FcRn-enabling strategies for improved thrombolytic therapy

改善溶栓治疗的 FcRn 启用策略

基本信息

批准号：
10684075
负责人：
Patrick McKenna Glassman
金额：
$ 24.9万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10684075
关键词：
Acute Adverse effects Affect Affinity Albumins Area Binding Biodistribution Biological Response Modifier Therapy Biomedical Research Blood Cells Blood Circulation Catabolism Charge Circulation Clinical Coagulation Process Coupling Cytolysis Data Development Diffusion Disease Dose Drug Delivery Systems Drug Kinetics Drug usage Endosomes Engineering Erythrocytes Event Eye Faculty Fc Receptor Filtration Functional disorder Genetic Grant Half-Life Hemorrhage Hemostatic Agents Hemostatic function Immunoglobulin G Individual Infusion procedures Injections Intervention Ischemic Stroke Kidney Kinetics Knockout Mice Knowledge Label Libraries Life Life Extension Ligand Binding Ligands Mediating Mentors Modeling Molecular Conformation Mus Mutation Myocardial Infarction Nature Pathologic Pathway interactions Patient-Focused Outcomes Penetration Pennsylvania Pharmaceutical Preparations Pharmacodynamics Pharmacological Treatment Physiological Plasma Plasma Proteins Plasminogen Activator Polymers Property Protein Engineering Proteins Pulmonary Embolism Recycling Research Resources Risk Role Safety Serum Proteins Structure Testing Therapeutic Therapeutic Uses Thrombin Thrombolytic Therapy Thrombosis Thrombus Time Tissues Transcend Universities Urokinase antibody engineering biological systems blood fractionation chemical conjugate compliance behavior cost design improved in silico in vivo inhibitor insight mathematical model member mouse model mutant nanobodies neonatal Fc receptor novel pharmacologic predictive modeling prophylactic receptor risk/benefit ratio side effect therapeutic protein thrombolysis thrombotic treatment strategy uptake

项目摘要

PROJECT SUMMARY/ABSTRACT While clinical use of therapeutic proteins has grown exponentially in recent decades, utility is often limited by unfavorable pharmacokinetics (PK), mediated by rapid elimination. One approach to overcome this limitation is half-life extension (HLE), achieved by attachment of biotherapeutics to polymers (PEG), plasma proteins (albumin, IgG), and blood cells. There is a paucity of data describing the impact of properties of cargo proteins and HLE-conferring ligands on PK of proteins tested using these strategies. One area where HLE has the potential to advance clinical therapy is acute, life-threatening, thrombosis (pulmonary embolism, ischemic stroke, etc.). The only pharmacologic treatment available for treatment of this condition is infusion of plasminogen activators, which have an unfavorable pharmacologic profile, mediated by a half-life of minutes, rapid inactivation in plasma, and severe adverse effects (e.g. hemorrhagic transformation). Pilot data demonstrates that conjugation of a derivative of urokinase selectively activated in thrombin-rich pathological thrombi (scuPA-T) to an albumin-binding nanobody (Nb) leads to PK that is identical to RBC-binding scuPA-T, an approach pioneered by Drs. Muzykantov and Cines, albeit with distribution in the plasma rather than the cellular fraction of blood. The central hypothesis of this proposal is that coupling of scuPA-T to albumin-binding ligands will provide prolonged circulation, mediated by the neonatal Fc receptor (FcRn), and selective thrombolysis of pathological thrombi, sparing hemostatic plugs from lysis. In the mentored stage, the impact of properties of the cargo drug on FcRn-enabled HLE will be identified, using FcRn knockout mice to directly elucidate the FcRn-mediated component of HLE conferred by albumin binding (Aim 1; K99). Based on pilot data, safety and efficacy of albumin-binding scuPA-T will be studied in a mouse model of pulmonary embolism. These results will be used to develop a predictive modeling platform that will be used to for further engineering and PK optimization of HLE-scuPA-T constructs (Aim 2; K99). With an eye on mechanistic and translational advancement of this strategy, the role of albumin-binding affinity on the PK of scuPA-T will be defined, using a newly developed library of nanobodies (Aim 3; R00). Additionally, thrombin-cleavable HLE ligands will be devised, permitting selective release of scuPA-T in thrombi, improving diffusion into clots and lysis (Aim 3; R00). Overarching themes of this proposal include identification of critical features of albumin-mediated HLE and mechanism-based modeling to guide optimization and reengineering of protein therapeutics. A mentoring team has been identified with expertise spanning the areas of research in this grant, namely, thrombosis and hemostasis, antibody engineering, and mathematical modeling of biological systems. Mentored research will be conducted at the University of Pennsylvania, which has a highly collegial and collaborative faculty and extensive resources available to conduct the proposed research. This proposal is geared towards gaining the expertise necessary to be successful as a tenured faculty member conducting high quality biomedical research.

项目概要/摘要虽然近几十年来治疗性蛋白质的临床应用呈指数级增长，但实用性往往受到以下因素的限制：由快速消除介导的不利药代动力学（PK）。克服此限制的一种方法是半衰期延长（HLE），通过将生物治疗药物附着到聚合物（PEG）、血浆蛋白上来实现（白蛋白、IgG）和血细胞。描述货物蛋白特性影响的数据很少和 HLE 赋予配体对使用这些策略测试的蛋白质的 PK。 HLE 拥有的领域之一推进临床治疗的潜力是急性的、危及生命的、血栓形成（肺栓塞、缺血性中风、 ETC。）。可用于治疗这种情况的唯一药物治疗是输注纤溶酶原激活剂，具有不利的药理学特征，由几分钟的半衰期介导，快速失活血浆中的浓度，以及严重的不良反应（例如出血性转化）。试点数据表明在富含凝血酶的病理性血栓中选择性激活的尿激酶衍生物（scuPA-T）与白蛋白结合纳米抗体 (Nb) 产生的 PK 与红细胞结合 scuPA-T 相同，这是一种首创的方法由博士。 Muzykantov 和 Cines，尽管分布在血浆中而不是血液的细胞部分中。该提案的中心假设是 scuPA-T 与白蛋白结合配体的偶联将提供由新生儿 Fc 受体 (FcRn) 介导的延长循环和选择性溶栓病理性血栓，避免止血塞溶解。在指导阶段，影响将使用 FcRn 敲除小鼠直接识别 FcRn 启用的 HLE 上的货物药物的特性阐明白蛋白结合赋予的 FcRn 介导的 HLE 成分（目标 1；K99）。基于试点将在小鼠肺栓塞模型中研究白蛋白结合 scuPA-T 的数据、安全性和有效性。这些结果将用于开发预测建模平台，该平台将用于进一步的工程设计 HLE-scuPA-T 构建体的 PK 优化（目标 2；K99）。着眼于机械和转化为了推进这一策略，将使用以下方法定义白蛋白结合亲和力对 scuPA-T PK 的作用：新开发的纳米抗体库（目标 3；R00）。此外，凝血酶可裂解的 HLE 配体将设计，允许在血栓中选择性释放 scuPA-T，改善扩散到凝块和溶解（目标 3；R00）。该提案的首要主题包括白蛋白介导的 HLE 的关键特征的识别和基于机制的建模，指导蛋白质疗法的优化和重新设计。辅导团队已确定具有跨越本拨款研究领域的专业知识，即血栓形成和止血、抗体工程和生物系统的数学建模。指导研究将是该研究在宾夕法尼亚大学进行，该大学拥有高度合作的师资队伍和广泛的研究成果。可用于开展拟议研究的资源。该提案旨在获得专业知识作为一名成功从事高质量生物医学研究的终身教员所必需的。