HRP20210990T1 - Proteini okosnične domene na bazi fibronektina koji se vežu na miostatin - Google Patents
Proteini okosnične domene na bazi fibronektina koji se vežu na miostatin Download PDFInfo
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- HRP20210990T1 HRP20210990T1 HRP20210990TT HRP20210990T HRP20210990T1 HR P20210990 T1 HRP20210990 T1 HR P20210990T1 HR P20210990T T HRP20210990T T HR P20210990TT HR P20210990 T HRP20210990 T HR P20210990T HR P20210990 T1 HRP20210990 T1 HR P20210990T1
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Claims (15)
1. Polipeptid koji sadrži desetu domenu fibronektinskog tipa III (10Fn3), naznačen time što se polipeptid se veže na miostatin s KD manjim od 500 nM i gdje jedna petlja od petlji BC, DE i FG u domeni 10Fn3 može imati jednu aminokiselinsku zamjenu prema odgovarajućim petljama BC, DE i FG u SEQ ID NO: 34, 39 i 75, odnosno te pri čemu:
(a) supstitucija jedne aminokiseline je u BC petlji gdje
(i) serin na položaju 3 BC petlje (SEQ ID NO: 34) supstituiran je aminokiselinom odabranom od skupina koja se sastoji od C, F, I, V, W i Y;
(ii) histidin na položaju 6 BC petlje (SEQ ID NO: 34) supstituiran je odabranom aminokiselinom iz skupine koju čine C, D, E, F, G, I, K, L, M, N, Q, R, S, T, V, W i Y;
(iii) glutamin na položaju 7 BC petlje (SEQ ID NO: 34) supstituiran je odabranom aminokiselinom iz skupine koju čine A, C, D, E, F, G, H, I, K, L, M, N, P, R, S, T, V, W i Y;
(iv) lizin na položaju 9 BC petlje (SEQ ID NO: 34) supstituiran je aminokiselinom odabranom od skupina koja se sastoji od A, C, G, H, I, L, M, N, Q, R, S, V, W i Y
(v) alanin na položaju 10 BC petlje (SEQ ID NO: 34) supstituiran je odabranom aminokiselinom iz skupine koju čine G, L, M i S; ili
(vi) asparagin na položaju 11 BC petlje (SEQ ID NO: 34) supstituiran je odabranom aminokiselinom iz skupine koju čine C, H, Q, S i Y;
(b) supstitucija jedne aminokiseline je u DE petlji u kojoj
(valin na položaju 5 DE petlje (SEQ ID NO: 39) supstituiran je aminokiselinom odabranom od skupina koja se sastoji od C, E, I, L, M, Q i T; ili
(c) supstitucija jedne aminokiseline je u FG petlji u kojoj
(i) valin na položaju 2 FG petlje (SEQ ID NO: 75) supstituiran je aminokiselinom odabranom od skupina koja se sastoji od A, C, I, L i M;
(ii) treonin na položaju 3 FG petlje (SEQ ID NO: 75) supstituiran je odabranom aminokiselinom iz skupine koju čine C, F, H, I, L, M, Q, R, S, V, W i Y;
(iii) asparaginska kiselina na položaju 4 FG petlje (SEQ ID NO: 75) supstituirana je odabranom aminokiselinom iz skupine koju čine A, C, D, E, F, G, H, I, L, M, N, P, Q, S, T, V, W i Y;
(iv) treonin na položaju 5 FG petlje (SEQ ID NO: 75) supstituiran je odabranom aminokiselinom iz skupine koju čine A, C, E, F, G, H, I, K, L, M, N, P, Q, R, S, V, W i Y;
(v) glicin na položaju 6 FG petlje (SEQ ID NO: 75) supstituiran je odabranom aminokiselinom iz skupine koju čine A, D, E, F, H, I, L, M, N, Q, S, T, V, W i Y;
(vi) tirozin na položaju 7 FG petlje (SEQ ID NO: 75) supstituiran je odabranom aminokiselinom iz skupine koju čine C, F, I, L, M, P, T, V i W;
(xii) leucin na položaju 8 FG petlje (SEQ ID NO: 75) supstituiran je odabranom aminokiselinom iz skupine koju čine C, F, H, I, L, M, N, Q, R, T, V, W i Y;
(xiii) lizin na položaju 9 FG petlje (SEQ ID NO: 75) supstituiran je aminokiselinom odabranom od skupina koju čine A, C, E, F, G, I, L, M, N, P, Q, R, S, T, V, W i Y;
(ix) tirozin na položaju 10 FG petlje (SEQ ID NO: 75) supstituiran je s W; ili
(x) lizin na položaju 11 FG petlje (SEQ ID NO: 75) supstituiran je aminokiselinom odabranom od grupa koju čine A, C, D, E, G, H, L, M, N, P, Q, R, S, T i V.
