Onxeo has pioneered a radically new approach of anti-cancer treatment to tackle emergence of resistance: the decoy agonist mechanism of action (MoA). Drugs based on this unprecedented MoA hijack and hyper activate therapeutic targets (decoy effect) leading to exhaustion (agonist effect). This breakthrough MoA has already shown, using our lead compound AsiDNA, target engagement and excellent safety profile in humans and importantly lack of resistance in multiple preclinical studies. These exciting results led us to develop a proprietary platform of oligonucleotides (platON) with decoy agonist properties: the new generation product OX401 targeting PARP, a target already validated in oncology.
OX401-induced PARP activation, NAD+ consumption and tumor cytotoxicity was monitored 2, 7 and 12 days after tumor and non-tumor cell treatment. Inhibition of the homologous recombination repair pathway was monitored by analyzing Rad51 protein recruitment to damage sites. Accumulation of cytoplasmic DNA fragments was monitored after DNA staining and microscopy analysis. OX401 effects on the innate immune response was assessed by following STING expression and activation and T-cell mediated anti-tumor cytotoxicity.
OX401 binds and hyper activates PARP diverting it away from its proper role in cancer cells. As a consequence, OX401 inhibits DNA repair due to PARP sequestration leading to accumulation of DNA breaks and cytoplasmic chromatin fragments which activate innate immunity through STING pathway. Moreover, OX401 increases the anti-tumor T-cell-dependent immune response. The sustained hyper-activation of PARP induced by OX401 leads to a rapid NAD+ consumption (below the viability threshold) and the nuclear translocation of mitochondrial apoptosis-inducing factor (AIF) (parthanatos). By these unprecedented properties on DNA repair and innate immunity in addition to major metabolic effects, OX401 displays a potent and selective tumor cytotoxicity without resistance emergence.
Our results provide a rationale for using OX401 as an immunomodulatory and “metabolic exhauster” agent, with a therapeutic interest in particular in appropriately selected tumors with metabolic deficiencies.
Onxeo.
Onxeo.
W. Jdey, V. Hayes, C. Zandanel, V. Trochon-Joseph, F. Bono: Employee: Onxeo.