IP Library › Granted Patent US 9,999,659
Granted Patent B2
US 9,999,659 · App. 15/367,711 · Granted Jun 19, 2018

Treatments using a peptide and/or vaccine

Inventors: Sylvia Brunner (Vienna, AT); Gergana Galabova (Vienna, AT); Gabriele Winsauer (Vienna, AT); Erika Bilcikova (Bratislava, SK); Claudia Juno (Vienna, AT); Pola Linzmayer-Hirt (Wiener Neudorf, AT); Birgit Schuh (Vienna, AT); Guenther Staffler (Vienna, AT)
Assignee: AFFIRIS AG
A61K39/0005A61K39/385A61K39/39A61K47/643A61K47/646A61K47/6415C12N9/6424C12N9/6454C12Y304/21061A61K2039/55505A61K2039/6081
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Quick Facts
Patent No.
US 9,999,659
App. No.
15/367,711
Granted
Jun 19, 2018
Kind
B2
Abstract

The present invention relates to a vaccine capable to induce the formation of antibodies directed to PCSK9 in vivo.

Claims (81)

1. A method for treating a disorder caused by hyperlipidemia, hypercholesterolemia and/or atherosclerosis, comprising administering a vaccine to a subject in need thereof,

wherein the vaccine comprises

at least one peptide consisting of 9 to 25 amino acid residues having the amino acid sequence

(SEQ ID NO: 1)

X 1 X 2 X 3 WX 4 X 5 X 6 RX 7 (X 8 ) m (X 9 ) n ,

wherein

X 1 is an amino acid residue selected from the group of uncharged amino acid residues, X 2 is an amino acid residue selected from the group of uncharged amino acid residues, X 3 is an amino acid residue selected from the group of uncharged amino acid residues, X 4 is an amino acid residue selected from the group consisting of asparagine, serine, alanine, glutamine and aspartic acid,

X 5 is an amino acid residue selected from the group consisting of leucine, glycine, alanine, tyrosine, aspartic acid, phenylalanine and valine, X 6 is an amino acid residue selected from the group of hydrophilic, negatively charged amino acid residues,

X 7 is an amino acid residue selected from the group of uncharged amino acid residues, X 8 is an amino acid residue selected from the group of uncharged amino acid residues selected from the group consisting of threonine, leucine, glutamine, alanine and serine,

X 9 is X 10 X 11 X 12 or a C-terminal truncated fragment thereof consisting of 1 or 2 amino acid residues,

X 10 is an amino acid residue, preferably an amino acid residue selected from the group of uncharged amino acid residues, X 11 is an amino acid residue, X 12 is an amino acid residue, m is 0 or 1,

n is 0 or 1, and

SEQ ID NO: 1 is not SIPWNLERITPPR (SEQ ID NO: 2) or a C-terminal truncated fragment thereof, and wherein the at least one peptide is coupled or fused to a pharmaceutically acceptable carrier.

2. A method for treating a disorder caused by hyperlipidemia, hypercholesterolemia and/or atherosclerosis, comprising:

administering an effective amount of at least one peptide consisting of 9 to 25 amino acid residues having the amino acid sequence

(SEQ ID NO: 1)

X 1 X 2 X 3 WX 4 X 5 X 6 RX 7 (X 8 ) m (X 9 ) n ,

wherein

X 1 is an amino acid residue selected from the group of uncharged amino acid residues,

X 2 is an amino acid residue selected from the group of uncharged amino acid residues, X 3 is an amino acid residue selected from the group of uncharged amino acid residues,

X 4 is an amino acid residue selected from the group consisting of asparagine, serine, alanine, glutamine and aspartic acid,

X 5 is an amino acid residue selected from the group consisting of leucine, glycine, alanine, tyrosine, aspartic acid, phenylalanine and valine,

X 6 is an amino acid residue selected from the group of hydrophilic, negatively charged amino acid residues,

X 7 is an amino acid residue selected from the group of uncharged amino acid residues, X 8 is an amino acid residue selected from the group of uncharged amino acid residues selected from the group consisting of threonine, leucine, glutamine, alanine and serine,

X 9 is X 10 X 11 X 12 or a C-terminal truncated fragment thereof consisting of 1 or 2 amino acid residues,

X 10 is an amino acid residue, preferably an amino acid residue selected from the group of uncharged amino acid residues,

X 11 is an amino acid residue, X 12 is an amino acid residue, in is 0 or 1,

n is 0 or 1, and

SEQ ID NO: 1 is not SIPWNLERITPPR (SEQ ID NO: 2) or a C-terminal truncated fragment thereof, and wherein the at least one peptide is coupled or fused to a pharmaceutically acceptable carrier,

to a subject in need thereof.

