Composition for treating HBV infection
Inventors
Martin, Perrine • Inchauspe, Geneviève • Silvestre, Nathalie • Schmitt, Doris • Evlachev, Alexei
Assignees
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Publication Number
US-10076570-B2
Publication Date
2018-09-18
Expiration Date
Abstract
The present invention provides a composition comprising hepatitis B virus (HBV) component(s), and which may be either nucleic acid- or polypeptide-based as well as nucleic acid molecules and vectors encoding such HBV component(s). It also relates to infectious viral particles and host cells comprising such nucleic acid molecules or vectors. It also provides composition and kits of parts comprising such nucleic acid molecules, vectors, infectious viral particles or host cells and the therapeutic use thereof for preventing or treating HBV infections.
Core Innovation
The invention provides immunogenic hepatitis B virus (HBV) compositions that include a polymerase moiety, a core moiety, and an env moiety originating from genotype D HBV virus. The env moiety is defined by SEQ ID NO: 12 and SEQ ID NO: 13 and does not include immunogenic domain(s) originating from preS1 and preS2 regions. The moieties are provided in adenoviral and MVA vector formats.
The document describes E1-defective adenoviral constructs for treatment of HBV infection, especially chronic HBV infection. The adenoviral particle or adenoviral vector includes a nucleic acid molecule encoding the polymerase moiety, the core moiety, and the env moiety, and is capable of inducing a T cell response against at least one of the HBV moieties. The subject is infected with or suspected to be infected with HBV from a genotype B or C.
The document also defines structural and sequence constraints intended to shape immunogenicity, including optional truncations of the polymerase and/or the core moiety. It reports evaluation of cross-reactivity of genotype D-based T cells against epitopes or variants from genotypes B and C.
Claims Coverage
The independent claims cover 5 inventive feature sets centered on an E1-defective adenoviral system encoding genotype D HBV polymerase, core, and env moieties for HBV treatment, together with vector, infectious adenoviral particle, host cell, and kit formats. The claims further define env sequences set forth in SEQ ID NO: 12 and SEQ ID NO: 13, exclusion of preS1/preS2 immunogenic domains, truncation options for polymerase or core, and kit composition variants.
E1-defective infectious adenoviral particle encoding genotype D HBV polymerase, core, and env moieties for genotype B/C subjects
An infectious adenoviral particle comprising a nucleic acid molecule encoding a polymerase moiety comprising at least 450 amino acid residues of a polymerase protein originating from a genotype D HBV virus; a core moiety comprising at least 100 amino acid residues of a core protein originating from a genotype D HBV virus; and an env moiety comprising a first amino acid sequence set forth in SEQ ID NO: 12 and a second amino acid sequence set forth in SEQ ID NO: 13, wherein said env moiety does not include any immunogenic domain(s) originating from preS1 and preS2 regions, for use in the treatment of an HBV infection in a subject infected with or suspected to be infected with an HBV from a genotype B or C, wherein said infectious adenoviral particle is E1-defective and capable of inducing a T cell response against at least one of said HBV moieties.
E1-defective adenoviral vector encoding genotype D HBV polymerase, core, and env moieties for genotype B/C subjects
An adenoviral vector comprising nucleic acid molecules encoding a polymerase moiety comprising at least 450 amino acid residues of a polymerase protein originating from a genotype D HBV virus; a core moiety comprising at least 100 amino acid residues of a core protein originating from a genotype D HBV virus; and an env moiety comprising a first amino acid sequence set forth in SEQ ID NO: 12 and a second amino acid sequence set forth in SEQ ID NO: 13, wherein said env moiety does not include any immunogenic domain(s) originating from preS1 and preS2 regions, for use in the treatment of an HBV infection in a subject infected with or suspected to be infected with an HBV from a genotype B or C, wherein said adenoviral vector is E1-defective and capable of inducing a T cell response against at least one of said HBV moieties.
Kit of parts including E1-defective adenoviral vector and/or infectious adenoviral particle and optional host cell and vehicle
A kit of parts for use in the treatment of an HBV infection comprising a plurality of active agents selected from an adenoviral vector encoding a polymerase moiety, a core moiety, and an env moiety defined by SEQ ID NO: 12 and SEQ ID NO: 13 and excluding immunogenic domain(s) originating from preS1 and preS2 regions, wherein either N-terminal truncation of the polymerase moiety is at least 45 and at most 50 amino acid residues or C-terminal truncation of the core moiety is at least 34 and at most 37 amino acid residues, and wherein said adenoviral vector is E1-defective; an infectious adenoviral particle of said adenoviral vector; a host cell comprising said adenoviral vector or said infectious adenoviral particle; and compositions comprising said adenoviral vector or said infectious adenoviral particle and a pharmaceutically acceptable vehicle and compositions comprising said host cell with a pharmaceutically acceptable vehicle.
