Targeting human nav1.7 variants for treatment of pain

• US 8,986,694 B1
• Filed: 08/29/2014
• Issued: 03/24/2015
• 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:
  US14/472,698
• Time in Patent Office: 207 Days
• Field of Search: None
• US Class Current: 424/146.1
• CPC Class Codes: C07K 16/2866 against receptors for cytokines, lymphokines, interferons
• CPC Class Codes: C07K 16/40 against enzymes
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding

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-2 heavy chain constant region that comprises an amino acid selected from the group consisting of;

a Pro at position 72 shown in SEQ ID NO;

6;

an Asn at position 75 shown in SEQ ID NO;

6;

a Phe at position 76 shown in SEQ ID NO;

6;

a Val at position 161 shown in SEQ ID NO;

6 and an Ala at position 257 shown in SEQ ID NO;

6; and

wherein said human comprises

(i) an IGHG2*01 human heavy chain constant region gene segment, or the human expresses antibodies comprising human gamma-2 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.

6. The method of claim 5, 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 a 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-2 heavy chain constant region of the antibody or fragment comprises IGHG2*01 amino acid sequence or an ADCC inactivated version thereof.

27. 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.

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-2 heavy chain constant region that comprises an amino acid selected from the group consisting of;

a Pro at position 72 shown in SEQ ID NO;

6;

an Asn at position 75 shown in SEQ ID NO;

6;

a Phe at position 76 shown in SEQ ID NO;

6;

a Val at position 161 shown in SEQ ID NO;

6 and an Ala at position 257 shown in SEQ ID NO;

6; and

and (ii) said human comprises an IGHG2*01 human heavy chain constant region gene segment, or the human expresses antibodies comprising human gamma-2 heavy chain constant regions comprising said amino acid selected from the group consisting of;

a Pro at position 72 shown in SEQ ID NO;

6;

an Asn at position 75 shown in SEQ ID NO;

6;

a Phe at position 76 shown in SEQ ID NO;

6;

a Val at position 161 shown in SEQ ID NO;

6 and an Ala at position 257 shown in SEQ ID NO;

6; 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.

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 a 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.

28. The method of claim 3, wherein the human gamma-2 heavy chain constant region of the antibody or fragment comprises IGHG2*01 amino acid sequence or an ADCC inactivated version thereof.