# US 7,745,581 B2 · T-bet compositions and methods of use thereof

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- Number: US 7,745,581 B2
- Document ID: US7745581B2
- Status: Granted
- Kind: B2
- Application number: 12/070,856
- Filed: 2008-02-21
- Published: 2008-12-04
- Granted: 2010-06-29
- Earliest claimed: 1999-06-02
- Assignees: President and Fellows of Harvard College
- Inventors: Laurie H. Glimcher; Susanne J. Szabo
- Web page: https://patentgrep.com/patent/US7745581B2

## CPC

- C07K 14/4705: {stimulating, promoting or activating activity}
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/06: Antianaemics
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 17/14: for baldness or alopecia
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/02: Ophthalmic agents
- A61P 27/14: Decongestants or antiallergics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- G01N 33/6866: {Interferon}
- G01N 33/6869: {Interleukin}
- G01N 33/6872: {Intracellular protein regulatory factors and their receptors, e.g. including ion channels}
- G01N 33/6875: {Nucleoproteins}
- G01N 33/74: involving hormones {or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors}
- A01K 2217/05: Animals comprising random inserted nucleic acids (transgenic)
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C07K 2319/00: Fusion polypeptide
- G01N 2500/00: Screening for compounds of potential therapeutic value
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)
- A01K: ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- 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)

## Abstract

Isolated nucleic acid molecules encoding T-bet, and isolated T-bet proteins, are provided. The invention further provides antisense nucleic acid molecules, recombinant expression vectors containing a nucleic acid molecule of the invention, host cells into which the expression vectors have been introduced and non-human transgenic animals carrying a T-bet transgene. The invention further provides T-bet fusion proteins and anti-T-bet antibodies. Methods of using the T-bet compositions of the invention are also disclosed, including methods for detecting T-bet activity in a biological sample, methods of modulating T-bet activity in a cell, and methods for identifying agents that modulate the activity of T-bet.

## Claims

### Claim 1

An isolated polypeptide comprising the amino acid sequence of SEQ ID NO:2.

### Claim 2

An isolated polypeptide comprising the amino acid sequence of SEQ ID NO:4.

### Claim 3 (depends on 1, 2)

A fusion polypeptide comprising the polypeptide of claim 1 or 2, operatively linked to a heterologous polypeptide.

### Claim 4 (depends on 3)

The fusion polypeptide of claim 3, wherein the heterologous polypeptide comprises an epitope tag.

### Claim 5 (depends on 4)

The fusion polypeptide of claim 4, wherein the epitope tag is a hemagglutinin epitope tag.

### Claim 6 (depends on 3)

The fusion polypeptide of claim 3, wherein the heterologous polypeptide is selected from the group consisting of GAL4 DNA binding domain, GAL4 transactivation domain, glutathione S-transferase (GST), maltose E binding protein, and protein A.

### Claim 7

An isolated polypeptide comprising an amino acid sequence which has at least 90% amino acid identity to the full length amino acid sequence of SEQ ID NO:2 wherein the polypeptide binds a consensus T-box site in DNA and induces IFN-γ production in CD4+ cells.

### Claim 8

An isolated polypeptide comprising an amino acid sequence which has at least 90% amino acid identity to the full length amino acid sequence of SEQ ID NO:4 wherein the polypeptide binds a consensus T-box site in DNA and induces IFN-γ production in CD4+ cells.

### Claim 9 (depends on 7, 8)

The polypeptide of claim 7 or 8, wherein the polypeptide has at least one activity selected from the group consisting of: inhibiting production of IL-2, and inducing the differentiation of Thp cells and Th2 cells into Th1 cells.

### Claim 10

An isolated polypeptide comprising the amino acid sequence encoded by the nucleic acid sequence of SEQ ID NO:1.

### Claim 11

An isolated polypeptide comprising the amino acid sequence encoded by the nucleic acid sequence of SEQ TD NO:3.

### Claim 12

An isolated polypeptide which is encoded by a nucleic acid molecule comprising a nucleotide sequence which has at least 90% nucleotide identity with SEQ ID NO:1 over its full length, and encodes a polypeptide that binds a consensus T-box site in DNA and induces IFN-γ production in CD4+ cells.

### Claim 13

An isolated polypeptide which is encoded by a nucleic acid molecule comprising a nucleotide sequence which has at least 90% nucleotide identity with SEQ ID NO:3 over its full length, and encodes a polypeptide that binds a consensus T-box site in DNA and induces IFN-γ production in CD4+ cells.

### Claim 14

An isolated polypeptide which is encoded by a nucleic acid molecule comprising a nucleotide sequence comprising at least 700 contiguous nucleotides of SEQ ID NO:1 which sequence encodes a polypeptide that binds a consensus T-box domain and induces IFN-γ production in CD4+ cells.

### Claim 15

An isolated polypeptide which is encoded by a nucleic acid molecule comprising a nucleotide sequence comprising at least 600 contiguous nucleotides of SEQ ID NO:3 which sequence encodes a polypeptide that binds a consensus T-box domain and induces IFN-γ production in CD4+ cells.