Abstract A132: DB-1317, a novel ADAM9-targeting antibody-drug conjugate, exhibits potent antitumor activity against multiple gastrointestinal cancers

Abstract Background: A disintegrin and metalloproteinase 9 (ADAM9) is highly expressed in various gastrointestinal cancers, and its expression level correlates with suppressive tumor microenvironment, metastasis and poor prognosis. DB-1317 is a novel ADAM9-targeting ADC with a topoisomerase inhibitor payload P1003 at drug-antibody ratio of 8. Here, the antitumor activity and safety profile of DB-1317 in preclinical models were evaluated. Methods: In vitro and in vivo anti-cancer activities of DB-1317 were evaluated in several human gastrointestinal cancer cell lines and cell-line-/patient-derived xenograft (CDX/PDX) models. Antibody dependent cell cytotoxicity (ADCC), cell cycle, cell apoptosis, and bystander killing assays were performed to explore the underlying mechanisms. Pharmacokinetics (PK) profiles were assessed in monkey and tumor bearing-mice. Safety profiles were also assessed in cynomolgus monkeys. Results: In vitro, DB-1317 inhibited proliferation of various human pancreatic, colorectal, and gastric cancer cells with ADAM9 expression. In vivo, DB-1317 showed strong anti-tumor activity in gastric (NUGC-4, NUGC-3, SNU-5, Hs746T) and pancreatic (HPAFII, Panc08.13) cancer models. The tumor growth inhibition (TGI) was greater than 70% in all the models after DB-1317 treatment at a single dose of 1 mg/kg. Furthermore, DB1317 showed potent anti-tumor efficacy in gastric and colorectal cancer PDX models across various levels of ADAM9 expression. Bystander killing effects and antibody-dependent cell-mediated cytotoxicity (ADCC) contribute to the antitumor activity of DB-1317. PK study performed by treatment of DB-1317 in Panc08.13 subcutaneous xenograft model demonstrated much higher exposure of payload from DB-1317 in the tumor than that in serum, implying that payload is selectively and effectively released in the tumor. DB-1317 displays favorable pharmacokinetic and toxicokinetic profiles in cynomolgus monkeys; in addition, DB-1317 is well-tolerated at a dose of up to 80 mg/kg in monkeys. Conclusions: DB-1317 demonstrated promising antitumor activities across various gastrointestinal cancers, with favorable PK and safety profiles. Citation Format: Shengchao Lin, Jun Yao, Junjie Yang, Rong Shi, Zhongyuan Zhu, Yang Qiu, Haiqing Hua. DB-1317, a novel ADAM9-targeting antibody-drug conjugate, exhibits potent antitumor activity against multiple gastrointestinal cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A132.