Novel monoclonal antibody for single dose treatment of acute CNS injury

单剂量治疗急性中枢神经系统损伤的新型单克隆抗体

• 批准号: 10023963
• 负责人: Anne-Marie Carbonell
• 金额: $ 20万
• 依托单位: ONCOSYNERGY, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10023963
• 关键词: Accelerometer; Achievement; Acute; American; Animal Model; Animals; Anti-Anxiety Agents; Antibodies; Anticoagulants; Anticonvulsants; Antidepressive Agents; Basement membrane; Biochemical; Brain; Brain Injuries; Brain Pathology; CD8B1 gene; Cells; Cellular Assay; Cerebral hemisphere hemorrhage; Cerebrum; Cessation of life; Chemosensitization; Clinical; Clinical Trials; Cognitive; Cognitive Therapy; Complex; Cortical Contusions; Dose; Emergency department visit; Endothelial Cells; Epitopes; Extravasation; FDA approved; Family Relationship; Family suidae; Freezing; Glioblastoma; Hematoma; Hospitalization; Hour; Immune; Immune system; In Vitro; Infiltration; Injury; Integrin alpha4; Integrin alpha4beta1; Integrins; Intervention; Intracranial Pressure; Intravenous; Ischemia; Leptomeninges; Leukocytes; Life; Ligand Binding; Ligands; Long-Term Effects; Lymphocyte; Magnetic Resonance Imaging; Maximum Tolerated Dose; Mediating; Medical Care Costs; Modeling; Molecular; Monoclonal Antibodies; Nervous System Trauma; Neurologic Dysfunctions; Occupational; Operative Surgical Procedures; PTPRC gene; Pathology; Patients; Pattern; Pediatric Hospitals; Peripheral; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacotherapy; Phase; Phase I Clinical Trials; Philadelphia; Play; Prevention; Production; Quality of life; Recurrence; Rehabilitation therapy; Role; Safety; Severities; Site; Skull Fractures; Small Business Technology Transfer Research; Speech; Stroke; Structure of choroid plexus; Therapeutic; Tissues; Translating; Trauma; Traumatic Brain Injury; Treatment Protocols; Vascular Cell Adhesion Molecule-1; actigraphy; animal efficacy; career; central nervous system injury; cerebral hemodynamics; chemokine; controlled cortical impact; cranium plastic repair; cross reactivity; cytokine; disability; economic impact; efficacy study; emergency settings; first responder; humanized monoclonal antibodies; immune activation; in vivo; inhibitor/antagonist; mortality; natalizumab; neurobehavioral; neuroimaging; neutrophil; nonhuman primate; novel; phase 2 study; prevent; primary outcome; psychosocial; receptor; recruit; secondary outcome; standard of care; symptom management; treatment arm; treatment optimization; ventricular system

