Novel anti-oxidant catalyst to treat IL-2 toxicity

治疗 IL-2 毒性的新型抗氧化催化剂

• 批准号: 6584942
• 负责人: Garry John Southan
• 金额: $ 34.07万
• 依托单位: INOTEK PHARMACEUTICALS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-14 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6584942
• 关键词: antiinflammatory agents; antioxidants; catalyst; combination chemotherapy; drug adverse effect; drug design /synthesis /production; hemodynamics; histopathology; immunotherapy; interleukin 2; laboratory mouse; metalloporphyrins; nitric oxide; peroxynitrites; sheep

DESCRIPTION (provided by applicant): IL-2 biotherapy of refractory malignancies may produce cardiovascular toxicities and hemodynamic alterations that are indistinguishable from those seen in septic shock. These host responses include a massive capillary leak syndrome, manifested as non-cardiogenic pulmonary edema and consequent respiratory failure. There is now substantial evidence that the inflammatory process to IL-2 biotherapy is mediated by profound alterations in the biosynthesis of the free radicals nitric oxide and superoxide anion, and their reaction product peroxynitrite. An effective anti-inflammatory treatment would reduce the toxicity of IL-2 treatment and encourage increased use of this highly promising antineoplastic therapy. To address this unmet need, Inotek is developing a novel class of ultrapotent peroxynitrite decomposition catalysts. The lead compound, the metalloporphyrin INO-1080, is dramatically protective in experimental models of systemic inflammatory shock. The investigators propose to establish "proof-of-principle" that INO-1080 reduces the hemodynamic biochemical, and histopathologic alterations in an experimental model of IL-2 biotherapy. First, the investigators will ensure that INO-1080 does not adversely impact the anti-tumor activity of IL-2. They will carry out these investigations in a murine model of pulmonary metastasis by syngeneic melanoma cells. Second, they will document in a large animal model that INO-1080 ameliorates shock and tissue injury induced by IL-2. The investigators will utilize a well-established ovine model of IL-2 induced shock. The investigators expect INO-1080 will reduce tissue injury, capillary leak, pulmonary hypertension, lipid peroxidation, and nitrotyrosine formation, and attenuate the loss of systemic vascular resistance. Confirmation of efficacy, coupled with evidence that INO-1080 does not adversely impact on the anti-tumor activity of IL-2, would justify clinical testing in population with refractory malignant melanoma.

描述（由申请人提供）：IL-2难治性恶性肿瘤的生物疗法可能会产生心血管毒性和血液动力学改变，与败血性休克中的患者无法区分。这些宿主反应包括大规模的毛细血管泄漏综合征，表现为非心脏病肺水肿和随之而来的呼吸衰竭。现在有大量证据表明，IL-2生物疗法的炎症过程是由自由基一氧化氮和超氧化物阴离子的生物合成的深刻改变介导的，以及其反应产物过氧硝酸盐。有效的抗炎治疗将降低IL-2治疗的毒性，并鼓励人们增加对这种高度有希望的抗肿瘤疗法的使用。为了满足这种未满足的需求，Inotek正在开发一类新型的超能力过氧分解催化剂。在全身炎症性休克的实验模型中，铅化合物，金属磷脂INO-1080具有显着保护性。研究人员建议在IL-2生物疗法的实验模型中建立INO-1080的“原理证明”，以减少血液动力学生化和组织病理学改变。首先，研究人员将确保INO-1080不会对IL-2的抗肿瘤活性产生不利影响。他们将在合成性黑色素瘤细胞的肺转移鼠模型中进行这些研究。其次，他们将记录在大型动物模型中，INO-1080可以改善IL-2引起的冲击和组织损伤。研究人员将利用IL-2诱发冲击的良好卵巢模型。研究人员预计INO-1080将减少组织损伤，毛细血管泄漏，肺动脉高压，脂质过氧化和硝基酪氨酸的形成，并减轻全身血管耐药性的丧失。确认功效，再加上INO-1080不会对IL-2的抗肿瘤活性产生不利影响，这将证明对难治性恶性黑色素瘤的临床测试是合理的。