# US 7,608,591 B2 · Targeted delivery to legumain-expressing cells

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- Number: US 7,608,591 B2
- Document ID: US7608591B2
- Status: Granted
- Kind: B2
- Application number: 11/288,978
- Filed: 2005-11-29
- Published: 2006-06-22
- Granted: 2009-10-27
- Earliest claimed: 2003-05-29
- Assignees: The Scripps Research Institute
- Inventors: Cheng Liu; Thomas S. Edgington
- Web page: https://patentgrep.com/patent/US7608591B2

## CPC

- A61F 13/0243: {characterised by the properties of the skin contacting layer, e.g. air-vapor permeability}
- A61F 13/00051: {Accessories for dressings}
- A61F 13/00059: {provided with visual effects, e.g. printed or colored}
- A61F 13/0233: {characterised by the oclusive layer skin contacting layer}
- 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 47/67: {Enzyme prodrug therapy, e.g. gene directed enzyme drug therapy [GDEPT] or VDEPT}
- B82Y 5/00: Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
- C07K 5/0606: {the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr}
- C07K 5/06113: {Asp- or Asn-amino acid}
- C07K 5/0806: {the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala}
- C07K 5/081: {the side chain containing O or S as heteroatoms, e.g. Cys, Ser}
- C07K 5/1008: {the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala}
- C07K 7/02: Linear peptides containing at least one abnormal peptide link
- C07K 9/005: {containing within the molecule the substructure [IMAGE cpc-sch-C07K-1009.gif] with m, n > 0 and m+n > 0, A, B, D, E being heteroatoms; X being a bond or a chain, e.g. muramylpeptides}
- G01N 33/57535: of the large intestine, e.g. colon, rectum or anus
- G01N 33/57557: {of other specific parts of the body, e.g. brain}
- A61F 2013/00123: {with elastic indicator}
- A61F 2013/00127: {fixation means}
- A61F 2013/00153: {coloured or with decoration pattern or printing}
- A61F 2013/00182: {with transparent part}
- A61F 2013/0028: {applying of mechanical pressure; passive massage}
- 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)
- G01N 2333/95: Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
- G01N 2500/00: Screening for compounds of potential therapeutic value
- A61F: FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS (dental prosthetics A61C)
- 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)
- B82Y: SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- 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)
- 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

The present invention relates to new agents and methods useful for preventing, treating and diagnosing diseases such as cancer. For example, the invention relates to prodrug agents useful for targeting and delivering cytotoxic drugs to cancerous cells.

## Claims

### Claim 1

A prodrug compound, comprising cytosine arabinoside or doxorubicin linked to a legumain peptide substrate having a peptide consisting of amino acid sequence Ala-Ala-Asn-Leu (SEQ ID NO:5) and wherein legumain cleaves the peptide at the link between the Asn and another amino acid to generate active cytosine arabinoside or doxorubicin from the prodrug.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the prodrug is substantially non-toxic to non-legumain expressing animal cells.

### Claim 3 (depends on 1)

The compound of claim 1, wherein the amino acid sequence comprises Boc-Ala-Ala-Asn-Leu (SEQ ID NO:4).

### Claim 4 (depends on 1)

The compound of claim 1, wherein the amino acid sequence comprises succinyl-Ala-Ala-Asn-Leu (SEQ ID NO:8).

### Claim 5 (depends on 1)

The compound of claim 1, wherein the peptide further comprises a protecting group.

### Claim 6 (depends on 5)

The compound of claim 5, wherein the protecting group is an amino protecting group.

### Claim 7 (depends on 5)

The compound of claim 5, wherein the protecting group is succinyl.

### Claim 8 (depends on 5)

The compound of claim 5, wherein the protecting group is t-butoxycarbonyl.

### Claim 9 (depends on 5)

The compound of claim 5, wherein the peptide further comprises an N-β-alanyl terminus.

### Claim 10 (depends on 1)

A pharmaceutical composition, comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 11 (depends on 1)

A method for treating a mammal having cancer comprising administering to the mammal the compound of claim 1 in amounts and at intervals effective to reduce or eliminate one or more of the symptoms associated with cancer.

### Claim 12 (depends on 11)

The method of claim 11, wherein the cancer is a solid cancer.

### Claim 13 (depends on 11)

The method of claim 11, wherein the cancer is breast cancer, colon cancer, lung cancer, prostate cancer, ovarian cancer, cancer of the central nervous system, lymphoma, or melanoma.

### Claim 14 (depends on 11)

The method of claim 11, wherein the cancer is autoimmune deficiency syndrome-associated Kaposi's sarcoma, cancer of the adrenal cortex, cancer of the cervix, cancer of the endometrium, cancer of the esophagus, cancer of the head and neck, cancer of the liver, cancer of the pancreas, cancer of the prostate, cancer of the thymus, carcinoid tumors, chronic lymphocytic leukemia, Ewing's sarcoma, gestational trophoblastic tumors, hepatoblastoma, multiple myeloma, non-small cell lung cancer, retinoblastoma, or tumors in the ovaries.

### Claim 15 (depends on 1)

A method for inhibiting metastasis of cancer in an animal, comprising administering the compound of claim 1 to the animal in amounts and at intervals effective to reduce or eliminate cancer metastasis.

### Claim 16 (depends on 1)

A method for inhibiting cell migration in an animal, comprising administering the compound of claim 1 to the animal in amounts and at intervals effective to reduce or eliminate cancer cell migration.

### Claim 17 (depends on 1)

A method of killing a cell in a tissue, comprising contacting the cell with the compound of claim 1 in amounts and at intervals effective to kill the cell, wherein the tissue comprises legumain.