Antibodies that potently neutralize hepatitis B virus and uses thereof
Inventors
Assignees
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Publication Number
US-12037381-B2
Publication Date
2024-07-16
Expiration Date
Abstract
The present invention relates to antibodies, and antigen binding fragments thereof, that bind to the antigenic loop region of hepatitis B surface antigen (HBsAg) and potently neutralize infection of both hepatitis B virus (HBV) and hepatitis delta virus (HDV). The invention also relates to epitopes to which the antibodies and antigen binding fragments bind, as well as to nucleic acids that encode and cells that produce such antibodies and antibody fragments. In addition, the invention relates to the use of the antibodies and antibody fragments of the invention in the diagnosis, prophylaxis and treatment of hepatitis B and hepatitis D.
Core Innovation
The invention relates to isolated antibodies, or antigen-binding fragments thereof, that bind the antigenic loop region of hepatitis B surface antigen (HBsAg) in the S domain, including an infectivity determinant associated with the CXXC motif, and neutralize hepatitis B virus (HBV) and hepatitis D virus (HDV). The disclosed antibodies show neutralization of HBV and HDV and are associated with promotion of clearance of HBsAg and HBV subviral particles (SVPs), as well as induction of seroconversion and broad reactivity across HBV genotypes and multiple infectious antigenic-loop mutants.
The antibodies are provided in defined antibody formats and molecular embodiments, including purified antibody, IgG, Fab, Fab’, F(ab’)2, Fv, and scFv, and an antibody comprising an Fc moiety. The document also describes epitope scope defined using SEQ ID-defined epitope motifs, Fc-moiety interactions including FcγRIIb binding, and Fc-engineering mutations.
The invention further includes antibodies with specified CDRH1, CDRH2, and CDRH3 amino acid sequences and specified CDRL1, CDRL2, and CDRL3 amino acid sequences defined by multiple alternative sets of SEQ ID NOs, together with related heavy-chain and light-chain variable domain sequences having at least 95% identity to specified combinations of SEQ ID NOs. Exemplary antibodies and variants are described with related nucleic acids, vectors, expression cells, pharmaceutical compositions, kits, and medical uses including prophylaxis, diagnosis, treatment, and monitoring for HBV and HDV, including chronic hepatitis B and liver transplant recurrence prevention.
Claims Coverage
The independent claims center on two inventive features: defined antibody or antigen-binding fragment sequence sets, and administration of those defined antibodies for treatment of hepatitis B and/or hepatitis D infection. The claims coverage merges the CDR-based isolated antibody subject matter with the method of treatment using an effective amount of the same defined antibody embodiments.
Defined CDR sequence sets for isolated antibody or antigen-binding fragment
An isolated antibody, or an antigen-binding fragment thereof, comprising CDRH1, CDRH2, and CDRH3 amino acid sequences and CDRL1, CDRL2, and CDRL3 amino acid sequences defined by multiple alternative sets of SEQ ID NOs.
Administering effective amount of the defined antibody to treat hepatitis B and/or hepatitis D
A method for treating a hepatitis B and/or a hepatitis D infection by administering to a subject in need thereof an effective amount of an antibody, or an antigen-binding fragment thereof, comprising the defined CDRH1 to CDRH3 and CDRL1 to CDRL3 amino acid sequences.
Overall, the claim coverage is anchored on antibodies or antigen-binding fragments defined by explicit CDRH1–CDRH3 and CDRL1–CDRL3 amino-acid sequence sets, and on methods that administer such defined antibodies in an effective amount to treat hepatitis B and/or hepatitis D infection. Dependent claim refinements further specify sequence-identity thresholds and additional clinical and combination scope.
Stated Advantages
Potent neutralization at low concentrations.
Promotion of clearance of HBsAg and HBV subviral particles (SVPs).
Induction of seroconversion.
Broad reactivity across HBV genotypes.
Activity against multiple infectious antigenic-loop mutants.
Promoting clearance and seroconversion, including serum anti-HBs titer monitoring.
Neutralization of HBV/HDV and binding to L- and S-HBsAg.
Allows diagnosis of HBV/HDV and diagnostic/monitoring kit applications based on HBsAg epitope recognition.
Documented Applications
Prophylaxis, diagnosis, treatment, and monitoring of hepatitis B and hepatitis D (HBV/HDV).
Treatment of chronic hepatitis B infection.
Prevention of liver transplant recurrence.
Post-exposure prophylaxis, including for non-immunized subjects.
Newborn prophylaxis.
HBV/HDV use cases involving hemodialysis.
Diagnosis and monitoring of HBV/HDV, including monitoring via serum anti-HBs titer and diagnostic/monitoring kit use based on HBsAg epitope recognition.
Combination use with polymerase inhibitors, interferons, checkpoint inhibitors, and other therapeutic-agent categories as stated in the document summary.
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