1B20 PCSK9 antagonists

Patent metadata

Field	Value
Publication number	US-8957194-B2
Application number	US-201213466433-A
Country	US
Kind code	B2
Filing date	May 8, 2012
Priority date	Feb 7, 2008
Publication date	Feb 17, 2015
Grant date	Feb 17, 2015

Abstract

Antagonists of human proprotein convertase subtilisin-kexin type 9 (“PCSK9”) are disclosed. The disclosed antagonists are effective in the inhibition of PCSK9 function and, accordingly, present desirable antagonists for use in the treatment of conditions associated with PCSK9 activity. The present invention also discloses nucleic acid encoding said antagonists, vectors, host cells, and compositions comprising the antagonists. Methods of making PCSK9-specific antagonists as well as methods of using the antagonists for inhibiting or antagonizing PCSK9 function are also disclosed and form important additional aspects of the present disclosure.

First claim

What is claimed is:

1. Isolated nucleic acids encoding a PCSK9-specific antagonist antibody or antigen binding fragment thereof wherein the antibody or antigen binding fragment thereof comprises:
a) a heavy chain variable region comprising CDR 1, 2, and 3 domains having the amino acid sequences of SEQ ID NO: 13, SEQ ID NO: 15, and SEQ ID NO: 17, respectively; and
b) a light chain variable region comprising CDR 1, 2, and 3 domains having the amino acid sequences of SEQ ID NO: 3, SEQ ID NO: 5, and SEQ ID NO:7, respectively; wherein the PCSK9-specific antibody or antigen binding fragment thereof antagonizes PCSK9-mediated inhibition of cellular LDL uptake.

2. The isolated nucleic acids of claim 1 , wherein the antibody or antigen binding fragment thereof comprises:
a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 11; and/or
b) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 27.

3. A vector comprising the nucleic acids of claim 1 .

4. An isolated host cell or population of host cells comprising the nucleic acids of claim 1 .

5. A method for producing a PCSK9-specific antagonist antibody or antigen binding fragment thereof, which comprises:
a) culturing the isolated cell(s) of claim 4 under conditions appropriate for production of the PCSK9-specific antagonist; and
b) isolating the PCSK9-specific antagonist produced.

6. The nucleic acids of claim 1 , wherein:
a) the variable heavy chain region CDRs 1, 2, and 3 are encoded by nucleic acid sequences of SEQ ID NO: 14, SEQ ID NO: 16, and SEQ ID NO: 18U, respectively; and
b) the variable light chain region CDRs 1, 2, and 3 are encoded by nucleic acid sequences of SEQ ID NO: 4, SEQ ID NO: 6, and SEQ ID NO: 8, respectively.

7. The isolated nucleic acids of claim 1 , wherein:
a) the heavy chain variable region is encoded by the nucleic acid sequence of SEQ ID NO: 12 and/or
b) the light chain variable region is encoded by the nucleic acid sequence of SEQ ID NO: 28.

Assignees

• Condra Jon H
• Cubbon Rose M
• Hammond Holly A
• Mccabe Timothy
• Pandit Shilpa
• Peterson Laurence B
• Santoro Joseph C
• Sitlani Ayesha
• Wood Dana D
• Mach Henryk
• Pixley Heidi
• Gregory Sonia M
• Blue Jeffrey T
• Wang Kevin
• Luo Peizhi Peter
• Nawrocki Denise K
• Zhong Pingyu
• Dong Feng
• Li Yan
• Merck Sharpe & Dohme Corp

Inventors

• Condra Jon H
• Cubbon Rose M
• Hammond Holly A
• Mccabe Timothy
• Pandit Shilpa
• Peterson Laurence B
• Santoro Joseph C
• Sitlani Ayesha
• Wood Dana D
• Mach Henryk
• Pixley Heidi
• Gregory Sonia M
• Blue Jeffrey T
• Wang Kevin
• Luo Peizhi Peter
• Nawrocki Denise K
• Zhong Pingyu
• Dong Feng
• Li Yan

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

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• C07K2317/56

  variable (Fv) region, i.e. VH and/or VL · CPC title

• C07K2317/77

  Internalization into the cell · CPC title