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

"人类" H. NOX "的工程"作为"延长"管理"的"氧气"输送"治疗" ' 项目总结/摘要 Omniox开发了一类可调的氧气输送剂，可显著缓解肿瘤缺氧， 提高放疗（RT）的疗效。这种名为H-NOX的治疗性蛋白质家族可以抑制 低氧肿瘤，而没有与早期氧合治疗相关的治疗负担和毒性。 由于辐射依赖于氧气来破坏DNA，因此侵袭性实体瘤中的缺氧是一个主要因素。 阻碍有效治疗。以前的SBIR资助的研究导致了H-NOX的鉴定 细菌来源的变体，OMX-4.80，在穿透和氧合缺氧肿瘤方面非常有效， 增强单次放射治疗后的肿瘤生长延迟。OMX-4.80不会导致心血管疾病， 与血红蛋白氧载体相关的肾毒性或高血压毒性。细菌的起源 主要候选者使其适合于大分割RT--如用于转移性脑的"射波刀"， 复发性原发性脑癌-然而，其免疫原性与长期给药方案不相容 在接受RT的800，000名患者中，> 80%的患者接受了分次RT（> 2周）。 在这项研究中，我们将评估一类新的治疗氧载体从人类H-NOX（hH-NOX） 同系物，其已被设计成具有与OMX-4.80类似的氧输送特性，但仍然存在 与目前在分次RT中使用的延长治疗时间表相容。 180个hH-NOX变体的聚焦突变体库，并鉴定了10个具有前景的氧结合的候选物 动力学在目标1中，Omniox将比较这10个样本组的氧亲和力、稳定性和NO反应性。 候选人，以确定具有最佳生化特性的主要候选人（和备份）。在目标2中，动物 将进行研究以表征电极导线的药代动力学、安全性和免疫原性特征 候选人在目的3中，使用免疫活性小鼠中的同基因肿瘤异种移植模型， 在Omniox的细菌H-NOX的临床前开发过程中进行了测试，我们将检查肿瘤的生物分布 和氧合的铅hH-NOX（目标3A），并证明减少原发性肿瘤生长， 重复hH-NOX给药结合分次RT（目标3B）。! ' 机密（c）2013 Omniox，Inc.不用于分发

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