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.