CD98hc Brain Shuttles for Delivering Off-the-shelf Neuroprotective Antibodies in Alzheimer's Disease

CD98hc 脑穿梭机为阿尔茨海默病提供现成的神经保护抗体

• 批准号: 10566062
• 负责人: Colin Fred Greineder
• 金额: $ 72.15万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10566062
• 关键词: Acceleration; Address; Adult; Adverse effects; Affect; Affinity; Age; Agonist; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease therapeutic; American; Amino Acid Transport System L; Amino Acids; Animal Model; Antibodies; Avidity; Biological Products; Bispecific Antibodies; Blood - brain barrier anatomy; Brain; Characteristics; Clinic; Clinical; Cognitive deficits; Combined Modality Therapy; Data; Dementia; Development; Disease; Dose; Endothelium; Enzyme-Linked Immunosorbent Assay; Epitopes; Functional disorder; Generations; Goals; Growth Factor; Hormones; Immunoglobulin G; Impaired cognition; Individual; Injections; Knowledge; Ligands; Mediating; Mus; Neurodegenerative Disorders; Neurons; Neuroprotective Agents; Outcome; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phosphorylation; Property; Proteins; Research; Safety; Signaling Molecule; Specificity; Synapses; TFRC gene; Technology; Testing; Therapeutic; Viral; Viral Vector; Western Blotting; Work; age effect; age related neurodegeneration; aged; antagonist; blood-brain barrier penetration; brain parenchyma; cerebrovascular; clinical efficacy; cross reactivity; efficacy evaluation; efficacy outcomes; human old age (65+); improved; insight; mouse model; neuroprotection; novel therapeutics; pre-clinical; preservation; prevent; receptor; small molecule therapeutics; targeted treatment; tau Proteins; tau-1; therapeutic development; therapeutic protein; uptake

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease. Biologics with potential to affect underlying pathophysiology have failed to display significant therapeutic benefits in the clinic. The inability of biologics to penetrate the blood-brain barrier (BBB) represents their biggest hurdle to clinical efficacy. A promising strategy to address this challenge is to fuse IgGs to a second affinity ligand that engages a cerebrovascular endothelial target and induces transport across the BBB. While nearly all prior efforts have focused on the transferrin receptor (TfR-1) as the prototypical endothelial target despite inherent delivery and safety challenges, we have developed a bispecific antibody shuttle that engages CD98hc, the heavy chain of the large neutral amino acid transporter (LAT-1). Notably, our preliminary data show preserved affinity and specificity of off-the-shelf IgGs incorporated into our first-generation CD98hc bispecific shuttle, superior brain retention of IgGs shuttled via CD98hc as compared to TfR-1, and preserved endothelial levels of CD98hc and brain uptake after saturating CD98hc shuttle doses.The overall objective of this proposal is to further the development of the CD98hc BBB shuttle by: i) defining the optimal characteristics for maximal IgG brain parenchymal delivery; ii) evaluating age- and disease-dependent effects on CD98hc-mediated transport; and iii) generating proof-of-concept efficacy data in an AD mouse model using agonist (anti-TrkB) and antagonist (anti- phospho-tau) antibodies alone and in combination. Our central hypothesis is that IgG transport via the CD98hc shuttles will increase parenchymal delivery and achieve brain concentrations and target engagement comparable to viral delivery, generating robust neuroprotection in a tau mouse model, including potential additive or synergistic neuroprotective effects by targeting two different neuroprotective pathways. Therefore, we propose in Aim 1 to optimize brain parenchymal delivery of a second-generation CD98hc antibody shuttle. We will test the impact of the valency, affinity, and epitope of CD98hc interaction on brain uptake and parenchymal delivery. The optimal dose and construct identified using adult mice will be tested in aged wild-type and PS19 (tau P301S) mice to evaluate the integrity of the transport pathway. Next, in Aim 2, we will assess the efficacy of individual neuroprotective antibody/CD98hc shuttles in PS19 mice. Validated antibodies against TrkB (C20, agonist) and phosphorylated tau (PHF1) will be individually delivered via our best CD98hc shuttle. Efficacy outcomes will be levels of phosphorylated and insoluble tau, neuronal and synaptic loss, and cognitive deficits. Efficacy will be tested in three modes of treatment, beginning at early, intermediate, and late stages of progression of AD pathology and cognitive decline. Finally, in Aim 3, the efficacy of combinations of antibody shuttles targeting multiple neuroprotective pathways in PS19 mice will be evaluated. These studies are expected to provide new fundamental knowledge related to the CD98hc transport pathway and preclinical data for bispecific AD therapeutics, including combination therapies that target mechanistically unique neuroprotective pathways.

阿尔茨海默氏病（AD）是最常见的与年龄相关的神经退行性疾病。具有潜力的生物制剂 影响潜在的病理生理学未能在诊所表现出明显的治疗益处。这 生物制剂无法穿透血脑屏障（BBB）是其临床效率的最大障碍。 应对这一挑战的有前途的策略是将IgG融合到第二个亲和力配体，以吸引 脑血管内皮靶标并诱导整个BBB的运输。虽然几乎所有先前的努力都有 专注于转铁蛋白受体（TFR-1）作为典型的内皮目标目的地继承和 安全挑战，我们开发了一种双特异性抗体班车，它与CD98HC互动，这是一个重链 大型中性氨基酸转运蛋白（LAT-1）。值得注意的是，我们的初步数据显示，保留了亲和力 纳入我们的第一代CD98HC双特异性班车的特异性IgG的特异性 与TFR-1相比，通过CD98HC穿梭的IgG的保留，并保留了CD98HC的内皮水平和 饱和CD98HC穿梭剂量后的大脑吸收。该提案的总体目标是进一步 CD98HC BBB班车的开发作者：i）定义最大IgG脑的最佳特征 实质输送； ii）评估对CD98HC介导的运输的年龄和疾病依赖性影响；和iii） 使用激动剂（抗TRKB）和拮抗剂（抗 - 单独和组合磷酸化抗体。我们的中心假设是IgG通过CD98HC运输 班车将增加副群的分娩并达到大脑浓度并靶向参与 与病毒递送相当，在tau小鼠模型中产生健壮的神经保护作用，包括潜在的添加剂 或通过靶向两种不同的神经保护途径来协同神经保护作用。因此，我们提出 在AIM 1中，以优化第二代CD98HC抗体班车的脑实质递送。我们将测试 CD98HC相互作用的价值，亲和力和表位对脑摄取和副群递送的影响。 使用成年小鼠鉴定的最佳剂量和构造将在老年野生型和PS19（TAU P301S）中进行测试 小鼠评估运输途径的完整性。接下来，在AIM 2中，我们将评估个体的效率 PS19小鼠中的神经保护抗体/CD98HC穿梭。经过验证的针对TRKB（C20，激动剂）和的抗体 磷酸化的TAU（PHF1）将通过我们最好的CD98HC班车单独交付。功效结果将是 功效将是 以三种治疗方式进行测试，从早期，中间和晚期阶段开始 病理和认知能力下降。最后，在AIM 3中，抗体穿梭靶向的组合效率 将评估PS19小鼠中多个神经保护途径。这些研究有望提供新的 与CD98HC传输途径和双特异性AD的临床前数据有关的基本知识 疗法，包括针对机械独特神经保护途径的联合疗法。