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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

抽象的甲状腺素运载蛋白淀粉样变性 (ATTR) 是一种罕见的、进行性的、最终致命的疾病，其特征是周围神经内运甲状腺素蛋白 (TTR) 蛋白异常细胞外沉积 (ATTR-PN) 和/或心脏内 (ATTR-CM) 有两种类型的 ATTR：(1) 遗传性 ATTR (hATTR)，其中不稳定。 TTR 基因突变是遗传性的，或 (2) ATTRwt，其中具有野生型 TTR 基因序列的人最近的估计表明，全球受 ATTR 影响的人数为大约 500,000；然而，这些患者群体被认为诊断严重不足。近年来，第一种疗法已被批准通过稳定 TTR 来治疗 ATTR 小分子（tafamidis 和 diflunisal）或通过反义降低 TTR 表达水平然而，并非所有患者都对治疗有反应，也不是所有患者都对治疗有反应。反应持续下降；疾病进展减慢但并未逆转。从正常 TTR 到淀粉样蛋白沉积的路径是通过单体中间体进行的，它是发现患者数量持续下降的原因是该实体的持续存在。与聚集有关的解离的单体中间体可能会导致更好的治疗方法其中本机 TTR 的总池保持不变，仅删除易于聚合的中间体。因此，ADRx 方法是使用专有抗体来结合这种中间聚集物质并从患者的血液中清除它是这种治疗的理想方法，因为它的半衰期长、高。中间体在血流中的亲和力、精确的特异性和可用性。通过专有的抗体发现计划，高效且特异性的单体结合抗体已其中一种抗体将用于在小鼠中进行概念验证实验。评估其从小鼠血液中消除这些异常聚集倾向单体的能力。由于缺乏现成的动物模型，新的 ATTR 治疗方法的开发工作受到阻碍虽然已经开发出转基因动物模型来模拟小鼠中的 TTR 沉积，但这些模型很难复制在人类 ATTR 患者中发现的 TTR 沉积模式，而且显示出很好的结果此外，沉积的数量、类型和位置存在差异，这些模型可能需要数月的时间才能沉积。发生，在某些情况下长达 24 个月，在下面的应用中，我们提出研究来表明我们的。专有抗体可以在短时间内有效地发现并清除动物体内的 TTR 中间体。如果成功，这些实验将显示动物体内 TTR 聚集形式的消耗这将为这些抗体的临床前开发迈出第一步。可作为独立疗法或与其他批准的药物联合用于 ATTR 患者。