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

• 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
• 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

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， 存活率，大多数这些疾病仍然总是致命的，由于显着的心脏和肾脏负荷的器官- 诊断时存在的淀粉样蛋白。因此，迫切需要能够 去除患者组织淀粉样蛋白，以补充旨在减少淀粉样蛋白产生的当前疗法， 形成蛋白质。免疫治疗，使用淀粉样蛋白结合抗体或抗体片段，如肽体 （肽融合抗体片段），以募集能够清除淀粉样蛋白的细胞，仍然是治疗淀粉样蛋白的主要方法。 选择实现淀粉样蛋白清除。然而，这些试剂的翻译需要证明 患者体内的淀粉样蛋白结合。这可以通过分子成像来实现，从而增强临床试验设计 和病人的选择。 我们的目标是开发和表征一种新的泛淀粉样蛋白结合的人肽体， 具有良好的成像能力和清除组织淀粉样蛋白的能力。我们建议的药物将我们的淀粉样蛋白-reac- 我们已经在一项1期成像试验中显示了活性合成肽与患者的淀粉样蛋白结合。 这些将与人免疫球蛋白Fc结构域融合以产生功能性肽体，其可以 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和特点的鼠肽体，表现出良好的淀粉样蛋白结合，并刺激宏观， 体外培养。该提议将评估各种肽在人源化肽体背景下的功效。 其目标是确定临床翻译的主要候选人。肽体的较小尺寸，相对于 与抗体的结合可以使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， 肽的选择将影响许多影响治疗效果的生物学因素。 我们已经开发了几种定量测定来评估肽体功能， 如纤维和患者来源的人淀粉样蛋白提取物。一种良好表征的全身性 淀粉样变性将用于评价放射性标记的肽体与淀粉样蛋白的体内特异性结合， SPECT成像、组织生物分布测量和显微放射自显影。光学成像的双重 将荧光团标记的人淀粉样蛋白植入小鼠体内， 吞噬作用和淀粉样蛋白的溶解。其他试验，包括稳定性、结构 计划了吞噬作用的表征、可开发性和诱导。 我们的长期目标是产生一种免疫肽体， 成像剂，以加强发展计划，并作为一个病人的选择工具，在临床上。的 识别将受益于肽体疗法的患者和有效的泛淀粉样蛋白治疗的组合 反应性试剂可为患有这些疾病的患者带来显著的临床益处。