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WO2022177230A1 - Composition pour le traitement de l'hépatite b comprenant un anticorps spécifique du vhb pour une combinaison avec une composition de vaccin - Google Patents

Composition pour le traitement de l'hépatite b comprenant un anticorps spécifique du vhb pour une combinaison avec une composition de vaccin Download PDF

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WO2022177230A1
WO2022177230A1 PCT/KR2022/002034 KR2022002034W WO2022177230A1 WO 2022177230 A1 WO2022177230 A1 WO 2022177230A1 KR 2022002034 W KR2022002034 W KR 2022002034W WO 2022177230 A1 WO2022177230 A1 WO 2022177230A1
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hbv
hepatitis
seq
virus
amino acid
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Inventor
Jaesung Jung
Woohyun Kim
Tae-Hee Kim
Genevieve Inchauspe
Perrine MARTON
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GC Biopharma Corp
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Green Cross Corp Korea
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/42—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum viral
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A61K39/29—Hepatitis virus
    • A61K39/292—Serum hepatitis virus, hepatitis B virus, e.g. Australia antigen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/081—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from DNA viruses
    • C07K16/082—Hepadnaviridae, e.g. hepatitis B virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/525—Virus
    • A61K2039/5256—Virus expressing foreign proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/10011—Adenoviridae
    • C12N2710/10041—Use of virus, viral particle or viral elements as a vector
    • C12N2710/10043—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2730/00—Reverse transcribing DNA viruses
    • C12N2730/00011—Details
    • C12N2730/10011—Hepadnaviridae
    • C12N2730/10111—Orthohepadnavirus, e.g. hepatitis B virus
    • C12N2730/10134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • the present invention relates to a composition for treating, or for use for treating hepatitis B comprising an HBV-specific antibody for use in combination with a vaccine composition, and more particularly to a pharmaceutical composition for treating, or for use for treating hepatitis B comprising an HBV-specific antibody having a specific amino acid sequence for use in treating hepatitis B in combination with an adenovirus-based therapeutic vaccine composition having a nucleotide sequence encoding a hepatitis B virus-specific antigen, and a method for treating hepatitis B using a combination of the pharmaceutical composition and the vaccine composition.
  • Hepatitis B virus is a virus that has a DNA genome belonging to the Hepadnaviridae family, and causes acute/chronic hepatitis B, leading to cirrhosis and hepatocellular carcinoma (HCC). 2 billion people, about 1/3 of the world's population, have signs of HBV infection, of which about 275 million are untreated and remain in chronic hepatitis B (CHB). More than 800,000 people die annually.
  • HBV hepatitis B virus
  • HBV chronic hepatitis B virus
  • Chronic HBV infection causes not only hepatitis and cirrhosis, but also liver cancer, and the incidence of liver cancer in chronically infected people is about 300 times higher than that of non-infected people.
  • Research conducted by the WHO has shown that about 80% of liver cancer is attributed to chronic hepatitis B.
  • NUC nucleos(t)ide analog
  • IFN- ⁇ interferon-alpha
  • the present applicant has developed an antibody (called “GC1102”) capable of binding to the surface antigen (HBsAg) of HBV as a therapeutic agent for chronic hepatitis B (refer to Korean Patent No. 10-1653261).
  • a therapeutic vaccine after removal of HBsAg, which exhibits the main immunosuppressive effect on HBV, from the bloodstream using an antibody was reported to have an improved antiviral effect due to an increased immune response (Clearing Persistent Extracellular Antigen of Hepatitis B Virus: An Immunomodulatory Strategy To Reverse Tolerance for an Effective Therapeutic Vaccination. J. Immunol. 2016;196:3079-3087).
  • the present applicant tried to improve the therapeutic effect using GC1102 in combination with a vaccine for hepatitis B treatment.
  • TG1050 the therapeutic agent for chronic hepatitis B developed by Transgene SA in France, is an adenovirus-type-5-based therapeutic vaccine formulation encoding HBV polymerase and core antigens as well as polypeptide domains of HBsAg (WO2013/007772). It has been proven that TG1050 has an effect of enhancing the immune response and the resulting antiviral effect in the AAV-HBV mouse model and phase 1 clinical trial is currently completed (TG1050, an immunotherapeutic to treat chronic hepatitis B, induces robust T cells and exerts an antiviral effect in HBV-persistent mice. GUT 2015;64:1961-1971).
  • the present inventors have found that administration of TG1050, a therapeutic agent for chronic hepatitis B, in combination with GC1102, an HBsAg-specific antibody, surprisingly and remarkably improves the therapeutic effect for hepatitis B due to the increased antiviral effect thereof. Based on this finding, the present invention has been completed.
  • the present invention provides a pharmaceutical composition comprising a hepatitis B virus (HBV)-specific antibody for treating, or for use for treating hepatitis B in combination with an adenovirus (AV)-based therapeutic vaccine composition having a nucleotide sequence encoding a hepatitis B virus-specific antigen, wherein the hepatitis B virus (HBV)-specific antibody comprises a heavy-chain variable region comprising HCDR1 of GFSLTKYK, HCDR2 of ISSTSRDI and HCDR3 of TRDGWL and a light-chain variable region comprising LCDR1 of QGIYNS, LCDR2 of STS and LCDR3 of YFVTPET.
