DK2281037T3 - Faktor VII-polypeptider som er modificerede og anvendelser deraf - Google Patents
Faktor VII-polypeptider som er modificerede og anvendelser deraf Download PDFInfo
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- DK2281037T3 DK2281037T3 DK09730852.2T DK09730852T DK2281037T3 DK 2281037 T3 DK2281037 T3 DK 2281037T3 DK 09730852 T DK09730852 T DK 09730852T DK 2281037 T3 DK2281037 T3 DK 2281037T3
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Claims (2)
- av Modificeret faktor Vil (FVII) polypeptid omfattende modificeringer i et FVII-polypeptid, hvori: modificeringerne er ved positioner svarende til position 286 og position 298 i et FVII-polypeptid med aminosyresekvensen angivet i SEQ ID NO: 3 eller i tilsvarende positioner ved overensstemmende loci i et FVII-polypeptid; modificeringen ved position 286 er en aminosyreudskiftning med en arginin (Arg, R); modificeringen ved position 298 er en aminosyreudskiftning med en glutamin (Gin, Q); og det modificerede FVII-polypeptid udviser forøget koagulationsaktivitet sammenlignet med et umodificeret FVII-polypeptid, som ikke har modificeringen ved position 286. Modificeret FVII-polypeptid ifølge krav 1, hvori modificeringen ved position 286 er udskiftning af Gin (Q) med Arg (R). Modificeret FVII-polypeptid ifølge krav 1, hvori modificeringen ved position 298 er udskiftning af Met (M) med Gin (Q). Modificeret FVII-polypeptid ifølge krav 1 omfattende modificeringerne Q286R og M298Q. Modificeret FVII-polypeptid ifølge ethvert af kravene 1-4, hvori: det umodificerede FVII-polypeptid omfatter en aminosyresekvens angivet i enhver af SEQ ID NOS: 1-3, 18-74, 98, 158 eller 343-353 eller en variant med mindst 60% sekvensidentitet med FVII'en ifølge enhver af SEQ ID NOS: 1-3, 18-74, 98, 158 eller 343-353. Modificeret FVII-polypeptid ifølge ethvert af kravene 1-5 omfattende en eller flere yderligere modificeringer ved en anden position i FVII-polypeptidet. Modificeret FVII-polypeptid ifølge krav 6, hvori en yderligere modificering er en aminosyreudskiftning ved en position svarende til en position valgt blandt 51, 52, 54, 60, 66, 68, 109, 119, 122, 124, 130, 132, 158, 161, 175, 196, 197, 199, 202, 216, 222, 237, 239, 257, 287, 290, 292, 294, 296, 305, 314, 318, 321, 337, 341, 366, 373, 374, 394, 395 og 396. Modificeret FVII-polypeptid ifølge krav 6, hvori en yderligere modificering er valgt blandt D196K, D196R, D196A, D196Y, D196F, D196W, D196L, D196I, K197Y, K197A, K197E, K197D, K197L, K197M, K197I, K197V, K197F, K197W, K199A, K199D, K199E, G237W, G237T, G237I, G237V, T239A, R290A, R290E, R290D, R290N, R290Q, R290K, R290M, R290V, K341E, K341R, K341Q, K341N, K341M, K341D, G237T238insA, G237T238insS, G237T238insV, G237T238insAS, G237T238insSA, D196K197insK, D196K197insR, D196K197insY, D196K197insW, D196K197insA, D196K197insM, K197l198insE, K197l198insY, K197l198insA, K197l198insS, T239S, T239N, T239Q, T239V, T239L, T239H, T239I, L287T, P321K, P321E, P321Y, P321S, Q366D, Q366E, Q366N, Q366T, Q366S, Q366V, Q366I, Q366L, Q366M, H373D, H373E, H373S, H373L, H373I, H373F, H373A, K161S, K161A, K161V, H216S, H216A, H216K, H216R, S222A, S222K, S222V, S222N, S222E, S222D, H257A, H257S, Gla Swap FIX , {Gla Swap FIX/E40L}, {Gla Swap FIX/K43I}, {Gla Swap FIX/Q44S}, {Gla Swap FIX/M19K}, {Gla Swap FIX/M19K/E40L/K43I/Q44S}, Gla Swap FX , Gla Swap Prot C, Gla Swap Prot S, Gla Swap Thrombin, S52A, S60A, E394N, P395A, R396S, R202S, A292N, A294S, G318N, A175S, K109N, A122N, G124S, A51N, T130N, E132S, S52N, P54S, S119N, L121S, T128N, P129A, Q66N, Y68S, S103S111 delinsQRLMEDICLPRWGCLWEDDF, H115S126delinsQRLMEDICLPRWGCLWEDDF, T128P134delinsQRLMEDICLPRWGCLWEDDF, S103S111 delinslEDICLPRWGCLWE, H115S126delinslEDICLPRWGCLWE, T128P134delinslEDICLPRWGCLWE, S103S111delinsDICLPRWGCLWED, H115S126delinsDICLPRWGCLWED, T128P134delinsDICLPRWGCLWED, P406inslEDICLPRWGCLW, P406insGGGSIEDICLPRWGCLW, P406insDICLPRWGCLWED, P406insGGGSDICLPRWGCLWED, S103S111 delinsSFGRGDIRNV, H115S126delinsSFGRGDIRNV, T127P134delinsSFGRGDI RNV, P406insCSFGRGDIRNVC, P406insGGGSCSFGRGDIRNVC, V158T, V158D, L287T og E296V. Modificeret FVII-polypeptid ifølge ethvert af kravene 6-8 omfattende modificeringer valgt blandt Q286R/M298Q/K341Q, Q286R/M298Q/K199E, Q286R/M298Q/Gla Swap FIX, Q286R/M298Q/Q366D, Q286R/M298Q/Q366N, Q286R/M298Q/H373F, {Gla Swap FIX/E40L}/Q286R/M298Q, {Gla Swap FIX/K43I}/Q286R/M298Q, {Gla Swap FIX/Q44SJ/Q286R/M298Q, {Gla Swap FIX/M19KJ/Q286R/M298Q, {Gla Swap FIX/M19K/E40L/K43I/Q44S}/Q286R/M298Q, T128N/P129A/Q286R/M298Q, V158D/Q286R/E296V/M298Q, Gla Swap FIX/T128N/P129A/Q286R/M298Q, T128N/P129A/S222A/H257A/Q286R/M298Q, T128N/P129A/Q286R/M298Q/H373F, S52A/S60A/Q286R/M298Q, Gla Swap FIX/S52A/S60A/Q286R/M298Q, S52A/S60A/S222A/H257A/Q286R/M298Q, S52A/S60A/Q286R/M298Q/H373F, T239V/Q286R/M298Q, S222A/T239V/H257A/Q286R/M298Q, Gla Swap FIX/T239V/Q286R/M298Q, T239V/Q286R/M298Q/H373F, T239I/Q286R/M298Q, S222A/T239I/H257A/Q286R/M298Q, Gla Swap FIX/T239I/Q286R/M298Q, T239I/Q286R/M298Q/H373F, Gla Swap FIX/S222A/Q286R/M298Q, Gla Swap FIX/S222A/Q286R/M298Q/H373F, V158D/Q286R/E296V/M298Q/H373F, H257A/Q286R/M298Q, H257S/Q286R/M298Q, S222A/H257S/Q286R/M298Q, H257S/Q286R/M298Q/H373F, S222A/Q286R/M298Q/H373F, S222A/Q286R/M298Q, T128N/P129A/A175S/Q286R/M298Q, A122N/G124S/A175S/Q286R/M298Q, T128N/P129A/A175S/S222A/H257A/Q286R/M298Q, A122N/G124S/A175S/S222A/H257A/Q286R/M298Q, T128N/P129A/A175S/Q286R/M298Q/H373F, A122N/G124S/A175S/Q286R/M298Q/H373F, {Gla