# US 2020/0399703 A1 · Diagnostic and therapeutic methods for the treatment of rheumatoid arthritis (ra)

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- Number: US 2020/0399703 A1
- Document ID: US20200399703A1
- Status: Published application
- Kind: A1
- Application number: 16/937,535
- Filed: 2020-07-23
- Published: 2020-12-24
- Earliest claimed: 2018-01-24
- Assignees: Genentech, Inc.; Queen Mary University of London
- Applicants: Genentech, Inc.; Queen Mary University of London
- Inventors: Myles LEWIS; Costantino PITZALIS; Nandhini RAMAMOORTHI; Michael John TOWNSEND; Jason HACKNEY
- Web page: https://patentgrep.com/patent/US20200399703A1

## CPC

- C12Q 1/6883: for diseases caused by alterations of genetic material
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- C07K 16/2866: {against receptors for cytokines, lymphokines, interferons}
- C07K 16/2887: {against CD20}
- C12Q 2600/106: Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
- C12Q 2600/118: Prognosis of disease development
- C12Q 2600/158: Expression markers
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## 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.

## Claims

### Claim 1

A method of predicting disease progression in an individual having rheumatoid arthritis (RA), the method comprising determining an expression level of one or more genes set forth in Table 1 in a sample from the individual, wherein a change in the expression level of the one or more genes relative to a reference expression level identifies the individual as one who is more likely to exhibit disease progression.

### Claim 2 (depends on 1)

The method of claim 1, wherein the change is an increase, and the one or more genes set forth in Table 1 are selected from one or more genes set forth in Table 2.

### Claim 3 (depends on 2)

The method of claim 2, wherein the one or more genes set forth in Table 2 comprise one or more of the following genes: CD180, CSF2, CXCL1, DENND1C, MMP10, SDC1, and UBASH3A.

### Claim 4 (depends on 3)

The method of claim 3, wherein the one or more genes set forth in Table 2 comprise two or more of the following genes: CD180, CSF2, CXCL1, DENND1C, MMP10, SDC1, and UBASH3A.

### Claim 5 (depends on 4)

The method of claim 4, wherein the one or more genes set forth in Table 2 comprise three or more of the following genes: CD180, CSF2, CXCL1, DENND1C, MMP10, SDC1, and UBASH3A.

### Claim 6 (depends on 5)

The method of claim 5, wherein the one or more genes set forth in Table 2 comprise four or more of the following genes: CD180, CSF2, CXCL1, DENND1C, MMP10, SDC1, and UBASH3A.

### Claim 7 (depends on 6)

The method of claim 6, wherein the one or more genes set forth in Table 2 comprise five or more of the following genes: CD180, CSF2, CXCL1, DENND1C, MMP10, SDC1, and UBASH3A.

### Claim 8 (depends on 7)

The method of claim 7, wherein the one or more genes set forth in Table 2 comprise six or more of the following genes: CD180, CSF2, CXCL1, DENND1C, MMP10, SDC1, and UBASH3A.

### Claim 9 (depends on 8)

The method of claim 8, wherein the one or more genes set forth in Table 2 comprise the seven following genes: CD180, CSF2, CXCL1, DENND1C, MMP10, SDC1, and UBASH3A.

### Claim 10 (depends on 9)

The method of claim 9, wherein the one or more genes set forth in Table 2 consist of the seven following genes: CD180, CSF2, CXCL1, DENND1C, MMP10, SDC1, and UBASH3A.

### Claim 11 (depends on 2, 3, 4, 5, 6, 7, 8, 9, 10)

The method of any one of claims 2-10, wherein the expression level of the one or more genes set forth in Table 2 is increased in the sample relative to the reference expression level, and the method further comprises administering to the individual a therapeutic agent other than, or in addition to, a disease modifying anti-rheumatic drug (DMARD).

### Claim 12 (depends on 1)

The method of claim 1, wherein the change is a decrease, and the one or more genes set forth in Table 1 are selected from one or more genes set forth in Table 3.