  • HBV hepatitis B virus
  • the present invention also provides a method for treating hepatitis B using a combination of the pharmaceutical composition comprising an HBV-specific antibody and the vaccine composition for treating hepatitis B.
  • the present invention also provides the use of the pharmaceutical composition comprising an HBV-specific antibody in combination with the vaccine composition for treating hepatitis B, for the treatment of hepatitis B.
  • the present invention also provides the use of the pharmaceutical composition comprising an HBV-specific antibody in combination with the vaccine composition for treating hepatitis B, for the manufacture of a therapeutic agent for hepatitis B.
  • FIG. 1 is a schematic diagram illustrating an experiment on the use of a combination of sGC1102 and TG1050.
  • FIGS. 2 to 6 show the results of the HBsAg ELISA experiment on the use of a combination of sGC1102 and TG1050.
  • FIGs 2a to 2e show the result of treatment with mIgG 20 mg/kg
  • FIGs 3a to 3d show the result of treatment with sGC1102 20 mg/kg
  • FIGs 4a to 4e show the result of treatment with TG1050 108 IU (V.P.: 2x109)
  • FIGs 5a to 5d show the result of treatment with sGC1102 20 mg/kg and Empty Ad.
  • FIGs 6a to 6d show the result of treatment with sGC1102 20 mg/kg and TG1050 108 IU (V.P.: 2x109), and boxes represent mice that were considered to undergo HBsAg loss because no HBsAg was detected (1 week before mouse sacrifice), line represented by ‘circle’ and line represented by ‘square’ represent HBsAg and sGC1102, respectively, and arrows under the X-axis represent the injection times of mIgG or sGC1102 and Empty Ad. or TG1050.
  • FIG. 7 is a graph showing the result of quantification of the amount of HBsAg in serum 1 week before mouse sacrifice, wherein the mean and standard error of the mean (SEM) are shown, and statistical analysis was performed using the Wilcoxon rank sum test (*: P-value ⁇ 0.05, **: P-value ⁇ 0.005).
  • FIG. 8 is a graph showing the result of quantification of HBV DNA (FIG. 8A) and AAV DNA (FIG. 8B) in liver tissue by quantitative real-time PCR, wherein the dots represented by ‘pentagon’ represent mice that lost HBsAg 1 week before mouse sacrifice, and the dots represented by ‘circle’ represent mice that retained HBsAg 1 week before mouse sacrifice, wherein the mean and standard error of the mean (SEM) are shown, and statistical analysis was performed using a Wilcoxon rank sum test (*: P-value ⁇ 0.05).
  • FIG. 9 shows the result of detection of HBV nucleocapsid in liver tissue homogenate using NAGE-Western blot, wherein the number shown at top of the gel represents an experimental animal number.
  • the antibody “GC1102” which can be effectively used to prevent or treat infection of mutant viruses resistant to conventional therapeutic agents, was administered in combination with the hepatitis B virus-specific antigen “TG1050” including an HBV core polypeptide, an HBV polymerase polypeptide, an HBV envelope polypeptide and a combination thereof. The cure rate thereof was detected. The result showed that the combined administration statistically significantly decreased the amount of HBsAg (HBV surface antigen) in the serum, and decreased hepatitis B virus (HBV) and AAV (adeno-associated virus) DNA in the liver, compared to single administration.
  • HBsAg HBV surface antigen
  • HBV hepatitis B virus
  • AAV adeno-associated virus
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a hepatitis B virus (HBV)-specific antibody for treating, or for use for treating hepatitis B in combination with an adenovirus (AV)-based therapeutic vaccine composition having a nucleotide sequence encoding a hepatitis B virus-specific antigen, wherein the hepatitis B virus (HBV)-specific antibody comprises a heavy-chain variable region comprising HCDR1 of GFSLTKYK (SEQ ID NO: 1), HCDR2 of ISSTSRDI (SEQ ID NO: 2) and HCDR3 of TRDGWL (SEQ ID NO: 3) and a light-chain variable region comprising LCDR1 of QGIYNS (SEQ ID NO: 4), LCDR2 of STS (SEQ ID NO: 5) and LCDR3 of YFVTPET (SEQ ID NO: 6).
  • HBV hepatitis B virus
  • AV adenovirus
  • the hepatitis B virus (HBV)-specific antibody comprises a heavy-chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 7 and a light-chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 8.
  • the antibody may comprise a variant thereof that has a sequence homology of 80% or more, preferably 90% or more, more preferably 95% or more, and most preferably 99% or more, with the amino acid sequence of each of SEQ ID NO: 1 to SEQ ID NO: 8, and an antibody or antigen-binding fragment thereof that has the same characteristics as the HBV-specific antibody according to the present invention also falls within the scope of the antibody according to the present invention.
  • the HBV-specific antibody or antigen-binding fragment thereof according to the present invention also includes an antibody or antigen-binding fragment thereof in which a part of the amino acid sequence in the antibody or antigen-binding fragment thereof according to the present invention is substituted through conservative substitution.
