Novel anti-oxidant catalyst to treat IL-2 toxicity

描述（由申请人提供）：IL-2生物治疗难治性恶性肿瘤可能产生心血管毒性和血流动力学改变，这与感染性休克的情况难以区分。这些宿主反应包括大量毛细血管渗漏综合征，表现为非心源性肺水肿和随后的呼吸衰竭。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阴离子及其反应产物过氧亚硝酸盐的生物合成的深刻改变所介导的。有效的抗炎治疗将降低IL-2治疗的毒性，并鼓励增加使用这种非常有前途的抗肿瘤治疗。为了解决这一未满足的需求，Inotek正在开发一种新型的超高效过氧亚硝酸盐分解催化剂。先导化合物，金属卟啉INO-1080，在全身性炎性休克的实验模型中具有显著的保护作用。研究人员建议建立“原理证明”，即INO-1080在IL-2生物治疗的实验模型中降低了血液动力学、生化和组织病理学的改变。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。他们将在同基因黑色素瘤细胞肺转移的小鼠模型中进行这些研究。其次，他们将在大型动物模型中证明INO-1080可以改善IL-2诱导的休克和组织损伤。研究人员将利用一种成熟的IL-2诱导的绵羊休克模型。研究人员希望INO-1080能减少组织损伤、毛细血管渗漏、肺动脉高压、脂质过氧化和硝基酪氨酸的形成，并减轻全身血管阻力的丧失。疗效的确认，加上INO-1080不会对IL-2的抗肿瘤活性产生不利影响的证据，将证明在难治性恶性黑色素瘤人群中进行临床试验是合理的。

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.