Abstract P135: Systemic targeting of a CNS tumor (medulloblastoma) using a novel cell-penetrating, nucleic acid binding, monoclonal antibody

Abstract

Abstract Targeting tumors of the central nervous system remains challenging given the physiological barriers preventing the delivery of therapeutics across the blood brain barrier (BBB). This is particularly true for nucleic acids, which degrade rapidly in serum and often fail to penetrate cells even with proper formulation into AAVs or LNPs. To overcome these barriers, many current efforts rely on invasive methods of delivery, including intrathecal or intraparenchymal injection. Here we report studies evaluating the ability of a novel cell-penetrating antibody, GMAB, to penetrate the BBB and target a CNS model of medulloblastoma (DAOY) following intravenous administration. Studies with fluorescently labeled GMAB demonstrated that the antibody readily penetrated into the CNS following systemic administration, achieving tumor-specific delivery while sparing surrounding normal brain tissue. Subsequent studies with 3p-hpRNA, a known activator of RIG-I, a cytosolic pattern recognition receptor which detects viral RNA and elicits a type-I interferon response, demonstrated that GMAB could deliver RNA ligands to tumors, resulting in significantly reduced intracranial tumor burden 10 days after a single-dose administered systemically while also preventing the development of spinal metastases. These results highlight a novel approach for the systemic delivery of immunostimulatory RNAs in a targeted manner to multiple tumors including often difficult to treat CNS tumors, which may offer treatment advantages over current approaches. Citation Format: Elias Quijano, Minsoo Khang, Bruce C. Turner, Stephen Squinto, Ranjit Bindra, W. Mark Saltzman, Peter Glazer. Systemic targeting of a CNS tumor (medulloblastoma) using a novel cell-penetrating, nucleic acid binding, monoclonal antibody [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P135.