METHODS OF TREATING ANAEMIA

• US 20160158357A1
• Filed: 02/11/2016
• Published: 06/09/2016
• Est. Priority Date: 07/15/2014
• Status: Active Grant

• Current Assignee: Kymab Limited
• Original Assignee: Kymab Limited
• Inventors: Clube, Jasper Rupert
• Granted Patent: US 9,439,963 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 38/177 Receptors; Cell surface antigens; Cell surface determinants
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: C07K 14/705 Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748
• 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 16/28 against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 16/40 against enzymes
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• 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 2317/732 Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/734 Complement-dependent cytotoxicity [CDC]
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: C07K 2319/70 containing domain for protein-protein interaction
• 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

Abstract

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

Claims

1. A method of treating or reducing the risk of anaemia in a human, the method comprising administering an anti-target-of-interest (TOI) trap, antibody or antibody fragment to the human, wherein the TOI is selected from (a) to (h):

(a) a bone morphogenetic protein 6 (BMP6) and the trap, antibody or antibody fragment specifically binds a human BMP6 encoded by a BMP6 nucleotide sequence comprising a SNP rs111588693;

(b) a human hemochromatosis protein (HFE) and the trap, antibody or antibody fragment specifically binds a human HFE encoded by a HFE nucleotide sequence comprising a SNP rs1799945 or rs1800562;

(c) a ferroportin and the trap, antibody or antibody fragment specifically binds a human ferroportin encoded by a ferroportin nucleotide sequence comprising a SNP rs11568350;

(d) a haemojuvelin and the trap, antibody or antibody fragment specifically binds a human haemojuvelin encoded by a haemojuvelin nucleotide sequence comprising a SNP rs7540883;

(e) a hepcidin and the trap, antibody or antibody fragment specifically binds a human hepcidin encoded by a hepcidin nucleotide sequence comprising a SNP rs146776859;

(f) a Matriptase-2 (TMPRSS6) and the trap, antibody or antibody fragment specifically binds a human TMPRSS6 encoded by a TMPRSS6 nucleotide sequence comprising a SNP rs855791, rs2543519 or rs2235324;

(g) a cubilin (CUBN) and the trap, antibody or antibody fragment specifically binds a human CUBN encoded by a CUBN nucleotide sequence comprising a SNP rs10904850 or rs1801224;

or

(h) a transferrin and the trap, antibody or antibody fragment specifically binds a human transferrin encoded by a transferrin nucleotide sequence comprising a SNP rs3811647; and

wherein the trap, antibody or antibody fragment comprises a human kappa chain constant region that comprises a Val at position 84 shown in SEQ ID NO;

93 or a Cys at position 87 shown in SEQ ID NO;

93 and wherein said human comprises

(i) an IGKC1*01 human kappa chain constant region gene segment, or the human expresses antibodies comprising human kappa chain constant regions comprising a Val corresponding to position 84 shown in SEQ ID NO;

93 or a Cys at position 87 shown in SEQ ID NO;

93; and

(ii) said nucleotide sequence encoding the selected TOI, wherein the nucleotide sequence comprises said SNP.

2. The method of claim 1, wherein the human is homozygous for said selected SNP.

3. The method of claim 1, wherein the anaemia is associated with a disease or condition selected from the group consisting of:

Anaemia of Chronic Inflammation (ACI);

Anaemia of Chronic Disease (ACD); and

anaemia associated with cancer, a kidney condition or graft versus host disease (GvHD).

4. The method of claim 1, comprising, before said administering, selecting a human comprising said TOI nucleotide sequence of (ii), wherein the human is the human of claim 1.

5. The method of claim 1, wherein the human has been determined to comprise said TOI nucleotide sequence of (ii).

6. The method of claim 1, comprising the step of determining that the human comprises said TOI nucleotide sequence of (ii), optionally, wherein the determining step is performed before administration of the trap, antibody, or antibody fragment to the human.

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

11. The method of claim 1, wherein said human is receiving or has received an anaemia treatment or has reduced responsiveness to an anaemia treatment.

13. The method claim 1, wherein said trap, antibody or fragment is administered by intravenous or subcutaneous injection or is comprised in an injectable preparation.

14. The method of claim 1, wherein the trap, antibody or fragment is human.

15. The method of claim 1, wherein said human is or has been further determined to be substantially resistant to an EPO anaemia treatment.

16. The method of claim 1, wherein said human is receiving or has received an EPO anaemia treatment or has reduced responsiveness to an EPO anaemia treatment.

9. The method of claim 9, 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 or wherein the assaying is performed in a multiplex format.

7. The method of claim 8, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding the selected TOI and comprising said selected SNP.

