Development of Novel sgp130-Fc Bioconjugates for TBI

用于 TBI 的新型 sgp130-Fc 生物共轭物的开发

• 批准号: 10601623
• 负责人: William E Haskins
• 金额: $ 48.5万
• 依托单位: GRYPHON BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10601623
• 关键词: Acute; Affect; Aftercare; Binding; Biological; Biological Assay; Biological Markers; Biological Products; Blocking Antibodies; Blood - brain barrier anatomy; Capillary Endothelial Cell; Cellular Immunity; Central Nervous System; Cerebrospinal Fluid; Chimeric Proteins; Chronic; Chronic Disease; Chronic Phase; Circular DNA; Circulation; Clinical; Clinical Data; Clinical Research; Clinical Trials; Cognitive; Cognitive deficits; Complement; Complex; Data; Development; Drug Kinetics; Environment; FDA approved; Family; Female; Future; Goals; Half-Life; Histologic; Homeostasis; Human; IgG1; Immune; Immunotherapy; Impaired cognition; In Vitro; Individual; Inflammation Mediators; Inflammatory; Injury; Interleukin-6; Knowledge; Lead; Link; Literature; Mediating; Memory; Mental Depression; Modeling; Monoclonal Antibodies; Mood Disorders; Morbidity - disease rate; Motor; Mus; Mutation; Nerve Degeneration; Nervous System Physiology; Nervous System Trauma; Neuropsychological Tests; Oligonucleotides; Outcome; Pathogenicity; Pathology; Pattern; Penetrance; Peripheral; Pharmaceutical Preparations; Phase; Process; Publishing; Rattus; Recombinants; Recovery; Rehabilitation therapy; Reporting; Research; Research Design; Risk; Risk Reduction; Serum; Signal Transduction; Small Business Innovation Research Grant; Specificity; T-Lymphocyte; TBI treatment; TFRC gene; Testing; Therapeutic; Traumatic Brain Injury; Traumatic Brain Injury recovery; Treatment Efficacy; Work; blood-brain barrier penetration; brain tissue; cell type; cerebral capillary; clinical biomarkers; cognitive performance; cognitive testing; controlled cortical impact; executive function; functional outcomes; glial activation; high risk; immune function; improved; improved outcome; in vivo; inflammatory marker; male; mouse model; mutant; neurobehavioral; neuroinflammation; neuroprotection; neutrophil; novel; novel therapeutics; performance tests; pre-clinical research; protective effect; public health relevance; receptor; risk mitigation; systemic inflammatory response; therapeutic target; tocilizumab; transcytosis; translational approach; translational potential; uptake

ABSTRACT 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.

摘要