Inhibition of Cardiac Device Induced Cellular Dysfunction in Pigs

描述（由申请人提供）：心脏器械的人工表面诱导接受旁路手术的患者的细胞活化和血小板功能障碍。虽然在此过程中可能会激活其他途径，但旁路途径（AP）激活似乎是生物材料表面诱导激活的全血模型中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循环模型，该模型证明了靶特异性mAb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。我们想利用猪的心肺转流模型来扩展这些新的发现，并诱导冠状动脉降支闭塞，以模拟临床环境。在通过CPB的循环期间和之后，预期过敏毒素、C3a和C5a以及活化的中性粒细胞、单核细胞和血小板的循环水平较高。结果，活化的中性粒细胞和单核细胞释放引起器官损伤的炎性介质，活化的血小板变得功能障碍。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计划在猪心肺转流模型中测试一种靶向特异性和高选择性单克隆抗体，该抗体可阻断AP活化、细胞活化、血小板功能障碍和失血。在本提案中，将使用拟定的猪心肺转流模型评价这些炎症事件对多器官衰竭的集体影响。在公认的CPB闭塞猪模型中进行概念验证是进一步开发NovelMed的电极导线生物制剂并将其推向临床应用的关键一步。 公共卫生相关性：每年花费数十亿美元用于预防接受心肺转流心脏手术以纠正冠状动脉部分或完全闭塞的心脏病患者的全身炎症反应。如果冠状动脉降支完全闭塞，则可能发生心力衰竭。目前尚无获批的CPB相关炎症反应的预防性治疗药物。当血流受阻时，缺血再灌注损伤可加重反应。目前尚无获批的IRI或CPB相关炎症反应治疗药物。NovelMed计划开发YalcioMab作为一种治疗方法，以预防在心肺转流术的猪缺血模型中由于AP激活而发生的并发症。

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.