Antibody immunization therapy for treatment of atherosclerosis

Abstract

The present invention relates to passive immunization for treating or preventing atherosclerosis using an isolated human antibody directed towards at least one oxidized fragment of apolipoprotein B in the manufacture of a pharmaceutical composition for therapeutical or prophylactical treatment of atherosclerosis by means of passive immunization, as well as method for preparing such antibodies, and a method for treating a mammal, preferably a human using such an antibody to provide for passive immunization.

1 .- 21 . (canceled)  
     
     
         22 . A purified antibody raised against fragments of apolipoprotein B 100, wherein said antibody comprises a variable heavy region (V H ) encoded by nucleic acid sequences selected from the group of sequences consisting of 
 (SEQ. ID. NO. 1)    (SEQ. ID. NO. 3)    (SEQ. ID. NO. 5)    (SEQ. ID. NO. 7)    (SEQ. ID. NO. 9)    (SEQ. ID. NO. 11)    (SEQ. ID. NO.19)    (SEQ. ID. NO. 21)    (SEQ. ID. NO. 23)    (SEQ. ID. NO. 25)    (SEQ. ID. NO. 29)    (SEQ. ID. NO. 31)    (SEQ. ID. NO. 33)    (SEQ. ID. NO. 35)    (SEQ. ID. NO. 37)    in combination with a variable light region (V L ) encoded by the nucleic acid sequences 144 selected from the group of sequences consisting of    (SEQ. ID. NO. 2)    (SEQ. ID. NO. 4)    (SEQ. ID. NO. 6)    (SEQ. ID. NO. 8)    (SEQ. ID. NO. 10)    (SEQ. ID. NO. 12)    (SEQ. ID. NO. 20)    (SEQ. ID. NO. 22)    (SEQ. ID. NO. 24)    (SEQ. ID. NO. 26)    (SEQ. ID. NO. 30)    (SEQ. ID. NO. 32)    (SEQ. ID. NO. 34)    (SEQ. ID. NO. 36)    (SEQ. ID. NO. 38)    
     
     
         23 . Antibody according to  claim 22 , wherein the antibody is characterized in that it comprises the variable heavy region (V H ) 
 (SEQ ID NO: 1)    and the variable light region (V L )    (SEQ ID NO: 2)    
     
     
         24 . Antibody according to  claim 22 , wherein the antibody is characterized in that it comprises 
 the variable heavy region (V H )                          (SEQ ID NO: 3)                   GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTC               CCTGAGACTCTCCTGTGCGGCCTCTGGATTCACCTTCAGTGACTACTACA           TGAGCTGGGTCCGCCAGGCTCCCGGGAAGGGGCTGGAGTGGGTATCGGGT           GTTAGTTGGAATGGCAGTAGGACGCACTATGCAGACTCTGTGAAGGGCCG           ATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGA           ACAGCCTGAGAGCCGAGGACACTGCCGTGTATTACTGTGCGAGAGCGGCT           AGGTACTCCTACTACTACTACGGTATGGACGTCTGGGGCCAAGGTACACT           GGTCACCGTGAGCAGC                                             and the variable light region (V L )                          (SEQ ID NO: 4)                   CAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAG               GGTCACCATCTCCTGTTCTGGAAGCAGCTCCAACATCGGAAATAATGCTG           TAAACTGGTATCAGCAGCTCCCAGGAACGGCCCCCAAACTCCTCATCTAT           GGGAATGATCGGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAA           GTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTCCGGTCCGAGGATG           AGGCTGATTATTACTGTCAGACCTGGGGCACTGGCCGGGGGGTATTCGGC           GGAGGAACCAAGCTGACGGTCCTAGGT                                           
     
     
         25 . Antibody according to  claim 22 , wherein the antibody is characterized in that it comprises 
 the variable heavy region (V H )                          (SEQ ID NO: 5)                   GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTC               CCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGTAGCTATTGGA           TGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAAGT           ATCAGTGGTAGTGGTCGTAGGACATACTACGCAGACTCCGTGCAGGGCCG           GTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGA           ACAGCCTGAGAGCCGAGGACACTGCCGTGTATTACTGTGCGAGATTGGTC           TCCTATGGTTCGGGGAGTTTCGGTTTTGACTACTGGGGCCAAGGTACACT           GGTCACCGTGAGCAGC                                             and the variable light region (V L )                          (SEQ ID NO: 6)                   CAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAG               GGTCACCATCTCTTGTTCTGGAAGCAGCTCCAATATCGGAAGTAATTATG           TATCCTGGTATCAGCAGCTCCCAGGAACGGCCCCCAAACTCCTCATCTAT           GGTAACTACAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAA           GTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTCCGGTCCGAGGATG           AGGCTGATTATTACTGTGCAGCATGGGATGACAGCCTGAGTGGTTGGGTG           TTCGGCGGAGGAACCAAGCTGACGGTCCTAGGT                                           
     
     
         26 . Antibody according to  claim 22 , wherein the antibody is characterized in that it comprises the variable heavy region (V H )  
       
         
           
                 
                 
               
                     
                 
                   (SEQ ID NO: 7) 
                     
                 
                 
                 
               
                   GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTC 
                     
                 
                     
                 
                   CCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAACGCCTGGA 
                 
                     
                 
                   TGAGCTGGGTCCGCCAGGTTCCAGGGAAGGGGCTGGAGTGGGTCTCAACT 
                 
                     
                 
                   CTTGGTGGTAGTGGTGGTGGTAGCACATACTACGCAGACTCCGTGAAGGG 
                 
                     
                 
