Abstract A100: Systemic targeting of therapeutic RNA into pancreatic tumors via an RNA-binding and cell-penetrating antibody

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers, in large part due to its high resistance to immunotherapies. PDAC is an unresponsive immunological tumor due to low frequency of neoantigens, the immunosuppressive microenvironment, the highly desmoplastic stroma, and low vascularity, all of which highly limit the infiltration of immune cells and therapeutic drugs. Thus, conventional and current approaches, such as immune checkpoint blockades, have shown minimal benefit for PDAC treatment, highlighting the urgent need to develop new therapeutic strategies to reprogram the tumor microenvironment and activate an effective antitumor immune response. We developed TMAB3, engineered from the lupus-derived antibody 3E10, capable of non-covalently binding and protecting RNAs for systemic tumor-targeted delivery. TMAB3 binds RNA with high affinity via a modified nucleic acid-binding pocket and selectively penetrates tumor cells by engaging the ENT2 nucleoside transporter, which is upregulated in PDAC and other malignancies. We complexed TMAB3 with 3p-hpRNA, an immunogenic RNA that activates RIG-I, a cytosolic sensor of viral RNA, triggering type I interferon responses and downstream antitumor immunity. In this study, we demonstrate that the intravenous administration of TMAB3/3p-hpRNA complexes specifically targets malignant cells within PDAC tumors in mice, significantly reduces tumor growth, and triples animal survival after only three acute doses. Furthermore, in orthotopic PDAC, we demonstrate that treatment with TMAB3/3p-hpRNA complexes mechanistically enhances intratumoral CD8+ T cell infiltration and activation, promotes the expression of interferon-stimulated genes, and shifts the immune landscape toward an activated phenotype. Notably, these therapeutic effects were reversed in T cell-deficient (Rag1 knockout) mice, confirming that efficacy depends on adaptive immunity and immunogenic tumor cell death. Additionally, single-cell RNA sequencing of the TMAB3/3p-hpRNA-treated PDAC tumors showed a reduction in malignant cells, upregulation of apoptotic genes, and increase expression of genes associated with an effective and active T cell response. In vitro co-culture experiments also showed that effective T cell activation required tumor cell expression of both ENT2 and RIG-I, highlighting the tumor-specific mechanism of action. Together, these findings introduce TMAB3 as a novel antibody-based platform for the systemic delivery of immunostimulatory RNAs to immunologically quiescent tumors. This strategy overcomes key delivery and immunogenicity barriers in PDAC, thereby unlocking the potential of RNA-based immunotherapies for cancers that are traditionally unresponsive to immune intervention. Citation Format: Diana Martinez-Saucedo, Elias Quijano, Zaira Ianniello, Natasha Pinto Medici, Madison Rackear, Haoting Chen, Luiz Lola-Pereira, Yanfeng Liu, Denise Hegan, Xinning Shan, Robert Tseng, Deanne Yugawa, Sumedha Chowdhury, Minsoo Khang, Wendy S. Woods, Nicholas Gosstola, Ranjit S. Bindra, Marie E. Robert, David A. Braun, Pablo Perez Pinera, W Mark. Saltzman, Luisa F. Escobar-Hoyos, Peter M. Glazer. Systemic targeting of therapeutic RNA into pancreatic tumors via an RNA-binding and cell-penetrating antibody [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3): nr A100.