Abstract 486P
Background
TIGIT (T-cell immunoglobulin and ITIM domain), which is expressed on T and NK cells, can interact with its ligands (i.e., CD155 and CD122), leading to inhibitory signaling in T cells and promoting exhaustion of lymphocytes. Although TIGIT is considered as a promising immune checkpoint molecule, the single-agent efficacy of anti-TIGIT therapy is limited. TGF-β (Transforming growth factor-beta), serves as an immune regulator in the tumor microenvironment (TME), is elevated in various tumor types and contributes to the resistance to checkpoint inhibitors. Consequently, a novel anti-TIGIT antibody fused with TGF-βRII protein (AK130) was designed to inhibit TIGIT-mediated immunosuppression while decreasing the TGF-β levels in the TME. Mutations were introduced in the Fc region of the antibody with IgG4 backbone, in order to avoid antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) to minimize lymphocyte loss.
Methods
Binding activity of AK130 with TIGIT or TGF-β were accessed by Elisa and flow cytometry. The bioactivity of AK130 to block the TIGIT or TGF-β signaling pathways was determined in luciferase reporter cell assays. Effector functions of AK130 were measured in ADCC and CDC assays. The anti-tumor activity of AK130 was investigated in BALB/c-hTIGIT transgenic mice implanted with H22 (a mouse hepatocarcinoma cell line) cells. Mice were treated with Isotype Control antibody, anti-HEL&TGF-β that could bind to TGF-β but not TIGIT or AK130 (4 mg/kg; 12 mg/kg; 36 mg/kg) via i.p. injection. The tumor volume was measured.
Results
AK130 could specifically bind to human TIGIT and TGF-β with high affinity. In reporter assays, AK130 efficiently blocked the interaction between TIGIT and CD155, as well as TGF-β1/TGF-β3 and TGFβ-RII. As expected, AK130 did not show ADCC or CDC activity when compared with tiragolumab. AK130 also demonstrated strong anti-tumor efficacy in mice.
Conclusions
AK130, a humanized Fc-mutant anti-TIGIT antibody fused with TGFβ-RII protein, shows great anti-tumor efficacy in a mouse tumor model and does not have ADCC and CDC effects, supporting its clinical development for the treatment of human cancers.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Akeso Biopharma Co., Ltd.
Funding
Akeso Biopharma Co., Ltd.
Disclosure
All authors have declared no conflicts of interest.