# US 8,541,002 B2 · Vaccine for treatment and prevention of herpes simplex virus infection

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- Number: US 8,541,002 B2
- Document ID: US8541002B2
- Status: Granted
- Kind: B2
- Application number: 10/571,716
- Filed: 2004-09-13
- Published: 2011-03-10
- Granted: 2013-09-24
- Earliest claimed: 2003-09-12
- Assignees: Agenus Inc.
- Applicants: Alemseged Truneh; Daniel L. Levey; Xiaoyan Mo; Kenneth P. Leclair; Ramesh S. Kashi; Chuanliang Liu
- Inventors: Alemseged Truneh; Daniel L. Levey; Xiaoyan Mo; Kenneth P. Leclair; Ramesh S. Kashi; Chuanliang Liu
- Web page: https://patentgrep.com/patent/US8541002B2

## CPC

- C07K 14/005: from viruses
- A61K 39/12: Viral antigens
- A61K 39/245: Herpetoviridae, e.g. herpes simplex virus
- A61K 39/39: characterised by the immunostimulating additives, e.g. chemical adjuvants
- A61K 39/395: Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/12: Antivirals
- A61P 31/22: for herpes viruses
- A61P 37/04: Immunostimulants
- A61K 39/00: Medicinal preparations containing antigens or antibodies (materials for immunoassay G01N33/53)
- A61K 2039/555: {characterised by a specific combination antigen/adjuvant}
- A61K 2039/55566: {Emulsions, e.g. Freund's adjuvant, MF59}
- A61K 2039/55577: {Saponins; Quil A; QS21; ISCOMS}
- A61K 2039/55583: {Polysaccharides}
- C12N 2710/16622: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
- C12N 2710/16634: Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
- C12N 2710/16671: Demonstrated in vivo effect
- 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)
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The present invention relates to methods and compositions for the prevention and treatment of herpes virus infections. The invention provides antigenic peptides, and pharmaceutical compositions comprising complexes of antigenic peptides and adjuvants that can activate an immune response against herpes viruses. The invention also provides methods of making the antigenic peptides and complexes of antigenic peptides and adjuvants. Methods of use of the pharmaceutical compositions are also provided.

## Claims

### Claim 1

A composition comprising at least ten different purified complexes of a stress protein noncovalently bound to an antigenic peptide, wherein said complexes each comprise a different antigenic peptide, and wherein each one of said different antigenic peptides comprises one or more HLA-binding epitopes of a different herpesvirus peptide selected from among herpesvirus peptides differing in amino acid sequence, wherein for ten of said complexes the amino acid sequence of each herpesvirus peptide is selected from the group consisting of SEQ ID NO: 3, 9, 21, 34, 35, 36, 37, 41, 42, and 44, wherein each one of said different antigenic peptides does not comprise the entire amino acid sequence of a herpes simplex virus protein.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the stress protein is a member of the hsp60, hsp70, or hsp90 family of stress proteins.

### Claim 3 (depends on 1)

The composition of claim 1, wherein the stress protein is hsc70, Hsp70, hsp90, hsp110, grp170, gp96, calreticulin, or combinations of two or more thereof.

### Claim 4 (depends on 1)

The composition of claim 1, wherein the stress protein is a human stress protein.

### Claim 5 (depends on 1)

The composition of claim 1 which further comprises one or more adjuvants.

### Claim 6 (depends on 5)

The composition of claim 5, wherein the adjuvant is a saponin or an immunostimulatory nucleic acid.

### Claim 7 (depends on 1)

A kit comprising a first container comprising the composition of claim 1, and at least one container comprising an adjuvant, a chemotherapeutic agent, an antibody, or a biological response modifier.

### Claim 8 (depends on 1)

A method of eliciting an immune response against HSV-1 or HSV-2 in an individual, the method comprising administering to the individual an immunogenic amount of the composition of claim 1.

### Claim 9 (depends on 8)

The method of claim 8, further comprising administering to the individual an adjuvant, an antibody, a biological response modifier, or a chemotherapeutic agent.

### Claim 10 (depends on 9)

The method of claim 9, wherein said chemotherapeutic agent is chosen from the group consisting of acyclovir, valacyclovir, pencyclovir, famcyclovir, cidofovir, and phosphonoformic acid, and combinations thereof.

### Claim 11 (depends on 9)

The method of claim 9, wherein said biological response modifier is IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IFNα, IFN-β, IFN-γ, TNFα, TNF β, G-CSF, GM-CSF, or TGF β.

### Claim 12 (depends on 8)

The method of claim 8, wherein the individual is a human.

### Claim 13 (depends on 1)

The composition of claim 1, wherein said different purified complexes are not obtained or purified from a cell.

### Claim 14 (depends on 1)

The composition of claim 1, wherein said different antigenic peptides do not include antigenic peptides comprising epitope(s) of HSV2 proteins other than those comprising the amino acid sequence of SEQ ID NO: 3, 9, 21, 34, 35, 36, 37, 41, 42, and 44, respectively.

### Claim 15 (depends on 1)

The composition of claim 1, wherein at least 50% of said at least ten plurality of different complexes comprise a herpesvirus peptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 9, 21, 34, 35, 36, 37, 41, 42, and 44.

### Claim 16 (depends on 1)

The composition of claim 1, wherein each of said different antigenic peptides do not comprise amino acid sequences that are adjacent to the amino acid sequence of each of the respective herpesvirus peptides.

### Claim 17 (depends on 3)

The composition of claim 3, wherein the stress protein is hsp70 or hsc70.

### Claim 18 (depends on 17)

The composition of claim 17, further comprising at least one other purified complex of a stress protein noncovalently bound to an antigenic peptide, wherein the antigenic peptide of the at least one other purified complex comprises one or more HLA-binding epitopes of a herpesvirus peptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 4-8, 16-18, 20, 23-25, 29, 33, 38, 39, 43, and 45-49.

