HVR-L1, koji sadrži aminokiselinski slijed SEQ ID NO: 9, HVR-L2, koji sadrži aminokiselinski slijed SEQ ID NO: 29, te HVR-L3, koji sadrži aminokiselinski slijed SEQ ID NO: 55, a varijabilna domena teškog lanca sadrži: HVR-H1, koji sadrži aminokiselinski slijed SEQ ID NO: 129, HVR-H2, koji sadrži aminokiselinski slijed SEQ ID NO: 155, te HVR-H3, koji sadrži aminokiselinski slijed SEQ ID NO: 190; ili
(b) varijabilna domena lakog lanca sadrži aminokiselinski slijed SEQ ID NO: 343, a varijabilna domena teškog lanca sadrži aminokiselinski slijed SEQ ID NO: 342.
7. Protutijelo protiv sortilina u skladu s bilo kojim od patentnih zahtjeva 1-4, pri čemu varijabilna domena lakog lanca sadrži: HVR-L1, koji sadrži aminokiselinski slijed SEQ ID NO: 9, HVR-L2, koji sadrži aminokiselinski slijed SEQ ID NO: 29, te HVR-L3, koji sadrži aminokiselinski slijed SEQ ID NO: 55, a varijabilna domena teškog lanca sadrži: HVR-H1, koji sadrži aminokiselinski slijed SEQ ID NO: 520, HVR-H2, koji sadrži aminokiselinski slijed SEQ ID NO: 533, te HVR-H3, koji sadrži aminokiselinski slijed SEQ ID NO: 553.
8. Protutijelo protiv sortilina u skladu s bilo kojim od patentnih zahtjeva 1-4 ili 7, pri čemu varijabilna domena lakog lanca sadrži aminokiselinski slijed SEQ ID NO: 343, a varijabilna domena teškog lanca sadrži aminokiselinski slijed SEQ ID NO: 648.
9. Protutijelo protiv sortilina u skladu s bilo kojim od patentnih zahtjeva 1-8, pri čemu protutijelo protiv sortilina ima IgG1 ili izotip IgG4, pri čemu izborno:
(a) protutijelo protiv sortilina ima ljudski izotip IgG1 i sadrži jednu ili više aminokiselinskih zamjena u Fc području na položaju ostatka kojeg se bira iz skupine koju čine: N297A, N297Q, D265A, L234A, L235A, C226S, C229S, P238S, E233P, L234V, P238A, A327Q, A327G, P329A, K322A, L234F, L235E, P331S, T394D, A330L, M252Y, S254T, T256E, te bilo koja njihova kombinacija, pri čemu je obrojčavanje ostataka u skladu s EU obrojčavanjem; ili
(b) protutijelo protiv sortilina ima ljudski izotip IgG4 i sadrži jednu ili više aminokiselinskih zamjena u Fc području na položaju ostatka kojeg se bira iz skupine koju čine: E233P, F234V, L234A/F234A, L235A, G237A, E318A, S228P, L236E, S241P, L248E, T394D, M252Y, S254T, T256E, N297A, N297Q, te bilo koja njihova kombinacija, pri čemu je obrojčavanje ostataka u skladu s EU obrojčavanjem, pri čemu izborno:
(i) Fc područje IgG1 dodatno sadrži jednu ili više dodatnih aminokiselinskih zamjena na položaju kojeg se bira iz skupine koju čine A330L, L234F, L235E, P331S, te bilo koja njihova kombinacija, pri čemu je obrojčavanje ostataka u skladu s EU obrojčavanjem;
(ii) Fc područje IgG1 ili IgG4 dodatno sadrži jednu ili više dodatnih aminokiselinskih zamjena na položaju kojeg se bira iz skupine koju čine M252Y, S254T, T256E, te bilo koja njihova kombinacija, pri čemu je obrojčavanje ostataka u skladu s EU obrojčavanjem; ili
(iii) Fc područje IgG4 dodatno sadrži aminokiselinsku zamjenu S228P u skladu s EU obrojčavanjem.
10. Protutijelo protiv sortilina u skladu s patentnim zahtjevom 9, pri čemu protutijelo protiv sortilina ima ljudski izotip IgG4 i sadrži aminokiselinsku zamjenu položajima ostataka S228P, F234A, te L235A, pri čemu je obrojčavanje položaja ostatka u skladu s EU obrojčavanjem.
11. Izolirana nukleinska kiselina koja sadrži nukleinski kiselinski slijed koji kodira protutijelo protiv sortilina u skladu s bilo kojim od patentnih zahtjeva 1-10.
12. Vektor koji sadrži nukleinsku kiselinu u skladu s patentnim zahtjevom 11.
13. Izolirana stanica domaćin koja sadrži vektor u skladu s patentnim zahtjevom 12.
14. Farmaceutski pripravak koji sadrži protutijelo protiv sortilina u skladu s bilo kojim od patentnih zahtjeva 1-10, kao i farmaceutski prihvatljivi nosač.
15. In vitro postupak povisivanja izvanstaničnih razina progranulina, snižavanja razina sortilina na staničnoj površini jedne ili više stanica i/ili smanjivanje eksprimiranja jednog ili više proupalnih medijatora, pri čemu se jedan ili više proupalnih medijatora može birati iz skupine koju čine IL-6, IL12p70, IL12p40, IL-1β, TNF-α, CXCL1, CCL2, CCL3, CCL4, te CCL5, koji se sastoji u stavljanju u kontakt jedne ili više stanica s protutijelom protiv sortilina u skladu s bilo kojim od patentnih zahtjeva 1-10.
16. Protutijelo u skladu s bilo kojim od patentnih zahtjeva 1 do 10, namijenjeno upotrebi u postupku sprječavanja, smanjivanja rizika od, ili liječenja bolesti, poremećaja ili ozljede kod osobe kojoj je to potrebno, pri čemu se bolest, poremećaj ili ozljedu bira iz skupine koju čine frontotemporalna demencija, progresivna supranuklearna klijenut, Alzheimerova bolest, vaskularna demencija, napadaji, distrofija mrežnice, amiotrofna lateralna skleroza, traumatska ozljeda mozga, ozljeda kralježnične moždine, demencija, moždani udar, Parkinsonova bolest, akutni diseminirani encefalomijelitis, degeneracija mrežnice, staračka makularna degeneracija, glaukom, multipla skleroza, septični šok, bakterijska infekcija, artritis, te osteoartritis.
17. Protutijelo u skladu s bilo kojim od patentnih zahtjeva 1 do 10, namijenjeno upotrebi u postupku liječenja koji se sastoji u inhibiranju jednog ili više od upale živčanog tkiva, aksonopatije za koju su karakteristični kratki aksonski izdanci i nenormalno grananje, aktiviranja mikroglija, te upalnog odgovora i/ili poticanja zacjeljivanja rana.
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