# US 8,568,977 B2 · Compositions and methods for diagnosis and treatment of tumors

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- Number: US 8,568,977 B2
- Document ID: US8568977B2
- Status: Granted
- Kind: B2
- Application number: 13/549,633
- Filed: 2012-07-16
- Published: 2012-11-22
- Granted: 2013-10-29
- Earliest claimed: 2006-06-20
- Assignees: The United States of America, as represented by the Secretary, Department of Health and Human Services
- Applicants: Vivian Takafuji; Xin Wei Wang; Paul K. Goldsmith
- Inventors: Vivian Takafuji; Xin Wei Wang; Paul K. Goldsmith
- Web page: https://patentgrep.com/patent/US8568977B2

## CPC

- C07K 16/2848: {against integrin beta3-subunit-containing molecules, e.g. CD41, CD51, CD61}
- A61P 35/00: Antineoplastic agents
- C07K 16/18: against material from animals or humans
- C07K 16/24: against cytokines, lymphokines or interferons
- C07K 16/2884: {against CD44}
- C07K 16/40: against enzymes
- G01N 33/57525: of the liver or pancreas
- 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}
- 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)
- A61K 2039/505: {comprising antibodies}
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- G01N 2333/52: Assays involving cytokines
- 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)
- 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

Based on the observation of the cooperation of osteopontin (OPN) and matrixmetalloproteinase-9 (MMP-9) in the promotion of the metastatic phenotype, therapies and diagnostic assays are disclosed for the treatment of a tumor that overexpresses OPN, such as hepatocellular carcinoma (HCC), for example metastatic HCC. In one example, methods of treating a tumor include administration of an agent that reduces cellular invasion resulting from the interaction between a fragment of OPN (OPN-5kD) generated by MMP-9 cleavage and CD44 receptor. Examples of such agents include fragments of OPN-5kD and antibodies specific for OPN-5kD. Therapeutic compositions are also provided that include such agents. Also provided are methods of diagnosing or prognosing a tumor, for example by detecting expression of OPN-5kD peptide or OPN-c mRNA in a biological sample obtained from the subject. Also provided are antibodies that specifically bind OPN-5kD.

## Claims

### Claim 1

A method of determining the metastatic potential of an OPN-expressing hepatocellular carcinoma (HCC) in a subject, comprising:
determining an amount of OPN-c expression in an HCC tumor sample obtained from the subject;
determining an amount of OPN-c expression in a sample obtained adjacent to the HCC tumor from the subject;
comparing the amount of OPN-c expression in the HCC tumor sample to the adjacent sample; and
determining that the subject has an OPN-expressing HCC with increased metastatic potential if a statistically significant increase in OPN-c expression in the HCC tumor sample compared to the adjacent sample is observed.

### Claim 2 (depends on 1)

The method of claim 1, wherein detecting the OPN-c comprises detecting OPN-c mRNA expression.

### Claim 3 (depends on 1)

The method of claim 1, wherein the subject is a human subject.

### Claim 4 (depends on 1)

The method of claim 1, wherein the OPN-c detected comprises SEQ ID NO: 3.

### Claim 5 (depends on 1)

The method of claim 1, wherein an at least 2-fold increase in OPN-c expression in the HCC tumor sample compared to the adjacent sample indicates that the subject has an OPN-expressing HCC with increased metastatic potential.

### Claim 6 (depends on 1)

The method of claim 1, wherein statistically similar relative amounts of OPN-c expression in the HCC tumor sample as compared to the adjacent sample indicates that the subject does not have an OPN-expressing HCC with increased metastatic potential.

### Claim 7 (depends on 1)

The method of claim 1, further comprising administering to the subject having an HCC with increased metastatic potential with a therapeutically effective amount of a peptide fragment of OPN-5kD or an antibody that binds to OPN-5kD.

### Claim 8 (depends on 7)

The method of claim 7, wherein the peptide fragment of OPN-5kD comprises SEQ ID NO: 5, 6, or 7.

### Claim 9 (depends on 7)

The method of claim 7, wherein the antibody that binds to OPN-5kD specifically binds to amino acids 30-36 of SEQ ID NO: 4.

### Claim 10 (depends on 7)

The method of claim 7, wherein the peptide fragment of OPN-5kD or the antibody that binds to OPN-5kD is administered subcutaneously.

### Claim 11 (depends on 1)

The method of claim 1, further comprising obtaining from the subject the HCC tumor sample and the sample adjacent to the HCC tumor.

### Claim 12 (depends on 1)

The method of claim 1, wherein determining the amount of OPN-c expression in the HCC tumor sample obtained from the subject and determining the amount of OPN-c expression in a sample obtained adjacent to the HCC tumor from the subject comprises contacting the HCC tumor sample and the sample obtained adjacent to the tumor with a nucleic acid probe that hybridizes to OPN-c nucleic acid molecules.