Reshaped human antibody to human interleukin-8

Abstract

The present invention discloses a reshaped human antibody against human IL-8 comprising: (A) L chains each comprising: (1) a human L chain C region; and, (2) an L chain V region comprising a human L chain FR, and an L chain CDR of mouse monoclonal antibody against human IL-8; and, (B) H chains each comprising: (1) a human H chain C region; and, (2) an H chain V region comprising a human H chain FR, and an H chain CDR of mouse monoclonal antibody against human IL-8. Since the majority of this reshaped human antibody originates in human antibody and the CDR has low antigenicity, the reshaped human antibody of the present invention has low antigenicity to humans, and can therefore be expected to be useful in medical treatment.

1 . A light chain (L chain) variable region (V region) of mouse monoclonal antibody against human Interleukin-8 (IL-8).  
     
     
         2 . An L chain V region as set forth in  claim 1  having the amino acid sequence or a portion thereof shown in SEQ ID NO: 26.  
     
     
         3 . A heavy chain (H chain) V region of mouse monoclonal antibody against human IL-8.  
     
     
         4 . An H chain V region as set forth in  claim 3  having the amino acid sequence or a portion thereof shown in SEQ ID NO: 27.  
     
     
         5 . Chimeric L chain comprising a human L chain constant region (C region), and an L chain V region of mouse monoclonal antibody against human IL-8.  
     
     
         6 . Chimeric L chain as set forth in  claim 5 , wherein said mouse L chain V region has the amino acid sequence or a portion thereof shown in SEQ ID NO: 26.  
     
     
         7 . Chimeric H chain comprising a human H chain C region, and an H chain V region of mouse monoclonal antibody against human IL-8.  
     
     
         8 . Chimeric H chain as set forth in  claim 7 , wherein said mouse H chain V-region has the amino acid sequence or a portion thereof shown in SEQ ID NO: 27.  
     
     
         9 . Chimeric antibody comprising: 
 (1) L chains each comprising a human L chain constant region (C region), and an L chain V region of mouse monoclonal antibody against human IL-8; and,    (2) H chains each comprising a human H chain C region, and an H chain V region of mouse monoclonal antibody against human IL-8.    
     
     
         10 . Chimeric antibody as set forth in  claim 9  wherein said mouse L chain V region has the amino acid sequence or a portion thereof shown in SEQ ID NO: 26, and said mouse H chain V region has the amino acid sequence or a portion thereof shown in SEQ ID NO: 27.  
     
     
         11 . A complementarity determining region (CDR) of an L chain V region of mouse monoclonal antibody against human IL-8.  
     
     
         12 . A CDR as set forth in  claim 11  having the amino acid sequence or a portion thereof shown below and in SEQ ID NO: 26. 
 CDR1: Arg Ala Ser/Glu Ile Ile/Tyr Ser Tyr/Leu Ala/  
 CDR2: Asn Ala Lys/Thr Leu Ala/Asp  
 CDR3: Gln His His/Phe Gly Phe/Pro Arg Thr/  
 
     
     
         13 . A CDR of an H chain V region of mouse monoclonal antibody against human IL-8.  
     
     
         14 . A CDR as set forth in  claim 13  having the amino acid sequence or a portion thereof shown below and in SEQ ID NO: 27. 
 CDR1: Asp Tyr Tyr/Leu Ser  
 CDR2: Leu Ile Arg/Asn Lys Ala/Asn Gly Tyr/Thr Arg Glu/ Tyr Ser Ala/Ser Val Lys/Gly  
 CDR3: Glu Asn Tyr/Arg Tyr Asp/Val Glu Leu/Ala Tyr/  
 
     
     
         15 . A reshaped human L chain V region of antibody against human IL-8 comprising: 
 (1) a framework region (FR) of a human L chain V region; and,    (2) a CDR of an L chain V region of mouse monoclonal antibody against human IL-8.    
     
     
         16 . A reshaped human L chain V region as set forth in  claim 15 , wherein said CDR has the amino acid sequence or a portion thereof shown in  claim 12 .  
     
     
         17 . A reshaped human L chain V region as set forth in claims  15  and  16 , wherein said FR is derived from human antibody REI.  
     
     
         18 . A reshaped human L chain V region as set forth in  claim 15 , wherein said L chain V region has the amino acid sequence or a portion thereof indicated as RVLa or RVLb in Table 2.  
     
