Antibody variants

Abstract

This invention relates to an antibody which is a modified version of a therapeutic antibody with affinity for a cell-surface antigen, said antibody having reduced affinity for the antigen compared with the therapeutic antibody as a result of a modification or modifications to the antibody molecule, wherein the antibody is capable of inducing immunological tolerance to the therapeutic antibody. The invention further relates to a method of inducing immunological tolerance to a therapeutic antibody comprising administering to a patient an antibody which is a modified version of the therapeutic antibody and which has reduced affinity for the antigen as compared with the therapeutic antibody.

1 . An antibody which is a modified version of a therapeutic antibody with affinity for a cell-surface antigen, said antibody having reduced affinity for the antigen compared with the therapeutic antibody as a result of a modification or modifications to the antibody molecule, wherein the antibody is capable of inducing immunological tolerance to the therapeutic antibody and wherein the antibody is not a mixed molecule antibody having an H or L chain of the therapeutic antibody paired with an L or H chain of an unrelated antibody.  
     
     
         2 . An antibody as claimed in  claim 1 , wherein the framework regions of the variable domains of the antibody have the same or substantially the same amino acid sequence as the therapeutic antibody framework regions.  
     
     
         3 . An antibody as claimed in  claim 1  or  claim 2 , wherein the modification comprises an alteration in at least one of the complementarity determining regions (CDRs).  
     
     
         4 . An antibody as claimed in  claim 3 , wherein the alteration is achieved by genetic manipulation of a nucleic acid coding for the CDR.  
     
     
         5 . An antibody as claimed in any one of  claims 1  to  4 , wherein the affinity of the antibody for the antigen is reduced to 50% or less of the affinity of the therapeutic antibody.  
     
     
         6 . An antibody as claimed in any one of  claims 1  to  5 , wherein the CDRs are foreign with respect to the constant region of the antibody.  
     
     
         7 . An antibody as claimed in any one of  claims 1  to  6 , wherein the CDRs are foreign with respect to the heavy and light chain variable domain framework regions.  
     
     
         8 . An antibody as claimed in  claim 7 , which is of substantially human origin other than the CDRs.  
     
     
         9 . An antibody as claimed in any one of  claims 1  to  8 , wherein the therapeutic antibody has affinity for CD52.  
     
     
         10 . An antibody as claimed in  claim 9 , wherein the therapeutic antibody is a humanised Campath-1 antibody  
     
     
         11 . An antibody as claimed in  claim 10 , wherein the modification comprises an alteration in (VH) CDR2.  
     
     
         12 . An antibody as claimed in  claim 11 , wherein the modification comprises a single or a double amino acid substitution in (VH) CDR2.  
     
     
         13 . An antibody as claimed in any one of  claims 1  to  12 , wherein the constant domains of the antibody have substantially the same amino acid sequence as the therapeutic antibody constant regions.  
     
     
         14 . A fragment of an antibody according to any one of  claims 1  to  13 , which fragment retains tolerance-inducing capability of the antibody.  
     
     
         15 . An antibody fragment as claimed in  claim 14 , which is a modified version of a therapeutic antibody fragment.  
     
     
         16 . An antibody or fragment as claimed in any one of  claims 1  to  15 , which is monovalent.  
     
     
         17 . An antibody or fragment as claimed in any one of  claims 1  to  16 , for inducing tolerance to the therapeutic antibody in a patient.  
     
     
         18 . A cell line which expresses an antibody or fragment as claimed in any one of  claims 1  to  17 .  
     
     
         19 . A method of producing an antibody which is a modified version of a therapeutic antibody with affinity for a cell-surface antigen, said antibody having reduced affinity for the antigen compared with the therapeutic antibody as a result of a modification or modifications to the antibody molecule, wherein the antibody is capable of inducing immunological tolerance to the therapeutic antibody, comprising maintaining a cell line as claimed in  claim 18  under conditions suitable for expression of said antibody or fragment thereof.  
     
     
         20 . The method of  claim 19 , further comprising recovering the antibody or fragment.  
     
     
         21 . The method of  claim 20 , further comprising isolating the antibody or fragment.  
     
     
         22 . A composition for administration to a patient, comprising an antibody or fragment as claimed in any one of  claims 1  to  17  or as produced by the method according to any one of  claims 19  to  21 , together with a physiologically acceptable diluent or carrier.  
     
     
         23 . The use of an antibody or fragment as claimed in any one of  claims 1  to  17  or as produced by the method according to any one of  claims 19  to  21 , in the manufacture of a medicament for the induction of tolerance.