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

• US 8,030,457 B2
• Filed: 08/22/2008
• Issued: 10/04/2011
• Est. Priority Date: 08/23/2007
• Status: Active Grant

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Inc.
• Inventors: Shen, Wenyan, Jackson, Simon Mark, Shan, Bei, King, Chadwick Terence
• Primary Examiner(s): WEN, SHARON X
• Application Number:
  US12/197,093
• Publication Number:
  US 20090142352A1
• Time in Patent Office: 1,138 Days
• Field of Search: None
• US Class Current: 530/388.24
• 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 neutralizing antigen binding protein that binds to a PCSK9 protein comprising the amino acid sequence of SEQ ID NO:

1, wherein the neutralizing antigen binding protein comprises;

a heavy chain polypeptide comprising the following complementarity determining regions (CDRs);

a heavy chain CDR1 that is a CDR1 in SEQ ID NO;

49;

a heavy chain CDR2 that is a CDR2 in SEQ ID NO;

49;

a heavy chain CDR3 that is a CDR3 in SEQ ID NO;

49 and a light chain polypeptide comprising the following CDRs;

a light chain CDR1 that is a CDR1 in SEQ ID NO;

23;

a light chain CDR2 that a CDR2 in SEQ ID NO;

23; and

a light chain CDR3 that is a CDR3 in SEQ ID NO;

23.

2. The isolated neutralizing antigen binding protein of claim 1, wherein the antigen binding protein is a LDLR competitive neutralizing antigen binding protein.

3. A pharmaceutical composition comprising at least one antigen binding protein according to claim 1, and a pharmaceutically acceptable excipient.

4. The isolated neutralizing antigen binding protein of claim 1, wherein the heavy chain polypeptide comprises all three of the following amino acid sequences:

SEQ ID NO;

308, SEQ IDNO;

175, and SEQ ID NO;

180.

5. The isolated neutralizing antigen binding protein of claim 1, wherein the heavy chain polypeptide comprises all three of the following amino acid sequences:

SEQ ID NO;

368, SEQ ID NO;

175, and SEQ ID NO;

180.

6. The isolated neutralizing antigen binding protein of claim 1, wherein the light chain polypeptide comprises all three of the following amino acid sequences:

SEQ ID NO;

158, SEQ ID NO;

162, and SEQ ID NO;

395.

7. The isolated neutralizing antigen binding protein of claim 6, wherein the heavy chain polypeptide comprises all three of the following amino acid sequences:

SEQ ID NO;

308, SEQ ID NO;

175, and SEQ ID NO;

180.

8. The isolated neutralizing antigen binding protein of claim 6, wherein the heavy chain polypeptide comprises all three of the following amino acid sequences:

SEQ ID NO;

368, SEQ ID NO;

175, and SEQ ID NO;

180.

9. The isolated neutralizing antigen binding protein of claim 1, wherein the light chain polypeptide comprises:

a CDR1 comprising SEQ ID NO;

158, a CDR2 comprising SEQ ID NO;

162, and a CDR3 comprising SEQ ID NO;

395.

10. The isolated neutralizing antigen binding protein of claim 1, wherein the heavy chain polypeptide comprises:

a CDR1 comprising SEQ ID NO;

308, a CDR2 comprising SEQ ID NO;

175, and a CDR3 comprising SEQ ID NO;

180.

11. The isolated neutralizing antigen binding protein of claim 1, wherein the heavy chain polypeptide comprises:

a CDR1 comprising SEQ ID NO;

368, a CDR2 comprising SEQ ID NO;

175, and a CDR3 comprising SEQ ID NO;

180.

12. The isolated neutralizing antigen binding protein of claim 10, wherein the light chain polypeptide comprises:

a CDR1 comprising SEQ ID NO;

158, a CDR2 comprising SEQ ID NO;

162, and a CDR3 comprising SEQ ID NO;

395.

13. The isolated neutralizing antigen binding protein of claim 11, wherein the light chain polypeptide comprises:

a CDR1 comprising SEQ ID NO;

158, a CDR2 comprising SEQ ID NO;

162, and a CDR3 comprising SEQ ID NO;

395.

14. The isolated neutralizing antigen binding protein of claim 1, wherein the heavy chain polypeptide comprises SEQ ID NO:

49 and the light chain polypeptide comprises SEQ ID NO;

23.

15. The isolated neutralizing antigen binding protein of claim 1, wherein each CDR is defined in accordance with the Kabat definition, the Chothia definition, the combination of the Kabat definition and the Chothia definition, the AbM definition, or the contact definition of CDR.

16. The isolated neutralizing antigen binding protein of claim 15, wherein each CDR is defined in accordance with the CDR definition of Kabat.

