Neurimmune, Schlieren, Switzerland.
Referral Center for Cardiac Amyloidosis and Department of Cardiology, Henri Mondor University Hospital, Créteil, France.
Nat Commun. 2021 May 25;12(1):3142. doi: 10.1038/s41467-021-23274-x.
Transthyretin amyloid (ATTR) cardiomyopathy is a debilitating disease leading to heart failure and death. It is characterized by the deposition of extracellular ATTR fibrils in the myocardium. Reducing myocardial ATTR load is a therapeutic goal anticipated to translate into restored cardiac function and improved patient survival. For this purpose, we developed the selective anti-ATTR antibody NI301A, a recombinant human monoclonal immunoglobulin G1. NI301A was cloned following comprehensive analyses of memory B cell repertoires derived from healthy elderly subjects. NI301A binds selectively with high affinity to the disease-associated ATTR aggregates of either wild-type or variant ATTR related to sporadic or hereditary disease, respectively. It does not bind physiological transthyretin. NI301A removes ATTR deposits ex vivo from patient-derived myocardium by macrophages, as well as in vivo from mice grafted with patient-derived ATTR fibrils in a dose- and time-dependent fashion. The biological activity of ATTR removal involves antibody-mediated activation of phagocytic immune cells including macrophages. These data support the evaluation of safety and tolerability of NI301A in an ongoing phase 1 clinical trial in patients with ATTR cardiomyopathy.
转甲状腺素蛋白淀粉样变（ATTR）心肌病是一种使人衰弱的疾病，可导致心力衰竭和死亡。其特征是细胞外 ATTR 纤维在心肌中的沉积。减少心肌 ATTR 负荷是一种治疗目标，预计可转化为恢复心脏功能和提高患者生存率。为此，我们开发了选择性抗-ATTR 抗体 NI301A，这是一种重组人源单克隆 IgG1。NI301A 是在对来自健康老年受试者的记忆 B 细胞库进行全面分析后克隆的。NI301A 选择性地以高亲和力结合分别与散发性或遗传性疾病相关的野生型或变体 ATTR 的疾病相关 ATTR 聚集物，但不与生理转甲状腺素蛋白结合。NI301A 以剂量和时间依赖的方式从源自患者的心肌中的巨噬细胞体外以及从源自患者的 ATTR 纤维移植的小鼠体内去除 ATTR 沉积物。ATTR 去除的生物学活性涉及包括巨噬细胞在内的吞噬免疫细胞的抗体介导的激活。这些数据支持在正在进行的ATTR 心肌病患者的 1 期临床试验中评估 NI301A 的安全性和耐受性。