     
         19 . A reshaped human H chain V region of antibody against human IL-8 comprising: 
 (1) an FR of a human H chain V region; and,    (2) a CDR of an H chain V region of mouse monoclonal antibody against human IL-8.    
     
     
         20 . A reshaped human H chain V region as set forth in  claim 19 , wherein said CDR has the amino acid sequence or a portion thereof shown in  claim 14 .  
     
     
         21 . A reshaped human H chain V region as set forth in claims  19  and  20 , wherein said FR1, FR2 and FR3 are derived from human antibody VDH26 and said FR4 is derived from human antibody 4B4.  
     
     
         22 . A reshaped human H chain V region as set forth in  claim 19 , wherein said H chain V region has the amino acid sequence or a portion thereof indicated as RVHa, RVHb, RVHc, RVHd, RVHe, RVHf, RVHg or RVHh in Tables 3 and 4.  
     
     
         23 . An L chain of reshaped human antibody against human IL-8 comprising: 
 (1) a human L chain C region; and,    (2) an L chain V region comprising a human L chain FR, and an L chain CDR of mouse monoclonal antibody against human IL-8.    
     
     
         24 . An L chain of reshaped human antibody as set forth in  claim 23 , wherein said human L chain C region is a human Cκ region, human L chain FR is derived from human antibody REI, and said L chain CDR has the amino acid sequence or a portion thereof shown in  claim 12 .  
     
     
         25 . An L chain of reshaped human antibody as set forth in  claim 23 , wherein said L chain V region has the amino acid sequence or a portion thereof indicated as RVLa or RVLb in Table 2.  
     
     
         26 . An H chain of reshaped human antibody against human IL-8 comprising: 
 (1) a human H chain C region; and,    (2) an H chain V region comprising a human H chain FR, and an H chain CDR of mouse monoclonal antibody against human IL-8.    
     
     
         27 . An H chain of reshaped human antibody as set forth in  claim 26 , wherein said human H chain C region is a human Cγ1 region, said human H chain FR1, FR2 and FR3 are derived from human antibody VDH26,.human H chain FR4 is derived from human antibody 4B4, and said H chain CDR has the amino acid sequence or a portion thereof shown in  claim 14 .  
     
     
         28 . An H chain of reshaped human antibody as set forth in  claim 26 , wherein said H chain V region has the amino acid sequence or a portion thereof indicated as RVHa, RVHb, RVHc, RVHd, RVHe, RVHf, RVHg and RVHh Tables 3 and 4.  
     
     
         29 . A reshaped human antibody against human IL-8 comprising: 
 (A) L chains each comprising: 
 (1) a human L chain C region; and,  
 (2) an L chain V region comprising a human L chain FR, and L chain CDR of mouse monoclonal antibody against human IL-8; and,  
   (B) an H chain comprising: 
 (1) a human H chain C region; and,  
 (2) an H chain V region comprising a human H chain FR, and H chain CDR of mouse monoclonal antibody against human IL-8.  
   
     
     
         30 . A reshaped human antibody as set forth in  claim 29 , wherein said L chain CDR has the amino acid sequence or a portion thereof shown in  claim 12 , and said H chain CDR has the amino acid sequence or a portion thereof shown in  claim 14 .  
     
     
         31 . A reshaped human antibody as set forth in  claim 29 , wherein said L chain CDR has the amino acid sequence or a portion thereof shown in  claim 12 , and said H chain CDR has the amino acid sequence or a portion thereof shown in claim  14 ; said human L chain FR is derived from human antibody REI; said human H chain FR1, FR2 and FR3 are derived from human antibody VDH26, human H chain FR4 is derived from human antibody 4B4, and said human L chain C region is a human Cκ region; and, said human H chain C region is a human Cγ1 region.  
     
     
         32 . A reshaped human antibody as set forth in  claim 29 , wherein said L chain CDR has the amino acid sequence or a portion thereof shown in  claim 12 , and said H chain CDR has the amino acid sequence or a portion thereof shown in claim  14 ; said human L chain FR is derived from human antibody REI; said human H chain FR1, FR2 and FR3 are derived from human antibody VDH26, human H chain FR4 is derived from human antibody 4B4, and said human L chain C region is a human Cκ region; and, said human H chain C region is Cγ4.  
     
     
         33 . A reshaped human antibody as set forth in  claim 29  wherein said L chain V region has the amino acid sequence or a portion thereof indicated as RVLa or RVLb in Table 2.  
     
