DK2396347T3 - Albumin variants and conjugates - Google Patents

Albumin variants and conjugates Download PDF

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DK2396347T3
DK2396347T3 DK10703295.5T DK10703295T DK2396347T3 DK 2396347 T3 DK2396347 T3 DK 2396347T3 DK 10703295 T DK10703295 T DK 10703295T DK 2396347 T3 DK2396347 T3 DK 2396347T3
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human
protein
chemokine
receptor
albumin
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Christopher John Arthur Finnis
Esben Peter Friis
Joanna Mary Hay
Jason Cameron
Darrell Sleep
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Albumedix As
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    • 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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/38—Albumins
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
    • C07K1/113—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides without change of the primary structure
    • 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
    • C07K14/76—Albumins
    • 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
    • C07K14/76—Albumins
    • C07K14/765—Serum albumin, e.g. HSA
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B5/00—ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • Organic Chemistry (AREA)
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Claims (29)

1. Et konjugationskompetent polypeptid omfattende: (i) en aminosyresekvens, der er mindst 60% identisk med resterne 1 til 585 i SEQ ID No. 1, hvor: a) der i en position svarende til position 34 i SEQ ID NO: 1 er en konjugationskompetent cysteinrest; og b) der andetsteds i polypeptidet er to eller flere konjugationskompetente cysteinrester; eller (ii) et fragment omfattende mindst 50% af aminosyresekvensen ifølge (i) eller omfattende et domæne af aminosyresekvensen ifølge (i), hvor: a) der i en position svarende til position 34 i SEQ ID NO: 1 er en konjugationskompetent cysteinrest; og b) der andetsteds i polypeptidet er to eller flere konjugationskompetente cysteinrester.
2. Et konjugationskompetent polypeptid omfattende: (i) en aminosyresekvens, der er mindst 60% identisk med resterne 1 til 585 i SEQ ID No. 1, hvor: a) der i en position svarende til position 34 i SEQ ID NO: 1 ikke er en konjugationskompetent cysteinrest; og b) der andetsteds i polypeptidet er tre eller flere konjugationskompetente cysteinrester; eller (ii) et fragment omfattende mindst 50% af aminosyresekvensen ifølge (i) eller omfattende et domæne af aminosyresekvensen ifølge (i), hvor a) der i en position svarende til position 34 i SEQ ID NO: 1 ikke er en konjugationskompetent cysteinrest; og b) der andetsteds i polypeptidet er tre eller flere konjugationskompetente cysteinrester.
3. Polypeptid ifølge krav 1 eller 2 omfattende konjugationskompetente cysteinrester i positioner svarende til positionerne 2 og 585 i SEQ ID No. 1.
4. Polypeptid ifølge et hvilket som helst af kravene 1 til 3 omfattende fire eller flere konjugationskompetente cysteinrester.
5. Polypeptid ifølge krav 4 omfattende: a) konjugationskompetente cysteinrester i positioner svarende til positionerne 2 og 585 i SEQ ID No. 1; og b) en konjugationskompetent cysteinrest i en eller begge positioner svarende til positionerne 364 og 562 i SEQ ID No. 1.
6. Polypeptid ifølge et hvilket som helst af kravene 1 til 5, hvor polypeptidet omfatter en eller flere af: a) substitution af en aminosyre, der ikke er cystein, med en cyste in i en position svarende til en position svarende til en hvilken som helst af resterne L585, Dl, A2, D562, A364, A504, E505, T79, E86, D129, D549, A581, D121, E82, S270, Q397 og A578 i SEQ ID No. 1; b) insertion af en cystein i en position, der støder op til N- eller C-siden af en aminosyre ved en position, der svarer til en hvilken som helst af resterne L585, Dl, A2, D562, A364, A504, E505, T79, E86, D129, D549, A581, D121, E82, S270, Q397 og A578 i SEQ ID No. 1; c) deletion af en cystein i en position svarende til en hvilken som helst af C360, C316, C75, C168, C558, C361, C91, C124, C169 og C567 med SEQ ID nr. 1 for at danne en konjugationskompetent cystein ved en hvilken som helst af C369, C361, C91, C177, C567, C316, C75, C169, C124 og C558; d) addition af en cystein til N-siden af den N-terminale rest af en albuminsekvens eller til C-siden af den C-terminale rest af en albuminsekvens; således at nettoresultatet af substitutions-, deletions-, additions- eller insertionshændelserne i (a), (b), (c) og (d) er, at antallet af konjugationskompetente cysteinrester af polypeptidsekvensen forøges i forhold til polypeptidet forud for substitutions, insertions, deletions og additionshændelserne.
