# US 7,374,767 B2 · Peptides for the treatment of cancer associated with the human papilloma virus (HPV) and other epithelial tumors

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- Number: US 7,374,767 B2
- Document ID: US7374767B2
- Status: Granted
- Kind: B2
- Application number: 10/499,458
- Filed: 2002-12-04
- Published: 2006-10-19
- Granted: 2008-05-20
- Earliest claimed: 2001-12-20
- Assignees: Centro de Ingenieria Genetica Y Biotechologia
- Inventors: Silvio Ernesto Perea Rodriguez; Osvaldo Reyes Acosta; Nelson Francisco Santiago Vispo; Yaquelin Puchades Izaguirre; Ricardo Silva Rodriguez; Alejandro Moro Soria; Alicia Santos Savio; Luis Javier González López; Belkis González Barrios
- Web page: https://patentgrep.com/patent/US7374767B2

## CPC

- C07K 14/005: from viruses
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 7/06: having 5 to 11 amino acids
- C12N 7/00: Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00)
- 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 48/00: Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- C07K 2319/10: containing a tag for extracellular membrane crossing, e.g. TAT or VP22
- C12N 2710/20022: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
- C12N 2710/20032: Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- 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

This invention is related to the Molecular Pharmacology field and especially to the development of peptides useful for treating epithelial tumors and mainly those associated to oncogenic types of HPVs. The main objective of this invention is to identify peptides whose structure permits to block the Casein Kinase II (CKII) phosphorylation domain by direct interaction with such a site. In the present invention it is shown eleven cyclic peptides with different aminoacid sequences which inhibit the CKII phosphorylation in vitro, exhibit cytotoxicity on HPV-16 transformed cells (CaSki) and also increase the sensitivity of these cells to the cytostatic effect of interferon (IFN). Furthermore, the invention relates to the use of these peptides conjugated or fused to other peptides and chemical compounds which penetrates into cells as well as with the use of both peptide and chemical mimetic molecules.

## Claims

### Claim 1

A peptide comprising an amino acid sequence as set forth in:
a).
CSVRQGPVQKC;
(SEQ ID NO: 1)
b).
CSSCQNSPALC;
(SEQ ID NO: 2)
c).
CQIPQRTATRC;
(SEQ ID NO: 3)
d).
CAKQRTDPGYC;
(SEQ ID NO: 4)
e).
CWMSPRHLGTC;
(SEQ ID NO: 5)
f).
CRNCTVIQFSC;
(SEQ ID NO: 6)
g).
CHYIAGTVQGC;
(SEQ ID NO: 7)
h).
CPLVSLRDHSC;
(SEQ ID NO: 8)
i).
CKQSYLHHLLC;
(SEQ ID NO: 9)
j).
CFQPLTPLCRC; or
(SEQ ID NO: 10)
k).
CQSYHELLLQC;
(SEQ ID NO: 11)
wherein the peptide binds and inhibits a Casein Kinase II (CKII) phosphorylation site.

### Claim 2 (depends on 1)

A peptide according to claim 1, wherein the peptide has a cyclic structure.

### Claim 3 (depends on 2)

A peptide according to claim 2, wherein the peptide is contained in a fusion polypeptide.

### Claim 4 (depends on 1)

A peptide according to claim 1, wherein the peptide is contained in a fusion polypeptide.

### Claim 5

A pharmaceutical composition comprising
a). a peptide selected from the group consisting of
i). CSVRQGPVQKC (SEQ ID NO: 1);
ii). CSSCQNSPALC (SEQ ID NO: 2);
iii). CQIPQRTATRC (SEQ ID NO: 3);
iv). CAKQRTDPGYC (SEQ ID NO: 4);
v). CWMSPRHLGTC (SEQ ID NO: 5);
vi). CRNCTVIQFSC (SEQ ID NO: 6);
vii). CHYIAGTVQGC (SEQ ID NO: 7);
viii). CPLVSLRDHSC (SEQ ID NO: 8);
ix). CKQSYLHHLLC (SEQ ID NO: 9);
x). CFQPLTPLCRC (SEQ ID NO: 10);
xi). CQSYHELLLQC (SEQ ID NO: 11);
and
b). a pharmaceutically-acceptable carrier.

### Claim 6 (depends on 5)

A pharmaceutical composition according to claim 5, further comprising a cytokine.

### Claim 7 (depends on 6)

A pharmaceutical composition according to claim 6, wherein the cytokine is interferon (IFN).

