DK2438087T3 - Trivalente nanobodykonstruktioner mod human respiratorisk syncytialvirus (hrsv) til forebyggelse og/eller behandling af luftvejsinfektioner - Google Patents
Trivalente nanobodykonstruktioner mod human respiratorisk syncytialvirus (hrsv) til forebyggelse og/eller behandling af luftvejsinfektioner Download PDFInfo
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Claims (14)
1. Trivalent polypeptid, der er rettet mod protein F fra hRSV, som er valgt blandt en hvilken som helst af (A) til (C): (A) trivalent polypeptid valgt blandt følgende polypeptider: a) SEQ ID NO: 142-145 og 162-165; b) polypeptider, der har en forskel i højst 3, fortrinsvis højst 2, mere fortrinsvis højst 1 aminosyre(r) i forhold til en af SEQ ID NO: 142-145 og 162-165, forudsat at: i) den første aminosyresekvens, der er indeholdt i polypeptidet, har en asparaginsyre (Asp, D) i position 1; og ii) polypeptidet binder protein F fra hRSV med den samme eller en højere affinitet, hvor affiniteten er målt ved hjælp af overfladeplasmonresonans, og/eller polypeptidet har den samme eller en højere potens, hvor potensen er bestemt ved hjælp af et mikroneutraliseringsassay, sammenlignet med polypeptidet uden forskellen i 3, 2 eller 1 aminosyre(r), c) SEQ ID NO: 77-79 og 158; d) polypeptider, der har en forskel i højst 3, fortrinsvis højst 2, mere fortrinsvis højst 1 aminosyre(r) i forhold til en af SEQ ID NO: 77-79 og 158, forudsat at: i) aminosyresekvenserne, der er indeholdt i polypeptidet, har en glutamin (Gin, Q) i position 105, en leucin (Leu, L) i position 78, en arginin (Arg, R) i position 83 og/eller en glutaminsyre (Glu, E) i position 85, hvor positionerne er bestemt i henhold til Kabat-nummerering; og ii) polypeptidet binder protein F fra hRSV med den samme eller en højere affinitet, hvor affiniteten er målt ved hjælp af overfladeplasmonresonans, og/eller polypeptidet har den samme eller en højere potens, hvor potensen er bestemt ved hjælp af et mikroneutraliseringsassay, sammenlignet med polypeptidet uden forskellen i 3, 2 eller 1 aminosyre(r), e) SEQ ID NO: 159-161; f) polypeptider, der har en forskel i højst 3, fortrinsvis højst 2, mere fortrinsvis højst 1 aminosyre(r) i forhold til en af SEQ ID NO: 159-161, forudsat at: i) aminosyresekvensen, der er indeholdt i polypeptidet har en prolin (Pro, P) i position 14, arginin (Arg, R) i position 19, leucin (Leu, L) i position 20 og leucin (Leu, L) i position 108, hvor positionerne er bestemt i henhold til Kabat-nummerering; og ii) polypeptidet binder protein F fra hRSV med den samme eller en højere affinitet, hvor affiniteten er målt ved hjælp af overfladeplasmonresonans, og/eller polypeptidet har den samme eller en højere potens, hvor potensen er bestemt ved hjælp af et mikroneutraliseringsassay, sammenlignet med polypeptidet uden forskellen i 3, 2 eller 1 aminosyre(r); (B) trivalent polypeptid, der omfatter eller består af tre aminosyresekvenser, der består af 4 rammeregioner og 3 komplementaritetsbestemmende regioner (CDR'er), hvor: - CDR1 er SEQ ID NO: 98; og - CDR2 er SEQ ID NO: 102; og - CDR3 er SEQ ID NO: 121, (C) trivalent polypeptid, der omfatter eller består af tre aminosyresekvenser, hvor hver aminosyresekvens er valgt blandt følgende a) til d): a) SEQ ID NO: 60-76; b) aminosyresekvenser, der har en forskel i højst 3, fortrinsvis højst 2, mere fortrinsvis højst 1 aminosyre(r) i forhold til en af SEQ ID NO: 60-76, forudsat at: i) aminosyresekvensen har en glutamin (Gin, Q) i position 105, hvor positionen er bestemt i henhold til Rabat-nummerering; og ii) aminosyresekvensen binder protein F fra hRSV med den samme eller en højere affinitet, hvor affiniteten er målt ved hjælp af overfladeplasmonresonans, og/eller aminosyresekvensen har den samme eller en højere potens, hvor potensen er bestemt ved hjælp af et mikroneutraliseringsassay, sammenlignet med aminosyresekvensen uden forskellen i 3, 2 eller 1 aminosyre(r), c) SEQ ID NO: 146-153; d) aminosyresekvenser, der har en forskel i højst 3, fortrinsvis højst 2, mere fortrinsvis højst 1 aminosyre (r) i forhold til en af SEQ ID NO: 146-153, forudsat at: i) aminosyresekvensen har en prolin (Pro, P) i position 14, arginin (Arg, R) i position 19, leucin (Leu, L) i position 20 og leucin (Leu, L) i position 108, hvor positionerne er bestemt i henhold til Kabat-nummerering; og ii) aminosyresekvensen binder protein F fra hRSV med den samme eller en højere affinitet, hvor affiniteten er målt ved hjælp af overfladeplasmonresonans, og/eller aminosyresekvensen har den samme eller en højere potens, hvor potensen er bestemt ved hjælp af et mikroneutraliseringsassay, sammenlignet med aminosyresekvensen uden forskellen i 3, 2 eller 1 aminosyre(r).
2. Trivalent polypeptid ifølge krav 1, der omfatter eller består af SEQ ID NO: 53, hvor den første glutaminsyre er blevet ændret til asparaginsyre, og hvor eventuelt i mindst én VHH-sekvens, der udgør en del af SEQ ID NO: 53, en eller flere aminosyrerester er blevet muteret med en mutation valgt blandt følgende: Val5Leu, Alal4Pro, Serl9R, Ile20Leu, Glu44Gly, Ala74Ser, Gly78Leu, Ala83Arg, Asp85Glu, Argl05Gln, Glnl08Leu og Gly54Asp; eller - hvor i mindst én VHH-sekvens, der udgør en del af SEQ ID NO: 53, en eller flere aminosyrerester er blevet muteret med en mutation valgt blandt følgende: Val5Leu, Alal4Pro, Serl9R, Ile20Leu, Glu44Gly, Ala74Ser, Gly78Leu, Ala83Arg, Asp85Glu, Argl05Gln, Glnl08Leu og Gly54Asp.
3. Trivalent polypeptid ifølge et hvilket som helst af kravene 1 til 2, der omfatter eller består af SEQ ID NO: 53, hvor i mindst én VHH-sekvens, der udgør en del af SEQ ID NO: 53, følgende aminosyrerester er blevet muteret: - Val5Leu, Alal4Pro, Glu44Gly, Gly78Leu, Ala83Arg, Asp85Glu, Argl05Gln og Glnl08Leu; - Ala83Arg, Asp85Glu, Argl05Gln og Glnl08Leu; - Gly78Leu, Ala83Arg, Asp85Glu og Argl05Gln; - Val5Leu, Alal4Pro, Glu44Gly, Gly78Leu, Ala83Arg, Asp85Glu, Argl05Gln, Glnl08Leu og Gly54Asp; - Ala83Arg, Asp85Glu, Argl05Gln, Glnl08Leu og Gly54Asp; - Gly78Leu, Ala83Arg, Asp85Glu, Argl05Gln og Gly54Asp; - Gly54Asp; - Alal4Pro, Serl9Arg, Ile20Leu og Glnl08Leu; - Alal4Pro, Serl9Arg, lle20Leu, Glnl08Leu og Ala83Arg; - Alal4Pro, Serl9Arg, Ile20Leu, Glnl08Leu og