Method of treating rheumatoid arthritis using antibody to IL6R

• US 9,017,678 B1
• Filed: 08/12/2014
• Issued: 04/28/2015
• 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:
  US14/457,536
• Time in Patent Office: 259 Days
• Field of Search: None
• US Class Current: 424/143.1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/118 Prognosis of disease development
• 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 or reducing the risk of rheumatoid arthritis in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds an IL6R protein that comprises a mutation Asp358Ala or Val385Ile in SEQ ID NO:

78;

wherein the antibody or fragment comprises a VH domain derived from the recombination of a human VH segment, a human D gene segment and a human JH segment, the human VH segment encoding (i) a CDR1 comprising a Phe at position 4 shown in SEQ ID NO;

109 and wherein said human comprises a VH gene segment encoding a CDR1 comprising a Phe at position 4 shown in SEQ ID NO;

109, or the human expresses VH domains that comprise a CDR1 comprising a Phe at position 4 shown in SEQ ID NO;

109;

or (ii) a FW3 comprising a Thr at position 33 shown in SEQ ID NO;

111 and wherein said human comprises a VH gene segment encoding a FW3 comprising a Thr at position 33 shown in SEQ ID NO;

111 or the human expresses VH domains that comprise a FW3 comprising a Thr at position 33 shown in SEQ ID NO;

111; and

wherein said human comprises a nucleotide sequence encoding said IL6R protein comprising said Asp358Ala or Val385Ile in SEQ ID NO;

78.

5. The method of claim 1, wherein said VH domain is derived from the recombination of human VH segment IGHV3-9*01, a human D gene segment and a human JH segment;

and said human comprises human VH segment IGHV3-9*01 or expresses VH domains derived from the recombination of human VH gene segment IGHV3-9*01, a human D gene segment and a human JH segment.

7. The method of claim 1, wherein said VH domain comprises the FW3 sequence of SEQ ID NO:

111.

9. The method of claim 1, wherein the antibody or fragment comprises a human gamma-1 heavy chain comprising said VH domain and a human gamma-1 heavy chain constant region that comprises an Asp at position 204 shown in SEQ ID NO:

81 and a Leu at position 206 shown in SEQ ID NO;

81 and wherein said human comprises an IGHG1*01 human heavy chain constant region gene segment.

10. The method of claim 1, wherein the antibody or fragment comprises an IGHG1*01 human heavy chain constant region.

11. The method of claim 1, wherein the human is of AMR, ASN or EUR ancestry.

12. 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.

14. The method of claim 1, wherein the human has been determined to comprise the nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO:

78 and/or an IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO;

78.

16. The method of claim 1, comprising the step of determining that the human comprises the nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or Val385Ile and/or an IL6R protein comprising said mutation Asp358Ala and/or Val385Ile, optionally, wherein the determining step is performed before administration of the antibody to the human.

17. The method of claim 16, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding a IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO:

78.

18. The method of claim 17, 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 IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO:

78 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises a nucleotide sequence encoding said mutation Asp358Ala and/or Val385Ile in SEQ ID NO;

78, thereby forming a complex when at least one nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO;

78 is present; and

detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO;

78.

19. The method of claim 17, 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.

20. The method of claim 17, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human.

21. The method of claim 1, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or Val385Ile in SEQ ID NO:

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

79, or said human is indicated as homozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or Val385Ile in SEQ ID NO;

78.

22. The method of claim 1, wherein said human is or has been further determined to be substantially resistant to an anti-TNF alpha treatment.

23. The method of claim 1, wherein said human is receiving or has received an anti-TNF alpha treatment or has reduced responsiveness to an anti-TNF alpha treatment.

24. The method of claim 1, wherein said antibody or antibody fragment is administered to the human separately or simultaneously with methotrexate or an anti-TNF alpha treatment.

25. The method of claim 1, wherein the nucleotide sequence comprises SNP rs2228145 and/or SNP rs28730736.

26. The method of claim 1, wherein said antibody or antibody fragment is administered by intravenous or subcutaneous administration or is comprised in an injectable preparation.

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

2. A method of treating or reducing the risk of an IL6R-mediated disease or condition in a human in need thereof, the method comprising administering to said human an antibody or fragment that specifically binds an IL6R protein that comprises a mutation Asp358Ala or Val385Ile in SEQ ID NO:

78;

wherein the antibody or fragment comprises a VH domain derived from the recombination of a human VH gene segment, a human D gene segment and a human JH segment, the human VH gene segment comprising (a) T at nucleotide number 86 shown in SEQ ID NO;

84 and wherein said human comprises a VH gene segment comprising T at nucleotide number 86 shown in SEQ ID NO;

84;

or (b) C at nucleotide number 272 shown in SEQ ID NO;

84 and wherein said human comprises a VH gene segment comprising T at nucleotide number 272 shown in SEQ ID NO;

84; and

wherein said human comprises a nucleotide sequence encoding said IL6R protein comprising said Asp358Ala or Val385Ile in SEQ ID NO;

78.

3. The method of claim 2, wherein each said human VH gene segment comprises SEQ ID NO:

108.

4. The method of claim 2, wherein each said human VH gene segment comprises SEQ ID NO:

110.

6. The method of claim 2, wherein said VH domain is derived from the recombination of human VH segment IGHV3-9*01, a human D gene segment and a human JH segment;

and said human comprises human VH segment IGHV3-9*01 or expresses VH domains derived from the recombination of human VH gene segment IGHV3-9*01, a human D gene segment and a human JH segment.

8. The method of claim 2, wherein the VH gene segment comprised by said human is a germline VH gene segment.

13. The method of claim 2 comprising, before said administering, selecting a human comprising said nucleotide sequence of (ii), wherein the human is the human of claim 2.

15. The method of claim 2, wherein the human has been determined to comprise the nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO:

78 and/or an IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO;

78.