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

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.