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Ischemia leads to the cellular expression of damage-associated molecular patterns (DAMPs), recognition of which by natural IgM antibodies (NIgM) results in activation of the complement system and the propagation of inflammation. We identified an IgM mAb, termed B4IgM, that recognizes a DAMP (annexin IV) and that reconstitutes cerebral ischemia reperfusion injury in otherwise protected antibody-deficient Rag1-/- mice. We took advantage of this injury recognition system by linking a complement inhibitor (Crry) to a B4IgM-derived single chain antibody (scFv) for site-targeted delivery of a therapeutic after stroke. Using a murine model of transient middle cerebral artery occlusion (MCAO), we show that a single dose of B4Crry administered IV up to 24 h after MCAO inhibited IgM and complement deposition in the ischemic brain and provided sustained neuroprotection up to 30 days. B4Crry treatment resulted in a significant reduction in cell death and tissue scarring (70% reduction, p<0.01), and significant improvements in neurological deficit scores (p<0.05), forelimb asymmetry (corner test, <0.05), and spatial learning (Barnes maze, p<0.05). We further investigated B4Crry treatment in the context of tissue-plasminogen activator (tPA) therapy using a microembolic model of ischemic stroke. A single dose of B4Crry administered at 2h, 4h, or 6h after ischemia demonstrated significant improvements in motor and cognitive recovery compared to vehicle with a comparable outcome to 2h t-PA therapy. However, administration of tPA at 4h or 6h was associated with increased risk of mortality and hemorrhage. Combination of B4Crry and tPA expanded the therapeutic window of tPA (more than 6 h) and reduced the incidence of post-stroke mortality and tPA-induced intracerebral hemorrhage. Combination therapy also showed an additive effect on motor and cognitive recovery measures over 30 days. Finally, we demonstrated that B4Crry does not increase the risk of post-stroke pneumonia in a mouse model, and demonstrate that B4Crry specifically targets the ischemic stroke hemisphere in both murine and human brains. These data indicate that B4Crry is a promising translational stroke therapeutic that can also augment the efficacy and safety profile of tPA therapy.