Humanised antibodies

Abstract

CDR-grafted antibody heavy and light chains comprise acceptor framework and donor antigen binding regions, the heavy chains comprising donor residues at at least one of positions (6, 23) and/or (24, 48) and/or (49, 71) and/or (73, 75) and/or (76) and/or (78) and (88) and/or (91). The CDR-grafted light chains comprise donor residues at at least one of positions (1) and/or (3) and (46) and/or (47) or at at least one of positions (46, 48, 58) and (71). The CDR-grafted antibodies are preferably humanized antibodies, having non human, e.g. rodent, donor and human acceptor frameworks, and may be used for in vivo therapy and diagnosis. A generally applicable protocol is disclosed for obtaining CDR-grafted antibodies.

The invention claimed is: 
     
       1. A humanised antibody molecule having affinity for an antigen and comprising a composite heavy chain and a complementary light chain, said composite heavy chain having a variable domain including complementarity determining regions (CDRs), wherein, according to the Kabat numbering system, in said composite heavy chain at least residues 26 to 35, 50 to 58 and 95 to 102 in the CDRs and at least residues 48, 49, 71, 73, 76, 78, 88, and 91 in the framework regions are non-human donor, provided that said heavy chain is not a chimeric antibody heavy chain having a donor variable domain and a human constant domain. 
     
     
       2. A humanised antibody molecule having affinity for a predetermined antigen and comprising a composite heavy chain and a complementary light chain, said composite heavy chain having a variable domain including complementarity determining regions (CDRs) and framework regions, wherein, according to the Kabat numbering system, in said composite heavy chain: said CDRs are non-human donor at residues 31 to 35, 50 to 58, and 95 to 102; and said framework regions are non-human donor at:
 a) residue 6; 
 b) one or more of residues 23 and 24; 
 c) one or more of residues 48 and 49; 
 d) one or more of residues 71 and 73; 
 e) residue 75; 
 f) one or more of residues 75, 76, and 78 76 and 78; and 
 f)g) one or more of residues 88 and 91, 
 
       provided that said heavy chain is not a chimeric antibody heavy chain having a donor variable domain and a human constant domain. 
     
     
       3. The antibody molecule of  claim 2  wherein residue 2 of said composite heavy chain is donor. 
     
     
       4. The antibody molecule of  claim 2  wherein residue 72 of said composite heavy chain is donor. 
     
     
       5. The antibody molecule of  claim 2  wherein residue 108 of said composite heavy chain is donor. 
     
     
       6. The antibody molecule of  claim 2  wherein residue 110 of said composite heavy chain is donor. 
     
     
       7. A humanised antibody molecule having affinity for an antigen and comprising a composite heavy chain and a complementary light chain, said composite heavy chain having a variable domain including complementarity determining regions (CDRs), wherein, according to the Kabat numbering system, in said composite heavy chain at least residues 31 to 35, 50 to 58 and 95 to 102 in the CDRs, and at least residues 6, 24, 48, 49, 71, 72, 73, and 78 in the framework regions are non-human donor, provided that said heavy chain is not a chimeric antibody heavy chain having a donor variable domain and a human constant domain. 
     
     
       8. A humanised antibody molecule having affinity for an antigen and comprising a composite heavy chain and a complementary light chain, said composite heavy chain having a variable domain including complementarity determining regions (CDRs), wherein, according to the Kabat numbering system, in said composite heavy chain at least residues 31 to 35, 50 to 58 and 95 to 102 in the CDRs, and at least residues 6, 24, 48, 49, 71, 73, 78, and 108 in the framework regions are non-human donor, provided that said heavy chain is not a chimeric antibody heavy chain having a donor variable domain and a human constant domain. 
     
     
       9. A humanised antibody molecule having affinity for an antigen and comprising a composite heavy chain and a complementary light chain, said composite heavy chain having a variable domain including complementarity determining regions (CDRs), wherein, according to the Kabat numbering system, in said composite heavy chain at least residues 31 to 35, 50 to 58 and 95 to 102 in the CDRs, and at least residues 6, 24, 48, 49, 71, 73, 78, and 110 in the framework regions are non-human donor, provided that said heavy chain is not a chimeric antibody heavy chain having a donor variable domain and a human constant domain. 
     
     
       10. A humanised antibody molecule having affinity for an antigen and comprising a composite heavy chain and a complementary light chain, said composite heavy chain having a variable domain including complementarity determining regions (CDRs), wherein, according to the Kabat numbering system, in said composite heavy chain at least residues 31 to 35, 50 to 58 and 95 to 102 in the CDRs, and at least residues 6, 24, 48, 49, 71, 73, 76, 78, 88, and 91 in the framework regions are non-human donor, provided that said heavy chain is not a chimeric antibody heavy chain having a donor variable domain and a human constant domain. 
     
     
       11. The humanised antibody molecule of  claim 10 , wherein residue 2 of said composite heavy chain is donor. 
     
     
       12. The humanised antibody molecule of  claim 10 , wherein residue 72 of said composite heavy chain is donor. 
     
     
       13. The humanised antibody molecule of  claim 10 , wherein residue 108 of said composite heavy chain is donor. 
     
     
       14. The humanised antibody molecule of  claim 10 , wherein residue 110 of said composite heavy chain is donor. 
     
     
       15. A humanised antibody molecule having affinity for an antigen and comprising a composite heavy chain and a complementary light chain, said composite heavy chain having a variable domain including complementarity determining regions (CDRs), wherein, according to the Kabat numbering system, in said composite heavy chain at least residues 31 to 35, 50 to 58 and 95 to 102 in the CDRs, and at least residues 6, 24, 48, 49, 71, 73, 76, and 78 in the framework regions are non-human donor, provided that said heavy chain is not a chimeric antibody heavy chain having a donor variable domain and a human constant domain. 
     
     
       16. The humanised antibody molecule of  claim 15 , wherein residue 2 of said composite heavy chain is donor. 
     
     
       17. The humanised antibody molecule of  claim 15 , wherein residue 72 of said composite heavy chain is donor. 
     
     
       18. The humanised antibody molecule of  claim 15 , wherein residue 108 of said composite heavy chain is donor. 
     
     
       19. The humanised antibody molecule of  claim 15 , wherein residue 110 of said composite heavy chain is donor.