Development of Novel sgp130-Fc Bioconjugates for TBI

用于 TBI 的新型 sgp130-Fc 生物共轭物的开发

基本信息

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
项目类别：
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

项目摘要

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.

抽象的患有中度至重度创伤性脑损伤 (TBI) 的个体面临多种长期损伤的高风险尽管人们对急性继发性损伤级联的了解有所增加，对于伴随继发性病症的慢性病理学的潜在机制知之甚少，因此，TBI 慢性、康复阶段的治疗方法存在差距。支持神经恢复并降低继发性疾病的风险。表明急性脑脊液 (CSF) IL-6 水平与严重 TBI 后的结局相关，并且第一周的这些时间性 IL-6 谱识别出潜在的亚急性和慢性外周炎症我们发表的研究表明，包括 IL-6 在内的与长期功能结果相关的标记物更高。受伤后前 3 个月内血清 sIL-6R 与整体认知能力较差相关在受伤后 6 个月和 12 个月进行评估，但 sgp130/sIL-6R 比率较高与更好的认知能力相关测试性能表明 sgp130 对 sIL-6R 相关“反式信号传导”具有潜在的保护作用。抑郁症也与 sIL-6R 水平有关，我们的临床数据显示 sIL-6R 对全球抑郁症有调节作用结果表明，高 sIL-6R 信号传导负载有利于有害的 IL-6“反式信号传导”环境，我们认为促进中枢神经系统损伤，而低建议的 sIL-6R 负载有利于我们建议的有益的经典信号传导这些临床数据表明 sIL-6R 是急性期后的可修改靶点。 TBI 恢复的康复阶段，sgp130 可能是改善预后的可行治疗方法。这些临床研究结果得到了使用皮质冲击损伤的体内研究的补充 (CCI) 小鼠和大鼠 TBI 模型显示 sgp130-Fc 生物缀合物可以减少认知缺陷、中枢神经系统亲然而，各种突变和与 CCI 相关的炎症信号传导和组织学损伤。 sgp130-Fc 的缀合物，包括抗转铁蛋白受体（抗 mTfR Oligo）sgp130-Fc 生物缀合物，可能促进血脑屏障 (BBB) 穿透并减少 TBI 后中枢神经系统 sIL-6R 反式信号传导。将重点关注体外概念验证研究，以开发和评估新型 sgp130-Fc 生物缀合物（带有 IgG1） mAb 作为同种型对照（第一阶段），开发新型抗 TfR Oligo/sgp130-Fc 生物缀合物并评估其使用 TBI 的 CCI 小鼠模型（第二阶段）在体内的影响我们将通过以下方式选择先导生物结合物候选物。对严重 CCI 后的雄性和雌性小鼠进行治疗后，测试 1° 和 2° 终点的疗效。包括 PK 测定、小胶质细胞激活/摄取、sIL-6R 反式信号传导阻断和治疗效果。将通过检查促炎和中枢神经系统的血清/中枢神经系统负荷减少来评估治疗效果生物标志物、脑组织保护、细胞免疫正常化和神经行为改善这项工作将支持未来开发可行的人类 sgp130-Fc 生物缀合物的研究。中度至重度TBI后的临床、阶段康复治疗。