Diagnostic and therapeutic methods for the treatment of rheumatoid arthritis (RA)

Patent metadata

Field	Value
Publication number	US-12319965-B2
Application number	US-202016937535-A
Country	US
Kind code	B2
Filing date	Jul 23, 2020
Priority date	Jan 24, 2018
Publication date	Jun 3, 2025
Grant date	Jun 3, 2025

Abstract

The present invention provides prognostic, predictive, and therapeutic methods for the treatment of rheumatoid arthritis (RA). The invention is based, at least in part, on the discovery that the expression level of one or more biomarkers described herein in a sample (e.g., a synovial tissue sample, a synovial fluid sample, or a combination thereof) from an individual having RA can be used in methods of determining whether an individual having RA is likely to exhibit disease progression, identifying an individual having RA who is likely to respond to a treatment including a disease modifying anti-rheumatic drug (DMARD), predicting responsiveness of an individual having RA to a treatment including a DMARD, selecting a therapy for an individual having RA, and treating an individual having RA, as well as related kits.

First claim

What is claimed is:

1. A method of identifying an individual having rheumatoid arthritis (RA) as one who is more likely to exhibit disease progression of RA when treated with a disease modifying anti-rheumatic drug (DMARD) and treating the individual, the method comprising:
(i) determining an expression level of CD180, CSF2, CXCL1, DENND1C, MMP10, SDC1, and UBASH3A in a sample from the individual, wherein the individual has an increased expression level of CD180, CSF2, CXCL1, DENND1C, MMP10, SDC1, and UBASH3A relative to a reference expression level, thereby identifying the individual as one who is more likely to exhibit disease progression when treated with a DMARD; and
(ii) administering a therapeutic agent other than a DMARD to the individual who has been identified as one who is more likely to exhibit disease progression.

2. A method of treating an individual having RA, the individual being identified as having an increased expression level of CD180, CSF2, CXCL1, DENND1C, MMP10, SDC1, and UBASH3A in a sample from the individual relative to a reference expression level, the method comprising administering to the individual a therapeutic agent other than a DMARD.

3. The method of claim 2 , wherein the expression level of CD180, CSF2, CXCL1, DENND1C, MMP10, SDC1, and UBASH3A is (a) an average of the expression levels of CD180, CSF2, CXCL1, DENND1C, MMP10, SDC1, and UBASH3A or (b) a median of the expression levels of CD180, CSF2, CXCL1, DENND1C, MMP10, SDC1, and UBASH3A.

4. The method of claim 3 , wherein the average of the expression levels of CD180, CSF2, CXCL1, DENND1C, MMP10, SDC1, and UBASH3A is an average of the normalized expression levels of CD180, CSF2, CXCL1, DENND1C, MMP10, SDC1, and UBASH3A or the median of the expression levels of CD180, CSF2, CXCL1, DENND1C, MMP10, SDC1, and UBASH3A is a median of the normalized expression levels of CD180, CSF2, CXCL1, DENND1C, MMP10, SDC1, and UBASH3A.

5. The method of claim 4 , wherein the normalized expression levels of CD180, CSF2, CXCL1, DENND1C, MMP10, SDC1, and UBASH3 are the expression levels of CD180, CSF2, CXCL1, DENND1C, MMP10, SDC1, and UBASH3A normalized to a reference gene.

6. The method of claim 5 , wherein the reference gene is ACTB, GAPDH, GUSB, HPRT1, PGK1, RPL19, TUBB, TMEM55B, or a combination thereof.

7. The method of claim 2 , wherein the reference expression level is a pre-assigned expression level of CD180, CSF2, CXCL1, DENND1C, MMP10, SDC1, and UBASH3A.

8. The method of claim 2 , wherein the reference expression level is the expression level of CD180, CSF2, CXCL1, DENND1C, MMP10, SDC1, and UBASH3A in a reference population of individuals having RA who have not previously been treated with a DMARD, the reference population of individuals consisting of a first subset of individuals who exhibited disease progression and a second subset of individuals who did not exhibit disease progression, wherein the reference expression level significantly separates the first and second subsets of individuals based on a significant difference between the expression level of CD180, CSF2, CXCL1, DENND1C, MMP10, SDC1, and UBASH3A in the first subset of individuals compared to that of the second subset of individuals.

9. The method of claim 8 , wherein the first subset of individuals exhibited disease progression and the second subset of individuals did not exhibit disease progression after about 12 months.

10. The method of claim 2 , further comprising determining one or more clinical covariates of the individual.

11. The method of claim 10 , wherein the one or more clinical covariates are one or more of: disease activity score 28-erythrocyte sedimentation rate (DAS28-ESR), disease activity score 28-C reactive protein (DAS28-CRP), rheumatoid factor (RF) titer, disease duration, baseline pathotype, and 12max ultrasound synovial thickening (USST) and ultrasound power Doppler (USPD) scores.

12. The method of claim 2 , wherein the expression level is a nucleic acid expression level.

13. The method of claim 12 , wherein the nucleic acid expression level is an mRNA expression level.

14. The method of claim 2 , wherein the expression level is a protein expression level.

15. The method of claim 2 , wherein the sample is a synovial sample.

16. The method of claim 2 , wherein the DMARD is methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, azathioprine, cyclophosphamide, cyclosporine, mycophenolate mofetil, or a combination thereof.

17. The method of claim 2 , wherein the therapeutic agent other than a DMARD is a B cell antagonist, a Janus kinase (JAK) antagonist, a tumor necrosis factor (TNF) antagonist, a decoy TNF receptor, a T cell costimulatory signal antagonist, an IL-1 receptor antagonist, an IL-6 receptor antagonist, or a combination thereof.

Assignees

• Genentech Inc
• Univ London Queen Mary

Inventors

• Lewis Myles
• Pitzalis Costantino
• Ramamoorthi Nandhini
• Townsend Michael John
• Hackney Jason

Classifications

• C12Q2600/158

  Expression markers · CPC title

• C12Q2600/118

  Prognosis of disease development · CPC title

• C12Q2600/106

  Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism · CPC title

• C07K16/2887

  against CD20 · CPC title

• C07K16/2866

  against receptors for cytokines, lymphokines, interferons · CPC title