Patent
Modified antibody fab fragments
| العنوان: | Modified antibody fab fragments |
|---|---|
| Patent Number: | 7,989,594 |
| تاريخ النشر: | August 02, 2011 |
| Appl. No: | 10/562746 |
| Application Filed: | July 01, 2004 |
| مستخلص: | The present invention provides antibody Fab fragments in which the heavy chain constant region terminates at the interchain cysteine of CH1. Also provided are antibody Fab fragments in which the heavy chain constant region terminates at the interchain cysteine of CH1 to which one or more effector molecules are attached. |
| Inventors: | Humphreys, David Paul (Maidenhead, GB); Heywood, Sam Philip (High Wycombe, GB) |
| Assignees: | Celltech R & D Limited (Slough, Berkshire, GB) |
| Claim: | 1. An antibody Fab fragment comprising a heavy chain constant region that terminates at the interchain cysteine of C H 1. |
| Claim: | 2. The antibody Fab fragment of claim 1 wherein the interchain cysteine of C H 1 is covalently linked to the interchain cysteine of C L . |
| Claim: | 3. The antibody Fab fragment of claim 1 wherein the interchain cysteine of C H 1 is at position 233 of the heavy chain of human IgG1, according to the Kabat numbering system. |
| Claim: | 4. The antibody Fab fragment of claim 1 wherein the interchain cysteine of C H 1 is at position 127 of the heavy chain of human IgM, IgE, IgG2, IgG3, or IgG4, according to the Kabat numbering system. |
| Claim: | 5. The antibody Fab fragment of claim 1 wherein the interchain cysteine of C H 1 is at position 128 of the heavy chain of human IgD or IgA2B, according to the Kabat numbering system. |
| Claim: | 6. The antibody Fab fragment of claim 1 wherein the interchain cysteine of C H 1 is at position 235 of the heavy chain of murine IgG, according to the Kabat numbering system. |
| Claim: | 7. The antibody Fab fragment of claim 1 wherein the interchain cysteine of the light chain constant region is at position 214 of the light chain of human IgG1 or murine IgG, according to the Kabat numbering system. |
| Claim: | 8. The antibody Fab fragment of claim 1 that has been modified by attachment of one or more effector molecules. |
| Claim: | 9. The antibody Fab fragment of claim 8 that has been modified by attachment of two or more effector molecules. |
| Claim: | 10. The antibody fragment of claim 9 wherein an effector molecule is attached to a cysteine in the light chain constant region and to a cysteine in the heavy chain constant region. |
| Claim: | 11. The antibody fragment of claim 10 wherein the cysteine residues in the heavy and light chain constant regions that are attached to effector molecules would otherwise be linked to each other via a disulphide bond if the effector molecules were not attached. |
| Claim: | 12. The antibody fragment of claim 11 wherein the light chain cysteine to which an effector molecule is attached is the interchain cysteine of C L and the heavy chain cysteine to which an effector molecule is attached is the interchain cysteine of C H 1. |
| Claim: | 13. The antibody Fab fragment of claim 8 wherein the effector molecule is PEG. |
| Claim: | 14. A composition comprising a mixture of two or more antibody Fab fragments wherein the mixture is enriched for the Fab fragments comprising a heavy chain constant region that terminates at the interchain cysteine of C H 1, and in which the heavy chains in the fragments are not covalently bonded to the light chains and the fragments have an effector molecule attached to a cysteine in the light chain constant region and the heavy chain constant region of the fragments. |
| Claim: | 15. The composition of claim 14 wherein greater than 50% of the mixture comprises the Fab fragments comprising a heavy chain constant region that terminates at the interchain cysteine of C H 1, and in which the heavy chains in the fragments are not covalently bonded to the light chains and the fragments have an effector molecule attached to a cysteine in the light chain constant region and the heavy chain constant region of the fragments. |
| Claim: | 16. A composition comprising an antibody Fab fragment of claim 1 , together with one or more pharmaceutically acceptable excipients, diluents or carriers. |
| Current U.S. Class: | 5303/871 |
| Patent References Cited: | WO89/01974 March 1989 WO93/06217 April 1993 98/25971 June 1998 WO 03/074679 September 2003 |
| Other References: | Pritsch et al. J. Clin. Invest. 1996 98;10:2235-2243. cited by examiner Vitetta et al. Science 2006 313:308-309. cited by examiner Chapman et al. Nature Biotechnology, 1999 17:780-783. cited by examiner Singh, Rajeeva et al., “Labeling of Antibodies by in situ Modification of Thiol Groups Generated from Selenol-Catalyzed Reduction of Native Disulfide Bonds”, Analytical Biochemistry, vol. 304, No. 2, May 15, 2002, pp. 147-156. cited by other Leong, S. R. et al., “Adapting Pharmacokinetic Properties of a Humanized Anti-Interleukin-8 Antibody for Therapeutic Applications Using Site-Specific Pegylation”, Cytokine, 2001, 16(3), 106-119. cited by other Tout, N. L. et al., “Phage Display and Bacterial Expression of a Recombinant Fab Specific for Pseudomonas Aeruginosa Serotype O6 Lipopolysaccharide”, Clinical and Diagnostic Laboratory Immunology, 1997, 4(2), 147-155. cited by other Khawli, L. A. et al., “Stable, Genetically Engineered F(ab')2 Fragments of Chimeric TNT-3 Expressed in Mammalian Cells”, Hybridoma and Hybridomics, 2002, 21(1), 11-18. cited by other Alfthan, K. et al., “Efficient Secretion of Murine Fab Fragments by Escherichia coli is Determined by the First Constant Domain of the Heavy Chain”, Gene., 1993, vol. 128, 203-209. cited by other Wels, J. A. et al., Definition of Mouse gene IgG-3 heavy chain constant region, GenBank Acc. No. X00915, published Nov. 14, 2006 at http://www.ncbi.nlm.nih.gov/nuccore/51816, 3 sheets. cited by other http://en.wikipedia.org/wiki/File :Engineered—monoclonal—antibodies. Svg, printed on Dec. 10, 2010, 1 sheet. cited by other Chapman, “PEGylated antibodies and antibody fragments for improved therapy: a review”, Advanced Drug Delivery Reviews, 54 (2002) 531-545. cited by other |
| Primary Examiner: | Dahle, Chun |
| Attorney, Agent or Firm: | McDonnell Boehnen Hulbert & Berghoff LLP |
| رقم الانضمام: | edspgr.07989594 |
| قاعدة البيانات: | USPTO Patent Grants |
| الوصف غير متاح. |