# US 10,441,650 B2 · Compositions and methods for the treatment or prevention of hepatitis B virus infection

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- Number: US 10,441,650 B2
- Document ID: US10441650B2
- Status: Granted
- Kind: B2
- Application number: 15/909,112
- Filed: 2018-03-01
- Published: 2018-11-01
- Granted: 2019-10-15
- Earliest claimed: 2011-02-12
- Assignees: GlobeImmune, Inc.
- Applicants: GlobeImmune, Inc.
- Inventors: David Apelian; Thomas H. King; Zhimin Guo; Claire Coeshott
- Web page: https://patentgrep.com/patent/US10441650B2

## CPC

- A61K 39/292: {Serum hepatitis virus, hepatitis B virus, e.g. Australia antigen}
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 36/06: Fungi, e.g. yeasts
- A61K 36/12: Filicopsida or Pteridopsida
- A61K 39/12: Viral antigens
- A61K 39/29: Hepatitis virus
- A61K 40/11: T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
- A61K 40/46: Viral antigens
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/46: Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 31/20: for DNA viruses
- A61P 37/02: Immunomodulators
- A61P 37/04: Immunostimulants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 14/005: from viruses
- C07K 14/02: Hepadnaviridae, e.g. hepatitis B virus
- 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 2039/51: {comprising whole cells, viruses or DNA/RNA}
- A61K 2039/521: {inactivated (killed)}
- A61K 2039/523: {expressing foreign proteins}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- A61K 2039/55: {characterised by the host/recipient, e.g. newborn with maternal antibodies}
- A61K 2039/55516: {Proteins; Peptides}
- A61K 2039/55588: {Adjuvants of undefined constitution}
- A61K 2039/6006: {Cells}
- A61K 2039/70: {Multivalent vaccine}
- C07K 2319/00: Fusion polypeptide
- C12N 2710/00022: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
- 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
- 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

Disclosed are yeast-based immunotherapeutic compositions, hepatitis B virus (HBV) antigens, and fusion proteins for the treatment and/or prevention of HBV infection and symptoms thereof, as well as methods of using the yeast-based immunotherapeutic compositions, HBV antigens, and fusion proteins for the prophylactic and/or therapeutic treatment of HBV and/or symptoms thereof.

## Claims

### Claim 1

An immunotherapeutic composition comprising:
a) a yeast vehicle; and
b) a fusion protein comprising HBV antigens, wherein the HBV antigens consist of:
a) an HBV surface antigen consisting of at least one immunogenic domain of hepatocyte receptor region of Pre-S1 of the HBV large surface antigen (L) and at least one immunogenic domain of HBV small surface antigen (S);
b) an HBV polymerase antigen consisting of at least one immunogenic domain of reverse transcriptase domain of HBV polymerase;
c) an HBV core antigen consisting of at least one immunogenic domain of HBV core protein; and
d) an HBV X antigen consisting of at least one immunogenic domain of full-length HBV X antigen;
and wherein the HBV antigens consist of an amino acid sequence that is at least 95% identical to positions 92 to 1025 of SEQ ID NO:92, wherein the composition elicits an HBV-specific immune response and wherein the fusion protein is expressed by the yeast vehicle.

### Claim 2 (depends on 1)

The immunotherapeutic composition of claim 1, wherein the HBV antigens are arranged in the following order, from N- to C-terminus, in the fusion protein: HBV surface antigen, HBV polymerase, HBV core antigen and HBV X antigen.

### Claim 3 (depends on 1)

The immunotherapeutic composition of claim 1, wherein the fusion protein comprises an amino acid sequence of SEQ ID NO:92.

### Claim 4 (depends on 1)

The immunotherapeutic composition of claim 1, wherein the amino acid sequence of the immunogenic domain of hepatocyte receptor region of Pre-S1 of the HBV large surface antigen (L) consists of positions 92 to 118 of SEQ ID NO:92.

