Introduction

Transthyretin cardiac amyloidosis (ATTR-CA) is a progressive disease that results from the accumulation of transthyretin (TTR) fibrils in the extracellular space of the myocardium, leading to heart failure.¹ The pathogenesis of ATTR-CA results from a reduction in cardiac compliance due to amyloid fibril deposition, but recent observations suggest that soluble TTR intermediate oligomers are toxic to cardiomyocytes and contribute to myocardial functional compromise.²

Recently, proof-of-mechanism and proof-of-concept have been established for the ability of monoclonal antibodies to induce Fc gamma-mediated clearance of extracellular beta-amyloid in patients with Alzheimer's disease.³ This led to the Food and Drug Administration approval of a drug that clears amyloid plaques and attenuates cognitive decline.³ In pre-clinical studies, several monoclonal antibodies have been shown to mediate Fc gamma-dependent clearance of aggregated TTR by macrophages in experimental models.^4-6 Very recently, an initial phase I study demonstrated the safety of this approach and provided initial hints of efficacy in reducing imaging-related pathology via magnetic resonance imaging and scintigraphy.⁷

In a recent preliminary observation, antibodies binding to TTR were described for the first time in two patients with ATTR-CA, and were associated with spontaneous clinical recovery and regression of imaging-related findings.⁸ However, this intriguing finding has not yet established a mechanistic role for these naturally occurring antibodies in facilitating amyloid removal.

We aimed to characterize in detail the spontaneously occurring purified antibodies to TTR oligomers and fibrils and test their related functional activities in vitro and in cellular and experimental models, supporting their potential involvement in the spontaneous regression of ATTR amyloidosis.

中文翻译：

---

转甲状腺素蛋白心脏淀粉样变性患者自发产生的天然抗甲状腺素蛋白抗体的功能作用

 介绍

转甲状腺素蛋白心脏淀粉样变性 （ATTR-CA） 是一种进行性疾病，由转甲状腺素蛋白 （TTR） 原纤维在心肌细胞外间隙积累导致心力衰竭。¹ ATTR-CA 的发病机制是由于淀粉样蛋白原纤维沉积导致心脏顺应性降低，但最近的观察表明，可溶性 TTR 中间寡聚体对心肌细胞有毒，并导致心肌功能受损。^{阿拉伯数字}

最近，已经建立了机制验证和概念验证，证明单克隆抗体能够诱导阿尔茨海默病患者 Fc γ 介导的细胞外 β-淀粉样蛋白清除。³ 这导致美国食品和药物管理局批准了一种清除淀粉样蛋白斑块和减轻认知能力下降的药物。³ 在临床前研究中，几种单克隆抗体已被证明在实验模型中介导巨噬细胞对聚集 TTR 的 Fc γ 依赖性清除。^4-6 最近，一项初步的 I 期研究证明了这种方法的安全性，并提供了通过磁共振成像和闪烁显像减少成像相关病理的疗效的初步暗示。⁷

在最近的一项初步观察中，首次在两名 ATTR-CA 患者中描述了与 TTR 结合的抗体，并且与自发临床恢复和影像学相关结果的消退有关。⁸ 然而，这一有趣的发现尚未确定这些天然存在的抗体在促进淀粉样蛋白去除方面的机制作用。

我们旨在详细表征自发发生的针对 TTR 寡聚体和原纤维的纯化抗体，并在体外、细胞和实验模型中测试它们的相关功能活性，支持它们可能参与 ATTR 淀粉样变性的自发消退。