  • the term “conservative substitution” refers to modification of a polypeptide including substitution of one or more amino acids with amino acids having similar biochemical properties without causing loss of the biological or biochemical function of the polypeptide.
  • the term “conservative amino acid substitution” refers to substitution of amino acid residues with amino acid residues having similar side chains thereto. Classes of amino acid residues having similar side chains are defined and are well known in the art. These classes include amino acids having basic side chains (e.g. lysine, arginine, histidine), amino acids having acidic side chains (e.g. aspartic acid, glutamic acid), amino acids having uncharged polar side chains (e.g.
  • glycine asparagine, glutamine, serine, threonine, tyrosine, cysteine
  • amino acids having non-polar side chains e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan
  • amino acids having beta-branched side chains e.g., threonine, valine, isoleucine
  • amino acids having aromatic side chains e.g., tyrosine, phenylalanine, tryptophan, histidine. It is expected that the antibody of the present invention has conservative amino acid substitutions and is still active.
  • HBV-specific antibody refers to an antibody that binds to HBV and inhibits the biological activity of HBV, and is used interchangeably with “anti-HBV antibody”.
  • anti-HBV antibody includes both a polyclonal antibody and a monoclonal antibody, but is preferably a monoclonal antibody, and may have an intact whole antibody form.
  • the whole antibody has a structure having two full-length light chains and two full-length heavy chains, and has a structure including a constant region, and each light chain is connected to a heavy chain by a disulfide bond.
  • the term “heavy chain” encompasses both a full-length heavy chain, which includes a variable domain (VH) comprising an amino acid sequence having a variable-region sequence sufficient for imparting specificity to an antigen and three constant domains (CH1, CH2 and CH3), and a fragment thereof.
  • VH variable domain
  • CH1, CH2 and CH3 constant domains
  • the term “light chain” encompasses all of a full-length light chain, which includes a variable domain (VL) comprising an amino acid sequence having a variable-region sequence sufficient for imparting specificity to an antigen and a constant domain (CL), and a fragment thereof.
  • CDR complementarity determining region
  • the cure rate for hepatitis B when the antibody was administered alone or in combination was detected.
  • the amount of HBsAg in the serum was statistically significantly reduced compared to when GC1102 or TG1050 was administered alone (administration of SGC1102 (mouse surrogate GC1102) alone: 216.6 ng/mL, administration of TG1050 alone: 470.6 ng/mL, and administration of a combination of sGC1102 and TG1050: 12.6 ng/mL), and HBV and AAV DNA in the liver were also reduced (administration of sGC1102 alone: log 4.9, administration of TG1050 alone: log 5.1, and administration of the combination of sGC1102 and TG1050: log 3.5).
  • the pharmaceutical composition comprising the hepatitis B virus-specific antibody according to the present invention is administered simultaneously or sequentially with the adenovirus (AV)-based therapeutic vaccine composition having a nucleotide sequence encoding a hepatitis B virus-specific antigen.
  • AV adenovirus
  • the pharmaceutical composition comprising the hepatitis B virus (HBV)-specific antibody for treating hepatitis B is administered once a week or once every two weeks for 10 to 20 weeks, and the adenovirus (AV)-based therapeutic vaccine composition having a nucleotide sequence encoding a hepatitis B virus-specific antigen is administered once a week for 2 to 5 weeks after 3 to 5 weeks from the first administration of the pharmaceutical composition, but is not limited thereto.
  • HBV hepatitis B virus
  • AV adenovirus
  • a unit dose of the hepatitis B virus-specific antibody is 5 to 50 mg/kg
  • a unit dose of the adenovirus (AV)-based therapeutic vaccine composition having a nucleotide sequence encoding a hepatitis B virus-specific antigen is 10 5 to 10 10 IU, but is not limited thereto.
  • the hepatitis B virus-specific antigen comprises an entire or partial sequence of a polypeptide selected from the group consisting of an HBV core polypeptide, an HBV polymerase polypeptide, an HBV envelope polypeptide and a combination thereof (see for example WO2013/007772).
  • HBV polymerase refers to a polypeptide having at least 500 amino acid residues contained in a native HBV polymerase protein. Preferably, the at least 500 amino acid residues are distributed over three functional domains, preferably over four domains normally present in the native HBV polymerase.
  • the term “HBV polymerase” encompasses native (e.g., naturally occurring) polymerase polypeptides as well as modified polymerases (e.g., mutant polymerase polypeptides) of any HBV strain, isolate or genotype which may be found, isolated or obtained in nature from sources of HBV, such as those cited above in connection with the term "HBV" and fragments thereof.
  • amino acid residues of the HBV polymerase described herein are numbered such that a Tyr residue is the 538th residue in the motif Tyr-Met-Asp-Asp (YMDD) based on the 832-amino-acid-long polymerase.
  • Numbering of amino acid residues with other polymerases can be conceived by those skilled in the art.
  • the term “native” or “naturally occurring” refers to an amino acid sequence or a nucleotide sequence that can be found, isolated and obtained from sources in nature, which is distinguished from that artificially modified or mutated by humans in research and practice (e.g., a mutant), when used in conjunction with any amino acid sequence (e.g., peptide, polypeptide, protein, etc.) or nucleotide sequence (e.g., gene, nucleic acid molecule, polynucleotide, etc.).
