Antibody peg positional isomers, compositions comprising same, and use thereof

• US 20060110382A1
• Filed: 05/28/2003
• Published: 05/25/2006
• Est. Priority Date: 05/28/2002
• Status: Active Grant

• Current Assignee: UCB SA
• Original Assignee: Celltech Group Limited (UCB SA)
• Inventors: Mozier, Ned M.
• Granted Patent: US 7,601,817 B2
• Time in Patent Office: Days
• US Class Current: 424/133.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 16/00 Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002
• CPC Class Codes: C07K 16/241 Tumor Necrosis Factors
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Abstract

The present invention relates to recombinant protein PEG positional isomers. More specifically, it relates to PEG positional isomers of an antibody having specificity for antigenic determinants of human tumor necrosis factor alpha (TNFα). More specifically, it relates to PEG positional isomers of CDP870. The present invention also relates to compositions comprising the PEG positional isomers and therapeutic uses of the composition for treating a disease medicated by TNFα including acute and chronic immune and immunoregulatory disorders and rheumatoid-or osteo-arthritis.

Claims

1. A recombinant protein PEG positional isomer.

2. The PEG positional isomer of claim 1 wherein said recombinant protein is an antibody.

3. The PEG positional isomer of claim 2 wherein said antibody has specificity for TNFα

.

4. The PEG positional isomer of claim 2 wherein said antibody is a Fab.

5. The PEG positional isomer of claim 4 wherein said Fab comprises a modified Fab fragment wherein the modification is the addition to the C-terminal end of its heavy chain one or more amino acids to allow the attachment of an effector or reporter molecule.

6. The PEG positional isomer of claim 5 wherein one of said additional amino acid(s) is a cysteine.

7. The PEG positional isomer of claim 6 wherein said effector is a polymer.

8. The PEG positional isomer of claim 7 wherein said polymer is polyethylene glycol.

9. The PEG positional isomer of claim 8 wherein said polyethylene glycol is a branched PEG.

10. The PEG positional isomer of claim 3 wherein said TNFα

antibody is CDP870.

11. The PEG positional isomer of claim 10 wherein the PEG is attached at Cys 214 of the light chain.

12. The PEG positional isomer of claim 11 further comprising a disulfide linkage between Cys 221 and Cys 227 of the heavy chain.

13. The PEG positional isomer of claim 11 further comprising an adduct at Cys 221 and Cys 227 of the heavy chain.

14. The PEG positional isomer of claim 13 wherein said adduct is glutathione or MEA.

15. A therapeutic or diagnostic composition comprising a recombinant protein and at least one PEG positional isomer of the protein in combination with a pharmaceutically acceptable excipient, diluent, or carrier.

16. The composition of claim 15 wherein said recombinant protein is an antibody.

17. The composition of claim 16 wherein said antibody has specificity for TNFα

.

18. The composition of claim 17 wherein said TNFα

antibody is CDP870.

19. The composition of claim 18 wherein said PEG positional isomer is an isomer of CDP870 having a PEG attached at Cys 214 of the light chain of CDP870.

20. The composition of claim 19 wherein said PEG positional isomer further comprises a disulfide linkage between Cys 221 and Cys 227 of the heavy chain.

21. The composition of claim 19 wherein said PEG positional isomer further comprises an adduct at Cys 221 and Cys 227 of the heavy chain.

22. The composition of claim 21 wherein said adduct is glutathione or MEA.

23. The composition of claim 19 wherein said PEG positional isomer comprises between about 1% and 20% of the total CDP870 antibody concentration.

24. The composition of claim 19 wherein said PEG positional isomer concentration is between about 1%and 10% of the total CDP870 antibody concentration.

25. The composition of claim 19 wherein said PEG positional isomer concentration is between about 1% and 5% of the total CDP870 antibody concentration.

26. The composition of claim 21 wherein said PEG positional isomer concentration is less than 5% of the total CDP870 antibody concentration.

27. The composition of claim 21 wherein said PEG positional isomer concentration is less than 1% of the total CDP870 antibody concentration.

28. The composition of claim 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 or 27 further comprising a CDP870 disulfide isomer having a disulfide linkage between Cys 214 of the light chain and Cys 227 of the heavy chain and a PEG attached at Cys 221 of the heavy chain.

29. The composition of claim 28 wherein the concentration of said CDP870 disulfide isomer is between about 10% and 20% of the total CDP870 antibody concentration.

30. The composition of claim 28 wherein the concentration of said CDP870 disulfide isomer is about 13% of the total CDP870 antibody concentration.