### Claim 19 (depends on 18)

The composition of claim 18, further comprising QS-21.

### Claim 20 (depends on 19)

The composition of claim 19, wherein the amount of the stress protein in the composition is in a range of 10 μg to 600 μg.

### Claim 21 (depends on 20)

The composition of claim 20, wherein the amount of the QS-21 in the composition is 10 μg, 25 μg, or 50 μg.

### Claim 22 (depends on 1)

The composition of claim 1 further comprising at least one other purified complex of a stress protein noncovalently bound to an antigenic peptide, wherein the antigenic peptide of the at least one other purified complex comprises one or more HLA-binding epitopes of a herpesvirus peptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 4-8, 16-18, 20, 23-25, 29, 33, 38, 39, 43, and 45-49.

### Claim 23 (depends on 1)

The composition of claim 1 further comprising at least one other purified complex of a stress protein noncovalently bound to an antigenic peptide, wherein the antigenic peptide of the at least one other purified complex comprises one or more HLA-binding epitopes of a herpesvirus peptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 1-2, 4-8, 10-20, 22-33, 38-40, 43, and 45-49.

### Claim 24 (depends on 2)

The composition of claim 2 further comprising at least one other purified complex of a stress protein noncovalently bound to an antigenic peptide, wherein the antigenic peptide of the at least one other purified complex comprises one or more HLA-binding epitopes of a herpesvirus peptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 1-2, 4-8, 10-20, 22-33, 38-40, 43, and 45-102.

### Claim 25 (depends on 8)

The method of claim 8, wherein the composition is administered to the individual biweekly.

### Claim 26 (depends on 8)

The method of claim 8, wherein the composition is administered to the individual by intradermal, subcutaneous, or mucosal administration.

### Claim 27 (depends on 8)

The method of claim 8, wherein the stress protein is a member of the hsp60, hsp70, or hsp90 family of stress proteins.

### Claim 28 (depends on 27)

The method of claim 27, wherein the stress protein is hsp70 or hsc70.

### Claim 29 (depends on 28)

The method of claim 28, wherein the composition further comprises at least one other purified complex of a stress protein noncovalently bound to an antigenic peptide, wherein the antigenic peptide of the at least one other purified complex comprises one or more HLA-binding epitopes of a herpesvirus peptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 4-8, 16-18, 20, 23-25, 29, 33, 38, 39, 43, and 45-49.

### Claim 30 (depends on 29)

The method of claim 29, wherein the composition further comprises QS-21.

### Claim 31 (depends on 30)

The method of claim 30, wherein the amount of the stress protein in the composition is in a range of 10 μg to 600 μg.

### Claim 32 (depends on 31)

The method of claim 31, wherein the amount of the QS-21 in the composition is 10 μg, 25 μg, or 50 μg.

### Claim 33 (depends on 21)

The method of claim 21, wherein the composition further comprises at least one other purified complex of a stress protein noncovalently bound to an antigenic peptide, wherein the antigenic peptide of the at least one other purified complex comprises one or more HLA-binding epitopes of a herpesvirus peptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 4-8, 16-18, 20, 23-25, 29, 33, 38, 39, 43, and 45-49.

### Claim 34 (depends on 1, 8)

The method of claim 8, wherein, prior to administering the immunogenic amount of the composition of claim 1, antibodies against an HSV antigen are detectable in serum from the individual.

### Claim 35 (depends on 1, 8)

The method of claim 8, wherein, prior to administering the immunogenic amount of the composition of claim 1, antibodies against an HSV antigen are not detectable in serum from the individual.

### Claim 36

A composition, comprising a plurality of different purified complexes of a stress protein noncovalently bound to an antigenic peptide, wherein said plurality of different complexes each comprise a different antigenic peptide, and wherein each one of said different antigenic peptides comprises one or more HLA-binding epitopes of a different herpesvirus peptide selected from among herpesvirus peptides differing in amino acid sequence, the amino acid sequence of each herpesvirus peptide selected from the group consisting of SEQ ID NO: 3, 9, 21, 34, 35, 36, 37, 41, 42, and 44, wherein each one of said different antigenic peptides is in a range of 8 amino acids to 45 amino acids in length.

### Claim 37 (depends on 36)

The composition of claim 36, wherein each one of said different antigenic peptides is in a range of 30 amino acids to 40 amino acids in length.

### Claim 38 (depends on 1)

The composition of claim 1, wherein the composition comprises at least 20 different purified complexes of a stress protein noncovalently bound to an antigenic peptide.

### Claim 39 (depends on 1)

The composition of claim 1, wherein the composition comprises at least 30 different purified complexes of a stress protein noncovalently bound to an antigenic peptide.

### Claim 40 (depends on 15)

The composition of claim 15, wherein each of said at least ten different complexes comprise a herpesvirus peptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 9, 21, 34, 35, 36, 37, 41, 42, and 44.

### Claim 41 (depends on 36)

The composition of claim 36, further comprising at least one other purified complex of a stress protein noncovalently bound to an antigenic peptide, wherein the antigenic peptide of the at least one other purified complex comprises one or more HLA-binding epitopes of a herpesvirus peptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 4-8, 16-18, 20, 23-25, 29, 33, 38, 39, 43, and 45-49.

### Claim 42 (depends on 41)

The composition of claim 41, wherein the antigenic peptide in the at least one other purified complex is in a range of 8 amino acids to 45 amino acids in length.

### Claim 43 (depends on 41)

The composition of claim 41, wherein the antigenic peptide in the at least one other purified complex is in a range of 30 amino acids to 40 amino acids in length.