  • any amino acid sequence e.g., peptide, polypeptide, protein, etc.
  • nucleotide sequence e.g., gene, nucleic acid molecule, polynucleotide, etc.
  • HBV a virus
  • cultured cells such as HepG2.2.15, HuH6-C15 (Sureau et al., 1986, Cell 47: 37; Sells et al., 1987, Proc. Natl. Acad. Sci. 84(4): 1005); HuH7.TA61 or HuH7.TA62 (Sun et al., 2006, J. Hepatol. 45(5): 636)
  • tissue cultures e.g., blood, plasma, serums, semen, saliva, tissue sections, biopsy specimens, etc.
  • the recombinant materials include, but are not limited to, HBV isolates (e.g., available from depository institutions), the HBV genome, genomic RNA or cDNA libraries, vectors including the HBV genome or fragment(s) thereof, or conventional vectors known to include such elements.
  • HBV isolates e.g., available from depository institutions
  • genomic RNA or cDNA libraries e.g., vectors including the HBV genome or fragment(s) thereof, or conventional vectors known to include such elements.
  • the term “native HBV polymerase” refers to an HBV polymerase encoded by ORF P of any naturally occurring HBV genotype, strain or isolate (e.g., a polypeptide of 832 to 845 amino acids, depending on the genotype), or a fragment thereof.
  • the term “native” also encompasses HBV polymerase polypeptides/peptides that are representative of a certain genotype and thus includes an amino acid sequence corresponding to a common or substantially common sequence that is typically determined after sequence alignment of various HBV polymerases of a certain genotype.
  • mutant refers to a polypeptide that exhibits one or more mutation(s) with respect to a native polypeptide. More specifically, the term “mutant polymerase polypeptide” refers to a polymerase polypeptide that originates from a native polymerase after being artificially mutated or altered by humans in a laboratory, as described herein. Any mutation(s) may result from substitution, insertion and/or deletion of one or more nucleotide/amino acid residue(s), and non-natural arrangements (e.g., fusion with foreign polypeptides/peptides), as well as any combination thereof. Several mutations may be determined in consideration of contiguous and/or non-contiguous residues.
  • Mutation(s) can be produced by various methods known to those skilled in the art, such as site-induced mutagenesis (e.g., Sculptor TM in-vitro mutagenesis system from Emersham, Les Ullis, France), PCR mutagenesis and DNA shuffling, and chemical synthesis techniques (e.g., obtaining synthetic nucleic acid molecules).
  • site-induced mutagenesis e.g., Sculptor TM in-vitro mutagenesis system from Emersham, Les Ullis, France
  • PCR mutagenesis and DNA shuffling e.g., PCR TM in-vitro mutagenesis system from Emersham, Les Ullis, France
  • chemical synthesis techniques e.g., obtaining synthetic nucleic acid molecules.
  • the mutation(s) contemplated by the present invention encompass deletion(s) and/or substitution(s) of one or more (contiguous or non-contiguous) amino acid residue(s) which are directly or indirectly involved in at least one enzymatic activity exhibited by the native HBV polymerase for the purpose of eliminating at least one enzymatic activity, such as polymerase activity and/or RNaseH activity.
  • the resulting mutant polymerase polypeptide overall has a high degree of homology (e.g. at least 80%) with the native HBV polymerase in the non-mutated portions.
  • HBV polymerase polypeptide may be selected from but not limited to the group of polypeptides consisting of:
  • the mutated RNaseH domain may comprise the amino acid sequence of SEQ ID NO: 10
  • the polypeptide comprising a mutated polymerase domain and a mutated RNaseH domain may comprise the amino acid sequence of SEQ ID NO: 11, but are not limited thereto.
  • core polypeptide refers to a polypeptide having at least 100 amino acid residues contained in a native HBV core (HBc) protein.
  • the term encompasses native (e.g., naturally occurring) core polypeptides of any HBV strain, isolate or genotype that can be found, isolated or obtained from a source of HBV in nature, such as those cited above, as well as modified core polypeptides and fragments thereof.
  • the HBV core polypeptide used in the present invention may originate from an HBV virus having a genotype that is the same as or different from the virus from which the mutant polymerase polypeptide originates. Preferably, both of them can originate from the genotype D virus, more specifically, from Y07587 isolates.
  • Core polypeptides and encoding sequences thereof may be produced by various methods known to those skilled in the art, such as chemical synthesis of the encoding sequences (e.g., obtaining synthetic nucleic acid molecules) or recombination means (e.g., site-induced mutagenesis of the corresponding nucleotide sequence, PCR mutagenesis or DNA shuffling).
  • any modification(s) may be considered in case where the resulting core preferably has significant immunogenic activity at a level that is the same as or higher than that of the native core polymerase polypeptide, when it is combined or fused with the mutant polymerase polypeptide described herein.
