Anti-PD1 antibodies and their use as therapeutics and diagnostics
Inventors
Li, Kang • Zhang, Tong • Song, Jing • Xu, Lanlan • Liu, Qi • Peng, Hao
Assignees
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Publication Number
US-10519235-B2
Publication Date
2019-12-31
Expiration Date
Abstract
Provided are antibodies that specifically bind to Programmed Death-1 (PD1, Pdcd-1, or CD279) and inhibit PD1-mediated cellular signaling and activities in immune cells, antibodies binding to a set of amino acid residues required for its ligand binding, and uses of these antibodies to treat or diagnose cancer, infectious diseases or other pathological disorders modulated by PD1-mediated functions.
Core Innovation
The invention relates to monoclonal antibodies that bind human PD-1 and suppress PD-1 mediated signal transduction. The antibodies comprise a PD-1 binding domain combined with an IgG4 Fc region having an amino acid mutation at position 228 and at least one additional amino acid mutation.
The at least one additional Fc mutation causes reduced binding to at least one Fcγ receptor relative to a reference IgG4 antibody having a mutation at position 228 and no other Fc region mutation. The Fc region residue numbering follows the EU numbering system.
The antibodies are characterized with functional activity related to immune activation and tumor growth, and the document emphasizes reducing Fc-mediated effector function such as antibody-dependent cell-mediated cytotoxicity (ADCC).
Claims Coverage
The independent claim is clm-00001. It covers a monoclonal antibody that binds human PD-1 and suppresses PD-1 mediated signal transduction, with a PD-1 binding domain and an IgG4 Fc region whose additional mutations reduce Fcγ receptor binding compared to a reference IgG4 antibody having only the position-228 mutation.
Monoclonal antibody suppressing PD-1 signal transduction with IgG4 Fc modifications
A monoclonal antibody which binds human PD-1, wherein the antibody suppresses PD-1 mediated signal transduction, comprising a PD-1 binding domain, and an IgG4 Fc region comprising an amino acid mutation at position 228 and at least one additional amino acid mutation.
Reduced Fcγ receptor binding relative to reference IgG4 with only position 228 mutation
The at least one additional mutation causes the antibody to exhibit reduced binding to at least one Fcγ receptor relative to Fc binding of a reference IgG4 antibody having a mutation at position 228 and no other Fc region mutation.
EU numbering for IgG4 Fc residue positions
The numbering of the residues in the IgG4 Fc region is that of the EU numbering system.
Overall, clm-00001 is centered on an anti-human PD-1 monoclonal antibody that suppresses PD-1 mediated signal transduction while carrying an IgG4 Fc region engineered with a position-228 mutation plus at least one additional mutation to reduce binding to at least one Fcγ receptor, benchmarked against a reference IgG4 antibody having only the position-228 mutation, with EU Fc numbering.
Stated Advantages
Suppresses PD-1 mediated signal transduction.
Exhibits reduced binding to at least one Fcγ receptor relative to a reference IgG4 antibody having only the position 228 mutation.
Reduced Fc-mediated effector function is described, including reduced ADCC.
Documented Applications
Immune activation and functional activity characterization are described, including inhibition of tumor growth in a human PBMC xenograft model.
Assay readouts described include IL-2 release, IFN-γ secretion, NK-mediated cytotoxicity, and inhibition of tumor growth in the human PBMC xenograft model.
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