Swap FIX /K43IJ/T128N/P129A/Q286R/M298Q, T128N/P129A/Q286R/M298Q/Q366N, {Gla Swap FIX /K43IJ/Q286R/M298Q/Q366N, {Gla Swap FIX /K43I}/ T128N/P129A/Q286R/M298Q/Q366N, V158D/Q286R/E296V/M298Q, T128N/P129A/Q286R/M298Q/Q366N/H373F, T239V/Q286R/M298Q/Q366N, T239I/Q286R/M298Q/Q366N, T128N/P129A/T239V/Q286R/M298Q, T128N/P129A/S222A/T239V/H257A/Q286R/M298Q, T128N/P129A/T239V/Q286R/M298Q/H373F, T128N/P129A/T239I/Q286R/M298Q og T128N/P129A/T239I/Q286R/M298Q/H373F. Modificeret FVIl-polypeptid ifølge ethvert af kravene 6-9 omfattende modificeringer valgt blandt T128N/P129A/Q286R/M298Q, T239I/Q286R/M298Q/Q366N, T239V/Q286R/M298Q/Q366N, T128N/P129A/Q286R/M298Q/Q366N/H373F, V158D/Q286R/E296V/M298Q/H373F, A122N/G124S/A175S/Q286R/M298Q/H373F, T128N/P129A/A175S/Q286R/M298Q/H373F, A122N/G124S/A175S/S222A/H257A/ Q286R/M298Q, T128N/P129A/A175S/S222A/H257A/Q286R/M298Q, A122N/G124S/ A175S/Q286R/M298Q, T128N/P129A/A175S/Q286R/M298Q, H257A/Q286R/M298Q, Gla Swap FIX/S222A/Q286R/M298Q, S222A/Q286R/M298Q, Gla Swap FIX/ S222A/Q286R/M298Q/H373F, S222A/Q286R/M298Q/H373F, S222A/H257S/Q286R/M298Q, T239I/Q286R/M298Q/H373F, S222A/T239I/H257A/Q286R/M298Q, T128N/P129A/T239I/Q286R/M298Q, Gla Swap FIX / T239I/Q286R/M298Q, T239I/Q286R/M298Q, T128N/P129A/S222A/T239V/H257A/Q286R/M298Q, S222A/T239V/H257A/Q286R/M298Q, T128N/P129A/T239V/Q286R/M298Q, Gla Swap FIX/T239V/Q286R/M298Q, V158D/Q286R/E296V/M298Q, T128N/P129A/Q286R/M298Q/H373F, Q286R/M298Q/H373F, {Gla Swap FIX K[43]l}/ T128N/P129A/Q286R/M298Q /Q366N, {Gla Swap FIX K[43]I}/Q286R/M298Q/Q366N, Q286R/M298Q/Q366N, S52A/S60A/S222A/H257A/Q286R/M298Q, T128N/P129A/S222A/H257A/Q286R/M298Q, S222A/H257A/Q286R/M298Q, {Gla Swap FIX/K[43]I}/T128N/P129A/Q286R/M298Q, Gla Swap FIX/S52A/S60A/ Q286R/M298Q, S52A/S60A/ Q286R/M298Q, {Gla Swap FIX/M[19]K}/ Q286R/M298Q, {Gla Swap FIX/Q[44]S}/ Q286R/M298Q, {Gla Swap FIX/K[43]I}/ Q286R/M298Q, {Gla Swap FIX/E[40]L}/ Q286R/M298Q og Gla Swap FIX /T128N/P129A/Q286R/M298Q. Modificeret FVI l-polypeptid ifølge ethvert af kravene 1-10, som indeholder et heterologt Gla domæne eller et tilstrækkeligt tilstødende del af Gla-domænet til at ændre phospholipidbinding. Modificeret FVI l-polypeptid ifølge ethvert af kravene 1-11 omfattende en aminosyresekvens angivet i enhver af SEQ ID NO: 138-141, 150, 154, 155, 157, 274- 278, 280, 282, 286-288, 293-295, 297, 302-304, 306, 311-313, 317, 318, 321, 322, 324-326, 328, 337-342, 355-358, 360 eller 364-371. Modificeret FVII-polypeptid ifølge ethvert af kravene 1-12, som er aktive eller aktiverede. Modificeret FVII-polypeptid ifølge ethvert af kravene 1-13 omfattende 2, 3, 4, 5, 6, 7 eller flere modificeringer. Modificeret FVII-polypeptid ifølge krav 11, hvori det heterologe Gla-domæne er valgt blandt et Gla-domæne i Faktor IX (FIX), Faktor X (FX), prothrombin, protein C, protein S, osteocalcin, matrix Gla protein, Growth-arrest-specifikt protein 6 (Gas6) og protein Z. Modificeret FVII-polypeptid ifølge krav 11 eller krav 15, hvori det heterologe Gla-domæne har en aminosyresekvens angivet i enhver af SEQ ID NOS: 83-91, 93 og 94, eller en tilstrækkelig del deraf at medføre phospholipidbinding. Modificeret FVII-polypeptid ifølge krav 11, hvori det native FVII-Gla-domæne indbefatter aminosyrerne 1-45 i et FVII-polypeptid med en aminosyresekvens angivet i SEQ ID NO: 3, eller i tilsvarende enheder i et FVII-polypeptid. Modificeret FVII-polypeptid ifølge ethvert af kravene 11-17, hvori det heterologe Gla-domæne indeholder en modificering i forhold til vildtype-formen af det heterologe Gla-domæne. Modificeret FVII-polypeptid ifølge krav 18, hvori: det heterologe Gla-domæne er et FIX-Gla-domæne; og modificeringen er en aminosyreudskiftning ved en position svarende til en position valgt blandt positioner 19, 40, 43 og 44 i FIX-Gla-domænet angivet i SEQ ID NO: 83. Modificeret FVII-polypeptid ifølge krav 19, hvori modificeringen er valgt blandt M19K, E40L, K43I og Q44S. Modificeret FVII-polypeptid ifølge ethvert af kravene 1-20, hvori modificeringen er M19K/E40L/K43I/Q44S. Modificeret FVII-polypeptid ifølge ethvert af kravene 1-20 omfattende modificeringer valgt blandt Q286R/M298Q/Gla Swap FIX, {Gla Swap FIX/E40L}/Q286R/M298Q, {Gla Swap FIX/K43I}/Q286R/M298Q, {Gla Swap FIX/Q44S}/Q286R/M298Q, {Gla Swap FIX/M19K}/Q286R/M298Q, {Gla Swap FIX/M19K/E40L/K43I/Q44S}/Q286R/M298Q, Gla Swap FIX/T128N/P129A/Q286R/M298Q, Gla Swap FIX/S52A/S60A/Q286R/M298Q, Gla Swap FIX/T239V/Q286R/M298Q, Gla Swap FIX/T239I/Q286R/M298Q, Gla Swap FIX/S222A/Q286R/M298Q, Gla Swap FIX/S222A/Q286R/M298Q/H373F, {Gla Swap FIX /K43IJ/T128N/P129A/Q286R/M298Q, {Gla Swap FIX /K43IJ/Q286R/M298Q/Q366N og {Gla Swap FIX /K43I}/ T128N/P129A/Q286R/M298Q/Q366N. Modificeret FVII-polypeptid ifølge ethvert af kravene 1-22 omfattende en eller flere yderligere aminosyremodificering(er), som øger resistensen til antithrombin-l 11, øger bindning og/eller affinitet til phospholipider, øger affinitet for vævsfaktor, øger intrinsic aktivitet, øger TF-afhængig aktivitet, øger koagulerende aktivitet, ændrer konfigurationen af polypeptidet til at ændre zymogenicitet, øger katalytisk eller koagulerende aktivitet ved at forskyde ligevægten mellem højaktive og mindre aktive FVIIa