### Claim 13 (depends on 12)

The method of claim 12, wherein the expression level of the one or more genes set forth in Table 3 is decreased in the sample relative to the reference expression level, and the method further comprises administering to the individual a therapeutic agent other than, or in addition to, a DMARD.

### Claim 14 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13)

The method of any one of claims 1-13, wherein disease progression is radiographic progression.

### Claim 15 (depends on 14)

The method of claim 14, wherein radiographic progression is characterized by an increase in ShSS.

### Claim 16 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14)

A method of treating an individual having RA, the method comprising administering a therapeutic agent other than, or in addition to, a DMARD to the individual, wherein the individual has been identified as one who is more likely to exhibit disease progression by the method of any one of claims 1-10, 12, 14, and 15.

### Claim 17

A method of treating an individual having RA, the individual being identified as having (i) an increased expression level of one or more genes set forth in Table 2 in a sample from the individual and/or (ii) a decreased expression level of one or more genes set forth in Table 3 in a sample from the individual relative to a reference expression level, the method comprising administering to the individual a therapeutic agent other than, or in addition to, a DMARD.

### Claim 18

A method of treating an individual having RA, the method comprising:
(a) determining an expression level of one or more genes set forth in Table 2 or Table 3 in a sample from the individual, wherein (i) the expression level of one or more genes set forth in Table 2 in the sample is determined to be increased and/or (ii) the expression level of one or more genes set forth in Table 3 is determined to be decreased relative to a reference expression level; and
(b) administering to the individual a therapeutic agent other than, or in addition to, a DMARD based on the expression level of the one or more genes set forth in Table 2 or Table 3 determined in step (a).

### Claim 19 (depends on 17, 18)

The method of claim 17 or 18, wherein the one or more genes set forth in Table 2 comprise one or more of the following genes: CD180, CSF2, CXCL1, DENND1C, MMP10, SDC1, and UBASH3A.

### Claim 20 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)

The method of any one of claims 1-19, wherein the expression level of the one or more genes set forth in Table 1 is an average of the expression level of the one or more genes set forth in Table 1.

### Claim 21 (depends on 20)

The method of claim 20, wherein the average of the expression level of the one or more genes set forth in Table 1 is an average of a normalized expression level of the one or more genes set forth in Table 1.

### Claim 22 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)

The method of any one of claims 1-19, wherein the expression level of the one or more genes set forth in Table 1 is a median of the expression level of the one or more genes set forth in Table 1.

### Claim 23 (depends on 22)

The method of claim 22, wherein the median of the expression level of the one or more genes set forth in Table 1 is a median of a normalized expression level of the one or more genes set forth in Table 1.

### Claim 24 (depends on 21, 23)

The method of claim 21 or 23, wherein the normalized expression level of the one or more genes set forth in Table 1 is the expression level of the one or more genes set forth in Table 1 normalized to a reference gene.

### Claim 25 (depends on 24)

The method of claim 24, wherein the reference gene is ACTB, GAPDH, GUSB, HPRT1, PGK1, RPL19, TUBB, TMEM55B, or a combination thereof.

### Claim 26 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25)

The method of any one of claims 1-25, wherein the reference expression level is a pre-assigned expression level of the one or more genes set forth in Table 1.

### Claim 27 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25)

The method of any one of claims 1-25, wherein the reference expression level is the expression level of the one or more genes set forth in Table 1 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 the one or more genes set forth in Table 1 in the first subset of individuals compared to that of the second subset of individuals.

### Claim 28 (depends on 27)

The method of claim 27, wherein the first subset of individuals exhibited disease progression and the second subset of individuals did not exhibit disease progression after about 12 months.

### Claim 29 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28)

The method of any one of claims 1-15 and 18-28, further comprising determining one or more clinical covariates of the individual.

### Claim 30 (depends on 16, 17)

The method of any one of claims 16, 17, and 19-28, wherein one or more clinical covariates has been determined for the individual.