8. The method of claim 9, wherein the assaying comprises contacting the biological sample with

a. 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 comprising said selected SNP or that specifically hybridizes to an antisense of said sequence, wherein said nucleic acid hybridizes to said selected SNP or hybridizes to an antisense sequence thereby forming a complex when at least one nucleotide sequence comprising said selected SNP is present;

and/or

b. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides of a nucleotide sequence comprising said selected SNP or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises said selected SNP thereby forming a complex when the nucleotide sequence comprising said selected SNP is present; and

c. detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises a nucleotide sequence encoding the selected TOI and comprising said selected SNP.

12. The method of claim 9, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine or saliva of said human.

17. A method of treating or reducing the risk of anaemia in a human patient in need thereof, the improvement comprising administering an anti-target-of-interest (TOI) trap, antibody or antibody fragment to the human, wherein the TOI is selected from (a) to (h):

(a) a bone morphogenetic protein 6 (BMP6) and the trap, antibody or antibody fragment specifically binds a human BMP6 encoded by a BMP6 nucleotide sequence comprising a SNP rs111588693;

(b) a human hemochromatosis protein (HFE) and the trap, antibody or antibody fragment specifically binds a human HFE encoded by a HFE nucleotide sequence comprising a SNP rs1799945 or rs1800562;

(c) a ferroportin and the trap, antibody or antibody fragment specifically binds a human ferroportin encoded by a ferroportin nucleotide sequence comprising a SNP rs11568350;

(d) a haemojuvelin and the trap, antibody or antibody fragment specifically binds a human haemojuvelin encoded by a haemojuvelin nucleotide sequence comprising a SNP rs7540883;

(e) a hepcidin and the trap, antibody or antibody fragment specifically binds a human hepcidin encoded by a hepcidin nucleotide sequence comprising a SNP rs146776859;

(f) a Matriptase-2 (TMPRSS6) and the trap, antibody or antibody fragment specifically binds a human TMPRSS6 encoded by a TMPRSS6 nucleotide sequence comprising a SNP rs855791, rs2543519 or rs2235324;

(g) a cubilin (CUBN) and the trap, antibody or antibody fragment specifically binds a human CUBN encoded by a CUBN nucleotide sequence comprising a SNP rs10904850 or rs1801224;

or

(h) a transferrin and the trap, antibody or antibody fragment specifically binds a human transferrin encoded by a transferrin nucleotide sequence comprising a SNP rs3811647; and

wherein the trap, antibody or antibody fragment comprises a human kappa chain constant region that comprises a Val at position 84 shown in SEQ ID NO;

93 or a Cys at position 87 shown in SEQ ID NO;

93 and wherein said human comprises

(i) an IGKC1*01 human kappa chain constant region gene segment, or the human expresses antibodies comprising human kappa chain constant regions comprising a Val corresponding to position 84 shown in SEQ ID NO;

93 or a Cys at position 87 shown in SEQ ID NO;

93; and

(ii) said nucleotide sequence encoding the selected TOI, wherein the nucleotide sequence comprises said SNP.

18. The method of claim 17, wherein the human patient is homozygous for said selected SNP.

19. The method of claim 17, comprising, before said administering, selecting a human patient comprising said TOI nucleotide sequence, wherein the human is the human of claim 17.

20. The method of claim 17, wherein the human patient has been determined to comprise said TOI nucleotide sequence.

21. The method of claim 17, comprising the step of determining that the human haemodialysis patient comprises said TOI nucleotide sequence, optionally, wherein the determining step is performed before administration of the trap, antibody, or antibody fragment to the human.

22. The method of claim 17, wherein the step of determining comprises assaying a biological sample from the human haemodialysis patient for a nucleotide sequence encoding said SNP.

23. The method of claim 22, 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 comprising said SNP or that specifically hybridizes to an antisense of said sequence, wherein said nucleic acid hybridizes to said SNP or hybridizes to an antisense sequence thereby forming a complex when at least one nucleotide sequence comprising said SNP is present;

and/or

at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides of a nucleotide sequence comprising said SNP or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises said SNP thereby forming a complex when the nucleotide sequence comprising said SNP is present; and

detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises a nucleotide sequence encoding TMPRSS6 and comprising said SNP.

24. The method of claim 22, 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 or wherein the assaying is performed in a multiplex format.

25. The method of claim 22, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine or saliva of said human.

26. The method of claim 17, wherein said human patient is or has been further determined to be substantially resistant to an anaemia treatment.

27. The method of claim 17, wherein said human patient is receiving or has received an anaemia treatment or has reduced responsiveness to an anaemia treatment.

28. The method of claim 17, wherein said trap, antibody, or antibody fragment is administered by intravenous or subcutaneous injection or is comprised in an injectable preparation.

29. The method of claim 17, wherein the trap, antibody, or antibody fragment is a human trap, antibody, or antibody fragment.