Therapeutic uses of anti-PCSK9 antibodies

• US 9,550,837 B2
• Filed: 06/12/2015
• Issued: 01/24/2017
• Est. Priority Date: 12/15/2008
• Status: Active Grant

• Current Assignee: Regeneron Pharmaceuticals Incorporated
• Original Assignee: Regeneron Pharmaceuticals Incorporated
• Inventors: Sleeman, Mark W., Martin, Joel H., Huang, Tammy T., MacDonald, Douglas
• Primary Examiner(s): STANFIELD, CHERIE MICHELLE
• Application Number:
  US14/737,488
• Publication Number:
  US 20150284474A1
• Time in Patent Office: 592 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate 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 39/08 Clostridium, e.g. Clostridium tetani
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/12 of the kidneys
• 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 3/04 Anorexiants; Antiobesity agents
• 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 5/14 of the thyroid hormones, e.g. T3, T4
• 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 16/1282 from Clostridium (G)
• CPC Class Codes: C07K 16/40 against enzymes
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/33 Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• 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 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/76 : 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 15/09 : Recombinant DNA-technology
• CPC Class Codes: C12Y 304/21061 : Kexin (3.4.21.61), i.e. proprotein convertase subtilisin/kexin type 9
• CPC Class Codes: G01N 2333/33 : from Clostridium (G)
• CPC Class Codes: G01N 33/56911 : Bacteria
• CPC Class Codes: Y10S 424/809 : involving immunoglobulin or antibody fragment, e.g. fab', fv, fc, heavy chain or light chain

Abstract

An human antibody or antigen-binding fragment of a human antibody that specifically binds and inhibits human proprotein convertase subtilisin/kexin type 9 (hPCSK9) characterized by the ability to reduce serum LDL cholesterol by 40-80% over a 24, 60 or 90 day period relative to predose levels, with little or no reduction in serum HDL cholesterol and/or with little or no measurable effect on liver function, as determined by ALT and AST measurements.

Claims

1. A method for treating a subject selected from the group consisting of:

a subject indicated for LDL apheresis, a subject with a PCSK9 gain of function mutation, and a subject with primary hypercholesterolemia who is statin intolerant or statin uncontrolled, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof which specifically binds hPCSK9, wherein the antibody or antigen-binding fragment comprises the heavy and light chain CDRs of a HCVR/LCVR amino acid sequence pair selected from the group consisting of SEQ ID NOs;

90/92 and 218/226.

2. The method of claim 1, wherein the antibody or antigen-binding fragment comprises heavy and light chain CDR amino acid sequences having SEQ ID NOs:

220, 222, 224, 228, 230 and 232.

3. The method of claim 2, wherein the antibody or antigen-binding fragment comprises an HCVR having the amino acid sequence of SEQ ID NO:

218 and an LCVR having the amino acid sequence of SEQ ID NO;

226.

4. The method of claim 1, wherein the antibody or antigen-binding fragment comprises heavy and light chain CDR amino acid sequences having SEQ ID NOs:

76, 78, 80, 84, 86 and 88.

5. The method of claim 4, wherein the antibody or antigen-binding fragment comprises an HCVR having the amino acid sequence of SEQ ID NO:

90 and an LCVR having the amino acid sequence of SEQ ID NO;

92.

6. The method of claim 1, wherein the antibody or antigen-binding fragment binds to the same epitope on hPCSK9 as an antibody comprising heavy and light chain CDR amino acid sequences having SEQ ID NOs:

220, 222, 224, 228, 230 and 232;

or SEQ ID NOs;

76, 78, 80, 84, 86 and 88.

7. The method of claim 1, wherein the antibody or antigen-binding fragment competes for binding to hPCSK9 with an antibody comprising heavy and light chain CDR amino acid sequences having SEQ ID NOs:

220, 222, 224, 228, 230 and 232;

or SEQ ID NOs;

76, 78, 80, 84, 86 and 88.

8. The method of claim 1, wherein the subject has familial hypercholesterolemia (FH).

9. The method of claim 8, wherein the familial hypercholesterolemia is heterozygous familial hypercholesterolemia (heFH).

10. The method of claim 8, wherein the familial hypercholesterolemia is homozygous familial hypercholesterolemia (hoFH).