Individuals with moderate-to-severe traumatic brain injuries (TBI) are at high risk for multiple long-term complications and poor neuro-recovery. Despite increased knowledge about acute secondary injury cascades, far less is known about mechanisms underlying the chronic pathology that accompany secondary conditions and influence TBI outcome. Thus, there is a gap in therapeutics for the chronic, rehabilitation phases of TBI that support neurorecovery and mitigate risk for secondary conditions. Our published clinical research suggests that acute cerebrospinal fluid (CSF) IL-6 levels are associated with outcome after severe TBI, and these temporal IL-6 profiles over the first week identified potential sub-acute and chronic peripheral inflammatory markers, including IL-6, that associate with long-term functional outcome. Our published work shows that higher serum sIL-6R during the first 3 months post-injury are associated with worse overall cognitive performance assessed 6- and 12- months post-injury, yet higher ratios of sgp130/sIL-6R are associated with better cognitive testing performance indicating a potential protective effect of sgp130 against sIL-6R associated "trans-signaling". Depression is also linked to sIL-6R levels, and our clinical data show a moderating effect of sIL-6R on global outcomes wherein high sIL-6R signaling loads favor a detrimental IL-6 "trans-signaling" environment that we propose facilitates CNS damage, while low sIL-6R loads favor beneficial classical signaling that we propose supports neurorecovery. These clinical data suggest that sIL-6R is a modifiable target in the post-acute rehabilitation phase of TBI recovery for which sgp130 may be a viable treatment that improves outcome. These clinical research findings are complemented by in vivo studies using the controlled cortical impact injury (CCI) model of TBI in mice and rats showing sgp130-Fc bioconjugates can reduce cognitive deficits, CNS pro- inflammatory signaling, and histological damage associated with CCI. However, various mutations and conjugations of sgp130-Fc, including anti-transferrin receptor (anti-mTfR Oligo) sgp130-Fc bioconjugates, may facilitate blood brain barrier (BBB) penetration and reduce CNS sIL-6R trans-signaling after TBI. Thus, this SBIR will focus on proof-of-concept in vitro studies to develop and assess novel sgp130-Fc bioconjugates, with IgG1 mAbs as isotype controls (Phase I), and develop novel anti-TfR Oligo/sgp130-Fc bioconjugates and assess their effects in vivo using the CCI mouse model of TBI (Phase II). We will select lead bioconjugate candidates by testing 1° and 2° endpoints for efficacy following treatment in male and female mice after severe CCI. These include PK assays, microglial activation/uptake, sIL-6R trans-signaling blockade, and treatment efficacy. Treatment efficacy will be assessed by examining reduced serum/CNS load of pro-inflammatory and CNS biomarkers, brain tissue sparing, normalization of cellular immunity, and improvements in neurobehavioral assessments. This work will support future studies developing viable human sgp130-Fc bioconjugates for clinical, rehabilitation phase treatment after moderate to severe TBI.
Public Health Relevance Statement: NARRATIVE Given the dearth of effective neuroprotective or neuroreparative treatments for TBI, this study carries great public health relevance in that it aims to establish novel sgp130-Fc bioconjugate agents as effective immunotherapies that facilitate neurorecovery in the post-acute phase of TBI and reduce risk from the many secondary conditions (e.g., cognitive dysfunction, mood disorders) linked to homeostatic disruptions in immune function after TBI. We have leveraged a reverse translational approach, grounded in clinical biomarker data, to identify sIL-6R signaling as a potential therapeutic target, and the benefits of sgp130-Fc observed in our pilot data in experimental TBI support the rationale for the study design and goals proposed, which aim to inform future TBI clinical trials with sgp130-Fc bioconjugates that are both compatible and safe for human use.
