Precision medicine by targeting rare human PCSK9 variants for cholesterol treatment

• US 10,611,849 B2
• Filed: 11/25/2014
• Issued: 04/07/2020
• Est. Priority Date: 12/17/2013
• Status: Active Grant

• Current Assignee: Kymab Limited (Sanofi )
• Original Assignee: Kymab Limited (Sanofi )
• Inventors: Clube, Jasper Rupert
• Primary Examiner(s): Wen, Sharon X
• Application Number:
  US14/552,816
• Publication Number:
  US 20150166677A1
• Time in Patent Office: 1,960 Days
• Field of Search: None
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07K 16/40 against enzymes
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/62 comprising only variable region components
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material

Abstract

The invention relates to human targets of interest (TOI), anti-TOI ligands, kits compositions and method.

Claims

1. A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need of treatment thereof wherein the human comprises VH segment SNP rs56069819, the method comprising

administering to said human an alirocumab antibody or antibody fragment thereof that specifically binds a human proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises an amino acid variation;

(a) wherein the antibody or fragment comprises a VH domain derived from the recombination of a human VH gene segment, human D gene segment and a human JH gene segment, and

(b) wherein the VH gene segment of (a) comprises SNP rs56069819; and

wherein

(i) the human expresses a PCSK9 comprising said amino acid variation; and

(ii) the human comprises said SNP.

2. The method of claim 1, wherein the VH gene segment of (a) is VH3-23*04 of SEQ ID NO:

39.

3. The method of claim 1, wherein the antibody or fragment comprises a human gamma-1 heavy chain constant region that comprises an Asp corresponding to position 204 of SEQ ID NO:

42 and a Leu corresponding to position 206 of SEQ ID NO;

42.

4. The method of claim 1, wherein the human comprises an IGHG1*01 human heavy chain constant region gene segment.

5. The method of claim 1, wherein the human is or has been determined to be substantially resistant to statin treatment.

6. The method of claim 1, wherein the human is receiving or has received statin treatment or has reduced responsiveness to statin treatment.

7. The method of claim 6, wherein the antibody or fragment is administered to the human separately or simultaneously with the statin treatment.

8. The method of claim 1, wherein the human has been diagnosed with at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication, and high blood pressure.

9. The method of claim 1, wherein the antibody or fragment treats or reduces the risk in the human of at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication, and high blood pressure.

10. The method of claim 1, wherein the antibody or fragment is administered by intravenous or subcutaneous administration and/or is comprised in an injectable preparation.

11. The method of claim 3, wherein the human comprises an IGHG1*01 human heavy chain constant region gene segment.

12. The method of claim 1, wherein the PCSK9 is encoded by the nucleotide sequence of SEQ ID NO:

30, SEQ ID NO;

31 or SEQ ID NO;

37.

13. The method of claim 1, wherein the method comprises administering alirocumab to the human.

14. The method of claim 2, wherein the method comprises administering alirocumab to the human.

15. The method of claim 3, wherein the method comprises administering alirocumab to the human.

16. The method of claim 4, wherein the method comprises administering alirocumab to the human.

17. The method of claim 5, wherein the method comprises administering alirocumab to the human.

18. The method of claim 6, wherein the method comprises administering alirocumab to the human.

19. The method of claim 7, wherein the method comprises administering alirocumab to the human.

20. The method of claim 8, wherein the method comprises administering alirocumab to the human.

21. The method of claim 9, wherein the method comprises administering alirocumab to the human.

22. The method of claim 10, wherein the method comprises administering alirocumab to the human.

23. The method of claim 11, wherein the method comprises administering alirocumab to the human.

24. The method of claim 12, wherein the method comprises administering alirocumab to the human.