3. The method according to claim 2 , wherein

X 1 is valine, serine or alanine;

X 2 is valine, isoleucine or glutamine;

X 4 is serine or asparagine;

X 6 is glutamic acid;

X 7 is leucine, isoleucine or threonine; and

X 8 is glutamine, threonine or leucine;

wherein the pharmaceutically acceptable carrier is a protein carrier selected from the group consisting of keyhole limpet haemocyanin (KLH), tetanus toxoid (TT), protein D and diphtheria toxin (DT); and

wherein the at least one peptide optionally comprises at its N- and/or C-terminus at least one cysteine residue bound directly or via a spacer sequence thereto.

4. A method for reducing LDLc in an individual in need thereof, comprising

administering an efficient amount of at least one peptide consisting of 9 to 25 amino acid residues having the amino acid sequence

(SEQ ID NO: 1)

X 1 X 2 X 3 WX 4 X 5 X 6 RX 7 (X 8 ) m (X 9 ) n ,

wherein

X 1 is an amino acid residue selected from the group of uncharged amino acid residues,

X 2 is an amino acid residue selected from the group of uncharged amino acid residues, X 3 is an amino acid residue selected from the group of uncharged amino acid residues,

X 4 is an amino acid residue selected from the group consisting of asparagine, serine, alanine, glutamine and aspartic acid,

X 5 is an amino acid residue selected from the group consisting of leucine, glycine, alanine, tyrosine, aspartic acid, phenylalanine and valine,

X 6 is an amino acid residue selected from the group of hydrophilic, negatively charged amino acid residues,

X 7 is an amino acid residue selected from the group of uncharged amino acid residues,

X 8 is an amino acid residue selected from the group of uncharged amino acid residues selected from the group consisting of threonine, leucine, glutamine, alanine and serine,

X 9 is X 10 X 11 X 12 or a C-terminal truncated fragment thereof consisting of 1 or 2 amino acid residues,

X 10 is an amino acid residue, preferably an amino acid residue selected from the group of uncharged amino acid residues,

X 11 is an amino acid residue, X 12 is an amino acid residue, in is 0 or 1,

n is 0 or 1, and

SEQ ID NO: 1 is not SIPWNLERITPPR (SEQ ID NO: 2) or a C-terminal truncated fragment thereof, and wherein the at least one peptide is coupled or fused to a pharmaceutically acceptable carrier,

to a subject in need thereof.

5. The method according to claim 4 , wherein

X 1 is valine, serine or alanine;

X 2 is valine, isoleucine or glutamine;

X 4 is serine or asparagine;

X 6 is glutamic acid;

X 7 is leucine, isoleucine or threonine; and

X 8 is glutamine, threonine or leucine;

wherein the pharmaceutically acceptable carrier is a protein carrier selected from the group consisting of keyhole limpet haemocyanin (KLH), tetanus toxoid (TT), protein D and diphtheria toxin (DT); and

wherein the at least one peptide optionally comprises at its N- and/or C-terminus at least one cysteine residue bound directly or via a spacer sequence thereto.

