Method of treating atopic dermatitis or asthma using antibody to IL4RA

• US 8,986,691 B1
• Filed: 08/29/2014
• Issued: 03/24/2015
• 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:
  US14/472,828
• Time in Patent Office: 207 Days
• Field of Search: None
• US Class Current: 424/143.1
• CPC Class Codes: C07K 16/2866 against receptors for cytokines, lymphokines, interferons
• CPC Class Codes: C07K 16/40 against enzymes
• 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 2600/158 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 atopic dermatitis or asthma in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a human IL4Ra protein that comprises a mutation selected from the group consisting of:

I75V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO;

67;

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 IL4Ra protein comprising said selected mutation.

2. The method of claim 1, wherein the IL4Ra comprises mutations I75V and Q576R in SEQ ID NO:

67 and optionally the disease is asthma.

3. The method of claim 1, wherein the nucleotide sequence of (ii) comprises nucleotide mutation-3223T (dB SNP numbering).

4. The method of claim 1, wherein said human gamma-4 heavy chain constant region that comprises SEQ ID NO:

73.

5. The method of any preceding claim, wherein the human expresses antibodies comprising human IGHG4*01 heavy chain constant regions.

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 clause 1.

7. The method of claim 1, wherein the human has been determined to comprise the nucleotide sequence that encodes an IL4RA protein comprising said mutation selected from the group consisting of I75V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO:

67 and/or an IL4RA protein comprising said mutation selected from the group consisting of I75V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO;

67.

8. The method of claim 1, comprising the step of determining that the human comprises (a) the nucleotide sequence that encodes an IL4RA protein comprising said mutation selected from the group consisting of I75V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO:

67 and/or (b) an IL4RA protein comprising said mutation said mutation selected from the group consisting of I75V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO;

67, optionally, wherein the determining step is performed before administration of the antibody to the human.

9. The method of claim 6, wherein the human has been determined to comprise the nucleotide sequence that encodes an IL4RA protein comprising said mutation selected from the group consisting of I75V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO:

67 and/or an IL4RA protein comprising said mutation selected from the group consisting of I75V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO;

67.

10. The method of claim 6, comprising the step of determining that the human comprises (a) the nucleotide sequence that encodes an IL4RA protein comprising said mutation selected from the group consisting of I75V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO:

67 and/or (b) an IL4RA protein comprising said mutation said mutation selected from the group consisting of I75V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO;

67, optionally, wherein the determining step is performed before administration of the antibody to the human.

11. The method of claim 8, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding a IL4RA protein comprising said mutation selected from the group consisting of I75V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO:

67.

12. The method of claim 11, 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 IL4RA protein comprising said mutation selected from the group consisting of I75V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO:

67 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises a nucleotide sequence encoding said mutation selected from the group consisting of I75V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO;

67, thereby forming a complex when at least one nucleotide sequence encoding the IL4RA protein comprising said mutation selected from the group consisting of I75V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO;

67 is present; and

detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the IL4RA protein comprising said mutation selected from the group consisting of I75V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO;

67.

13. The method of claim 11, 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.

14. The method of claim 11 or 13, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human.

15. The method of claim 1, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the IL4RA protein comprising said mutation selected from the group consisting of I75V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO:

67, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO;

68, or said human is indicated as homozygous for a nucleotide sequence encoding the IL4RA protein comprising said mutation selected from the group consisting of I75V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO;

67.

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

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

18. The method of claim 1, wherein the nucleotide sequence comprises one or more SNPs selected from the group consisting of rs1805010, rs1805011, rs1805012, rs1805015, rs1801275 and rs1805016.

19. 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.

20. The method of claim 1, wherein the antibody is a human antibody.