STX-1, a first-in-class ADC targeting DPP4 protein, acts as an anticancer andsenolytic treatment

Author Block: Benjamin Le Calvé, Delphine Dayde, Grégoire Jouffroy, Omayma Asbai, Virginie Lelarge, Justine Choeur, Thierry Mathieu, Florence Lhospice and Eric Angevin

Starkage Therapeutics, Lille, France, Gustave Roussy, Villejuif, France

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Abstract: 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.