Depletion of Dendritic Cells by Immunotoxin as Therapy for Myocardial Infarction

通过免疫毒素消耗树突状细胞来治疗心肌梗塞

基本信息

批准号：
8523960
负责人：
MICHAEL W FANGER
金额：
$ 99.81万
依托单位：
CELDARA MEDICAL, LLC
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8523960
关键词：
American Antigen-Presenting Cells Autopsy Blood Bone Marrow Brain C57BL/6 Mouse Cardiac Cause of Death Chest Chimeric Proteins Chronic Clinic Clinical Paths Collaborations Complex Dendritic Cells Development Dose Equilibrium Feces Goals Heart Histology Hospitalization Hospitals Human ITGAX gene Immune response Immunologist Immunotoxin Therapy Immunotoxins In Vitro Inflammatory Response Ischemia Kidney Lead Letters Link Liver Lung Marketing Maximum Tolerated Dose Measures Modeling Mus Myocardial Infarction Myocardial rupture Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Preparation Pseudomonas aeruginosa toxA protein Quality of life Reperfusion Therapy Role Safety Schedule Seminal Spleen Surgical Models Theoretical model Therapeutic Time Tissues Toxic effect Transgenic Mice United States Urine Work Wound Healing authority cell type combat design effective therapy efficacy testing heart function improved in vivo mannose receptor morphometry mortality mouse model myocardial infarct sizing novel therapeutic intervention pre-clinical research clinical testing response safety testing

项目摘要

DESCRIPTION (provided by applicant): MI is the leading cause of death in the developed world, including the United States. In 2005 over 8.1 million Americans had an MI; 30% died before reaching hospital and 10% died after hospitalization. It is the 70% who reach hospital that we believe we can help - a million lives in the balance and an improved quality of life for millions more - in the US alone. The goal of these studies is to bring a novel therapeutic approach to myocardial infarction (MI) and ischemia-reperfusion (IR) wound healing to the clinic. The approach is both strikingly effective and exactly contrary to conventional wisdom. In a murine model we have shown that temporary depletion of dendritic cells (DC) during MI wound healing results in an 80% improvement in cardiac function and a 65% reduction in MI size. Cardiac function is the greatest determinant of survival post-MI. We will continue the development of this seminal discovery into a human therapy by completing preclinical murine safety and efficacy testing in our proprietary transgenic (TG) mouse model. The product is a human mannose receptor (hMR) targeted fusion protein designed to deplete DC post-MI. The previously unrecognized role for DC in MI wound healing is noteworthy for at least two reasons. First, immunologists and cardiologists have conventionally thought that depletion of DC post-MI would result in catastrophe: i.e. weakened tissues (cardiac rupture) and no new vasculature. Second, the beneficial effect of DC depletion is startling in its magnitude (up to 80% improvement in heart function vs. controls). A treatment that temporarily depletes DC is nothing short of a paradigm shift that we believe will lead to a sharp reduction in mortality and profound improvements in the lives of patients. In Phase I, we demonstrated safety and efficacy of a hMR-targeted immunotoxin in a highly human- relevant murine model. In Phase II we will complete pre-clinical testing through rigorous dose optimization as well as safety and efficacy studies in murine models and human histology and blood work (in vitro). The compelling safety and efficacy results combined with the lack of a suitable second species means the work described herein is expected to be sufficient for a successful IND application. We are engaged in continuing discussions with both clinicians and the FDA regarding this pre-clinical path as well as the design of a Phase I clinical trial. We will bring the drug to market in collaboration with or strategic partners. Initial results suggest that this strategy may lead to a sharp reduction in mortality and profound improvements in the lives of victims of MI.

描述（由申请人提供）：心肌梗死是发达国家（包括美国）的首要死因。 2005 年，超过 810 万美国人患有心肌梗死； 30%在到达医院之前死亡，10%在住院后死亡。我们相信我们可以帮助到医院的 70% 的患者——仅在美国，就有 100 万人的生命悬而未决，并改善了数百万人的生活质量。这些研究的目标是将一种新颖的心肌梗死（MI）和缺血再灌注（IR）伤口愈合治疗方法引入临床。这种方法非常有效，而且与传统观念完全相反。在小鼠模型中，我们发现，在 MI 伤口愈合过程中暂时消耗树突状细胞 (DC) 可以使心脏功能改善 80%，并使 MI 大小缩小 65%。心脏功能是心肌梗死后生存的最大决定因素。我们将通过在我们专有的转基因（TG）小鼠模型中完成临床前小鼠安全性和功效测试，继续将这一开创性发现发展为人类疗法。该产品是一种人甘露糖受体 (hMR) 靶向融合蛋白，旨在消除 MI 后的 DC。 DC 在心肌梗死伤口愈合中的作用此前未被认识到，这一点值得注意，至少有两个原因。首先，免疫学家和心脏病学家传统上认为心肌梗死后 DC 的消耗会导致灾难：即组织衰弱（心脏破裂）并且没有新的脉管系统。其次，DC 耗竭的有益效果令人震惊（与对照组相比，心脏功能改善高达 80%）。暂时消耗 DC 的治疗方法无异于一种范式转变，我们相信这将导致死亡率急剧下降并显着改善患者的生活。在第一阶段，我们在与人类高度相关的小鼠模型中证明了 hMR 靶向免疫毒素的安全性和有效性。在第二阶段，我们将通过严格的剂量优化以及小鼠模型和人类组织学和血液工作（体外）的安全性和有效性研究来完成临床前测试。令人信服的安全性和有效性结果加上缺乏合适的第二个物种意味着本文描述的工作预计足以成功进行 IND 申请。我们也正在与临床医生和 FDA 就这一临床前路径进行持续讨论作为 I 期临床试验的设计。我们将与战略合作伙伴合作将该药物推向市场。初步结果表明，这一策略可能会大幅降低死亡率并显着改善心肌梗死受害者的生活。