ET-32HYPOXIA REDUCTION IN INTRACRANIAL GLIOBLASTOMA MODELS BY OMX-4.80P A PEGylated ENGINEERED H-NOX OXYGEN CARRIER THAT IS LONG-LASTING IN CIRCULATION AND SAFE

摘要

BACKGROUND: Hypoxic cells in solid tumors are resistant to radiotherapy. Omniox has developed a novel class of oxygen carrier proteins termed H-NOX, engineered to deliver oxygen selectively into hypoxic tissues. Previous studies have shown that one of our H-NOX candidates, OMX-4.80, penetrates intracranial glioblastoma (GB) tumors in mice, and in a dose dependent manner decreases tumor hypoxia and extends survival when combined with radiotherapy. However, we discovered that the circulation half-life of OMX-4.80 is ∼1h in dogs, which may limit clinical utility. To improve the circulation half-life, we developed a PEGylated version of OMX-4.80 (OMX-4.80P). The aim of this study was to characterize the pharmacokinetic and safety profile of OMX-4.80P and examine its effect on tumor hypoxia. METHODS: After intravenous administration of OMX-4.80P to mice and rats bearing GB tumors, we collected tumors, blood and plasma, and analyzed OMX-4.80P pharmacokinetics, immunogenicity and its effects on blood cell counts and chemistries. We evaluated OMX-4.80P bio-distribution by immunohistochemistry and its effect on tumor hypoxia by ELISA of endogenous (HIF-1a) and exogenous (pimonidazole) hypoxia markers. RESULTS: Compared to OMX-4.80, OMX-4.80P has an increased stability and circulation half-life (30h vs. 1h), significantly longer tumor accumulation (48h vs. 4h), and is not immunogenic. Furthermore, OMX-4.80P crosses the blood tumor barrier in several different intracranial rodent GB models and reduces HIF-1a and pimonidazole accumulation by ∼50%. Pharmacokinetic and toxicology studies in rodents and dogs showed that OMX-4.80P is well tolerated, and has a circulation half-life of ∼52h in dogs. The resulting exposure is expected to be sufficient for OMX-4.80P to accumulate in human GB tumors and reduce hypoxia. CONCLUSIONS: In summary, the increased retention of OMX-4.80P in circulation, the longer exposure achieved in solid tumors and efficiency in delivering oxygen into hypoxic tissues suggest OMX-4.80P is a promising IND candidate for radiation therapy enhancement in GB.