  • Suitable modifications include truncation of at least 10 amino acid residues and at most 41 amino acid residues normally present at the C-terminus of the native core polypeptide or within a part of the C-terminus thereof, with particular preference for truncation extending from residue 143, 144, 145, 146, 147, 148 or 149 to the C-terminus (residue 183).
  • the HBV core polypeptide may comprise a sequence in which the C-terminus is truncated at the position of residue 148 or 149 in the amino acid sequence of SEQ ID NO: 12.
  • envelope (or HBsAg) polypeptide refers to one or more fragments of an HBV envelope, such fragments having from approximately 15 to approximately 100 amino acid residues, and preferably at least 20 and at most 60 consecutive amino acids and comprising at least one B and/or T cell epitope specific for T helper (TH) cells and/or for cytotoxic T (CTL) cells normally present in a native HBsAg protein.
  • TH T helper
  • CTL cytotoxic T
  • epitope(s) can be restricted to various MHC class I and/or class II antigens (e.g., A2, A24, DR, DP, etc).
  • the one or more envelope polypeptide(s) used in the invention do not include any portions of HBV preS1 and preS2 polypeptides.
  • the HBV envelope polypeptide(s) used in the present invention may originate from an HBV virus having a genotype that is the same as or different from the virus from which the mutant polymerase and/or core polypeptides originate. Preferably, it/they originate from the genotype D virus, more specifically, from Y07587 isolates. Envelope polypeptides and encoding sequences thereof may be produced by various methods known to those skilled in the art, such as chemical synthesis of the encoding sequences (e.g., obtaining synthetic nucleic acid molecules) or recombination means (e.g., site-induced mutagenesis of the corresponding nucleotide sequence, PCR mutagenesis or DNA shuffling).
  • HBV envelope polypeptides that can be used in the invention are described in the art (e.g., WO93/03764; WO94/19011; Desombere et al., 2000, Clin. Exp. Immunol 122: 390; Loirat et al., 2000, J. Immunol. 165: 4748; Schirmbeck et al, 2002, J. Immunol 168: 6253; Depla et al, 2008, J. Virol. 82: 435 and WO2011/015656).
  • Particularly preferred HBV envelope polypeptides include the env1 and env2 domains described in WO2011/015656.
  • "Env1" corresponds to the portion of a native HBsAg from approximately position 14 to approximately position 51 and “Env2” to the HBsAg portion from approximately position 165 to approximately position 194.
  • the HBV envelope polypeptide comprises at least one sequence of domain selected from the group consisting of an HBV envelope domain Env1 having the amino acid sequence of SEQ ID NO: 13 and an HBV envelope domain Env2 having the amino acid sequence of SEQ ID NO: 14.
  • the combination is a form of fusion.
  • the present invention relates to a fusion protein including the HBV polymerase polypeptide described herein and a substance to be fused therewith.
  • the substance to be fused with the HBV polymerase polypeptide is one or more fragment(s) of an HBV envelope polypeptide that has a specific preference for env1 and env2 domains or an HBV core polypeptide that has a specific preference for a core polypeptide that is truncated at the C-terminus, particularly truncated at residue 148.
  • the HBV core polypeptide is fused with the N-terminus of the HBV polymerase polypeptide described herein in conformity with the structural frame to form a fusion protein having a (modified or native) core polypeptide starting with the initiator Met and having no stop codon, a HBV polymerase polypeptide (having no Met initiator) and a stop codon.
  • the one or more fragments of the HBV envelope polypeptide can be positioned in the fusion protein at the N-terminus, at the C-terminus and/or internally, e.g., within the HBV polymerase polypeptide (for example in place of the portion lacking in the mutated polymerase and/or RNaseH domains) or in between the core and the HBV polymerase polypeptide. It is within the reach of the skilled person to define accordingly the need and location of the translation-mediating regulatory elements (e.g., the initiator Met and codon STOP at the N- and C-termini of the fusion protein).
  • the translation-mediating regulatory elements e.g., the initiator Met and codon STOP at the N- and C-termini of the fusion protein.
  • the hepatitis B virus-specific antigen may comprise the amino acid sequence of SEQ ID NO: 15, but is not limited thereto.
  • any related term such as the term “disrupt” as used in connection with a given enzymatic activity herein, may mean “eliminate” (there is no residual activity) or “significantly reduce” (residual activity is 20% or less of the activity exhibited by a native polymerase).
  • isolated refers to a protein, polypeptide, peptide, polynucleotide, plasmid vector, viral vector or host cell that has been removed from its natural environment (e.g., has been separated from at least one other component with which it is naturally associated).
  • HBsAg loss is maintained for at least 3 months, preferably at least 4 months, and more preferably at least 6 months, but is not limited thereto.
  • the hepatitis B may be chronic hepatitis B, but is not limited thereto.
  • the present invention is directed to a method for treating hepatitis B using a combination of a pharmaceutical composition comprising a hepatitis B virus (HBV)-specific antibody for treating hepatitis B and an adenovirus (AV)-based therapeutic vaccine composition having a nucleotide sequence encoding a hepatitis B virus-specific antigen, wherein the hepatitis B virus (HBV)-specific antibody comprises a heavy-chain variable region comprising HCDR1 of GFSLTKYK (SEQ ID NO: 1), HCDR2 of ISSTSRDI (SEQ ID NO: 2) and HCDR3 of TRDGWL (SEQ ID NO: 3), and a light-chain variable region comprising LCDR1 of QGIYNS (SEQ ID NO: 4), LCDR2 of STS (SEQ ID NO: 5) and LCDR3 of YFVTPET (SEQ ID NO: 6).
