Humanized anti-HMGB1 antibody or antigen-binding fragment thereof
Inventors
Takada, Kenzo • Torashima, Takashi • Nishibori, Masahiro
Assignees
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Publication Number
US-9550825-B2
Publication Date
2017-01-24
Expiration Date
Abstract
The present invention provides a humanized anti-HMGB1 antibody which specifically binds to a sequence consisting of the C-terminal 8 amino acid residues (EEEDDDDE) of HMGB1 protein and is effective for treatment or prevention of various inflammatory diseases related to this protein, as well as an antigen-binding fragment thereof. The present invention also provides a pharmaceutical composition comprising such an antibody or antigen-binding fragment thereof.
Core Innovation
The invention relates to a humanized antibody, or an antigen-binding fragment thereof, that specifically binds an amino acid sequence EEEDDDDE (SEQ ID NO: 60) present in the C-terminal domain of HMGB1 and is capable of neutralizing the biological activity of HMGB1. The antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL).
The VH and VL are defined using specific CDR amino-acid sequences and framework regions with optional mutations in the framework regions. In another embodiment, the VH has 90% or more identity with the amino acid sequence of SEQ ID NO: 41 and the VL has 90% or more identity with the amino acid sequence of SEQ ID NO: 42.
The disclosed embodiments include isolated nucleic acid encoding the antibody, expression vector, and host cell embodiments, and pharmaceutical compositions for treatment or prevention of HMGB1-related inflammatory diseases. Functional support includes inhibition of HMGB1–RAGE binding, inhibition of HMGB1-induced TNF-α release, and in vivo sepsis model death-protection with maintained survival after antibody administration.
Claims Coverage
The patent includes two independent claims. Across these claims, the inventive features focus on epitope specificity to the HMGB1 C-terminal 8-aa acidic tail sequence, neutralization of HMGB1 biological activity, and defined VH/VL variable-region composition using either specific CDR/framework sequences or 90% identity relative to specified VH and VL reference sequences.
HMGB1 C-terminal epitope binding and neutralization
A humanized antibody or antigen-binding fragment thereof that specifically binds EEEDDDDE (SEQ ID NO: 60) present in the C-terminal domain of HMGB1 protein and is capable of neutralizing the biological activity of HMGB1 protein, comprising a heavy chain variable region (VH) and a light chain variable region (VL).
Defined VH and VL variable-region composition with CDRs and optional framework mutations
The VH comprises heavy chain CDR1, CDR2, and CDR3 of SEQ ID NOs: 7, 8, and 9, respectively, and framework regions FR1-FR4 of SEQ ID NOs: 43, 44, 45, and 46, respectively, with optional deletions, substitutions, and/or additions in the framework regions; the VL comprises light chain CDR1, CDR2, and CDR3 of SEQ ID NOs: 10, 11, and 12, respectively, and framework regions FR1-FR4 of SEQ ID NOs: 47, 48, 49, and 50, respectively, with optional deletions, substitutions, insertions, and/or additions in the framework regions.
VH and VL defined by 90% or more identity to reference sequences
A humanized antibody or antigen-binding fragment thereof that specifically binds EEEDDDDE (SEQ ID NO: 60) present in the C-terminal domain of HMGB1 protein and is capable of neutralizing the biological activity of HMGB1 protein, comprising a VH having 90% or more identity with SEQ ID NO: 41 and a VL having 90% or more identity with SEQ ID NO: 42.
Overall, the claim coverage centers on a humanized antibody that binds the HMGB1 C-terminal amino acid sequence EEEDDDDE (SEQ ID NO: 60) and neutralizes HMGB1 biological activity, with the variable regions defined either by specific CDR/framework sequences with optional framework mutations or by 90% or more identity to specified VH and VL reference sequences.
Stated Advantages
Neutralizes the biological activity of HMGB1 protein.
Specifically binds the HMGB1 C-terminal domain amino acid sequence EEEDDDDE (SEQ ID NO: 60).
Inhibits HMGB1–RAGE binding.
Inhibits HMGB1-induced TNF-α release.
Provides in vivo death-protection in a sepsis model with maintained survival after antibody administration.
Documented Applications
Treatment or prevention of HMGB1-related inflammatory diseases using the humanized antibody that neutralizes HMGB1 biological activity.
Use in an in vivo sepsis model for death-protection with maintained survival after antibody administration.
Pharmaceutical compositions comprising the humanized antibody or antigen-binding fragment for the stated treatment or prevention context.
Isolated nucleic acid encoding the humanized antibody, expression vector, and host cell embodiments for producing the antibody.
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