US 2004O247603A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0247603 A1 Sabbadini (43) Pub. Date: Dec. 9, 2004 (54) COMPOSITIONS AND METHODS FOR THE (60) Provisional application No. 60/257,926, filed on Dec. TREATMENT AND PREVENTION OF 22, 2000. CANCER, ANGIOGENESIS, AND NFLAMMATION Publication Classification (75) Inventor: Roger A. Sabbadini, Lakeside, CA (51) Int. Cl." ..................... A61K 39/395; A61K 31/685; (US) A61K 31/739 (52) U.S. Cl. ............................ 424/155.1; 514/78; 514/54 Correspondence Address: FOLEY & LARDNER P.O. BOX 80278 (57) ABSTRACT SAN DIEGO, CA 92138-0278 (US) (73) Assignee: Medlyte, Inc. Methods and compositions are disclosed that are useful for the prevention and/or treatment of cancer, angiogenesis, and (21) Appl. No.: 10/820,582 inflammation. The beneficial effects of the compositions and methods are achieved through the use of pharmaceutical (22) Filed: Apr. 7, 2004 compositions that include agents that bind Spingolipids or Sphingolipid metabolites. In one embodiment the agent is an Related U.S. Application Data antibody or antibody derivative. In some embodiments, the agent is a receptor of a Sphingolipid or a Sphingolipid (62) Division of application No. 10/028,156, filed on Dec. metabolite. Also disclosed are methods for identifying and 21, 2001. isolating therapeutic agents. US 2004/0247603 A1 Dec. 9, 2004 COMPOSITIONS AND METHODS FOR THE typically caused by the constriction or blockage of the blood TREATMENT AND PREVENTION OF CANCER, vessels Supplying it. Ischemia occurs any time that blood ANGIOGENESIS, AND INFLAMMATION flow to a tissue is reduced below a critical level. This reduction in blood flow can result from: (i) the blockage of RELATED APPLICATIONS a vessel by an embolus (blood clot); (ii) the blockage of a vessel due to atherosclerosis; (iii) the breakage of a blood 0001. This application is a divisional of U.S. application vessel (a bleeding stroke); (iv) the blockage of a blood vessel Ser. No. 10/028,156, filed Dec. 21, 2001, which claims due to acute vasoconstriction; (v) a myocardial infarction priority to U.S. patent application Ser. No. 60/257,926 (when the heart stops, the flow of blood to organs is reduced entitled “Compositions and Methods for the Treatment and and ischemia results); (vi) trauma; (vii) Surgery, during Prevention of Cardiac and Myocardial Disorders” by Sab which blood flow to a tissue or organ needs to be reduced or badini, Roger A., filed Dec. 22, 2000, each of which are stopped to achieve the aims of Surgery (e.g., angioplasty, hereby incorporated by reference in their entireties, includ heart and lung/heart transplants); (viii) exposure to certain ing all Tables, Figures, and claims. agents, e.g., dobutamine or adenosine (Lagerqvist et al., Br. 0002 This application is related to U.S. patent applica Heart J. 68:282-285, 1992) or (ix) anti-neoplastic and other tion Ser. No. 10/029,372, Ser. No. 10/028,156, and Ser. No. chemotherapeutic agents, Such as doxorubicin, that are car 10/028,520, and U.S. application Ser. No. 10/029,401, each diotoxic. entitled “Compositions and Methods for the Treatment and Prevention of Cardiovascular Diseases and Disorders, and 0008) Even if the flow rate (volume/time) of blood is for Identifying Agents. Therapeutic Therefor” by Sabbadini, adequate, ischemia may nonetheless occur due to hypoxia. Roger A., and filed Dec. 21, 2001, each of which are hereby “Hypoxia” refers to conditions in which the oxygen content incorporated by reference in their entireties, including all of blood is insufficient to Satisfy normal cellular oxygen Tables, Figures, and claims. requirements. Hypoxic blood is, by definition, distinct from normoxic blood, i.e., blood in which the oxygen content is FIELD OF THE INVENTION Sufficient to Satisfy normal cellular oxygen requirements. Such conditions include but are not limited to forms of heart 0003. The invention relates generally to the area of failure that adversely affect cardiac pumping Such as hyper treatment and/or prevention of cardiovascular and cere tension, arrhythmias, Septic shock, trauma, cardiomyopa brovascular diseases, disorders and physical trauma. The thies and congestive heart disease. beneficial effect of the invention is achieved through the use of pharmaceutical compositions that contain agents that 0009 Myocardial ischemic disorders occur when cardiac interfere with the production and/or biological activities of blood flow is restricted (ischemia) and/or when oxygen Sphingolipids and their metabolites. The invention is also Supply to the heart muscle is compromised (hypoxia) Such drawn to methods for isolating, formulating and using that the heart's demand for Oxygen is not met by the Supply. pharmaceutical compositions, and kits