konfigurationer til fordel for de højaktive konfigurationer, øger resistensen til proteaser, mindsker glycosylering, øger glycosylering, reducerer immunogenicitet, øger stabiliteten og/eller faciliterer kemisk binding. Modificeret FVII-polypeptid ifølge ethvert af kravene 1-23 omfattende en eller flere yderligere aminosyremodificering(er) valgt blandt S279C/V302C, L280C/N301C, V281C/V302C, S282C/V299C, indsættelse af et tyrosin ved position 4, F4S, F4T, P10Q, P10E, P10D, P10N, Q21N, R28F, R28E, I30C, I30D, I30E, K32D, K32Q, K32E, K32G, K32H, K32T, K32C, K32A, K32S, D33C, D33F, D33E, D33K, A34C, A34E, A34D, A34I, A34L, A34M, A34V, A34F, A34W, A34Y, R36D, R36E, T37C, T37D, T37E, K38C, K38E, K38T, K38D, K38L, K38G, K38A, K38S, K38N, K38H, L39E, L39Q, L39H, W41N, W41C, W41E, W41D, I42R, I42N, I42S, I42A, I42Q, I42N, I42S, I42A, I42Q, I42K, S43Q, S43N, Y44K, Y44C, Y44D, Y44E, S45C, S45D, S45E, D46C, A51N, S53N, G58N, G59S, G59T, K62E, K62R, K62D, K62N, K62Q, K62T, L65Q, L65S, L65N, F71D, F71Y, F71E, F71Q, F71N, P74S, P74A, A75E, A75D, E77A, E82Q, E82N, E82S, E82T T83K, N95S, N95T, G97S, G97T, Y101N, D104N, T106N, K109N, E116D, G117N, G124N, S126N, T128N, L141C, L141D, L141E, E142D, E142C, K143C, K143D, K143E, R144E, R144C, R144D, N145Y, N145G, N145F, N145M, N145S, N145I, N145L, N145T, N145V, N145P, N145K, N145H, N145Q, N145E, N145R, N145W, N145D, N145C, K157V, K157L, K157I, K157M, K157F, K157W, K157P, K157G, K157S, K157T, K157C, K157Y, K157N, K157E, K157R, K157H, K157D, K157Q, V158L, V158I, V158M, V158F, V158W, V158P, V158G, V158S, V158T, V158C, V158Y, V158N, V158E, V158R, V158K, V158H, V158D, V158Q, A175S, A175T, G179N, I186S, I186T, V188N, R202S, R202T, I205S, I205T, D212N, E220N, I230N, P231N, P236N, G237N, Q250C, V253N, E265N, T267N, E270N, A274M, A274L, A274K, A274R, A274D, A274V, A274I, A274F, A274W, A274P, A274G, A274T, A274C, A274Y, A274N, A274E, A274H, A274S, A274Q, F275H, R277N, F278S, F278A. F278N, F278Q, F278G, L280N, L288K, L288C, L288D, D289C, D289K, L288E, R290C, R290G, R290A, R290S, R290T, R290K, R290D, R290E, G291E, G291D, G291C, G291N, G291K, A292C, A292K, A292D, A292E, T293K, E296V, E296L, E296I, E296M, E296F, E296W, E296P, E296G, E296S, E296T, E296C, E296Y, E296N, E296K, E296R, E296H, E296D, E296Q, M298V, M298L, M298I, M298F, M298W, M298P, M298G, M298S, M298T, M298C, M298Y, M298N, M298K, M298R, M298H, M298E, M298D, P303S, P303T, R304Y, R304F, R304L, R304M, R304G, R304T, R304A, R304S, R304N, L305V, L305Y, L305I, L305F, L305A, L305M, L305W, L305P, L305G, L305S, L305T, L305C, L305N, L305E, L305K, L305R, L305H, L305D, L305Q, M306D, M306N, D309S, D309T, Q312N, Q313K, Q313D, Q313E, S314A, S314V, S314I, S314M, S314F, S314W, S314P, S314G, S314L, S314T, S314C, S314Y, S314N, S314E, S314K, S314R, S314H, S314D, S314Q, R315K, R315G, R315A, R315S, R315T, R315Q, R315C, R315D, R315E, K316D, K316C, K316E, V317C, V317K, V317D, V317E, G318N, N322Y, N322G, N322F, N322M, N322S, N322I, N322L, N322T, N322V, N322P, N322K, N322H, N322Q, N322E, N322R, N322W, N322C, G331N, Y332S, Y332A, Y332N, Y332Q, Y332G, D334G, D334E, D334A, D334V, D334I, D334M, D334F, D334W, D334P, D334L, D334T, D334C, D334Y, D334N, D334K, D334R, D334H, D334S, D334Q, S336G, S336E, S336A, S336V, S336I, S336M, S336F, S336W, S336P, S336L, S336T, S336C, S336Y, S336N, S336K, S336R, S336H, S336D, S336Q, K337L, K337V, K337I, K337M, K337F, K337W, K337P, K337G, K337S, K337T, K337C, K337Y, K337N, K337E, K337R, K337H, K337D, K337Q, K341E, K341Q, K341G, K341T, K341A, K341S, G342N, H348N, R353N, Y357N, 1361N, F374P, F374A, F374V, F374I, F374L, F374M, F374W, F374G, F374S, F374T, F374C, F374Y, F374N, F374E, F374K, F374R, F374H, F374D, F374Q, V376N, R379N, L390C, L390K, L390D, L390E, M391D, M391C, M391K, M391N, M391E, R392C, R392D, R392E, S393D, S393C, S393K, S393E, E394K, P395K, E394C, P395D, P395C, P395E, R396K, R396C, R396D, R396E, P397D, P397K, P397C, P397E, G398K, G398C, G398D, G398E, V399C, V399D, V399K, V399E, L400K, L401K, L401C, L401D, L401E, R402D, R402C, R402K, R402E, A403K, A403C, A403D, A403E, P404E, P404D, P404C, P404K, F405K, P406C, K32N/A34S, K32N/A34T, F31N/D33S, F31N/D33T, I30N/K32S, I30N/K32T, A34N/R36S, A34N/R36T, K38N/F40S, K38N/F40T, T37N/L39S, T37N/L39T, R36N/K38S, R36N/K38T, L39N/W41S, L39N/W41T, F40N/I42S, F40N/I42T, I42N/Y44S, I42N/Y44T, Y44N/D46S, Y44N/D46T, D46N/D48S, D46N/D48T, G47N/Q49S, G47N/Q49T, K143N/ N145S, K143N/ N145T, E142N/R144S, E142N/R144T, L141N/K143S, L141N/K143T, I140N/E142S, I140N/E142T, R144N/A146S, R144N/A146T, A146N/K148S, A146N/K148T, S147N/P149S/, S147N/P149T, R290N/A292S, R290N/A292T, D289N/G291S, D289N/G291T, L288N/R290S, L288N/R290T, L287N/D289S, L287N/D289T, A292N/A294S, A292N/A294T, T293N/L295S, T293N/L295T, R315NA/317S, R315NA/317T, S314N/ K316S, S314N/ K316T, Q313N/ R315S, Q313N/ R315T, K316N/G318S, K316N/G318T, V317N/D319S, V317N/D319T, K341N/ D343S, K341N/ D343T, S339N/K341S, S339N/K341T, D343N/G345S, D343N/G345T, R392N/E394S, R392N/E394T, L390N/ R392S, L390N/ R392T, K389N/M391S, K389N/M391T, S393N/P395S, S393N/P395T, E394N/R396S, E394N/R396T, P395N/P397S, P395N/P397T, R396N/G398S, R396N/G398T, P397NA/399S, P397N/V399T, G398N/L400S, G398N/L400T, V399N/L401S, V399N/L401T, L400N/R402S, L400N/R402T, L401N/A403S, L401N/A403T, R402N/P404S, R402N/P404T, A403N/F405S, A403N/F405T, P404N/P406S og P404N/P406T.