     
         34 . A reshaped human antibody as set forth in  claim 29 , wherein said H chain V region has the amino acid sequence or a portion thereof indicated as RVHa, RVHb, RVHc, RVHd, RVHe, RVHf, RVHg or RVHh in Tables 3 and 4.  
     
     
         35 . DNA that codes for a chimeric L chain of antibody against human IL-8 containing: 
 (1) a human L chain C region; and,    (2) an L chain V region of mouse monoclonal antibody against human IL-8.    
     
     
         36 . DNA as set forth in  claim 35 , wherein said L chain V region codes for the amino acid sequence or a portion thereof shown in SEQ ID NO: 26.  
     
     
         37 . DNA as set forth in  claim 35 , wherein the DNA that codes for said L chain V region has the nucleotide sequence or a portion thereof shown in SEQ ID NO: 26.  
     
     
         38 . DNA that codes for a chimeric H chain of antibody against human IL-8 containing: 
 (1) a human H chain C region; and,    (2) an H chain V region of mouse monoclonal antibody against human IL-8.    
     
     
         39 . DNA as set forth in  claim 38 , wherein said H chain V region has the amino acid sequence or a portion thereof shown in SEQ ID NO: 27.  
     
     
         40 . DNA as set forth in  claim 38 , wherein said H chain V region has the nucleotide sequence or a portion thereof shown in SEQ ID NO: 27.  
     
     
         41 . DNA that codes for an L chain V region of mouse monoclonal antibody against human IL-8.  
     
     
         42 . DNA as set forth in  claim 41 , wherein said L chain V region codes for the amino acid sequence or a portion thereof shown in SEQ ID NO: 26.  
     
     
         43 . DNA as set forth in  claim 41 , wherein the DNA that codes for said L chain V region has the nucleotide sequence of a portion thereof shown in SEQ ID NO: 26.  
     
     
         44 . DNA that codes for an H chain V region of mouse monoclonal antibody against human IL-8.  
     
     
         45 . DNA as set forth in  claim 44 , wherein said H chain V region codes for the amino acid sequence or a portion thereof shown in SEQ ID NO: 27.  
     
     
         46 . DNA as set forth in  claim 44 , wherein the DNA that codes for said H chain V region has the nucleotide sequence or a portion thereof shown in SEQ ID NO: 27.  
     
     
         47 . DNA that codes for CDR of an L chain V region of mouse monoclonal antibody against human IL-8.  
     
     
         48 . DNA that codes for CDR as set forth in  claim 47 , wherein said CDR codes for the amino acid sequence or a portion thereof shown in  claim 12 .  
     
     
         49 . DNA that codes for CDR as set forth in  claim 47 , wherein said CDR has the nucleotide sequence or a portion thereof shown in SEQ ID NO: 26.  
     
     
         50 . DNA that codes for CDR of an H chain V region of mouse monoclonal antibody against human IL-8.  
     
     
         51 . DNA that codes for CDR as set forth in  claim 50 , wherein said CDR has the amino acid sequence or a portion thereof shown in  claim 14 .  
     
     
         52 . DNA that codes for CDR as set forth in  claim 50 , wherein said CDR has the nucleotide sequence or a portion thereof shown in SEQ ID NO: 27.  
     
     
         53 . DNA that codes for a reshaped human L chain V region of antibody against human IL-8 comprising: 
 (1) FR of a human L chain V region; and,    (2) CDR of an L chain V region of mouse monoclonal antibody against human IL-8.    
     
     
         54 . DNA that codes for a reshaped human L chain V region as set forth in  claim 53 , wherein said CDR has the amino acid sequence or a portion thereof shown in  claim 12 .  
     
     
         55 . DNA that codes for a reshaped human L chain V region as set forth in claims  53  and  54 , wherein said FR is derived from human antibody REI.  
     
     
         56 . DNA as set forth in  claim 53 , wherein said L chain V region codes for the amino acid sequence or a portion thereof indicated as RVLa or RVLb in Table 2.  
     
     
         57 . DNA as set forth in  claim 53  having the nucleotide sequence of a portion thereof shown in SEQ ID NO: 62 or SEQ ID NO: 65.  
     
     
         58 . DNA that codes for a reshaped human H chain V region of antibody against human IL-8 comprising: 
 (1) FR of a human H chain V region; and,    (2) CDR of an H chain V region of mouse monoclonal antibody against human IL-8.    
     
