Pre-targeting immunotherapy for light chain (AL) amyloidosis

轻链淀粉样变性(AL)是最常见的系统性淀粉样病，估计有4500例 在美国，每年都有新的病例。AL是一种复杂的浆细胞相关疾病，其特征是形成 由错误折叠的单抗免疫球蛋白轻链组成的不容溶解的免疫惰性蛋白纤维 细胞外淀粉样纤维成分可沉积在任何器官或组织中，导致功能丧失、发病、 最终，死亡。尽管几十年来积极的研究和对病理学的理解不断加深 机制上，AL仍然无法治愈，患者预后很差，中位生存期不到3 好几年了。 对AL患者的有效临床治疗，除了化疗外，还需要去除 破坏性的组织淀粉样蛋白，使器官功能得以恢复。一种成熟的淀粉样蛋白治疗方法 清除是通过使用淀粉样蛋白反应性抗体来优化沉积物。尽管前景看好，但初步的 两项正在进行的抗AL淀粉样抗体临床试验的结果表明，它们可能对 只有大约50%的患者。为了解决这一不足，我们开发了一种策略，它使用一种新颖的 将泛淀粉样蛋白反应性多肽和线性表位序列相结合的双功能“多肽” 增强当前免疫治疗性抗体的有效性并扩大其用途，如嵌合抗体 试剂，11-1F4。 在这项提案中，我们将评估和表征由淀粉样蛋白反应性多肽组成的多肽。 P5+14和11-1f4识别的高亲和力表位(0.3 nM)。使用一种体外定量的电池 结合分析以及体内双能SPECT成像和组织生物分布研究，我们将 量化多肽介导的淀粉样蛋白靶向11-1f4抗体的效果。最后，我们会 利用全身性和局限性淀粉样变性小鼠模型，研究多肽抗体的能力 体内诱导淀粉样蛋白去除的免疫疗法。我们预计这部小说，分两个阶段进行优化 免疫治疗将提高以11-1F4为基础的治疗AL患者的疗效，并有可能推广 这种抗体对其他形式的系统性淀粉样病的效用。 淀粉样变性仍然是一种毁灭性的不治之症。此应用程序的目标是开发 同时与淀粉样蛋白和11-1F4单抗结合的双功能肽产生一种新的 AL淀粉样变性的免疫治疗。这种方法将补充和扩展现有的基于抗体的方法 去除淀粉样蛋白的治疗，从而恢复器官功能并确保长期存活和缓解 对于急性白血病患者。

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.