Anti-lag-3 antibodies and methods of use thereof
Inventors
Wilson, Nicholas Stuart • Savitsky, David Adam • Jennings, Shawn Michael • van Dijk, Marc • Mundt, Cornelia Anne
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11993651-B2
Publication Date
2024-05-28
Expiration Date
Abstract
The instant disclosure provides antibodies that specifically bind to LAG-3 (e.g., human LAG-3) and antagonize LAG-3 function. Also provided are pharmaceutical compositions comprising these antibodies, nucleic acids encoding these antibodies, expression vectors and host cells for making these antibodies, and methods of treating a subject using these antibodies.
Core Innovation
The invention relates to an isolated antibody that specifically binds human LAG-3 (CD223). The antibody comprises heavy chain variable regions and light chain variable regions with complementarity determining regions CDRH1, CDRH2, CDRH3, and CDRL1, CDRL2, and CDRL3, defined by specified amino-acid sequence patterns and SEQ ID NOs, with permitted substitutions and explicit exclusions of certain CDR sequences.
The disclosed antibodies include specified SEQ ID NO embodiments and humanized or human gene-encoded framework sequences. The heavy chain and light chain variable regions are characterized with framework region usage using Kabat, Chothia, IMGT, AbM, MacCallum, and EU numbering systems, and optional constant-region formats including human IgG and IgA constant regions with selected mutations such as N297A, N297Q, and S228P.
Functional embodiments include antagonism of LAG-3, reduced LAG-3 signaling and/or binding to MHC class II, ligand blocking, cross-competition for binding, and binding to specific LAG-3 epitopes within defined LAG-3 sequence regions. The antibodies are also associated with increased T-cell activation and increased IL-2 and TNFα, including combination contexts with anti-PD-1 and/or anti-CTLA-4, and are described in pharmaceutical compositions, diagnostic and prognostic uses, and conjugated formats.
Claims Coverage
The independent claims center on an isolated antibody specifically binding human LAG-3, with six CDRs constrained by defined sequence patterns, allowed substitutions, and explicit exclusions. Dependent features refine the antibody by specific variable-region identities, human framework derivation, selected constant-region formats and mutations, and optional conjugation formats.
CDR-constrained isolated anti-human LAG-3 antibody
An isolated antibody specifically binds human LAG-3 and comprises a heavy chain variable region comprising CDRH1, CDRH2, and CDRH3 and a light chain variable region comprising CDRL1, CDRL2, and CDRL3, wherein the CDRs are defined by specified amino acid sequence patterns and SEQ ID NOs with permitted substitutions and explicit exclusions.
Specific variable-region sequences via SEQ ID NO identity
An isolated antibody comprises heavy-chain and/or light-chain variable regions having amino acid sequences corresponding to specified SEQ ID NOs.
Human-derived framework regions using specified IGHV and IGKV sequence IDs
An isolated antibody comprises heavy-chain and/or light-chain variable framework regions derived from human gene-encoded amino acid sequences, optionally selected from specified IGHV and IGKV sequence IDs.
Selected constant-region formats and effector-related mutations
An isolated antibody comprises a heavy chain constant region selected from specified human IgG and IgA constant regions with optional inclusion of mutations N297A, N297Q, and/or S228P, and optionally includes a non-fucosylated IgG1 heavy chain constant region.
Conjugation to cytotoxic, cytostatic, toxin, radionuclide, or detectable label
An isolated antibody is conjugated to a cytotoxic agent, cytostatic agent, toxin, radionuclide, or detectable label.
Overall, the claims are centered on an isolated antibody specifically binding human LAG-3, defined by constrained CDR sequences with allowed substitutions and explicit exclusions. Dependent features refine the antibody by variable-region sequence identities, human framework regions, constant-region formats and selected mutations, and optional conjugation to agent or label types.
Stated Advantages
Antagonism of LAG-3 is described.
Reduced LAG-3 signaling and/or reduced LAG-3 binding to MHC class II is described.
Increased IL-2 and TNFα are described in combination contexts.
Increases T-cell activation.
Provides ligand blocking and characterized binding behavior for the anti-LAG-3 antibodies.
Documented Applications
Use in combination with checkpoint antibodies anti-PD-1 and/or anti-CTLA-4 is described.
Use in connection with stimulation contexts involving PBMCs and TILs is described.
Pharmaceutical composition and use targeting via specified routes of administration and disease contexts is described.
Therapeutic use to increase T-cell activation is described.
Cancer immunotherapy by inhibiting LAG-3 to increase T-cell activation is described.
Treatment of cancer is described.
Treatment of infectious disease is described.
Treatment indications extend to nervous-system disorders, including synucleinopathy and Parkinson’s.
Combination therapy options for treatment are described.
Diagnostic and prognostic monitoring using immunohistochemistry, ELISA, and labeled antibody detection with biological samples is described.
Use of nucleic acids/polynucleotides encoding LAG-3 antibodies, with production via expression vectors and host-cell expression frameworks, is described.
Interested in licensing this patent?