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.

阿尔茨海默病（Alzheimer's disease，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的药物在临床上未能显示出显著的治疗益处。的 生物制剂不能穿透血脑屏障（BBB）是其临床功效的最大障碍。 解决这一挑战的有希望的策略是将IgG融合到第二亲和配体上， 脑血管内皮靶向并诱导跨BBB的运输。尽管几乎所有先前的努力 关注转铁蛋白受体（TfR-1）作为原型内皮靶点，尽管其具有固有的递送， 安全挑战，我们已经开发了一种双特异性抗体穿梭体，其接合CD 98 hc， 大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的亲和力和 整合到我们的第一代CD 98 hc双特异性穿梭、上级脑中的现成IgG的特异性 与TfR-1相比，通过CD 98 hc穿梭的IgG的保留，并保留了CD 98 hc的内皮水平， 本提案的总体目标是进一步研究CD 98 hc穿梭剂量饱和后的脑摄取。 通过以下方式开发CD 98 hc BBB穿梭：i）定义最大IgG脑的最佳特征， 实质递送; ii）评估年龄和疾病对CD 98 hc介导的转运的依赖性影响;和iii） 在AD小鼠模型中使用激动剂（抗TrkB）和拮抗剂（抗TrkB）产生概念验证功效数据。 磷酸-tau）抗体单独和组合。我们的中心假设是IgG通过CD 98 hc转运， 穿梭机将增加实质递送并实现脑浓度和靶点接合 与病毒递送相当，在tau小鼠模型中产生稳健的神经保护，包括潜在的添加剂 或通过靶向两种不同的神经保护通路的协同神经保护作用。所以我们提出 目的1是优化第二代CD 98 hc抗体穿梭体的脑实质递送。我们将测试 CD 98 hc相互作用的效价、亲和力和表位对脑摄取和实质递送的影响。 将在老年野生型和PS19（tau P301 S）中测试使用成年小鼠确定的最佳剂量和构建体。 小鼠，以评估运输途径的完整性。接下来，在目标2中，我们将评估个体 神经保护性抗体/CD 98 hc穿梭。经验证的抗TrkB抗体（C20，激动剂）和 磷酸化的tau（PHF 1）将通过我们最好的CD 98 hc穿梭体单独递送。疗效结局将是 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。疗效将是 在AD进展的早期、中期和晚期阶段开始的三种治疗模式中进行测试 病理学和认知能力下降。最后，在目标3中，确定了抗体穿梭靶向的组合的功效。 将评价PS19小鼠中的多种神经保护途径。这些研究有望为 与CD 98 hc转运途径相关的基础知识和双特异性AD的临床前数据 治疗剂，包括靶向机制上独特的神经保护途径的组合疗法。