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Publication Number
US-10537633-B2
Publication Date
2020-01-21
Expiration Date
Abstract
The invention provides monoclonal antibodies that specifically bind to TIGIT. The monoclonal antibodies have the capacity for substantial activation of T cells and natural killer cells by inhibiting binding of TIGIT to CD155. The monoclonal antibodies can be used for treatment of cancer and infectious disease, among other applications.
Core Innovation
The invention relates to anti-TIGIT monoclonal antibodies that bind to a TIGIT polypeptide and inhibit TIGIT-CD155 interaction. The antibodies are defined by specific heavy chain CDR1, CDR2, and CDR3 amino acid sequences and specific light chain CDR1, CDR2, and CDR3 amino acid sequences. The described antibodies thereby provide a targeted binding mechanism against extracellular TIGIT and the TIGIT-CD155 axis.
The monoclonal antibodies are characterized by functional properties on immune cells, including inhibition of TIGIT binding to CD155 and increased intrinsic T-cell activation and antigen-specific T-cell activation in the presence of antigen presenting cells expressing CD155. The antibodies are also described to increase natural killer cell activation, with cytokine measurements including IL-2, IL-6, TNFα, and IFNγ. Additional described effects include increased production of pro-inflammatory cytokines and reduced production of anti-inflammatory cytokines.
The described antibody formats and variants include chimeric, humanized, or veneered antibodies, and human IgG1 kappa or IgG4 kappa isotypes, with intact antibodies and fragment formats such as scFv, Fab, and F(ab')2. Functional tailoring is described via optional effector-function reduction. The document also describes therapeutic use contexts, including cancer and infectious diseases such as HIV/SIV, and includes combination with other immune checkpoint inhibitors.
Claims Coverage
The document contains two independent claims. Both claims define a monoclonal antibody by the same specific heavy- and light-chain CDR sequences, and one independent claim further adds functional immune-cell properties.
Defined TIGIT-binding antibody CDR sequences
A monoclonal antibody that binds to a TIGIT polypeptide comprising a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 11, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 12, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 13, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 15, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 16, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 17.
TIGIT binding inhibition and immune-cell activation properties
A monoclonal antibody that binds to a TIGIT polypeptide comprising the same heavy chain CDR1, CDR2, and CDR3 sequences and light chain CDR1, CDR2, and CDR3 sequences, wherein the antibody has one or more properties selected from inhibiting binding of TIGIT to CD155, increasing intrinsic T-cell activation, increasing antigen-specific T-cell activation, increasing natural killer cell activation, increasing T-cell production of at least one pro-inflammatory cytokine, and reducing T-cell production of at least one anti-inflammatory cytokine.
Across the independent claims, the antibody is defined by specific TIGIT-binding heavy- and light-chain CDR sequences (SEQ ID NOs 11, 12, 13, 15, 16, 17), with one claim further requiring one or more immune-functional properties such as CD155 binding inhibition and increases/decreases in cytokine-associated T-cell and NK-cell activation.
Stated Advantages
Inhibits binding of TIGIT to CD155.
Increases intrinsic T-cell activation as measured by IL-2 production.
Increases antigen-specific T-cell activation as measured by IL-2 production.
Increases natural killer cell activation as measured by production of IL-2, IL-6, TNFα or IFNγ.
Increases T-cell production of at least one pro-inflammatory cytokine.
Reduces T-cell production of at least one anti-inflammatory cytokine.
Documented Applications
TIGIT immunophenotyping/detection on human PBMC subsets and tumor cells using HuTIG1-IgG1.AA and HuTIG3-IgG1.AA.
Assessment of NK-cell mediated cytotoxicity against K562 with HuTIG1-IgG1.AA or HuTIG3-IgG1.AA.
Cross-reactive receptor occupancy assessment in cynomolgus monkeys.
Synergistic IFNγ increase with HuTIG1-IgG1.AA plus anti-PD-L1 in human moDC/CD4 co-cultures.
Therapeutic use in cancer.
Therapeutic use in infectious diseases, including HIV/SIV.
Therapeutic use in combination with other immune checkpoint inhibitors.
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