- 25. Modificeret FVII-polypeptid ifølge ethvert af kravene 1-24, hvori: det umodificerede FVIl-polypeptid har en aminosyresekvens angivet i SEQ ID NO: 3 eller en variant med mindst 60% sekvensidentitet med FVII'en ifølge enhver af SEQ ID NOS: 1-3, 18-74, 98, 158 eller 343-353. Modificeret FVI l-polypeptid ifølge krav 1, som omfatter modificeringerne T128N/P129A/Q286R/M298Q. Modificeret FVI l-polypeptid ifølge krav 26, hvis aminosyresekvens består af sekvensen angivet i SEQ ID NO: 280. Modificeret FVI l-polypeptid ifølge ethvert af kravene 1-25, som er et modent polypeptid. Modificeret FVI l-polypeptid ifølge ethvert af kravene 1-26, som er et enkeltkædet polypeptid eller et tokædet polypeptid. Nukleinsyremolekyle omfattende en nukleotidsekvens, som koder for et modificeret FVI l-polypeptid ifølge ethvert af kravene 1-27. Vektor omfattende nukleinsyremolekylet ifølge krav 30. Celle omfattende vektoren ifølge krav 31. Modificeret FVI l-polypeptid ifølge ethvert af kravene 1-29, til anvendelse i behandling af en sygdom eller tilstand, som behandles ved administration af FVI I eller en pro-koagulant. Modificeret FVI l-polypeptid ifølge krav 33, hvori sygdommen eller tilstanden behandles ved administration af et zymogen eller en aktiv form af FVII. Modificeret FVI l-polypeptid ifølge krav 33 eller krav 34, hvori sygdommen eller tilstanden, som skal behandles, er valgt blandt koagulationsdefekter, hæmatologiske lidelser, hæmoragiske lidelser, hemofili, faktor Vll-mangel, blødningsforstyrrelser, kirurgisk blødning eller blødning resulterende fra traumer. Modificeret FVIl-polypeptid ifølge krav 35, hvori sygdommen eller tilstanden er hæmofili og hæmofilien er hæmofili A eller hæmofili B eller hæmofili C. Modificeret FVI l-polypeptid ifølge krav 27, hvori polypeptidet er den aktiverede tokædeform som resulterer af spaltning mellem aminosyrerne Arg152 og Ile153, de første og anden kæder består henholdsvis af aminosyrer 1-152 og 153-406 af SEQ ID NO: 280 forbundet til hinanden via en disulfidbinding. Aktiveret tokædet form af det modificerede FVI l-polypeptid ifølge krav 37, hvori FVII-polypeptidet er zymogenlignende. Aktiveret tokædet form af det modificerede FVI l-polypeptid ifølge krav 37, hvori FVII-polypeptidet er fuldt aktiveret. Aktiveret tokædet form af det modificerede FVI l-polypeptid ifølge krav 37, hvori FVII-polypeptidet indbefatter mindst en post-translationel modificering valgt blandt O-bundet glycosylering, N-bundet glycosylering, carboxylering af glutaminsyre til y-carboxyglutaminsyre og hydroxylering af asparaginsyre til β-hydroxyasparaginsyre. Farmaceutisk sammensætning omfattende den aktiverede tokædede form af det modificerede FVI l-polypeptid ifølge krav 37 og en farmaceutisk acceptabel bærer. Sammensætning ifølge krav 41, som er formuleret til intravenøs, parenteral, intramuskulær eller subkutan administration. Sammensætning ifølge krav 41, som er frysetørret. Aktiveret tokædet form af det modificerede FVI l-polypeptid ifølge ethvert af kravene 37-40 til anvendelse i behandling af en patient med hæmofili A med inhibitorer eller hæmofili B med inhibitorer. Farmaceutisk præparat omfattende en terapeutisk effektiv koncentration eller mængde af et modificeret FVI l-polypeptid ifølge ethvert af kravene 1-29 og 37-40, eller er nukleinsyremolekyle ifølge krav 30 eller en vektor ifølge krav 31 eller en celle ifølge krav 32 i et farmaceutisk acceptabel vehikel. Farmaceutisk sammensætning ifølge krav 45, som er formuleret til enkel dosisadministration.
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Families Citing this family (66)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7700341B2 (en) * | 2000-02-03 | 2010-04-20 | Dendreon Corporation | Nucleic acid molecules encoding transmembrane serine proteases, the encoded proteins and methods based thereon |
| TWI353991B (en) | 2003-05-06 | 2011-12-11 | Syntonix Pharmaceuticals Inc | Immunoglobulin chimeric monomer-dimer hybrids |
| AU2005244271B2 (en) | 2004-04-12 | 2010-04-08 | Vertex Pharmaceuticals Incorporated | Cleavage of VEGF and VEGF receptor by wildtype and mutant MT-SP1 |
| WO2007031559A2 (en) | 2005-09-14 | 2007-03-22 | Novo Nordisk Health Care Ag | Human coagulation factor vii polypeptides |
| MX2008004693A (es) | 2005-10-21 | 2008-09-03 | Catalyst Biosciences Inc | Proteasas modificadas que inhiben la activacion del complemento. |
| WO2007149406A2 (en) * | 2006-06-19 | 2007-12-27 | Nautilus Technology Llc | Modified coagulation factor ix polypeptides and use thereof for treatment |
| NZ596269A (en) | 2006-07-05 | 2012-12-21 | Catalyst Biosciences Inc | Protease screening methods and proteases identified thereby |
| EP2481797A1 (en) * | 2007-04-13 | 2012-08-01 | Catalyst Biosciences, Inc. | Modified factor VII polypeptides and uses thereof |
| TWI465247B (zh) | 2008-04-11 | 2014-12-21 | Catalyst Biosciences Inc | 經修飾的因子ｖｉｉ多肽和其用途 |
| RU2563231C2 (ru) | 2009-06-25 | 2015-09-20 | Дзе Юниверсити Оф Норт Каролина Эт Чепел Хилл | Химерные молекулы фактора vii |
| HRP20191305T1 (hr) | 2010-07-09 | 2019-10-18 | Bioverativ Therapeutics Inc. | Preradive jednolančane molekule i polipeptidi izrađeni koristeći iste |
| US8895291B2 (en) | 2010-10-08 | 2014-11-25 | Terumo Bct, Inc. | Methods and systems of growing and harvesting cells in a hollow fiber bioreactor system with control conditions |
| TWI595004B (zh) | 2010-11-03 | 2017-08-11 | 介控生化科技公司 | 經修飾之第九因子多胜肽及其用途 |
| US20140046277A1 (en) * | 2011-04-15 | 2014-02-13 | Gamma Therapeutics, Inc. | Fast-clotting wound dressings |
| WO2012149463A1 (en) * | 2011-04-29 | 2012-11-01 | The University Of North Carolina At Chapel Hill | Chimeric factor vii molecules with enhanced half life and methods of use |
| CA2838833A1 (en) | 2011-06-10 | 2012-12-13 | Biogen Idec Ma Inc. | Pro-coagulant compounds and methods of use thereof |
| EP2554161A1 (en) | 2011-08-02 | 2013-02-06 | LFB Biotechnologies | Pharmaceutical composition comprising factor VII encapsulated in micelles |
| DK3326642T3 (da) * | 2012-02-14 | 2021-02-22 | Opko Biologics Ltd | Langtidsvirkende koagulationsfaktorer og brugen deraf |
