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: 10353419
• 负责人: JONATHAN S WALL
• 金额: $ 44.33万
• 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/10353419
• 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; Lead; 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; base; clinical development; clinical implementation; clinical translation; extracellular; fluorophore; imaging agent; imaging study; improved; in vivo; lead candidate; macrophage; microautoradiography; molecular imaging; mouse model; next generation; novel; optical imaging; 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.

尽管几十年来对淀粉样蛋白疾病的发病机制进行了研究，患者的病情也有所改善 存活下来，这些疾病中的大多数仍然是致命的，因为器官的重大心脏和肾脏负荷- 诊断时出现的致病淀粉样蛋白。因此，迫切需要具备以下条件的代理商 去除患者组织淀粉样蛋白，以补充目前旨在减少淀粉样蛋白产生的治疗方法- 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，如多肽 (多肽融合抗体片段)，招募能够清除淀粉样蛋白的细胞，仍然是治疗的主要方法 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 患者中的淀粉样蛋白结合。这可以通过分子成像来实现，从而增强临床试验设计 以及临床上的病人选择。 我们的目标是开发和鉴定一种新的与泛淀粉样蛋白结合的人多肽抗体，这种多肽抗体很容易被识别。 具有成像能力和清除组织淀粉样蛋白的能力。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展示了它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，产生功能性多肽抗体，它可以 通过Fc受体激活巨噬细胞，促进组织淀粉样蛋白的清除。我们已经开发了- OpED并鉴定了一种表现出良好的淀粉样蛋白结合并刺激巨噬细胞的鼠多肽抗体 体外培养的噬菌体。这项建议将在人源化多肽的背景下评估各种多肽的有效性。 IES的目标是确定临床翻译的主要候选者。相对较小的多肽 TO抗体可能会使组织淀粉样蛋白更有效地积聚，特别是在心脏和肾脏，以及 多肽的选择会影响许多影响疗效的生物学因素。 我们已经开发了几种定量分析方法来评估多肽功能，使用合成的淀粉样蛋白- 比如纤维和病人提取的人类淀粉样蛋白。一种具有良好特征的系统性红斑狼疮小鼠模型 淀粉样变性将被用来评估体内放射性标记多肽与淀粉样蛋白的特异性结合 SPECT成像、组织生物分布测量和显微放射自显影。DUAL的光学成像 植入小鼠体内的荧光素标记的人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、结构性 吞噬作用的特征、发展和诱导是计划的。 我们的长期目标是产生一种可以作为伴侣的免疫治疗性多肽 增强显像剂的开发程序，并在临床上作为患者选择的工具。这个 确定将受益于多肽治疗的患者和有效的泛淀粉样蛋白的组合 反应性试剂可为这些疾病的患者带来显著的临床益处。