7. Polypeptid ifølge et hvilket som helst af kravene 1 til 6, hvor mindst én cysteinrest er substitueret med en anden aminosyrerest, fortrinsvis Ser, Thr, Val eller Ala.
8. Polypeptid ifølge et hvilket som helst af kravene 1 til 7 omfattende 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 eller 20 konjugationskompetente cysteinrester.
9. Polypeptid ifølge et hvilket som helst af kravene 1 til 8, hvor der, når polypeptidet omfatter tre eller flere konjugationskompetente cysteinrester, når polypeptidet er foldet, er en afstand på mindst 10 Å mellem to eller flere af de konjugationskompetente cysteinrester.
10. Polypeptid ifølge et hvilket som helst af kravene 1 til 9, hvor en eller flere af de konjugationskompetente cysteiner er konjugeret til et bioaktivt molekyle.
11. Polypeptid ifølge et hvilket som helst af kravene 1 til 10, hvor polypeptidet har mindst 70, 75, 80, 85, 90 eller 95% identitet med SEQ ID No. 1.
12. Polypeptid ifølge et hvilket som helst af kravene 1 til 11, hvor polypeptidet har mindst 95% sekvensidentitet til SEQ ID NO: 1 og omfatter konjugationskompetente rester positioneret ved: (a) A2 + L585, (b) A2 + A364 + D562 + L585C, (c) A2 og tilstødende C-siden af C-terminalen af albuminet (d) T79 + A364; (e) A364 4 Dl; (f) T79 + D562 4 A364; (g) D562 + A364 + Dl; (h) T79 + D562 + A364 + A504; (i) T79 4 D562 4 A364 4 L585; (j) T79 + D562 + A364 + Dl; (k) T79 + D562 4 A364 + L585 + Dl; (I) E86 4 D562 4 A364 + A504 4 A2; (m) S270 4 A581; (n) S270 4 D129; (o) S270 4 A581 4 E82; (p) S270 4 A581 4 D129; (q) S270 4 A581 4 E82 4 D129; (r) S270 4 A581 4 E82 4 D129 4 Q397; (s) C369 4 C177; (t) A364 4 A581; (u) T79 4 A364 4 A581; (v) A364 4 A581 4 D129; (w) A364 4 C177; (x) D562 4 C369; (y) D129 4 C369; (z) A581 4 C369; eller (ai) D562 4 D129 4 C369.
13. Polypeptid ifølge et hvilket som helst af kravene 1 til 12, hvor polypeptidet yderligere omfatter en yderligere linker, hvortil en bioaktiv forbindelse kan være bundet.
14. Fusionspolypeptid omfattende et konjugationskompetent polypeptid ifølge et hvilket som helst af kravene 1 til 13 og et bioaktivt polypeptid.
15. Polynukleotid, som koder for et polypeptid ifølge et hvilket som helst af kravene 1 til 14.
16. Plasmid omfattende polynukleotidet ifølge krav 15.
17. Værtscelle omfattende et polynukleotid ifølge krav 15 og/eller et plasmid ifølge krav 16.
18. Værtscelle ifølge krav 17, som er en gærcelle, fortrinsvis en Saccharomyces cerevisiae-celle.
19. Konjugat, der omfatter en bioaktiv forbindelse og et polypeptid ifølge et hvilket som helst af kravene 1 til 14, hvor den bioaktive forbindelse er bundet til polypeptidet via en konjugationskompetent cysteinrest i polypeptidet.
20. Konjugat ifølge krav 19 yderligere omfattende en eller flere yderligere bioaktive forbindelser, hvor hver bioaktiv forbindelse er bundet til polypeptidet via en konjugationskompetent cysteinrest i polypeptidet.
21. Fremgangsmåde til fremstilling af et polypeptid ifølge et hvilket som helst af kravene 1 til 14, omfattende: a) dyrkning af værtscellen ifølge krav 17 eller 18 under betingelser, der tillader ekspression af polypeptidet; og b) udvinding af polypeptidet fra værtscellen og/eller fra værtscellevækstmediet.
22. Fremgangsmåde til fremstilling af et konjugat ifølge krav 19 eller 20, som omfatter at forbinde en bioaktiv forbindelse med polypeptidet ifølge et hvilket som helst af kravene 1 til 14 via en konjugationskompetent cysteinrest i polypeptidet.
