Anti-Tim-3 antibodies and use thereof
Inventors
Zhang, Tong • Xue, Liu • Liu, Qi • Peng, Hao • Wei, Min • Li, Kang
Assignees
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Publication Number
US-11203637-B2
Publication Date
2021-12-21
Expiration Date
Abstract
Provided are antibodies that specifically bind to T-cell immunoglobulin domain and mucin domain 3 (Tim-3). The anti-Tim-3 antibodies can be used to treat, prevent or diagnose immune, cancerous, infectious diseases or other pathological disorders that may be modulated by Tim-3-mediated functions.
Core Innovation
The disclosure describes anti–Tim-3 (HAVCR2/CD366) antibodies capable of binding human Tim-3. The antibodies are defined by heavy chain variable region (VH) and light chain variable region (VL) sequences that include specific VH-CDR1, VH-CDR2, and VH-CDR3 amino acid sequences and specific VL-CDR1, VL-CDR2, and VL-CDR3 amino acid sequences, with alternative VH/VL combinations using defined sequence identifiers (SEQ ID NOs) and variants with conservative substitutions.
The disclosure provides antibodies designed for durable/persistent Tim-3 receptor internalization. It further characterizes functional effects as reduced effector functions, including no detectable ADCC and no detectable CDC, while maintaining immune activation. The disclosed functional profile includes enhanced IFN-γ secretion, and the antibodies show synergy with an anti–PD-1 mAb, including 317-4B6/IgG4mt10, in vitro.
The disclosure also reports in vivo characterization using a human xenograft tumor model. In this context, the anti–Tim-3 antibodies are described as inhibiting tumor growth, including when used in combination with anti–PD-1 mAb therapy. Additional assay context is described for binding affinity and receptor downmodulation/internalization, along with immune functional outcomes and combination therapy results.
Claims Coverage
The independent claim is directed to an antibody defined by specific VH and VL CDR amino-acid sequences, with alternative VH/VL combinations. Across the dependent claims referenced in the disclosure, the scope further refines the antibody by adding quantitative sequence-identity constraints, selecting antibody formats and immunoglobulin subclasses/variants, and defining immune-therapy combination contexts, including synergy with PD-1/PD-L1 checkpoint targeting via a named anti–PD-1 mAb.
Cdr-defined human Tim-3 binding antibody
An antibody capable of binding to human Tim-3, comprising a heavy chain variable region (VH) with VH-CDR1 of SEQ ID NO 3, VH-CDR2 of SEQ ID NO 26, and VH-CDR3 of SEQ ID NO 5, and a light chain variable region (VL) with VL-CDR1 of SEQ ID NO 6, VL-CDR2 of SEQ ID NO 7, and VL-CDR3 of SEQ ID NO 27; with alternative VH/VL configurations comprising SEQ ID NO 3, SEQ ID NO 4 or SEQ ID NO 26, SEQ ID NO 5, and VL-CDR1 of SEQ ID NO 6, VL-CDR2 of SEQ ID NO 7, with VL-CDR3 of SEQ ID NO 27 or SEQ ID NO 8.
Sequence identity constrained variants for light chain
An antibody in which the light chain comprises a light chain amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO 15, 24, 34, or 38.
Binding-fragment antibody formats
An antibody characterized as being in one of the forms Fab, F(ab’)2, Fv, or a single-chain Fv (ScFv).
Reduced or eliminated effector function via variant heavy chain constant region
An antibody characterized by a variant heavy chain constant region from IgG1, IgG2, IgG3, or IgG4 that provides reduced or eliminated effector function.
Combination treatment with a second therapeutic agent
A method further providing that the antibody is administered together with a second therapeutic agent or procedure chosen from specified cancer-treatment and immunotherapy modalities.
Combination with named anti–PD-1 mAb 317-4B6
A method of administering the antibody together with the anti–PD-1 mAb 317-4B6 or 317-4B6/IgG4mt10.
Overall, the claim set covers anti–Tim-3 antibodies defined by specific VH/VL CDR amino-acid sequences, with dependent refinements that constrain sequence identity, specify antibody formats, define variant constant regions to reduce or eliminate effector function, and cover combination therapeutic administration, including combination with anti–PD-1 mAb 317-4B6 or 317-4B6/IgG4mt10.
Stated Advantages
Reduced effector functions, including no detectable ADCC.
Reduced effector functions, including no detectable CDC.
Enhanced IFN-γ secretion.
Synergy with an anti–PD-1 mAb, including 317-4B6/IgG4mt10, in vitro.
Inhibition of tumor growth in a human xenograft tumor model.
Documented Applications
Cancer therapy, including immune-checkpoint targeted combination with anti–PD-1 mAb 317-4B6 or 317-4B6/IgG4mt10, with reported inhibition of tumor growth in a human xenograft tumor model.
Synergistic immune functional activity with anti–PD-1 mAb in vitro.
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