Authors:

Hongjun Li, Chunming Wang, Huanhuan Guo, Xinlai Yao, Weiwei Sun, Di Sun, Yupeng Zhu, Xiangyu Xu, Zhenzhi Yan, Chengwei Jiang, Shengjie Zhang, Xiwen Wu, Yingdi Luo, Yadong Dai, Lisa Zheng, Fan Zhang, Fei Teng, Xueming Qian, Yi Gu. Mabspace Biosciences (Suzhou) Co., Limited, Suzhou, China, HJB (Hangzhou) Co., Limited, Hangzhou, China

Abstract:

Treatment with immune checkpoint inhibitors, including anti-PD(L)-1 antibodies, has demonstrated durable responses in patients with PD-L1 expressing tumors. However, not all patients with PD-L1 expression respond to the treatment due to de novo or acquired resistance to checkpoint inhibitors. The evidence from a number of studies showed that transforming growth factor β (TGF-β) signaling in the tumor microenvironment is associated with a poor response or resistance, and inhibition of TGF-β signaling can induce tumor T cell infiltration/activation and potentiate tumor response to immune checkpoint therapy. TST005 is a bifunctional fusion protein composed of the truncated extracellular domain of the TGF-βRII receptor (a TGF-β trap) fused to a humanized anti-PD-L1 IgG1 antibody (AM4B6 mAb) with ablated Fc immune effector function. TST005 bound to human/cyno PD-L1 with high affinity and blocked the PD-1/PD-L1 interaction potently in a cell-based reporter assay. Similarly, TST005 also bound to TGF-β1, 2 and 3 isoforms with high affinity and inhibited the activation of TGF-β receptor mediated signaling. In a superantigen stimulation assay with human peripheral blood mononuclear cells (PBMCs), TST005 enhanced T cell activation significantly as measured by interferon-γ (IFN-γ) production, as compared to TGF-β trap or AM4B6 mAb alone. In contrast, TST005 did not exert any cytokine release effect on human naïve PBMCs in vitro. TST005 showed a dose-proportional linear PK profile with single IV infusion in mice, and a negative correlation between plasma TST005 concentration and its pharmacodynamic marker TGF-β1 level was established. Furthermore, in the MC38/hPD-L1 xenograft mouse model, compared with TGF-β trap or AM4B6 mAb, TST005 increased the infiltration of activated CD8+ T cells into the tumor, and it resulted in tumor regression starting from 3mg/kg. Of particular interest, in the EMT6/hPD-L1 xenograft model which responds only moderately to PD-L1 inhibitors, TST005 induced significant tumor growth inhibition and regression starting from 10mg/kg. In conclusion, we have demonstrated that TST005 has enhanced immunomodulatory properties and can induce potent antitumor activity in preclinical tumor models that are not sensitive to PD-1/PD-L1 monotherapy. These results provide the rationale for further clinical evaluation of TST005 in patients with advanced solid tumors and less optimal response to first generation PD(L)-1 based immunotherapy.