### Claim 5 (depends on 1)

The immunotherapeutic composition of claim 1, wherein the amino acid sequence of the immunogenic domain of the HBV small surface antigen (S) consists of positions 119-343 of SEQ ID NO:92.

### Claim 6 (depends on 1)

The immunotherapeutic composition of claim 1, wherein the immunogenic domain of the reverse transcriptase domain of HBV polymerase consists of positions 346 to 690 of SEQ ID NO:92.

### Claim 7 (depends on 1)

The immunotherapeutic composition of claim 1, wherein the amino acid sequence of the HBV core antigen consists of positions 691 to 872 of SEQ ID NO:92.

### Claim 8 (depends on 1)

The immunotherapeutic composition of claim 1, wherein the amino acid sequence of the HBV X antigen consists of positions 873 to 1025 of SEQ ID NO:92.

### Claim 9 (depends on 1)

The immunotherapeutic composition of claim 1, wherein the yeast vehicle is from Saccharomyces cerevisiae.

### Claim 10 (depends on 1)

The immunotherapeutic composition of claim 1, wherein the yeast vehicle is a whole yeast.

### Claim 11 (depends on 10)

The immunotherapeutic composition of claim 10, wherein the whole yeast is heat-inactivated.

### Claim 12

A yeast expressing a fusion protein comprising HBV antigens, wherein the HBV antigens consist of:
a) an HBV surface antigen consisting of at least one immunogenic domain of hepatocyte receptor region of Pre-S1 of the HBV large surface antigen (L) and at least one immunogenic domain of HBV small surface antigen (S);
b) an HBV polymerase antigen consisting of at least one immunogenic domain of reverse transcriptase domain of HBV polymerase;
c) an HBV core antigen consisting of at least one immunogenic domain of HBV core protein;
d) an HBV X antigen consisting of at least one immunogenic domain of full-length HBV X antigen; and
wherein the HBV antigens consist of an amino acid sequence that is at least 95% identical to positions 92 to 1025 of SEQ ID NO:92.

### Claim 13 (depends on 12)

The yeast of claim 12, wherein the fusion protein consists of an amino acid sequence of SEQ ID NO:92.

### Claim 14 (depends on 1)

A method of treating hepatitis B virus (HBV) infection or at least one symptom resulting from HBV infection in a subject, comprising administering to the subject that has been infected with HBV the immunotherapeutic composition of claim 1.

### Claim 15 (depends on 14)

The method of claim 14, wherein the subject is administered the immunotherapeutic composition in a dose from 0.1 Y.U. to 100 Y.U.

### Claim 16 (depends on 14)

The method of claim 14, wherein the immunotherapeutic composition comprises:
a) a yeast comprising a fusion protein; and
b) the fusion protein comprising an amino acid sequence that is at least 95% identical to SEQ ID NO:92.

### Claim 17 (depends on 14)

The method of claim 14, further comprising administering to the subject an anti-viral compound.

### Claim 18 (depends on 17)

The method of claim 17, wherein the anti-viral compound is a compound selected from the group consisting of a nucleotide analogue reverse transcriptase inhibitor and tenofovir disoproxil fumarate (TDF).

### Claim 19 (depends on 14)

The method of claim 14, wherein the subject is receiving anti-viral treatment.

### Claim 20

A fusion protein comprising HBV antigens, wherein the HBV antigens consist of:
a) an HBV surface antigen consisting of at least one immunogenic domain of hepatocyte receptor region of Pre-S1 of the HBV large surface antigen (L) and at least one immunogenic domain of HBV small surface antigen (S);
b) an HBV polymerase antigen consisting of at least one immunogenic domain of reverse transcriptase domain of HBV polymerase;
c) an HBV core antigen consisting of at least one immunogenic domain of HBV core protein;
d) an HBV X antigen consisting of at least one immunogenic domain of full-length HBV X antigen; and
wherein the HBV antigens consist of an amino acid sequence that is at least 95% identical to positions 92 to 1025 of SEQ ID NO:92.

### Claim 21 (depends on 20)

A recombinant nucleic acid molecule encoding the fusion protein of claim 20.