# US 2021/0275680 A1 · Use of the tas1r3 protein as a marker for therapeutic, diagnostic, and/or prognostic purposes for tumors that express said protein

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- Number: US 2021/0275680 A1
- Document ID: US20210275680A1
- Status: Published application
- Kind: A1
- Application number: 16/962,151
- Filed: 2019-01-15
- Published: 2021-09-09
- Earliest claimed: 2018-01-15
- Applicants: FundacióN Insitituto De InvestigacióN Sanitaria De Santiago De Compostela (Fidis); Servizo Galego De SAúDe
- Inventors: María DE LA FUENTE FREIRE; Rafael LÓPEZ LÓPEZ; Marta ALONSO NOCELO; Abi Judit VÁZQUEZ RÍOS
- Web page: https://patentgrep.com/patent/US20210275680A1

## CPC

- G01N 33/57585: {involving compounds identifiable in body fluids}
- A61K 47/62: the modifying agent being a protein, peptide or polyamino acid
- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 47/6851: {the antibody targeting a determinant of a tumour cell}
- A61K 47/6907: {the form being a microemulsion, nanoemulsion or micelle}
- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- G01N 33/57557: {of other specific parts of the body, e.g. brain}
- G01N 33/5759: {involving compounds localised on the membrane of tumour or cancer cells}
- G01N 33/5758: {involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites}
- G01N 2333/726: G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH
- G01N 2800/52: Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
- 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)
- 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)
- 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

In the present invention, the use of the TAS1R3 receptor as a biomarker for application in cancer diagnosis, monitoring, and therapy is described for the first time. In this sense, the authors of the present invention have demonstrated that TAS1R3 is a biomarker of interest in oncology, useful for the diagnosis of the disease, and capable of providing relevant information thereupon, to monitor the evolution, select the treatment, and selectively direct therapeutic molecules. It has been determined that it is possible to identify therapies against this receptor, and that it is also possible to direct conjugates and controlled release systems of drugs, such as nanoparticles, observing a very effective intracellular accumulation thereof in primary, disseminated and metastatic tumor cells. On the other hand, the presence of TAS1R3 in circulating tumor cells (CTCs) has also been demonstrated. These are tumor cells released into the bloodstream by the primary tumor and are considered key factors in the creation of metastases, so that their detection in early stages will serve as an early detector of metastasis, and are also useful in monitoring the disease and evaluating of the response to drugs.

## Claims

### Claim 1

(canceled)

### Claim 2

A method for the in vitro diagnosis of tumor presence, neoplasia or metastatic presence in a patient, the method comprising:
a) providing at least one biological sample isolated from the patient, and determining the level of expression of TAS1R3 in the cells of said biological sample, and
c) comparing said level of expression with the level of expression of the TAS1R3 receptor in a biological sample of a healthy individual, or of a part of a healthy organ or tissue or biological sample without tumor presence, or with a reference value,
wherein an increased level of expression compared to the level of expression of the TAS1R3 receptor in a biological sample of a healthy individual, or of a part of a healthy organ or tissue or biological sample without tumor presence, or with a reference value, is indicative of tumor presence, neoplasia or metastatic presence in a patient.

### Claim 3

A method for the in vitro prognosis of the clinical course of a patient who suffers from tumor presence, neoplasia or metastatic presence in a patient, the method comprising:
a) providing at least one biological sample isolated from the patient, and determining the expression of TAS1R3 in the cells of said biological sample, and
c) comparing said level of expression with the level of expression of the TAS1R3 receptor in a biological sample from the same patient obtained at a time earlier from the time in which the biological sample of part a) was obtained, or with a reference value,
wherein an increased level of expression compared to the level of expression of the TAS1R3 receptor in the biological sample obtained at a time earlier from the time in which the biological sample of part a) was obtained, or with a reference value, is indicative of a negative clinical evolution of the patient.

### Claim 4

A method for the in vitro monitoring of the clinical course of a patient suffering from tumor presence, neoplastic or metastatic presence, the method comprising:
a) providing at least one biological sample isolated from the patient, and determining the expression of TAS1R3 in the cells of said biological sample, and
c) comparing said level of expression with the level of expression of the TAS1R3 receptor in a biological sample from the same patient obtained at a time earlier from the time in which the biological sample of part a) was obtained, or with a reference value,
wherein an increased level of expression compared to the level of expression of the TAS1R3 receptor in a biological sample from the same patient obtained at a time earlier from the time in which the biological sample of part a) was obtained, or with a reference value, is indicative of a negative clinical evolution of the patient.

