Anti-PCSK9 and methods for treating lipid and cholesterol disorders

• US 8,598,320 B2
• Filed: 10/27/2008
• Issued: 12/03/2013
• Est. Priority Date: 10/26/2007
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme LLC (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: Hedrick, Joseph A., Monsma, Frederick James Jr., Churakova, Tatyana, Hollenbaugh, Diane
• Primary Examiner(s): DUFFY, BRADLEY
• Application Number:
  US12/739,761
• Publication Number:
  US 20110033465A1
• Time in Patent Office: 1,863 Days
• Field of Search: None
• US Class Current: 530/387.3
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 31/397 having four-membered rings, e.g. azetidine
• 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• 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 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 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

Abstract

The present invention provides compositions and methods for treating disorders of cholesterol and lipid metabolism by administration of an anti-PCSK9 antibody or a peptide inhibitor of PCSK9.

Claims

1. An isolated antibody or antigen binding fragment thereof, which binds to a PCSK9 protein, comprising:

(a) CDR-H1 (SEQ ID NO;

     51), CDR-H2 (SEQ ID NO;

     52) and CDR-H3 (SEQ ID NO;

     53) of an immunoglobulin heavy chain variable region which comprises the amino acid sequence of SEQ ID NO;

50; and

(b) CDR-L1 (SEQ ID NO;

     55), CDR-L2 (SEQ ID NO;

     56) and CDR-L3 (SEQ ID NO;

     57) of an immunoglobulin light chain variable region which comprises the amino acid sequence of SEQ ID NO;

54.

2. The antibody or antigen-binding fragment thereof of claim 1, wherein the antibody is selected from the group consisting of:

a monoclonal antibody, a labeled antibody, a bivalent antibody, a bispecific antibody, a chimeric antibody, a recombinant antibody, a humanized antibody or a bispecific antibody.

3. The antibody or antigen binding fragment thereof of claim 1, wherein the antigen binding fragment is selected from the group consisting of:

an scfv, an scfv dimer, a dsfv, a (dsfv)2, a dsFv-dsfv′

, a bispecific ds diabody, an Fv, an Fab′

, an Fab′

, and an F(ab′

)2.

4. The antigen binding fragment of claim 1 which is linked to an immunoglobulin constant region polypeptide.

5. The polypeptide of claim 4 wherein the constant region polypeptide is a κ

light chain, γ

1 heavy chain, γ

2 heavy chain, γ

3 heavy chain or γ

4 heavy chain.

6. A composition comprising the antibody or antigen binding fragment of claim 1 in association with a chemotherapeutic agent.

7. The composition of claim 6, wherein the chemotherapeutic agent is selected from the group consisting of:

a cardiovascular agent, an adrenergic blocker, an antihypertensive agent, an angiotensin system inhibitor, an angiotensin-converting enzyme inhibitor, a coronary vasodilator, a diuretic, an adrenergic stimulant, and an HMG-CoA reductase inhibitor.

8. The composition of claim 7, wherein the chemotherapeutic agent a cardiovascular agent.

9. The composition of claim 6, wherein the chemotherapeutic agent is selected from the group consisting of ezetimibe and simvastatin.