Pre-targeting immunotherapy for light chain (AL) amyloidosis

轻链 (AL) 淀粉样变性的预靶向免疫治疗

• 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
• 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

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) 是系统性淀粉样蛋白疾病最常见的形式，估计有 4,500 美国每年都有新病例。 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惰性蛋白原纤维 细胞外淀粉样原纤维可以沉积在任何器官或组织中，导致功能丧失、发病、 以及最终的死亡。尽管数十年的积极研究和对病理学的了解不断增加 AL 仍无法治愈，患者预后较差，中位生存期低于 3 年。 AL 患者的有效临床管理除了化疗外还需要去除 破坏组织的淀粉样蛋白，从而使器官功能得以恢复。一种经过验证的淀粉样蛋白方法 去除是通过使用淀粉样反应性抗体对沉积物进行调理。尽管前景广阔，但初步 两项正在进行的抗 AL 淀粉样蛋白抗体临床试验的结果表明，它们可能有效 仅约50%的患者。为了解决这个缺陷，我们开发了一种策略，使用一种新颖的方法 双功能“肽”——结合了泛淀粉样蛋白反应肽和线性表位序列—— 增强现有免疫治疗抗体的功效并扩展其用途，例如嵌合抗体 试剂，11-1F4。 在本提案中，我们将评估和表征由淀粉样反应肽组成的肽 p5+14 和 11-1F4 识别的高亲和力表位 (0.3 nM)。使用一组体外定量 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 量化肽介导的 11-1F4 抗体淀粉样蛋白靶向的功效。最后，我们将 使用全身性和局部淀粉样变性小鼠模型研究肽抗体的能力 免疫疗法诱导体内淀粉样蛋白去除。我们预计这种新颖的两阶段调理作用 免疫疗法将增强基于 11-1F4 的治疗对 AL 患者的疗效，并可能延长治疗时间 该抗体对其他形式的系统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且无法治愈的疾病。该应用程序的目标是开发 双功能肽同时结合淀粉样蛋白和 11-1F4 单克隆抗体，产生新型 AL 淀粉样变性的免疫疗法。这种方法将补充和扩展当前基于抗体的方法 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 对于 AL 患者。