Abstract 4767: XON11, a novel multi-target antibody in pancreas cancer

Abstract Background: Pancreatic cancer continues to be one of the most lethal cancer types, with a 5-year overall survival rate of only 12%. It poses one of the toughest challenges in oncology, as chemotherapy and immunotherapy have not significantly improved patient outcomes. Consequently, there is an urgent need for new therapeutic approaches. XON11 is a new polyclonal antibody targeting several pancreatic cancer antigens, including KrasG12D. The aim of these studies was to assess the tolerance and efficacy of XON11 in non-clinical pancreatic cancer models. Material and methods: XON11 ability to induce Complement Dependent Cytotoxicity (CDC) and apoptosis compared to gemcitabine was tested in a panel of human pancreas cancer cell (MiaPaca, Aspc1, Capan, Panc1) after 24h of incubation. The capacity of XON11 and gemcitabine to impair tumorsphere formation and growth was investigated in pancreatic cancer cells for 11 days. In vivo XON11 and gemcitabine tolerance and efficacy was evaluated in NMRI nude mice after intraperitoneal dosing at 40 mg/kg tri-weekly for 4 weeks. Results: XON11 showed potent and selective anti-proliferative activity in a panel of human pancreatic Kras muted cancer cell lines, including those resistant to gemcitabine. It induced specific tumor cell cytotoxicity (Mean EC50 = 25.85 µg/mL) without affecting healthy cells (PBMC) at this concentration. XON11 displayed significantly higher potency against pancreatic cancers compared to gemcitabine. It was able to kill up to 97% of the cancer cells, whereas gemcitabine's maximum effect reached 30%. XON11 induced both caspase 8 and caspase 9 (suggesting activation of both apoptosis pathways). Furthermore, it induced a dose- response loss of mitochondrial membrane potential and ROS generation in different pancreatic cell lines. In contrast to gemcitabine, XON11 significantly decreased Aspc1 tumorspheres viability after treatment (>75% of cytotoxicity). In addition, XON11 completely inhibited sphere formation from 33µg/ml. XON11 was significantly effective against tumor growth in two xenograft mouse models and well tolerated in mice after repeated intraperitoneal dosing at 40 mg/kg over 28 days. Conclusion: Based on its high potency and tolerance, XON11 can provide a novel and promising therapy for fighting recurrent pancreatic cancer. Citation Format: Carine Ciron, Ophelie Dauphouy, Pierre-Joseph Royer, Gwenaelle Evanno, Odile Devaux, Firas Bassissi. XON11, a novel multi-target antibody in pancreas cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4767.