| GB201910190D0 (en) | 2012-04-16 | 2019-08-28 | Cantab Biopharmaceuticals Patents Ltd | Optimised subsutaneous therapeutic agents |
| SG11201500579SA (en) | 2012-07-25 | 2015-02-27 | Catalyst Biosciences Inc | Modified factor x polypeptides and uses thereof |
| JP2015532307A (ja) | 2012-10-15 | 2015-11-09 | ノヴォ・ノルディスク・ヘルス・ケア・アーゲー | 凝固因子ｖｉｉポリペプチド |
| JP2015533152A (ja) | 2012-10-15 | 2015-11-19 | ノヴォ・ノルディスク・ヘルス・ケア・アーゲー | 第ｖｉｉ因子コンジュゲート |
| KR102047235B1 (ko) | 2012-12-24 | 2019-11-22 | 바이엘 헬스케어 엘엘씨 | 단작용성 인자 vii 폴리펩티드 |
| TWI828269B (zh) | 2013-03-15 | 2024-01-01 | 美商百歐維拉提夫治療公司 | 因子ix多肽調配物 |
| CN103397009B (zh) * | 2013-08-16 | 2015-06-03 | 安源生物科技(上海)有限公司 | 改良型人凝血因子FVII-Fc融合蛋白及其制备方法与用途 |
| CN105637088A (zh) | 2013-10-15 | 2016-06-01 | 诺和诺德保健股份有限公司 | 凝固因子vii多肽 |
| WO2015070014A1 (en) | 2013-11-08 | 2015-05-14 | Biogen Idec Ma Inc. | Procoagulant fusion compound |
| JP6612227B2 (ja) | 2013-11-16 | 2019-11-27 | テルモ ビーシーティー、インコーポレーテッド | バイオリアクターにおける細胞増殖 |
| AR099328A1 (es) * | 2014-02-12 | 2016-07-13 | Novo Nordisk As | Conjugados de factor vii |
| US11008547B2 (en) | 2014-03-25 | 2021-05-18 | Terumo Bct, Inc. | Passive replacement of media |
| MX378899B (es) | 2014-05-26 | 2025-03-10 | Academisch Ziekenhuis Leiden | Proteinas prohemostaticas para el tratamiento de hemorragias. |
| WO2016049421A1 (en) | 2014-09-26 | 2016-03-31 | Terumo Bct, Inc. | Scheduled feed |
| US11390687B2 (en) | 2015-01-02 | 2022-07-19 | Takeda Pharmaceutical Company Limited | Bispecific antibodies against plasma kallikrein and Factor XII |
| WO2017004592A1 (en) | 2015-07-02 | 2017-01-05 | Terumo Bct, Inc. | Cell growth with mechanical stimuli |
| JP7068160B2 (ja) | 2015-07-21 | 2022-05-16 | 武田薬品工業株式会社 | 第ＸＩＩａ因子のモノクローナル抗体阻害剤 |
| KR102775461B1 (ko) | 2016-04-01 | 2025-02-28 | 어비디티 바이오사이언시스 인크. | 핵산-폴리펩타이드 조성물 및 이의 용도 |
| JP2019515904A (ja) * | 2016-04-14 | 2019-06-13 | アイコニック セラピューティクス，インコーポレイテッド | 新血管新生に関連する障害を治療するための組成物および方法 |
| WO2017205667A1 (en) | 2016-05-25 | 2017-11-30 | Terumo Bct, Inc. | Cell expansion |
| US11104874B2 (en) | 2016-06-07 | 2021-08-31 | Terumo Bct, Inc. | Coating a bioreactor |
| US11685883B2 (en) | 2016-06-07 | 2023-06-27 | Terumo Bct, Inc. | Methods and systems for coating a cell growth surface |
| US20200317749A1 (en) * | 2016-07-01 | 2020-10-08 | Denali Therapeutics Inc. | Albumin variants for enhanced serum half-life |
| US20210284715A1 (en) * | 2017-02-06 | 2021-09-16 | Applied Stemcell, Inc. | Coagulation factor viii mimetic protein and uses thereof |
| WO2018184028A2 (en) | 2017-03-31 | 2018-10-04 | Terumo Bct, Inc. | Cell expansion |
| US12234441B2 (en) | 2017-03-31 | 2025-02-25 | Terumo Bct, Inc. | Cell expansion |
| US11624046B2 (en) | 2017-03-31 | 2023-04-11 | Terumo Bct, Inc. | Cell expansion |
| PE20201462A1 (es) * | 2017-09-05 | 2020-12-17 | Gladiator Biosciences Inc | Metodo de direccionamiento de exosomas |
| CN111372612A (zh) | 2017-09-27 | 2020-07-03 | 西吉隆医疗股份有限公司 | 包含活性细胞的方法、组合物和可植入元件 |
| US11110180B2 (en) | 2017-10-04 | 2021-09-07 | Avidity Biosciences Inc. | Nucleic acid-polypeptide compositions and uses thereof |
| WO2019136180A2 (en) * | 2018-01-04 | 2019-07-11 | Avidity Biosciences Llc | Heteroduplex nucleic acid molecules and uses thereof |
| US20210145889A1 (en) | 2018-04-04 | 2021-05-20 | Sigilon Therapeutics, Inc. | Methods, compositions, and implantable elements comprising stem cells |
| WO2019195055A1 (en) | 2018-04-04 | 2019-10-10 | Sigilon Therapeutics, Inc. | Implantable particles and related methods |
| US20220128545A1 (en) * | 2018-07-06 | 2022-04-28 | Children's Medical Center Corporation | Methods and compositions for analyzing platelets by mass cytometry |
| UY38389A (es) | 2018-09-27 | 2020-04-30 | Sigilon Therapeutics Inc | Dispositivos implantables para terapia celular y métodos relacionados |
| CA3142283A1 (en) | 2019-06-06 | 2020-12-10 | Avidity Biosciences, Inc. | Nucleic acid-polypeptide compositions and uses thereof |
| US12006499B2 (en) | 2019-06-06 | 2024-06-11 | Avidity Biosciences, Inc. | Una amidites and uses thereof |
| WO2021030787A1 (en) | 2019-08-15 | 2021-02-18 | Catalyst Biosciences, Inc. | Modified factor vii polypeptides for subcutaneous administration and on-demand treatment |
| US20230083751A1 (en) * | 2019-12-30 | 2023-03-16 | Nanjing GenScript Biotech Co., Ltd. | Method For Constructing Gene Mutation Library |
| JP7759719B2 (ja) * | 2020-02-27 | 2025-10-24 | オムロン株式会社 | 流量測定装置 |
| GB2619893A (en) | 2021-03-23 | 2023-12-20 | Terumo Bct Inc | Cell capture and expansion |
| US12209689B2 (en) | 2022-02-28 | 2025-01-28 | Terumo Kabushiki Kaisha | Multiple-tube pinch valve assembly |
| USD1099116S1 (en) | 2022-09-01 | 2025-10-21 | Terumo Bct, Inc. | Display screen or portion thereof with a graphical user interface for displaying cell culture process steps and measurements of an associated bioreactor device |
| US20260102435A1 (en) | 2022-10-11 | 2026-04-16 | Sigilon Therapeutics, Inc. | Engineered cells and implantable elements for treatment of disease |
| CN120035657A (zh) | 2022-10-11 | 2025-05-23 | 西吉隆医疗股份有限公司 | 用于治疗疾病的经工程化的细胞和可植入元件 |
| US12385818B2 (en) | 2023-02-14 | 2025-08-12 | Saudi Arabian Oil Company | Modeling gas desorption in a subsurface reservoir |
| CN118126161B (zh) * | 2024-03-26 | 2025-10-24 | 福州大学 | 一种凝血因子FXIa的多肽抑制剂及其在抗凝治疗方面的应用 |
| CN119372186B (zh) * | 2024-12-30 | 2025-04-15 | 深圳市卫光生物制品股份有限公司 | 一种重组人凝血因子vii的纯化方法和应用 |
Family Cites Families (133)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4522811A (en) | 1982-07-08 | 1985-06-11 | Syntex (U.S.A.) Inc. | Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides |
| US4952496A (en) | 1984-03-30 | 1990-08-28 | Associated Universities, Inc. | Cloning and expression of the gene for bacteriophage T7 RNA polymerase |
| GR860984B (en) | 1985-04-17 | 1986-08-18 | Zymogenetics Inc | Expression of factor vii and ix activities in mammalian cells |
| DK323587D0 (da) | 1987-06-25 | 1987-06-25 | Novo Industri As | Protein |
| US5283187A (en) | 1987-11-17 | 1994-02-01 | Brown University Research Foundation | Cell culture-containing tubular capsule produced by co-extrusion |
| US4892538A (en) | 1987-11-17 | 1990-01-09 | Brown University Research Foundation | In vivo delivery of neurotransmitters by implanted, encapsulated cells |
