STX-1：一种靶向DPP4蛋白的首创ADC，兼具抗癌和衰老细胞清除作用

Antibody-drug conjugates (ADCs) are innovative cancer therapies which, unlike conventional chemotherapies, enhance the anti-tumor effect while limiting adverse effects. However, it is necessary to discover new therapeutic targets that will enable the development of future generations of ADCs. Here we present an original ADC, called STX-1, targeting DPP4 protein and exhibiting both anticancer and senolytic activities. DPP4 is a type II glycoprotein that has intrinsic dipeptidyl peptidase IV (DPPIV) activity and is implicated in broad and various physiological processes, including metabolism of glucose, activation of T lymphocytes, and cell adhesion. This protein has also been known as a cell surface marker associated with varied malignancies and as a part of cancer stem cells in mesothelioma and colon carcinoma. More recently, studies have shown that its expression is a major hallmark of senescence. DPP4 therefore appears to be a promising therapeutic target in the treatment of certain types of cancer, targeting not only tumor but also senescent tumor cells.STX-1 is composed of a humanized IgG1 antibody directed against DPP4 (anti-DPP4 mAb) conjugated to four topoisomerase I inhibitor Exatecan with cathepsin B sensitive linker. The preclinical datasets display in vitro complete characterization of STX-1 associated to high internalization of the ADC, strong affinity to DPP4 protein and cytotoxic activity on several cancer models specifically related to target expression. Moreover, senescence induction in cancer cell lines through chemo- or radiotherapy exposure, boosts DPP4 expression and increases significantly antigen density at the plasma membrane. Despite the cell cycle arrest induced by senescence, cancer cells remain sensitive to STX-1 treatment. In vivo , administration of intravenous (IV) doses of STX-1 is associated with potent anti-tumor activity in pancreas and liver cancer xenograft models whose effectiveness depends on the level of DPP4 expression. However, pretreatment of mice by a combination of Trametinib/Palbociclib induces senescence in tumor, boost expression of DPP4 and allows a better anti-tumor activity of STX-1. Finally, in toxicology studies in mice expressing human form of DPP4, STX-1 was well tolerated, at dose levels up to 100 mg/kg, 21 days after administration. To conclude, STX-1 is associated with strong anti-tumor activity in different cancer models, whereas synergistic combination activity to senescence phenotype induction in tumors. The data presented support future clinical development of STX-1 for the treatment of gastric, pancreatic and liver cancer indications.