Methods for treating cardiovascular disease using a soluble CTLA4 molecule

Abstract

The present invention relates to compositions and methods for treating cardiovascular system diseases by administering to a subject soluble CTLA4 molecules that block endogenous B7 molecules from binding their ligands.

1 . A method for treating a cardiovascular disease comprising administering to a subject an effective amount of a soluble CTLA4 molecule comprising an extracellular domain of a CTLA4 molecule, or portion thereof which binds a B7 antigen expressed on activated B cells, wherein the extracellular domain of the CTLA4 molecule comprises the amino acids shown in SEQ ID NO:17 beginning with methionine at position +1 or with alanine at position −1 and ending with aspartic acid at position 124, wherein the cardiovascular disease is selected from the group consisting of: coronary heart disease (CHD); restensosis; peripheral arterial disease; coronary bypass grafting surgery; carotid artery disease; arteritis; myocarditis; unstable angina (UA); unstable refractory angina; stable angina (SA); chronic stable angina; acute coronary syndrome (ACS); myocardial infarction; acute myocardial infarction (AMI), including first or recurrent myocardial infarction, non-Q wave myocardial infarction, non-ST-segment elevation myocardial infarction and ST-segment elevation myocardial infarction and wherein the method does not comprise administering a TNF/TNFR blocking molecule, soluble gp39, soluble CD40, antibodies which bind to CD40, or monoclonal antibodies to gp39. 
     
     
         2 . The method of  claim 1 , wherein said cardiovascular disease is selected from the group consisting of: coronary heart disease (CHD); unstable angina (UA); unstable refractory angina; stable angina (SA); chronic stable angina; acute coronary syndrome (ACS); myocardial infarction; acute myocardial infarction (AMI), including first or recurrent myocardial infarction, non-Q wave myocardial infarction, non-ST-segment elevation myocardial infarction and ST-segment elevation myocardial infarction. 
     
     
         3 . The method of  claim 1 , wherein said cardiovascular disease is associated with at least one marker of inflammation selected from the group consisting of CRP, hsCRP, IL-10, CD40L, sCD40L, IL-6, sICAM-1, TNF-α, white blood cell count, fibrinogen, and serum amyloid A. 
     
     
         4 . The method of  claim 3 , wherein said marker of inflammation is selected from the group consisting of CRP, hsCRP, IL-6, and TNF-α. 
     
     
         5 . The method of  claim 1 , wherein the effective amount the soluble CTLA4 molecule is about 0.1 to 100 mg/kg weight of the subject, about 0.5 to 100 mg/kg weight of a subject 0.5 to 5 mg/kg weight of a subject, about 5 to 10 mg/kg weight of a subject, about 10 to 15 mg/kg weight of a subject, about 15 to 20 mg/kg weight of a subject, about 20 to 25 mg/kg weight of a subject, about 25 to 30 mg/kg weight of a subject, about 30 to 35 mg/kg weight of a subject, about 35 to 40 mg/kg weight of a subject, about 40 to 45 mg/kg of a subject, about 45 to 50 mg/kg weight of a subject, about 50 to 55 mg/kg weight of a subject, about 55 to 60 mg/kg weight of a subject, about 60 to 65 mg/kg weight of a subject, about 65 to 70 mg/kg weight of a subject, about 70 to 75 mg/kg weight of a subject, about 75 to 80 mg/kg weight of a subject, about 80 to 85 mg/kg weight of a subject, about 85 to 90 mg/kg weight of a subject, about 90 to 95 mg/kg weight of a subject, about 95 to 100 mg/kg weight of a subject, about 2 to 10 mg/kg weight of a subject, about 0.1 to 4 mg/kg weight of a subject, about 0.1 to 0.5 mg/kg weight of a subject, about 0.5 to 1.0 mg/kg weight of a subject, about 1.0 to 1.5 mg/kg weight of a subject, about 1.5 to 2.0 mg/kg weight of a subject, about 2.0 to 2.5 mg/kg weight of a subject, about 2.5 to 3.0 mg/kg weight of a subject, about 3.0 to 3.5 mg/kg weight of a subject, about 3.5 to 4.0 mg/kg weight of a subject, about 4.0 to 4.5 mg/kg weight of a subject, about 4.5 to 5.0 mg/kg weight of a subject, about 5.0 to 5.5 mg/kg weight of a subject, about 5.5 to 6.0 mg/kg weight of a subject, about 6.0 to 6.5 mg/kg weight of a subject, about 6.5 to 7.0 mg/kg weight of a subject, about 7.0 to 7.5 mg/kg weight of a subject, about 7.5 to 8.0 mg/kg weight of a subject, about 8.0 to 8.5 mg/kg weight of a subject, about 8.5 to 9.0 mg/kg weight of a subject, about 9.0 to 9.5 mg/kg weight of a subject, about 9.5 to 10.0 mg/kg weight of a subject, about 0.1 to 2 mg/kg weight of a subject, about 2 to 4 mg/kg weight of a subject, about 4 to 6 mg/kg weight of a subject, about 6 to 8 mg/kg weight of a subject, about 8 to 10 mg/kg weight of a subject, about 10 to 12 mg/kg weight of a subject, about 12 to 14 mg/kg weight of a subject, about 14 to 16 mg/kg weight of a subject, about 16 to 18 mg/kg weight of a subject, about 18 to 20 mg/kg weight of a subject, about 0.5 mg/kg weight of the subject, 2 mg/kg weight of the subject, 10 mg/kg weight of the subject, about 0.5 mg/kg to 100 weight of the subject, about 0.5 to 10 mg/kg weight of a subject, about 0.1 to 20 mg/kg weight of a subject, about 500 mg for a subject weighing less than 60 kg, 750 mg for a subject weighing between 60-100 kg or 1000 mg for a subject weighing more than 100 kg. 
     
