Abstract 3421: XON7, a new emerging multitarget immunotherapy against metastatic soft tissue sarcomas

Abstract Context: Soft tissue sarcomas (STS) are rare and heterogeneous malignancies originating from mesenchymal tissues, comprising over 50 subtypes. While surgery and radiotherapy are effective for localized disease, advanced and metastatic STS have poor outcomes due to limited efficacy of standard treatments like doxorubicin and frequent therapeutic resistance. Advances in molecular profiling have enabled targeted therapies, such as PARP inhibitors, but their effectiveness remains limited by the diversity of STS and resistance mechanisms. In this study, we evaluate the safety and efficacy of XON7, a first-in-class glyco-humanized polyclonal antibody (GH-pAb), as a novel therapeutic approach to address these challenges. Methods: XON7’s antitumor efficacy was tested in a panel of primary patient-derived sarcoma tumors and established sarcoma cell lines using CellTiter-Glo assay. Mechanisms of action assessed included complement-dependent cytotoxicity (CDC), apoptosis, antibody-dependent cell cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Apoptotic pathways were explored via caspase 8/9 activation, reactive oxygen species (ROS) production, and mitochondrial membrane potential. In vitro 3D cultures, XON7's impact on tumor growth, spheroid formation, and metastasis was evaluated. In vivo XON7 efficacy was evaluated in patient-derived xenograft (PDX) models of STS, with tri-weekly treatments initiated at tumor volumes of 150-200 mm3. Results: XON7 acts via plural MOA (CDC, apoptosis and ADCP), it demonstrated a potent anti-tumor activity in a panel of soft tissue sarcoma cells, with cytotoxicity ranging from 60% to 100% at a concentration of 300 µg/ml. Apoptotic induction involved both intrinsic and extrinsic pathways as evidenced by caspase 8/9 activation, ROS generation and loss of mitochondrial membrane potential. In 3D culture, repeated exposure to XON7 at a concentration of 300µg/ml significantly reduced the surface and viability of spheroids (liposarcoma SW872 cell line). XON7 also demonstrated its ability to reduce tumorogenicity and metastasis in a transwell invasion assay. In a PDX mice model of dedifferentiated liposarcoma, XON7 inhibited tumor growth by 50% over 48 days. Conclusion: XON7 characterized by its plurality of action and potent antitumor efficacy, currently under clinical evaluation, XON7 emerges as a promising immunotherapy for soft tissue sarcomas. Citation Format: Carine Ciron, Gwenaelle Evanno, Pierre-Joseph Royer, Odile Duvaux, Firas Bassissi. XON7, a new emerging multitarget immunotherapy against metastatic soft tissue sarcomas [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 3421.