17. The isolated neutralizing antigen binding protein of claim 15, wherein each CDR is defined in accordance with the CDR definition of Chothia.

18. The isolated neutralizing antigen binding protein of claim 15, wherein each CDR is defined in accordance with the combination of the Kabat definition and the Chothia definition.

19. An isolated neutralizing human monoclonal antibody that binds to a PCSK9 protein comprising:

a heavy chain polypeptide comprising the following complementarity determining regions (CDRs);

a heavy chain CDR1 that is a CDR1 in SEQ ID NO;

49;

a heavy chain CDR2 that is a CDR2 in SEQ ID NO;

49;

a heavy chain CDR3 that is a CDR3 in SEQ ID NO;

49; and

a light chain polypeptide comprising the following CDRs;

a light chain CDR1 that is a CDR1 in SEQ ID NO;

23;

a light chain CDR2 that a CDR2 in SEQ ID NO;

23; and

a light chain CDR3 that is a CDR3 in SEQ ID NO;

23,

wherein each CDR is defined in accordance with the CDR definition of Kabat.

20. The isolated neutralizing human monoclonal antibody of claim 19, wherein the heavy chain polypeptide comprises all three of the following amino acid sequences:

SEQ ID NO;

308, SEQ ID NO;

175, and SEQ ID NO;

180.

21. The isolated neutralizing human monoclonal antibody of claim 19, wherein the heavy chain polypeptide comprises all three of the following amino acid sequences:

SEQ ID NO;

368, SEQ ID NO;

175, and SEQ ID NO;

180.

22. The isolated neutralizing human monoclonal antibody of claim 20, wherein the light chain polypeptide comprises all three of the following sequences:

SEQ ID NO;

158, SEQ ID NO;

162, and SEQ ID NO;

395.

23. The isolated neutralizing human monoclonal antibody of claim 21, wherein the light chain polypeptide comprises all three of the following sequences:

SEQ ID NO;

158, SEQ ID NO;

162, and SEQ ID NO;

395.

24. The isolated neutralizing human monoclonal antibody of claim 19, wherein the heavy chain polypeptide comprises SEQ ID NO:

49 and the light chain polypeptide comprises SEQ ID NO;

23.

25. An isolated neutralizing human monoclonal antibody that binds to a PCSK9 protein comprising:

a heavy chain polypeptide comprising;

the amino acid sequence of SEQ ID NO;

180;

the amino acid sequence of SEQ ID NO;

175; and

the amino acid sequence of SEQ ID NO;

308; and

a light chain polypeptide comprising;

the amino acid sequence of SEQ ID NO;

395;

the amino acid sequence of SEQ ID NO;

162; and

the amino acid sequence of SEQ ID NO;

158.

26. An isolated neutralizing human monoclonal antibody that binds to a PCSK9 protein comprising:

a heavy chain polypeptide comprising the following complementarity determining regions (CDRs);

a heavy chain CDR1 that is a CDR1 in SEQ ID NO;

308 or a CDR1 in SEQ ID NO;

368;

a heavy chain CDR2 that is a CDR2 in SEQ ID NO;

175;

a heavy chain CDR3 that is a CDR3 in SEQ ID NO;

180; and

a light chain polypeptide comprising the following CDRs;

a light chain CDR1 that is a CDR1 in SEQ ID NO;

158;

a light chain CDR2 that is a CDR2 in SEQ ID NO;

162; and

a light chain CDR3 that is a CDR3 in SEQ ID NO;

395.

27. An isolated neutralizing human monoclonal antibody that binds to a PCSK9 protein comprising:

a heavy chain polypeptide comprising the following complementarity determining regions (CDRs);

a heavy chain CDR1 that is a CDR1in SEQ ID NO;

49;

a heavy chain CDR2 that is a CDR2 in SEQ ID NO;

49;

a heavy chain CDR3 that is a CDR3 in SEQ ID NO;

49, wherein the heavy chain polypeptide comprises;

the amino acid sequence of SEQ ID NO;

180;

the amino acid sequence of SEQ ID NO;

175; and

the amino acid sequence of SEQ ID NO;

308; and

a light chain polypeptide comprising the following CDRs;

a light chain CDR1 that is a CDR1 in SEQ ID NO;

23;

a light chain CDR2 that a CDR2 in SEQ ID NO;

23; and

a light chain CDR3 that is a CDR3 in SEQ ID NO;

23, wherein the light chain polypeptide comprises;

the amino acid sequence of SEQ ID NO;

395;

the amino acid sequence of SEQ ID NO;

162; and

the amino acid sequence of SEQ ID NO;

158.