Targeting human NAV1.7 variants for treatment of pain

• US 8,992,927 B1
• Filed: 08/29/2014
• Issued: 03/31/2015
• Est. Priority Date: 07/15/2014
• Status: Active Grant

• Current Assignee: Kymab Limited
• Original Assignee: Kymab Limited
• Inventors: Clube, Jasper Rupert
• Primary Examiner(s): WEN, SHARON X
• Application Number:
  US14/472,685
• Time in Patent Office: 214 Days
• Field of Search: None
• US Class Current: 424/146.1
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: C07K 16/28 against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 16/2866 against receptors for cytokines, lymphokines, interferons
• CPC Class Codes: C07K 2317/528 CH4 domain
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational 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 Nav1.7 protein that comprises a mutation selected from the group consisting of:

1161W, 1919G, 490N, 1002L, 422D and 943L in SEQ ID NO;

75;

wherein the antibody or antibody fragment comprises a human gamma-4 heavy chain constant region that comprises an amino acid selected from the group consisting of;

a Leu at position 189 shown in SEQ ID NO;

73 and 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 said selected amino acid;

and wherein

(ii) said human comprises a nucleotide sequence encoding said Nav1.7 protein comprising said selected mutation in SEQ ID NO;

75.

2. The method of claim 1, wherein said amino acid is 1161W.

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

7. 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.

9. The method of claim 1, wherein the human has been determined to comprise the nucleotide sequence that encodes a Nav1.7 protein comprising said amino acid.

10. The method of claim 1, comprising the step of determining that the human comprises (a) the nucleotide sequence that encodes an Nav1.7 protein comprising said amino acid, optionally wherein the determining step is performed before administration of the antibody to the human.

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

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

22. The method of claim 1, wherein said human has been diagnosed with pain.

24. The method of claim 1, wherein the nucleotide sequence comprises one or more SNPs selected from the group consisting of rs6746030, rs3750904, rs58022607, rs4369876, rs13402180 and rs12478318.

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

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

73 or an ADCC inactivated version thereof, optionally wherein the human gamma-4 heavy chain constant region comprises 228P and/or 235E.

3. A method of treating or reducing the risk of pain in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a human Nav1.7 protein encoded by a nucleotide sequence that comprises a SNP selected from the group consisting of:

rs6746030, rs3750904, rs58022607, rs4369876, rs13402180 and rs12478318;

wherein (i) the antibody or fragment comprises a human gamma-4 heavy chain constant region that comprises an amino acid selected from the group consisting of a Leu at position 189 shown in SEQ ID NO;

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

73 and (ii) said human comprises an IGHG4*01 human heavy chain constant region gene segment, or the human expresses antibodies comprising human gamma-4 heavy chain constant regions comprising said amino acid selected from the group consisting of Leu at position 189 shown in SEQ ID NO;

73 and Arg at position 289 shown in SEQ ID NO;

73; and

wherein (iii) said human comprises a nucleotide sequence encoding a human Nav1.7 protein comprising said SNP selected from the group consisting of rs6746030, rs3750904, rs58022607, rs4369876, rs13402180 and rs12478318.

4. The method of claim 3, wherein the SNP is rs6746030.

6. The method of claim 3, wherein the constant region gene segment comprised by said human is a germline gene segment.

8. The method of claim 3 comprising, before said administering, selecting a human comprising said nucleotide sequence of (ii), wherein the human is the human of claim 3.

11. The method of claim 3, wherein the human has been determined to comprise the nucleotide sequence comprising said SNP.

12. The method of claim 3, comprising the step of determining that the human comprises (a) the nucleotide sequence comprising said SNP, optionally wherein the determining step is performed before administration of the antibody to the human.

13. The method of claim 12, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence comprising said SNP.

14. The method of claim 13, 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 an Nav1.7 protein comprising said SNP, thereby forming a complex when at least one 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 the Nav1.7 nucleotide sequence comprising said SNP.

15. The method of claim 13, 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.

16. The method of claim 13, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human.

17. The method of claim 3, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the Nav1.7 protein and comprising said SNP, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO:

76, or said human is indicated as homozygous for a nucleotide sequence encoding the Nav1.7 protein and comprising said SNP.

20. The method of claim 3, wherein said human is or has been further determined to be substantially resistant to a pain treatment.

21. The method of claim 3, wherein said human is receiving or has received a pain treatment or has reduced responsiveness to a pain treatment.

23. The method of claim 3, wherein said human has been diagnosed with pain.

27. The method of claim 3, wherein said antibody or fragment is administered by inhaled, intravenous or subcutaneous administration and/or is comprised in an inhalable or injectable preparation.

28. The method of claim 3, wherein the human gamma-4 heavy chain constant region of the ligand comprises the amino acid sequence of SEQ ID NO:

73 or an ADCC inactivated version thereof, optionally wherein the human gamma-4 heavy chain constant region comprises 228P and/or 235E.