Precision Medicine by targeting VEGF-A variants for treatment of retinopathy

• US 9,062,105 B1
• Filed: 11/07/2014
• Issued: 06/23/2015
• 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:
  US14/536,129
• Time in Patent Office: 228 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61F 2009/00863 Retina
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61N 5/062 Photodynamic therapy, i.e. excitation of an agent
• 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 16/2866 against receptors for cytokines, lymphokines, interferons
• CPC Class Codes: C07K 16/40 against enzymes
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• 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 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• 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
• CPC Class Codes: C12Q 2600/172 : Haplotypes

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 retinopathy in a human, the method comprising administering to said human an anti-VEGF-A ligand that specifically binds to a human VEGF-A that is expressed by a VEGF-A nucleotide sequence comprising a SNP selected from the group consisting of:

rs699947;

rs833061;

rs2010963;

rs3025039;

rs699946;

rs2146323;

rs1413711;

rs833068;

rs833069;

rs3025000 and rs1570360;

wherein the ligand comprises a human gamma-1 heavy chain constant region that comprises an amino acid selected from the group consisting of;

an Asp corresponding to position 204 of SEQ ID NO;

42 and a Leu corresponding to position 206 of SEQ ID NO;

42; and

wherein said human comprises

(i) an IGHG1*01 human heavy chain constant region gene segment, or the human expresses antibodies comprising human gamma-1 heavy chain constant regions comprising said selected amino acid and

(ii) a VEGF-A nucleotide sequence comprising said selected SNP.

2. The method of claim 1, wherein the ligand is an anti-VEGF-A trap;

antibody;

or antibody fragment.

3. The method of claim 1, wherein the retinopathy is diabetic retinopathy (DR) or retinopathy of prematurity (ROP).

4. The method of claim 1, wherein the SNP is selected from the group consisting of rs699947, rs833061, rs2010963, rs3025039 and rs699946;

optionally wherein the human is homozygous for said SNP.

5. The method of claim 1, wherein the SNP is selected from the group consisting of rs699947, rs2146323, rs1413711, rs699946, rs833068, rs833069 and rs3025000;

optionally wherein the human is homozygous for said SNP.

6. The method of claim 1, wherein the method further comprises treating the human with photodynamic therapy.

7. The method of claim 1, wherein the human comprises

A:

(a) a HTRA1 nucleotide sequence comprising SNP rs11200638;

(b) an ARMS2 nucleotide sequence comprising SNP rs10490924;

(c) a CFH nucleotide sequence comprising SNP rs800292, a T at the position of rs1061170 or an A at the position of rs3766404;

(d) a complement component 2 (C2) nucleotide sequence comprising SNP rs547154;

(e) a prothrombin nucleotide sequence comprising SNP rs1799963;

(f) a MTHFR nucleotide sequence comprising SNP rs1801133;

(g) a Factor V nucleotide sequence comprising SNP rs6025;

or (h) a VEGFR2 nucleotide sequence comprising SNP rs4576072 or rs6828477;

or

B;

(a′

) a HTRA1 nucleotide sequence comprising SNP rs11200638;

(b′

) an ARMS2 nucleotide sequence comprising SNP rs10490924;

(c′

) a CFH nucleotide sequence comprising SNP rs800292;

or (d′

) a complement component 2 (C2) nucleotide sequence comprising SNP rs547154;

or

C;

(i) an ARMS2 nucleotide sequence comprising a G at the position of SNP rs10490924;

(ii) a CFH nucleotide sequence comprising a T at the position of SNP rs1061170 or rs3766404;

(iii) a prothrombin nucleotide sequence comprising SNP rs1799963;

(iv) a MTHFR nucleotide sequence comprising SNP rs1801133;

(v) a Factor V nucleotide sequence comprising SNP rs6025;

or (vi) a VEGFR2 nucleotide sequence comprising SNP rs4576072 or rs6828477.

8. The method of claim 1, wherein the ligand comprises an IGHG1*01 human heavy chain constant region.

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

10. The method of claim 1, wherein the human has been determined to comprise said VEGF-A nucleotide sequence of (ii).

11. The method of claim 1, comprising the step of determining that the human comprises the nucleotide sequence of (ii), optionally, wherein the determining step is performed before administration of the antibody to the human.

12. The method of claim 11, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence of (ii).

13. The method of claim 12, wherein the assaying comprises contacting the biological sample with

a. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides that can specifically hybridize to and identify in the biological sample a nucleotide sequence comprising said selected SNP or that specifically hybridizes to an antisense of said sequence, wherein said nucleic acid hybridizes to said selected SNP or hybridizes to an antisense sequence thereby forming a complex when at least one nucleotide sequence comprising said selected SNP is present;

and/or

b. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides of a nucleotide sequence comprising said selected SNP or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises said selected SNP thereby forming a complex when the nucleotide sequence comprising said selected 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 nucleotide sequence of (ii).

14. The method of claim 12, 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.

15. The method of claim 1, wherein said human is or has been further determined to be substantially resistant to sunitinib, bevacizumab or ranizumab treatment.

16. The method of claim 1, wherein said human is receiving or has received sunitinib, bevacizumab or ranizumab treatment or has reduced responsiveness to sunitinib, bevacizumab or ranizumab treatment.

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

18. The method of claim 1, wherein said human has been diagnosed with an ocular condition, optionally DR or ROP.

19. The method of claim 1, wherein said ligand is administered by intraocular injection or by topical administration to the eye and/or is comprised in an injectable preparation or topical ocular preparation.

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

21. The method of claim 2, wherein the ligand is human.

22. The method of claim 1, wherein the method comprises administering an anti-PDGF-B or anti-PDGFR-B ligand to the human simultaneously or sequentially with the anti-VEGF-A ligand.

23. The method of claim 22, wherein the anti-PDGF-B or PDGFR-B ligand is an anti-PDGF-B or PDGFR-B antibody or fragment, an anti-PDGF-B or PDGFR-B trap or an anti-PDGF-B or PDGFR-B aptamer.

24. The method of claim 1, wherein the method comprises administering an anti-Ang2 or anti-Tie2 ligand to the human simultaneously or sequentially with the anti-VEGF-A ligand.

25. The method of claim 1, wherein the human is greater than 60 years of age.

26. The method of claim 1, wherein the human is suffering from type I diabetes.

27. The method of claim 1, wherein the human is suffering from type II diabetes.

28. The method of claim 2, wherein the trap is a ligand comprising first and second VEGF-A receptor domain sequences fused to a human gamma 1 heavy chain constant region.