Project Terms: Affect; After Care; After-Treatment; post treatment; Aftercare; Clinical Treatment Moab; mAbs; monoclonal Abs; Monoclonal Antibodies; Biological Assay; Assay; Bioassay; Biologic Assays; Biological Products; Biologic Products; Biological Agent; biologics; biopharmaceutical; biotherapeutic agent; Blood - brain barrier anatomy; Blood-Brain Barrier; Hemato-Encephalic Barrier; bloodbrain barrier; Cerebrospinal Fluid; cerebral spinal fluid; spinal fluid; Chronic Disease; Chronic Illness; chronic disorder; Clinical Research; Clinical Study; Clinical Trials; Complement; Complement Proteins; Mental Depression; depression; Circular DNA; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Environment; Family; Female; Future; Goals; Half-Life; Homeostasis; Autoregulation; Physiological Homeostasis; Human; Modern Man; IgG1; Cellular Immunity; Cell Mediated Immunology; Cell-Mediated Immunity; 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; Interleukin-6; B cell differentiation factor; B cell stimulating factor 2; B-Cell Differentiation Factor; B-Cell Differentiation Factor-2; B-Cell Stimulatory Factor-2; BCDF; BSF-2; BSF2; HPGF; Hepatocyte-Stimulating Factor; Hybridoma Growth Factor; IFN-beta 2; IFNB2; IL-6; IL6 Protein; MGI-2; Myeloid Differentiation-Inducing Protein; Plasmacytoma Growth Factor; interferon beta 2; Lead; Pb element; heavy metal Pb; heavy metal lead; Literature; male; Memory; Morbidity - disease rate; Morbidity; Mus; Mice; Mice Mammals; Murine; Mutation; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Nerve Degeneration; Neuron Degeneration; neural degeneration; neurodegeneration; neurodegenerative; neurological degeneration; neuronal degeneration; Nervous System Physiology; Neurologic function; Neurological function; nervous system function; Neuropsychological Tests; Neuropsychologic Tests; neutrophil; Blood Neutrophil; Blood Polymorphonuclear Neutrophil; Marrow Neutrophil; Neutrophilic Granulocyte; Neutrophilic Leukocyte; Polymorphonuclear Cell; Polymorphonuclear Leukocytes; Polymorphonuclear Neutrophils; Oligonucleotides; Oligo; oligos; Pathology; Drug Kinetics; Pharmacokinetics; Publishing; Rattus; Common Rat Strains; Rat; Rats Mammals; Rehabilitation therapy; Medical Rehabilitation; Rehabilitation; rehab therapy; rehabilitative; rehabilitative therapy; Research; Research Design; Study Type; study design; Risk; Signal Transduction; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Specificity; T-Lymphocyte; T-Cells; thymus derived lymphocyte; Testing; Work; Mediating; Chimera Protein; Fusion Protein; Chimeric Proteins; injuries; Injury; improved; Peripheral; Acute; Chronic; Clinical; Phase; biologic; Biological; Histologically; Histologic; Link; Blood Serum; Serum; Individual; Recovery; inflammatory mediator; Inflammation Mediators; uptake; Blocking Antibodies; Therapeutic; Inflammatory; Impaired cognition; Cognitive Disturbance; Cognitive Impairment; Cognitive decline; Cognitive function abnormal; Disturbance in cognition; cognitive dysfunction; cognitive loss; Knowledge; Immune; Immunes; Complex; cell type; Pattern; Chronic Phase; brain tissue; Penetrance; Mood Disorders; Affective Disorders; mutant; receptor; Receptor Protein; transcytosis; neuroprotection; neuroprotective; Cognitive deficits; cognitive defects; novel; Reporting; Nervous System Trauma; Nervous System Injuries; Nervous System damage; Neurological Damage; Neurological Injury; Neurological trauma; neurotrauma; Modeling; performance tests; Traumatic Brain Injury; Brain Trauma; traumatic brain damage; Central Nervous System; CNS Nervous System; Neuraxis; executive function; executive control; Pathogenicity; reduce risk; reduce risks; reduce that risk; reduce the risk; reduce these risks; reduces risk; reduces the risk; reducing risk; reducing the risk; risk-reducing; Risk Reduction; Molecular Interaction; Binding; Capillary Endothelial Cell; Cellular Immune Function; immune function; TFRC gene; CD71; TFR gene; TFR protein; TFR1; TFRC; TRFR; Transferrin Receptor; Transferrin Receptor 1; Data; Motor; Recombinants; in vivo; Clinical Data; Cognitive; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Process; Development; developmental; neurobehavioral; controlled cortical impact; neural inflammation; neuroinflammatory; neuroinflammation; functional outcomes; intervention efficacy; therapeutic efficacy; therapy efficacy; Treatment Efficacy; Outcome; protective effect; preclinical research; pre-clinical research; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; murine model; mouse model; therapeutic target; translation strategy; translational strategy; translational approach; high risk; public health relevance; FDA approved; inflammation marker; inflammatory marker; bio-markers; biologic marker; biomarker; Biological Markers; risk mitigation; TBI therapy; traumatic brain injury therapy; traumatic brain injury treatment; TBI treatment; cognitive performance; cognitive assessment; cognitive testing; TBI recovery; recovery after TBI; recovery after traumatic brain injury; Traumatic Brain Injury recovery; glial cell activation; glial activation; brain capillary; cerebral capillary; clinically useful biomarkers; clinical biomarkers; improved outcome; systemic inflammation; systemic inflammatory response; BBB penetration; bloodbrain barrier penetration; blood-brain barrier penetration; Actemra; tocilizumab; translational potential; translational opportunities; Circulation
