Antibody molecules specific to human tumour necrosis factor alpha
There is disclosed antibody molecules containing at least one CDR derived from a mouse monoclonal antibody having specificity for human TNFα. There is also disclosed a CDR grafted antibody wherein at least one of the CDRs is a hybrid CDR. Further disclosed are DNA sequences encoding the chains of the antibody molecules, vectors, transformed host cells and uses of the antibody molecules in the treatment of diseases mediated by TNFα.
1. An antibody molecule having specificity for human TNFα, comprising
a) a heavy chain wherein the variable domain comprises
(i) the sequence given in SEQ ID NO:1 for CDRH1,
(ii) the sequence given in SEQ ID NO:2 or SEQ ID NO:7, for CDRH2, and
(iii) the sequence given in SEQ ID NO:3 for CDRH3; and
b) a light chain wherein the variable domain comprises
(i) the sequence given in SEQ ID NO:4 for CDRL1,
(ii) the sequence given in SEQ ID NO:5 for CDRL2, and
(iii) the sequence given in SEQ ID NO:6 for CDRL3.
2. The antibody molecule of claim 1 , which comprises SEQ ID NO:2 for CDRH2.
3. The antibody molecule of claim 1 , which is a CDR-grafted antibody molecule.
4. The antibody molecule of claim 3 , wherein the variable domains comprise human acceptor framework regions.
5. The antibody molecule of claim 4 , wherein the human acceptor framework regions of the variable domain of the heavy chain are based on a human group 1 consensus sequence and comprise donor residues at positions 28, 69, and 71 according to Kabat numbering.
6. The antibody molecule of claim 4 , wherein the human acceptor framework regions of the variable domain of the heavy chain are based on a human group 1 consensus sequence and comprise donor residues at positions 28, 38, 46, 67, 69, and 71 according to Kabat numbering.
7. The antibody molecule of claim 4 , wherein the human acceptor framework regions of the variable domain of the heavy chain are based on a human group 3 consensus sequence and comprise donor residues at positions 27, 28, 30, 48 49, 69, 71, 73, 76, and 78 according to Kabat numbering.
8. The antibody molecule of claim 4 , wherein the human acceptor framework regions of the variable domain of the light chain are based on human group 1 consensus sequence and comprise donor residues at positions 46 and 60 according to Kabat numbering.
9. The antibody molecule of claim 1 , which is a Fab or Fab′ fragment.
10. The antibody molecule of claim 1 , which is a modified Fab′ fragment, having at the C-terminal end of its heavy chain one or more amino acids to allow attachment of an effector or reporter molecule.
11. The antibody molecule of claim 10 , wherein the additional amino acids form a modified hinge region containing one or two cysteine residues to which the effector or reporter molecule may be attached.
12. The antibody molecule of claim 10 , having covalently attached to an amino acid at or towards the C-terminal end of its heavy chain an effector or reporter molecule.
13. The antibody molecule of claim 12 , which comprises an effector molecule.
14. The antibody molecule of claim 13 , wherein the effector molecule comprises one or more polymers.
15. The antibody molecule of claim 14 , wherein the one or more polymers is/are an optionally substituted straight or branched chain polyalkylene, polyalkenylene or polyoxyalkylene polymer or a branched or unbranched polysaccharide.
16. The antibody molecule of claim 11 , wherein a maleimide group is covalently linked to a single thiol group in the modified hinge region.
17. The antibody molecule of claim 16 , wherein a lysine is covalently linked to the maleimide group.
18. The antibody molecule of claim 17 , wherein a methoxypoly(ethyleneglycol) polymer having a molecular weight of about 20000 Da is attached to each of the amine groups of the lysine.
19. The antibody molecule of claim 15 , wherein the polymer has an average molecular weight of about 500 to 50000 Da.
20. The antibody molecule of claim 19 , wherein the polymer has an average molecular weight of about 25000 to 40000 Da.
21. The antibody molecule of claim 15 , wherein the polymer is methoxypoly(ethyleneglycol) with a molecular weight of about 25000 to 40000 Da.
22. The antibody according to claim 21 , which has the formula:
wherein n is about 420.