23. Fremgangsmåde ifølge krav 21, hvor værtscellen udviser forøget chaperoneaktivitet.
24. Fremgangsmåde ifølge krav 21 eller 22, som yderligere omfatter bestemmelse af receptorbindingskapacitet og/eller polypeptidets konjugationskompetence og udvælgelse af et polypeptid, der har receptorbindende kapacitet og/eller konjugationskompetence.
25. Sammensætning omfattende et konjugat ifølge krav 19 eller 20 og mindst én farmaceutisk acceptabel bærer eller diluent.
26. Konjugat ifølge krav 19 eller 20 til anvendelse til behandling af sygdom, til behandling af en sygdomstilstand og/eller til diagnosticering.
27. Gel omfattende et polypeptid ifølge et hvilket som helst af kravene 1 til 14 og/eller et konjugat ifølge et hvilket som helst af kravene 19 eller 20.
28. Anvendelse af et polypetid ifølge et hvilket som helst af kravene 1 til 14 og/eller et konjugat ifølge krav 19 eller 20 til fremstilling af en gel.
29. Konjugat ifølge krav 19, 20 eller et konjugat til anvendelse til behandling af sygdom, til behandling af sygdomstilstande og/eller til diagnosticering ifølge 26 eller en sammensætning ifølge krav 25, hvor det bioaktive molekyle er valgt blandt: 4-1 BB ligand, 5-helix, et humant CC-chemokin, et humant L105-chemokin, et humant L105-chemokin betegnet huL105_3, et monokin induceret af gamma-interferon (MIG), et partielt CXCR4B-protein, et trombocyt-basisprotein (PBP), al-antitrypsin, ACRP-30-homolog, Komplementkomponent Clq C, Ade-Noid-eksprimeret Chemokin (ADEC), aFGF, FGF-1, AGF, AGF-protein, Albumin, et etoposid, angiostatin, miltbrand-vaccine, Antistoffer, der er specifikke for collapsin, antistasin, Anti-TGF beta-familie-antistoffer, antithrombin III, APM-1, ACRP-30, Famoxin, apo-lipoprotein-specier, Arylsulfatase B, b57 Protein, BCMA, Beta-tromboglobulin-protein (beta-TG), bFGF, FGF2, blodkoagulationsfaktorer, BMP-behandling Enzym Furin, BMP-10, BMP-12, BMP-15, BMP-17, BMP-18, BMP-2B, BMP-4, BMP-5, BMP-6, BMP-9, Knoglemorfogen-protein-2, Calcitonin, Calpain-10a, Calpain-10b, Calpain-10c, Kræftvaccine, Carboxypeptidase, CC-chemokin, MCP2, CCR5-variant, CCR7, CCR7, CDlla Mab, CD137, 4-1 BB-Receptor-protein, CD20 Mab, CD27, CD27L, CD30, CD30-ligand, CD33-immunotoksin, CD40, CD40L, CD52 Mab, Cerebus-Protein, Chemokin Eotaxin, Chemokin hIL-8, Chemokin hMCPl, Chemokin hMCPla, Chemokin hMCPlb, Chemokin hMCP2, Chemokin hMCP3, Chemokine hSDFlb, Chemokin MCP-4, chemokin-TECK og TECK-variant, chemokinlignende protein IL-8M1 fuldlængde og modent, chemokinlignende protein IL-8M10 fuldlængde og modent, chemokinlignende protein IL-8M3, chemokinlignende protein IL-8M8 Fuldlængde og Modent, chemokinlignende protein IL-8M9 Fuldlængde og Modent, Chemokinlignende protein PF4-414 Fuldlængde og Modent, chemokin-lignende protein PF4-426 Fuldlængde og Modent, Chemokinlignende protein PF4-M2 Fuldlængde og Moden, koleravaccine, chondromodulin-lignende protein, c-kit-ligand, SCF, mastcel levækstfaktor, MGF, Fibrosarcoma-afledt stamcellefaktor, CNTF og fragment deraf (såsom CNTFAxl5'(Axokine™)), koagulationsfaktorer i både præ- og aktive former, collagener, Complement C5 Mab, Bindevævsaktiverende protein-III, CTAA16.88 Mab , CTAP-III, CTLA4-Ig, CTLA-8, CXC3, CXC-chemokin-receptor 3, cyanovirin-N, Darbepoetin, designeret exodus, designeret