ANTIGEN BINDING PROTEINS TO PROPROTEIN CONVERTASE SUBTILISIN KEXIN TYPE 9 (PCSK9)

• US 20090326202A1
• Filed: 05/28/2009
• Published: 12/31/2009
• Est. Priority Date: 08/23/2007
• Status: Active Grant

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Inc.
• Inventors: Chan, Joyce Chi Yee, Shen, Wenyan, Jackson, Simon Mark, Shan, Bei, King, Chadwick Terence
• Granted Patent: US 8,563,698 B2
• Time in Patent Office: Days
• US Class Current: 530/387.1
• 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

1-36. -36. (canceled)

37. An isolated PCSK9-specific antagonist that antagonizes PCSK9'"'"'s inhibition of cellular LDL uptake.

38. An isolated PCSK9-specific antagonist that antagonizes PCSK9'"'"'s inhibition of cellular LDL uptake and binds to human PCSK9 with an equilibrium dissociation constant (KD) of less than 1200 nM.

39. The PCSK9-specific antagonist of claim 38 that binds to human PCSK9 with a KD of less than 500 nM.

40. The PCSK9-specific antagonist of claim 38 that binds to human PCSK9 with a KD of less than 100 nM.

41. The PCSK9-specific antagonist of claim 38 that binds to human PCSK9 with a KD of less than 5 nM.

42. An isolated PCSK9-specific antagonist that antagonizes PCSK9'"'"'s inhibition of cellular LDL uptake at an IC₅₀ of less than 500 nM.

43. The PCSK9-specific antagonist of claim 42 that antagonizes PCSK9'"'"'s inhibition of cellular LDL uptake at an IC₅₀ of less than 200 nM.

44. The PCSK9-specific antagonist of claim 42 that antagonizes PCSK9'"'"'s inhibition of cellular LDL uptake at an IC₅₀ of less than 100 nM.

45. An isolated PCSK9-specific antagonist that antagonizes PCSK9'"'"'s inhibition of cellular LDL uptake by at least 20%.

46. An isolated PCSK9-specific antagonist that antagonizes PCSK9'"'"'s inhibition of cellular LDL uptake by at least 50%.

47. An isolated PCSK9-specific antagonist that antagonizes PCSK9'"'"'s inhibition of cellular LDL uptake by at least 60%.

48. An isolated PCSK9-specific antibody molecule that antagonizes PCSK9'"'"'s inhibition of cellular uptake by at least 20%.

49. An isolated antigen binding molecule that binds to PCSK9 and reduces PCSK9'"'"'s ability to inhibit cellular LDL uptake.

50. The isolated antigen binding molecule of claim 49, wherein the antigen binding molecule is an isolated antigen binding protein.

51. An isolated antigen binding molecule that reduces PCSK9'"'"'s ability to inhibit LDL uptake by cells and binds to human PCSK9 with an equilibrium dissociation constant (K_D) of less than 10⁻

6 M.

52. The isolated antigen binding molecule of claim 51, wherein the isolated antigen binding molecule is an antigen binding protein.

53. The isolated antigen binding protein of claim 52 that binds to human PCSK9 with a K_D of less than 10⁻

7 M.

54. The isolated antigen binding protein of claim 52 that binds to human PCSK9 with a K_D of less than 10⁻

8 M.

55. The isolated antigen binding protein of claim 52 that binds to human PCSK9 with a K_D of less than 10⁻

8 or less than 10<sup>−

9</sup> M.

56. An isolated antigen binding molecule that binds to PCSK9 and reduces PCSK9'"'"'s inhibition of cellular LDL uptake at an IC₅₀ of no more than 100 nM.

57. The isolated antigen binding molecule of claim 56, wherein the antigen binding molecule is an antigen binding protein, and where the IC₅₀ is 100 nM.

59. An isolated antigen binding molecule that binds to PCSK9 and reduces PCSK9'"'"'s inhibition of cellular LDL uptake by at least about 25%.

60. The isolated antigen binding molecule of claim 59, wherein the antigen binding molecule is an antigen binding protein and wherein the antigen binding protein reduces PCSK9'"'"'s inhibition of cellular LDL uptake by about 50%.

61. The isolated antigen binding molecule of claim 59, wherein the antigen binding molecule is an antigen binding protein and wherein the antigen binding protein reduces PCSK9'"'"'s inhibition of cellular LDL uptake by at least about 50%.

62. An isolated PCSK9-specific antibody that binds to PCSK9 and reduces PCSK9'"'"'s inhibition of cellular LDL uptake by at least about 25%.

63. The isolated PCSK9-specific antibody of claim 62 that binds to PCSK9 and reduces PCSK9'"'"'s inhibition of cellular LDL uptake by about 25%.

64. The isolated PCSK9-specific antibody of claim 62 that binds to PCSK9 and reduces PCSK9'"'"'s inhibition of cellular LDL uptake by at least about 50%.

65. The isolated PCSK9-specific antibody of claim 62 that binds to PCSK9 and reduces PCSK9'"'"'s inhibition of cellular LDL uptake by about 50%.