Efficient Brain Delivery of Neuroprotective TrkB Agonist Antibodies in Alzheimer’s Disease Using CD98hc Bispecific Shuttles

使用 CD98hc 双特异性穿梭细胞有效脑部递送神经保护性 TrkB 激动剂抗体治疗阿尔茨海默病

• 批准号: 10786022
• 负责人: Michael John Lucas
• 金额: $ 6.95万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10786022
• 关键词: Acceleration; Affect; Affinity; Age; Agonist; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease therapy; American; Amino Acid Transport System L; Animal Model; Antibodies; Antibody Affinity; Antibody Dissociations; Antibody Specificity; Area; Biological Products; Bispecific Antibodies; Blood - brain barrier anatomy; Brain; Characteristics; Cognitive deficits; Combined Modality Therapy; Data; Dementia; Development; Disease; Endothelium; Enzyme-Linked Immunosorbent Assay; Epitopes; Evaluation; Fluorescence-Activated Cell Sorting; Functional disorder; Future; Generations; Goals; Human; Immunoglobulin G; Libraries; Ligands; Mediating; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Outcome; Pathway interactions; Patients; Proteins; Receptor Activation; Research; Side; Signal Transduction; Sorting; Surface; Synapses; TFRC gene; Testing; Therapeutic; Therapeutic antibodies; Time; Transgenic Mice; Variant; Viral; Western Blotting; Wild Type Mouse; Work; Yeasts; age related neurodegeneration; antagonist; blood-brain barrier penetration; brain parenchyma; cerebrovascular; clinical efficacy; design; improved; insight; mouse model; mutant; neuroprotection; novel therapeutics; pre-clinical; preservation; prevent; small molecule therapeutics; tau Proteins; therapeutic development; therapeutic protein

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease. Despite the great potential of biologics (e.g., therapeutic antibodies) to affect AD pathophysiology, these agents are generally unable to penetrate the blood-brain barrier (BBB), which represents their biggest hurdle to clinical efficacy. One promising strategy is to use bispecific antibody BBB shuttles, which involve fusing IgGs to a second affinity ligand that engages a cerebrovascular endothelial target and induces transport across the BBB. While most previous work has focused on BBB shuttles that target transferrin receptor (TfR-1), my lab has developed a BBB shuttle that engages CD98hc, the heavy chain of the large neutral amino acid transporter (LAT-1). Notably, our preliminary data demonstrate superior brain parenchymal delivery and retention of IgGs shuttled via CD98hc as compared to those shuttled via TfR-1. Importantly, this first-generation CD98hc shuttle enables brain delivery of off-the-shelf IgGs simply by attaching a single-chain CD98hc antibody to the C-terminus of one of the two IgG heavy chains. The objectives of this proposal are twofold: i) to define the optimal CD98hc shuttle characteristics (CD98hc single-chain affinity, valency, and epitope) for maximal brain parenchymal delivery and retention to guide the design of second-generation CD98hc shuttles; and ii) to generate proof-of-concept efficacy data in an AD mouse model (tau, PS19) using a TrkB agonist antibody that induces neuroprotective signaling. For the first objective, I hypothesize that BBB shuttles with monovalent CD98hc single-chain antibodies (as used in the first- generation shuttle) and reduced CD98hc single-chain antibody affinity (relative to the first-generation shuttle) will maximize antibody concentrations in the brain parenchyma by improving antibody dissociation at the abluminal side of the brain endothelium, as observed for TfR-1 shuttles. For the second objective, I hypothesize that CD98hc shuttles that deliver TrkB agonist IgGs to the brain parenchyma of tau transgenic mice will reduce neuronal and synaptic loss and cognitive deficits. This hypothesis is supported by the partial efficacy of non- shuttled TrkB antibodies delivered systemically and high efficacy of viral brain delivery of the TrkB ligand in AD mouse models. Therefore, I propose in Aim 1 to develop an optimized second-generation CD98hc shuttle by evaluating the impact of CD98hc single-chain antibody affinity, valency, and epitope on antibody concentrations in the mouse brain parenchyma as a function of time. Next, in Aim 2, I propose to evaluate the ability of a first- generation CD98hc shuttle to deliver a TrkB agonist IgG to the brain parenchyma, to activate TrkB in wild-type and tau (PS19) transgenic mice, and to mediate neuroprotection in tau transgenic mice. A key expected outcome is the development of an optimized CD98hc shuttle that can be used to deliver a wide range of existing therapeutic antibodies to the brain parenchyma. A second key expected outcome is preclinical data for TrkB agonism in AD mouse models. These findings are expected to enable future studies of single and combination therapies using antagonist and agonist antibodies that target mechanistically unique pathways.

阿尔茨海默病（AD）是最常见的与年龄相关的神经退行性疾病。尽管伟大