Method of reducing total cholesterol level by administering matrilin-2 polypeptide
The present invention provides, in part, methods and compositions for treating lipid disorders comprising administering a polypeptide that inhibits PCSK9. A novel method for identifying polypeptides that interact with PCSK9 is also provided.
1. A method for reducing total cholesterol level, low density lipoprotein cholesterol level, apolipoprotein B level, total cholesterol/high density lipoprotein ratio or low density lipoprotein/high density lipoprotein ratio, comprising administering to a patient with a disorder of cholesterol or lipid homeostasis, a therapeutically effective amount of a composition comprising matrilin-2 polypeptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 1, amino acids 24-956 of SEQ ID NO: 2 and SEQ ID NO: 2.
2. The method of claim 1 , wherein the matrilin-2 polypeptide binds specifically to a Proprotein Convertase Subtilisin/kexin 9 (PCSK9) catalytic domain in SEQ ID NO: 46 or to a domain of PCSK9 which interacts with an LDL receptor EGF-A domain.
3. The method of claim 1 , wherein the matrilin-2 polypeptide is administered with another chemotherapeutic agent.
4. The method of claim 3 , wherein the chemotherapeutic agent is selected from the group consisting of ezetimibe and simvastatin.
5. The method of claim 1 , wherein the polypeptide is fused to an immunoglobulin.
6. The method of claim 5 , wherein the immunoglobulin is a γ1 or γ4 or monomeric variant thereof.
7. The method of claim 6 wherein the immunoglobulin comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 5-9.
8. The method of claim 1 , wherein the matrilin-2 polypeptide comprises the amino acid sequence of SEQ ID NO: 1.
9. The method of claim 1 , wherein the matrilin-2 polypeptide comprises amino acids 24-956 of SEQ ID NO: 2.
10. A method for treating hypercholesterolemia, comprising administering to a patient with the disorder of cholesterol or lipid homeostasis, a therapeutically effective amount of a composition comprising matrilin-2 polypeptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 1, amino acids 24-956 of SEQ ID NO: 2 and SEQ ID NO: 2.
11. The method of claim 10 , wherein the matrilin-2 polypeptide binds specifically to a Proprotein Convertase Subtilisin/kexin (PCSK9) catalytic domain in SEQ ID NO: 46 or to a domain of PCSK9 which interacts with an LDL receptor EGF-A domain.
12. The method of claim 10 , wherein the matrilin-2 polypeptide is administered with another chemotherapeutic agent.
13. The method of claim 12 , wherein the chemotherapeutic agent is selected from the group consisting of ezetimibe and simvastatin.
14. The method of claim 10 , wherein the polypeptide is fused to an immunoglobulin.
15. The method of claim 14 , wherein the immunoglobulin is a γ1 or γ4 or monomeric variant thereof.
16. The method of claim 15 wherein the immunoglobulin comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 5-9.
17. The method of claim 10 , wherein the matrilin-2 polypeptide comprises the amino acid sequence of SEQ ID NO: 1.
18. The method of claim 10 , wherein the matrilin-2 polypeptide comprises amino acids 24-956 of SEQ ID NO: 2.