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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.

Novel cucurmosin‐based immunotoxin targeting programmed cell death 1‐ligand 1 with high potency against human tumor in vitro and in vivo