Temporal Biomarker-Powered Immunotherapy Targeting GFAP for Traumatic Brain Injury

靶向 GFAP 的时间生物标志物驱动的免疫疗法治疗创伤性脑损伤

基本信息

批准号：
10253356
负责人：
William E Haskins
金额：
$ 49.91万
依托单位：
GRYPHON BIO, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10253356
关键词：
Active Immunization Acute Affinity Animals Antibodies Anxiety Astrocytes Benefits and Risks Binding Biological Assay Biological Markers Blood Circulation Brain Buffers C-terminal C57BL/6 Mouse Calpain Cells Cessation of life Cleaved cell Clinic Clinical Clinical Data Cognition Cognitive Complement 1q Complex Contusions DNA Binding Data Decision Making Development Diffuse Dose Enrollment Enzyme-Linked Immunosorbent Assay Epitopes Extracellular Fluid FDA approved Glial Fibrillary Acidic Protein Glutamate Transporter Glutamates Goals Hour Human IgG1 IgG2 Immunization Immunoglobulin G Immunotherapy In Vitro Infusion procedures Injury Intravenous Knockout Mice Laboratories Lead Legal patent Lesion Macaca fascicularis Magnetic Resonance Imaging Measures Mediating Medicine Microglia Modeling Monitor Monoclonal Antibodies Morbidity - disease rate Motor Mus N-terminal Nature Nerve Degeneration Nervous System Trauma Neurofilament-H Neurofilament-L Neurons Oligonucleotides Opsonin Outcome Outcome Measure Passive Immunotherapy Patients Phagocytes Phagocytosis Pharmacodynamics Phase Plasma Post-Traumatic Epilepsy Predisposition Proteins Publications Rattus Recovery Recurrence Reporting Research Retina Retinal Ganglion Cells Route Safety Sampling Seizures Specificity Stress Structure Synapses TBI Patients TFRC gene Testing Therapeutic Therapeutic Monoclonal Antibodies Toxic effect Translations Traumatic Brain Injury Variant Vascular Endothelial Cell Work antibody conjugate antibody immunotherapy attenuation axon injury base biomarker signature brain cell brain repair controlled cortical impact cytotoxic efficacy study fluid percussion injury improved in vitro activity in vivo in vivo evaluation injured lead candidate mortality mouse model neoantigens neurobehavioral neurofilament neuroinflammation neuronal cell body neuropathology neurotoxic neurotoxicity nonhuman primate novel novel therapeutics pharmacodynamic biomarker precision medicine preclinical study predictive marker preservation protective effect protein aggregation receptor targeted biomarker tau Proteins tau-1 therapeutic target transcytosis treatment response ubiquitin C-terminal hydrolase uptake

项目摘要

ABSTRACT Traumatic brain injury (TBI) is a leading cause of mortality and morbidity in the US, with over two million new patients each year and no FDA-approved therapeutics. TBI induces an early, high concentration wave of cytotoxic glutamate into synapses that exceeds the buffering capacity of astroglial glutamate transporters (e.g. GLT-1), causing injury and death of brain cells. Under these neurotrauma conditions, the calpain- generated, 38 kDa core breakdown product of glial fibrillary acidic protein (GBDP) was released from injured astrocytes within hours to days post-injury. In parallel, other protein “debris” are released from neuronal cell bodies (ubiquitin C terminal hydrolase 1 /UCH-L1) and injured axons (neurofilament-heavy /pNF-H and light /NF-L, Tau and phosphorylated Tau /p-Tau). In fact, our most recent clinical data from TRACK-TBI and CENTER-TBI multicenter consortium studies showed that GFAP/GDBPs are the most the abundant protein debris released into the circulation after TBI. Significantly, we and others discovered that GBDPs are prone to form protein aggregates that are neurotoxic when externalized. Grus and coworkers reported that anti-GFAP antibodies have neuroprotective effects on cultured neuro-retinal cells and on retinal ganglion cells in organotypic culture under stress. Similarly, GBDP active immunization was neuroprotective in a mouse model of TBI, including attenuation of GBDP levels, reduction of key neuropathological biomarkers of TBI, and improvement of neurofunctional outcomes. Therefore, our central hypothesis is that passive immunotherapy with effector-competent IgG monoclonal antibodies (mAbs) against GBDP will accelerate brain repair and improve cognition and other outcome measures in TBI patients. Our proposed mechanism of action is the beneficial opsonization of neurotoxic GBDP debris by anti-GBDP mAb (IgG), followed by accelerated phagocytosis by activated FcγR+ phagocytes. Our content of use is TBI patients with a significant injury, as defined by moderate to severe TBI patients with initial GCS of 6-12 and elevated levels of selected acute temporal predictive biomarkers for targeted enrollment. Our proposed route of administration is intravenous multiday infusion of anti-GBDP mAbs to maximize brain exposure, with subacute temporal pharmacodynamic (PD) biomarkers (such as GBDP, NFL, Tau and p-Tau) to track treatment response and adjust dosing. In this project, we leverage our synergistic expertise to test our hypothesis with (Phase I) proof-of-concept in vitro and cell-based studies prior to (Phase II) in vivo dose-ranging and efficacy studies to prioritize and characterize our lead anti-GBDP mAb immunotherapy candidates. Our preliminary preclinical studies now show that pre-injury, active immunization with GDBP AND post- injury passive immunotherapy with anti-GBDP mAbs are safe and beneficial in TBI mice. Moreover, we show how PD biomarkers might be employed to track treatment response and adjust dosing for successful translation from the laboratory to the clinic and to aid in meaningful benefit–risk decision-making.

