Engineering of human H-NOX as an oxygen delivery therapeutic for prolonged admini

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Engineering'of'Human'H.NOX'as'an'Oxygen'Delivery'Therapeutic'for'Prolonged'Administration' ' ' Project Summary/Abstract Omniox has developed a class of tunable oxygen-delivery agents that significantly alleviate tumor hypoxia to enhance the efficacy of radiotherapy (RT). This family of therapeutic proteins, called H-NOX, can oxygenate hypoxic tumors without the treatment burden and toxicity associated with earlier oxygenation therapies. Because radiation relies on oxygen to damage DNA, the lack of oxygen in aggressive solid tumors is a major impediment to effective treatment. Previous SBIR-funded studies resulted in the identification of an H-NOX variant of bacterial origin, OMX-4.80, that is highly effective in penetrating and oxygenating hypoxic tumors and enhancing tumor growth delay after single radiation treatments. OMX-4.80 does not result in cardiovascular, renal, or hypertensive toxicities associated with hemoglobin-based oxygen carriers. The bacterial origin of the lead candidate makes it appropriate for hypofractionated RT-such as Cyberknife" for metastatic brain and recurrent primary brain cancer-however, its immunogenicity is incompatible with prolonged dosing schemes (> 2 weeks) of fractionated RT in >80% of the 800,000 patients that receive RT. In this study, we will evaluate a novel class of therapeutic oxygen carriers from human H-NOX (hH-NOX) homologues, which have been engineered with similar oxygen delivery properties to OMX-4.80, yet remain compatible with the prolonged treatment schedules currently used in fractionated RT. We have screened a focused mutant library of 180 hH-NOX variants, and identified 10 candidates with promising oxygen-binding kinetics. In Aim 1, Omniox will compare the oxygen affinity, stability and NO reactivity of this panel of 10 candidates to identify a lead candidate (and backups) with optimal biochemical properties. In Aim 2, animal studies will be performed to characterize the pharmacokinetic, safety and immunogenicity profile of the lead candidate. In Aim 3, using a syngeneic tumor xenograft model in immunocompetent mice developed and tested during Omniox' preclinical development of the bacterial H-NOX, we will examine tumor biodistribution and oxygenation of the lead hH-NOX (Aim 3A) and demonstrate reduction in primary tumor growth through repeated hH-NOX dosing in conjunction with fractionated RT (Aim 3B).! ! ' CONFIDENTIAL (c)2013 Omniox, Inc. NOT FOR DISTRIBUTION