6. The method according to claim 2 , wherein the at least one peptide is selected from the group consisting of TIPWNLERIT (SEQ ID NO: 5), VIPWNLERIT (SEQ ID NO: 6), AIPWNLERIT (SEQ ID NO: 7), SVPWNLERIT (SEQ ID NO: 8), SVPWNLERIT (SEQ ID NO: 9), SAPWNLERIT (SEQ ID NO: 10), SGPWNLERITPPR (SEQ ID NO: 11), SITWNLERIT (SEQ ID NO: 12), SIAWNLERIT (SEQ ID NO: 13), SIVWNLERITPPR (SEQ ID NO: 14), SIVWNLERIT (amino acids 1-10 of SEQ ID NO: 14), SIPWALERIT (SEQ ID NO: 22), SIPWQLERITPPR (SEQ ID NO: 23), SIPWDLERITPPR (SEQ ID NO: 24), SIPWNAERIT (SEQ ID NO: 25), SIPWNGERIT (SEQ ID NO: 26), SIPWNYERIT (SEQ ID NO: 27), SIPWNDERIT (SEQ ID NO: 28), SIPWNFERITPPR (SEQ ID NO: 29), SIPWNVERITPPR (SEQ ID NO: 30), SIPWNLDRITPPR (SEQ ID NO: 32), SIPWNFERIT (amino acids 1-10 of SEQ ID NO: 29), SIPWNVERIT (amino acids 1-10 of SEQ ID NO: 30), SIPWNLDRIT (amino acids 1-10 of SEQ ID NO: 32), SIPWNLERLT (SEQ ID NO: 36), SIPWNLERTT (SEQ ID NO: 37), SIPWNLERAT (SEQ ID NO: 38), SIPWNLERIL (SEQ ID NO: 39), SIPWNLERIQ (SEQ ID NO: 40), SIPWNLERIA (SEQ ID NO: 41), SIPWNLERISPPR (SEQ ID NO: 42), SIPWNLERIS (amino acids 1-10 of SEQ ID NO: 42), SIPWNLERITAPR (SEQ ID NO: 43), SIPWNLERITSPR (SEQ ID NO: 44), SIPWNLERITPAR (SEQ ID NO: 45), SIPWNLERITPVR (SEQ ID NO: 46), SIPWNLERITPTR (SEQ ID NO: 47), SIPWNLERITPNR (SEQ ID NO: 48), SIPWNLERITPPA (SEQ ID NO: 49), SIPWNLERITPPK (SEQ ID NO: 50), SIPWNLERITPPS (SEQ ID NO: 51), SIPWNLERITPPL (SEQ ID NO: 52), VIPWNLERLT (SEQ ID NO: 53), VIPWNLERTT (SEQ ID NO: 54), VIPWNLERIL (SEQ ID NO: 55), VIPWNLERILPPR (SEQ ID NO: 101), VIPWNLERIQ (SEQ ID NO: 56), SVPWNLERLT (SEQ ID NO: 57), SVPWNLERTT (SEQ ID NO: 58), SVPWNLERIL (SEQ ID NO: 59), SVPWNLERIQ (SEQ ID NO: 60), SVPWNLERIQPPR (SEQ ID NO: 106), SIPWSLERTTPPR (SEQ ID NO: 107), SQPWNLERLT (SEQ ID NO: 61), SQPWNLERIL (SEQ ID NO: 62), SQPWNLERIQ (SEQ ID NO: 63), SIPWSLERLT (SEQ ID NO: 64), SIPWSLERTT (SEQ ID NO: 65), SIPWSLERIL (SEQ ID NO: 66), SIPWSLERIQ (SEQ ID NO: 67), VQPWSLERTL (SEQ ID NO: 68), SQPWSLERTL (SEQ ID NO: 69), VQPWNLERLQ (SEQ ID NO: 71), VQPWSLERLL (SEQ ID NO: 72) SVPWSLERLT (SEQ ID NO: 73) and SIPWSLERITPPR (SEQ ID NO: 87).