### Claim 31 (depends on 29, 30)

The method of claim 29 or 30, 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.

### Claim 32 (depends on 31)

The method of claim 31, wherein the clinical covariate is DAS28-ESR.

### Claim 33 (depends on 31)

The method of claim 31, wherein the clinical covariate is a RF titer.

### Claim 34 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33)

The method of any one of claims 1-33, wherein the expression level is a nucleic acid expression level.

### Claim 35 (depends on 34)

The method of claim 34, wherein the nucleic acid expression level is an mRNA expression level.

### Claim 36 (depends on 35)

The method of claim 35, wherein the mRNA expression level is determined by direct digital counting of nucleic acids, RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, or a combination thereof.

### Claim 37 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33)

The method of any one of claims 1-33, wherein the expression level is a protein expression level.

### Claim 38 (depends on 37)

The method of claim 37, wherein the protein expression level is determined by an immunoassay, liquid chromatography-mass spectrometry (LC-MS) technology, nephelometry, aptamer technology, or a combination thereof.

### Claim 39

A method of identifying an individual having RA who may benefit from a treatment comprising a DMARD, the method comprising determining a myeloid eigengene score from a sample from the individual, wherein a myeloid eigengene score from the sample that is at or above a reference myeloid eigengene score identifies the individual as one who may benefit from a treatment comprising a DMARD.

### Claim 40

A method for selecting a therapy for an individual having RA, the method comprising determining a myeloid eigengene score from a sample from the individual, wherein a myeloid eigengene score from the sample that is at or above a reference myeloid eigengene score identifies the individual as one who may benefit from a treatment comprising a DMARD.

### Claim 41 (depends on 39, 40)

The method of claim 39 or 40, further comprising determining a lymphoid eigengene score from the sample from the individual, wherein a lymphoid eigengene score that is at or above a reference lymphoid eigengene score identifies the individual as one who may benefit from a treatment comprising a DMARD.

### Claim 42 (depends on 39, 40, 41)

The method of any one of claims 39-41, wherein the myeloid eigengene score from a sample is at or above a reference myeloid eigengene score, and the method further comprises administering to the individual a therapeutically effective amount of a DMARD.

### Claim 43 (depends on 39, 40, 41)

A method of treating an individual having RA, the method comprising administering a DMARD to the individual, wherein the individual has been identified as one who is more likely to benefit from a treatment comprising a DMARD by the method of any one of claims 39-41.

### Claim 44

A method of treating RA in an individual identified as having a myeloid eigengene score from a sample from the individual that is at or above a reference myeloid eigengene score, the method comprising administering to the individual a DMARD.

### Claim 45 (depends on 44)

The method of claim 44, wherein prior to the administering, a lymphoid eigengene score from a sample from the individual has been determined to be at or above a reference lymphoid eigengene score.

### Claim 46

A method of treating an individual having RA, the method comprising:
(a) determining a myeloid eigengene score from a sample from the individual, wherein the myeloid eigengene score from the sample is determined to be at or above a reference myeloid eigengene score; and
(b) administering to the individual a DMARD based on the myeloid eigengene score determined in step (a).

### Claim 47 (depends on 46)

The method of claim 46, wherein prior to the administering, the method further comprises determining a lymphoid eigengene score from the sample from the individual, wherein a lymphoid eigengene score in the sample is determined to be at or above a reference lymphoid eigengene score.

### Claim 48 (depends on 39, 40, 41, 42, 43, 44, 45, 46, 47)

The method of any one of claims 39-47, wherein the reference myeloid eigengene score is from a reference population of individuals having RA who have been treated with a DMARD therapy, the population of individuals consisting of a first subset of individuals who responded to the DMARD therapy and a second subset of individuals who did not respond to the DMARD therapy, wherein the reference myeloid eigengene score significantly separates the first and second subsets of individuals, based on a significant difference between the myeloid eigengene score in the first subset of individuals compared to that of the second subset of individuals.

