Type I Interferon Signatures and Methods of Use

• US 20200131241A1
• Filed: 10/25/2019
• Published: 04/30/2020
• Est. Priority Date: 10/26/2018
• Status: Active Application

• Current Assignee: Janssen Biotech, Inc. (Johnson & Johnson)
• Original Assignee: Janssen Biotech, Inc. (Johnson & Johnson)
• Inventors: Cesaroni, Matteo, Chevrier, Marc, Jordan, Jarrat, Schreiter, Jessica
• Application Number:
  US16/663,527
• Publication Number:
  US 20200131241A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/54 characterised by the route of administration
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07K 14/56 IFN-alpha
• CPC Class Codes: C07K 16/249 Interferons
• 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 2317/94 Stability, e.g. half-life, pH, temperature or enzyme-resistance
• CPC Class Codes: C12Q 1/6809 Methods for determination or identification of nucleic acids involving differential detection
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 1/6886 for cancer immunoassay for cancer G01N33/574
• CPC Class Codes: C12Q 2539/00 Reactions characterised by analysis of gene expression or genome comparison
• CPC Class Codes: C12Q 2545/114 involving a quantitation step
• 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
• CPC Class Codes: G16H 20/10 relating to drugs or medications, e.g. for ensuring correct administration to patients
• CPC Class Codes: G16H 50/30 for calculating health indices; for individual health risk assessment

Abstract

Type I interferon (IFN-I) signatures are useful in methods of diagnosing whether a subject (or patient) with IFN-I mediated disease will be responsive to treatment with an IFN-I inhibitor and treating or refraining from treating the subjects.

Claims

1. ) A method of treating a subject having a type I interferon (IFN-I) mediated disease that is responsive to treatment with an IFN-I inhibitor, comprising:

a) providing a biological sample from the subject;

b) assaying gene expression of genes DHX58, EIF2AK2, HERC5, IFI44, IFI44L, IFI6, IRF7, PARP9, PLSCR1 and SAMD9L in the biological sample;

c) determining a combined expression value of the genes DHX58, EIF2AK2, HERC5, IFI44, IFI44L, IFI6, IRF7, PARP9, PLSCR1 and SAMD9L in the biological sample; and

d) treating the subject with the IFN-I inhibitor when the combined expression value is equal to or higher than a threshold value.

3. ) The method of claim 1, wherein the combined expression value is a sum of log 2 fold changes of normalized differential expression between the biological sample and a biological sample obtained from one or more healthy controls (SUM log 2(2{circumflex over ( 

)}−

ddCT)) of genes DHX58, EIF2AK2, HERC5, IFI44, IFI44L, IFI6, IRF7, PARP9, PLSCR1 and SAMD9L and the threshold value is SUM log 2(2{circumflex over ( 

)}−

ddCT) of 8.725.

4. ) The method of claim 1, wherein the combined expression value is a POISE Score of Formula I:

POISE Score=70−

|43.7251664−

SUM log 2(2{circumflex over ( 

)}<sup>−

ddCT</sup>)| (Formula I) and the threshold value is the POISE Score of between 30 and 40.

5. ) The method of claim 4, wherein the threshold value is the POISE score of 35.

6. ) The method of claim 1, wherein the biological sample is a blood sample or a tissue sample.

7. ) The method of claim 1, wherein the IFN-I mediated disease is systemic lupus erythematosus (SLE), type I diabetes, psoriasis, primary Sjö

gren'"'"'s disease, systemic sclerosis, rheumatoid arthritis, transplant rejection, dermatomyositis, polymyositis, Aicardi-Goutiè

res syndrome, Sting associated vasculopathy with onset in infancy (SAVI) or chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE).

8. ) The method of claim 7, wherein SLE comprises lupus nephritis, cutaneous lupus or lupus with central nervous system (CNS) manifestations.

9. ) The method of claim 1, wherein the IFN-I inhibitor is a molecule that blocks interaction of IFN-I with IFNAR, an antagonistic antibody that binds IFN-I, an antagonistic antibody that binds IFNAR, an inhibitor of Tyk2, Jak1, TLR7, TLR8, TLR9 or STING, a modulator or depletor of plasmacytoid dendritic cells;

or an agent that degrades nucleic acids.

