# US 2020/0399698 A1 · Methods of determining response to tnf alpha blockers

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- Number: US 2020/0399698 A1
- Document ID: US20200399698A1
- Status: Published application
- Kind: A1
- Application number: 16/971,007
- Filed: 2019-02-19
- Published: 2020-12-24
- Earliest claimed: 2018-02-19
- Assignees: Genefron Ltd.; Yissum Research Development Company of the Hebrew University of Jerusalem
- Applicants: Genefron Ltd.; Yissum Research Development Company of the Hebrew University of Jerusalem Ltd.
- Inventors: Yoav SMITH
- Web page: https://patentgrep.com/patent/US20200399698A1

## CPC

- C12Q 1/6876: Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q 1/6883: for diseases caused by alterations of genetic material
- C12Q 2600/106: Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
- C12Q 2600/158: Expression markers
- G01N 2800/102: Arthritis; Rheumatoid arthritis, i.e. inflammation of peripheral joints
- G01N 2800/60: Complex ways of combining multiple protein biomarkers for diagnosis
- 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
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

Methods and kits for predicting the response of a subject to an anti-TNFα therapy, in high accuracy, are provided.

## Claims

### Claim 1

A method for determining and treating a subject suitable to receive anti-TNFα therapy, the method comprising the step of:
a. determining an expression level sum of three genes in a biological sample obtained from the subject, wherein said three genes are
i. MX1
ii. at least one gene selected from IFI6 and OAS3, and
iii. at least one gene selected from the group consisting of: IFI6, OAS1, OAS3, DDX58, RSAD2, IFIT1, IFIT3, IFI44, IFI44L, IFITM3, and HERC5; and
b. generating a diagnosis regarding suitability to receive anti-TNFα therapy wherein:
an expression level sum above a predetermined threshold, is indicative of the subject being suitable to receive anti-TNFα therapy, and
an expression level sum below a predetermined threshold, is indicative of the subject being unsuitable to receive anti-TNFα therapy,
c. treating said subject being suitable to receive anti-TNFα therapy, with anti-TNFα therapy;
thereby treating a subject suitable to receive anti-TNFα therapy.

### Claim 2 (depends on 1)

The method of claim 1, wherein said biological sample is peripheral blood mononuclear cell (PBMC), or whole blood.

### Claim 3 (depends on 1)

The method of claim 1, wherein said subject suffers from rheumatoid arthritis.

### Claim 4 (depends on 1)

The method of claim 1, wherein said anti-TNFα therapy is TNFα blocker therapy.

### Claim 5 (depends on 1)

The method of claim 1, wherein said third gene is selected from IFI6, OAS1, OAS3, DDX58, RSAD2, and HERC5.

### Claim 6 (depends on 1)

The method of claim 1, wherein said three genes are MX1, IFI6 and OAS3.

### Claim 7 (depends on 1)

The method of claim 1, wherein said predetermined threshold is between 0.2-0.5.

### Claim 8 (depends on 1)

The method of claim 1, further comprising treating said suitable subjects with anti-TNFα therapy.

### Claim 9 (depends on 1)

The method of claim 1, further comprising transmitting the diagnosis to the subject.

### Claim 10

A kit comprising reagents adapted to specifically determine the expression level of MX1, and at least one of IFI6, and OAS3.

### Claim 11 (depends on 10)

The kit of claim 10, comprising reagents adapted to specifically determine the expression level of MX1, IFI6 and OAS3.

### Claim 12 (depends on 10)

The kit of claim 10, further comprising at least one reagent adapted to specifically determine the expression level of a gene selected from IFI6, OAS1, OAS3, DDX58, RSAD2, IFIT1, IFIT3, IFI44, IFI44L, IFITM3, and HERC5.

### Claim 13 (depends on 10)

The kit of claim 10, further comprising at least one reagent adapted to specifically determine the expression level of a gene selected from IFI6, OAS1, OAS3, DDX58, RSAD2, and HERC5.

### Claim 14 (depends on 10)

The kit of claim 10, wherein said reagents are selected from nucleic acid hybridization or amplification reagents, and a plurality of nucleic acid-specific probes or amplification primers.

### Claim 15 (depends on 10)

The kit of claim 10, further comprising any one of: (i) detectable tags or labels, (ii) solutions for rendering a nucleic acid susceptible to hybridization, (iii) solutions for lysing cells, (iv) solutions for the purification of nucleic acids, (v) any combination of (i), (ii), (iii), (iv) and (v).

### Claim 16 (depends on 10)

The kit of claim 10, further comprising at least one reagent adapted to specifically determine the expression level of at least one house-keeping gene.

### Claim 17 (depends on 10)

The kit of claim 10, consisting of:
a. at least one reagent adapted to specifically determine the expression level of MX1
b. at least one reagent adapted to specifically determine the expression level of at least one gene selected from IFI6 and OAS3;
c. at least one reagent adapted to specifically determine the expression level of at least one gene selected from IFI6, OAS1, OAS3, DDX58, RSAD2, IFIT1, IFIT3, IFI44, IFI44L, IFITM3, and HERC5, wherein said gene is not the gene selected in (b); and
d. at least one reagent adapted to specifically determine the expression level of at least one house-keeping gene.

### Claim 18 (depends on 5, 14)

The kit of claim 14 or 5, wherein said house-keeping gene is a gene that is not differentially expressed between subjects that respond and subjects that do not respond to anti-TNFα therapy.

### Claim 19 (depends on 10)

The kit of claim 10, consisting of:
a. at least one reagent adapted to specifically determine the expression level of MX1
b. at least one reagent adapted to specifically determine the expression level of at least one gene selected from IFI6 and OAS3; and
c. at least one reagent adapted to specifically determine the expression level of at least one gene selected from IFI6, OAS1, OAS3, DDX58, RSAD2, IFIT1, IFIT3, IFI44, IFI44L, IFITM3, and HERC5, wherein said gene is not the gene selected in (b).

### Claim 20 (depends on 19)

The kit of claim 19, consisting of at least one reagent adapted to specifically determine the expression level of MX1, at least one reagent adapted to specifically determine the expression level of IFI6 and at least one reagent adapted to specifically determine the expression level of OAS3.