Synergistic Effect of AJW200, a von Willebrand Factor Neutralizing Antibody with Low Dose Tissue Plasminogen Activator Following Embolic Stroke in Rabbits (P05.233)

OBJECTIVE: The von Willebrand factor(vWF) is an acute stroke response protein involved in platelet aggregation, adhesion, inflammation, and thrombus formation, responses that occur following a thrombo-embolic stroke. We hypothesize that an anti-vWF antibody(Ab) may be used as adjunctive therapy with tissue plasminogen activator(tPA) to promote functional or behavioral recovery following stroke. BACKGROUND: In this proof-of-concept study, which used a rigorous blinded and randomized design, we studied treatment with the anti-vWF-Ab, AJW200(0.30 mg/kg), alone or in combination with a rabbit low-dose of tPA(0.9 mg/kg) using the rabbit small clot embolic stroke model(RSCEM) with behavioral function as the endpoint. Efficacy was compared to a positive control, a standard rabbit optimized dose of tPA(3.3 mg/kg). DESIGN/METHODS: The study used young male New Zealand white rabbits(2.2-2.5 kg). IACUC approved the procedures used in this translational study. Embolic strokes, behavioral and quantal analysis were performed as described previously (Lapchak, Translational Stroke Research 1(2), 96-107, 2010). RESULTS: AJW200, or control IgG were administered IV 1 hour following embolization, and behavior was measured 48 hours later so that an effective stroke dose (P50) could be calculated. A beneficial treatment significantly increases P50(mg clot) compared to control. AJW200 increased P50 by 28%(p>0.05) compared to the control IgG-treated group. AJW200 plus low-dose tPA significantly increased P50 by 74%(p 0.05). Standard dose tPA increased the P 50 by 154%(p CONCLUSIONS: In conclusion, we have demonstrated significant efficacy for the combination of AJW200 plus low dose tPA on a clinically relevant endpoint, behavior. It should be noted that while combination therapy improved behavior, it also increased the appearance of hematomas at the injection site and peripheral bleeding at incision sites. Our studies suggest that the combination therapy may be useful to improve clinical outcome in AIS patients. Supported by: NS060685 (PAL) and R43 NS061374 (XF). Disclosure: Dr. Lapchak has received personal compensation in an editorial capacity for Journal of Neurology and Neurophysiology as Editor-in-Chief. Dr. Doyan has nothing to disclose. Dr. Fan has received personal compensation for activities with AvantGen Inc. Dr. Fan holds stock and/or stock options in AvantGen Inc. Dr. Fan has received research support from AvantGen Inc. Ms. Woods has received personal compensation for activities with AvantGen Inc as an employee.