Antigen binding proteins to proprotein convertase subtilisin kexin type 9 (PCSK9)

• US 8,883,983 B2
• Filed: 04/24/2014
• Issued: 11/11/2014
• Est. Priority Date: 08/23/2007
• Status: Active Grant

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Inc.
• Inventors: Jackson, Simon Mark, Walker, Nigel Pelham Clinton, Piper, Derek Evan, Shen, Wenyan, King, Chadwick Terence, Ketchem, Randal Robert, Mehlin, Christopher, Carabeo, Teresa Arazas
• Primary Examiner(s): WEN, SHARON X
• Application Number:
  US14/261,065
• Publication Number:
  US 20140228547A1
• Time in Patent Office: 201 Days
• Field of Search: None
• US Class Current: 530/388.26
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/22 of acyclic acids, e.g. pravastatin
• CPC Class Codes: A61K 31/366 having six-membered rings, e.g. delta-lactones
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/405 Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/66 Phosphorus compounds
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• 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 2299/00 : Coordinates from 3D structures of peptides, e.g. proteins or enzymes
• CPC Class Codes: C07K 2317/14 : Specific host cells or culture conditions, e.g. components, pH or temperature
• CPC Class Codes: C07K 2317/34 : Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C12N 15/1137 : against enzymes viral enzymes C12N15/1131; receptors C12N15/1138

Abstract

Antigen binding proteins that interact with Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) are described. Methods of treating hypercholesterolemia and other disorders by administering a pharmaceutically effective amount of an antigen binding protein to PCSK9 are described. Methods of detecting the amount of PCSK9 in a sample using an antigen binding protein to PCSK9 are described.

Claims

1. An isolated monoclonal antibody that binds an epitope on hPCSK9 comprising one or more of residues 207, 208, 162, 164, 167, 132, 351, 390, 413, 123, 129, 311, 313, or 337 of SEQ ID NO:

1, and wherein the monoclonal antibody blocks binding of PCSK9 to LDLR.

2. The isolated monoclonal antibody of claim 1, wherein the isolated monoclonal antibody is a neutralizing antibody.

3. The isolated monoclonal antibody of claim 2, wherein the isolated monoclonal antibody is a human antibody.

4. The isolated monoclonal antibody of claim 2, wherein the epitope comprises a structural epitope.

5. The isolated monoclonal antibody of claim 4, wherein the epitope comprises residue R207.

6. The isolated monoclonal antibody of claim 4, wherein the epitope comprises residue D208.

7. The isolated monoclonal antibody of claim 4, wherein the epitope comprises residue D162.

8. The isolated monoclonal antibody of claim 4, wherein the epitope comprises residue R164.

9. The isolated monoclonal antibody of claim 4, wherein the epitope comprises residue E167.

10. The isolated monoclonal antibody of claim 4, wherein the epitope comprises residue T132.

11. The isolated monoclonal antibody of claim 4, wherein the epitope comprises residue S351.

12. The isolated monoclonal antibody of claim 4, wherein the epitope comprises residue A390.

13. The isolated monoclonal antibody of claim 4, wherein the epitope comprises residue A413.

14. The isolated monoclonal antibody of claim 4, wherein the epitope comprises residue S123.

15. The isolated monoclonal antibody of claim 4, wherein the epitope comprises residue E129.

16. The isolated monoclonal antibody of claim 4, wherein the epitope comprises residue A311.

17. The isolated monoclonal antibody of claim 4, wherein the epitope comprises residue D313.

18. The isolated monoclonal antibody of claim 4, wherein the epitope comprises residue D337.

19. The isolated monoclonal antibody of claim 1, wherein the epitope comprises at least two of residues 207, 208, 162, 164, 167, 132, 351, 390, 413, 123, 129, 311, 313, or 337 of SEQ ID NO:

1.

20. The isolated monoclonal antibody of claim 1, wherein the epitope comprises at least three of residues 207, 208, 162, 164, 167, 132, 351, 390, 413, 123, 129, 311, 313, or 337 of SEQ ID NO:

1.

21. The isolated monoclonal antibody of claim 1, wherein the epitope comprises at least four of residues 207, 208, 162, 164, 167, 132, 351, 390, 413, 123, 129, 311, 313, or 337 of SEQ ID NO:

1.

22. The isolated human monoclonal antibody of claim 1, wherein the isolated monoclonal antibody was produced by a CHO cell.

23. The isolated human monoclonal antibody of claim 1, wherein the isolated monoclonal antibody binds to PCSK9 with a K_D of less than or equal to 5×

10<sup>−

9</sup> M.

24. The isolated human monoclonal antibody of claim 1, wherein the isolated monoclonal antibody comprises a light chain region that comprises an amino acid sequence of SEQ ID NO:

157.

25. An isolated monoclonal neutralizing antibody specific for PCSK9 that binds at least one of amino acid residues 207, 208, 162, 164, 167, 132, 351, 390, 413, 123, 129, 311, 313, or 337 of SEQ ID NO:

1, and wherein the monoclonal antibody blocks binding of PCSK9 to LDLR.

26. The isolated monoclonal neutralizing antibody of claim 25, wherein the isolated monoclonal neutralizing antibody is human, and wherein the isolated monoclonal neutralizing antibody comprises a light chain that comprises the amino acid sequence of SEQ ID NO:

157.

27. The isolated monoclonal neutralizing antibody of claim 25, wherein the isolated monoclonal antibody binds to at least two of amino acid residues 207, 208, 162, 164, 167, 132, 351, 390, 413, 123, 129, 311, 313, or 337 of SEQ ID NO:

1.

28. The isolated monoclonal neutralizing antibody of claim 25, wherein the isolated monoclonal antibody binds to at least three of amino acid residues 207, 208, 162, 164, 167, 132, 351, 390, 413, 123, 129, 311, 313, or 337 of SEQ ID NO:

1.

29. The isolated monoclonal neutralizing antibody of claim 25, wherein the isolated monoclonal antibody binds to at least four of amino acid residues 207, 208, 162, 164, 167, 132, 351, 390, 413, 123, 129, 311, 313, or 337 of SEQ ID NO:

1.

30. The isolated monoclonal neutralizing antibody of claim 25, wherein the isolated monoclonal antibody competes for binding to PCSK9 with an antibody comprising a heavy chain variable region having an amino acid sequence of SEQ ID NO:

49 and a light chain variable region having an amino acid sequence of SEQ ID NO;

23.