Structural and functional characterization of a monoclonal antibody blocking TIGIT

Area of Science:

• Immunology
• Cancer Biology
• Therapeutic Development

Background:

• TIGIT (T cell immunoglobulin and ITIM domain) is an immune checkpoint receptor on T and NK cells.
• Cancer cells express ligands like PVR that bind TIGIT, suppressing anti-tumor immune responses.
• TIGIT signaling represents a promising target for novel cancer immunotherapies.

Purpose of the Study:

• To develop and characterize a novel monoclonal antibody targeting human TIGIT.
• To evaluate the efficacy of the TIGIT-targeting antibody in modulating immune cell function and anti-tumor activity.

Main Methods:

• Phage display was used to generate anti-TIGIT single-chain variable fragments (scFvs).
• An IgG4 antibody, MG1131, was developed from the scFvs.
• Structural analysis determined the binding mode of MG1131 to TIGIT.
• In vitro assays assessed immune cell function (NK cell killing, Treg suppression, IFN-γ secretion).
• In vivo studies evaluated tumor growth inhibition and T cell infiltration in mice.

Main Results:

• MG1131 binds TIGIT with high affinity, blocking the TIGIT-PVR interaction.
• MG1131 enhances NK cell-mediated tumor cell lysis.
• MG1131 inhibits immunosuppressive regulatory T cells and restores T cell function in cancer patients.
• MG1131 treatment increases T cell infiltration into tumors and reduces tumor growth in mouse models.

Conclusions:

• MG1131 effectively blocks TIGIT-mediated immunosuppression.
• MG1131 demonstrates significant potential as a cancer immunotherapy agent by enhancing effector immune cell functions.
• The developed antibody positively modulates T cell and NK cell activity while negatively impacting regulatory T cells.