  • HBV hepatitis B virus
  • AV adenovirus
  • the hepatitis B virus (HBV)-specific antibody comprises a heavy-chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 7 and a light-chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 8.
  • the pharmaceutical composition comprising the hepatitis B virus-specific antibody according to the present invention is administered simultaneously or sequentially with the adenovirus (AV)-based therapeutic vaccine composition having a nucleotide sequence encoding a hepatitis B virus-specific antigen.
  • AV adenovirus
  • the pharmaceutical composition comprising the hepatitis B virus-specific antibody for treating hepatitis B is administered once a week or once every two weeks for 10 to 20 weeks, and the adenovirus (AV)-based therapeutic vaccine composition having a nucleotide sequence encoding a hepatitis B virus-specific antigen is administered once a week for 2 to 5 weeks after 3 to 5 weeks from the first administration of the pharmaceutical composition, but is not limited thereto.
  • AV adenovirus
  • a unit dose of the hepatitis B virus-specific antibody is 5 to 50 mg/kg
  • a unit dose of the adenovirus (AV)-based therapeutic vaccine composition having a nucleotide sequence encoding a hepatitis B virus-specific antigen is 10 5 to 10 10 IU, but is not limited thereto.
  • the hepatitis B virus-specific antigen includes an entire or partial sequence of a polypeptide selected from the group consisting of an HBV core polypeptide, an HBV polymerase polypeptide, an HBV envelope polypeptide and a combination thereof.
  • the HBV polymerase polypeptide may be selected from, but not limited to, the group of polypeptides consisting of:
  • the mutated RNaseH domain may comprise the amino acid sequence of SEQ ID NO: 10
  • the polypeptide comprising a mutated polymerase domain and a mutated RNaseH domain may comprise the amino acid sequence of SEQ ID NO: 11, but are not limited thereto.
  • the HBV core polypeptide may comprise a sequence in which the C-terminus is truncated at the position of residue 148 or 149 in the amino acid sequence of SEQ ID NO: 12.
  • the HBV envelope polypeptide comprises at least one sequence of domain selected from the group consisting of an HBV envelope domain Env1 having the amino acid sequence of SEQ ID NO: 13 and an HBV envelope domain Env2 having the amino acid sequence of SEQ ID NO: 14.
  • the hepatitis B virus-specific antigen may comprise the amino acid sequence of SEQ ID NO: 15, but is not limited thereto.
  • HBsAg loss is maintained for at least 3 months, preferably at least 4 months, and more preferably at least 6 months, but is not limited thereto.
  • the hepatitis B may be chronic hepatitis B, but is not limited thereto.
  • the present invention is directed to the use of the pharmaceutical composition comprising an HBV-specific antibody in combination with the vaccine composition for treating hepatitis B for the treatment of hepatitis B.
  • the present invention is directed to the use of the pharmaceutical composition comprising an HBV-specific antibody in combination with the vaccine composition for treating hepatitis B for the manufacture of a therapeutic agent for hepatitis B.
  • the use of the present invention includes “the use of the pharmaceutical composition comprising an HBV-specific antibody in combination with the vaccine composition for treating hepatitis B, for the treatment of hepatitis B” described above, and thus an overlapping description is omitted.
  • GC1102 is a fully human monoclonal antibody comprising a heavy-chain variable region having the amino acid sequence of SEQ ID NO: 7 and a light-chain variable region having the amino acid sequence of SEQ ID NO: 8.
  • ADA anti-drug antibody
  • sGC1102 surrogate GC1102 was produced by substitution with mouse IgG, which was used in mouse experiments.
  • Sigma mouse immunoglobin (mIgG) was used as a negative control group.
  • a powder was dissolved at 10 mg/ml in 1xPBS and was diluted to 20 mg/kg with 1xPBS upon administration.
  • TG1050 is an adenovirus-type-5-based therapeutic vaccine developed by Transgene SA, and comprises a nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 15, which is a hepatitis B virus-specific antigen. Specifically, TG1050 can express a fusion protein including a truncated core domain, a modified polymerase domain, and some HBsAg domains. TG1050 was stored in a deep freezer at -70°C and thawed at the time of administration.
  • the negative control group empty adenovirus, was also stored/administered through the same process as above.
  • mice Six months after the last administration of sGC1102, the mice were sacrificed and liver tissue was separated therefrom and stored at -70°C.
  • Example 1-2 Chemicals and reagents
  • Example 1-3 Devices and equipment
  • mice were classified into 5 groups, namely a negative control group containing mIgG 20 mg/kg, a group administered with sGC1102 20 mg/kg alone, a group administered with TG1050 10 8 IU (V.P: 2x10 9 ) alone, a group administered with a combination of sGC1102 20 mg/kg and empty adenovirus 10 8 IU (V.P: 2x10 9 ), and a group administered with a combination of sGC1102 20 mg/kg and TG1050 10 8 IU (V.P: 2x10 9 ), and each group included 16 to 17 chronic hepatitis B mice.