| US5052558A (en) | 1987-12-23 | 1991-10-01 | Entravision, Inc. | Packaged pharmaceutical product |
| US5033252A (en) | 1987-12-23 | 1991-07-23 | Entravision, Inc. | Method of packaging and sterilizing a pharmaceutical product |
| US5033352A (en) | 1989-01-19 | 1991-07-23 | Yamaha Corporation | Electronic musical instrument with frequency modulation |
| US5304482A (en) | 1989-03-06 | 1994-04-19 | The Board Of Regents Of The University Of Texas System | Serine protease mutants of the chymotrypsin superfamily resistant to inhibition by their cognate inhibitors |
| US5580560A (en) | 1989-11-13 | 1996-12-03 | Novo Nordisk A/S | Modified factor VII/VIIa |
| JP3330932B2 (ja) | 1990-01-29 | 2002-10-07 | ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト | 抗凝固剤タンパク質 |
| US5583107A (en) | 1990-09-04 | 1996-12-10 | Cor Therapeutics, Inc. | Agents affecting thrombosis and hemostasis |
| WO1998035689A1 (en) | 1997-02-14 | 1998-08-20 | American Red Cross | Expression of active human factor ix in mammary tissue of transgenic animals |
| US20040087498A1 (en) | 1991-02-28 | 2004-05-06 | Novo Nordisk Health Care Ag | Modified factor VII |
| US5997864A (en) * | 1995-06-07 | 1999-12-07 | Novo Nordisk A/S | Modified factor VII |
| US5817788A (en) | 1991-02-28 | 1998-10-06 | Zymogenetics, Inc. | Modified factor VII |
| US5788965A (en) | 1991-02-28 | 1998-08-04 | Novo Nordisk A/S | Modified factor VII |
| US5861374A (en) | 1991-02-28 | 1999-01-19 | Novo Nordisk A/S | Modified Factor VII |
| US5323907A (en) | 1992-06-23 | 1994-06-28 | Multi-Comp, Inc. | Child resistant package assembly for dispensing pharmaceutical medications |
| US20050032690A1 (en) | 1997-09-10 | 2005-02-10 | Rojkjaer Lisa Payne | Factor VII polypeptides for preventing formation of inhibitors in subjects with haemophilia |
| US6017882A (en) | 1997-10-23 | 2000-01-25 | Regents Of The University Of Minnesota | Modified vitamin K-dependent polypeptides |
| US7247708B2 (en) | 1997-10-23 | 2007-07-24 | Regents Of The University Of Minnesota | Modified vitamin K-dependent polypeptides |
| US6693075B1 (en) | 1997-10-23 | 2004-02-17 | Regents Of The University Of Minnesota | Modified vitamin K-dependent polypeptides |
| DE19937219A1 (de) | 1999-08-06 | 2001-02-08 | Aventis Behring Gmbh | Verfahren zur Reindarstellung der den Blutgerinnungsfaktor VII aktivierenden Protease, ihres Proenzyms oder eines Gemisches beider Proteine mittels Ionenaustauscherchromatographie |
| WO2001032711A2 (en) | 1999-10-21 | 2001-05-10 | Board Of Trustees Of The University Of Arkansas | Adeno-associated virus aav rep78 major regulatory protein, mutants thereof and uses thereof |
| US20050287153A1 (en) | 2002-06-28 | 2005-12-29 | Genentech, Inc. | Serum albumin binding peptides for tumor targeting |
| US7700341B2 (en) | 2000-02-03 | 2010-04-20 | Dendreon Corporation | Nucleic acid molecules encoding transmembrane serine proteases, the encoded proteins and methods based thereon |
| US6797504B1 (en) | 2000-09-08 | 2004-09-28 | Dendreon San Diego Llc | Inhibitors of serine protease activity of matriptase or MTSP1 |
| EP1982732A3 (en) | 2000-02-11 | 2011-06-08 | Bayer HealthCare LLC | Factor VII or VIIA-like conjugates |
| US7220837B1 (en) | 2000-04-28 | 2007-05-22 | Regents Of The University Of Minnesota | Modified vitamin K-dependent polypeptides |
| EP1280548B1 (en) | 2000-05-03 | 2013-12-11 | Novo Nordisk Health Care AG | Subcutaneous administration of coagulation factor VII |
| US6905683B2 (en) | 2000-05-03 | 2005-06-14 | Novo Nordisk Healthcare A/G | Human coagulation factor VII variants |
| AU2001254624A1 (en) | 2000-05-03 | 2001-11-12 | Novo-Nordisk A/S | Human coagulation factor vii variants |
| EP1282438B1 (en) | 2000-05-10 | 2005-08-03 | Novo Nordisk Health Care AG | Use of pharmaceutical composition comprising a factor viia and a factor xiii |
| US20030211094A1 (en) | 2001-06-26 | 2003-11-13 | Nelsestuen Gary L. | High molecular weight derivatives of vitamin k-dependent polypeptides |
| HUP0301246A3 (en) | 2000-09-13 | 2005-12-28 | Novo Nordisk Healthcare Ag | Human coagulation factor vii variants |
| RU2326126C2 (ru) * | 2000-09-13 | 2008-06-10 | Ново Нордиск Хелт Кэр Аг | Полипептид фактора vii свертывания крови, его получение и применение |
| EP1325127B1 (en) | 2000-10-02 | 2009-03-11 | Novo Nordisk Health Care AG | Method for the production of vitamin k-dependent proteins |
| AU2002218029A1 (en) | 2000-11-09 | 2002-05-21 | The Scripps Research Institute | Modified factor viia |
| EP1359935A1 (en) | 2001-02-05 | 2003-11-12 | Novo Nordisk Health Care AG | Combined use of factor vii polypeptides and factor ix polypeptides |
| EP1377306A1 (en) | 2001-03-09 | 2004-01-07 | Dyax Corp. | Serum albumin binding moieties |
| US20040133930A1 (en) | 2002-03-11 | 2004-07-08 | Cooper Julian D. | Production of high levels of transgenic factor ix without gene rescue, and its therapeutic uses |
| AU2002305052A1 (en) | 2001-03-13 | 2002-09-24 | Corvas International, Inc. | Nucleic acid molecules encoding a transmembrane serine protease 7, the encoded polypeptides and methods based thereon |
| US7235638B2 (en) | 2001-03-22 | 2007-06-26 | Novo Nordisk Healthcare A/G | Coagulation factor VII derivatives |
| EP1383884A4 (en) | 2001-03-22 | 2004-12-15 | Dendreon Corp | SERINE PROTEASE CVSP14 CODING NUCLEIC ACID MOLECULES, THE CODED POLYPEPTIDES AND METHODS THEREOF |
| IL157842A0 (en) | 2001-03-22 | 2004-03-28 | Novo Nordisk Healthcare Ag | Coagulation factor vii derivatives |
| NZ527971A (en) | 2001-03-27 | 2006-03-31 | Dendreon Corp | Nucleic acid molecules encoding a transmembrane serine protease 9, the encoded polypeptides and methods based thereon |
| WO2002092841A2 (en) | 2001-05-14 | 2002-11-21 | Dendreon San Diego Llc | Nucleic acid molecules encoding a transmembrane serine protease 10, the encoded polypeptides and methods based thereon |
| WO2002095007A2 (en) | 2001-05-23 | 2002-11-28 | Dendreon San Diego Llc | Conjugates activated by cell surface proteases and therapeutic uses thereof |