Asp85Glu; - Alal4Pro, Serl9Arg, Ile20Leu, Glnl08Leu og Argl05Gln; Alal4Pro, Serl9Arg, Ile20Leu, Glnl08Leu, Ala83Arg og Asp85Glu; Alal4Pro, Serl9Arg, Ile20Leu, Glnl081eu, Ala83Arg og Argl05Gln; Alal4Pro, Serl9Arg, Ile20Leu, Glnl08Leu, Asp85Glu og Argl05Gln; - Alal4Pro, Serl9Arg, Ile20Leu, Glnl08Leu, Ala83Arg, Asp85Glu og Argl05Gln. - GlulAsp; - GlulAsp, Val5Leu, Alal4Pro, Glu44Gly, Gly78Leu, Ala83Arg, Asp85Glu, Argl05Gln og Glnl08Leu; - GlulAsp, Ala83Arg, Asp85Glu, Argl05Gln og Glnl08Leu; - GlulAsp, Gly78Leu, Ala83Arg, Asp85Glu og Argl05Gln; - GlulAsp, Val5Leu, Alal4Pro, Glu44Gly, Gly78Leu, Ala83Arg, Asp85Glu, Argl05Gln, Glnl08Leu og Gly54Asp; GlulAsp, Ala83Arg, Asp85Glu, Argl05Gln, Glnl08Leu og Gly54Asp; GlulAsp, Gly78Leu, Ala83Arg, Asp85Glu, Argl05Gln og Gly54Asp; - GlulAsp og Gly54Asp; - GlulAsp, Alal4Pro, Serl9Arg, Ile20Leu og Glnl08Leu; GlulAsp, Alal4Pro, Serl9Arg, Ile20Leu, Glnl08Leu og Ala83Arg; GlulAsp, Alal4Pro, Serl9Arg, Ile20Leu, Glnl08Leu og Asp85Glu; GlulAsp, Alal4Pro, Serl9Arg, Ile201eu, Glnl08Leu og Argl05Gln; - GlulAsp, Alal4Pro, Serl9Arg, Ile20Leu, Glnl08Leu, Ala83Arg og Asp85Glu; - GlulAsp, Alal4Pro, Serl9Arg, Ile20Leu, Glnl08Leu, Ala83Arg og Argl05Gln; - GlulAsp, Alal4Pro, Serl9Arg, Ile20Leu, Glnl08Leu, Asp85Glu og Argl05Gln; eller - GlulAsp, Alal4Pro, Serl9Arg, Ile20Leu, Glnl08Leu, Ala83Arg, Asp85Glu og Argl05Gln.
4. Trivalent polypeptid ifølge et hvilket som helst af kravene 1 til 3, der omfatter eller består af én af SEQ ID NO: 77-79, 142-145 og 158-165.
5. Fremgangsmåde til fremstilling af et trivalent polypeptid ifølge et hvilket som helst af kravene 1 til 4, hvilken fremgangsmåde mindst omfatter trinene kobling af tre monovalente aminosyresekvenser eller monovalente konstruktioner valgt blandt: a) SEQ ID NO: 60-76; b) aminosyresekvenser, der har en forskel i højst 3, fortrinsvis højst 2, mere fortrinsvis højst 1 aminosyre (r) i forhold til en af SEQ ID NO: 60-76, forudsat at: i) aminosyresekvensen har en glutamin (Gin, Q) i position 105, hvor positionen er bestemt i henhold til Kabat-nummerering; og ii) aminosyresekvensen binder protein F fra hRSV med den samme eller en højere affinitet, hvor affiniteten er målt ved hjælp af overfladeplasmonresonans, og/eller aminosyresekvensen har den samme eller en højere potens, hvor potensen er bestemt ved hjælp af et mikroneutraliseringsassay, sammenlignet med aminosyresekvensen uden forskellen i 3, 2 eller 1 aminosyre (r); c) SEQ ID NO: 146-153; d) aminosyresekvenser, der har en forskel i højst 3, fortrinsvis højst 2, mere fortrinsvis højst 1 aminosyre(r) i forhold til en af SEQ ID NO: 146-153, forudsat at: i) aminosyresekvensen har en prolin (Pro, P) i position 14, arginin (Arg, R) i position 19, leucin (Leu, L) i position 20 og leucin (Leu, L) i position 108, hvor positionerne er bestemt i henhold til Kabat-nummerering; og ii) aminosyresekvensen binder protein F fra hRSV med den samme eller en højere affinitet, hvor affiniteten er målt ved hjælp af overfladeplasmonresonans, og/eller aminosyresekvensen har den samme eller en højere potens, hvor potensen er bestemt ved hjælp