### Claim 49 (depends on 48)

The method of claim 48, wherein the first subset of individuals responded to the DMARD therapy and the second subset did not respond to the DMARD therapy after about six months following the initiation of the DMARD therapy.

### Claim 50 (depends on 41, 42, 43, 45)

The method of any one of claims 41-43, 45, and 47-49, wherein the reference lymphoid eigengene score is from a reference population of individuals having RA, the population of individuals consisting of a first subset of individuals who responded to DMARD therapy and a second subset of individuals who did not respond to DMARD therapy, wherein the reference lymphoid eigengene score significantly separates the first and second subsets of individuals, based on a significant difference between the lymphoid eigengene score in the first subset of individuals compared to that of the second subset of individuals.

### Claim 51 (depends on 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50)

The method of any one of claims 39-50, wherein the individual has not been previously treated with a DMARD.

### Claim 52 (depends on 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50)

The method of any one of claims 39-50, wherein the individual has been previously treated with a DMARD.

### Claim 53

A method for monitoring the response of an individual having RA to treatment with a DMARD, the method comprising:
(a) determining a first myeloid eigengene score from a sample from the individual at a first time point during or after administration of a DMARD;
(b) determining a second myeloid eigengene score from a sample from the individual at second time point; and
(c) comparing the first myeloid eigengene score with the second myeloid eigengene score, wherein a decrease in the second myeloid eigengene score relative to the first myeloid eigengene score is predictive of an individual who is likely to respond treatment with a DMARD.

### Claim 54 (depends on 53)

The method of claim 53, further comprising:
(a) determining a first lymphoid eigengene score from a sample from the individual at a first time point during or after administration of a DMARD;
(b) determining a second lymphoid eigengene score from a sample from the individual at second time point; and
(c) comparing the first lymphoid eigengene score with the second lymphoid eigengene score, wherein a decrease in the second lymphoid eigengene score relative to the first lymphoid eigengene score is predictive of an individual who is likely to respond treatment with a DMARD.

### Claim 55 (depends on 53, 54)

The method of claim 53 or 54, wherein the second myeloid eigengene score is decreased relative to the first myeloid eigengene score, and the method further comprises administering an additional dose of a DMARD to the individual.

### Claim 56 (depends on 55)

The method of claim 55, wherein the second lymphoid eigengene score is decreased relative to the first lymphoid eigengene score.

### Claim 57 (depends on 53, 54, 55, 56)

The method of any of claims 53-56, wherein the individual has been previously treated with a DMARD.

### Claim 58 (depends on 53, 54, 55, 56, 57)

The method of any one of claims 53-57, wherein the decrease is between about 1.25-fold to about 5-fold.

### Claim 59 (depends on 58)

The method of claim 58, wherein the decrease is between about 1.25-fold to about 2-fold.

### Claim 60 (depends on 59)

The method of claim 59, wherein the decrease is between about 1.25-fold to about 1.5-fold.

### Claim 61 (depends on 53, 54, 55, 56, 57, 58, 59, 60)

The method of any one of claims 53-60, wherein the decrease is at least about 1.25-fold.

### Claim 62 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61)

The method of any one of claims 1-61, wherein the sample is a synovial sample.

### Claim 63 (depends on 62)

The method of claim 62, wherein the synovial sample is a synovial tissue sample or a synovial fluid sample.

### Claim 64 (depends on 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63)

The method of any one of claims 11 and 13-63, wherein the DMARD is methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, azathioprine, cyclophosphamide, cyclosporine, mycophenolate mofetil, or a combination thereof.

### Claim 65 (depends on 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 62)

The method of any one of claims 11, 13-38, 62, and 63, 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.

### Claim 66 (depends on 65)

The method of claim 65, wherein the JAK antagonist is tofacitinib.

### Claim 67 (depends on 65)

The method of claim 65, wherein the IL-6 receptor antagonist is tocilizumab.

### Claim 68 (depends on 65)

The method of claim 65, wherein the B cell antagonist is rituximab.