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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.

摘要