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Publication Number
US-12404318-B2
Publication Date
2025-09-02
Expiration Date
Abstract
The present disclosure provides methods for treating HBV infection using combination therapies, and related kits and compositions for use. The components of the combination therapies include an inhibitor of HBV gene expression or an agent that reduces HBV antigenic load, and an anti-HBV antibody.
Core Innovation
The invention relates to treating chronic hepatitis B virus (HBV) infection or an HBV-associated disease in a subject in need thereof by administering an agent that reduces HBV antigenic load or inhibits HBV gene expression. In particular, the agent is an siRNA that inhibits expression of an HBV transcript, with a sense strand comprising SEQ ID NO:7 and an antisense strand comprising SEQ ID NO:8, together with defined nucleotide chemistry and linkage features including 2′-O-methyl and 2′-fluoro nucleotides, (Agn)=GNA, phosphorothioate linkage, and L96.
The invention also administers an anti-HBV antibody in combination with the siRNA. The anti-HBV antibody is characterized by specific CDR amino acid sequences according to SEQ ID NOs for CDRH1, CDRH2, CDRH3, and CDRL1, CDRL2, and CDRL3, and in an additional independent method by specified light-chain and heavy-chain amino acid sequences (SEQ ID NO:73 and SEQ ID NO:71).
The disclosure also provides anti-HBV antibody sequence information for HBC34 and HBC24, including detailed antibody regions and SEQ ID number mappings. For HBC34, engineered variants including HBC34v7 are described alongside defined heavy-chain and light-chain sequence regions and CDR assignments, and the antibody description further includes Fc moiety options, including FcRn half-life extension and FcγR binding mutations.
In parallel, the invention is directed to RNA interference as an HBV gene-expression inhibition and antigenic-load reduction agent, and a combination-therapy framework is described that pairs an HBV-targeting siRNA agent with an anti-HBV antibody. The reported outcomes include reductions in HBV markers such as HBV DNA, HBsAg, and HBeAg, and synergistic effects relative to monotherapies.
Claims Coverage
The consolidated record contains three independent claims: two method claims and one kit claim. Across these independent claims, the coverage centers on administering a specific chemically modified HBV siRNA together with a defined anti-HBV antibody defined by CDR sequence identifiers, and in one claim by specific light- and heavy-chain sequence identifiers.
Combination treatment with defined HBV siRNA and anti-HBV antibody CDRs
A method of treating chronic HBV infection or an HBV-associated disease by administering an siRNA that inhibits expression of an HBV transcript, wherein the siRNA comprises a sense strand (SEQ ID NO:7) and an antisense strand (SEQ ID NO:8) with defined nucleotide chemistry including 2′-O-methyl and 2′-fluoro nucleotides, (Agn)=GNA, phosphorothioate linkage, and L96, and administering an anti-HBV antibody comprising CDRH1, CDRH2, CDRH3 and CDRL1, CDRL2, CDRL3 sequences according to specified SEQ ID NOs.
Kit containing HBV siRNA composition and anti-HBV antibody composition
A kit comprising a pharmaceutical composition comprising an RNAi agent targeting an mRNA encoded by an HBV gene, with sense strand SEQ ID NO:7 and antisense strand SEQ ID NO:8 and the specified nucleotide chemistry and L96, together with a pharmaceutical composition comprising an anti-HBV antibody comprising CDRH1, CDRH2, CDRH3 and CDRL1, CDRL2, CDRL3 amino acid sequences according to specified SEQ ID NOs, each with a pharmaceutically acceptable excipient.
Treatment of chronic HBV or HDV by administering defined anti-HBV antibody chains and defined HBV siRNA
A method of treating chronic HBV infection or an HDV infection by administering an anti-HBV antibody comprising a light chain amino acid sequence according to SEQ ID NO:73 and a heavy chain amino acid sequence according to SEQ ID NO:71, and administering an siRNA comprising sense strand SEQ ID NO:7 and antisense strand SEQ ID NO:8 with defined nucleotide chemistry including 2′-O-methyl and 2′-fluoro nucleotides, (Agn)=GNA, phosphorothioate linkage, and L96.
The independent claims cover treating chronic HBV or HBV-associated disease using a specifically defined HBV siRNA with defined nucleotide modifications together with an anti-HBV antibody defined by CDR sequences, providing a kit that includes both the defined RNAi agent composition and the defined antibody composition, and treating chronic HBV or HDV using a specifically defined anti-HBV antibody chain definition together with the same defined HBV siRNA definition.
Stated Advantages
Reductions in HBV markers including HBV DNA, HBsAg, and HBeAg were reported.
Synergistic effects were reported for the siRNA–antibody combination therapy compared with monotherapies.
Documented Applications
Treating chronic hepatitis B virus infection or an HBV-associated disease in a subject in need thereof using a defined HBV siRNA and an anti-HBV antibody.
A kit for delivering the defined HBV siRNA and the defined anti-HBV antibody compositions.
Treating chronic HBV infection or an HDV infection in a subject in need thereof using an anti-HBV antibody and the specified HBV siRNA.
Combination-therapy treatment context pairing an HBV-targeting siRNA agent with an anti-HBV antibody, including a Phase 2 clinical trial concept for the siRNA–antibody regimen.
In vivo model evidence including an AAV/HBV mouse model and a uPA/SCID (PXB-Mouse®) humanized hepatocyte model.
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