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

使用一氧化氮中性、可调氧结合 PRO 进行肿瘤放射增敏

• 批准号: 8735850
• 负责人: AJIT S SHAH
• 金额: $ 100万
• 依托单位: OMNIOX, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-25 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8735850
• 关键词: Affinity; Attenuated; Back; Binding; Binding Proteins; Biodistribution; Biological; Biological Markers; Biopsy; Brain Neoplasms; Budgets; California; Cancer Patient; Canis familiaris; Capital; Clinical; Clinical Management; Clinical Trials; Collaborations; Companions; Coupled; DNA Damage; Data; Development; Dose; EF5; Funding; Glioblastoma; Glioma; Goals; Guidelines; Heme; Hemoglobin; Hour; Human; Hypoxia; Ionizing radiation; Lead; Licensing; Malignant Neoplasms; Manufacturer Name; Maximum Tolerated Dose; Measures; Modeling; Mus; Newly Diagnosed; Nitric Oxide; Operative Surgical Procedures; Orphan; Oxygen; Patients; Penetration; Pharmacodynamics; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Plague; Positron-Emission Tomography; Property; Proteins; Publishing; Radiation; Radiation therapy; Radiation-Sensitizing Agents; Radiosensitization; Randomized; Rattus; Recurrence; Regimen; Reporting; Resected; Risk; Route; Safety; Schedule; Series; Small Business Innovation Research Grant; Solid; Solid Neoplasm; Surface; Technology; Temperature; Therapeutic; Time; Tissues; Toxic effect; Toxicity Tests; Toxicokinetics; Translating; Tumor Oxygenation; Universities; abstracting; base; cancer cell; cancer radiation therapy; clinically relevant; design; drug development; effective therapy; improved; interest; killings; meetings; mouse model; novel therapeutics; oncology; outcome forecast; pre-clinical; pre-clinical research; programs; radiation effect; safety study; safety testing; standard of care; temozolomide; therapeutic development; tumor; tumor growth; working group

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.

项目摘要/摘要 通过第一阶段和第二阶段SBIR NCI支持，Omniox已经开发出一种突破性的携氧蛋白OMX-4.80，该蛋白为肿瘤输送氧气，并极大地减少缺氧。这份IIB期提案描述了在某些癌症中启用IND的研究和1b期临床试验，有可能扩大到其他一系列缺氧性实体癌症，以加强放射治疗(RT)。在肿瘤缺氧和放射治疗领域的领导者的支持下，在蛋白质氧载体和肿瘤药物开发的专家的领导下，Omniox专注于将OMX-4.80的有前途的临床前数据转化为患者。Omniox已收到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100万美元的NCI资金；最初的A系列条款说明书描述了100万美元的资金承诺，这取决于这项提案的资金情况。 低氧是实体瘤的一个共同特征，被认为是肿瘤放射治疗(放疗)临床治疗的主要障碍。电离辐射需要氧气才能破坏DNA并杀死癌细胞。肿瘤明显缺氧的癌症患者的生存预后往往很差。鉴于低氧的临床相关性，放射治疗领域的一个长期目标是通过减弱或利用这种病理生理状态来有效地使实体肿瘤放射增敏。 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，并被Omniox独家许可用于治疗开发。H-NOX对一氧化氮(NO)是中性的，与以血红蛋白为基础的氧载体的高NO反应性和高血压特性相比是有利的；可以进行调节以实现特定的氧气亲和力；在80℃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大小、肿瘤性或组织靶向性。有关H-NOX引线OMX-4.80的临床前数据证实，静脉注射后，它显示出临床相关的肿瘤生物分布，并在数小时内显著减少缺氧。此外，在原位肿瘤模型中，当联合RT时，首选候选方案可显著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。本II期B期方案是根据美国国立卫生研究院S辐射调节剂工作组发布的辐射增强疗法开发指南(DIRM报告)编写的，介绍了通过1期试验持续进行的临床前研究、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的临床开发的浓厚兴趣。