Inhibition of Cardiac Device Induced Cellular Dysfunction in Pigs

描述(由申请人提供)：心脏装置的人工表面在接受搭桥手术的患者中诱导细胞激活和血小板功能障碍。在生物材料表面诱导激活的全血模型中，其他途径可能被激活，而替代途径(AP)激活似乎是细胞激活和血小板功能障碍的重要机制之一。我们的假设是基于体外全血循环模型，该模型显示靶向特异性单抗几乎完全抑制了细胞激活、血小板功能障碍和炎症介质的释放。我们希望利用猪的体外循环模型来扩展这些新的发现，并诱导冠状动脉下降，以模拟临床情况。在体外循环期间和之后，预计循环中会出现高水平的过敏性毒素、C3a和C5a，以及激活的中性粒细胞、单核细胞和血小板。结果，激活的中性粒细胞和单核细胞释放炎症介质，导致器官损伤，激活的血小板功能障碍。这些事件可导致血栓形成、血小板减少和严重出血并发症。NovelMed打算在猪的体外循环模型中测试一种靶向特异性和高选择性的单抗，该抗体可以阻断AP激活、细胞激活、血小板功能障碍和失血。这些炎症事件对多器官衰竭的集体影响将在本提案中使用拟议的猪体外循环模型进行评估。在公认的体外循环猪闭塞模型中进行概念验证是进一步发展NovelMed的铅生物学并将其推向临床的关键一步。 公共卫生相关性：每年花费数十亿美元预防心脏手术患者的全身炎症反应，这些患者接受体外循环心脏手术，以纠正冠状动脉的部分或完全闭塞。如果冠状动脉降支完全闭塞，就可能发生心力衰竭。目前还没有被批准的预防CPB相关炎症反应的疗法。当血流处于闭塞状态时，缺血再灌注损伤可加重反应。目前还没有批准的治疗IRI或CPB相关炎症反应的方法。NovelMed打算开发YalcioMab作为一种治疗方法，以防止在体外循环下激活AP导致的猪缺血模型中发生的并发症。

DESCRIPTION (provided by applicant): Artificial surfaces of cardiac devices induce cellular activation and platelet dysfunction in patients undergoing bypass procedure. While other pathways may be activated during this process, alternative pathway (AP) activation appears to be one of the important mechanisms for cellular activation and platelet dysfunction in the whole blood model of biomaterial surface-induced activation. Our hypothesis is based on the ex vivo whole blood circulation model demonstrating near complete inhibition of cellular activation, platelet dysfunction, and release of inflammatory mediators by a target-specific mAb. We would like to extend these novel findings utilizing a pig model of cardiopulmonary bypass with an induced occlusion of the descending coronary artery to mimic the clinical setting. During and following circulation through the CPB, high circulating levels of anaphylatoxins, C3a and C5a, and activated neutrophils, monocytes, and platelets are expected. As a result, activated neutrophils and monocytes release inflammatory mediators that cause organ damage and activated platelets become dysfunctional. These events can cause thrombosis, thrombocytopenia, and severe bleeding complications. NovelMed intends to test a target-specific and highly selective monoclonal antibody that blocks AP activation, cellular activation, platelet dysfunction, and blood loss in a pig model of cardiopulmonary bypass. Collective effects of these inflammatory events on multiple organ failure will be evaluated in this proposal using the proposed pig cardiopulmonary bypass model. Proof of concept in a well-accepted pig model of occlusion with CPB is a critical step for furthering the development of NovelMed's lead biologic and moving it towards clinical use. PUBLIC HEALTH RELEVANCE: Billions of dollars are spent annually to prevent systemic inflammatory response in cardiac patients undergoing cardiac procedures with cardiopulmonary bypass to correct partial or complete occlusion of the coronary artery. Cardiac failure can occur if the coronary descending artery is completely occluded. There is currently no approved prophylactic therapeutic for CPB-associated inflammatory responses. When the blood flow in the occluded, ischemia reperfusion injury can exacerbate the response. There is no approved therapeutic for IRI or for CPB associated inflammatory response. NovelMed intends to develop YalcioMab as a treatment to prevent complications that occur as a result of AP activation in the pig model of ischemia with cardiopulmonary bypass.