# US 2008/0187577 A1 · Immunogenic compositions comprising progastrin and uses thereof

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- Number: US 2008/0187577 A1
- Document ID: US20080187577A1
- Status: Published application
- Kind: A1
- Application number: 12/002,979
- Filed: 2007-12-19
- Published: 2008-08-07
- Earliest claimed: 2006-12-19
- Assignees: Board of Regents, The University of Texas System
- Inventors: Pomila Singh; Gurpreet Singh
- Web page: https://patentgrep.com/patent/US20080187577A1

## CPC

- A61K 39/0005: {Vertebrate antigens (from snakes A61K39/38)}
- A61K 38/2207: {Gastrins; Cholecystokinins [CCK]}
- A61K 39/001102: {Receptors, cell surface antigens or cell surface determinants}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- C07K 14/595: Gastrins; Cholecystokinins [CCK]
- C07K 16/26: against hormones {; against hormone releasing or inhibiting factors}
- C07K 2317/77: Internalization into the cell
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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

The present invention is drawn to immunotherapeutic methods to treat tumors/cancers that produce progastrin ectopically or are dependent on progastrin for their growth. Disclosed herein are immunogenic compositions comprising agents that target progastrin, agents that target the progastrin receptor, annexin II, or both. Such a composition may be administered in combination with chemotherapy or to an individual who had been previously subjected to chemotherapy or radiation therapy. The cancers that may be treated using such a composition may include but are not limited to colon cancer, breast cancer, lung cancer or pancreatic cancer.

## Claims

### Claim 1

A composition, comprising:
an agent targeting progastrin, wherein said agent comprises progastrin or a fragment thereof, an antibody directed against said progastrin or the fragment thereof or specific siRNA against progastrin, a pharmaceutically acceptable adjuvant, a delivery system or a combination thereof; or
an agent targeting annexin II, wherein said agent comprises an antibody directed against annexin II, annexin II specific siRNA or an annexin II specific antisense oligonucleotide, a pharmaceutically acceptable adjuvant, a delivery system or a combination thereof; or
both of said agents.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the progastrin or the fragment thereof is a peptide, a recombinant protein or a fusion protein.

### Claim 3 (depends on 2)

The composition of claim 2, wherein the peptide comprises modified or unmodified amino acid residues of progastrin.

### Claim 4 (depends on 3)

The composition of claim 3, wherein the modified amino acid residues of the peptide comprises alanine instead of arginine at positions 36, 37, 73 and/or 74 and/or alanine instead of lysine at positions 53 and/or 54.

### Claim 5 (depends on 2)

The composition of claim 2, wherein the recombinant protein is produced in E. coli, yeast, salmonella, BCG, vaccinia or other expression system.

### Claim 6 (depends on 2)

The composition of claim 2, wherein the fusion protein comprises multiple copies of progastrin in tandem fused with one or more non-human proteins or multiple copies of progastrin in tandem fused with one or more non-human proteins and tagged at N-terminal or C-terminal.

### Claim 7 (depends on 6)

The composition of claim 6, wherein the non-human protein is a protein from E. coli, yeast, streptococcus or other eukaryotes.

### Claim 8 (depends on 7)

The composition of claim 7, wherein the non-human protein from other eukaryotes is Tetanus Toxoid, Diphtheria toxin, AraC, TrpR or Psts.

### Claim 9 (depends on 6)

The composition of claim 6, wherein the tag at the N or C-terminal is hexa histidine, GST, cellulose binding protein, chitin binding protein, protein-A, Protein-G or Dihydrofolate reductase.

### Claim 10 (depends on 1)

The composition of claim 1, wherein the adjuvant is CFA, IFA, Ribi, emulsion, MDPs, a polysaccharide or a lipopolysaccharide DNA.

### Claim 11 (depends on 10)

The composition of claim 10, wherein the lipopolysaccharide DNA is a CpG sequence.

### Claim 12 (depends on 1)

The composition of claim 1, wherein the delivery system is a nanoparticle, liposome, PLG or hydrogel.

### Claim 13 (depends on 12)

The composition of claim 12, wherein the hydrogel is chitosan alginates or chitosan metal chelates.

### Claim 14 (depends on 1)

The composition of claim 1, wherein the composition is a lyophilised powder that is reconstituted, a suspension or an emulsion.

