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

基本信息

批准号：
10164043
负责人：
Anne-Marie Carbonell
金额：
$ 4.4万
依托单位：
ONCOSYNERGY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10164043
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

项目摘要

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.

项目概要创伤性脑损伤 (TBI) 具有重大的社会和经济影响，迄今为止，FDA 尚无此类影响。经批准的预防或逆转 TBI 的药物疗法紧急情况下的护理标准重点关注。首先是稳定患者，其次是脑血流动力学的管理。手术清除血肿、修复颅骨骨折、缓解颅内压。干预措施旨在控制症状，可能包括抗凝剂、抗惊厥剂、抗焦虑剂、归根结底，目前治疗 TBI 的方法只能起到改善作用，并不能缓解症状。生化损伤是脑损伤的原因，因此，对这种药物的需求存在显着的未满足的需求。限制或预防与 TBI 相关的继发性神经损伤的药物是多种药物。大脑、外周和免疫系统之间复杂相互作用的系统病理学。多年来，来自 TBI 患者和脑损伤动物模型的越来越多证据表明，外周免疫激活增强 TBI 引起的神经功能障碍和脑病理学。重要的是，淋巴细胞的脑侵袭很大程度上取决于白细胞晚期的相互作用抗原4（VLA-4；整合素α4β1）与内皮细胞上的血管细胞粘附分子1（VCAM-1）。其他β1整合素也可能参与其中，从而产生潜在的逃逸机制，因此，针对多个β1。整合素可能介导白细胞侵袭中枢神经系统，具有限制或预防的治疗潜力 OncoSynergy 开发了 OS2966，这是一种专有的、首创的。我们的 IND 支持研究证明了同类人源化单克隆泛 CD29/β1 整合素/ITGB1 抗体。每周重复静脉注射 OS2966 在非人类灵长类动物中具有良好的耐受性，没有死亡， 2019 年 3 月，临床症状、大体病理学或最大耐受剂量 (MTD) 达到（高达 35 毫克/千克）。 FDA 批准我们的 IND 启动针对复发性胶质母细胞瘤患者使用脑内注射的 I 期临床试验 OS2966的已知药理学和安全性特征为快速交付提供了强有力的支持。在成功完成概念验证研究后，将该药物转化为 TBI 的临床试验。我们建议与费城儿童医院的 Todd Kilbaugh 博士合作进行第一阶段 STTR 项目评估 OS2966 在高保真猪 TBI 模型中的功效。该 I 期 STTR 项目的进展将使进一步的 II 期研究能够优化 OS2966 的治疗方案 TBI 的多个猪模型，并将 OS2966 推进到 TBI 患者的 2 期概念验证疗效研究。