Recombinant antibodies for human therapy

Abstract

Chimeric antibodies including an Old World monkey portion and a human portion, nucleic acid encoding such antibodies, Old World monkey monoclonal antibodies, and methods for their production and use.

What is claimed is:  
     
         1 . A recombinant antibody comprising a human, a chimpanzee or a first Old World monkey immunoglobulin constant region and an antigen-binding portion of a second Old World monkey immunoglobulin variable region; wherein said first and second Old World monkey can be the same or different.  
     
     
         2 . A recombinant antibody comprising an immunoglobulin heavy or light chain having specificity for a particular known antigen having a constant region homologous to a corresponding constant region of a human, chimpanzee or first Old World monkey antibody, 
 a framework region homologous to a corresponding human, chimpanzee or second Old World monkey framework region, and    an antigen-binding portion homologous to a third Old World monkey antigen-binding portion, wherein said first, second, and third Old World monkey can be the same or different.    
     
     
         3 . A recombinant antibody comprising an immunoglobulin constant region which is not immunogenic to a human, a framework region which is essentially not immunogenic to a human, and an antigen-binding portion of a first Old World monkey immunoglobulin variable region.  
     
     
         4 . The antibody of  claim 1 ,  2  or  3  wherein said antibody binds specifically to a human antigen.  
     
     
         5 . The antibody of  claim 3  wherein said constant region is homologous to a constant region of a human, a chimpanzee or a second old World monkey immunoglobulin constant region, wherein said first and second Old World monkey can be the same or different.  
     
     
         6 . The antibody of  claim 3  wherein said framework region is homologous to a human, chimpanzee or Old World monkey framework region.  
     
     
         7 . The antibody of  claim 1 ,  2  or  3  wherein one said Old World monkey is a Rhesus monkey.  
     
     
         8 . The antibody of  claim 1 ,  2  or  3  wherein one said Old World monkey is a cynomolgus monkey.  
     
     
         9 . The antibody of  claim 1 ,  2 , or  3  wherein one said Old World monkey is a baboon.  
     
     
         10 . A recombinant antibody comprising a first Old World monkey immunoglobulin constant region and a second antigen-binding portion of a different Old World monkey immunoglobulin variable region.  
     
     
         11 . The antibody of  claim 10 , wherein said antibody binds specifically to a human antigen.  
     
     
         12 . The antibody of  claim 1 ,  2 ,  3 ,  5 ,  6 ,  10  or  11  wherein said antibody binds specifically to human antigens chosen from CD58, VCAM, VLA4, CD2, LFA3, ELAM, LAM, CD25, CD4, CD19, CD20, CD23, CD41, CD44, CD54, TNFα, TNFβ, Tn antigen, IL-1, IL-8, human T-cell receptor, CD3, CD28, CD8, CD11a, CD11b, CD18, CD5a, CD11c, CD45, neu oncogene product, MDR-1, TGFα, TGFα receptor, PDGF, and CD71.  
     
     
         13 . The antibody of  claim 4  wherein said antibody binds specifically to human antigens chosen from CD58, VCAM, VLA4, CD2, LFA3, ELAM, LAM, CD25, CD4, CD19, CD20, CD23, CD41, CD44, CD54, TNFα, TNFβ, Tn antigen, IL-1, IL-8, human T-cell receptor, CD3, CD28, CD8, CD11a, CD11b, CD11c, CD18, CD5a, CD45, neu oncogene product, MDR-1, TGFα, TGFα receptor, PDGF, and CD71.  
     
     
         14 . The antibody of  claim 7  wherein said antibody binds specifically to human antigens chosen from CD58, VCAM, VLA4, CD2, LFA3, ELAM, LAM, CD23, CD25, CD4, CD19, CD20, CD41, CD44, CD54, TNFα, TNFβ, Tn antigen, IL-1, IL-8, human T-cell receptor, CD3, CD28, CD8, CD11a, CD11b, CD11c, CD18, CD5a, CD45, neu oncogene product, MDR-1, TGFα, TGFα receptor, PDGF, and CD71.  
     
     
         15 . The antibody of  claim 8  wherein said antibody binds specifically to human antigens chosen from CD58, VCAM, VLA4, CD2, LFA3, ELAM, LAM, CD23, CD25, CD4, CD19, CD20, CD41, CD44, CD54, TNFα, TNFβ, Tn antigen, IL-1, IL-8, human T-cell receptor, CD3, CD28, CD8, CD11a, CD11b, CD11c, CD18, CD5a, CD45, neu oncogene product, MDR-1, TGFα, TGFα receptor, PDGF, and CD71.  
     
     
         16 . The antibody of  claim 9  wherein said antibody binds specifically to human antigens chosen from CD58, VCAM, VLA4, CD2, LFA3, ELAM, LAM, CD25, CD4, CD19, CD20, CD23, CD41, CD44, CD54, TNFα, TNFβ, Tn antigen, IL-1, IL-8, human T-cell receptor, CD3, CD28, CD8, CD11a, CD11b, CD11c, CD18, CDSA, CD45, neu oncogene product, MDR-1, TGFα, TGFα receptor, PDGF, and CD71.  
     
