Mimetic peptides

Patent metadata

Field	Value
Publication number	US-10087234-B2
Application number	US-201314440790-A
Country	US
Kind code	B2
Filing date	Nov 6, 2013
Priority date	Nov 6, 2012
Publication date	Oct 2, 2018
Grant date	Oct 2, 2018

Abstract

The invention relates to mimetic peptides of epitope(s) of Apolipoprotein A-I, diagnostic immunoassays comprising such mimetic peptides, as well as methods for diagnosing and methods for preventing and/or treating a cardiovascular disease.

First claim

The invention claimed is:

1. A mimetic peptide of an epitope of Apolipoprotein A-I (ApoA-I), wherein said mimetic peptide is capable of specifically binding to an anti-ApoA-I antibody and is selected from the group consisting of:
(i) SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 19, or SEQ ID NO: 20;
(ii) a variant of an amino acid sequence SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 19, or SEQ ID NO: 20, wherein said variant consists in an amino acid sequence which is
a. identical to any one of SEQ ID NO: 8, SEQ ID NO:9, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 19, and SEQ ID NO: 20, except that 1, 2, 3, 4, 5, or 6 amino acids of said sequences are substituted and/or chemically modified, without aborting the capacity of said mimetic peptide to specifically bind to an anti-ApoA-I antibody, or
b. identical to any one of SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 19, and SEQ ID NO: 20, except that 1, 2, or 3 amino acids are deleted without aborting the capacity of said mimetic peptide to specifically bind to an anti-ApoA-I antibody; and

(iii) any combination of two of amino acid sequences under (i), and/or under (ii);

wherein the mimetic peptide has an internal cross-linking between at least two non-contiguous amino acids.

2. The mimetic peptide according to claim 1 , wherein the peptide is selected from the group consisting of SEQ ID NO: 8 and SEQ ID NO: 9.

3. The mimetic peptide according to claim 1 , wherein the internal cross-linking is a lactam bridge formed between two amino acids Xaa at positions n and n+4 on said peptide sequence.

4. The mimetic peptide according to claim 1 , wherein the internal cross-linking is a hydrocarbon staple linking two amino acids Xaa at positions n and n+7 of said peptide sequence, wherein Xaa at position n is a modified alanine of formula (I): —NH—C(CH 3 )(R)—C(O)— wherein R is a hydrocarbon staple —(CH 2 ) 6 —CH═CH—(CH 2 ) 3 — linked to a subsequent Xaa at position n+7, and wherein Xaa at position n+7 is a modified alanine of formula (I): —NH—C(CH 3 )(R′)—C(O)— wherein R′ is a single bond linked to the hydrocarbon staple from said Xaa at position n.

5. The mimetic peptide according to claim 1 , wherein the internal cross-linking is a hydrocarbon staple linking two amino acids Xaa at positions n and n+4 of said peptide sequence, wherein Xaa at position n is a modified alanine of formula (I): —NH—C(CH 3 )(R)—C(O)— wherein R is a hydrocarbon staple —(CH 2 ) 3 —CH═CH—(CH 2 ) 3 — linked to a subsequent Xaa at position n+4, and wherein Xaa at position n+4 is a modified alanine of formula (I): —NH—C(CH 3 )(R′)—C(O)— wherein R′ is a single bond linked to the hydrocarbon staple from said Xaa at position n.

6. The mimetic peptide according to claim 1 , wherein:
(i) the peptide consists of SEQ ID NO: 19 or a said variant thereof and the internal cross-linking is a lactam bridge linking a Glutamic acid (E) at position 19 and a Lysine (K) at position 23; or
(ii) the peptide consists of SEQ ID NO: 15 or said variant thereof and the internal cross-linking is a hydrocarbon staple linking (R)-2-(7′-octenyl)-Alanine at position 16 and (S)-2-(4′-pentenyl)-Alanine at position 23; or
(iii) the peptide consists of SEQ ID NO: 16 or said variant thereof and the internal cross-linking is a hydrocarbon staple linking (S)-2-(4′-pentenyl)-Alanine at position 13 and (S)-2-(4′-pentenyl)-Alanine at position 17; or
(iv) the peptide consists of SEQ ID NO: 17 or said variant thereof and the internal cross-linking is a hydrocarbon staple linking (R)-2-(7′-octenyl)-Alanine at position 9 and (S)-2-(4′-pentenyl)-Alanine at position 16.

