Systemic amyloidosis is a fatal disorder caused by pathological extracellular deposits of amyloid fibrils that are always coated with the normal plasma protein, serum amyloid P component (SAP). The small-molecule drug, miridesap, [(R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC)] depletes circulating SAP but leaves some SAP in amyloid deposits. This residual SAP is a specific target for dezamizumab, a fully humanized monoclonal IgG1 anti-SAP antibody that triggers immunotherapeutic clearance of amyloid. We report the safety, pharmacokinetics, and dose-response effects of up to three cycles of miridesap followed by dezamizumab in 23 adult subjects with systemic amyloidosis (ClinicalTrials.gov identifier: NCT01777243). Amyloid load was measured scintigraphically by amyloid-specific radioligand binding of ¹²³I-labeled SAP or of ^99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid. Organ extracellular volume was measured by equilibrium magnetic resonance imaging and liver stiffness by transient elastography. The treatment was well tolerated with the main adverse event being self-limiting early onset rashes after higher antibody doses related to whole body amyloid load. Progressive dose-related clearance of hepatic amyloid was associated with improved liver function tests. ¹²³I-SAP scintigraphy confirmed amyloid removal from the spleen and kidneys. No adverse cardiac events attributable to the intervention occurred in the six subjects with cardiac amyloidosis. Amyloid load reduction by miridesap treatment followed by dezamizumab has the potential to improve management and outcome in systemic amyloidosis.

系统性淀粉样变性是由淀粉样原纤维的病理性细胞外沉积物引起的致命疾病，淀粉样蛋白原纤维总是被正常血浆蛋白、血清淀粉样蛋白 P 成分 (SAP) 包被。小分子药物 miridesap，[(R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxy acid (CPHPC)]耗尽循环 SAP，但在淀粉样蛋白沉积物中留下一些 SAP。这种残留的 SAP 是 dezamizumab 的特定靶点，dezamizumab 是一种完全人源化的单克隆 IgG1 抗 SAP 抗体，可触发免疫治疗清除淀粉样蛋白。我们报告了 23 名全身性淀粉样变性成人受试者（ClinicalTrials.gov 标识符：NCT01777243）中最多三个周期的 miridesap 和 dezamizumab 的安全性、药代动力学和剂量反应效应。淀粉样蛋白负载通过闪烁扫描法测量淀粉样蛋白特异性放射性配体结合¹²³ I 标记的 SAP 或^99m Tc-3,3-diphosphono-1,2-propanodicarboxy acid。通过平衡磁共振成像测量器官细胞外体积，通过瞬时弹性成像测量肝脏硬度。该治疗耐受性良好，主要不良事件是与全身淀粉样蛋白负荷相关的较高抗体剂量后自限性早发性皮疹。肝淀粉样蛋白的渐进性剂量相关清除与肝功能测试的改善有关。¹²³I-SAP 闪烁显像证实从脾脏和肾脏中去除了淀粉样蛋白。6 名患有心脏淀粉样变性的受试者没有发生可归因于干预的不良心脏事件。通过 miridesap 治疗和 dezamizumab 降低淀粉样蛋白负荷有可能改善系统性淀粉样变性的管理和结果。