af et mikroneutraliseringsassay, sammenlignet med aminosyresekvensen uden forskellen i 3, 2 eller 1 aminosyre(r), e) SEQ ID NO: 138-141 og 154-157; f) aminosyresekvenser, der har en forskel i højst 3, fortrinsvis højst 2, mere fortrinsvis højst 1 aminosyre(r) i forhold til en af SEQ ID NO: 138-141 og 154-157, forudsat at: i) aminosyresekvensen har en asparaginsyre (Asp, D) i position I, hvor positionen er bestemt i henhold til Kabat-nummerering; og ii) aminosyresekvensen binder protein F fra hRSV med den samme eller en højere affinitet, hvor affiniteten er målt ved hjælp af overfladeplasmonresonans, og/eller aminosyresekvensen har den samme eller en højere potens, hvor potensen er bestemt ved hjælp af et mikroneutraliseringsassay, sammenlignet med aminosyresekvensen uden forskellen i 3, 2 eller 1 aminosyre (r), og for eksempel en eller flere linkere.
6. Nukleinsyre- eller nukleotidsekvens, der koder for et polypeptid ifølge et hvilket som helst af kravene 1 til 4.
7. Vært eller værtscelle, der udtrykker et polypeptid ifølge et hvilket som helst af kravene 1 til 4 og/eller omfatter en nukleinsyre- eller nukleotidsekvens ifølge krav 6.
8. Sammensætning, der omfatter et polypeptid ifølge et hvilket som helst af kravene 1 til 4 eller en nukleinsyre-eller nukleotidsekvens ifølge krav 6.
9. Sammensætning ifølge krav 8, som er en farmaceutisk sammensætning.
10. Farmaceutisk sammensætning, der omfatter et polypeptid ifølge et hvilket som helst af kravene 1 til 4 og et bæremateriale, der er egnet til pulmonal fremføring.
II. Fremgangsmåde til fremstilling af et polypeptid ifølge et hvilket som helst af kravene 1 til 4 eller en sammensætning ifølge et hvilket som helst af kravene 8 eller 9, hvilken fremgangsmåde mindst omfatter trinene: a) ekspression i en egnet værtscelle eller værtsorganisme eller i et andet egnet ekspressionssystem af en nukleinsyre-eller nukleotidsekvens ifølge krav 6, eller dyrkning og/eller opretholdelse af en vært eller værtscelle ifølge krav 7 under betingelser, der er således, at værten eller værtscellen udtrykker og/eller producerer et polypeptid ifølge et hvilket som helst af kravene 1 til 4 eller en sammensætning ifølge et hvilket som helst af kravene 8 eller 9, eventuelt efterfulgt af: b) isolering og/eller oprensning af det således opnåede polypeptid ifølge et hvilket som helst af kravene 1 til 4.
12. Polypeptid ifølge et hvilket som helst af kravene 1 til 4 og/eller sammensætning ifølge et hvilket som helst af kravene 8 eller 9 til anvendelse til forebyggelse og/eller behandling af mindst én af luftvejssygdom, infektion i de øvre luftveje, infektion i de nedre luftveje, bronchiolitis, pneumoni, dyspnø, hoste, pibende vejrtrækning og astma.
13. Farmaceutisk anordning, der er egnet til pulmonal fremføring, som omfatter et polypeptid ifølge et hvilket som helst af kravene 1 til 4.
14. Farmaceutisk anordning ifølge krav 13, som er en inhalator til væsker, en aerosol eller en pulverinhalator, som omfatter et polypeptid ifølge et hvilket som helst af kravene 1 til 4.
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