486P AK130, a first-in-class Fc-mutant anti-TIGIT antibody fused with TGF-βRII protein, elicits potent anti-tumor efficacy in pre-clinical studies

TIGIT (T-cell immunoglobulin and ITIM domain), which is expressed on T NK cells, can interact with its ligands (i.e., CD155 CD122), leading to inhibitory signaling in cells promoting exhaustion of lymphocytes. Although considered as a promising immune checkpoint molecule, the single-agent efficacy anti-TIGIT therapy limited. TGF-β (Transforming growth factor-beta), serves an regulator tumor microenvironment (TME), elevated various types contributes resistance inhibitors. Consequently, novel antibody fused TGF-βRII protein (AK130) was designed inhibit TIGIT-mediated immunosuppression while decreasing levels TME. Mutations were introduced Fc region IgG4 backbone, order avoid antibody-dependent cell-mediated cytotoxicity (ADCC) complement-dependent (CDC) minimize lymphocyte loss. Binding activity AK130 or accessed by Elisa flow cytometry. The bioactivity block pathways determined luciferase reporter cell assays. Effector functions measured ADCC CDC anti-tumor investigated BALB/c-hTIGIT transgenic mice implanted H22 (a mouse hepatocarcinoma line) cells. Mice treated Isotype Control antibody, anti-HEL&TGF-β that could bind but not (4 mg/kg; 12 36 mg/kg) via i.p. injection. volume measured. specifically human high affinity. In assays, efficiently blocked interaction between CD155, well TGF-β1/TGF-β3 TGFβ-RII. As expected, did show when compared tiragolumab. also demonstrated strong mice. AK130, humanized Fc-mutant TGFβ-RII protein, shows great model does have effects, supporting clinical development for treatment cancers.