### Claim 8 (depends on 5)

A pharmaceutical composition according to claim 5, wherein the peptide has a cyclic structure.

### Claim 9 (depends on 8)

A pharmaceutical composition according to claim 8, further comprising a cytokine.

### Claim 10 (depends on 9)

A pharmaceutical composition according to claim 9, wherein the cytokine is interferon (IFN).

### Claim 11

A method for inhibiting tumor cell proliferation, comprising administering to a mammal an effective amount of a peptide comprising an amino acid sequence as set forth in:
a). CSVRQGPVQKC (SEQ ID NO: 1);
b). CSSCQNSPALC (SEQ ID NO: 2);
c). CQIPQRTATRC (SEQ ID NO: 3);
d). CAKQRTDPGYC (SEQ ID NO: 4);
e). CWMSPRHLGTC (SEQ ID NO: 5);
f). CRNCTVIQFSC (SEQ ID NO: 6);
g). CHYIAGTVQGC (SEQ ID NO: 7);
h). CPLVSLRDHSC (SEQ ID NO: 8);
i). CKQSYLHHLLC (SEQ ID NO: 9);
j). CFQPLTPLCRC (SEQ ID NO: 10); or
k). CQSYHELLLQC (SEQ ID NO: 11),
wherein the peptide binds and inhibits a Casein Kinase II (CKII) phosphorylation site.

### Claim 12 (depends on 11)

A method according to claim 11, wherein the tumor is a human papillomavirus (HPV)-associated tumor.

### Claim 13 (depends on 11)

A method according to claim 11, wherein the tumor is a premalignant human papillomavirus (HPV)-associated tumor.

### Claim 14 (depends on 11)

A method according to claim 11, further comprising administering a cytokine.

### Claim 15 (depends on 14)

A method according to claim 14, wherein the cytokine is interferon (IFN).

### Claim 16 (depends on 11)

A method according to claim 11, wherein the mammal is infected with human papillomavirus (HPV) and is resistant toward treatment with interferon (IFN).

### Claim 17 (depends on 11)

A method according to claim 11, wherein the peptide has a cyclic structure.

### Claim 18 (depends on 17)

A method according to claim 17, wherein the tumor is a human papillomavirus (HPV)-associated tumor.

### Claim 19 (depends on 17)

A method according to claim 17, wherein the tumor is a premalignant human papillomavirus (HPV)-associated tumor.

### Claim 20 (depends on 17)

A method according to claim 17, further comprising administering a cytokine.

### Claim 21 (depends on 20)

A method according to claim 20, wherein the cytokine is interferon (IFN).

### Claim 22 (depends on 17)

A method according to claim 17, wherein the mammal is infected with human papillomavirus (HPV) and is resistant toward treatment with interferon (IFN).

### Claim 23 (depends on 11)

A method according to claim 11, wherein the peptide is contained in a fusion polypeptide.

### Claim 24 (depends on 23)

A method according to claim 23, wherein the tumor is a human papillomavirus (HPV)-associated tumor.

### Claim 25 (depends on 23)

A method according to claim 23, further comprising administering a cytokine.

### Claim 26 (depends on 25)

A method according to claim 25, wherein the cytokine is interferon (IFN).

### Claim 27 (depends on 23)

A method according to claim 23, wherein the mammal is infected with human papillomavirus (HPV) and is resistant toward treatment with interferon (IFN).

### Claim 28

A mammalian expression vector comprising a nucleotide sequence that encodes a peptide comprising an amino acid sequence as set forth in:
a). CSVRQGPVQKC (SEQ ID NO: 1);
b). CSSCQNSPALC (SEQ ID NO: 2);
c). CQIPQRTATRC (SEQ ID NO: 3);
d). CAKQRTDPGYC (SEQ ID NO: 4);
e). CWMSPRHLGTC (SEQ ID NO: 5);
f). CRNCTVIQFSC (SEQ ID NO: 6);
g). CHYIAGTVQGC (SEQ ID NO: 7);
h). CPLVSLRDHSC (SEQ ID NO: 8);
i). CKQSYLHHLLC (SEQ ID NO: 9);
j). CFQPLTPLCRC (SEQ ID NO: 10); or
k). CQSYHELLLQC (SEQ ID NO: 11).

### Claim 29 (depends on 28)

A mammalian expression vector according to claim 28, wherein the peptide has a cyclic nature.

### Claim 30 (depends on 28)

A mammalian expression vector according to claim 28, wherein the peptide is contained in a fusion polypeptide.