PROJECT SUMMARY Traumatic brain injury (TBI) represents a significant societal and economic impact. To date, there are no FDA- approved pharmacotherapies to prevent or reverse TBI. The standard of care in an emergency setting focuses first on stabilizing the patient and secondly on management of cerebral hemodynamics. The patient may undergo surgery to remove hematomas, repair skull fractures, and relieve intracranial pressure. Pharmacological interventions are aimed at symptom management and may include anticoagulants, anticonvulsants, anxiolytics, and antidepressants. Ultimately, the current approaches to treating TBI are ameliorative and do not mitigate the biochemical insult that is the cause of brain damage. Hence, there is a significant unmet need for pharmacological agents to limit or prevent secondary neurological damage associated with TBI. TBI is a multi- system pathology with complex interactions between the brain, the periphery, and the immune system. In recent years, mounting evidence from both TBI patients and animal models of brain injury suggest a critical role for peripheral immune activation in the potentiation of TBI-induced neurological dysfunction and brain pathology. Importantly, cerebral invasion of lymphocytes crucially depends on the interaction of the leukocyte very late antigen-4 (VLA-4; integrin α4β1) with vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells. However, other β1 integrins may also be involved, creating a potential escape mechanism. Hence, targeting multiple β1 integrins which may mediate leukocyte invasion of the CNS has therapeutic potential to limit or prevent secondary neurological damage associated with TBI. OncoSynergy has developed OS2966, a proprietary, first- in-class humanized monoclonal pan-CD29/β1 integrin/ITGB1 antibody. Our IND-enabling studies demonstrated that repeat weekly intravenous dosing of OS2966 is well tolerated in non-human primates with no mortality, clinical signs, gross pathology, or maximum tolerated dose (MTD) reached (up to 35 mg/kg). In March 2019, FDA cleared our IND to initiate a Phase I clinical trial in patients with recurrent glioblastoma using intracerebral delivery of OS2966. The known pharmacology and safety profiles of OS2966 provide a strong support to quickly translate this drug to clinical trials for TBI, upon the successful completion of the proof-of-concept study. Hence, we propose to collaborate with Dr. Todd Kilbaugh at Children's Hospital of Philadelphia to conduct this Phase I STTR project to evaluate the efficacy of OS2966 in a high-fidelity porcine model of TBI. Successful achievement of this Phase I STTR project will enable further Phase II studies to optimize the treatment regimen of OS2966 in multiple porcine models of TBI and advance OS2966 to Phase 2 proof of concept efficacy studies in TBI patients.

项目摘要 创伤性脑损伤（TBI）是一个重大的社会和经济影响。到目前为止，没有FDA- 获得批准的药物治疗，以预防或逆转TBI。紧急情况下的护理标准侧重于 首先是稳定病人，其次是管理脑血流动力学。患者可能会经历 手术切除血肿，修复颅骨骨折，减轻颅内压。药理 干预措施的目的是控制症状，可能包括抗凝血剂、抗惊厥剂、抗焦虑剂， 和抗抑郁药最后，目前治疗TBI的方法是改善性的，并且不能减轻TBI的严重性。 是导致脑损伤的生化损伤因此，有一个重大的未满足的需要， 本发明提供了限制或预防与TBI相关的继发性神经损伤的药理学试剂。TBI是一种多- 系统病理学与大脑，外周和免疫系统之间的复杂相互作用。近几 多年来，来自TBI患者和脑损伤动物模型的越来越多的证据表明， 外周免疫激活增强TBI诱导的神经功能障碍和脑病理学。 重要的是，脑内淋巴细胞的侵入非常晚地依赖于白细胞的相互作用 抗原-4（VLA-4;整合素α4β1）与血管细胞粘附分子-1（VCAM-1）在内皮细胞上的作用。然而，在这方面， 其他β1整联蛋白也可能参与，产生潜在的逃逸机制。因此，针对多个β1 可能介导白细胞侵入CNS的整联蛋白具有限制或预防白细胞侵入CNS的治疗潜力。 与创伤性脑损伤相关的继发性神经损伤OncoSynergy开发了OS 2966，这是一个专有的，第一个- 类内人源化单克隆泛CD 29/β1整联蛋白/ITGB 1抗体。我们的IND研究表明， OS 2966每周重复静脉给药在非人灵长类动物中耐受良好，无死亡， 临床体征、大体病理学或达到的最大耐受剂量（MTD）（高达35 mg/kg）。2019年3月， FDA批准了我们的IND，开始在复发性胶质母细胞瘤患者中进行I期临床试验， 操作系统2966。OS 2966的已知药理学和安全性特征为快速 在成功完成概念验证研究后，将这种药物转化为TBI的临床试验。因此，我们认为， 我们建议与费城儿童医院的托德·基尔博博士合作， STTR项目旨在评价OS 2966在高保真TBI猪模型中的疗效。成功实现 该I期STTR项目的完成将使进一步的II期研究能够优化OS 2966的治疗方案， TBI的多个猪模型，并将OS 2966推进到TBI患者中的概念疗效研究的2期验证。