Precision medicine for cholesterol treatment

• US 9,914,769 B2
• Filed: 07/15/2014
• Issued: 03/13/2018
• Est. Priority Date: 07/15/2014
• 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:
  US14/331,730
• Publication Number:
  US 20160017051A1
• Time in Patent Office: 1,337 Days
• Field of Search: None
• CPC Class Codes: A61F 2009/00863 Retina
• 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: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61N 5/062 Photodynamic therapy, i.e. excitation of an agent
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/22 against growth factors ; against growth regulators
• CPC Class Codes: C07K 16/2866 against receptors for cytokines, lymphokines, interferons
• CPC Class Codes: C07K 16/40 against enzymes
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: C12Q 2600/172 : Haplotypes

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, the method comprising administering to said human an alirocumab antibody or fragment thereof that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9),

wherein the antibody or fragment thereof comprises:

a human IGHG1*01 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; and

the antibody or fragment thereof comprises;

(i) a VH domain derived from the recombination of a human VH gene segment, human D gene segment and a human JH gene segment, wherein the VH gene segment (a) comprises SNP rs56069819;

or (b) is VH3-23*04 of SEQ ID NO;

38;

or

(ii) a VH domain comprising the framework 1 sequence of SEQ ID NO;

40;

 

and wherein

(iii) said human comprises and expresses an IGHG1*01 human heavy chain constant region gene segment, or the human expresses antibodies comprising human gamma-1 heavy chain constant regions comprising an Asp corresponding to position 204 of SEQ ID NO;

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

42;

(iv) said human comprises said VH gene segment when said antibody or fragment is according to (i);

or expresses a VH domain comprising the framework 1 sequence of SEQ ID NO;

40 when said antibody or fragment is according to (ii); and

(v) said human comprises a nucleotide sequence encoding said PCSK9.

2. The method of claim 1, wherein said human has been diagnosed with at least one condition selected from the group consisting of:

a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication, and high blood pressure.

3. The method of claim 1, further comprising a step of selecting a human comprising said gene segment constant region or domain of (iii) and/or (iv) before administering to said human the antibody or fragment thereof.

4. The method of claim 1, wherein said antibody or fragment thereof reduces the risk in said human of a stroke.

5. The method of claim 2, wherein said antibody or fragment thereof reduces the risk in said human of a stroke.

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

7. The method of claim 1, wherein the human has been determined to comprise the gene segment nucleotide sequence of (iii) or (iv).

8. The method of claim 1, comprising the step of determining that the human comprises the gene segment nucleotide sequence of (iii) and/or (iv) or expresses the gene segment nucleotide sequence of (iii) and/or (iv).

9. The method of claim 8, wherein the determining step is performed before administration of the antibody or fragment thereof to the human.

10. The method of claim 8, wherein the step of determining comprises assaying a biological sample from the human for the gene segment nucleotide sequence of (iii) and/or (iv).

11. The method of claim 10, wherein the assaying comprises contacting the biological sample with

at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides that can specifically hybridize to and identify in the biological sample a nucleotide sequence of (iii) or (iv), or that specifically hybridizes to an antisense of said sequence;

and

detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises said nucleotide sequence of (iii) or (iv).

12. The method of claim 10, wherein the assaying comprises nucleic acid amplification and optionally one or more methods selected from sequencing, next generation sequencing, nucleic acid hybridization, and allele-specific amplification.

13. The method of claim 10, wherein the assaying is performed in a multiplex format.

14. The method of claim 10, further comprising obtaining the biological sample from the human.

15. The method of claim 14, wherein said biological sample comprises serum, blood, feces, tissue, a cell, urine and/or saliva of said human.

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

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

18. The method of claim 1, wherein the human is further administered a statin.

19. The method of claim 18, wherein said antibody or fragment thereof and said statin are administered separately or simultaneously.

20. The method of claim 1, wherein said human is indicated as heterozygous for a nucleotide sequence of (i).

21. The method of claim 20, wherein said human is further indicated as comprising the gene segment nucleotide sequence of (iii) and/or (iv).

22. The method of claim 1, wherein said human is indicated as homozygous for a gene segment nucleotide sequence of (iii) and/or (iv).