抽象的创伤性脑损伤（TBI）是美国死亡率和发病率的主要原因，每年超过200万名新患者，没有FDA批准的疗法。 TBI 诱导早期，高浓度的细胞毒性谷氨酸到突触中超过星形胶质细胞谷氨酸转运蛋白（例如GLT-1）的缓冲能力，导致脑细胞的损伤和死亡。在这些神经疾病条件下，钙蛋白酶生成的38 kDa核心分解产物的胶质原纤维酸性蛋白（GBDP）为伤害后几小时内从受伤的星形胶质细胞释放。并行，其他蛋白“碎屑”是从神经元细胞体释放的（泛素C末端水解酶1 /UCH-L1）和受伤的轴突（神经丝（神经丝），PNF-H和Light /nf-L，Tau和磷酸化的tau /p-tau）。实际上，我们来自Track-TBI和中心-TBI多中心联盟研究表明，GFAP/GDBP是最多的 TBI后，绝对蛋白质碎片释放到循环中。重要的是，我们和其他人发现GBDP容易形成神经毒性的蛋白质聚集体当外部化时。格鲁斯和同事报告说抗GFAP抗体具有神经保护作用对培养的神经视网膜细胞和视网膜神经节细胞的影响压力下有机培养。同样，GBDP主动免疫抑制为 TBI小鼠模型中的神经保护作用，包括GBDP水平的衰减，减少TBI的关键神经病理生物标志物和改善神经功能的结果。因此，我们的中心假设是被动的具有效应能力的IgG单克隆抗体（mAb）的免疫疗法针对 GBDP将加速大脑修复并改善认知和其他结果指标在TBI患者中。我们提出的作用机制是对抗GBDP MAB（IgG）的神经毒性GBDP碎片，然后加速活化的FcγR+吞噬细胞的吞噬作用。我们的使用内容是TBI患者严重伤害，由中度至重度TBI患者定义，初始GC为6-12 以及针对目标的选定急性临时预测生物标志物的水平升高注册。我们提出的给药途径是静脉内输注的抗GBDP mAbs以最大程度地暴露脑暴露用于跟踪的药效学（PD）生物标志物（例如GBDP，NFL，TAU和P-TAU）治疗反应并调整剂量。在这个项目中，我们利用我们的协同作用通过（I阶段）体外和基于细胞的概念验看来检验我们的假设的专业知识在（II期）体内剂量 - 量和效率研究之前的研究优先级和表征我们的铅抗GBDP MAB免疫疗法候选。我们的初步临床前研究现在表明，受伤前，使用GDBP的主动免疫和后用抗GBDP mAB损伤被动免疫疗法在TBI中是安全且有益的老鼠。此外，我们展示了如何雇用PD生物标志物来跟踪治疗反应并调整剂量，以成功地从实验室转换为诊所并协助有意义的福利 - 风险决策。