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), causinginjury 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 andCENTER-TBI multicenter consortium studies showed that GFAP/GDBPs are the mostthe 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 measuresin TBI patients. Our proposed mechanism of action is the beneficial opsonization ofneurotoxic GBDP debris by anti-GBDP mAb (IgG), followed by acceleratedphagocytosis by activated FcγR+ phagocytes. Our content of use is TBI patients with asignificant injury, as defined by moderate to severe TBI patients with initial GCS of 6-12and elevated levels of selected acute temporal predictive biomarkers for targeted enrollment. Our proposed route of administration is intravenous multiday infusion ofanti-GBDP mAbs to maximize brain exposure, with sub acute 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.
Public Health Relevance Statement: Narrative
Traumatic brain injury (TBI) is a leading cause of mortality and morbidity around the world with approximately two million new patients each year in the US alone and no approved medicines. We hypothesize that immunotherapy with monoclonal antibodies (mAbs) will accelerate nature's own mechanisms for devouring some of the most abundant and harmful brain cell debris that is released into the extracellular fluid of the brain during TBI. If successful, then mAb immunotherapy will be the first precision medicine to accelerate brain repair and improve cognition for TBI patients.
Project Terms: Animals ; Antibodies ; Monoclonal Antibodies ; Clinical Treatment Moab ; mAbs ; Epitopes ; Antigenic Determinants ; Binding Determinants ; Anxiety ; Astrocytes ; Astrocytus ; Astroglia ; astrocytic glia ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Blood Circulation ; Bloodstream ; Circulation ; Brain ; Brain Nervous System ; Encephalon ; Buffers ; Calpain ; Ca2+-Activated Protease ; Calcium-Activated Neutral Protease ; Calcium-Activated Neutral Proteinase ; Calcium-Activated Protease ; Calcium-Dependent Neutral Protease ; Calcium-Dependent Neutral Proteinase ; Desminase ; Papain-Like Cysteine Protease ; Cells ; Cell Body ; Cognition ; Complement 1q ; C1 q ; C1q ; Complement C1q ; Contusions ; Bruise ; Cessation of life ; Death ; Decision Making ; Enzyme-Linked Immunosorbent Assay ; ELISA ; Post-Traumatic Epilepsy ; Post-Traumatic Seizure Disorder ; Posttraumatic Epilepsy ; Posttraumatic Seizure Disorder ; Traumatic Epilepsy ; Extracellular Fluid ; Glial Fibrillary Acidic Protein ; Astroprotein ; GFA-Protein ; GFAP ; Glial Fibrillary Acid Protein ; Glial Intermediate Filament Protein ; Glutamates ; L-Glutamate ; glutamatergic ; Goals ; Human ; Modern Man ; Immunoglobulin G ; 7S Gamma Globulin ; IgG ; IgG1 ; IgG2 ; Immunization ; Immunologic Sensitization ; Immunologic Stimulation ; Immunological Sensitization ; Immunological Stimulation ; Immunostimulation ; Immunotherapy ; Immune mediated therapy ; Immunologically Directed Therapy ; immune therapeutic approach ; immune therapeutic interventions ; immune therapeutic regimens ; immune therapeutic strategy ; immune therapy ; immune-based therapies ; immune-based treatments ; immuno therapy ; In Vitro ; Laboratories ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Macaca fascicularis ; Crab-Eating Macaque ; Crab-Eating Monkey ; Cynomolgus Monkey ; Cynomolgus macaque ; M fascicularis ; M. fascicularis ; Magnetic Resonance Imaging ; MR Imaging ; MR Tomography ; MRI ; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance ; NMR Imaging ; NMR Tomography ; Nuclear Magnetic Resonance Imaging ; Zeugmatography ; Medicine ; Morbidity - disease rate ; Morbidity ; mortality ; Mus ; Mice ; Mice Mammals ; Murine ; Nerve Degeneration ; Neuron Degeneration ; neural degeneration ; neurodegeneration ; neurodegenerative ; neurological degeneration ; neuronal degeneration ; neurofilament ; Neurons ; Nerve Cells ; Nerve Unit ; Neural Cell ; Neurocyte ; neuronal ; Oligonucleotides ; Oligo ; oligos ; Opsonin ; Legal patent ; Patents ; Patients ; Phagocytes ; Phagocytic Cell ; amebocyte ; Phagocytosis ; Plasma ; Blood Plasma ; Plasma Serum ; Reticuloendothelial System, Serum, Plasma ; Proteins ; Publications ; Scientific Publication ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; Recurrence ; Recurrent ; Research ; Retina ; Retinal Ganglion Cells ; retinal ganglion ; Safety ; Seizures ; Specificity ; Stress ; Synapses ; Synaptic ; synapse ; Testing ; Translations ; Work ; Glutamate Transporter ; Glutamate Translocase ; Glutamate Transport Glycoprotein ; Measures ; tau Proteins ; MT-bound tau ; microtubule bound tau ; microtubule-bound tau ; tau ; tau factor ; Ï Proteins ; Mediating ; Outcome Measure ; brain repair ; ubiquitin C-terminal hydrolase ; Ubiquitin C-Terminal Esterase ; Ubiquitin Carboxy-Terminal Esterase ; Ubiquitin Carboxy-Terminal Hydrolase ; Ubiquitin Thiolesterase ; Injury ; injuries ; base ; improved ; Acute ; Clinical ; Diffuse ; Phase ; Variant ; Variation ; Active Immunization ; Microglia ; Hortega cell ; gitter cell ; mesoglia ; microglial cell ; microgliocyte ; perivascular glial cell ; Knockout Mice ; KO mice ; Knock-out Mice ; Null Mouse ; Predisposition ; Susceptibility ; Lesion ; nonhuman primate ; non-human primate ; Recovery ; uptake ; tau-1 ; p-tau ; p-Ï ; phospho-tau ; phospho-Ï ; phosphorylated tau ; Therapeutic ; cleaved ; Cleaved cell ; Intravenous ; Nature ; Hour ; Complex ; Clinic ; Route ; Infusion ; Infusion procedures ; brain cell ; Receptor Protein ; receptor ; transcytosis ; antibody conjugate ; neural cell body ; soma ; neuronal cell body ; attenuation ; passive immune therapy ; passive immunotherapeutics ; Passive Immunotherapy ; Toxicities ; Toxic effect ; Structure ; novel ; Benefits and Risks ; Reporting ; Nervous System Injuries ; Nervous System damage ; Neurological Damage ; Neurological Injury ; Neurological trauma ; neurotrauma ; Nervous System Trauma ; Pharmacodynamics ; Modeling ; Sampling ; Brain Trauma ; traumatic brain damage ; Traumatic Brain Injury ; neuropathology ; DNA Binding Interaction ; DNA bound ; DNA Binding ; Molecular Interaction ; Binding ; Vascular Endothelial Cell ; CD71 ; TFR gene ; TFR protein ; TFR1 ; TFRC ; TRFR ; Transferrin Receptor ; Transferrin Receptor 1 ; TFRC gene ; Dose ; Affinity ; cytotoxic ; Data ; Motor ; in vivo ; Clinical Data ; Cognitive ; Enrollment ; enroll ; Neurofilament-H ; NF-H ; Neurofilament-L ; NF-L ; Monitor ; C57BL/6 Mouse ; Development ; developmental ; preclinical study ; pre-clinical study ; injured ; neurobehavioral ; fluid percussion injury ; controlled cortical impact ; neuroinflammation ; neuroinflammatory ; protein aggregation ; insoluble aggregate ; protein aggregate ; Outcome ; TBI Patients ; Patients with traumatic brain injury ; protective effect ; N-terminal ; NH2-terminal ; C-terminal ; Therapeutic Monoclonal Antibodies ; MAb Therapeutics ; monoclonal antibody drugs ; therapeutic mAbs ; neurotoxic ; neurotoxicity ; neuron toxicity ; neuronal toxicity ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; mouse model ; murine model ; therapeutic target ; FDA approved ; treatment response ; response to treatment ; therapeutic response ; Biological Markers ; bio-markers ; biologic marker ; biomarker ; in vitro activity ; precision medicine ; precision-based medicine ; predictive marker ; predictive biomarkers ; predictive molecular biomarker ; axon injury ; axon damage ; axonal damage ; axonal injury ; targeted biomarker ; pharmacodynamic biomarker ; pharmacodynamic marker ; efficacy study ; neoantigens ; neo-antigen ; neo-epitopes ; neoepitopes ; antibody immunotherapy ; preservation ; lead candidate ; in vivo evaluation ; in vivo testing ; biomarker signature ;