     
         6 . The method of  claim 1 , wherein the soluble CTLA4 molecule is a CTLA4 fusion molecule. 
     
     
         7 . The method of  claim 6 , wherein the CTLA4 fusion molecule comprises an extracellular domain of a CTLA4 molecule which binds a B7-1 or B7-2 antigen expressed on activated B cells joined to a non-CTLA4 molecule. 
     
     
         8 . The method of  claim 7 , wherein the non-CTLA4 molecule comprises an amino acid sequence which alters the solubility or affinity of the soluble CTLA4 molecule. 
     
     
         9 . The method of  claim 8 , wherein the amino acid sequence which alters the solubility or affinity comprises an immunoglobulin moiety. 
     
     
         10 . The method of  claim 9 , wherein the immunoglobulin moiety comprises one or more mutations to alter effector function. 
     
     
         11 . The method of  claim 9 , wherein the immunoglobulin moiety comprises a hinge and any or all of the cysteine residues within the hinge are substituted with serine. 
     
     
         12 . The method of  claim 9 , wherein the immunoglobulin moiety is an immunoglobulin constant region or portion thereof. 
     
     
         13 . The method of  claim 12 , wherein the immunoglobulin constant region or portion thereof is mutated to alter effector function. 
     
     
         14 . The method of  claim 12 , wherein the immunoglobulin constant region comprises a hinge, CH2 and CH3 regions of an immunoglobulin molecule. 
     
     
         15 . The method of  claim 12 , wherein the immunoglobulin constant region or portion thereof is a human or monkey immunoglobulin constant region or portion thereof. 
     
     
         16 . The method of  claim 6 , wherein the CTLA4 fusion molecule is CTLA4Ig. 
     
     
         17 . The method of  claim 16 , wherein the CTLA4Ig is shown in SEQ ID NO: 19 beginning with methionine at position +1 or with alanine at position −1 and ending with lysine at position +357. 
     
     
         18 . The method of  claim 1 , wherein the soluble CTLA4 molecule is administered in combination with at least one additional therapeutic agent that is not a TNF/TNFR blocking molecule. 
     
     
         19 . The method of  claim 18 , wherein said additional therapeutic agent is selected from the group consisting of anti-coagulant or coagulation inhibitory agents, anti-platelet or platelet inhibitory agents, thrombin inhibitors, Vitamin K antagonists, glycoprotein IIb/IIIa receptor antagonists, thrombolytic or fibrinolytic agents, anti-arrhythmic agents, anti-hypertensive agents, angiotensin converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers (ARBs), beta-blockers, calcium channel blockers (L-type and T-type), cardiac glycosides, diuretics, mineralocorticoid receptor antagonists, phosphodiesterase inhibitors, cholesterol/lipid lowering agents and lipid profile therapies, anti-diabetic agents, anti-depressants, anti-inflammatory agents (steroidal and non-steroidal), anti-osteoporosis agents, hormone replacement therapies, oral contraceptives, anti-obesity agents, anti-anxiety agents, anti-proliferative agents, anti-tumor agents, anti-ulcer and gastroesophageal reflux disease agents, growth hormone and/or growth hormone secretagogues, thyroid mimetics (including thyroid receptor antagonist), anti-infective agents, anti-viral agents, anti-bacterial agents, and anti-fungal agents.