                   CCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAA 
                 
                     
                 
                   TGAACAGCCTGAGAGCCGAGGACACTGCCGTGTATTACTGTGCGAAGTTA 
                 
                     
                 
                   GGGGGGCGATCCCGATATGGGCGGTGGCCCCGCCAATTTGACTACTGGGG 
                 
                     
                 
                   CCAAGGTACACTGGTCACCGTGAGCAGC 
                 
                     
                 
             
                
                
               
            
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         and the variable light region (V L )  
         
           
             
                   
                   
                 
                       
                   
                     (SEQ ID NO: 8) 
                       
                   
                   
                 
                     CAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAG 
                   
                       
                   
                     GGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGAAATAACTATG 
                   
                       
                   
                     TATCCTGGTATCAGCAGCTCCCAGGAACGGCCCCCAAACTCCTCATCTAT 
                   
                       
                   
                     AGTAATAATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAA 
                   
                       
                   
                     GTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTCCGGTCCGAGGATG 
                   
                       
                   
                     AGGCTGATTATTACTGTGCAGCATGGGATGACAGCCTGAGTCATTGGCTG 
                   
                       
                   
                     TTCGGCGGAGGAACCAAGCTGACGGTCCTAGGT 
                   
                       
                   
               
                  
                  
                 
              
               
                  
                  
                  
                  
                  
                  
                  
                  
                  
                  
                  
                  
                  
                  
                 
              
             
           
         
       
     
     
         27 . Antibody according to  claim 22 , wherein the antibody is characterized in that it comprises 
 the variable heavy region (V H )                          (SEQ ID NO: 9)                   GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTC               CCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACA           TGAGCTGGATCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAAGT           ATCAGTGGCCGTGGGGGTAGTTCCTACTACGCAGACTCCGTGAGGGGCCG           GTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGA           ACAGCCTGAGAGCCGAGGACACTGCCGTGTATTACTGTGCGAGACTTTCC           TACAGCTATGGTTACGAGGGGGCCTACTACTTTGACTACTGGGGCCAGGG           TACACTGGTCACCGTGAGCAGC                                             and the variable light region (V L )                          (SEQ ID NO: 10)                   CAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAG               AGGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAAT           TATGTATCCTGGTATCAGCAGCTCCCAGGAACGGCCCCCAAACTCCTC           ATCTATAGGAATAATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCT           GGCTCCAAGTCTGGCACCTTAGCCTCCCTGGCCATCAGTGGGCTCCGG           TCCGAGGATGAGGCTGATTATTACTGTGCAACCTGGGATGACAGCCTG           AATGGTTGGGTGTTCGGCGGAGGAACCAAGCTGACGGTCCTAGGT                                           
     
     
         28 . Antibody according to  claim 22 , wherein the antibody is characterized in that it comprises 
 the variable heavy region (V H )                          (SEQ ID NO: 11)                   GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGG               TCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTAT           GCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTC           TCATCCATTAGTAGTAGTGGTCGTTTCATTTACTACGCAGACTCAATG           AAGGGCCGCTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTAT           CTGCAAATGAACAGCCTGAGAGCCGAGGACACTGCCGTGTATTACTGT           ACGAGGCTCCGGAGAGGGAGCTACTTCTGGGCTTTTGATATCTGGGGC           CAAGGTACACTGGTCACCGTGAGCAGC                                             and the variable light region (V L )                          (SEQ ID NO: 12)                   CAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAG               AGGGTCACCATCTCCTGTTCTGGAAGCAGCTCCAACATTGGCGGTGAG           TCTGTATCCTGGTATCAGCAGCTCCCAGGAACGGCCCCCAAACTCCTC           ATCTATAGTAATAATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCT           GGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTCCGG           TCCGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACAGCCTG           AATGGTTGGGTGTTCGGCGGAGGAACCAAGCTGACGGTCCTAGGT                                           
     
     
         29 - 50 . (canceled)  
     
     
         51 . Pharmaceutical composition comprising an isolated human antibody directed towards at least one oxidized fragment of apolipoprotein B 100 for treatment of atherosclerosis by means of passive immunization, which antibody is present in combination with a pharmaceutical excipient.  
     
     
         52 . An antibody according to  claim 55 , wherein the antibody is characterized in that it comprises the variable heavy region (V H ) encoded by the nucleic sequence (SEQ. ID. NO. 27).  
     
     
         53 . An antibody according to  claim 55 , wherein the antibody is characterized in that it comprises the variable light region (V L ) encoded by the nucleic sequence (SEQ. ID. NO. 28).  
     
     
         54 . An antibody according to claims  22  and  55 , wherein the antibody is characterized in that it has been raised against the apolipoprotein B 100 comprising an amino acid sequence encoded by the nucleic acid sequence (SEQ. ID. NO. 70).  
     
     
         55 . A purified antibody raised against fragments of apolipoprotein B 100, wherein the antibody is characterized in that it comprises the variable heavy region (V H ) encoded by nucleic acid sequence (SEQ. ID. NO. 27) 
 and the variable light region (V L ) encoded by nucleic acid sequence (SEQ. ID. NO. 28).    
     
     
         56 . An antibody according to  claim 54  wherein the heavy variable region (V H ) comprises a region encoded by nucleic acid sequence (SEQ. ID. NO. 27) in combination with a light variable region encoded by nucleic acid sequence (SEQ. ID. NO. 28) conjugated to an oxidized fragment encoded by nucleic acid sequence (SEQ. ID. NO. 70).