Immunotherapeutic for ATTR/AL Cardiac Amyloidosis

心脏淀粉样变性的特征在于心脏中蛋白质纤维的心肌积聚， 最常见的类型是野生型和遗传性甲状腺素运载蛋白（ATTR）和轻链（AL）淀粉样变性。这是一个 严重的，进行性的，通常是致命的疾病。我们相信有可能开发一种泛淀粉样蛋白治疗剂 它可以治疗所有的心脏淀粉样变性，并且可以靶向患者，无论他们是否患有AL，野生型或 突变型ATTR淀粉样变性。我们已经确定了一个新的合成多肽家族， 检测淀粉样沉积物中硫酸乙酰肝素的独特形式，并结合到不同蛋白质amy的表面， 类原纤维（图1）。硫酸乙酰肝素是所有淀粉样蛋白沉积物的主要和普遍存在的组分， 与通常在细胞外基质中发现的硫酸乙酰肝素不同。它存在于淀粉样蛋白中， 高得多的密度和高硫酸化，因此可以特异性靶向。所述肽，p5和 延长形式p5+14在体外和鼠模型体内显示与淀粉样蛋白沉积物结合。无线电- 标记的形式命名为124 I-p5 +14，目前正在开发作为泛淀粉样蛋白成像剂， 人类包括心脏淀粉样变性在内的多器官淀粉样变性的检测、定量和监测 科目 我们建议开发和表征p5抗体融合物的人源化版本（称为hIgp 5）， 其中P5肽直接融合于人源化抗体轻链。新的抗体-肽fu- 将在各种体外ATTR和AL淀粉样蛋白结合研究中定量评价锡永构建体。加- 我们将采用基于荧光的方法来测量它们诱导淀粉样蛋白摄取的能力， 体外携带局部荧光人类淀粉样瘤的小鼠，可以通过光学显微镜进行非侵入性监测， CAL成像将用于体内研究。 我们的目标是开发一种泛淀粉样变性治疗剂，1）结合所有类型的淀粉样蛋白2）杠杆作用 多个结合位点3）保持高度特异性4）用作治疗剂的骨架和5）用于IMAG， 作为疾病生物标志物和生物标志物监测治疗干预的结果。我们的研究 该策略可能导致一种泛淀粉样蛋白抗体治疗剂，该治疗剂在清除淀粉样蛋白纤维中非常有效， 心脏和开拓者，以一种变革性的治疗心脏淀粉样变性患者。

Cardiac amyloidosis is characterized by myocardial accumulation of protein fibrils in the heart and the most common types are wild-type and hereditary transthyretin (ATTR) and light-chain (AL) amyloidosis. It is a severe, progressive and often lethal disorder. We believe it is possible to develop a pan amyloid therapeutic that can treat all cardiac amyloidosis and can target patients irrespective of whether they have AL, wild-type or mutant ATTR amyloidosis. We have identified a novel family of synthetic, polybasic peptides that specifically detect a unique version of heparan sulfate in amyloid deposits and binds to the surface of diverse protein amy- loid fibrils (Fig 1). Heparan sulfate, which is a major and ubiquitous component of all amyloid deposits is struc- turally distinct from the heparan sulfate normally found in the extra-cellular matrix. It is present in amyloid in a much higher density and is hypersulfated, and can therefore be specifically targeted. The peptides, p5 and the elongated form p5+14, were shown to bind to amyloid deposits in vitro and in vivo in a murine model. A radio- labeled version designated 124I-p5+14, is currently being developed as a pan-amyloid imaging agent for the detection, quantification and monitoring of multi-organ amyloidosis including cardiac amyloidosis in human subjects. We propose to develop and characterize a humanized version of the p5 antibody-fusion (termed hIgp5), in which the p5 peptide is fused directly to the humanized antibody light chain. The new antibody-peptide fu- sion construct will be quantitatively evaluated in various in vitro ATTR and AL amyloid binding studies. Addi- tionally, we will employ florescence based methods of measuring their ability to induce uptake of amyloid in vitro. Mice bearing localized fluorescent human amyloidomas, which can be non-invasively monitored by opti- cal imaging, will be used for in vivo studies. Our goal is to develop a pan amyloidosis therapeutic agent to 1) bind all types of amyloid 2) leverage multiple binding sites 3) remain highly specific 4) serve as a backbone for therapeutics and 5) utilize for imag- ing as a disease biomarker and a biomarker to monitor outcomes from therapeutic intervention. Our research strategy could lead to a pan amyloid antibody therapeutic that is highly effective in clearing amyloid fibrils from the heart and a trailblazer to a transformative therapy for cardiac amyloidosis patients.