huL105___7, DIL-40, Dnase, EDAR, EGF-receptor Mab, ENA-78, Endostatin, Eotaxin, Epithelial neutrophil-aktiverende protein-78, EPO-receptor, erythropoietin (EPO) og EPO-mimics, Eutropin, Exodus-protein, Faktor IX, Faktor VII, Faktor VIII, Faktor X og Faktor XIII, FAS Ligand-hæmmende Protein (DcR3), FasL, FGF, FGF-12, Fibroblast-vækstfaktor-homologfaktor-1, FGF-15, FGF-16, FGF-18, FGF-3, INT-2, FGF-4, gelonin, HST-1, HBGF-4, FGF-5, FGF-6, heparin-bindende secerneret transformerende faktor 2, FGF-8, FGF-9, Glia-aktiverende faktor, fibrinogen, fit-1, flt-3-ligand, Follikel-stimulerende hormon-alpha-subunit, Follikel-stimulerende hormon-beta subunit, Follitropin, Fraktalkin, fragment, myofibrillar-protein Troponin I, FSH, Galactosidase, Galectin-4, G-CSF, GDF-1, Genterapi, Gliom-afledt vækstfaktor, glucagon, glucagon-lignende peptider, glucocere-brosidase, glucoseoxidase, Glucosidase, glycodelin-A, progesteron-associeret endometrial-protein, GM-CSF, gonadotropin, Granulocyt-kemotaktisk protein-2 (GCP-2), Granulocyt-makrofag-koloni-stimulerende faktor, væksthormon, Vækstrelateret onkogen-alpha (GRO-alpha), Vækstrelateret onkogen-beta (G RO-Beta), Vækstrelateret onkogen-gamma (GRO-gamma), hAPO-4, TROY, hCG, Hepatitus B-overfladeantigen, Hepatitus B-vaccine, HER2-receptormab, hirudin, HIV gpl20, HIV gp41, HIV-inhibitorpeptid, HIV-protease-hæmmende peptider, HIV-1-proteasehæmmere, HPV-vaccine, Human 6CKine-protein, Human Act-2-protein, human adipogenese-hæmmende faktor, human B-celle-stimulerende factor-2-receptor, Human beta-chemokin H1305 (MCP-2), Human CC chemokin DGWCC, Humant CC-chemokin-ELC-protein, Humant CC-type chemokin-interleukin C, Human CCC3-protein, Human CCF18-chemokin, Human CC-type chemokin-protein betegnet SLC (sekundær lymfoid chemokin), Human chemokin beta-8 korte former, human chemokin CIO, human chemokin CC-2, human chemokin CC-3, human chemokin CCR-2, Human chemokin Ckbeta-7, Human chemokin ENA-78, Human chemokin-eotaxin, Human chemokin GROalpha, Human chemokin GRObeta, Human chemokin HCC-1, Human chemokin HCC-1, Human chemokin 1-309, Human chemokin IP-10, Human chemokin L105_3, Human chemokin L105_7, Human chemokin MIG, Human chemokin MIG-beta protein, Human chemokine MIP-lalpha, Human chemokine MlPlbeta, Human chemokin MIP-3alpha, Human chemokin MIP-3beta Human chemokin PF4, Human chemokinprotein 331D5, Humant chemokinprotein 61164, human chemokin-receptor CXCR3, human chemokin SDFlalpha, Human chemokin SDFlbeta, human chemokin ZSIG-35, human Chrl9Kin-protein, human CKbeta-9, human CX3C 111 aminosyre chemokin, Human DNAX interleukin-40, Human DVic-1 CC-chemokin, Human EDIRF I-proteinsekvens, Human EDIRF II-proteinsekvens, Human eosinocyt CC-type chemokine-eotaxin, Human eosinophil-eksprimeret chemokin (EEC), Human Fast twich skeletmuskel troponin C, Human Fast twich skeletmuskel Troponin I, Human Fast twich skeletmuskel Troponin subunit C, Human Fast twich skeletmuskel Troponin subunit I Protein, Human Fast twich skeletmuskel Troponin subunit T, Human føtal milt-eksprimeret chemokin, FSEC, Human GM-CSF-receptor, Human Gro-alpha chemokin, human gro-beta chemokin, human grogamma chemokin, Human IL-16 protein, human IL-1RD10 proteinsekvens, human IL-1 RD9, Human IL-5-receptor alpha-kæde, Human