# US 8,465,747 B2 · Identification, optimization and use of cryptic HLA-B7 epitopes for immunotherapy

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- Number: US 8,465,747 B2
- Document ID: US8465747B2
- Status: Granted
- Kind: B2
- Application number: 12/373,408
- Filed: 2007-07-12
- Published: 2011-10-20
- Granted: 2013-06-18
- Earliest claimed: 2006-07-12
- Assignees: Vaxon Biotech
- Applicants: Kostantinos (Kostas) Kosmatopoulos; Stéphanie Graff-Dubois; Jeanne Menez-Jamet
- Inventors: Kostantinos (Kostas) Kosmatopoulos; Stéphanie Graff-Dubois; Jeanne Menez-Jamet
- Web page: https://patentgrep.com/patent/US8465747B2

## CPC

- A61K 39/0005: {Vertebrate antigens (from snakes A61K39/38)}
- A61K 39/0011: {Cancer antigens}
- A61K 40/11: T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
- A61K 40/4246: {Telomerase or [telomerase reverse transcriptase [TERT]}
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 37/04: Immunostimulants
- 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
- C07K 14/005: from viruses
- C07K 14/4748: {Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE}
- C07K 14/70539: {MHC-molecules, e.g. HLA-molecules}
- 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 39/00: Medicinal preparations containing antigens or antibodies (materials for immunoassay G01N33/53)
- A61K 2039/54: {characterised by the route of administration}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- A61K 2039/572: {cytotoxic response}
- C12N 2740/16122: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
- C12N 2740/16222: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
- C12N 2740/16322: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
- 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)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The invention provides methods for identifying a HLA-B*0702-restricted cryptic epitope in an antigen, as well as methods for increasing the immunogenicity of HLA-B*0702-restricted cryptic epitopes. The HLA-B*0702-restricted cryptic epitopes and their cognate immunogenic epitopes are useful for stimulating an immune reaction against the cryptic epitopes in a subject. Accordingly, the invention further provides pharmaceutical compositions comprising a HLA-B*0702-restricted cryptic epitope or a cognate immunogenic epitope thereof, and vaccination kits comprising such epitopes. The novel materials of the invention are particularly useful for efficiently treating patients having an HLA-B*0702 phenotype.

## Claims

### Claim 1

A cryptic HLA-B*0702-restricted epitope consisting of APRSPLAPS (SEQ ID NO: 2).

### Claim 2

An immunogenic HLA-B*0702-restricted epitope, which is derived from the cryptic HLA-B*0702-restricted epitope APRSPLAPS (SEQ ID NO: 2), by substituting its C-terminal amino-acid with a leucine.

### Claim 3 (depends on 1)

A chimeric polypeptide, comprising the cryptic HLB-B*0702-restricted epitope according to claim 1 and one, two, or more HLA-B*0702-restricted cryptic epitopes selected from the group consisting of APRSPLAPS (SEQ ID NO: 2), SPKANKEIL (SEQ ID NO: 3), GPKHSDCLA (SEQ ID NO: 4), and DPRRLVQLL (SEQ ID NO: 1).

### Claim 4 (depends on 2)

A chimeric polypeptide, comprising the immunogenic HLA-B*0702-restricted epitope according to claim 2 and one, two, or more immunogenic HLA-B*0702-restricted epitopes selected from the group consisting of APRSPLAPL (SEQ ID NO: 6), APKANKEIL (SEQ ID NO: 7), APKHSDCLA (SEQ ID NO: 8), and APRRLVQLL (SEQ ID NO: 5).

### Claim 5 (depends on 1)

A pharmaceutical composition comprising at least, as an active principle, a HLA-B*0702-restricted cryptic epitope according to claim 1.

### Claim 6 (depends on 5)

The pharmaceutical composition of claim 5, which is a vaccine.

### Claim 7

A kit of parts comprising, in separate formulations, a first peptide having the sequence APRSPLAPS (SEQ ID NO: 2), and a second peptide having the sequence APRSPLAPL (SEQ ID NO: 6).

### Claim 8 (depends on 3)

A kit of parts comprising, in separate formulations, a first chimeric polypeptide according to claim 3, and a second chimeric polypeptide comprising the immunogenic HLA-B*0702-restricted epitope APRSPLAPL (SEQ ID NO: 6) and one, two, or more immunogenic HLA-B*0702-restricted epitopes selected from the group consisting of APRSPLAPL (SEQ ID NO: 6), APKANKEIL (SEQ ID NO: 7), APKHSDCLA (SEQ ID NO: 8), and APRRLVQLL (SEQ ID NO: 5), wherein the HLA-B*0702-restricted immunogenic epitopes of the second chimeric polypeptide are cognate to the HLA-B*0702-restricted cryptic epitopes comprised in the first chimeric polypeptide.

### Claim 9 (depends on 7)

The kit according to claim 7, which is a vaccination kit, wherein said first and second peptides or chimeric polypeptides are in separate vaccination doses.

### Claim 10 (depends on 9)

The vaccination kit according to claim 9, which comprises 2 or 3 doses of second peptide or chimeric polypeptide, and 3, 4, 5, 6 or up to 50 doses of first peptide.

### Claim 11 (depends on 9)

The vaccination kit according to claim 9, wherein each dose comprises 1 to 5 mg of peptide.

### Claim 12 (depends on 9)

The vaccination kit according to claim 9, wherein the vaccination doses are formulated for subcutaneous injection.

### Claim 13 (depends on 2)

A pharmaceutical composition comprising at least, as an active principle, an immunogenic epitope according to claim 2.

### Claim 14 (depends on 3)

A pharmaceutical composition comprising at least, as an active principle, a chimeric polypeptide according to claim 3.

### Claim 15 (depends on 4)

A pharmaceutical composition comprising at least, as an active principle, a chimeric polypeptide according to claim 4.

### Claim 16 (depends on 8)

The kit according to claim 8, which is a vaccination kit, wherein said first and second chimeric polypeptides are in separate vaccination doses.

### Claim 17 (depends on 16)

The vaccination kit according to claim 16, which comprises 2 or 3 doses of second chimeric polypeptide, and 3, 4, 5, 6 or up to 50 doses of first chimeric polypeptide.

### Claim 18 (depends on 16)

The vaccination kit according to claim 16, wherein each dose comprises 1 to 20 mg of chimeric polypeptide.

### Claim 19 (depends on 16)

The vaccination kit according to claim 16, wherein the vaccination doses are formulated for subcutaneous injection.