Therapeutic Immunodepletion of a Transthyretin Aggregation Intermediate

转甲状腺素蛋白聚集中间体的治疗性免疫耗竭

• 批准号: 10383792
• 负责人: MARCIN APOSTOL
• 金额: $ 25.61万
• 依托单位: ADRX, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10383792
• 关键词: Affect; Affinity; Alzheimer' s Disease; Amyloid; Amyloid deposition; Amyloidosis; Animal Model; Animals; Antibodies; Antisense Oligonucleotides; Binding; Biological Assay; Blood; Blood Circulation; Blood specimen; Clinical Trials; Control Groups; Deposition; Detection; Diagnosis; Diflunisal; Disease; Disease Progression; Dissociation; Dose; Drug Kinetics; Early Diagnosis; Effectiveness; Enzyme-Linked Immunosorbent Assay; Functional disorder; Future; Genes; Half-Life; Heart; Hour; Human; Immunoassay; Inherited; Lead; Life Expectancy; Link; Location; Modeling; Monoclonal Antibodies; Mus; Mutation; Nervous system structure; Outcome; Patients; Pattern; Peripheral Nerves; Persons; Pharmaceutical Preparations; Phase; Prealbumin; Proteins; Quality of life; Recombinants; Serum; Specificity; Technology; Therapeutic; Time; Tissues; Transgenic Animals; Transgenic Mice; Work; antibody detection; base; detection assay; disease diagnosis; efficacy testing; experience; experimental study; extracellular; improved; in vivo; monomer; mortality; mouse model; nanomolar; neonatal Fc receptor; nonhuman primate; novel; novel therapeutics; patient population; preclinical development; prevent; programs; rapid diagnosis; screening; single molecule; small molecule; therapeutic development

ABSTRACT Transthyretin amyloidosis (ATTR) is a rare, progressive, and ultimately fatal condition characterized by the abnormal extracellular deposition of transthyretin (TTR) protein within the peripheral nerves (ATTR-PN) and/or within the heart (ATTR-CM). There are two types of ATTR: (1) hereditary ATTR (hATTR), where the destabilizing mutation in the TTR-gene is inherited, or (2) ATTRwt, in which people with the wild-type TTR-gene sequence develop the disease sporadically. Recent estimates put the worldwide number of people affected by ATTR at approximately 500,000; however, these patient populations are thought to be significantly underdiagnosed. In recent years, the first therapeutics have been approved to treat ATTR either through stabilization of TTR with a small molecule (tafamidis and diflunisal) or reduction of TTR expression levels through antisense oligonucleotides (patisiran and inotersen). However, not all patients respond to treatment and those that do respond continue to decline; disease progression is slowed but not reversed. The path from normal TTR to amyloid deposition proceeds through a monomeric intermediate and it is hypothesized that the reason patients continue to decline is due to its continued presence. Targeting the entity implicated in aggregation, the dissociated monomeric intermediate, could lead to a better therapeutic approach where the total pool of native TTR remains unaltered and only the aggregation prone intermediate is removed. Hence, the ADRx approach is to use a proprietary antibody to bind this intermediate aggregating species and clear it from the patient’s blood. An antibody is an ideal approach for this therapeutic due to its long half-life, high affinity, exquisite specificity, and availability of the intermediate within the bloodstream. Through a proprietary antibody discovery program, highly potent and specific monomer binding antibodies have been discovered. One of these antibodies will be used to perform proof-of-concept experiments in mice to evaluate its ability to deplete these aberrant aggregation-prone monomers from the blood of mice. Novel ATTR therapeutic development efforts have been hindered by the lack of readily available animal models to test efficacy. While transgenic animal models have been developed to mimic TTR deposition in mice, these models poorly replicate the TTR deposition patterns found in human ATTR patients and furthermore show great variance in amount, type, and location of deposition. Additionally, these models can take months for deposition to occur, in some cases upwards of 24 months. In the following application we propose studies to show that our proprietary antibody can efficiently find and clear the TTR intermediate within an animal on a short timescale. If successful, these experiments will show the depletion of the aggregating form of TTR from an animal for the first time. This will establish the first step in preclinical development of these antibodies towards a therapeutic that can be used in ATTR patients as a stand-alone therapy or in combination with other approved drugs.

抽象的 经胆囊素淀粉样变性（ATTR）是一种罕见，进行的，最终是致命状况，其特征是 外周神经（attr-pn）和/或 内心（attr-cm）。 atter有两种类型：（1）遗传属性（HATTR），其中不稳定 ttr-gene中的突变是遗传的，或（2）attrwt，其中具有野生型TTR序列的人 偶尔发展疾病。最近的估计使全球受att At影响的人数 约500,000;但是，这些患者人群被认为诊断出明显不足。 近年来，第一个理论已被批准通过稳定TTR的属性来治疗ATT 小分子（tafamidis and difunisal）或通过反义降低TTR表达水平 寡核苷酸（Patisiran和Inotersen）。但是，并非所有患者都对治疗做出反应， 响应继续下降；疾病进展缓慢，但不逆转。 从正常TTR到淀粉样沉积的路径通过单体中间体进行，它是 假设患者继续下降的原因是由于其继续存在。针对实体 分解的单体中间体在汇总实施，可能导致更好的治疗方法 如果天然TTR的总库保持不变，并且仅易于聚集中间体。 因此，ADRX方法是使用专有抗体来结合该中间聚集物质和 从患者的血液中清除它。抗体是这种疗法的理想方法，因为它的半衰期很高，高 亲和力，独家特异性和血液中中间体的可用性。 通过专有抗体发现程序，高潜力和特定的单体结合抗体具有 被发现。这些抗体之一将用于在小鼠中执行概念验证实验 评估其从小鼠血液中巧妙的这些异常聚集的单体的能力。 由于缺乏随时可用的动物模型而阻碍了新颖的attry热发展工作 测试效率。尽管已经开发了转基因动物模型以模仿小鼠的TTR沉积，但这些 模型不良复制人类ATT患者中发现的TTR沉积模式，此外显示出很大的表现 沉积的数量，类型和位置方差。此外，这些模型可能需要几个月的时间才能进行沉积 发生，在某些情况下超过24个月。在以下应用中，我们建议研究表明我们的 专有抗体可以在短时间内有效地找到并清除动物中的TTR中间体。 如果成功，这些实验将显示从动物的TTR的聚集形式的耗竭。 第一次。这将确定这些抗体对治疗的临床前开发的第一步 可以在ATT患者中用作独立治疗，也可以与其他认可的药物一起使用。