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Published on: July 5, 2018
Structural and functional characterization of a monoclonal antibody blocking TIGIT
Bo-Seong Jeong1, Hyemi Nam2, Jeewon Lee2
1Department of Biological Sciences, Kaist Institute for the Biocentury, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
Abstract:
TIGIT is an immune checkpoint receptor that is expressed on subsets of activated T cells and natural killer (NK) cells. Several ligands for TIGIT, including poliovirus receptor (PVR), are expressed on cancer cells and mediate inhibitory signaling to suppress antitumor activities of the immune cells. Many studies support that the TIGIT signaling is a potential target for cancer immunotherapy. We developed an IgG4-type monoclonal antibody against human TIGIT, designated as MG1131, using a phage display library of single-chain variable fragments (scFvs). MG1131 interacts with TIGIT much more tightly than PVR does. The crystal structure of a scFv version of MG1131 bound to TIGIT was determined, showing that MG1131 could block the PVR-TIGIT interaction and thus the immunosuppressive signaling of TIGIT. Consistently, MG1131 is bound to TIGIT-expressing cells and interferes with PVR binding to these cells. Moreover, MG1131 increased NK cell-mediated tumor killing activities, inhibited immunosuppressive activity of regulatory T (Treg) cells from healthy donors, and restored interferon-γ secretion from peripheral blood mononuclear cells derived from multiple myeloma patients. MG1131 also increased T cell infiltration to the tumor site and inhibited tumor growth in mice. Collectively, these data indicate that MG1131 modulates the effector functions of T cells and NK cells positively and Treg cells negatively.
Insights
A new antibody, MG1131, targets TIGIT (T cell immunoglobulin and ITIM domain) to enhance anti-tumor immunity. This immunotherapy approach boosts T cell and NK cell activity while suppressing regulatory T cells, showing promise in preclinical models.
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.
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