1B20 PCSK9 antagonists
View Patent ↗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.
1. An isolated PCSK9-specific antagonist antibody or antigen-binding fragment thereof which comprises:
(a) a heavy chain variable region comprising CDR1, 2 and 3 domains; said CDR1 domain comprising the amino acid sequence set forth in SEQ ID NO: 13; said CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 15; and said CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 17; and
(b) a light chain variable region comprising CDR1, 2 and 3 domains; said CDR1 domain comprising the amino acid sequence set forth in SEQ ID NO: 3; said CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 5, and said CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 7;
wherein said PCSK9-specific antagonist antibody or fragment antagonizes PCSK9-mediated inhibition of cellular LDL uptake.
2. The PCSK9-specific antagonist antibody or antigen-binding fragment thereof Of claim 1 wherein the CDR1, 2 and 3 domains are in a human germline variable region in the respective CDR1, 2 and 3 regions thereof.
3. The PCSK9-specific antagonist antibody or antigen-binding fragment thereof of claim 1 that binds to human PCSK9 with an equilibrium dissociation constant of less than 1200 nM,
4. The PCSK9-specific antagonist antibody or antigen-binding fragment thereof of claim 1 that antagonizes PCSK9-mediated inhibition of cellular LDL uptake at an IC 50 of less than 500 nM.
5. The PCSK9-specific antagonist antibody or antigen-binding fragment thereof of claim 1 that antagonizes PCSK9-mediated inhibition of cellular uptake by at least 20%.
6. The PCSK9-specific antagonist antibody or antigen-binding fragment thereof of claim 1 which comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 11 and/or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 27.
7. The PCSK9-specific antagonist antibody or antigen-binding fragtherit thereof of claim 1 which comprises a heavy chain having constant immunoglobulin sequence comprising the amino acid sequence set forth in SEQ ID NO: 24,
8. An isolated PCSK9-specific antagonist antibody or antigen-binding fragment thereof which comprises:
(a) a light chain comprising the amino acid sequence set forth in SEQ ID NO: 26; and
(b) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 25;
wherein said PCSK9-specific antagonist antibody or fragment antagonizes PCSK9-mediated inhibition of cellular LDL uptake.
9. An isolated PCSK9-specific antagonist antibody or antigen-binding fragment thereof which comprises:
(a) a heavy chain variable region comprising CDR1, 2 and 3 domains; said CDR 1 domain comprising the amino acid sequence set forth in SEQ ID NO: 37; said CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 38; and said CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 39; and a light chain variable region comprising COR1, 2 and 3 domains; said CDR1 domain comprising the amino acid sequence set forth in SEQ ID NO: 40; said CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 41, and said CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 42;
(b) a heavy chain variable region comprising CDR1, 2 and 3 domains; said CDR 1 domain compriing the amino acid sequence set forth in SEQ ID NO: 37; said CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 97; and said CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 98; and a light chain variable region comprising CDR1, 2 and 3 domains; said CDR1 domain comprising the amino acid sequence set forth in SEQ ID NO: 99; said CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 100, and said CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 101; or
(c) a heavy chain variable region comprising the amino acid sequence set forth in any one of SEQ ID NOs: 45-96 or 102-107 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:27;
wherein said PCSK9-specific antagonist antibody or fragment antagonizes PCSK9-mediated inhibition of cellular LDL uptake.
10. A composition comprising the PCSK9-specific antagonist antibody or antigen-binding fragment thereof of claim 1 and a pharmaceutically acceptable carrier.
11. A composition comprising the PCSK9-specific antagonist antibody or antigen-binding fragment thereof of claim 1 and a further therapeutic drug.
12. The Composition of claim 11 wherein the further therapeutic drug is a cholesterol absorption inhibitor or a cholesterol synthesis inhibitor.
13. A composition comprising the PCSK9-specific antagonist antibody or antigen-binding fragment thereof of claim 9 and a pharmaceutically acceptable carrier.
14. An isolated host cell or population of host cells in vitro or in situ comprising a PCSK9-specific antagonist antibody or antigen-binding fragment thereof of claim 1 .
15. The host cell of claim 14 which is a Pichia celIor a Chinese hamster ovary cell.
16. An isolated host cell or population of host cells in vitro or in situ comprising a PCSK9-specific antagonist antibody or antigen-binding fragment thereof of claim 9 .
17. The host cell of claim 16 which is a Pichia cell or a Chinese hamster ovary cell.
18. A method for lowering plasma low density lipoprotein level in a patient which comprises administering the PCSK9-specific antagonist antibody or antigen-binding fragment thereof of claim 1 to the patient.
19. The method of claim 18 wherein the patient is administered a further therapeutic drug.
20. The method of claim 19 wherein the further therapeutic drug is acholesterol absorption inhibitor or a cholesterol synthesis inhibitor.
21. A method for treating a medical condition mediated by PCSK9 activity in a patient comprising administering a therapeutically effective amount of PCSK9-specific antagonist antibody or antigen-binding fragment thereof of claim 1 to the patient.
22. The method of claim 21 wherein the medical condition is hypercholesterolemia, coronary heart disease, metabolic syndrome or acute coronary syndrome.