創勝集團 - 全整合型國際化生物制藥公司
創勝集團, 生物藥, 抗體, 藥物研發
08 Apr, 2022
Author: Huanhuan Guo, Xinlai Yao, Chunming Wang, linlin Mao, Hongjun Li, Shuang Lu, Di Sun, Chengwei Jiang, Shenjie Zhang, Lisa Zheng, Fan Zhang, Fei Teng, Steven Yu, Yi Gu, Xueming Qian
Mabspace Biosciences (Suzhou) Co., Limited, Suzhou, China, HJB (Hangzhou)Co., Limited, Hangzhou, China
Antibodies targeting PD1/PD-L1 are emerging as effective cancer immunotherapies, however, not all patients with PD-L1 expression respond to the treatment. A growing body of data demonstrates the pivotal roles of the master regulators from the tumor microenvironment (TME), such as transforming growth factor β (TGF-β), in the development of resistance to Immune checkpoint inhibitors. Therefore, co-inhibition of TGF-β signaling is expected to enhance the antitumor responses of PD1/PD-L1-based immunotherapies. 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 with ablated Fc immune effector function. Previously we showed the potent antitumor activity of TST005 in MC38/hPD-L1 and EMT6/hPD-L1 xenograft models. Here we report TST005 anti-tumor activities in MC38 colorectal cancer and EMT-6 breast cancer models compared to M7824 (Merck’s PD-L1/TGF-βRII) analog and its safety profiles following single or repeated doses in rats and non-human primates (NHP).
TGF-β1 depletion from the plasma of MC38 tumor–bearing mice was observed even at the lowest dose (1mg/kg). At higher dose (10mg/kg), TGF-β1 depletion persisted longer. The same trend was also found in MC38 tumor tissue. In EMT-6 tumor model upon TST005 treatment (30mg/kg), TST005 showed better tumor inhibition compared to M7824 analog at high dose (30mg/kg), which correlates well with the extent of TGF-β1 depletion. For TST005, TGF-β1 depletion was persistent throughout all time points tested (up to Day 14) in plasma and tumor tissue compared to M7824 analog at the same dose/dosing frequency. TST005 treatment (3mg/kg,10mg/kg) significantly lowered phosphorylated SMAD2 (pSMAD2) in MC38 tumors.
TST005 was well tolerated in both rats and monkeys, no significant safety issues were observed following single or repeated doses in general toxicity studies and safety pharmacology assessment, the exposure of TST005 in both species was comparable between two genders and increased in an approximately dose-proportional manner. No cytokine release was observed in monkeys. Based on the exposure of TST005 in monkeys and predicted exposure at First in Human (FIH) dose, the safety margin of TST005 will be higher than 200 and 500 folds calculated on Cmax and AUC respectively.
In conclusion, we have demonstrated the antitumor activity of TST005 in PD/PD-L1 sensitive and resistant tumor models as well as the safety profile in NHP, TST005 has been granted for phase 1 clinical trials in USA (NCT04958434).