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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.

尽管对淀粉样蛋白病的发病机制进行了数十年的研究，并在患者中有所改善