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）是最常见的具有潜在潜力的年龄相关神经退行性疾病。 影响潜在病理生理学的方法未能在临床上显示出显着的治疗效果。 生物制剂无法穿透血脑屏障（BBB）是其临床疗效的最大障碍。 解决这一挑战的一个有前途的策略是将 IgG 与第二个亲和配体融合，该配体与 脑血管内皮靶向并诱导穿过 BBB 的转运，而几乎所有先前的努力都已实现。 专注于转铁蛋白受体（TfR-1）作为典型的内皮靶标，尽管其固有的传递和 为了应对安全挑战，我们开发了一种双特异性抗体穿梭机，它可以结合 CD98hc（CD98hc）， 值得注意的是，我们的初步数据显示了大中性氨基酸转运蛋白（LAT-1）的亲和力和保留。 现成 IgG 的特异性并入我们的第一代 CD98hc 双特异性穿梭机、高级大脑 与 TfR-1 相比，保留了通过 CD98hc 穿梭的 IgG，并保留了 CD98hc 和 CD98hc 的内皮水平 CD98hc 穿梭剂量饱和后的大脑摄取。该提案的总体目标是进一步 通过以下方式开发 CD98hc BBB 穿梭机： i) 定义最大 IgG 脑的最佳特征 实质传递；ii) 评估对 CD98hc 介导的转运的年龄和疾病依赖性影响； 使用激动剂（抗 TrkB）和拮抗剂（抗 TrkB）在 AD 小鼠模型中生成概念验证功效数据 我们的中心假设是 IgG 通过 CD98hc 转运。 航天飞机将增加实质输送并实现大脑集中和目标参与 与病毒传递相当，在 tau 小鼠模型中产生强大的神经保护作用，包括潜在的添加剂 或通过针对两种不同的神经保护途径产生协同神经保护作用。 在目标 1 中，我们将测试第二代 CD98hc 抗体穿梭机的脑实质递送。 CD98hc 相互作用的价态、亲和力和表位对脑摄取和实质递送的影响。 使用成年小鼠确定的最佳剂量和结构将在老年野生型和 PS19 (tau P301S) 中进行测试 接下来，在目标 2 中，我们将评估个体的功效。 神经保护性抗体/CD98hc 在 PS19 小鼠中穿梭，经过验证的 TrkB（C20，激动剂）抗体和 磷酸化 tau (PHF1) 将通过我们最好的 CD98hc 穿梭机单独递送，功效结果将是。 磷酸化和不溶性 tau 蛋白水平、神经元和突触损失以及认知缺陷。 从 AD 进展的早期、中期和晚期开始，对三种治疗模式进行了测试 最后，在目标 3 中，抗体穿梭靶向组合的功效。 PS19 小鼠的多种神经保护途径将得到评估，这些研究有望提供新的成果。 与 CD98hc 转运途径相关的基础知识和双特异性 AD 的临床前数据 疗法，包括针对机制上独特的神经保护途径的联合疗法。