Precision medicine by targeting human NAV1.9 variants for treatment of pain

• US 9,139,648 B1
• Filed: 03/23/2015
• Issued: 09/22/2015
• 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:
  US14/665,579
• Time in Patent Office: 183 Days
• Field of Search: None
• 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 pain in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a human Nav1.9 protein that comprises a mutation in SEQ ID NO:

137, the mutation being selected from the group consisting of;

I381T, K419N, A582T, A681D, A842P, L1158P, F1689L, L811P, R225C, A808G, V909I, R86G, T1609I and G481E;

wherein

(i) the antibody or fragment comprises a human gamma-4 heavy chain constant region that comprises a Leu at position 189 shown in SEQ ID NO;

73 or an Arg at position 289 shown in SEQ ID NO;

73 and wherein said human comprises

(i) an IGHG4*01 human heavy chain constant region gene segment, or the human expresses antibodies comprising human gamma-4 heavy chain constant regions comprising a Leu at position 189 shown in SEQ ID NO;

73 or an Arg at position 289 shown in SEQ ID NO;

73; and

wherein

(ii) said human comprises a nucleotide sequence encoding said Nav1.9 protein comprising said selected mutation in SEQ ID NO;

137.

2. The method of claim 1, wherein said mutation is selected from the group consisting of I381T, K419N, A582T, A681D, A842P, L1158P and F1689L.

3. The method of claim 2, wherein the condition is small fibre neuropathy, numbness, tingling, cramps, joint pain, decreased vibration sensitivity or abnormal warmth or cold sensation.

4. The method of claim 1, wherein said mutation is A808G or R225C.

5. The method of claim 1, wherein the constant region gene segment comprised by said human is a germline gene segment.

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

7. The method of claim 1, wherein the human has been determined to comprise the nucleotide sequence that encodes a Nav1.9 protein comprising said selected mutation and/or a Nav1.9 protein comprising said selected mutation.

8. The method of claim 1, comprising the step of determining that the human comprises (a) the nucleotide sequence that encodes a Nav1.9 protein comprising said selected mutation and/or (b) a Nav1.9 protein comprising said selected mutation, optionally, wherein the determining step is performed before administration of the antibody to the human.

9. The method of claim 8, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding a Nav1.9 protein comprising said selected mutation.

10. The method of claim 9, wherein the assaying comprises

contacting the biological sample with at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides of a nucleotide sequence encoding a Nav1.9 protein comprising said selected mutation or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises a nucleotide sequence encoding said selected mutation, thereby forming a complex when at least one nucleotide sequence encoding the Nav1.9 protein comprising said selected mutation is present;

and

detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the Nav1.9 protein comprising said selected mutation.

11. 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 and/or wherein the assaying is performed in a multiplex format.

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

13. The method of claim 1, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the Nav1.9 protein comprising said selected mutation, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO:

138 or said human is indicated as homozygous for a nucleotide sequence encoding the Nav1.9 protein comprising said selected mutation.

14. The method of claim 1, wherein said human is or has been further determined to be substantially resistant to a pain or itching treatment.

15. The method of claim 1, wherein said human is receiving or has received a pain or itching treatment or has reduced responsiveness to a pain or itching treatment.

16. The method of claim 1, wherein said pain is neuropathic pain or inflammatory pain.

17. The method of claim 1, wherein said method reduces a symptom of neuropathic pain or inflammatory pain.

18. The method of claim 1, wherein said human has been diagnosed with neuropathic pain or inflammatory pain.

19. The method of claim 1, wherein said antibody or antibody fragment treats or reduces the risk in said human of neuropathic pain or inflammatory pain.

20. The method of claim 1, wherein the nucleotide sequence comprises one or more SNPs selected from the group consisting of rs33985936, rs78812474, rs72869687 and rs13059805.

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

22. The method of claim 1, wherein the human gamma-4 heavy chain constant region of the antibody or fragment comprises the amino acid sequence of SEQ ID NO:

73 or an ADCC inactivated version thereof.

23. The method of claim 1, wherein the human gamma-4 heavy chain constant region comprises 228P and 235E.

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