Anti-PCSK9 antibodies and use thereof

Patent metadata

Field	Value
Publication number	US-9255154-B2
Application number	US-201313795674-A
Country	US
Kind code	B2
Filing date	Mar 12, 2013
Priority date	May 8, 2012
Publication date	Feb 9, 2016
Grant date	Feb 9, 2016

Abstract

The present invention is directed to antibodies and fragments thereof having binding specificity for PCSK9. Another embodiment of this invention relates to the antibodies described herein, and binding fragments thereof, comprising the sequences of the V H , V L and CDR polypeptides described herein, and the polynucleotides encoding them. The invention also contemplates conjugates of anti-PCSK9 antibodies and binding fragments thereof conjugated to one or more functional or detectable moieties. The invention also contemplates methods of making said anti-PCSK9 antibodies and binding fragments thereof. Embodiments of the invention also pertain to the use of anti-PCSK9 antibodies, and binding fragments thereof, for the diagnosis, assessment and treatment of diseases and disorders associated with PCSK9.

First claim

What is claimed is:

1. An isolated antibody or antigen-binding fragment thereof that binds to proprotein convertase subtilisin/kexin type 9 (PCSK9), comprising a heavy chain and a light chain that each comprise complementarity determining regions (CDRs), wherein:
(a) the variable heavy chain comprises the CDR1 sequence of SEQ ID NO: 4, the CDR2 sequence of SEQ ID NO: 6, and the CDR3 sequence of SEQ ID NO: 8; and the variable light chain comprises the CDR1 sequence of SEQ ID NO: 24, the CDR2 sequence of SEQ ID NO: 26, and the CDR3 sequence of SEQ ID NO: 28; or
(b) the variable heavy chain comprises the CDR1 sequence of SEQ ID NO: 684, the CDR2 sequence of SEQ ID NO: 686, and the CDR3 sequence of SEQ ID NO: 688; and the variable light chain comprises the CDR1 sequence of SEQ ID NO: 704, the CDR2 sequence of SEQ ID NO: 706, and the CDR3 sequence of SEQ ID NO: 708; or
(c) the variable heavy chain comprises the CDR1 sequence of SEQ ID NO: 724, the CDR2 sequence of SEQ ID NO: 726, and the CDR3 sequence of SEQ ID NO: 728; and the variable light chain comprises the CDR1 sequence of SEQ ID NO: 744, the CDR2 sequence of SEQ ID NO: 746, and the CDR3 sequence of SEQ ID NO: 748; or
(d) the variable heavy chain comprises the CDR1 sequence of SEQ ID NO: 764, the CDR2 sequence of SEQ ID NO: 766, and the CDR3 sequence of SEQ ID NO: 768; and the variable light chain comprises the CDR1 sequence of SEQ ID NO: 784, the CDR2 sequence of SEQ ID NO: 786, and the CDR3 sequence of SEQ ID NO: 788; or
(e) the variable heavy chain comprises the CDR1 sequence of SEQ ID NO: 844, the CDR2 sequence of SEQ ID NO: 846, and the CDR3 sequence of SEQ ID NO: 848; and the variable light chain comprises the CDR1 sequence of SEQ ID NO: 864, the CDR2 sequence of SEQ ID NO: 866, and the CDR3 sequence of SEQ ID NO: 868.

2. The antibody or antigen-binding fragment thereof of claim 1 , wherein:
(i) the variable heavy chain comprises a sequence at least 90% identical to SEQ ID NO: 2, the variable light chain comprises a sequence at least 90% identical to SEQ ID NO: 22, and the variable heavy and light chains comprise the CDRs according to (a); or
(ii) the variable heavy chain comprises a sequence at least 90% identical to SEQ ID NO: 682, the variable light chain comprises a sequence at least 90% identical to SEQ ID NO: 702, and the variable heavy and light chains comprise the CDRs according to (b); or
(iii) the variable heavy chain comprises a sequence at least 90% identical to SEQ ID NO: 722, the variable light chain comprises a sequence at least 90% identical to SEQ ID NO: 742, and the variable heavy and light chains comprise the CDRs according to (c); or
(iv) the variable heavy chain comprises a sequence at least 90% identical to SEQ ID NO: 762, the variable light chain comprises a sequence at least 90% identical to SEQ ID NO: 782, and the variable heavy and light chains comprise the CDRs according to (d); or
(v) the variable heavy chain comprises a sequence at least 90% identical to SEQ ID NO: 842, the variable light chain comprises a sequence at least 90% identical to SEQ ID NO: 862, and the variable heavy and light chains comprise the CDRs according to (e).

