A novel cucurmosin-based immunotoxin targeting PD-L1 with high potency against human tumor in vitro and in vivo.

Immunotoxins are antibody-cytotoxin chimeric molecule 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 in the end due to primary/secondary resistance. In order to optimize the therapeutic efficacy of anti-PD-L1 monoclonal antibody (mAb), we used Durvalumab as the payload and CUS245C , a type I ribosome-inactivating protein (RIP) isolated from cucurbita moschata, as the toxin moiety, to construct PD-L1-specific IT (named D-CUS245C ) through the engineered cysteine residue. In vitro, D-CUS245C selectively killed PD-L1 positive tumor cells. At the same time, in vivo studies showed that D-CUS245C had obvious anti-tumor effect on PD-L1 positive 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.