### Claim 15 (depends on 14)

The composition of claim 14, wherein the composition is administered intramuscularly, subcutaneously, intravenously, intranasally, orally or intrarectally.

### Claim 16 (depends on 1)

The composition of claim 1, wherein the amount of progastrin or a fragment thereof in the administered composition is 1 μg to 100 mg.

### Claim 17 (depends on 1)

The composition of claim 1, wherein the volume of composition administered is 100 ul to 2 ml.

### Claim 18 (depends on 1)

A method of inhibiting proliferation of a neoplastic cell, comprising:
contacting the neoplastic cell with the composition of claim 1, wherein said composition comprises either an agent that targets progastrin or an agent that targets annexin II or both, such that said contact inhibits the growth-inducing activity of progastrin in the cell, thereby inhibiting the proliferation of the neoplastic cell.

### Claim 19 (depends on 18)

The method of claim 18, wherein said composition blocks binding of the progastrin to a receptor on the cell, blocks binding of a protein that binds progastrin, induces an immune response against progastrin or against receptors of progastrin, downregulates expression of progastrin or annexin II at the nucleic acid level or protein level, blocks internalization of progastrin in the cell or a combination thereof.

### Claim 20 (depends on 19)

The method of claim 19, wherein the receptor is Annexin II.

### Claim 21 (depends on 19)

The method of claim 19, wherein the protein that binds Progastrin has molecular weights ranging from 40 KDa to 50 KDa.

### Claim 22 (depends on 19)

The method of claim 19, wherein the protein that binds progastrin is an agonist or antagonist of progastrin or an inhibitor of progastrin or progastrin binding molecule.

### Claim 23 (depends on 18)

The method of claim 18, wherein said neoplastic cell is a cancer cell.

### Claim 24 (depends on 23)

The method of claim 23, wherein said cancer cell is colon cancer cell, breast cancer cell, lung cancer cell, pancreatic cancer cell or any other cancer cell that expresses gastrin gene or is dependent on gastrin gene products for growth.

### Claim 25 (depends on 1)

A method of treating a cancer in an individual, comprising:
administering pharmacologically effective amount of the composition of claim 1 to said individual, wherein said composition comprises either an agent that targets progastrin or an agent that targets annexin II or both, such that said administration inhibits gastrin-induced proliferation of cancer cells, thereby treating the cancer in the individual.

### Claim 26 (depends on 25)

The method of claim 25, further comprising:
administering an anticancer drug to the individual.

### Claim 27 (depends on 26)

The method of claim 26, wherein the anticancer drug is administered prior to, concurrent with or sequentially with said administration.

### Claim 28 (depends on 26)

The method of claim 26, wherein the anticancer agent is a chemotherapeutic agent, an anti-angiogenic agent or anti-epidermal growth factor agent.

### Claim 29 (depends on 28)

The method of claim 28, wherein the chemotherapeutic agent, the anti-angiogenic agent or the anti-epidermal growth factor agent is administered either alone or in combination.

### Claim 30 (depends on 28)

The method of claim 28, wherein the chemotherapeutic agent 5FU, Camptosar (CPT11), Eloxitan (Oxaliplatin), Lavamisol, Leucovorin, or irinotecan.

### Claim 31 (depends on 29)

The method of claim 29, wherein the anti-angiogenic agent is Avastin.

### Claim 32 (depends on 29)

The method of claim 29, wherein the anti-epidermal growth factor receptor family agents is Erbitux.

### Claim 33 (depends on 25)

The method of claim 25, wherein said inhibition of proliferation is due to blocking of binding of progastrin to a receptor on the cell, blocking of binding of a protein that binds progastrin, eliciting an immune response against progastrin or receptors of progastrin, downregulating expression of progastrin or annexin II at the nucleic acid or protein level, blocking internalization of progastrin in the cell or a combination thereof.

### Claim 34 (depends on 25)

The method of claim 25, wherein the individual has detectable levels of progastrin, is in the primary stages of cancer, has full blown cancer, has tumors induced due to growth-inducing effect of progastrin or has previously been subjected to chemotherapy or radiation therapy.

### Claim 35 (depends on 34)

The method of claim 34, wherein the cancer is colon cancer, breast cancer, lung cancer, pancreatic cancer or any other cancer that expresses gastrin gene or is dependent on gastrin gene products for growth.