and medical devices Coronary artery disease (CAD) arising from arteriosclerosis, comprising Such compositions. particularly atherosclerosis, is the most common cause of ischemia, and has Symptoms Such as Stable or unstable BACKGROUND OF THE INVENTION angina pectoris. CAD can lead to acute myocardial infarc tions (AMI) and sudden cardiac death. The spectrum of 0004. The following description includes information ischemic conditions which result in heart failure is referred that may be useful in understanding the present invention. It to as Acute Coronary Syndrome (ACS). Reperfusion injury is not an admission that any of the information provided is often a consequence of ischemia, in particular when herein, or any publication specifically or implicitly refer anti-coagulants, thrombolytic agents, or anti-anginal medi enced herein, is prior art, or even particularly relevant, to the cations are used or when the cardiac vasculature is Surgically presently claimed invention. opened by angioplasty or by coronary artery grafting. 0005 Cardiovascular Diseases and Disorders 0010 Cardiotoxic agents are those materials which 0006 Ischemic heart disease is the leading cause of death would cause a loSS of cardiac function, including negative in the U.S. Each year approximately 1.5 million people inotropy, arthyTHmias, heart failure, and cell death (both Suffer heart attacks (myocardial infarctions), of which /3 (i.e. apoptotic and necrotic). about 500,000) are fatal. In addition, about 6.75 million 0011 Presently, treatments for acute myocardial infarc Americans Suffer from angina pectoris, the most common tion and other cardiac diseases include but are not limited to manifestation of cardiac ischemia. Angina pectoris is a mechanical devices and associated procedures therewith painful feeling of pressure in the chest that results from (e.g., coronary angioplasty; Grines et al., N. Engl. J. Med. ischemic heart disease. In total, there are 13.5 million 3298:673-679, 1993); thrombolytic agents such as streptoki patients living with ischemic heart disease in the U.S. nase, tpA, and derivatives thereof. Adjuvants to these thera Americans in the high-risk categories for this disease pies include beta-blockers, aspirin and heparin, and glyco include perSons having one or more indicators/risk factors protein (GP) IIb/IIIa inhibitors (Antman et al., Circ. therefor, including but not limited to hypertension, high 99:2720-2732, 1999). GPIIb/IIIa inhibitors decrease platelet levels of serum cholesterol and a family history of heart aggregation and thrombus formation (for a review, see disease. Many people have at least one of these indicator/ Topol, Lancet 353:227-231, 1999). Examples include but risk factors, for example, there are 50 million Americans are not limited to monoclonal antibodies (e.g., abciximab), diagnosed with hypertension alone. cyclic peptides (e.g., eptifibatide), and nonpeptide peptido 0007 “Ischemia' is a condition associated with an inad mimetics (e.g., tirofibian, lamifiban, xemilofiban, Sibrafiban, equate flow of oxygenated blood to a part of the body, and lefrada?ibian). US 2004/0247603 A1 Dec. 9, 2004 0012 Preventive treatments include but are not limited to e.g. hydration, monitoring neurological Status, blood pres those that reduce a patient's cholesterol levels by, e.g., diet Sure control, and/or anti-platelet or anti-coagulation therapy. management and pharmacological intervention. Statins are Heparin has been administered to Stroke patients with lim one type of agent that have been used to reduce cholesterol ited and inconsistent effectiveness. In Some circumstances, levels. Statins are believed to act by inhibiting the activity of the ischemia resolves itself over a period of time due to the HMG-CoA reductase, which in turn increases the hepatic fact that Some thrombi get absorbed into the circulation, or production of cholesterol receptors (Nickenig et al., Circ. fragment and travel distally over a period of a few days. In 100:2131-2134, 1999). The hepatic cholesterol receptors 1996, the Food and Drug Administration approved the use of bind cholesterol and remove it from blood. Such agents tissue plasminogen activator (t-PA) or Activase(E), for treat include but are not limited to lovastatin, Simvastatin, prav ing acute Stroke. However, treatment with Systemic t-PA is astatin, fluvastatin (Lennernas, Clin. Pharmackinet. 32:403 asSociated with increased risk of intracerebral hemorrhage 425, 1997). These and other statins slows the progression of and other hemorrhagic complications. Aside from the coronary artery disease, and may induce regression of ath administration of thrombolytic agents and heparin, there are erosclerotic lesions in patients. It is not known, however, no therapeutic options