Abstract 3003: OMX-4.80P, a novel H-NOX oxygen carrier that oxygenates hypoxic tumors in multiple tumor models and canine cancer patients, downregulates HIF-1 pathway and increases response to radiation therapy leading to cures

Abstract

Abstract BACKGROUND: Omniox has engineered OMX-4.80P, a PEGylated H-NOX oxygen carrier, as a long-acting therapeutic candidate to enhance radiotherapy (RT) in the treatment of glioblastoma and other solid tumors. Here, we describe the pre-clinical profile of OMX-4.80P, demonstrating it is well tolerated, long-lasting in circulation and tumors, and it penetrates deep into tumor tissue reducing hypoxia and altering hypoxic phenotype by downregulating HIF-1 pathway. Furthermore, it dramatically enhances RT leading to tumor cures. METHODS: We assessed the ability of OMX-4.80P to penetrate tumor tissue and reduce hypoxia in multiple orthotopic and immunocompetent mouse and rat models of glioblastoma and other tumors as well as in spontaneous canine brain tumors in veterinary patients. We measured the efficacy of OMX-4.80P in NSCLC tumors (H460 and Calu 6), and its activity in intracranial glioblastoma models in nude mice (U251), immunocompetent rats (F98) and in spontaneous canine brain tumors. We assessed exogenous hypoxia markers (pimonidazole and CCI-103F) and hypoxia inducible transcriptional factor HIF-1 by IHC and ELISA, and HIF-1 downstream targets by IHC and qRT PCR. We also conducted toxicology and pharmacokinetic studies in mice, rats and in naïve and oncology patient dogs. RESULTS: In xenograft studies of large, hypoxic, radioresistant tumors, single doses of OMX-4.80P in combination with RT result in apparent tumor cures in ∼30-50% of tumors compared to 0% cures in RT-only groups. We observed good penetration into mouse and rat intracranial and subcutaneous tumors (∼1 cm3), and into spontaneous canine brain tumors, that resulted in hypoxia reduction, as assessed by OxyLite pO2 probe and pimonidazole and CCI-103F, leading to downregulation of the HIF-1 pathway. Observed dramatic drop in HIF-1α, VEGF, GLUT-1 and PDL-1 levels suggests OMX-4.80P has profound effects on tumor cell phenotype beyond radiosensitization. Pharmacokinetic and toxicology studies using single or multiple supratherapeutic and therapeutic doses of OMX-4.80P in rodents and dogs demonstrated that it has a circulation half-life of ∼20h in rats and ∼30-40h in dogs, and that it is well tolerated. Finally, OMX-4.80P has no detectable immunogenic response. CONCLUSIONS: The preclinical data demonstrating hypoxia reduction, HIF-1 pathway downregulation and radiation enhancement, and promising PK and toxicology profile of OMX-4.80P support its clinical development as a radiosensitizer for multiple types of hypoxic tumors. Furthermore, its ability to alter key downstream effectors of the HIF-1 pathway suggest it may have potential to alter tumor biology and enhance patient responses to variety of targeted and chemo therapies by affecting tumor drug resistance, immune responsiveness, angiogenesis, metabolism and invasion. Citation Format: Ana Krtolica, Natacha Le Moan, Jen Getz, Tina Davis, Sarah Ng, Catherine Bedard, Andrew Davis, Philberta Leung, Laura Serwer, Kevin Tanaka, Tim Keating, Feng Yan, Teri Guerrero, Michael Kent, Peter Dickinson, Jonathan Winger, Stephen P. L. Cary. OMX-4.80P, a novel H-NOX oxygen carrier that oxygenates hypoxic tumors in multiple tumor models and canine cancer patients, downregulates HIF-1 pathway and increases response to radiation therapy leading to cures. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3003. doi:10.1158/1538-7445.AM2015-3003