     
         17 . The antibody of  claim 10  wherein each said Old World monkey is selected from the group consisting of baboon, Rhesus, and cynomolgus monkeys.  
     
     
         18 . The antibody of  claim 1 ,  2  or  3  wherein said antigen-binding portion comprises one or more CDR regions of an Old World monkey variable region.  
     
     
         19 . The antibody of  claim 1 ,  2  or  3  wherein said antigen-binding portion comprises the whole variable region of an Old World monkey.  
     
     
         20 . Nucleic acid encoding a recombinant antibody comprising a first Old World monkey immunoglobulin antigen-binding portion.  
     
     
         21 . The nucleic acid of  claim 20  wherein said recombinant antibody comprises a human, chimpanzee or second Old World monkey constant region, wherein said first and second Old World monkey may be the same or different.  
     
     
         22 . The nucleic acid of  claim 21  wherein said antibody comprises a framework region of a second Old World monkey, a human or a chimpanzee antibody, wherein said first and second Old World monkey may be the same or different.  
     
     
         23 . The nucleic acid of  claim 20  wherein said antigen-recognizing portion comprises the whole variable region of said Old World monkey antibody.  
     
     
         24 . The nucleic acid of  claim 20  wherein said antigen-recognizing portion comprises one or more CDR regions of said first Old World monkey variable region.  
     
     
         25 . The nucleic acid of  claim 20 ,  21 , or  22  wherein said first and second Old World monkey are separately selected from the group consisting of baboon, Rhesus and cynomolgus monkeys.  
     
     
         26 . A monoclonal antibody, or a Fab or Fv or (Fab) 2  fragment thereof, formed by an immortalized Old World monkey B-cell.  
     
     
         27 . The monoclonal antibody of  claim 26  wherein said B-cell is a cynomolgus B-cell.  
     
     
         28 . The monoclonal antibody of  claim 26  wherein said B-cell is a Rhesus B-cell.  
     
     
         29 . The monoclonal antibody of  claim 26  wherein said B-cell is a baboon B-cell.  
     
     
         30 . The monoclonal antibody of  claim 26 ,  27 ,  28  or  29  wherein said antibody is produced to a human antigen.  
     
     
         31 . The monoclonal antibody of  claim 26 ,  27 ,  28  or  29  wherein said antibody binds specifically to human antigens chosen from CD58, VCAM, VLA4, CD2, LFA3, ELAM, LAM, CD25, CD4, CD19, CD20, CD 23, CD41, CD44, CD54, TNFα, TNFβ, Tn antigen, IL-1, IL-8, human T-cell receptor, CD3, CD28, CD8, CD11a, CD18, CD11b, CD11c, C5a, CD45, neu oncogene product, MDR-1, TGFα, TGFα receptor, PDGF, and CD71.  
     
     
         32 . A method for isolating the variable region of an Old World monkey antibody gene, comprising the steps of: 
 contacting nucleic acid from the Old World monkey, and a primer complementary to the nucleic acid sequence encoding a 5′ leader sequence of said antibody gene, to form a hybrid complex; and    amplifying said nucleic acid in said hybrid complex to produce amplified nucleic acid.    
     
     
         33 . The method of  claim 32 , wherein said nucleic acid is DNA or cDNA.  
     
     
         34 . The method of  claim 32  wherein said primer is complementary to the non-coding strand of a 5′ leader sequence of a human or old World monkey antibody gene.  
     
     
         35 . The method of  claim 32  wherein said amplifying step produces sufficient nucleic acid to place within a vector.  
     
     
         36 . A method for isolating the variable region of an Old World monkey antibody gene, comprising the steps of: 
 contacting RNA from an Old World monkey with reverse transcriptase to form cDNA,    contacting said cDNA with a primer complementary to the cDNA at a location encoding a 5′ leader sequence of said antibody gene, to form a hybrid complex, and amplifying said nucleic acid in said hybrid complex to produce amplified nucleic acid.    
     
     
         37 . A method for producing a recombinant antibody to a human antigen, said antibody being not immunogenic in a human, comprising the steps of: 
 raising an Old World monkey antibody to said antigen in an Old World monkey,    isolating an Old World monkey nucleic acid encoding an antigen-binding portion of a variable region of said Old World monkey antibody,    providing a human nucleic acid encoding a human constant region of a human antibody,    ligating said Old World monkey nucleic acid and said human nucleic acid to form a recombinant nucleic acid, and    expressing said recombinant nucleic acid to produce said recombinant antibody.    
     
     
         38 . The method of  claim 37  wherein said antigen-binding portion comprises one or more CDR regions of an Old World monkey variable region.  
     
     
         39 . The method of  claim 37  wherein said antigen-binding portion comprises the whole variable region of an Old World monkey.  
     