Kit of parts with a single E1-defective infectious adenoviral particle encoding genotype D HBV polymerase, core, and env
A kit of parts for use in the treatment of an HBV infection comprising a plurality of active agents including a single infectious adenoviral particle comprising a nucleic acid molecule encoding a polymerase moiety comprising at least 450 amino acid residues of a polymerase protein originating from a genotype D HBV virus; a core moiety comprising at least 100 amino acid residues of a core protein originating from a genotype D HBV virus; and an env moiety comprising a first amino acid sequence set forth in SEQ ID NO: 12 and a second amino acid sequence set forth in SEQ ID NO: 13, wherein said env moiety does not include any immunogenic domain(s) originating from preS1 and preS2 regions; wherein either N-terminal truncation of the polymerase moiety is at least 45 and at most 50 amino acid residues or C-terminal truncation of the core moiety is at least 34 and at most 37 amino acid residues, and wherein said infectious adenoviral particle is E1-defective; and a host cell comprising said single infectious adenoviral particle, and compositions comprising said single infectious adenoviral particle or said host cell and a pharmaceutically acceptable vehicle.
Kit of parts with two E1-defective infectious adenoviral particles collectively encoding genotype D HBV polymerase, core, and env
A kit of parts for use in the treatment of an HBV infection comprising a plurality of active agents including two infectious adenoviral particles whose collectively comprise a nucleic acid molecule encoding a polymerase moiety comprising at least 450 amino acid residues of a polymerase protein originating from a genotype D HBV virus; a core moiety comprising at least 100 amino acid residues of a core protein originating from a genotype D HBV virus; and an env moiety comprising a first amino acid sequence set forth in SEQ ID NO: 12 and a second amino acid sequence set forth in SEQ ID NO: 13, wherein said env moiety does not include any immunogenic domain(s) originating from preS1 and preS2 regions; wherein either N-terminal truncation of the polymerase moiety is at least 45 and at most 50 amino acid residue truncation or C-terminal truncation of the core moiety is at least 34 and at most 37 amino acid residue truncation, and wherein said two infectious adenoviral particles are each E1 defective; and a host cell comprising said two infectious adenoviral particles, and compositions comprising said two infectious adenoviral particles or said host cell and a pharmaceutically acceptable vehicle.
Across the independent claims, the claimed subject matter centers on E1-defective adenoviral vectors/particles encoding genotype D HBV polymerase, core, and an env defined by SEQ ID NO: 12 and SEQ ID NO: 13 while excluding preS1/preS2 immunogenic domains. The claims also define truncation options for polymerase N-terminus or core C-terminus, and direct use or kit formats toward inducing T cell responses for HBV treatment in subjects infected or suspected to be infected with genotype B or C.
Stated Advantages
Capable of inducing a T cell response against at least one of the HBV moieties.
Directed for treatment of an HBV infection, especially chronic HBV infection.
Supports cross-reactive recognition across HBV genotypes B, C, and D for major variants for conserved epitopes, with recognition varying by epitope variant category.
Documented Applications
For use in a subject infected with or suspected to be infected with an HBV for the treatment of an HBV infection, especially chronic HBV infection, wherein the infectious adenoviral particle or adenoviral vector is E1-defective and the subject has HBV genotype B or C.
A kit of parts for use in the treatment of an HBV infection, including adenoviral vector and/or infectious adenoviral particle formats, optionally with a host cell and compositions with a pharmaceutically acceptable vehicle.
A two-step cross-reactivity program involving in silico analysis of HBV genotype B/C/D sequence conservation and epitope variant frequencies, followed by in vivo testing with peptide variants to assess cross-reactivity of T cell responses.
Immunogenicity and cross-reactivity assessment in HLA-A2 transgenic mice using adenovirus vectors and MVA vectors, and reported CD8 and CD4 responses against HLA-A2 epitopes spanning Polymerase, Core, and Env domains.
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