| WO2003004681A2 (en) | 2001-07-03 | 2003-01-16 | Dendreon San Diego Llc | Nucleic acid molecules encoding a transmembrane serine protease 20, the encoded polypeptides and methods based thereon |
| US7419949B2 (en) | 2001-07-16 | 2008-09-02 | Novo Noridsk Healthcare A/G | Single-dose administration of factor VIIa |
| US7052868B2 (en) | 2001-09-27 | 2006-05-30 | Novo Nordisk Healthcare A/G | Human coagulation factor VII polypeptides |
| ATE532858T1 (de) | 2001-09-27 | 2011-11-15 | Novo Nordisk Healthcare Ag | Menschliche gerinnungsfaktor-vii-polypeptide |
| HUP0402158A2 (hu) | 2001-10-02 | 2005-01-28 | Novo Nordisk Health Care Ag | Rekombináns fehérjék előállítási eljárása eukarióta sejtekben |
| WO2003031585A2 (en) | 2001-10-09 | 2003-04-17 | Dendreon Corporation | Transmembrane serine protease 25 |
| JP3862996B2 (ja) | 2001-10-31 | 2006-12-27 | 帝人ファイバー株式会社 | ポリトリメチレンテレフタレートフィラメント糸およびその製造方法 |
| US6960657B2 (en) | 2001-11-02 | 2005-11-01 | Novo Nordisk Healthcare A/G | Human coagulation factor VII polypeptides |
| ES2490590T3 (es) | 2001-11-02 | 2014-09-04 | Novo Nordisk Health Care Ag | Polipéptidos de factor VII de coagulación humana |
| US7291587B2 (en) | 2001-11-09 | 2007-11-06 | Novo Nordisk Healthcare A/G | Pharmaceutical composition comprising factor VII polypeptides and TAFI polypeptides |
| AU2002357004A1 (en) | 2001-11-20 | 2003-06-10 | Dendreon San Diego Llc | Nucleic acid molecules encoding serine protease 17, the encoded polypeptides and methods based thereon |
| EP1458407A1 (en) | 2001-12-21 | 2004-09-22 | Novo Nordisk A/S | Liquid composition of modified factor vii polypeptides |
| RU2357751C2 (ru) | 2001-12-21 | 2009-06-10 | Ново Нордиск Хелт Кэр Аг | Жидкая композиция полипептидов фактора vii |
| US7700733B2 (en) | 2002-04-30 | 2010-04-20 | Bayer Healthcare Llc | Factor VII or VIIa polypeptide variants |
| EP1361284A1 (en) | 2002-05-10 | 2003-11-12 | Direvo Biotech AG | Process for generating sequence-specific proteases by directed evolution and use thereof |
| AU2003269880A1 (en) | 2002-05-21 | 2003-12-22 | Dendreon Corporation | Nucleic acid molecules encoding a transmembrane serine protease 12, the encoded polypeptides and methods based thereon |
| US20040001801A1 (en) | 2002-05-23 | 2004-01-01 | Corvas International, Inc. | Conjugates activated by cell surface proteases and therapeutic uses thereof |
| WO2003106493A1 (en) | 2002-06-14 | 2003-12-24 | Dyax Corporation | Protein analysis |
| BR0311978A (pt) | 2002-06-21 | 2005-03-22 | Novo Nordisk Healthcare Ag | Preparação, método para preparar a mesma, formulação farmacêutica, métodos para tratar de uma sìndrome responsiva ao fator vii, para prevenir hemorragias indesejáveis, para prevenir coagulação sanguìnea indesejável e para prevenir as reações mediadas pelo fator tecidual, e, uso de uma preparação |
| MXPA04012496A (es) | 2002-06-21 | 2005-09-12 | Novo Nordisk Healthcare Ag | Glicoformos del factor vii pegilados. |
| WO2004005471A2 (en) | 2002-07-02 | 2004-01-15 | Dendreon Corporation | Serine protease 16 |
| US6911323B2 (en) | 2002-09-25 | 2005-06-28 | Novo Nordisk Healthcare A/G | Human coagulation factor VII polypeptides |
| WO2004029090A1 (en) | 2002-09-25 | 2004-04-08 | Novo Nordisk Health Care Ag | Human coagulation factor vii polypeptides |
| EP1549677B1 (en) | 2002-09-30 | 2011-04-13 | Bayer HealthCare LLC | FVII OR FVIIa VARIANTS HAVING INCREASED CLOTTING ACTIVITY |
| MXPA05003493A (es) | 2002-10-02 | 2005-09-30 | Catalyst Biosciences | Metodos para generar y seleccionar proteasas con especificidad alterada. |
| US20060024289A1 (en) | 2002-10-02 | 2006-02-02 | Ruggles Sandra W | Cleavage of VEGF and VEGF receptor by wild-type and mutant proteases |
| US7939304B2 (en) | 2002-10-02 | 2011-05-10 | Catalyst Biosciences, Inc. | Mutant MT-SP1 proteases with altered substrate specificity or activity |
| AU2004221758B2 (en) | 2003-03-18 | 2010-07-22 | Novo Nordisk Health Care Ag | Method for the production of GLA-residue containing serine proteases |
| DK2085470T3 (da) * | 2003-03-20 | 2012-08-06 | Bayer Healthcare Llc | FVII- eller FVIIa-varianter |
| WO2007022512A2 (en) * | 2005-08-19 | 2007-02-22 | Neose Technologies, Inc. | Glycopegylated factor vii and factor viia |
| CA2528239A1 (en) | 2003-06-05 | 2004-12-16 | Canadian Blood Services | Mutants of the factor vii epidermal growth factor domain |
| WO2004110469A2 (en) | 2003-06-13 | 2004-12-23 | Novo Nordisk Health Care Ag | Formulations comprising factor viia and a factor vii related polypeptide |
| US20060116324A1 (en) | 2003-06-13 | 2006-06-01 | Novo Nordisk Healthcare A/G | Novel formulations |
| EP1633865B1 (en) | 2003-06-18 | 2011-09-28 | Bayer Pharma Aktiengesellschaft | New biological entities and the use thereof |
| US20050002897A1 (en) | 2003-06-18 | 2005-01-06 | Ulrich Haupts | Biological entities and the pharmaceutical or diagnostic use thereof |
| DK1644504T3 (da) | 2003-06-19 | 2010-05-25 | Bayer Healthcare Llc | Faktor VII- eller -VIIA-Gla-domænevarianter |
| WO2005023308A1 (en) | 2003-09-05 | 2005-03-17 | Maxygen Holdings Ltd. | Formulations of vitamin k-dependent polypeptides and sulfoalkyl ether cycloextrins |
| EP1664291B1 (en) | 2003-09-09 | 2012-02-29 | Novo Nordisk Health Care AG | Coagulation factor vii polypeptides |
| EP2392655A3 (en) | 2003-09-09 | 2012-02-29 | Novo Nordisk Health Care AG | Coagulation factor VII polypeptides |
| WO2005032581A2 (en) | 2003-10-07 | 2005-04-14 | Novo Nordisk Health Care Ag | Hybrid molecules having factor vii/viia activity |
| JP2007511604A (ja) | 2003-11-18 | 2007-05-10 | アイコニック セラピューティクス インコーポレイティッド | キメラタンパク質の均質製剤 |
| WO2005068620A1 (en) | 2004-01-07 | 2005-07-28 | Novo Nordisk Health Care Ag | Method for the production of recombinant proteins |
| JP2007522805A (ja) | 2004-02-03 | 2007-08-16 | ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト | 新規化合物 |
| AU2005244271B2 (en) | 2004-04-12 | 2010-04-08 | Vertex Pharmaceuticals Incorporated | Cleavage of VEGF and VEGF receptor by wildtype and mutant MT-SP1 |
| WO2005100556A2 (en) | 2004-04-12 | 2005-10-27 | Catalyst Biosciences | Cleavage of vegf and vegf receptor by wild-type and mutant proteases |
| KR20070008645A (ko) | 2004-05-04 | 2007-01-17 | 노보 노르디스크 헬스 케어 악티엔게젤샤프트 | 폴리펩티드의 ｏ-연결된 단백당형 및 그들의 제조 방법 |
