Novel monoclonal antibody for single dose treatment of acute CNS injury

项目总结 创伤性脑损伤(TBI)具有重大的社会和经济影响。到目前为止，还没有FDA- 经批准的预防或逆转脑损伤的药物疗法。紧急情况下的护理标准侧重于 首先是患者的稳定，其次是脑血流动力学的管理。患者可能会经历 清除血肿、修复颅骨骨折和减轻颅内压的手术。药理作用 干预措施的目标是症状管理，可能包括抗凝剂、抗惊厥药、抗焦虑药、 还有抗抑郁药。归根结底，目前治疗脑损伤的方法是改善的，并不能缓解 生化侮辱是导致大脑损伤的原因。因此，存在着大量未得到满足的需求 限制或预防与脑损伤相关的继发性神经损害的药物。TBI是一个多层次的 大脑、外周和免疫系统之间复杂的相互作用的系统病理学。在最近 多年来，来自脑外伤患者和脑损伤动物模型的越来越多的证据表明，脑损伤在脑损伤中的关键作用 外周免疫激活在脑损伤所致神经功能障碍和脑病理中的作用。 重要的是，淋巴细胞的脑侵袭在很晚的时候取决于白细胞的相互作用。 抗原-4(vla-4；α4β1)与血管细胞黏附分子-1(VCAM-1)结合于内皮细胞。然而， 其他β-1整合素也可能参与其中，形成一种潜在的逃逸机制。因此，以多个β1为目标 可能介导白细胞侵袭中枢神经系统的整合素具有限制或预防的治疗潜力 与脑外伤相关的继发性神经损害。OncoSynergy开发了OS2966，这是第一个 人源化单抗PAN-CD29/β-1整合素/ITGB1抗体。我们的支持IND的研究表明 在非人类灵长类动物中，每周重复静脉注射OS2966是很好的耐受性，没有死亡， 临床体征、大体病理或最大耐受量(MTD)达到(最高35 mg/kg)。2019年3月， FDA批准我们的IND启动使用脑内注射治疗复发性胶质母细胞瘤患者的I期临床试验 交付OS2966。已知的OS2966的药理和安全性特征为快速 在成功完成概念验证研究后，将该药物转化为脑损伤的临床试验。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这一阶段的工作 评估OS2966在高保真猪脑损伤模型中的疗效的STTR项目。成功的成就 这一第一阶段STTR项目的实施将使进一步的第二阶段研究能够优化OS2966的治疗方案 颅脑损伤的多种猪模型和OS2966推进到第二阶段的概念验证疗效研究。

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.