     
         59 . DNA that codes for a reshaped human H chain V region as set forth in  claim 58 , wherein said CDR has the amino acid sequence or a portion thereof shown in  claim 14 .  
     
     
         60 . DNA that codes for a reshaped human H chain V region as set forth in claims  58  and 59, wherein said FR1, FR2 and FR3 is derived from human antibody VDH26, and FR4 are derived from human antibody 4B4.  
     
     
         61 . DNA that codes for a reshaped human H chain V region as set forth in  claim 58 , wherein said H chain V region codes for the amino acid sequence or a portion thereof indicated as RVHa, RVHb, RVHc, RVHd, RVHe, RVHf, RVHg or RVHh in Tables 3 and 4.  
     
     
         62 . DNA as set forth in  claim 48  having the nucleotide sequence or a portion thereof shown in SEQ ID NO: 38, 41, 44, 45, 48, 51, 54 or 55.  
     
     
         63 . DNA that codes for a reshaped human L chain of antibody against human IL-8 comprising: 
 (1) a human L chain C region; and,    (2) an L chain V region comprising human FR, and CDR of mouse monoclonal antibody against human IL-8.    
     
     
         64 . DNA as set forth in  claim 63 , wherein said L chain V region codes for the amino acid sequence or a portion thereof indicated as RVLa or RVLb in Table 2.  
     
     
         65 . DNA as set forth in  claim 63 , wherein said L chain V region has the nucleotide sequence or a portion thereof shown in SEQ ID NO: 62 or SEQ ID NO: 65.  
     
     
         66 . DNA as set forth in claims  63 ,  64  and  65 , wherein said human L chain C region is a human L chain Cκ region.  
     
     
         67 . DNA that codes for a reshaped human H chain of antibody against human IL-8 comprising: 
 (1) a human H chain C region; and,    (2) an H chain V region comprising human FR, and CDR of mouse monoclonal antibody against human IL-8.    
     
     
         68 . DNA that codes for reshaped human H chain as set forth in  claim 67  wherein said H chain V region codes for the amino acid sequence or a portion thereof indicated as RVHa, RVHb, RVHc, RVHd, RVHe, RVHf, RVHg or RVHh in Tables 3 and 4.  
     
     
         69 . DNA as set forth in  claim 67 , wherein said H chain V region has the nucleotide sequence or a portion thereof shown in SEQ ID NO: 38, 41, 44, 45, 48, 51, 54 or 55.  
     
     
         70 . DNA as set forth in claims  67 ,  68  or  69 , wherein said human H chain C region is a human H chain Cγ1 region.  
     
     
         71 . DNA as set forth in claims  67 ,  68  or  69 , wherein said human H chain C region is a human H chain Cγ4 region.  
     
     
         72 . A vector containing DNA as set forth in any one of claims  35 ,  36 ,  37 ,  38 ,  39 ,  40 ,  63 ,  64 ,  65 ,  66 ,  67 ,  68 ,  69 ,  70  and  71 .  
     
     
         73 . A host cell transformed by a vector as set forth in  claim 72 .  
     
     
         74 . A process for producing chimeric antibody against human IL-8 comprising the steps of culturing host cells transformed simultaneously with an expression vector containing DNA as set forth in any one of claims  35 ,  36  and  37 , and an expression vector containing DNA as set forth in any one of claims  38 ,  39  and  40 , and recovering the target antibody.  
     
     
         75 . A process for producing chimeric antibody against human IL-8 comprising the steps of culturing host cells transformed with an expression vector containing DNA as set forth in any one of claims  35 ,  36  and  37 , and DNA as set forth in any one of claims  38 ,  39  and  40 , and recovering the target antibody.  
     
     
         76 . A process for producing reshaped human antibody against human IL-8 comprising the steps of culturing host cells transformed simaltaneously with an expression vector containing DNA as set forth in any one of claims  63 ,  64 ,  65  and  66 , and an expression vector containing DNA as set forth in any one of claims  67 ,  68 ,  69 ,  70  and  71 , and recovering the target antibody.  
     
     
         77 . A process for producing reshaped human antibody against human IL-8 comprising the steps of culturing host cells transformed with an expression vector containing DNA as set forth in any one of claims  63 ,  64 ,  65  and  66 , and DNA as set forth in any one of claims  67 ,  68 ,  69 ,  70  and  71 , and recovering the target antibody.