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(12) Patent Application Publication (10) Pub. No.: US 2014/0227350 A1 Wang Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2014/0227350 A1 Wang Et Al US 20140227350A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0227350 A1 Wang et al. (43) Pub. Date: Aug. 14, 2014 (54) ANNEXIN A2 AND TISSUE PLASMINOGEN Publication Classification ACTIVATOR FORTREATING VASCULAR DISEASE (51) Int. Cl. A638/49 (2006.01) (71) Applicant: The General Hospital Corporation, A638/17 (2006.01) Boston, MA (US) (52) U.S. Cl. CPC ................. A61K 38/49 (2013.01); A61K 38/17 (72) Inventors: Xiaoying Wang, West Roxbury, MA (2013.01) (US); Eng Lo, Newton, MA (US) USPC ........................ 424/450; 424/94.64; 424/94.3 (21) Appl. No.: 14/197.988 (57) ABSTRACT The use of thA to treat hemorrhagic transformation, neuro toxicity has been limited to short treatment time windows (22) Filed: Mar. 5, 2014 because a high dose of t?A required to generate Sufficient amounts of the enzyme plasmin for clot lysis. The present Related U.S. Application Data invention combines tRA with recombinant Annexin A2 result ing in thrombolysis without hemorrhagic transformation at (63) Continuation of application No. 12/918,726, filed on delayed times after stroke. This embodiment allows the Oct. 20, 2010, now abandoned, filed as application No. administration of a lower, non-neurotoxic, tRA dose. Our PCT/US09/01057 on Feb. 19, 2009. results suggest this novel combination for stroke therapy may (60) Provisional application No. 61/030,033, filed on Feb. greatly improve both efficacy and safety, and prolong tPA 20, 2008. therapeutic time window. Patent Application Publication Aug. 14, 2014 Sheet 1 of 6 US 2014/0227350 A1 A. a 14 Ces 12 10 E E O C B. -0-tpA -- tA 25-tRA 5-O-tRA 1.( O O O5 1.2 2.5 rA2 (g/m) Figure 1 Patent Application Publication Aug. 14, 2014 Sheet 2 of 6 US 2014/0227350 A1 m L-tpA - H-tRPA - L-toA -- A2 : 4. O 2 O 3O 6O 90 12O 5 LS 30 60 lschemia (min) After Treatment (min) an r E 2 S O E ass 2. O O E 5 O O D 5 O o O -PA M-tpA H-PA A2 FIGURE 2 Patent Application Publication Aug. 14, 2014 Sheet 3 of 6 US 2014/0227350 A1 Safe HA -it k r. FIGURE 3 Patent Application Publication Aug. 14, 2014 Sheet 4 of 6 US 2014/0227350 A1 -ArcA. Figure 3 (cont'd) Patent Application Publication Aug. 14, 2014 Sheet 5 of 6 US 2014/0227350 A1 A. Pre-ischemia 5 Ischemia (JThrombolysis E N u M 40 E 2O LitPA-A2 B. C. After Throboy'ss FIGURE 4 US 2014/0227350 A1 Aug. 14, 2014 ANNEXIN A2 AND TISSUE PLASMINOGEN medium comprising Annexin A2 and tissue plasminogen acti ACTIVATOR FORTREATING VASCULAR vator (tPA); and b) administering said medium to said patient DISEASE under conditions such that said symptoms are reduced. In one embodiment, the vascular disorder is selected from the group FIELD OF INVENTION comprising stroke, myocardial infarction, pulmonary embo 0001. The present invention is related to the field of vas lism, deep vein thrombosis or intracerebral hematoma. In one cular disorders. In particular, the present invention is related embodiment, the Annexin A2 and the tRA have a dose ratio of to the treatment and management of diseases including, but 2:1. In one embodiment, the medium comprises a carrier. In not limited to, stroke, myocardial infarction, deep vein throm one embodiment, the Annexin A2 and the tBA are attached to bosis, or pulmonary embolism. For example, a patient having the carrier. In one embodiment, the carrier is selected from the Suffered a vascular disorder may be administered a composi group comprising a liposome or a microparticle. In one tion comprising tPA and Annexin A2. In Such cases, the tBA embodiment, the medium comprises a liquid. In one embodi dose may be reduced Such that the risk of hemorrhagic side ment, the administering is intravenous. In one embodiment, effects are minimal. the patient is a human. In one embodiment, the patient is a non-human. BACKGROUND 0007. In one embodiment, the present invention contem plates a method comprising: a) providing: i) a patient exhib 0002. Each year, about 600,000 American suffer from iting symptoms associated with a recently incurred stroke, ii) stroke. Thrombolytic therapy with tissue plasminogen acti a medium comprising Annexin A2 and tissue plasminogen vator (tPA) is the only FDA-approved medicine for achieving activator (tPA), wherein Annexin A2 and tRA have a dose ratio both vascular reperfusion and clinical benefit, but only 2-5% of 2:1; and, b) administering said medium to said human of stroke patients receive tea in the US. In part, this because Subject under conditions such that said symptoms are tPA therapy unfortunately increases the risk of intracerebral reduced. In one embodiment, the administering occurred less hemorrhage by approximately 10-fold. Perhaps even more than three hours after said stroke. In one embodiment, the importantly, there is accumulating evidence from experimen administering occurred less than six hours after said stroke. In tal