TST005 is the second bi-functional anti-PD-L1 and TGF-β trap fusion protein entering the global clinical stage. It simultaneously targets two immuno-suppressive pathways, transforming growth factor -β (TGF-β) and programmed cell death ligand-1 (PD-L1), that are commonly used by cancer cells to evade the immune system.
TST005 displayed potent activity in vitro in reversing TGF-β induced T-cell suppression. In multiple syngeneic tumor models, TST005 induced significant increase of CD8 T-cell infiltration into PD-L1 expressing tumors and displayed dose-dependent tumor growth inhibition in tumor model not sensitive to PD-(L)1 treatment due to high level TGF-β. TST005 is well tolerated in non-human primates and displayed a linear PK profile. TST005 is a potential differentiated bi-functional immunotherapy candidate with improved therapeutic window.
Binding by PD-L1 on the tumor cells to its receptor PD-1 on activated T-cells delivers a negative signal that blocks T-cell proliferation, survival and effector functions. On the other hand, TGF- produced either by immune cells, tumor cells or stromal fibroblast, can block T-cell infiltration and inhibit the ability of T-cell to kill tumor cells.
TST005 is a bi-functional fusion protein composed of the truncated extracellular domain of the TGF-RII receptor serving as a TGF- trap fused to a humanized anti-PD-L1 IgG1 antibody (AM4B6 mAb). By blocking both PD-L1-interaction with PD-1 and TGF- mediated inhibitory activities on T-cell infiltration and T-cell activity, PD-L1/TGF- bi-functional antibodies can effectively prevent tumor cells from escaping immune regulation.
TST005 is a bi-functional fusion protein designed to simultaneously block PD-L1 and reduce TGF-β signaling. The study shows that at the same dose, TST005 can more thoroughly inhibit the TGF-β pathway in tumors compared to M7824, so it displayed better anti-tumor activities in pre-clinical studies with tolerable safety profiles.