| WO2005123119A2 (en) | 2004-06-10 | 2005-12-29 | Catalyst Biosciences, Inc. | Administration of neutral endopeptidase to treat inflammatory bowel disease |
| US20080058255A1 (en) | 2004-06-21 | 2008-03-06 | Novo Nordisk Healthcare A/G | Glycosylation-Disrupted Factor VII Variants |
| CA2570330A1 (en) | 2004-06-21 | 2005-12-29 | Novo Nordisk Health Care A/S | Use of factor viia or factor viia equivalents for preventing or attenuating haemorrhage growth, and/or oedema generation following intracerebral haemorrhage (ich) |
| WO2006014253A2 (en) | 2004-07-02 | 2006-02-09 | Genentech, Inc. | Factor viia variants |
| US20090004175A1 (en) | 2004-07-16 | 2009-01-01 | Novo Nordick Health Care A/G | Methods for Optimizing Forming Vlla-Based Hemostatic Treatment |
| JP2008507990A (ja) | 2004-08-02 | 2008-03-21 | ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト | Ｆｖｉｉの抱合体 |
| BRPI0514396A2 (pt) | 2004-08-17 | 2009-05-12 | Csl Behring Gmbh | polipeptìdeos dependentes de vitamina k modificada |
| EP1797192A1 (en) | 2004-09-29 | 2007-06-20 | Novo Nordisk Health Care AG | Modified proteins |
| EP1827486A2 (en) | 2004-12-22 | 2007-09-05 | Direvo Biotech AG | Targeted use of engineered enzymes |
| JP2008525381A (ja) | 2004-12-23 | 2008-07-17 | ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト | 関心のあるビタミンｋ依存性タンパク質を含んでなる組成物中におけるタンパク質混入物の量の減少 |
| US20080188400A1 (en) | 2005-04-26 | 2008-08-07 | Maxygen Holdings Ltd. | Methods For Treating Bleeding |
| RU2440810C2 (ru) | 2005-04-28 | 2012-01-27 | Ново Нордиск Хелс Кеа Аг | Закрытый контейнер, содержащий активированный полипептид фактора vii, способы его получения и набор и способ применения набора |
| EP1726643A1 (en) | 2005-05-27 | 2006-11-29 | Direvo Biotech AG | Method for the provision, identification and selection of proteases with altered sensitivity to activity-modulating substances |
| WO2006134173A2 (en) | 2005-06-17 | 2006-12-21 | Novo Nordisk Health Care Ag | Selective reduction and derivatization of engineered proteins comprising at least one non-native cysteine |
| WO2006134174A2 (en) | 2005-06-17 | 2006-12-21 | Novo Nordisk Health Care Ag | Dimeric and multimeric fviia compound |
| US20090017007A1 (en) | 2005-08-26 | 2009-01-15 | Maxygen Holdings Ltd. | Liquid factor vii composition |
| WO2007026020A1 (en) | 2005-09-01 | 2007-03-08 | Novo Nordisk Health Care Ag | Purification of coagulation factor vii polypeptides |
| WO2007031559A2 (en) * | 2005-09-14 | 2007-03-22 | Novo Nordisk Health Care Ag | Human coagulation factor vii polypeptides |
| WO2007039475A1 (en) | 2005-09-21 | 2007-04-12 | Novo Nordisk Health Care Ag | Human coagulation factor vii polypeptides |
| US20090221484A1 (en) | 2005-10-07 | 2009-09-03 | Novo Nordisk A/S | Use of Factor VII Polypeptides for Neuroprotection |
| MX2008004693A (es) | 2005-10-21 | 2008-09-03 | Catalyst Biosciences Inc | Proteasas modificadas que inhiben la activacion del complemento. |
| WO2007149406A2 (en) | 2006-06-19 | 2007-12-27 | Nautilus Technology Llc | Modified coagulation factor ix polypeptides and use thereof for treatment |
| NZ596269A (en) | 2006-07-05 | 2012-12-21 | Catalyst Biosciences Inc | Protease screening methods and proteases identified thereby |
| WO2008009635A2 (en) | 2006-07-17 | 2008-01-24 | Novo Nordisk Health Care Ag | Factor viia analogues with increased activity for treating thrombocytopenia |
| EP2114379A2 (en) | 2006-12-20 | 2009-11-11 | Bayer HealthCare LLC | Factor vii and viia compositions |
| EP1952822A1 (en) * | 2007-01-26 | 2008-08-06 | Novo Nordisk A/S | Factor VII polypeptides with increased affinity to platelets |
| EP2481797A1 (en) | 2007-04-13 | 2012-08-01 | Catalyst Biosciences, Inc. | Modified factor VII polypeptides and uses thereof |
| US9102962B2 (en) | 2007-10-16 | 2015-08-11 | Shiu Nan Chen | Production method for solid cultured active mushroom mycelium and fruit-body metabolites (AMFM) products thereof |
| GB0800938D0 (en) * | 2008-01-18 | 2008-02-27 | Ge Healthcare Uk Ltd | Multiplex cell signalling assay |
| TWI465247B (zh) | 2008-04-11 | 2014-12-21 | Catalyst Biosciences Inc | 經修飾的因子ｖｉｉ多肽和其用途 |
| US8266208B2 (en) | 2008-11-06 | 2012-09-11 | Joseph Mahon | Method and system for sharing documents among members of an online community |
| RU2563231C2 (ru) | 2009-06-25 | 2015-09-20 | Дзе Юниверсити Оф Норт Каролина Эт Чепел Хилл | Химерные молекулы фактора vii |
| CN201753815U (zh) | 2010-07-27 | 2011-03-02 | 江森自控空调冷冻设备(无锡)有限公司 | 三通结构 |
| TWI595004B (zh) | 2010-11-03 | 2017-08-11 | 介控生化科技公司 | 經修飾之第九因子多胜肽及其用途 |
| SG11201500579SA (en) | 2012-07-25 | 2015-02-27 | Catalyst Biosciences Inc | Modified factor x polypeptides and uses thereof |
| JP2015532307A (ja) | 2012-10-15 | 2015-11-09 | ノヴォ・ノルディスク・ヘルス・ケア・アーゲー | 凝固因子ｖｉｉポリペプチド |
| WO2021030787A1 (en) | 2019-08-15 | 2021-02-18 | Catalyst Biosciences, Inc. | Modified factor vii polypeptides for subcutaneous administration and on-demand treatment |
-
2009
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- 2009-04-10 SI SI200931368T patent/SI2281037T1/sl unknown
- 2009-04-10 EP EP13162174.0A patent/EP2679678B1/en active Active
- 2009-04-10 JP JP2011504007A patent/JP2011517942A/ja active Pending
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2010
- 2010-10-03 IL IL208373A patent/IL208373A/en active IP Right Grant
- 2010-10-13 CO CO10127271A patent/CO6331368A2/es not_active Application Discontinuation
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2013
- 2013-04-14 IL IL225740A patent/IL225740A/en active IP Right Grant
- 2013-07-30 US US13/987,492 patent/US9476037B2/en active Active
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2014
- 2014-01-09 JP JP2014002379A patent/JP5976021B2/ja not_active Expired - Fee Related
- 2014-07-31 JP JP2014155757A patent/JP5659312B1/ja not_active Expired - Fee Related
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2016
- 2016-09-07 US US15/258,908 patent/US10160961B2/en active Active
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2018
- 2018-11-02 US US16/179,642 patent/US11203749B2/en active Active
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