TUMOR RADIOSENSITIZATION USING A NITRIC-OXIDE-NEUTRAL, TUNABLE OXYGEN-BINDING PRO

项目概要/摘要 通过 I 期和 II 期 SBIR NCI 支持，Omniox 开发了一种突破性的携氧蛋白 OMX-4.80，可以向肿瘤输送氧气并大大减少缺氧。该 IIB 期提案描述了某些癌症的 IND 支持研究和 1b 期临床试验，有可能扩展到一系列其他缺氧实体癌症，以增强放射治疗 (RT)。在肿瘤缺氧和 RT 领域领导者的支持下，在蛋白质氧载体和肿瘤药物开发专家的领导下，Omniox 专注于将 OMX-4.80 有前景的临床前数据转化为患者。 Omniox 已获得高净值投资者和风险投资集团的承诺，将在三年内每年提供约 100 万美元的 NCI 资金；最初的 A 轮投资意向书描述了 100 万美元的资金承诺，该资金承诺以该提案的资助为条件。 缺氧是实体瘤的一个常见特征，被认为是放射治疗（放射治疗，RT）临床治疗癌症的主要障碍。电离辐射需要氧气来破坏 DNA 并杀死癌细胞。肿瘤明显缺氧的癌症患者往往生存预后较差。考虑到缺氧的临床相关性，放射治疗领域的长期目标是通过减弱或利用这种病理生理状态来有效地对实体瘤进行放射增敏。 血红素一氧化氮/氧结合 (H-NOX) 蛋白最初是在加州大学伯克利分校发现的，并独家授权给 Omniox 用于治疗开发。 H-NOX对一氧化氮（NO）呈中性，与基于血红蛋白的氧载体的高NO反应性和高血压特性相媲美；可以调整以获得特定的氧亲和力；在 80°C 以上结构稳定，在室温下化学稳定数周；并且可以进行表面修饰以改变尺寸、渗透特性或组织靶向。主要 H-NOX OMX-4.80 的临床前数据表明，它在静脉注射后表现出临床相关的肿瘤生物分布，并在多个小时内显着减少缺氧。此外，在原位肿瘤模型中，与放疗结合使用时，主要候选药物可显着减少肿瘤生长并延长总生存期。最后，在毒性测试中，H-NOX 蛋白表现出很强的安全性，没有任何困扰其他肿瘤氧合技术的重大安全或毒性问题。该 IIB 期提案是根据 NCI 放射调节剂工作组发布的放射增强疗法开发指南（DIRM 报告）编写的，并描述了通过 1 期试验进行的持续临床前研究、安全性测试和临床开发。这项研究的成功完成应该会引起投资者对支持进一步临床开发的浓厚兴趣。

PROJECT SUMMARY/ABSTRACT Through Phase I and II SBIR NCI support, Omniox has developed a breakthrough oxygen carrying protein, OMX-4.80, that delivers oxygen to tumors and greatly reduces hypoxia. This Phase IIB proposal describes IND-enabling studies and Phase 1b clinical trials in certain cancers, with the potential to expand to a range of other hypoxic solid cancers, to enhance radiation therapy (RT). Backed by leaders in the field of tumor hypoxia and RT, and led by experts in protein-based oxygen carriers and oncology drug development, Omniox is focused on translating promising preclinical data of OMX-4.80 into patients. Omniox has received commitments from high net worth investors and venture capital groups to match NCI funding for ~$1million per year for three years; the initial series A termsheet describes a $1million funding commitment that is conditional on the funding of this proposal. Hypoxia, a common feature of solid tumors, is considered a major obstacle for the clinical management of cancer by radiation therapy (radiotherapy, RT). Oxygen is required by ionizing radiation to damage DNA and kill cancer cells. Cancer patients with significantly hypoxic tumors tend to have a poor prognosis for survival. Given the clinical relevance of hypoxia, a long-time objective in the field of RT has been to effectively radiosensitize solid tumors by attenuating or exploiting this pathophysiological state. The heme-nitric oxide/oxygen-binding (H-NOX) proteins were initially discovered at the University of California, Berkeley and are exclusively licensed to Omniox for therapeutic development. H-NOX are neutral towards nitric oxide (NO), comparing favorably with the high NO reactivity and hypertensive properties of hemoglobin-based oxygen carriers; can be tuned to achieve specific oxygen affinities; are structurally stable above 80 ¿C, and chemically stable for weeks at room temperature; and can be surface-modified to alter size, oncotic properties, or tissue targeting. Preclinical data on the lead H-NOX, OMX-4.80, established that it demonstrates clinically relevant tumor biodistribution after IV administration, and significantly reduces hypoxia over multiple hours. Additionally, in orthotopic tumor models, the lead candidate generated a significant reduction in tumor growth and an extension in overall survival when coupled with RT. Finally, in toxicity testing, the H-NOX protein demonstrated a strong safety profile, without any of the significant safety or toxicity concerns that have plagued other tumor oxygenation technologies. This Phase IIB proposal has been prepared in accordance with guidelines for developing radiation enhancement therapies (DIRM report) as published by the NCI¿s Radiation Modifier Working Group and describes the continued preclinical research, safety testing, and clinical development through Phase 1 trials. Successful completion of this study should result in significant investor interest in supporting further clinical development.