7. The method according to claim 4 , wherein the at least one peptide is selected from the group consisting of TIPWNLERIT (SEQ ID NO: 5), VIPWNLERIT (SEQ ID NO: 6), AIPWNLERIT (SEQ ID NO: 7), SVPWNLERIT (SEQ ID NO: 8), SQPWNLERIT (SEQ ID NO: 9), SAPWNLERIT (SEQ ID NO: 10), SGPWNLERITPPR (SEQ ID NO: 11) SITWNLERIT (SEQ ID NO: 12), SIAWNLERIT (SEQ ID NO: 13), SIVWNLERITPPR (SEQ ID NO: 14), SIVWNLERIT (amino acids 1-10 of SEQ ID NO: 14), SIPWSLERIT (SEQ ID NO: 21), SIPWALERIT (SEQ ID NO: 22), SIPWQLERITPPR (SEQ ID NO: 23), SIPWDLERITPPR (SEQ ID NO: 24), SIPWNGERIT (SEQ ID NO: 25), SIPWNGERIT (SEQ ID NO: 26), SIPWNGERIT (SEQ ID NO: 27), SIPWNDERIT (SEQ ID NO: 28), SIPWNFERITPPR (SEQ ID NO: 29), SIPWNVERITPPR (SEQ ID NO: 30), SIPWNLDRITPPR (SEQ ID NO: 32), SIPWNFERIT (amino acids 1-10 of SEQ ID NO: 29), SIPWNGERIT (amino acids 1-10 of SEQ ID NO: 30), SIPWNLDRIT (amino acids 1-10 of SEQ ID NO: 32), SIPWNLERLT (SEQ ID NO: 36), SIPWNLERTT (SEQ ID NO: 37), SIPWNLERAT (SEQ ID NO: 38), SIPWNLERIL (SEQ ID NO: 39), SIPWNLERIQ (SEQ ID NO: 40), SIPWNLERIA (SEQ ID NO: 41), SIPWNLERISPPR (SEQ ID NO: 42), SIPWNLERIS (amino acids 1-10 of SEQ ID NO: 42), SIPWNLERITAPR (SEQ ID NO: 43), SIPWNLERITSPR (SEQ ID NO: 44), SIPWNLERITPAR (SEQ ID NO: 45), SIPWNLERITPVR (SEQ ID NO: 46), SIPWNLERITPTR (SEQ ID NO: 47), SIPWNLERITPNR (SEQ ID NO: 48), SIPWNLERITPPA (SEQ ID NO: 49), SIPWNLERITPPK (SEQ ID NO: 50), SIPWNLERITPPS (SEQ ID NO: 51), SIPWNLERITPPL (SEQ ID NO: 52), VIPWNLERLT (SEQ ID NO: 53), VIPWNLERTT (SEQ ID NO: 54), VIPWNLERIL (SEQ ID NO: 55), VIPWNLERILPPR (SEQ ID NO: 101), VIPWNLERIQ (SEQ ID NO: 56), SVPWNLERLT (SEQ ID NO: 57), SVPWNLERTT (SEQ ID NO: 58), SVPWNLERIL (SEQ ID NO: 59), SVPWNLERIQ (SEQ ID NO: 60), SVPWNLERIQPPR (SEQ ID NO: 106), SIPWSLERTTPPR (SEQ ID NO: 107), SQPWNLERLT (SEQ ID NO: 61), SQPWNLERIL (SEQ ID NO: 62), SQPWNLERIQ (SEQ ID NO: 63), SIPWSLERLT (SEQ ID NO: 64), SIPWSLERTT (SEQ ID NO: 65), SIPWSLERIL (SEQ ID NO: 66), SIPWSLERIQ (SEQ ID NO: 67), VQPWSLERTL (SEQ ID NO: 68), SQPWSLERTL (SEQ ID NO: 69), VQPWNLERLQ (SEQ ID NO: 71), VQPWSLERLL (SEQ ID NO: 72) SVPWSLERLT (SEQ ID NO: 73) and SIPWSLERITPPR.

