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.

项目摘要创伤性脑损伤（TBI）代表着重大的社会和经济影响。迄今为止，没有FDA- 批准的药物疗法可预防或反向TBI。紧急环境中的护理标准聚焦首先是稳定患者，其次是在脑血液动力学的治疗上。病人可能会经历手术可去除血肿，修复头骨骨折并挽救颅内压。药理干预措施针对SEM管理，可能包括抗凝剂，抗惊厥药，抗焦虑药，和抗抑郁药。最终，当前治疗TBI的方法是改善的，不会减轻生化侮辱是脑损伤的原因。因此，对药理剂限制或预防与TBI相关的继发神经系统损害。 TBI是一个多大脑，外围和免疫系统之间具有复杂相互作用的系统病理学。最近多年来，来自TBI患者和脑损伤动物模型的越来越多的证据表明， TBI诱导的神经功能障碍和脑病理学增强的外周免疫激活。重要的是，淋巴细胞的大脑入侵完全取决于白细胞的相互作用抗原4（VLA-4;整联蛋白α4β1）在内皮细胞上具有血管细胞粘附分子-1（VCAM-1）。然而，其他β1整联蛋白也可能涉及，从而产生潜在的逃生机制。因此，针对多个β1 可能介导CNS的白细胞入侵的整合素具有限制或预防的治疗潜力与TBI相关的继发神经系统损害。 Oncosynergy开发了OS2966，这是一个专有的，首先类人源化的单克隆pan-CD29/β1整合素/ITGB1抗体。我们的指导研究证明了 OS2966的每周重复静脉注射剂量在非人类隐私中耐受性良好，没有死亡率，达到临床体征，总病理或最大耐受剂量（MTD）（高达35 mg/kg）。 2019年3月， FDA清除了我们的IND，以使用脑内脑内的复发性胶质母细胞瘤患者进行I期临床试验 OS2966的交付。 OS2966已知的药理学和安全概况为快速的概念证明研究成功完成后，将此药物转换为TBI的临床试验。因此，我们建议与费城儿童医院的托德·基尔博博士合作进行I阶段I STTR项目评估OS2966在TBI的高保真猪模型中的效率。成功的成就 I阶段I的STTR项目将使进一步的II期研究优化OS2966的治疗方案 TBI的多种猪模型和将OS2966推进到TBI患者的概念有效性研究的第2阶段证明。