7. The mimetic peptide according to claim 1 , consisting of SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 20; or a said variant thereof.

8. The mimetic peptide of an epitope of ApoA-I according to claim 1 , wherein said mimetic peptide is selected from the group consisting of:
(i) SEQ ID NO: 8 or SEQ ID NO: 9;
(ii) an amino acid sequence identical to any one of the sequences under (i) except that 1, 2, or 3 amino acids of said sequences are deleted without aborting the capacity of said mimetic peptide to specifically bind to an anti-ApoA-I antibody;
(iii) an amino acid sequence identical to any one of the sequences under (i) except that 1, 2, 3, 4, 5, or 6 amino acids of said sequence are substituted and/or chemically modified, without aborting the capacity of said mimetic peptide to specifically bind to an anti-ApoA-I antibody; and
(iv) any combination of amino acid sequences under (i), (ii), and/or (iii).

9. The mimetic peptide according to claim 8 , wherein the peptide is SEQ ID NO: 8.

10. The mimetic peptide according to claim 6 , having the free amino group at the N-terminal end acetylated and the free carboxy group at the C-terminal end amidated.

11. A pharmaceutical composition comprising at least one mimetic peptide according to claim 1 and at least one pharmaceutically acceptable carrier.

12. A kit for detecting anti-ApoA-I antibodies in a biological fluid sample, comprising at least one mimetic peptide according to claim 1 or a combination thereof for coupling, or already coupled to a solid matrix as solid phase support.

13. A method for detecting endogenous anti-ApoA-I antibodies in a biological fluid sample of a mammalian subject comprising:
(a) contacting said biological fluid sample to a solid matrix having at least one mimetic peptide according to claim 1 coupled thereto, wherein the contacting is under conditions sufficient for binding an anti-ApoA-I antibody present in said biological fluid sample to said at least one mimetic peptide through antigen-antibody interactions;
(c) removing any unbound antibody from the surface of said solid matrix; and
(d) detecting the presence of an antigen-antibody complex bound to said solid matrix wherein the presence of said complex is indicative that the biological fluid sample contains endogenous anti-ApoA-I antibodies, wherein detection of bound antibodies under step (d) is carried out by a detection method selected from an optical detection, a mass variation detection and an electrical detection technique.

14. The method according to claim 13 , wherein the presence of an antigen-antibody complex is indicative that a subject suffers from a cardiovascular disease.

15. The method according to claim 13 , wherein the presence of an antigen-antibody complex is indicative that a subject suffers from at least one disorder selected from the group consisting of acute chest pain, acute coronary syndrome, rheumatoid arthritis, systemic lupus erythematosus, severe carotid stenosis, end-stage renal disease and periodontitis.

16. A method for treating an anti-ApoA-I antibody related cardiovascular disease in a subject in need thereof, the method comprising administering a mimetic peptide according to claim 1 to said subject.

17. The method according to claim 16 , wherein an anti-ApoA-I antibody related cardiovascular disease is selected from the group consisting of acute chest pain and acute coronary syndrome.

18. The method according to claim 16 , wherein said mimetic peptide has an amino acid sequence consisting of SEQ ID NO: 19; or a variant thereof wherein 1, 2, 3, 4, or 5 amino acids of said sequence are substituted and/or chemically modified without aborting the capacity of said mimetic peptide to bind specifically to an anti-ApoAI antibody; or a variant thereof wherein 1, 2, or 3 amino acids of said sequ

Assignees

• Les Hopitaux Univ De Geneve
• Univ Geneve
• Hoffmann La Roche
• Hoffmann La Roche

Inventors

• Vuilleumier Nicolas
• Pagano Sabrina
• Hartley Oliver
• Gaertner Hubert
• Camillo Teixeira Priscila
• Cutler Paul
• Ferber Philippe

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P13/12

  of the kidneys · CPC title