INHIBITORS OF PCSK9 FOR TREATMENT OF LIPOPROTEIN METABOLISM DISORDERS

• US 20180193376A1
• Filed: 03/18/2016
• Published: 07/12/2018
• Est. Priority Date: 03/20/2015
• Status: Active Grant

• Current Assignee: Aarhus Universitet (Ministeriet For Forskning Innovation OG Videregående UD- Dannelser)
• Original Assignee: Aarhus Universitet (Ministeriet For Forskning Innovation OG Videregående UD- Dannelser)
• Inventors: Gustafsen, Camilla, Madsen, Peder Sondergaard, Pedersen, Simon Glerup
• Granted Patent: US 10,688,119 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 31/185 Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids hydroxamic acids A61K31/16; peroxy acids A61K31/327
• CPC Class Codes: A61K 31/727 Heparin; Heparan
• CPC Class Codes: A61K 31/737 Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate A61K31/727 takes precedence
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 16/40 against enzymes
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/622 Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/74 Inducing cell proliferation
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C08B 37/0075 Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present disclosure relates to inhibitors of proprotein convertase subtilisin-like/kexin type 9 (PCSK9) for the treatment of lipoprotein metabolism disorders.

Claims

1. (canceled)

2. An antibody or antigen-binding fragment thereof that specifically binds a binding region within the HSPG binding site of PCSK9 (SEQ ID NO:

1), said site within amino acid residues 78 to 167 of PCSK9 (SEQ ID NO;

     1).

3. The antibody or antigen-binding fragment of claim 2, wherein said compound binds to one or more amino acids selected from the group consisting of R93, R96, R97, R104, R105, K136, H139, R165 and R167 of PCSK9 (SEQ ID NO:

1).

10. The antibody or antigen-binding fragment of claim 2, wherein the fragment is selected from the group consisting of Fab, Fab′

, F(ab′

)₂ and Fv fragments.

11. The antibody or antigen-binding fragment of claim 2, wherein the antibody is a single chain antibody.

13. The antibody or antigen-binding fragment of claim 2, wherein the antibody or antigen-binding fragment thereof comprises:

(i) a heavy chain variable region or a humanized version thereof, comprising at least one of the three CDRs as defined by SEQ ID NO;

10, SEQ ID NO;

11 or SEQ ID NO;

12, and

(ii) a light chain variable region comprising or a humanized version thereof, comprising at least one of the three CDRs as defined by SEQ ID NO;

13, SEQ ID NO;

14 or SEQ ID NO;

15.

14. The antibody or antigen-binding fragment of claim 2 comprising a heavy chain variable region or a humanized version thereof as defined by SEQ ID NO:

7 and/or a light chain variable region or a humanized version thereof as defined by SEQ ID NO;

5.

15. The antibody or antigen-binding fragment of claim 2, wherein the antibody or antigen-binding fragment thereof comprises:

(iii) a heavy chain variable region or a humanized version thereof, comprising at least one of the three CDRs as defined by SEQ ID NO;

16, SEQ ID NO;

17 or SEQ ID NO;

18, and

(iv) a light chain variable region comprising or a humanized version thereof, comprising at least one of the three CDRs as defined by SEQ ID NO;

19, SEQ ID NO;

20 or SEQ ID NO;

21.

16. The antibody or antigen-binding fragment of claim 2, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region or a humanized version thereof as defined by SEQ ID NO:

9 and/or a light chain variable region or a humanized version thereof as defined by SEQ ID NO;

3.

55. A method of treatment of a disorder of lipoprotein metabolism in a subject in need thereof, said method comprising administering to said subject the antibody or antigen-binding fragment as defined in claim 2.

96. The antibody or antigen-binding fragment of claim 2 wherein said site is within the the HSPG binding site of PCSK9 (SEQ ID NO:

1) at amino acid residues 78 to 92, amino acid residues 93 to 97, amino acid residues 98 to 103, amino acid residues 104 to 105, amino acid residues 106 to 135, amino acid residues 136 to 139, amino acid residues 140 to 164, and/or amino acid residues 165 to 167.

97. The antibody or antigen-binding fragment according to claim 2, wherein the antibody or antigen-binding fragment comprises:

(i) a heavy chain variable region or a humanized version thereof, comprising (i) heavy chain CDR1 comprising SEQ ID NO;

10;

(ii) heavy chain CDR2 comprising SEQ ID NO;

11; and

(iii) heavy chain CDR3 comprising SEQ ID NO;

12; and

(ii) a light chain variable region comprising or a humanized version thereof, comprising (i) light chain CDR1 comprising SEQ ID NO;

13;

(ii) light chain CDR2 comprising SEQ ID NO;

14; and

(iii) light chain CDR3 comprising SEQ ID NO;

15.

98. The antibody or antigen-binding fragment according to claim 2, wherein the antibody or antigen-binding fragment comprises:

(i) a heavy chain variable region or a humanized version thereof, comprising (i) heavy chain CDR1 comprising SEQ ID NO;

16;

(ii) heavy chain CDR2 comprising SEQ ID NO;

17; and

(iii) heavy chain CDR3 comprising SEQ ID NO;

18; and

(ii) a light chain variable region comprising or a humanized version thereof, comprising (i) light chain CDR1 comprising SEQ ID NO;

19;

(ii) light chain CDR2 comprising SEQ ID NO;

20; and

(iii) light chain CDR3 comprising SEQ ID NO;

21.

103. The method according to claim 55, wherein the disorder of lipoprotein metabolism is dyslipidemia.

104. The method according to claim 103, wherein the dyslipidemia is hypercholesterolemia, hyperlipidemia or hypertriglyceridemia.

105. The method according to claim 55, wherein the disorder of lipoprotein metabolism is selected from the group consisting of sitosterolemia, metabolic syndrome, xanthoma, obesity and diabetes.

106. The method according to claim 55, wherein the disorder of lipoprotein metabolism is coronary heart disease.

107. The method according to claim 55, wherein the disorder of lipoprotein metabolism is selected from the group consisting of atherosclerosis, arteriosclerosis, acute coronary syndrome, hypertension, angina, and vascular inflammation.

4-9. -9. (canceled)

12. (canceled)

17-34. -34. (canceled)

35. A method of treating a disorder of lipoprotein metabolism in a subject in need thereof comprising administering to said subject a therapeutically acceptable amount of a compound comping comprising heparin, a heparin mimetic, or a heparin analogue.

36. The method of claim 35, wherein the compound:

(a) has a general structure of formula (I);

51. The method of claim 35, wherein the disorder of lipoprotein metabolism is selected from the group consisting of dyslipidemia.

99. The method of claim 51, wherein the dyslipidemia is hypercholesterolemia, hyperlipidemia or hypertriglyceridemia.

100. The method of claim 35 wherein the disorder of lipoprotein metabolism is selected from the group consisting of sitosterolemia, metabolic syndrome, xanthoma, obesity and diabetes.

101. The method according to claim 35, wherein the disorder of lipoprotein metabolism is coronary heart disease.

102. The method according to claim 35, wherein the disorder of lipoprotein metabolism is selected from the group consisting of atherosclerosis, arteriosclerosis, acute coronary syndrome, hypertension, angina, and vascular inflammation.

37-50. -50. (canceled)

52-54. -54. (canceled)

56-95. -95. (canceled)