2. Polipeptid prema zahtjevu 1, naznačen time, da
(a) supstitucija jedne aminokiseline je u BC petlji i pri čemu
(i) serin na položaju 3 BC petlje (SEQ ID NO: 34) supstituiran je aminokiselinom odabranom od skupina koja se sastoji od F i W;
(ii) histidin na položaju 6 BC petlje (SEQ ID NO: 34) supstituiran je odabranom aminokiselinom iz skupine koju čine C, F, G, I, K, L, M, N, R, S, T, V, W i Y;
(iii) glutamin na položaju 7 BC petlje (SEQ ID NO: 34) supstituiran je odabranom aminokiselinom iz skupine koju čine A, C, E, F, H, I, K, L, M, P, R, S, T, V i Y; (iv) lizin na položaju 9 BC petlje (SEQ ID NO: 34) supstituiran je aminokiselinom odabranom od skupina koja se sastoji od A, C, H, L, M, N, R, V, W i Y;
(v) alanin na položaju 10 BC petlje (SEQ ID NO: 34) supstituiran je odabranom aminokiselinom iz skupine koju čine G i L;
(vi) asparagin na položaju 11 BC petlje (SEQ ID NO: 34) supstituiran je odabranom aminokiselinom iz skupine koju čine H i Q;
(b) supstitucija jedne aminokiseline je u DE petlji u kojoj
(vii) valin na položaju 5 DE petlje (SEQ ID NO: 39) supstituiran je aminokiselinom odabranom od skupina koja se sastoji od C, E, I, L i M; ili
(c) supstitucija jedne aminokiseline je u FG petlji u kojoj
(i) valin na položaju 2 FG petlje (SEQ ID NO: 75) supstituiran je s I;
(ii) treonin na položaju 3 FG petlje (SEQ ID NO: 75) supstituiran je odabranom aminokiselinom iz skupine koju čine C, F, I, L, M, V, W i Y;
(iii) asparaginska kiselina na položaju 4 FG petlje (SEQ ID NO: 75) supstituirana je odabranom aminokiselinom iz skupine koju čine A, C, E, F, G, H, I, L, M, N, Q, S, T i V;
(iv) treonin na položaju 5 FG petlje (SEQ ID NO: 75) supstituiran je odabranom aminokiselinom iz skupine koju čine A, C, F, G, I, L, M, N, Q, S, T, V, W i Y;
(v) glicin na položaju 6 FG petlje (SEQ ID NO: 75) supstituiran je odabranom aminokiselinom iz skupine koju čine A, S, T i W;
(vi) tirozin na položaju 7 FG petlje (SEQ ID NO: 75) supstituiran je odabranom aminokiselinom iz skupine koju čine F, I, V i W;
(vii) leucin na položaju 8 FG petlje (SEQ ID NO: 75) supstituiran je odabranom aminokiselinom iz skupine koju čine F, H, I, M, V, W i Y;
(viii) lizin na položaju 9 FG petlje (SEQ ID NO: 75) supstituiran je aminokiselinom odabranom od skupina koja se sastoji od A, C, F, G, I, L, M, T, V i W;
(ix) tirozin na položaju 10 FG petlje (SEQ ID NO: 75) supstituiran je s W; ili
(x) lizin na položaju 11 FG petlje (SEQ ID NO: 75) supstituiran je aminokiselinom odabranom od grupa koju čine A, G, K, M, P, Q i R.
3. Polipeptid u skladu s patentnim zahtjevom 1 ili 2, naznačen time što domena 10Fn3 nadalje sadrži N-terminalni produžni slijed koji sadrži aminokiselinsku sekvencu SEQ ID NO: 307.
4. Polipeptid prema bilo kojem od zahtjeva 1-3, naznačen time, da domena 10Fn3 nadalje sadrži C-terminalni produžetak sekvenca koja sadrži aminokiselinsku sekvencu EI.
5. Polipeptid prema bilo kojem od zahtjeva 1-4, naznačen time, da polipeptid sadrži aminokiselinsku sekvencu najmanje 90% identičnu bilo kojem od SEQ ID NO: 331, 273, 281 ili 118.
6. Polipeptid prema bilo kojem od zahtjeva 1-5, naznačen time, da nadalje sadrži jedan ili više odabranih farmakokinetičkih (PK) ostataka iz skupine koju čine polietilen glikol, sijalična kiselina, Fc, Fc fragment, transferin, serumski albumin, serum protein koji veže albumin i protein koji veže imunoglobulin u serumu.
7. Polipeptid prema zahtjevu 6, naznačen time, da su PK ostatak i polipeptid povezani preko veznika koji sadrži amino kiselinsku sekvencu odabranu iz skupine koja se sastoji od SEQ ID NO: 181-187.
8. Polipeptid prema zahtjevu 7, naznačen time, da je PK ostatak Fc.
9. Pripravak, naznačen time, da sadrži polipeptid prema bilo kojem od zahtjeva 1-8 i farmaceutski prihvatljiv nosač.
10. Nukleinska kiselina koja kodira polipeptid prema bilo kojem od zahtjeva 1-5 i 7.
11. Stanica koja sadrži nukleinsku kiselinu prema zahtjevu 10.
12. Polipeptid prema bilo kojem od zahtjeva 1-8 ili pripravak iz zahtjeva 9, naznačen time, da se koristi u metodi za liječenje mišića, neurološki ili metabolički poremećaj povezan s gubitkom mišića i/ili atrofijom mišića ili degenerativnim poremećajem kostiju.
13. Polipeptid ili pripravak za uporabu prema zahtjevu 12, naznačen time, da subjekt ima mišićnu distrofiju.
14. Polipeptid ili pripravak za uporabu prema zahtjevu 13, naznačen time, da subjekt ima Duchenneovu mišićnu distrofiju.
15. Polipeptid ili pripravak za uporabu prema bilo kojem od zahtjeva 12-14, naznačen time, da se polipeptid sastoji od aminokiselinske sekvence SEQ ID NO: 273.
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2016
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