8. The method according to claim 1 , wherein X 1 is valine, serine or alanine.

9. The method according to claim 1 , wherein X 2 is valine, isoleucine or glutamine.

10. The method according to claim 1 , wherein X a is serine or asparagine.

11. The method according to claim 1 , wherein X 6 is glutamic acid.

12. The method according to claim 1 , wherein X 7 is leucine, isoleucine or threonine.

13. The method according to claim 1 , wherein X 8 is glutamine, threonine or leucine.

14. The method according to claim 1 , wherein the at least one peptide is selected from the group consisting of

TIPWNLERIT (SEQ ID NO: 5), VIPWNLERIT (SEQ ID NO: 6), AIPWNLERIT (SEQ ID NO: 7), SVPWNLERIT (SEQ ID NO: 8), SQPWNLERIT (SEQ ID NO: 9), SAPWNLERIT (SEQ ID NO: 10), SGPWNLERITPPR (SEQ ID NO: I), SITWNLERIT (SEQ ID NO: 12), SIAWNLERIT (SEQ ID NO: 13), SIVWNLERITPPR (SEQ ID NO: 14), SIVWNLERIT (amino acids 1-10 of SEQ ID NO: 14), SIPWALERIT (SEQ ID NO: 22), SIPWQLERITPPR (SEQ ID NO: 23), SIPWDLERITPPR (SEQ ID NO: 24), SIPWNAERIT (SEQ ID NO: 25), SIPWNGERIT (SEQ ID NO: 26), SIPWNFERIT (SEQ ID NO: 27), SIPWNDERIT (SEQ ID NO: 28), SIPWNFERITPPR (SEQ ID NO: 29), SIPWNVERITPPR (SEQ ID NO: 30), SIPWNLDRITPPR (SEQ ID NO: 32), SIPWNFERIT (amino acids 1-10 of SEQ ID NO: 29), SIPWNVERIT (amino acids 1-10 of SEQ ID NO: 30), SIPWNLDRIT (amino acids 1-10 of SEQ ID NO: 32), SIPWNLERLT (SEQ ID NO: 36), SIPWNLERTT (SEQ ID NO: 37), SIPWNLERAT (SEQ ID NO: 38), SIPWNLERIL (SEQ ID NO: 39), SIPWNLERIQ (SEQ ID NO: 40), SIPWNLERIA (SEQ ID NO: 41), SIPWNLERISPPR (SEQ ID NO: 42), SIPWNLERIS (amino acids 1-10 of SEQ ID NO: 42), SIPWNLERITAPR (SEQ ID NO: 43), SIPWNLERITSPR (SEQ ID NO: 44), SIPWNLERITPAR (SEQ ID NO: 45), SIPWNLERITPVR (SEQ ID NO: 46), SIPWNLERITPTR (SEQ ID NO: 47), SIPWNLERITPNR (SEQ ID NO: 48), SIPWNLERITPPA (SEQ ID NO: 49), SIPWNLERITPPK (SEQ ID NO: 50), SIPWNLERITPPS (SEQ ID NO: 51), SIPWNLERITPPL (SEQ ID NO: 52), VIPWNLERLT (SEQ ID NO: 53), VIPWNLERTT (SEQ ID NO: 54), VIPWNLERIL (SEQ ID NO: 55), VIPWNLERILPPR (SEQ ID NO: 101), VIPWNLERIQ (SEQ ID NO: 56), SVPWNLERLT (SEQ ID NO: 57), SVPWNLERTT (SEQ ID NO: 58), SVPWNLERIL (SEQ ID NO: 59), SVPWNLERIQ (SEQ ID NO: 60), SVPWNLERIQPPR (SEQ ID NO: 106), SIPWSLERTTPPR (SEQ ID NO: 107), SQPWNLERLT (SEQ ID NO: 61), SQPWNLERIL (SEQ ID NO: 62), SQPWNLERIQ (SEQ ID NO: 63), SIPWSLERLT (SEQ ID NO: 64), SIPWSLERTT (SEQ ID NO: 65), SIPWSLERIL (SEQ ID NO: 66), SIPWSLERIQ (SEQ ID NO: 67), VQPWSLERTL (SEQ ID NO: 68), SQPWSLERTL (SEQ ID NO: 69), VQPWNLERLQ (SEQ ID NO: 71), VQPWSLERLL (SEQ ID NO: 72) and SVPWSLERLT (SEQ ID NO: 73).

15. The method according to claim 1 , wherein the at least one peptide is selected from the group consisting of SIPWSLERITPPR (SEQ ID NO: 87), SIPWSLERTT (SEQ ID NO: 65), SIPWSLERTTPPR (SEQ ID NO: 107), VIPWNLERIL (SEQ ID NO: 55), VIPWNLERILPPR (SEQ ID NO: 101), SVPWNLERIQ (SEQ ID NO: 60) and SVPWNLERIQPPR (SEQ ID NO: 106).

16. The method according to claim 1 , wherein the at least one peptide comprises at its N- and/or C-terminus at least one cysteine residue bound directly or via a spacer sequence thereto.

17. The method according to claim 1 , wherein the pharmaceutically acceptable carrier is a protein carrier.

18. The method according to claim 17 , wherein the protein carrier is selected from the group consisting of keyhole limpet haemocyanin (KLH), tetanus toxoid (TT), protein D and diphtheria toxin (DT).

19. The method according to claim 1 , wherein the vaccine is formulated with an adjuvant.

Assignments (1)
CONFIRMATORY ASSIGNMENT Recorded May 11, 2022
From: AFFIRIS AG
To: AFFIRIS CVD GMBH
Reel/Frame 059929/0690 →
Priority Claims (1)
EP 12182241 · Aug 29, 2012 · regional
Continuity (2)
Continuation 14418139
Related Publication 20170112908A1 · Apr 27, 2017