  • Example 2-2 HBsAg ELISA (Enzyme-linked immunosorbent assay)
  • An ELISA strip plate was coated with 100 ⁇ L of sGC1102 (5 ⁇ g/mL) diluted in PBS at 4°C overnight.
  • Unbound HBsAg was removed by washing 4 times with PBST (PBS containing 0.05% tween 20). An enzyme substrate was added thereto and incubated at room temperature for 30 minutes.
  • the enzyme substrate reaction was terminated by adding 1.6N sulfuric acid to each well. Absorbance was measured with a Microplate reader at 450 nm. For HBsAg detection, the obtained value was used after conversion to ng/mL using a standard curve with a known concentration of hHBsAg (subtype: ay). Each experiment was performed in duplicate.
  • the genomic DNA was extracted from 10 mg of liver tissue using an AccuPrep Genomic DNA Extraction kit (BIONEER, Cat no. K-3032), and then real-time PCR was performed using SYBR green reagents.
  • the number of DNA copies per ⁇ g of genomic DNA in the cell was calculated and graphed using a prism software.
  • Example 2-4 NAGE (Native Agarose Gel Electrophoresis)-Western blot
  • liver tissue in 500 ⁇ L of 2X lysis buffer (from 10X cell lysis buffer; Cell signaling Technology, Cat no. #9803) was incubated on ice for 10 minutes and then centrifuged at 13,000 rpm at 4°C for 15 minutes.
  • 2X lysis buffer from 10X cell lysis buffer; Cell signaling Technology, Cat no. #9803
  • the protein was assayed using a PierceTM BCA Protein Assay Kit (ThermoFisher) and then a lysate containing a total of 10 ⁇ g of protein was loaded on a 1% agarose gel using 1X Tris acetate-EDTA (TAE) buffer.
  • TAE Tris acetate-EDTA
  • the loaded protein was transferred to a PVDF membrane (Bio-Rad, Cat# 1620177) by a capillary method using a 20X SSC buffer, and was then detected by a general Western blot method.
  • the transferred PVDF membrane was blocked by reacting with 4% skim milk at room temperature for 1 hour.
  • the membrane was reacted with an anti-HBcAg antibody diluted to 1:1000 with 4% skim milk at room temperature for 3 hours, and was then repeatedly washed 3 times with 1X TBST (TBS containing 0.05% tween 20) for 10 minutes.
  • 1X TBST TBS containing 0.05% tween 20
  • the membrane was reacted with a horseradish peroxidase-conjugated anti-rabbit secondary antibody diluted to 1:5000 with 4% skim milk at room temperature for 1 hour, and was then repeatedly washed 3 times with 1X TBST (TBS containing 0.05% tween 20) for 10 minutes.
  • 1X TBST TBS containing 0.05% tween 20
  • the mouse spleen was crushed using a cell strainer (40 ⁇ m) and transferred to a 15 mL conical tube with 10 mL complete RPMI medium (10% FBS, 1% antibiotic-antimycotic, 1X 2-mercaptoethanol).
  • the number of splenocytes was measured and the cell concentration was adjusted to 2 X 10 6 cells/mL.
  • 2 X 10 5 cells/100 ⁇ L and 100 ⁇ L of stimulation overlapping peptide (final conc. 2 ⁇ g/mL) + IL-2 (final conc. 10 U/mL) were added to the well of the ELISpot plate and incubated in a cell incubator at 37°C for 40 hours.
  • the color development reaction was performed using an XEL486 Kit (R&D systems), and the number of spots in the plate obtained in accordance with the manufacturer’s protocol was measured using an iSpot reader spectrum device.
  • HBsAg of the mIgG control group was observed at 465.7 ng/mL.
  • the group administered with sGC1102 alone, the group administered with TG1050 alone, and the group administered with a combination of sGC1102 and Empty Ad. had HBsAg of 216.6 ng/mL, 470.6 ng/mL, and 419.6 ng/mL, respectively, which were not statistically significant different from the mIgG control group.
  • the group administered with a combination of sGC1102 and TG1050 had HBsAg of 12.6 ng/mL, which was statistically significantly decreased compared to the mIgG control group and the single-administered group (FIGS. 2 to 7 and Table 6).
  • the mean of HBV DNA in the liver of the mIgG-administered group was found to be approximately 1.5 X 10 5 copies per ⁇ g of genomic DNA, and was found to be approximately 8.2 X 10 4 copies per ⁇ g of genomic DNA in the group administered with sGC1102 alone, which was 1.8 times lower than the negative control group, but the difference was not statistically significant. It was found that the mean of HBV DNA in the liver of the group administered with TG1050 alone was about 1.1 X 10 5 copies, which was about 1.4 times lower than that of the mIgG negative control group, but the difference was not statistically significant (FIG. 8A).
  • the mean of HBV DNA in the liver of the group administered with a combination of sGC1102 and TG1050 was about 3.3 X 10 3 copies per ⁇ g of genomic DNA, which was statistically significantly reduced compared to the negative control group, that is, the mIgG-administered group, the group administered with sGC1102 alone, and the group administered with a combination of sGC1102 and empty Ad.
