Inhibition of Cardiac Device Induced Cellular Dysfunction in Pigs

描述（由申请人提供）：心脏装置的人造表面诱导旁路手术患者的细胞活化和血小板功能障碍。虽然在这一过程中可能会激活其他途径，但在生物材料表面诱导激活的全血模型中，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。我们的假设是基于离体全血液循环模型，该模型显示了一种靶向特异性单抗对细胞活化、血小板功能障碍和炎症介质释放的几乎完全抑制。我们想扩展这些新发现，利用猪体外循环模型与诱导冠状动脉降支闭塞来模拟临床环境。在CPB循环期间和之后，预计会出现高水平的过敏毒素、C3a和C5a以及活化的中性粒细胞、单核细胞和血小板。因此，活化的中性粒细胞和单核细胞释放炎症介质，导致器官损伤和活化的血小板功能失调。这些事件可引起血栓、血小板减少症和严重的出血并发症。NovelMed计划在猪体外循环模型中测试一种靶向特异性和高选择性的单克隆抗体，该抗体可阻断AP活化、细胞活化、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。在被广泛接受的CPB闭塞猪模型中验证概念是进一步发展NovelMed领先生物制剂并将其推向临床应用的关键一步。

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.