# US 9,751,914 B2 · Polypeptides and antibodies for treating HBV infection and related diseases

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- Number: US 9,751,914 B2
- Document ID: US9751914B2
- Status: Granted
- Kind: B2
- Application number: 14/406,940
- Filed: 2013-06-06
- Published: 2015-09-03
- Granted: 2017-09-05
- Earliest claimed: 2012-06-11
- Assignees: Xiamen University; Xiamen Innovax Biotech Co., Ltd.
- Applicants: Xiamen University; Xiamen Innovax Biotech Co., Ltd.
- Inventors: Quan Yuan; Tianying Zhang; Wenxin Luo; Yixin Chen; Jun Zhang; Ningshao Xia
- Web page: https://patentgrep.com/patent/US9751914B2

## CPC

- C07K 14/005: from viruses
- A61K 39/12: Viral antigens
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 31/20: for DNA viruses
- A61P 37/04: Immunostimulants
- C07K 7/06: having 5 to 11 amino acids
- C07K 16/082: Hepadnaviridae (F), e.g. hepatitis B virus
- C12P 21/02: having a known sequence of two or more amino acids, e.g. glutathione
- G01N 33/56983: {Viruses}
- A61K 39/00: Medicinal preparations containing antigens or antibodies (materials for immunoassay G01N33/53)
- A61K 2039/505: {comprising antibodies}
- A61K 2039/6037: {Bacterial toxins, e.g. diphteria toxoid [DT], tetanus toxoid [TT]}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C12N 7/00: Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00)
- C12N 2710/00034: Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
- C12N 2730/10122: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
- C12N 2730/10134: Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
- G01N 2333/02: Hepadnaviridae, e.g. hepatitis B virus
- 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
- C12P: FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE {(brewing of beer C12C; producing vinegar C12J; producing specific peptides or proteins C07K; producing enzymes C12N9/00; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; measuring or testing processes involving enzymes or microorganisms C12Q; measuring or testing processes involving nucleic acid amplification reactions C12Q1/6844; fermentation processes to form a food composition, A21 or A23; compounds in general, see the relevant compound class, e.g. C01, C07)}
- 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)
- 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 epitope peptides (or mutants thereof) for treating hepatitis B virus infection, recombinant proteins comprising such epitope peptides (or mutants thereof) and carrier proteins, and uses of such epitope peptides (or mutants thereof) and recombinant proteins. The present invention also relates to antibodies against such epitope peptides, cell lines producing said antibodies, and uses thereof. Furthermore, the present invention relates to vaccines or pharmaceutical compositions for treating or alleviating one or more symptoms associated with hepatitis B virus infection, which comprise the recombinant proteins or antibodies according to the invention, respectively.

## Claims

### Claim 1

A method for reducing serum level of HBV DNA and/or HBsAg in a subject, comprising administering to a subject infected with HBV and in need of reducing serum level of HBV DNA and/or HBsAg an effective amount that results in significant reductions of serum level of HBV DNA and/or HBsAg of:
(a) an isolated epitope peptide consisting of 4-38 consecutive amino acid residues of HBsAg protein and comprising amino acid residues from positions 121 to 124 of HBsAg protein, or a mutant thereof, wherein the mutant differs from the epitope peptide merely by conservative substitution of one or several amino acid residues and retains the biological function of the epitope peptide;
(b) a recombinant protein comprising the epitope peptide or mutant thereof of (a) and a carrier protein;
(c) an isolated nucleic acid molecule comprising a nucleotide sequence encoding the epitope peptide or mutant thereof of (a) or the recombinant protein;
(d) a vector comprising the isolated nucleic acid molecule of (c); or
(e) a pharmaceutical composition comprising the epitope peptide or mutant thereof of (a) or the recombinant protein of (b) or the isolated nucleic acid molecule of (c) or the vector of (d), and a pharmaceutically acceptable carrier and/or excipient.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the epitope peptide consists of 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5 or 4 consecutive amino acid residues of HBsAg protein, and comprises amino acid residues from positions 121 to 124 of HBsAg protein.

### Claim 3 (depends on 1)

The method according to claim 1, wherein the amino acid residues from positions 121 to 124 of HBsAg protein are as shown in SEQ ID NO: 10.

### Claim 4 (depends on 1)

The method according to claim 1, wherein the epitope peptide consists of 7-38 consecutive amino acid residues of HBsAg protein and comprising amino acid residues from positions 119 to 125 of HBsAg protein.

### Claim 5 (depends on 1)

The method according to claim 1, wherein the epitope peptide consists of any of the following:
(1) the amino acid residues from positions 119-125 of HBsAg protein;
(2) the amino acid residues from positions 113-127 of HBsAg protein;
(3) the amino acid residues from positions 115-125 of HBsAg protein;
(4) the amino acid residues from positions 113-135 of HBsAg protein; and
(5) the amino acid residues from positions 111-148 of HBsAg protein.

### Claim 6 (depends on 1)

The method according to claim 1, wherein the mutant differs from the epitope peptide merely by conservative substitution of 1, 2, 3 or 4 amino acid residues.

### Claim 7 (depends on 1)

The method according to claim 1, wherein the epitope peptide or mutant thereof has an amino acid sequence selected from the group consisting of SEQ ID NO:1-7 and 10.

### Claim 8 (depends on 1)

The method according to claim 1, wherein the recombinant protein is not a naturally occurring protein.

### Claim 9 (depends on 1)

The method according to claim 1, wherein in the recombinant protein, the epitope peptide or mutant thereof is linked to the carrier protein, optionally via a linker.

### Claim 10 (depends on 9)

The method according to claim 9, wherein the linker is a rigid or flexible linker.

### Claim 11 (depends on 1)

The method according to claim 1, wherein the carrier protein is CRM197 protein or a fragment thereof, and wherein the epitope peptide or mutant thereof is linked to the N-terminus or C-terminus of the CRM197 protein or fragment thereof, optionally via a linker.

### Claim 12 (depends on 11)

The method according to claim 11, wherein the fragment of the CRM197 protein comprises or consists of aa 1-190 of CRM197, or comprises or consists of aa 1-389 of CRM197.

### Claim 13 (depends on 1)

The method according to claim 1, wherein the carrier protein is HBcAg or a fragment thereof, wherein the amino acids from positions 79 to 81 of the HBcAg are replaced with the epitope peptide or mutant thereof, and wherein the epitope peptide or mutant thereof is linked to the HBcAg or fragment thereof optionally via a linker.

### Claim 14 (depends on 13)

The method according to claim 13, wherein the fragment of HBcAg comprises or consists of aa 1-149 of HBcAg.

### Claim 15 (depends on 1)

The method according to claim 1, wherein the carrier protein is WHcAg or a fragment thereof (such as aa 1-149 of WHcAg), wherein the amino acids from positions 79 to 81 of the WHcAg are replaced with the epitope peptide or mutant thereof, and wherein the epitope peptide or mutant thereof is linked to the WHcAg or fragment thereof, optionally via a linker.

### Claim 16 (depends on 15)

The method according to claim 15, wherein the fragment of WHcAg comprises or consists of aa 1-149 of WHcAg.

### Claim 17 (depends on 1)

The method according to claim 1, wherein the recombinant protein has an amino acid sequence selected from a group consisting of SEQ ID NO: 47-53, 56, and 58-97.

### Claim 18 (depends on 1)

The method according to claim 1, wherein the pharmaceutically acceptable carrier and/or excipient is an adjuvant.