Anti-PCSK9 antibodies

• US 10,023,654 B2
• Filed: 12/13/2016
• Issued: 07/17/2018
• 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:
  US15/377,364
• Publication Number:
  US 20170096496A1
• Time in Patent Office: 581 Days
• 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. An antibody or antigen-binding fragment of an antibody that specifically binds hPCSK9, comprising:

a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO;

76;

b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO;

78;

c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO;

80;

d) a light chain complementarity determining region 1 (LCDR1) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO;

84;

e) a light chain complementarity determining region 2 (LCDR2) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO;

86; and

f) a light chain complementarity determining region 3 (LCDR3) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO;

88.

2. The antibody or antigen-binding fragment of an antibody of claim 1, wherein the antibody or antigen-binding fragment of the antibody binds an epitope comprising amino acid residue 238 of hPCSK9 (SEQ ID NO:

755).

3. The antibody or antigen-binding fragment of an antibody of claim 1, wherein the antibody or antigen-binding fragment of the antibody binds a human PCSK9 with GOF mutation D374Y (“

hPCSK9(D374Y)”

).

4. An antibody or antigen-binding fragment of an antibody that specifically binds hPCSK9, comprising a heavy chain variable region comprising an amino acid sequence that is at least 95% identical to SEQ ID NO:

90; and

a light chain variable region comprising an amino acid sequence that is at least 95% identical to SEQ ID NO;

92.

5. The antibody or antigen-binding fragment of an antibody of claim 4, wherein the antibody or antigen-binding fragment of the antibody binds an epitope comprising amino acid residue 238 of hPCSK9 (SEQ ID NO:

755).

6. The antibody or antigen-binding fragment of an antibody of claim 4, wherein the antibody or antigen-binding fragment of the antibody binds a human PCSK9 with GOF mutation D374Y (“

hPCSK9(D374Y)”

).

7. An antibody or antigen-binding fragment of an antibody that specifically binds hPCSK9, comprising:

a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence that is at least 98% identical to SEQ ID NO;

76;

b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence that is at least 98% identical to SEQ ID NO;

78;

c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence that is at least 98% identical to SEQ ID NO;

80;

d) a light chain complementarity determining region 1 (LCDR1) comprising an amino acid sequence that is at least 98% identical to SEQ ID NO;

84;

e) a light chain complementarity determining region 2 (LCDR2) comprising an amino acid sequence that is at least 98% identical to SEQ ID NO;

86; and

f) a light chain complementarity determining region 3 (LCDR3) comprising an amino acid sequence that is at least 98% identical to SEQ ID NO;

88.

8. The antibody or antigen-binding fragment of an antibody of claim 7, wherein the antibody or antigen-binding fragment of the antibody binds an epitope comprising amino acid residue 238 of hPCSK9 (SEQ ID NO:

755).

9. The antibody or antigen-binding fragment of an antibody of claim 7, wherein the antibody or antigen-binding fragment of the antibody binds a human PCSK9 with GOF mutation D374Y (“

hPCSK9(D374Y)”

).

10. An antibody or antigen-binding fragment of an antibody that specifically binds hPCSK9, comprising a heavy chain variable region comprising an amino acid sequence that is at least 98% identical to SEQ ID NO:

90; and

a light chain variable region comprising an amino acid sequence that is at least 98% identical to SEQ ID NO;

92.

11. The antibody or antigen-binding fragment of an antibody of claim 10, wherein the antibody or antigen-binding fragment of the antibody binds an epitope comprising amino acid residue 238 of hPCSK9 (SEQ ID NO:

755).

12. The antibody or antigen-binding fragment of an antibody of claim 10, wherein the antibody or antigen-binding fragment of the antibody binds a human PCSK9 with GOF mutation D374Y (“

hPCSK9(D374Y)”

).

13. An antibody or antigen-binding fragment of an antibody that specifically binds hPCSK9, comprising:

a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence that is at least 99% identical to SEQ ID NO;

76;

b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence that is at least 99% identical to SEQ ID NO;

78;

c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence that is at least 99% identical to SEQ ID NO;

80;

d) a light chain complementarity determining region 1 (LCDR1) comprising an amino acid sequence that is at least 99% identical to SEQ ID NO;

84;

e) a light chain complementarity determining region 2 (LCDR2) comprising an amino acid sequence that is at least 99% identical to SEQ ID NO;

86; and

f) a light chain complementarity determining region 3 (LCDR3) comprising an amino acid sequence that is at least 99% identical to SEQ ID NO;

88.

14. The antibody or antigen-binding fragment of an antibody of claim 13, wherein the antibody or antigen-binding fragment of the antibody binds an epitope comprising amino acid residue 238 of hPCSK9 (SEQ ID NO:

755).

15. The antibody or antigen-binding fragment of an antibody of claim 13, wherein the antibody or antigen-binding fragment of the antibody binds a human PCSK9 with GOF mutation D374Y (“

hPCSK9(D374Y)”

).

16. An antibody or antigen-binding fragment of an antibody that specifically binds hPCSK9, comprising a heavy chain variable region comprising an amino acid sequence that is at least 99% identical to SEQ ID NO:

90; and

a light chain variable region comprising an amino acid sequence that is at least 99% identical to SEQ ID NO;

92.

17. The antibody or antigen-binding fragment of an antibody of claim 16, wherein the antibody or antigen-binding fragment of the antibody binds an epitope comprising amino acid residue 238 of hPCSK9 (SEQ ID NO:

755).

18. The antibody or antigen-binding fragment of an antibody of claim 16, wherein the antibody or antigen-binding fragment of the antibody binds a human PCSK9 with GOF mutation D374Y (“

hPCSK9(D374Y)”

).