Pre-targeting immunotherapy for light chain (AL) amyloidosis

轻链 (AL) 淀粉样变性的预靶向免疫治疗

基本信息

批准号：
9292835
负责人：
JONATHAN S WALL
金额：
$ 35万
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：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9292835
关键词：
Address Affinity Amyloid Amyloid Fibrils Amyloidosis Antibodies Autologous Stem Cell Transplantation Binding Biodistribution Biological Assay Cardiac Cessation of life Clinical Clinical Management Clinical Trials Clone Cells Complement Complex Deposition Diagnosis Disease Disease model Disease remission Epitopes Etiology Excision Functional disorder Goals Heparin Binding Human Immunologics Immunotherapeutic agent Immunotherapy In Vitro Libraries Light Light-Chain Immunoglobulins Linear Sequence Epitopes Measurement Mediating Metadata Methods Monoclonal Antibodies Morbidity - disease rate Multiple Myeloma Mus Organ Pathogenesis Pathologic Pathology Patients Peptides Phase I Clinical Trials Plasma Cells Prealbumin Proteins Protocols documentation Radiolabeled Reagent Research Resources Secure Series System Testing Therapeutic Uses Therapeutic antibodies Tissues Visceral Work base chemotherapy experience extracellular imaging agent in vitro Assay in vivo loss of function mortality mouse model novel outcome forecast primary amyloidosis of light chain type programs single photon emission computed tomography synthetic peptide treatment response

项目摘要

Light chain amyloidosis (AL) is the most common form of systemic amyloid disease, with an estimated 4,500 new cases each year in the US. AL is a complex plasma cell-related disease characterized by the formation of insoluble, immunologically-inert protein fibrils composed of misfolded monoclonal immunoglobulin light chain components Extracellular amyloid fibrils can deposit in any organ or tissue causing loss of function, morbidity, and, ultimately, death. Despite decades of active research and increased understanding of pathological mechanisms, AL remains incurable, and the prognosis for patients is poor with a median survival of less than 3 years. Effective clinical management of patients with AL requires, in addition to chemotherapy, removal of destructive tissue amyloid so that organ function can be allowed to recover. A proven method of amyloid removal is opsonization of the deposits by using amyloid-reactive antibodies. Although promising, preliminary results from two ongoing clinical trials of anti-AL amyloid antibodies indicate that they may be effective in only approximately 50% of patients. To address this deficiency we have developed a strategy that uses a novel bifunctional “peptope” – that combines a pan-amyloid-reactive peptide and a linear epitope sequence – to enhance the efficacy and extend the utility of current immunotherapeutic antibodies, such as the chimeric reagent, 11-1F4. In this proposal, we will evaluate and characterize a peptope comprised of the amyloid-reactive peptide p5+14 and a high affinity epitope (0.3 nM) recognized by 11-1F4. Using a battery of quantitative in vitro binding assays as well as in vivo dual-energy SPECT imaging and tissue biodistribution studies, we will quantify the efficacy of peptope-mediated amyloid targeting of the 11-1F4 antibody. Finally, we will investigate, using mouse models of systemic and localized amyloidosis, the ability of peptope-antibody immunotherapy to induce amyloid removal in vivo. We anticipate that this novel, two-stage opsonizing immunotherapy will enhance the efficacy of 11-1F4-based therapy in patients with AL and potentially extend the utility of this antibody to other forms of systemic amyloid disease. AL amyloidosis remains a devastating and incurable disease. The goal of this application is to develop bifunctional peptides that simultaneously bind amyloid and the 11-1F4 monoclonal antibody to generate a novel immunotherapy for AL amyloidosis. This approach will complement and extend current antibody-based therapies for amyloid removal, thereby restoring organ function and securing long term survival and remission for patients with AL.

轻链淀粉样变性（AL）是全身性淀粉样蛋白疾病的最常见形式，估计为4,500 每年在美国的新案件。 Al是一种复杂的浆细胞相关疾病，其特征是形成由错误折叠的单克隆免疫球蛋白轻链组成的不溶性，免疫启动蛋白质原纤维成分细胞外淀粉样蛋白原纤维可以沉积在任何器官或组织中，导致功能丧失，发病率，最终是死亡。尽管进行了数十年的积极研究并增加了对病理的理解 AL的机制仍然无法治愈，患者的预后较差，中位存活率小于3 年。除了化学疗法外，有效的AL患者还需要去除破坏性组织淀粉样蛋白，以便可以使器官功能恢复。淀粉样蛋白的一种经过验证的方法去除是通过使用淀粉样蛋白反应性抗体对沉积物的调整。虽然很有希望，但初步抗淀粉样抗体的两项正在进行的临床试验的结果表明，它们可能有效大约50％的患者。为了解决这种缺陷，我们制定了一种使用小说的策略双功能“肽” - 结合泛淀粉样蛋白反应性肽和线性表位序列 - 提高效率并扩展当前免疫治疗抗体的效用，例如嵌合试剂，11-1F4。在此提案中，我们将评估和表征淀粉样蛋白反应性肽的辣椒 P5+14和11-1f4识别的高亲和力表位（0.3 nm）。使用一系列体外定量结合测定以及体内双能SPECT成像和组织生物分布研究，我们将量化胡椒介导的11-1F4抗体的淀粉样蛋白靶向的效率。最后，我们会的使用全身性和局部淀粉样变性的小鼠模型，调查胡椒抗体的能力免疫疗法在体内诱导淀粉样蛋白去除。我们预计这本小说，两阶段的打击免疫疗法将提高基于AL的患者的11-1f4疗法的效率，并可能延长这种抗体对其他形式的全身性淀粉样蛋白疾病的效用。 Al淀粉样变性仍然是一种毁灭性和无法治愈的疾病。该应用的目的是开发仅结合淀粉样蛋白和11-1f4单克隆抗体的双功能肽产生一种新颖 AL淀粉样变性的免疫疗法。这种方法将完成并扩展基于电流的基于抗体去除淀粉样蛋白的疗法，从而恢复器官功能并确保长期生存和缓解适用于AL的患者。