10. ) The method of claim 9, wherein the antagonistic antibody that binds IFN-I comprises:

a) a heavy chain variable region 1 (HCDR1) of SEQ ID NO;

11, a HCDR2 of SEQ ID NO;

12, a HCDR3 of SEQ ID NO;

13, a light chain variable region 1 (LCDR1) of SEQ ID NO;

14, a LCDR2 comprising the amino acid sequence GAS and a LCDR3 of SEQ ID NO;

16;

b) a heavy chain variable region (VH) of SEQ ID NO;

17 and a light chain variable region (VL) of SEQ ID NO;

18;

or

c) a heavy chain (HC) of SEQ ID NO;

19 and a light chain (LC) of SEQ ID NO;

20, or any combination thereof.

11. ) The method of claim 10, wherein the antagonistic antibody that binds IFN-I is administered at a dose of about 10 mg/kg.

12. ) The method of claim 11, wherein the antagonistic antibody that binds IFN-I is administered at a dose of about 10 mg/kg once every two weeks.

2. ) The method of claim 2, wherein the combined expression value is a sum of normalized threshold cycle (CT) values (SUMΔ

CT) of genes DHX58, EIF2AK2, HERC5, IFI44, IFI44L, IFI6, IRF7, PARP9, PLSCR1 and SAMD9 and the threshold value is SUMΔ

CT of 57.474.

13. ) A method of determining whether a subject having a type I interferon (IFN-I) mediated disease is responsive to treatment with an IFN-I inhibitor and deciding whether to treat the subject, comprising:

a) providing a biological sample from the subject;

b) assaying gene expression of genes DHX58, EIF2AK2, HERC5, IFI44, IFI44L, IFI6, IRF7, PARP9, PLSCR1 and SAMD9L in the biological sample;

c) determining a combined expression value of the genes DHX58, EIF2AK2, HERC5, IFI44, IFI44L, IFI6, IRF7, PARP9, PLSCR1 and SAMD9L in the biological sample;

d) diagnosing the subject with the IFN-I mediated disease as responsive to treatment with the IFN-I inhibitor when the combined expression value is equal to or higher than a threshold value or diagnosing the subject with the IFN-I mediated disease as non-responsive to treatment with the IFN-I inhibitor when the combined expression value is less than a threshold value; and

e) administering the IFN-I inhibitor to the subject diagnosed as responsive to treatment with the IFN-I inhibitor or refraining from administering the IFN-I inhibitor to the subject diagnosed as non-responsive to treatment with the IFN-I inhibitor.

14. ) The method of claim 13, wherein the combined expression value is a sum of normalized threshold cycle (CT) values (SUMΔ

CT) of genes DHX58, EIF2AK2, HERC5, IFI44, IFI44L, IFI6, IRF7, PARP9, PLSCR1 and SAMD9L and the threshold value is SUMΔ

CT of 57.474.

15. ) The method of claim 13, wherein the combined expression value is a sum of log 2 fold changes of normalized differential expression between the biological sample and a biological sample obtained from one or more healthy controls (SUM log 2(2{circumflex over ( 

)}−

ddCT)) of genes DHX58, EIF2AK2, HERC5, IFI44, IFI44L, IFI6, IRF7, PARP9, PLSCR1 and SAMD9L and the threshold value is SUM log 2(2{circumflex over ( 

)}−

ddCT) of 8.725.

16. ) The method of claim 13, wherein the combined expression value is a POISE Score of Formula I:

POISE Score=70−

|43.7251664−

SUM log 2(2{circumflex over ( 

)}<sup>−

Δ

Δ

CT</sup>)| (Formula I) and the threshold value is the POISE Score of between 30 and 40.

17. ) The method of claim 16, wherein the threshold value is the POISE score of 35.

18. ) The method of claim 13, wherein the biological sample is a blood sample or a tissue sample.

19. ) The method of claim 13, wherein the IFN-I mediated disease is systemic lupus erythematosus (SLE), type I diabetes, psoriasis, primary Sjö

gren'"'"'s disease, systemic sclerosis, rheumatoid arthritis, transplant rejection, dermatomyositis, polymyositis, Aicardi-Goutiè

res syndrome, Sting associated vasculopathy with onset in infancy (SAVI) or chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE).

