Immunotherapeutic for ATTR/AL Cardiac Amyloidosis

心脏淀粉样变性的特征是心肌中蛋白质纤维在心脏和心脏中的堆积 最常见的类型是野生型和遗传性转甲状腺素(ATTR)和轻链淀粉样变性(AL)。这是一个 严重的，进行性的，常常是致命的疾病。我们相信有可能开发一种泛淀粉样蛋白疗法 它可以治疗所有心脏淀粉样变性，并可以针对患者，无论他们是AL，野生型或 突变型Attr淀粉样变性。我们已经确定了一种新的合成多肽家族，这种多肽具有特异性 在淀粉样蛋白沉积中检测到一种独特版本的硫酸乙酰肝素，并结合到不同蛋白质的表面。 类纤维(图1)。硫酸乙酰肝素是所有淀粉样蛋白沉积的主要和普遍存在的成分，其结构是... 与通常在细胞外基质中发现的硫酸乙酰肝素截然不同。它存在于淀粉样蛋白中 密度要高得多，而且是过硫酸盐，因此可以作为特定的目标。多肽、P5和 在体外和体内的小鼠模型中，延长的P5+14被证明与淀粉样蛋白沉积结合。一台收音机- 标号为124I-P5+14的标记版本目前正在作为泛淀粉样蛋白显像剂开发，用于治疗 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 研究对象。 我们建议开发和鉴定人源化的P5抗体融合版本(称为hIgp5)， 其中P5肽直接与人源化抗体轻链融合。新抗体--多肽FU-1 Sion结构将在各种体外ATTR和AL淀粉样蛋白结合研究中进行定量评估。另外-- 此外，我们将使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。 体外培养。携带局部荧光人类淀粉样瘤的小鼠，可通过光学显微镜进行非侵入性监测 CAL成像，将用于活体研究。 我们的目标是开发一种泛淀粉样变性治疗剂，以结合所有类型的淀粉样蛋白杠杆 多个结合位点3)保持高度特异性4)作为治疗的主干和5)用于成像- 作为疾病生物标记物和监测治疗干预结果的生物标记物。我们的研究 该策略可能导致一种泛淀粉样抗体疗法，该疗法在清除淀粉样蛋白纤维方面非常有效 心脏和心脏淀粉样变性患者变革性治疗的先驱。

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.