IL-6 receptor, Human IL-8 receptor-protein hIL8RA, Humant IL-8-receptorprotein hIL8RB, Humant IL-9-receptorprotein, Human IL-9-receptorprotein-variant #3, Humant IL-9-receptorprotein-variantfragment, Humant IL-9 receptorproteinvariantfragment #3, Human interleukin 1 delta, Human interleukin 10, human interleukin 18, human interleukin 18-derivater, Human interleukin-1 beta precursor, Human interleukin-l-receptor accessory-protein, Human interleukin-1 receptor antagonist beta, Human interleukin-1 type-3 receptor, Human interleukin-10 (precursor), Human interleukiη-11 -receptor, Human interleukin-12 40 kD-subunit, Human interleukin-12 beta-l-receptor, Human interleukin-12 beta-2 receptor, Human Interleukin-12 p35 protein, Human Interleukin-12 p40 protein, Human Interleukin-12-receptor, Human interleukin-13-alpha-receptor, human interleukin-13 beta-receptor, human interleukin-15, human interleukin-15-receptor fra klon PI, Human interleukin-17 receptor, human interleukin-18-protein (IL-18), Human interleukin-3, human interleukin-3-receptor, Human interleukin-3-variant, Human interleukin-4-receptor, Human interleukin-5, Human interleukin-6, Human interleukin-7, Human interleukin-8 (IL-8), Human intraceilulær IL-1 receptor-antagonist, Human IP-10 og HIV-1 gpl20-hypervariabelt regionsfusionsprotein, Human IP-10 og human Muc-l-kerneepitop (VNT) fusionsprotein, human lever og aktiveringsreguleret chemokin (LARC), Human Lkn-1 Fuldlængde og Modent protein, Humant bryst-associeret chemokin (MACK)-protein Fuld længde og Modent, Human moden chemokin Ckbeta-7, humant modent gro-alpha, Humant modent grogamma polypeptid, der anvendes til behandling af sepsis, humant MCP-3 og humant Muc-l-kerneepitop (VNT)-fusionsprotein, Human MI10 protein, Human MI1A protein, Human monocyt-kemoattraktant-faktor hMCP-1, Human monocyt-kemoattraktantfaktor hMCP-3, Human monocyt-kemotaktisk proprotein (MCPP)-sekvens, Human neurotactin chemokin-lignende domæne, Human non-ELR CXC chemokin H174, Human non-ELR CXC chemokin IP10, Human non-ELR CXC chemokin Mig, Human PAI-1 mutanter, Humant protein med IL-16-aktivitet, Human sekundær lymfoid chemokin (SLC), Human SISD protein, Human STCP-1, Human stromal celle-afledt chemokin , SDF-1, human T-celle-blandet lymfocyt-reaktionsekspression-chemokin (TMEC), Human tymus og aktiveringsreguleret cytokin (TARC), humant thymus-eksprimeret, human TNF-alpha, human TNF-beta (LT-alpha), human type CC chemokin-eotaxin 3-proteinsekvens, human type II interleukin- 1-receptor Human vildtype interleukin-4 (hlL-4)-protein, humant ZCHEMO-8-protein, humaniseret anti-VEGF-antistoffer og fragmenter deraf, Hyaluronidase, ICE 10 kD subunit, ICE 20 kD subunit, ICE 22 kD subunit, Iduronat-2-sulfatase, Iduronidase, IL-1 alpha, IL-1 beta, IL-1 inhibitor (IL-li), IL-1 Moden, IL-10 receptor, IL-11, IL-12 p40 subunit, IL- 13, IL-14, IL-15, IL-15-receptor, IL-17, IL-17-receptor, IL-19, IL-li-fragmenter, ILl-receptor-antagonist, IL-21 (TIF), IL-3 indeholdende fusionsprotein, IL-3 mutant-proteiner, IL-3-varianter, IL-4, IL-4 mutein, IL-4 mutein Y124G, IL-4 mutein Y124X, IL-4 muteiner, II-5-receptor, IL-6, Π-6-receptor, IL-7-receptorklon, IL-8-receptor, IL-9-mature proteinvariant (Metll7 version), immunoglobuliner eller immunoglobulin-baseret