### Claim 5

A method for monitoring the response to treatment of a patient suffering from tumor presence, neoplastic or metastatic presence, the method comprising:
a) providing at least one biological sample isolated from the patient, and determining the expression of TAS1R3 in the cells of said biological sample, and
c) comparing said level of expression with the level of expression of the TAS1R3 receptor in a biological sample from the same patient obtained at a time earlier from the time in which the biological sample of part a) was obtained, or with a reference value,
wherein an increased level of expression compared to the level of expression of the TAS1R3 receptor in a biological sample from the same patient obtained at a time earlier from the time in which the biological sample of part a) was obtained, or with a reference value, is indicative of lack of response to treatment.

### Claim 6 (depends on 2)

The method according to claim 2, wherein the determination of the expression of TAS1R3 in the cells of a biological sample is carried-out with aptamers, antibodies or fragments thereof from the list consisting of Fv, Fab, Fab ‘and F(ab’)2, scFv, or with diabodies, triabodies, tetrabodies and/or humanized antibodies capable of selectively binding to the TAS1R3 receptor.

### Claim 7 (depends on 6)

The method according to claim 6, wherein said aptamers, antibodies or fragments thereof, or diabodies, triabodies, tetrabodies and/or humanized antibodies, are capable of selectively binding to any of the sequences SEQ ID NO 1 or SEQ ID NO 2.

### Claim 8 (depends on 2)

The method according to claim 2, wherein the tumor present is a solid tumor, or wherein the patient has a disease selected from the group consisting of: breast cancer, melanoma, uveal melanoma, pancreatic cancer, lung cancer, prostate cancer, stomach cancer, head and neck cancer, sarcoma, glioblastoma, neuroblastoma, cancer of the colon and rectum, cancer of the head and neck, renal and bladder cancer, and hepatocarcinoma.

### Claim 9

A method of directing therapies against tumor cells, the method comprising administering ligands of a cellular membrane receptor TAS1R3 to a patient in need thereof wherein the ligands of a cellular membrane receptor TAS1R3 are in the form of conjugates or immunotoxins.

### Claim 10

A method of in vivo tumor diagnosis, the method comprising administering ligands of a cellular membrane receptor TAS1R3 to a subject, wherein the ligands of a cellular membrane receptor TAS1R3 are in the form of conjugates with radiopharmaceuticals.

### Claim 11

A method for tumor therapy or tumor identification, comprising administering to a subject a conjugate that comprises:
a) a specific target agent capable of interacting or binding the TAS1R3 receptor, and,
b) a cytotoxic agent, a radioisotope, a nanostructure or a nanoemulsion.

### Claim 12 (depends on 11)

The method according to claim 11, wherein the target agent capable of interacting or binding with the TAS1R3 receptor is selected from the group consisting of: mono and disaccharides; artificial sweeteners; cyclamate; neoesperidin; dihydrochalcone; sweetness inhibitors; proteins; antibodies or fragments of antibodies; peptides, aptamers, and small molecules.

### Claim 13 (depends on 11)

The method according to claim 11, wherein the target agent is selected from the group consisting of: aptamers, antibodies, fragments of antibodies consisting of: Fv, Fab, Fab′ and F(ab′)2, scFv, diabodies, triabodies, tetrabodies and humanized antibodies, wherein said target agents are capable of selectively binding to any of the sequences SEQ ID NO 1 or SEQ ID NO 2.

### Claim 14

A conjugate that comprises:
a) a specific target agent selected from the list consisting of: brazzein and lactisole, and
b) a cytotoxic agent, a radioisotope, a nanostructure or a nanoemulsion.

### Claim 15 (depends on 11)

The method according to claim 11, wherein said tumor is selected from the group consisting of: breast cancer, melanoma, uveal melanoma, cancer pancreas, lung cancer, prostate cancer, stomach cancer, head and neck cancer, sarcoma, glioblastoma, neuroblastoma, cancer of the colon and rectum, cancer of the head and neck, kidney and bladder cancer, and hepatocarcinoma.