  • Vs mIgG about 46 times
  • vs GC1102 about 25 times
  • sGC1102+Empty Ad was about 25 times
  • the mean of the AAV DNA in the group administered with a combination of sGC1102 and TG1050 was 5.0 X 10 2 copies per ⁇ g of genomic DNA, which was statistically significantly reduced compared to the mIgG negative control group, the group administered with sGC1102 alone and the group administered with a combination of sGC1102 and Empty Ad (vs mIgG: about 12 times, vs GC1102: about 10 times, sGC1102+Empty Ad: about 12 times), and which was about 10-15 times lower than that of the group administered with TG1050 alone.
  • the template DNA in the liver was not significantly reduced by administration of sGC1102 or TG1050 alone, but that the template DNA in the liver was significantly reduced by administration with a combination of sGC1102 and TG1050. This suggests that the antiviral effect can reduce the template DNA in liver cells or reduce the number of liver cells in which the virus is present.
  • HBV nucleocapsid in the liver was determined depending on visualization of the band by a Western blot method. The experiment was repeated three times, and a case where a band was visually observed during at least one experiment was considered to be "detectable" (red arrow in FIG. 9).
  • HBsAg loss rate in serum of the group administered with sGC1102 was slightly different from the undetectable nucleocapsid rate (HBsAg loss rate vs undetectable nucleocapsid rate: the group administered with sGC1102 alone; 56.3% vs 37.5%, the group administered with a combination of sGC1102 and TG1050; 93.8% vs 81.2%), but there was no difference between the HBsAg loss rate and the undetectable nucleocapsid rate of the group administered with TG1050 alone (the same as 64.7%) (Table 7).
  • administering in combination of the HBV vaccine therapeutic agent “TG1050” and the antibody “GC1102” capable of binding to the HBV surface antigen (HBsAg), which have different mechanisms of action, is very effective in preventing or treating hepatitis B caused by HBV infection, compared to single administration of TG1050 or GC1102.
  • HBV surface antigen HBV surface antigen

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Abstract

La présente invention concerne une composition pharmaceutique destinée au traitement ou à une utilisation dans le traitement de l'hépatite B. La composition comprend un anticorps spécifique du VHB destiné à être utilisé en combinaison avec une composition de vaccin et, plus précisément, une composition pharmaceutique pour traiter l'hépatite B, comprenant un anticorps spécifique du VHB présentant une séquence d'acides aminés spécifique destinée à être utilisée dans le traitement de l'hépatite B en combinaison avec une composition de vaccin thérapeutique à base d'adénovirus présentant une séquence nucléotidique codant un antigène spécifique du virus de l'hépatite B, et une méthode de traitement de l'hépatite B à l'aide d'une combinaison de la composition pharmaceutique et de la composition de vaccin. Selon la présente invention, la co-administration de l'agent thérapeutique vaccinal anti-VHB "TG1050" et de l'anticorps "GC1102" apte à se lier à l'antigène de surface du VHB (HBsAg), qui ont différents mécanismes d'action, est très efficace dans la prévention ou le traitement de l'hépatite B provoquée par l'infection au VHB, comparativement à une administration unique de TG1050 ou de GC1102.
PCT/KR2022/002034 2021-02-17 2022-02-10 Composition pour le traitement de l'hépatite b comprenant un anticorps spécifique du vhb pour une combinaison avec une composition de vaccin Ceased WO2022177230A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20150029699A (ko) * 2012-07-10 2015-03-18 주식회사 녹십자 B형 간염 돌연변이 바이러스 감염의 예방 또는 치료용 항체 조성물
WO2016020538A1 (fr) * 2014-08-08 2016-02-11 Transgene Sa Traitement en association d'un vaccin contre le hbv et d'un anticorps pour traiter des infections à hbv.
US9512412B2 (en) * 2011-07-12 2016-12-06 Transgene S.A. HBV polymerase mutants

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US9512412B2 (en) * 2011-07-12 2016-12-06 Transgene S.A. HBV polymerase mutants
KR20150029699A (ko) * 2012-07-10 2015-03-18 주식회사 녹십자 B형 간염 돌연변이 바이러스 감염의 예방 또는 치료용 항체 조성물
WO2016020538A1 (fr) * 2014-08-08 2016-02-11 Transgene Sa Traitement en association d'un vaccin contre le hbv et d'un anticorps pour traiter des infections à hbv.

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SENTHIL K. CHINNAKANNAN, TAMSIN N. CARGILL, TIMOTHY A. DONNISON, M. AZIM ANSARI, SARAH SEBASTIAN, LIAN NI LEE, CLAIRE HUTCHINGS, P: "The Design and Development of a Multi-HBV Antigen Encoded in Chimpanzee Adenoviral and Modified Vaccinia Ankara Viral Vectors; A Novel Therapeutic Vaccine Strategy against HBV", VACCINES, vol. 8, no. 2, pages 1 - 20, XP055762410, DOI: 10.3390/vaccines8020184 *

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