D molekyler eller fragment af enten (for eksempel a Small Modular ImmunoPharmaceutical™ ("SMIP"), eller dAb, Fab'-fragmenter, F(ab')2, scAb, scFv eller scFv-fragment), herunder men ikke begrænset til plasminogen, Influenzavaccine, Inhibin-alpha, Inhibin-beta, insulin, insulin-lignede vækstfaktor, Integrin Mab, inter-alpha trypsin-hæmmer, Interferon gamma-inducerende protein (IP-10), interferoner (såsom interferon alpha-specier og sub-specier, interferon-beta-specier og sub-specier, interferon gamma-specier og sub-specier), Interleukin 6, Interleukin 8 (IL-8)-receptor, Interleukin 8-receptor B, Interleukin-lalpha, Interleukin-2- receptor-associeret protein p43, interleukin-3, interleukin-4 muteiner, Interleukin-8 (IL-S)-protein, interleukin-9, Interleukin-9 (IL-9)-Modent protein (Thrll7 version), interleukiner (så som IL10, IL11 and IL2), japansk encephalitis-vaccine, Kalikrein-hæmmer, Keratinocyt-vækstfaktor, Kunltz domæneprotein (så som aprotlnin, amyloid precursor-protein og de, der er beskrevet i WO 03/066824, med eller uden albumin-fusioner), LACI, lactoferrin, Latent TGF-beta bindingsprotein II, leptin, Lever-eksprimeret chemokin-1 (LVEC-1), Lever-eksprimeret chemokin-2 (LVEC-2), LT-alpha, LT-beta, Luteinization-hormon, Lymevaccine, Lymphotactin, Macrophage-afledt chemokinanalog MDC (n+1), Macrophage-afledt chemokinanalog MDC-eyfy, Macrophage-afledt chemokinanalog MDC-yl, Macrophage-afledt-chemokin (MDC), Maspin, Protease-hæmmer 5, MCP-l-receptor, MCP-1 a, MCP-1 b, MCP-3, MCP-4-receptor, M-CSF, Melanoma-hæmmende protein, Membran-bundne proteiner, Metll7 humany interleukin 9, MIP-3 alpha, MIP-3 beta, MIP-Gamma, MIRAP, Modificeret Rantes, monoclonalt antistof, MP52, Mutant Interleukin 6 S176R, myofibrillær kontraktilt protein Troponin I, Natriuretisk Peptid, Nerve-Vækstfaktor-beta, Nervevækstfaktor- beta 2, Neuropilin-1, Neuropilin-2, Neurotactin, Neurotrophin-3, Neurotrophin-4, Neurotrophin-4a, Neurotrophin-4b, Neurotrophin-4c, Neurotrophin-4d, Neutrophilaktiverende peptid-2 (NAP-2), NOGO-66-receptor, NOGO-A, NOGO-B, NOGO-C, Nyt beta-chemokin-designeret PTEC, N-terminal-modificeret chemokin GroHEK/hSDF-lalpha, N-terminal modificeret GroHEK/hSDF-lbeta, N-terminal-modificeret chemokin met-hSDF-1 alpha, N-terminal-modificeret chemokin met-hSDF-1 beta, OPGL, Osteogen-protein-1, OP-1, BMP-7, Osteogen-protein -2, 0X40, ACT-4, OX40L, Oxytocin (Neurophysin I), parathyroid-hormon, Patched, Patched-2, PDGF-D, Pertussis toxoid, hypofysær-eksprimeret chemokin (PGEC), Placental-vækstfaktor, Placental-vækstfaktor-2, Plasminogen-aktivatorhæmmer -1, Plasminogen-aktivator-hæmmer-2, trombocyt-afledt vækstfaktor, trombocyt-afledt vækstfaktor Bv-sis, trombocyt-afledt vækstfaktor precursor A, Trombocyt-afledt vækstfaktor precursor B, trombocyt Mab, trombocyt-afiedt endothel-celle-vækstfaktor (PD-ECGF), Trombocyt-afledt vækstfaktor A-kæde, Trombocyt-afledt vækstfaktor B-kæde, polypeptid anvendt til behandling af sepsis, Preproapolipoprotein ”milano"-variant, Preproapolipoprotein "paris"-variant, pre-thrombin, Primat CC chemokin "ILINCK", Primat CXC chemokin "IBICK", proinsulin, Prolactin, Prolactin2, prosaptid, Protease-hæmmende peptider, Protein C, Protein S, pro-thrombin, prourokinase, RANTES, RANTES 8-68, RANTES 