20. ) The method of claim 19, wherein SLE comprises lupus nephritis, cutaneous lupus or lupus with central nervous system (CNS) manifestations.

21. ) The method of claim 13, wherein the IFN-I inhibitor is a molecule that blocks interaction of IFN-I with IFNAR, an antagonistic antibody that binds IFN-I, an antagonistic antibody that binds IFNAR, an inhibitor of Tyk2, Jak1, TLR7, TLR8, TLR9 or STING, a modulator or depletor of plasmacytoid dendritic cells;

or an agent that degrades nucleic acids.

22. ) The method of claim 21, wherein the antagonistic antibody that binds IFN-I comprises:

a) a heavy chain variable region 1 (HCDR1) of SEQ ID NO;

11, a HCDR2 of SEQ ID NO;

12, a HCDR3 of SEQ ID NO;

13, a light chain variable region 1 (LCDR1) of SEQ ID NO;

14, a LCDR2 comprising the amino acid sequence GAS and a LCDR3 of SEQ ID NO;

16;

b) a heavy chain variable region (VH) of SEQ ID NO;

17 and a light chain variable region (VL) of SEQ ID NO;

18;

or

c) a heavy chain (HC) of SEQ ID NO;

19 and a light chain (LC) of SEQ ID NO;

20, or any combination thereof.

23. ) The method of claim 22, wherein the antagonistic antibody that binds IFN-I is administered at a dose of about 10 mg/kg.

24. ) The method of claim 23, wherein the antagonistic antibody that binds IFN-I is administered at a dose of about 10 mg/kg once every two weeks.

25. ) An in vitro method for predicting and/or diagnosing that a subject has an IFN-I mediated disease, comprising

a) providing a biological sample from the subject;

b) assaying gene expression of genes DHX58, EIF2AK2, HERC5, IFI44, IFI44L, IFI6, IRF7, PARP9, PLSCR1 and SAMD9L in the biological sample;

c) determining a combined expression value of the genes DHX58, EIF2AK2, HERC5, IFI44, IFI44L, IFI6, IRF7, PARP9, PLSCR1 and SAMD9L in the biological sample; and

d) predicting and/or diagnosing that the subject has the IFN-I mediated disease when the combined expression value is equal to or higher than a threshold value.

26. ) The method of claim 25, wherein the combined expression value is a sum of normalized threshold cycle (CT) values (SUMΔ

CT) of genes DHX58, EIF2AK2, HERC5, IFI44, IFI44L, IFI6, IRF7, PARP9, PLSCR1 and SAMD9L and the threshold value is SUMΔ

CT of 57.474.

27. ) The method of claim 25, wherein the combined expression value is a sum of log 2 fold changes of normalized differential expression between the biological sample and a biological sample obtained from one or more healthy controls (SUM log 2(2{circumflex over ( 

)}−

ddCT)) of genes DHX58, EIF2AK2, HERC5, IFI44, IFI44L, IFI6, IRF7, PARP9, PLSCR1 and SAMD9L and the threshold value is SUM log 2(2{circumflex over ( 

)}−

ddCT) of 8.725.

28. ) The method of claim 25, wherein the combined expression value is a POISE Score of Formula I:

POISE Score=70−

|43.7251664−

SUM log 2(2{circumflex over ( 

)}<sup>−

ddCT</sup>)| (Formula I) and the reference value is the POISE Score of between 30 and 40.

29. ) The method of claim 28, wherein the reference value is the POISE score of 35.

30. ) The method of claim 25, wherein the biological sample is a blood sample or a tissue sample.

31. ) The method of claim 30, wherein gene expression is assayed using quantitative Polymerase Chain Reaction (qPCR) or microarray, or both.

32. ) The method of claim 31, wherein gene expression is measured at the mRNA level.

33. ) The method of claim 25, wherein the IFN-I mediated disease is systemic lupus erythematosus (SLE), type I diabetes, psoriasis, primary Sjö

gren'"'"'s disease, systemic sclerosis, rheumatoid arthritis, transplant rejection, dermatomyositis, polymyositis, Aicardi-Goutiè

res syndrome, Sting associated vasculopathy with onset in infancy (SAVI) or chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE).