Activity of DEM301, a novel anti-DEM-TXX antibody-drug conjugate for the treatment of gastrointestinal tumors.

159 Background: DEM301 is a novel antibody-drug conjugate (ADC) consisting of a humanized, afucosylated monoclonal antibody conjugated to a topoisomerase I inhibitor attached via a cleavable linker. DEM301 specifically targets human DEM-TXX, a cell-surface glycoprotein implicated in cell adhesion and highly expressed in gastrointestinal cancers. DEM301 delivers potent anti-tumor activity in preclinical models, while maintaining a favorable tolerability profile in human-DEM-TXX transgenic mice. Methods: DEM-TXX expression was characterized by immunohistochemistry (IHC) and immunofluorescence microscopy. DEM301 binding, internalization, cytotoxicity, and antibody-dependent phagocytosis (ADCP) were assessed in vitro . Anti-tumor activity was evaluated in cell line- and patient-derived xenograft models of colorectal, gastric, and pancreatic cancers. To enable non-clinical safety and syngeneic efficacy studies, a knock-in mouse expressing the human DEM-TXX extracellular domain ( DEM-TXX hECD KI) was generated. Results: DEM-TXX is expressed in a significant portion of GI tumors with greatest prevalence in colorectal cancer (CRC). In normal tissues, expression is also detected in colon and stomach; in the colon, localization is restricted to the basolateral membrane. DEM301 efficiently binds to DEM-TXX (K D =0.54 nM), internalizes in target cells, and mediates marked cytotoxicity and ADCP in vitro. DEM301 demonstrated potent anti-tumor activity across colon, gastric and pancreatic preclinical tumor models (Table 1). Treatment with DEM301 resulted in complete responses (CRs) and partial responses (PRs) in both small and large CRC and gastric CDX tumors, with 10/10 CRs observed in the RKO CRC model. In addition, DEM301 treatment resulted in significant efficacy in a CRC PDX model. DEM301 showed robust anti-tumor efficacy in CT26-DEM-TXX hECD tumors in DEM-TXX hECD KI mice and was tolerated with no dose-limiting toxicities observed up to 160mg/kg, underscoring the favorable therapeutic window of DEM301. Conclusions: DEM301, a novel DEM-TXX-targeted ADC, demonstrated potent anti-tumor efficacy in preclinical models of GI tumors and a favorable safety profile in a humanized DEM-TXX mouse model, supporting advancement toward clinical development. DEM301 efficacy in xenograft tumor models. Model Dose (mg/kg) Regimen TGI (%) vs. hIgG1-aF TGI p vs. hIgG1-aF CR; PR (N total) RKO 6 Single dose 106 *