models and clinical studies that tRA can have neurotoxic one embodiment, the administering occurred less than twelve actions separate from its beneficial clot lysis properties, tRA hours after said stroke. In one embodiment, the tBA dose is at neurotoxicity may further exacerbate ischemic brain damage, least two-fold lower than the currently recommended dose. In particularly in the 50% of patients who have no perfusion one embodiment, the tRA dose is at least three-fold lower than improvement after receiving intravenous tFA. the currently recommended dose. In one embodiment, the tRA 0003. Many clinical trials attempting to provide neuropro dose is at least four-fold lower than the currently recom tection following stroke have failed. While, to date, tRA mended dose. based thrombolytic therapy is the only FDA-approved treat 0008. In one embodiment, the present invention contem ment for achieving vascular reperfusion and clinical benefit, plates a medium comprising Annexin A2 and tissue plasmi this agent is given to only about 2-5% of stroke patients (25. nogen activator (tPA). In one embodiment, the Annexin A2 26). This may be related, in part, to the elevated risks of and the tBA have a dose ratio of 2:1. In one embodiment, the symptomatic intracranial hemorrhage, and a short therapeutic medium further comprises a carrier. In one embodiment, the time window in order to decrease the clinical risk of tRA's Annexin A2 and the tBA are attached to the carrier. In one limitations. Specifically, tRA therapy limitations include: (1) embodiment, the carrier comprises a liposome population. In short 3 hr treatment time window, (2) risk of intracerebral hemorrhage, and (3) neurotoxicity. Others have tried to find one embodiment, the carrier comprises a microparticle popu other lytics with equal thrombolysis properties for safe and lation. In one embodiment, the medium comprises a liquid. effective reperfusion at longer times after stroke onset. One 0009. In one embodiment, the present invention contem example is the vampire bat saliva molecule desmoteplase. plates a kit comprising a medium comprising Annexin A2 and However, the recent completion of a desmoteplase (DIAS-2) tissue plasminogen activator (tPA). In one embodiment, the clinical trial failed. So the problem of a safe and effective use medium further comprises a carrier. In one embodiment, the oftBA in the treatment of stroke remains unsolved. tPA and the Annexin A2 are attached to said carrier. In one 0004 What is needed is a composition and method that embodiment, the kit further comprises a sheet of instructions increases the thrombolytic efficacy of tA, while reducing regarding administration of said medium following a vascular neurotoxicity and the risk of hemorrhagic transformation. disorder. In one embodiment, the vascular disorder is selected from the group comprising stroke, myocardial infarction, SUMMARY pulmonary embolism, deep vein thrombosis or intracerebral hematoma. In one embodiment, the kit further comprises a 0005. The present invention is related to the field of vas Syringe. In one embodiment, the kit further comprises an cular disorders. In particular, the present invention is related intravenous catheter. In one embodiment, the kit further com to the treatment and management of diseases including, but prises an intravenous drip bag capable of fluid communica not limited to, stroke, myocardial infarction, deep vein throm tion with said intravenous catheter. bosis, or pulmonary embolism. For example, a patient having Suffered a vascular disorder may be administered a composi DEFINITIONS tion comprising Annexin A2 and tRA. In Such cases, the tBA dose may be reduced Such that the risk of hemorrhagic side 0010. The term “attached as used herein, refers to any effects are minimal. interaction between a medium (or carrier) and a drug. Attach 0006. In one embodiment, the present invention contem ment may be reversible or irreversible. Such attachment plates a method comprising: a) providing: i) a patient exhib includes, but is not limited to, covalent bonding, ionic bond iting symptoms associated with a vascular disorder, and ii) a ing, Van der Waals forces or friction, and the like. A drug is US 2014/0227350 A1 Aug. 14, 2014 attached to a medium (or carrier) if it is impregnated, incor compound has its intended effect on the patient. For example, porated, coated, in Suspension with, in Solution with, mixed one method of administering is by an indirect mechanism with, etc. using a medical device Such as, but not limited to a Syringe, an 0011. The term “medium' as used herein, refers to any intravenous catheter, etc. A second exemplary method of material, or combination of materials, which may serve as administering is by a direct mechanism Such as, local tissue vehicle for delivering of a drug, or carrier, to a treatment point administration (i.e., for example, extravascular placement), (e.g., a thrombosis, a stenosis etc.).
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