Human monoclonal antibodies against oxidized ldl receptor and medicinal use thereof

Abstract

Various human monoclonal antibodies that bind to human LOX-1 and inhibit the binding of in-vivo LOX-1 ligands to LOX-1, and the LOX-1-mediated incorporation of the ligands into cells, were obtained by immunizing human antibody-producing transgenic mice (created by genetic engineering) with soluble human oxidized LDL receptor (LOX-1). Furthermore, the human monoclonal antibodies were found to be effective in preventing and treating a variety of diseases.

1 . A human monoclonal antibody, or a portion thereof, which binds to the human oxidized LDL receptor.  
     
     
         2 . The human monoclonal antibody according to  claim 1 , or a portion thereof, which has the activity to inhibit the binding of oxidized LDL to a human oxidized LDL receptor or to inhibit the human oxidized LDL receptor-mediated incorporation of oxidized LDL into cells.  
     
     
         3 . The human monoclonal antibody according to  claim 1  or  2 , or a portion thereof, which belongs to the immunoglobulin class of IgG1 or IgG4.  
     
     
         4 . The human monoclonal antibody according to any one of  claims 1  to  3 , or a portion thereof, wherein the association rate constant (ka) in the binding between the human monoclonal antibody and human oxidized LDL receptor is 1.0×10 4  (1/M.Sec) or higher.  
     
     
         5 . The human monoclonal antibody according to any one of  claims 1  to  3 , or a portion thereof, wherein the dissociation rate constant (kd) between the human monoclonal antibody and human oxidized LDL receptor is 1.0×10 −2  (1/Sec) or lower.  
     
     
         6 . The human monoclonal antibody according to any one of  claims 1  to  3 , or a portion thereof, wherein the dissociation constant (Kd) between the human monoclonal antibody and human oxidized LDL receptor is 1.0×10 −6  (M) or lower.  
     
     
         7 . The human monoclonal antibody according to  claim 4 , or a portion thereof, wherein the association rate constant (ka) is 1.0×10 5  (1/M.Sec) or higher.  
     
     
         8 . The human monoclonal antibody according to  claim 5 , or a portion thereof, wherein the dissociation rate constant (kd) is 1.0×10 −4  (1/Sec) or lower.  
     
     
         9 . The human monoclonal antibody according to  claim 6 , or a portion thereof, wherein the dissociation constant (Rd) is 1.0×10 −7  (M) or lower.  
     
     
         10 . The human monoclonal antibody according to  claim 9 , or a portion thereof, wherein the dissociation constant (Kd) is 1.0×10 −8  (M) or lower.  
     
     
         11 . The human monoclonal antibody according to any one of  claims 1  to  10 , or a portion thereof, which is derived from a transgenic non-human mammal having the ability to produce human antibodies.  
     
     
         12 . The human monoclonal antibody according to  claim 11 , or a portion thereof, which is obtained by immunizing a transgenic non-human mammal having the ability to produce human antibodies with cells expressing human oxidized LDL receptor, a soluble membrane fraction from the cells, the entire human oxidized LDL receptor or a portion thereof.  
     
     
         13 . The human monoclonal antibody according to  claim 11  or  12  or a portion thereof, wherein the transgenic non-human mammal is a transgenic mouse.  
     
     
         14 . A cell producing the human monoclonal antibody according to any one of  claims 1  to  13 .  
     
     
         15 . The cell according to  claim 14 , which is a fused cell that has obtained the ability to produce the human monoclonal antibody as a result of cell fusion between a mammalian B cell and mammalian myeloma cell.  
     
     
         16 . The cell according to  claim 14 , which is a transgenic cell transformed by introducing into the cell either or both DNAs encoding a heavy chain and a light chain of the human monoclonal antibody.  
     
     
         17 . A pharmaceutical composition comprising the human monoclonal antibody according to any one of  claims 1  to  13 , or a portion thereof, and a pharmaceutically acceptable carrier.  
     
     
         18 . The pharmaceutical composition according to  claim 17 , which is used to inhibit the binding between an in-vivo ligand of human oxidized LDL receptor and human oxidized LDL receptor or the incorporation of the ligand into cells expressing the oxidized LDL receptor.  
     
     
         19 . The pharmaceutical composition according to  claim 17 , which is used to treat arteriosclerosis.  
     
     
         20 . The pharmaceutical composition according to  claim 18 , which is used to treat a disease caused by the binding of blood platelets or activated blood platelets to the oxidized LDL receptor, or the incorporation of blood platelets or activated blood platelets into cells expressing the oxidized LDL receptor.  
     
     
         21 . The pharmaceutical composition according to  claim 20 , wherein the disease involves the symptoms of thrombocytopenia.  
     
     
         22 . The pharmaceutical composition according to  claim 20 , wherein the disease is a kidney disease.  
     
     
         23 . The pharmaceutical composition according to  claim 17 , which is used to inhibit leukocyte infiltration into tissues.  
     
     
         24 . The pharmaceutical composition according to  claim 23 , wherein leukocyte infiltration into tissues is observed in inflammatory reactions during arteriosclerosis, during myocardial ischemic reperfusion injury, after percutaneous transluminal coronary recanalization (PTCR), or after percutaneous transluminal coronary angioplasty (PTCA).  
     
     
         25 . The pharmaceutical composition according to  claim 17 , which is used to treat inflammation.  
     
     
         26 . The pharmaceutical composition according to  claim 25 , wherein the inflammation is due to arteriosclerosis, myocardial ischemic reperfusion injury, after percutaneous transluminal coronary recanalization (PTCR), or after percutaneous transluminal coronary angioplasty (PTCA).  
     
     
         27 . The pharmaceutical composition according to  claim 17 , which is used to treat vascular restenosis after percutaneous transluminal coronary recanalization (PTCR) or percutaneous transluminal coronary recanalization (PTCR).  
     
     
         28 . A pharmaceutical composition for suppressing or preventing thrombus formation, wherein the pharmaceutical composition comprises a substance that has the activity of inhibiting the binding of an in-vivo ligand of human oxidized LDL receptor, or the incorporation of the ligand into cells expressing the oxidized LDL receptor.  
     
     
         29 . The pharmaceutical composition according to  claim 28 , wherein the substance is a monoclonal antibody, or a portion thereof, which binds to the human oxidized LDL receptor.  
     
     
         30 . The pharmaceutical composition according to  claim 29 , wherein the monoclonal antibody, or a portion thereof, is the human monoclonal antibody according to any one of  claims 1  to  13 , or a portion thereof.