Compositions and methods for treating ischemic heart disease

Abstract

The present disclosure is directed to the treatment of ischemic heart disease and clinical conditions associated with ischemic heart disease. A composition containing a monoclonal antibody directed against gastric inhibitory polypeptide is administered. This results in cardioprotective effects against acute myocardial infarction, such as a decrease in circulating triglycerides, total cholesterol, and low-density lipoproteins, and an increase in the ratio of high-density lipoprotein to total cholesterol.

1 . A method of treating ischemic heart disease or clinical manifestations thereof, comprising:
 administering to a person a composition comprising a pharmaceutically effective amount of a molecular antagonist of gastric inhibitory polypeptide (GIP),   wherein the molecular antagonist comprises at least one complementarity determining region (CDR) with at least 80% identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 31, SEQ ID NO: 32, and SEQ ID NO: 33.   
     
     
         2 . The method of  claim 1 , wherein the molecular antagonist comprises a light chain variable domain having a first CDR and a second CDR, each CDR having at least 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, and SEQ ID NO: 24. 
     
     
         3 . The method of  claim 1 , wherein the molecular antagonist comprises a light chain variable domain having a first CDR with at least 80% identity to the amino acid sequence of SEQ ID NO: 20, a second CDR with at least 80% identity to the amino acid sequence of SEQ ID NO: 21, and a third CDR with at least 85% identity to the amino acid sequence of SEQ ID NO: 22. 
     
     
         4 . The method of  claim 1 , wherein the molecular antagonist comprises a light chain variable domain having at least 80% identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO: 19. 
     
     
         5 . The method of  claim 1 , wherein the molecular antagonist comprises a heavy chain variable domain having a first CDR with at least 80% identity to the amino acid sequence of SEQ ID NO: 31, a second CDR with at least 80% identity to the amino acid sequence of SEQ ID NO: 32, and a third CDR with at least 80% identity to the amino acid sequence of SEQ ID NO: 33. 
     
     
         6 . The method of  claim 1 , wherein the molecular antagonist comprises a heavy chain variable domain having at least 80% identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30. 
     
     
         7 . The method of  claim 1 , wherein the molecular antagonist comprises a light chain variable domain and a heavy chain variable domain;
 wherein the light chain variable domain comprises a first CDR and a second CDR, each CDR having at least 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, and SEQ ID NO: 24; and   wherein the heavy chain variable domain comprises a first CDR with at least 80% identity to the amino acid sequence of SEQ ID NO: 31, a second CDR with at least 80% identity to the amino acid sequence of SEQ ID NO: 32, and a third CDR with at least 80% identity to the amino acid sequence of SEQ ID NO: 33.   
     
     
         8 . The method of  claim 1 , wherein the molecular antagonist is a single-chain variable fragment (scFv), an F(ab′) 2  fragment, a Fab or Fab′ fragment, a diabody, a triabody, a tetrabody, or a monoclonal antibody. 
     
     
         9 . The method of  claim 1 , wherein the molecular antagonist comprises a light chain variable domain and a heavy chain variable domain;
 wherein the light chain variable domain has at least 80% identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO: 19; and   wherein the heavy chain variable domain has at least 80% identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30.   
     
     
         10 . The method of  claim 9 , wherein the molecular antagonist is a monoclonal antibody with a light chain variable domain having at least 80% identity to SEQ ID NO: 18, and a heavy chain variable domain having at least 80% identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30. 
     
     
         11 . The method of  claim 9 , wherein the molecular antagonist is a whole monoclonal antibody with a light chain variable domain having at least 90% identity to SEQ ID NO: 18, and a heavy chain variable domain having at least 90% identity to SEQ ID NO: 29. 
     
     
         12 . The method of  claim 1 , wherein the molecular antagonist binds to an amino acid sequence of GIP, the amino acid sequence being selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4. 
     
     
         13 . The method of  claim 1 , wherein the molecular antagonist is a monoclonal antibody comprising human constant regions. 
     
     
         14 . The method of  claim 1 , wherein the molecular antagonist has a molecular weight of about 30 kDa to about 500 kDa. 
     
     
         15 . The method of  claim 1 , wherein the molecular antagonist has a binding affinity for GIP characterized by an IC 50  of about 0.1 nM to about 7 nM. 
     
     
         16 . The method of  claim 1 , wherein the composition is administered intravenously, intraperitoneally, or subcutaneously. 
     
     
         17 . The method of  claim 1 , wherein the composition further comprises a pharmaceutical excipient selected from the group consisting of buffering agents, surfactants, preservative agents, bulking agents, polymers, and stabilizers. 
     
     
         18 . The method of  claim 1 , wherein the composition is in the form of a powder, injection, solution, suspension, or emulsion. 
     
     
         19 . The method of  claim 1 , wherein the composition contains the molecular antagonist in an amount of from about 0.1 to about 1000 milligram per milliliter of the composition. 
     
     
         20 . The method of  claim 1 , wherein the composition is lyophilized; or
 wherein the clinical manifestations thereof related to ischemic heart disease include stable angina pectoris, unstable angina, acute coronary syndrome; ST elevation myocardial infarction, non-ST elevation myocardial infarction, and unstable angina.