     
         40 . The method of  claim 37 , wherein said method further comprises the step of immortalizing a cell able to produce said old World monkey antibody.  
     
     
         41 . The method of  claim 37 , further comprising the step of identifying the Old World monkey nucleic acid encoding a variable region of said Old World monkey antibody.  
     
     
         42 . The method of  claim 40  wherein said immortalizing is by hybridoma fusion.  
     
     
         43 . The method of  claim 40  wherein said immortalizing is by viral transformation.  
     
     
         44 . The method of  claim 40  wherein said immortalizing is by single B-cell cloning.  
     
     
         45 . The method of  claim 40  wherein said immortalizing is by library construction.  
     
     
         46 . The method of  claim 37  wherein said human constant region is selected to have a desired isotype.  
     
     
         47 . The method of  claim 37  wherein said method further comprises selecting a B-cell from said Old World monkey.  
     
     
         48 . The method of  claim 47  wherein said B-cell is obtained from peripheral blood lymphocytes, lymph node, bone marrow or spleen.  
     
     
         49 . The method of  claim 37  wherein said method further comprises screening cells of said old World monkey for production of said antibody.  
     
     
         50 . The method of  claim 37  wherein said expressing is within a producer cell line.  
     
     
         51 . The method of  claim 37  wherein said isolating comprises immunoglobulin gene rescue of said variable region.  
     
     
         52 . The method of  claim 30 , wherein said antigen is selected from CD58, VCAM, VLA4, CD2, LFA3, ELAM, LAM, CD25, CD4, CD19, CD20, CD23, CD41, CD44, CD54, TNFα, TNFβ, Tn antigen, IL-1, IL-8, human T-cell receptor, CD3, CD28, CD8, CD18, CD11a, CD11b, CD11c, C5a, CD45, neu oncogene product, MDR-1, TGFα, TGFα receptor, PDGF, and CD71.  
     
     
         53 . A method for treating a human having an antigen, wherein said human is in need of treatment, comprising the step of administering a therapeutically effective amount of a recombinant antibody specific for said antigen, wherein said antibody comprises a human or chimpanzee or first Old World monkey constant region and an antigen-binding portion of a second Old World monkey variable region.  
     
     
         54 . The method of  claim 53  wherein said human suffers from cancer, and said antigen is a tumor antigen.  
     
     
         55 . The method of  claim 53  wherein said human suffers from an auto-immune response, and said antigen is an antigen involved in an autoimmune response in the human.  
     
     
         56 . The method of  claim 53  wherein said antigen is a receptor expressed on a host cell.  
     
     
         57 . The method of  claim 53  wherein said antibody comprises portions homologous to human and Old World monkey antibodies.  
     
     
         58 . The method of  claim 53  or  57  wherein said antigen is selected from CD58, VCAM, VLA4, CD2, LFA3, ELAM, LAM, CD25, CD4, CD19, CD20, CD23, CD41, CD44, CD54, TNFα, TNFβ, Tn antigen, IL-1, IL-8, human T-cell receptor, CD3, CD28, CD8, CD18, CD11a, CD1b, CD11c, C5a, CD45, neu oncogene product, MDR-1, TGFα, TGFα receptor, PDGF, and CD71.  
     
     
         59 . The method of  claim 53  wherein said antigen-binding portion comprises one or more CDR regions of an Old World monkey variable region.  
     
     
         60 . The method of  claim 53  wherein said antigen-binding portion comprises the whole variable region of an Old World monkey.  
     
     
         61 . A recombinant antibody comprising 
 (1) a constant region of a heavy chain of a human antibody;    (2) a constant region of a light chain of said human antibody;    (3) a variable region of a heavy chain of an Old World monkey antibody against a human antigen; and (4) a variable region of a light chain of said Old World monkey antibody.    
     
     
         62 . Recombinant nucleic acid comprising at least one CDR region from the variable region in SEQ.ID NOS. 15 or 16.  
     
     
         63 . A pharmaceutical composition comprising a therapeutically or prophylactically effective amount of an antibody of any of  claim 1 ,  2 ,  3 ,  10  or  26  in a pharmaceutically acceptable carrier.  
     
     
         64 . The pharmaceutical composition of claim  63  where said antibody binds specifically to CD58, VCAM, VLA4, CD2, LFA3, ELAM, LAM, CD25, CD4, CD19, CD20, CD23, CD41, CD44, CD54, TNFα, TNFβ, Tn antigen, IL-1, IL-8, human T-cell receptor, CD3, CD28, CD8, CD18, CD11a, CD11b, CD11c, C5a, CD45, neu oncogene product, MDR-1, TGFα, TGFα receptor, PDGF, or CD71.  
     
     
         65 . A method for treatment of a disease chosen from rheumatoid arthritis, eczema and an immunomodulatory disease comprising the step of providing a pharmaceutical composition of claim  63  to a human suffering from said disease.