Development of a Theranostic Immunotherapy for Systemic Amyloidosis

系统性淀粉样变性治疗诊断免疫疗法的开发

基本信息

批准号：
10579884
负责人：
JONATHAN S WALL
金额：
$ 44.82万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10579884
关键词：
Affinity Amyloid Amyloid Fibrils Amyloidosis Animals Antibodies Binding Biodistribution Biological Assay Biological Factors Cardiac Cells Cessation of life Chinese Hamster Ovary Cell Clinic Clinical Clinical Trials Clinical Trials Design Companions Complement Deposition Development Diagnosis Disease Disease remission Drug Design Drug Kinetics Evaluation Excision Exhibits Family Fc Immunoglobulins Fc Receptor Fc domain Functional disorder Goals Half-Life Heart Heterogeneity Histologic Human IgG1 Image Immune system Immunoglobulin Fragments Immunologics Immunotherapeutic agent Immunotherapy Implant In Vitro Incidence Iodine Kidney Label Macrophage Mass Spectrum Analysis Measurement Mediating Methods Monoclonal Antibodies Monoclonal Antibody Therapy Morbidity - disease rate Mus Organ Outcome PET/CT scan Pathogenesis Pathology Patient Selection Patient-Focused Outcomes Patients Peptides Performance Peripheral Nerves Phagocytes Phagocytosis Phagocytosis Induction Phagolysosome Phase Plasma Population Production Program Development Protein Precursors Proteins Radiolabeled Reagent Research Specificity Survival Rate Therapeutic Time Tissues Translations Treatment Efficacy Variant X-Ray Computed Tomography amyloid imaging clinical development clinical implementation clinical translation efficacy evaluation extracellular fluorophore imaging agent imaging study improved in vivo lead candidate microautoradiography molecular imaging mouse model next generation novel optical imaging patient screening patient stratification prevent programs recruit single photon emission computed tomography success synthetic peptide theranostics therapy design tool trial design uptake whole body imaging

项目摘要

Despite decades of research into the pathogenesis of amyloid disease, and improvements in patient survival, most of these disorders remain invariably fatal due to significant cardiac and renal loads of organ- compromising amyloid present at the time of diagnosis. Consequently, there is an urgent need for agents that remove patient tissue amyloid, to complement current therapies designed to reduce the production of amyloid- forming protein. Immunotherapy, using amyloid-binding antibodies or antibody fragments such as peptibodies (peptide-fused antibody fragments), to recruit cells capable of clearing amyloid, is still the principle method of choice for achieving amyloid clearance. However, translation of these reagents requires demonstration of amyloid-binding in patients. This can be achieved by molecular imaging, thereby enhancing clinical trial design and patient selection in the clinic. Our goal is to develop and characterize a novel pan-amyloid-binding human peptibody that is readily la- beled of imaging and capable of clearing tissue amyloid. The agents we propose incorporate our amyloid-reac- tive synthetic peptides, which we have already shown bind amyloid in patients in a Phase 1 imaging trial. These will be fused to a human immunoglobulin Fc domain to generate a functional peptibodies, which can engage macrophages through Fc-receptors and facilitate clearance of tissue amyloid. We have already devel- oped and characterized a murine peptibody that exhibits excellent amyloid binding and stimulates macro- phages in vitro. This proposal will assess the efficacy of various peptides in the context of humanized peptibod- ies with the goal of identifying a lead candidate for clinical translation. The smaller size of peptibodies, relative to antibodies may allow more efficient accumulation in tissue amyloid, notably in the heart and kidney, and the choice of peptide will influence many biological factors that impact therapeutic efficacy. We have developed several quantitative assays to assess peptibody function using both synthetic amyloid- like fibrils and patient-derived human amyloid extracts. A well-characterized murine model of systemic amyloidosis will be used to evaluate the specific binding of radiolabeled peptibody with amyloid in vivo by SPECT imaging, tissue biodistribution measurements, and microautoradiography. Optical imaging of dual fluorophore-labeled human amyloid implanted in mice will be used to assess macrophage-mediated phagocytosis and dissolution of amyloid in real time. Other assays including stability, structural characterization, developability, and induction of phagocytosis are planned. Our long term goal is to generate an immunotherapeutic peptibody that can also serve as a companion imaging agent to enhance the development program and serve as a patient-selection tool in the clinic. The combination of identifying patients that would benefit from peptibody therapy, and an efficacious pan-amyloid reactive reagent could result in significant clinical benefit for patients with these diseases.

尽管对淀粉样蛋白疾病的发病机制进行了数十年的研究，并且患者的病情有所改善生存，由于器官的显着心脏和肾脏负荷，大多数这些疾病仍然是致命的。诊断时存在损害淀粉样蛋白。因此，迫切需要代理去除患者组织淀粉样蛋白，以补充当前旨在减少淀粉样蛋白产生的疗法形成蛋白质。免疫疗法，使用淀粉样蛋白结合抗体或抗体片段，例如肽体（肽融合抗体片段），招募能够清除淀粉样蛋白的细胞，仍然是主要方法实现淀粉样蛋白清除的选择。然而，这些试剂的翻译需要证明患者体内淀粉样蛋白结合。这可以通过分子成像来实现，从而增强临床试验设计以及诊所的患者选择。我们的目标是开发并表征一种新型的泛淀粉样蛋白结合人类肽体，该肽体易于制备成像的底部并且能够清除组织淀粉样蛋白。我们建议的药物结合了我们的淀粉样蛋白反应- 活性合成肽，我们已经在一期成像试验中证明其与患者体内的淀粉样蛋白结合。这些将与人免疫球蛋白 Fc 结构域融合以生成功能性肽体，该肽体可以通过 Fc 受体与巨噬细胞结合并促进组织淀粉样蛋白的清除。我们已经开发了—— OPed 并表征了一种鼠肽体，该肽体表现出优异的淀粉样蛋白结合并刺激宏观体外噬菌体。该提案将评估各种肽在人源化肽抗体背景下的功效。其目标是确定临床转化的主要候选者。肽体的尺寸相对较小抗体可能会允许淀粉样蛋白在组织中更有效地积累，特别是在心脏和肾脏中，并且肽的选择将影响许多影响治疗效果的生物学因素。我们开发了几种定量测定法，使用合成淀粉样蛋白来评估肽体功能如原纤维和患者来源的人类淀粉样蛋白提取物。一个良好表征的全身系统性小鼠模型淀粉样变性将用于评估放射性标记肽体与淀粉样蛋白在体内的特异性结合 SPECT 成像、组织生物分布测量和显微放射自显影。双光学成像植入小鼠体内的荧光团标记的人类淀粉样蛋白将用于评估巨噬细胞介导的实时吞噬和溶解淀粉样蛋白。其他分析包括稳定性、结构分析吞噬作用的表征、可开发性和诱导均已计划。我们的长期目标是产生一种免疫治疗性肽体，它也可以作为伴侣显像剂可增强开发计划并作为临床患者选择工具。这结合识别将从肽体治疗中受益的患者和有效的泛淀粉样蛋白反应试剂可以为患有这些疾病的患者带来显着的临床益处。