9-68, RANTES-peptid, RANTES-receptor, Rekombinant interleukin-16, Resistin, restri ctocin, Retro vi ra I - p rotea se - h æ m m e re, ricin, Rotavirus-vaccine, RSV Mab, saporin, sarcin, Secernerede og Transmembrane-polypeptider, serum cholinesterase, serum-protein (såsom en blodkoagulationsfaktor), Opløselig BMP-Receptor Kinase Protein-3, Opløselig VEG F-Receptor, Stamcelle-hæmmendefaktor, Straphylococcus-vaccine, Stromal-afledt Faktor-1 alpha, Stromal-afledt Faktor-1 beta, Substans P (tachykinin), TI249 peptid, T20 peptid, T4 Endonuclease, TACI, Tarc, TGF-beta 1, TGF-beta 2, Thrll7 human interleukin-9, thrombin, thrombopoietin, Thrombopoietin derivatl, Thrombopoietin derivat2, Thrombopoietin derivats, Thrombopoietin derivat4, Thrombopoietin derivats, Thrombopoietin derivat6, Thrombopoietin derivat?, Thymus-eksprimeret chemokin (TECK), Thyroid-stimulerende Hormon, flåt-antikoagulerende peptid, Tim-l-protein, TNF-alpha-precursor, TNF-R, TNF-RII, TNF p75-Receptor, Death-Receptor, tPA, transferrin, transformrende vækstfaktor beta, Troponin-peptider, Afkortede monocyt-chemotaktisk protein 2 (6-76), Afkortet RANTES-protein (3-68), tumor-nekrosefaktor, Urinsyresalt-Oxidase, urokinase, Vasopressin (Neurophysin II), VEGF R-3, flt-4, VEGF-Receptor, KDR, flk-1, VEGF-110, VEGF-121, VEGF-138, VEGF-145, VEGF-162, VEGF-165, VEGF-182, VEGF-189, VEGF-206, VEGF-D, VEGF-E, VEGF-X, von Willebrand's faktor, Vildtype monocyt-chemotaktisk protein 2, ZTGF-beta 9, 13-cis-Retinoic Acid, 2-CdA, 2-Chlorodeoxyadenosine, 5-Azacitidine, 5-Fluorouracil, 5-FU, 6-Mercaptopurine, 6-MP, 6-TG, 6-Thioguanine, Abraxane, Accutane®, Actinomycin-D, Adriamycin®, Adrucil®, Agrylin®, Ala-Cort®, Aldesleukin, Alemtuzumab, ALIMTA, Alitretinoin, Alkaban-AQ®, Alkeran®, All -Trans-Retinsyre, Alpha-Interferon, Altretamin, Amethopterin, Amifostin, Aminoglutethimid, Anagrelid, Anandron®, Anastrozol, Arabinosylcytosin, Ara-C, Aranesp®, Aredia®, Arimidex®, Aromasin®, Arranon®, Arsenitrioxid, Asparaginase, ATRA, Avastin®, Azacitidin, BCG, BCNll, Bevacizumab, Bexaroten, BEXXAR®, Bicalutamid, BiCNU, Blenoxan®, Bleomycin, Bortezomib, Busulfan, Busulfex®, C225, Calcium Leucovorin, Campath®, Camptosar®, Camptothecin-11, Capecitabin, Carat™, Carboplatin, Carmustin, Carmustin Wafer, Casodex®, CC-5013, CCNU, CDDP, CeeNu, Cerubidine®, Cetuximab, Chlorambucil, Cisplatin, Citrovorumfaktor, Ciadribin, Cortison, Cosmegen®, CPT-11, Cyclophosphamid, Cytadren®, Cytarabin, Cytarabin Liposomal, Cytosar-U®, Cytoxan®, Dacarbazin, Dacogen, Dactinomycin, Darbepoetin Alpha, Dasatinib, Daunomycin, Daunorubicin, Daunorubicin Hydrochlorid, Daunorubicin Liposomal, Daunoxome®, Decadron, Decitabine, Delta-Cortef®, Deltasone®, Denileukin Diftitox, Depocyt™, Dexamethason, Dexamethasonacetat, Dexamethason Natriumphosphat, Dexason, Dexrazoxan, DHAD, DIG, Diodex, Docetaxel, Doxil®, Doxorubicin, Doxorubicin Liposomal, Droxia™, DTIC, DTIC-Dome®, Duralone®, Efudex®, Eligard ™, Ellence ™, Eioxatin ™, Eispar®, Emcyt®, Epirubicin, Epoetin Alpha, Erbitux™, Erlotinib, Erwinia L-Asparaginase, Estramustin, Ethyol, Etopofos®, Etoposid, Etoposidphosphat, Eulexin®, Evista®, Exemestane, Fareston®, Faslodex®, Femara®, Filgrastim, Floxuridin, Fludara®, Fludarabin, Fluoroplex®, Fluorouracil, Fluorouracil (creme), Fluoxymesteron, Flutamid, Folinsyre, FUDR®, Fulvestrant, G-CSF, Gefitinib, Gemcitabin, Gemtuzumab ozogamicin, Gemzar®, Gleevec™, Gliadel® Wafer, Goserelin, Granulocyt Makrophag-Koloni-Stimulerende Faktor, Halotestin®, Herceptin®, Hexadrol, Hexalen®, Hexamethylmelamin, HMM, Hycamtin®, Hydrea®, Hydrocortacetat®, Hydrocortison, Hydrocortison Natriumphosphat, Hydrocortison Natriumsuccinat, Hydrocortonphosphat, Hydroxyurea, Ibritumomab, Ibritumomab Tiuxetan, Idamycin®, Idarubicin, Ifex®, IFN-alpha, Ifosfamid, IL-11, IL-2, Imatinibmesylat, Imidazolcarboxamid, Interferon alpha, Interferon Alpha-2b (PEG-konjugat), Interleukin-2, Interleukin-11, Intron A® (interferon alpha-2b), Iressa®, Irinotecan, Isotretinoin, Kidrolase®, Lanacort®, Lapatinib, L-Asparaginase, LCR, Lenalidomid, Letrozol, Leucovorin, Leukeran, Leukine™, Leuprolid, Leurocristin, Leustatin™, Liposomal Ara-C, Liquid Pred®, Lomustin, L-PAM, L-Sarcolysin, Lupron®, Lupron Depot®, Matulane®, Maxidex, Mechlorethamin, Mechlorethamin Hydrochlorid, Medralone®, Medrol®, Megace®, Megestrol, Megestrolacetat, Melphalan, Mercaptopurin, Mesna, Mesnex™, Methotrexat, Methotrexat-natrium, Methylprednisolon, Meticorten®, Mitomycin, Mitomycin-C, Mitoxantron, M-Prednisol®, Mustargen®, Mustine, Mutamycin®, Myleran®, Mylocel™, Mylotarg®, Navelbine®, Nelarabine, Neosar®, Neulasta™, Neumega®, Neupogen®, Nexavar®, Nilandron®, Nilutamid, Nipent®, Nitrogen-Mustard, Novaldex®, Novantrone®, Octreotid, Octreotidacetat, Oncospar®, Oncovin®, Ontak®, Onxal™, Oprevelkin, Orapred®, Orasone®, Oxaliplatin, Paclitaxel, Paclitaxelproteinbundet, Pamidronat, Panitumumab, Panretin®, Paraplatin®, Pediapred®, PEG-Interferon, Pegaspargase, Pegfilgrastim, PEG-INTRON™, PEG-L-Asparaginase, PEMETREXED, Pentostatin, Phenylalanin-Mustard, Platinol®, Platinol-AQ®, Prednisolon, Prednison, Prelone®, Procarbazin, PROCRIT®, Proleukin®, Prolifeprospan 20 med Carmustinimplantat, Purinethol®, Raloxifene, Revlimid®, Rheumatrex®, Rituxan®, Rituximab, Roferon-A® (Interferon Alpha-2a), Rubex®, Rubidomycinhydrochlorid, Sandostatin®, Sandostatin LAR®, Sargramostim, Solu-Cortef®, Solu-Medrol®, Sorafenib, SPRYCEL™, STI-571, Streptozocin, SU11248, Sunitinib, Sutent®, Tamoxifen, Tarceva®, Targretin®, Taxol®, Taxotere®, Temodar®, Temozolomid, Teniposid, TESPA, Thalidomid, Thalomid®, Theracys®, Thioguanin, Thioguanine Tabloid®, Thiophosphoamid, Thioplex®, Thiotepa, TICE®, Toposar®, Topotecan, Toremifen, Tositumomab, Trastuzumab, Tretinoin, Trexall™, Trisenox®, TSPA, TYKERB®, VCR, Vectibix™, Velban®, Velcade®, Vepesid®, Vesanoid®, Viadur™, Vidaza®, Vinblastin, Vinblastinsulfat, Vincasar Pfs®, Vincristin, Vinorelbine, Vinorelbintartrat, VLB, VM-26, Vorinostat, VP-16, Vumon®, Xeloda®, Zanosar®, Zevalin™, Zinecard®, Zoladex®, Zoledronsyre, Zolinza, Zometa®, Carbon-11, Carbon-14, Chrom-51, Cobalt-57, Cobalt-58, Erbium-169, Fluor-18, Gallium-67, Gold-198, Indium-111, Indium-113m, Lodin-123, Lodin -125, Lodine-131, Jern-59, Krypton-81m, Nitrogen-13, Oxygen-15, Phosphor-32, Rhenium-186, Rubidium-82, Samarium-153, Selenium-75, Strontium-89, Technetium-99m, Thallium-201, Tritium, Xenon-127, Xenon-133, Yttrium-90, Gadolinium, Magnetit, Mangan, Technetium, 1125, 1131, P32, TI201, lopamidol, PET-FDG.
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