Immunotherapy for Stroke: A New Hope of Treatment (P07.004)

Abstract

Objective: Tissue-type plasminogen activator (tPA, endogenous and exogenous) has two faces in acute ischemic stroke: beneficial fibrinolysis in the vascular bed, but damaging effects on the neurovascular unit and the brain parenchyma. To improve this profile, we used our knowledge of the underlying molecular (patho)physiology to develop a novel treatment strategy for stroke, relying on antibodies targeting the pro-neurotoxic effects of tPA. Background As the result of the occlusion of a cerebral artery by a blood clot. To date, the only clinical treatment is the use of tissular Plasminogen Activator (tPA, Actilyse®) for its fibrinolytic activity but with a certain risk of haemorrhagic transformation and of neurotoxicity through a modulation of NMDA receptors. The aim here was to validate a strategy of passive immunotherapy preventing the interaction of tPA with the NMDAr in a model of thromboembolic stroke with tPA-induced reperfusion in mice. Design/Methods: After production and characterization of antibodies (αATD-NR1) that specifically prevent the interaction of tPA with the ATD-NR1 of N-methyl-d-aspartate receptors, we have evaluated their efficacy in a model of murine thromboembolic stroke with or without recombinant tPA-induced reperfusion, coupled to MRI, near-infrared fluorescence imaging, and behavior assessments. Results: In vitro, αATD-NR1 prevented the proexcitotoxic effect of tPA without altering N-methyl-d-aspartate-induced neurotransmission. In vivo, based on a dedicated model of murine thrombo-embolic stroke, we demonstrate the efficiency of immunotherapy in a complete pre-clinical screen: after a single administration (alone or with late thrombolysis), antibodies dramatically reduce ischemic brain injuries, improve long-term neurological outcome and, in parallel, attenuate critical ischemic events including blood-brain barrier leakage and activation of MMP-3, MMP-9, and the PDGF-CC pathway. Conclusions: Thus, the prospect of this immunotherapy is an extension of the range of treatable patients, whether used as a monotherapy or, in combinations, to extend the therapeutic window for thrombolysis. Supported by: The INSERM, the French Ministry of Research and Technology, and the Eurostroke-Arise Program (FP7). Disclosure: Dr. Macrez has nothing to disclose. Dr. Defer has received personal compensation for activities with BiogenIdec, Novartis, Teva Pharmaceutical Industries Ltd, Merck Serono, and Guerbet. Dr. Vivien has nothing to disclose. Dr. Ali has nothing to disclose.