Novel cucurmosin‐based immunotoxin targeting programmed cell death 1‐ligand 1 with high potency against human tumor in vitro and in vivo
Caiyun Zhang, Jiani Xiong, Yinxiang Lan, Jingyu Wu, Chengyan Wang, Zhihong Huang, Jizhen Lin, Jieming Xie
Abstract
Abstract Immunotoxins are Ab‐cytotoxin chimeric molecules with mighty cytotoxicity. Programmed cell death 1‐ligand 1 (PD‐L1), is a transmembrane protein expressed mainly in inflammatory tumor tissues and plays a pivotal role in immune escape and tumor progression. Although PD‐L1 immune checkpoint therapy has been successful in some cases, many patients have not benefited enough due to primary/secondary resistance. In order to optimize the therapeutic efficacy of anti‐PD‐L1 mAb, we used durvalumab as the payload and CUS 245C , a type I ribosome‐inactivating protein isolated from Cucurbita moschata , as the toxin moiety, to construct PD‐L1‐specific immunotoxin (named D‐CUS 245C ) through the engineered cysteine residue. In vitro, D‐CUS 245C selectively killed PD‐L1 + tumor cells. In vivo studies also showed that D‐CUS 245C had obvious antitumor effect on PD‐L1 + human xenograft tumors in nude mice. In conclusion, in the combination of the toxin with mAb, this study developed a new immunotoxin targeting PD‐L1, emphasizing a novel and promising treatment strategy and providing a valuable way to optimize cancer immunotherapy.