3. The antibody or antigen-binding fragment thereof of claim 1 , wherein:
(i) the variable heavy chain comprises a sequence at least 95% identical to SEQ ID NO: 2, the variable light chain comprises a sequence at least 95% identical to SEQ ID NO: 22, and the variable heavy and light chains comprise the CDRs according to (a); or
(ii) the variable heavy chain comprises a sequence at least 95% identical to SEQ ID NO: 682, the variable light chain comprises a sequence at least 95% identical to SEQ ID NO: 702, and the variable heavy and light chains comprise the CDRs according to (b); or
(iii) the variable heavy chain comprises a sequence at least 95% identical to SEQ ID NO: 722, the variable light chain comprises a sequence at least 95% identical to SEQ ID NO: 742, and the variable heavy and light chains comprise the CDRs according to (c); or
(iv) the variable heavy chain comprises a sequence at least 95% identical to SEQ ID NO: 762, the variable light chain comprises a sequence at least 95% identical to SEQ ID NO: 782, and the variable heavy and light chains comprise the CDRs according to (d); or
(v) the variable heavy chain comprises a sequence at least 95% identical to SEQ ID NO: 842, the variable light chain comprises a sequence at least 95% identical to SEQ ID NO: 862, and the variable heavy and light chains comprise the CDRs according to (e).

4. The antibody or antigen-binding fragment thereof of claim 1 , wherein:
(i) the variable heavy chain comprises SEQ ID NO: 2, the variable light chain comprises SEQ ID NO: 22, and the variable heavy and light chains comprise the CDRs according to (a); or
(ii) the variable heavy chain comprises SEQ ID NO: 682, the variable light chain comprises SEQ ID NO: 702, and the variable heavy and light chains comprise the CDRs according to (b); or
(iii) the variable heavy chain comprises SEQ ID NO: 722, the variable light chain comprises SEQ ID NO: 742, and the variable heavy and light chains comprise the CDRs according to (c); or
(iv) the variable heavy chain comprises SEQ ID NO: 762, the variable light chain comprises SEQ ID NO: 782, and the variable heavy and light chains comprise the CDRs according to (d); or
(v) the variable heavy chain comprises SEQ ID NO: 842, the variable light chain comprises SEQ ID NO: 862, and the variable heavy and light chains comprise the CDRs according to (e).

5. The antibody or antigen-binding fragment thereof of claim 1 , which is selected from the group consisting of chimeric, humanized, and human antibodies or antibody fragments, and scFvs, Fab fragments, Fab′ fragments, monovalent antibody fragments, and F(ab′)2 fragments.

6. The antibody or antigen-binding fragment thereof of claim 1 , which lacks N-glycosylation and/or O-glycosylation.

7. The antibody or antigen-binding fragment thereof of claim 1 , which comprises a human constant domain.

8. The antibody or antigen-binding fragment thereof of claim 7 , wherein said human constant domain comprises an IgG1, IgG2, IgG3, or IgG4 constant domain.

9. The antibody or antigen-binding fragment thereof of claim 1 , which comprises an Fc region that has been modified to alter at least one of effector function, half-life, proteolysis, or glycosylation.

10. The antibody or antigen-binding fragment thereof of claim 9 , wherein the Fc region contains one or more mutations that alters or eliminates N- and/or O-glycosylation.

11. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof is humanized.

12. The antibody or antigen-binding fragment thereof of claim 1 , which when administered to a human subject inhibits or neutralizes at least one biological effect elicited by PCSK9.

13. The antibody or antigen-binding fragment thereof of claim 1 , which, when administered to a human subject, reduces serum cholesterol and/or inhibits the binding of PCSK9 to LDLR.

14. The antibody or antigen-binding fragment thereof of claim 1 , which binds to human PCSK9 with a K D that is less than about 100 nM.

15. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof is attached to one or more detectable moieties.

16. The antibody or antigen-binding fragment thereof of claim 15 , wherein the detectable moiety comprises a fluorescent dye, enzyme, substrate, bioluminescent material, radioactive material, chemiluminescent moiety, or mixtures thereof.

Assignees

• Alderbio Holdings Llc
• Alderbio Holdings Llc

Inventors

• Feldhaus Andrew Lawrence
• Garcia-Martinez Leon F
• Dutzar Benjamin H
• Ojala Ethan Wayne
• Kovacevich Brian Robert
• Anderson Katie Olson
• Fan Pei
• Billgren Jens
• Stewart Erica Ann
• Akatsuka Corinne C
• Mcneill Patricia Dianne
• Mitchell Danielle Marie
• Allison Dan Scott
• Latham John A

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P9/12

  Antihypertensives · CPC title