ET-31RADIOSENSITIZATION BY OMX-4.80P A PEGylated H-NOX OXYGEN CARRIER THAT PENETRATES AND OXYGENATES HYPOXIC TUMORS IN PRECLINICAL MODELS OF GLIOBLASTOMA AND OTHER HYPOXIC CANCERS

摘要

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 (GB) and other solid tumors. We have previously described the un-PEGylated OMX-4.80 variant, which can penetrate intracranial mouse GB tumors, release oxygen exclusively into hypoxic tumor tissue, and enhance tumor growth delay and survival when combined with RT. However, OMX-4.80 has a short circulation half-life that limits its clinical potential. Here, we describe the pre-clinical profile of PEGylated OMX-4.80 (OMX-4.80P), demonstrating it is well tolerated, long-lasting in circulation and tumors, and is significantly more efficacious than OMX-4.80. METHODS: We PEGylated OMX-4.80 to increase its circulation half-life while retaining its ability to preferentially accumulate in tumors and selectively release oxygen to hypoxic microenvironments. We characterized the efficacy of OMX-4.80P in large, hypoxic, radioresistant tumors, and its activity in intracranial GB models in nude mice and immunocompetent rats. We also conducted toxicology and pharmacokinetic studies in multiple animal models including naïve 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. Interestingly, the larger molecular size of OMX-4.80P (∼120kDa) did not prevent its passing the blood-tumor barrier in mouse and rat intracranial tumors and resulted in hypoxia reduction. 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 ∼24h in rats and ∼52h in dogs, compared to 1-2h for OMX-4.80, and that it is well tolerated. Finally, OMX-4.80P has no detectable immunogenic response. CONCLUSIONS: The preclinical efficacy data, and promising pharmacokinetic and toxicology profile, of OMX-4.80P support its clinical development for the enhancement of radiotherapy in GB patients.