Monoclonal antibodies to proprotein convertase subtilisin kexin type 9 (PCSK9)

• US 9,920,134 B2
• Filed: 06/30/2011
• Issued: 03/20/2018
• 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, Shan, Bei, Shen, Wenyan, Chan, Joyce Chi Yee, King, Chadwick Terrence, Ketchem, Randal Robert, Mehlin, Christopher, Carabeo, Teresa Arazas, Cao, Qiong
• Primary Examiner(s): Wen, Sharon X
• Application Number:
  US13/174,423
• Publication Number:
  US 20120093818A1
• Time in Patent Office: 2,455 Days
• 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. A monoclonal antibody that binds to a PCSK9 protein, wherein the PCSK9 protein comprises the amino acid sequence of SEQ ID NO:

1, wherein the monoclonal antibody comprises a light chain complementarity determining region (CDR) CDR1 that is a CDR1 in SEQ ID NO;

46;

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

46; and

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

46, and wherein the monoclonal antibody comprises a heavy chain CDR1 that is a CDR1 in SEQ ID NO;

60;

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

60; and

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

60.

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

3. The monoclonal antibody of claim 1 that selectively binds to PCSK9, wherein said monoclonal antibody binds to PCSK9 with a K_d that is less than 100 pM.

4. The monoclonal antibody of Claim 1, wherein the monoclonal antibody binds to a PCSK 9 protein of SEQ ID NO:

303 in a first manner, wherein the monoclonal antibody binds to a variant of PCSK9 in a second manner, wherein said PCSK9 variant has at least one point mutation at a position selected from the group consisting of;

207, 208, 162, 164, and 167 of SEQ ID NO;

303, wherein the first manner comprises a first EC50, a first Bmax, or a first EC50 and a first Bmax, wherein the second manner comprises a second EC50, a second Bmax, ora second EC50 and a second Bmax, and wherein a value for the first manner is different from a value for the second manner.

5. The monoclonal antibody of claim 4, wherein the first manner comprises a first Bmax, wherein the second manner comprises a second Bmax that is different from the first Bmax, and wherein said PCSK9 variant has at least one point mutation selected from the group consisting of:

D162R, R164E, and E167R.

6. The monoclonal antibody of claim 4, wherein the monoclonal antibody binds to PCSK9 at a location that overlaps with a location that LDLR binds to PCSK9.

7. The monoclonal antibody of Claim 2, wherein when the monoclonal antibody is bound to PCSK9, the monoclonal antibody is positioned 5 angstroms or less from at least one of the following residues of PCSK9:

5153, S188, 1189, Q190, S191, D192, R194, E197, G198, R199, V200, D224, R237, D238, K243, S373, D374, 5376, T377, or F379.

8. The monoclonal antibody of Claim 1, wherein said monoclonal antibody binds to human PCSK9 with a K_D of 1×

10⁻

7 or tighter.

9. The monoclonal antibody of Claim 1, wherein said monoclonal antibody binds to human PCSK9 with a K_D of 1×

10⁻

9 or tighter.

10. The monoclonal antibody of Claim 1, wherein said monoclonal antibody binds to human PCSK9 with a K_D in a picoMolar range.

11. The monoclonal antibody of Claim 1, wherein said monoclonal antibody binds to human PCSK9 with a K_D in a nanoMolar range.

12. The monoclonal antibody of Claim 1, wherein said monoclonal antibody binds to murine PCSK9 with a K_D in a nanoMolar range.

13. The monoclonal antibody of Claim 1, wherein said monoclonal antibody binds to cynomolgus monkey PCSK9 with a K_D in a picoMolar range.

14. The monoclonal antibody of Claim 1, wherein said monoclonal antibody is a human antibody.

15. The monoclonal antibody of Claim 1, wherein said monoclonal antibody is a humanized antibody.

16. The monoclonal antibody of Claim 1, wherein said monoclonal antibody is neutralizing antibody.

17. The monoclonal antibody of claim 1, wherein the monoclonal antibody comprises a light chain comprising an amino acid sequence of SEQ ID NO:

46, and wherein the monoclonal antibody comprises a heavy chain comprising an amino acid sequence of SEQ ID NO;

60.