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Human antibodies that bind human TNF.alpha. |
| 7521050 |
Human antibodies that bind human TNF.alpha.
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| Patent Drawings: | |
| Inventor: |
Salfeld, et al. |
| Date Issued: |
April 21, 2009 |
| Application: |
11/233,252 |
| Filed: |
September 21, 2005 |
| Inventors: |
Salfeld; Jochen G. (North Grafton, MA)
Allen; Deborah J. (London, GB)
Hoogenboom; Hendricus R. J. M. (Hasselt, BE)
Kaymakcalan; Zehra (Westborough, MA)
Labkovsky; Boris (Marlborough, MA)
Mankovich; John A. (Andover, MA)
McGuinness; Brian T. (Cambridge, GB)
Roberts; Andrew J. (Cambridge, GB)
Sakorafas; Paul (Newton, MA)
Schoenhaut; David (Clifton, NJ)
Vaughan; Tristan J. (Cambridge, GB)
White; Michael (Framingham, MA)
Wilton; Alison J. (Cambridge, MA)
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| Assignee: |
Abbott Biotechnology Ltd. (Hamilton, BM) |
| Primary Examiner: |
Saunders; David A |
| Assistant Examiner: |
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| Attorney Or Agent: |
Lahive & Cockfield, LLPHanley, Esq.; Elizabeth A.Cowles; Cristin Howley |
| U.S. Class: |
424/142.1; 424/145.1; 424/158.1; 424/484; 424/486; 424/810; 530/388.15; 530/388.23; 530/868 |
| Field Of Search: |
424/142.1; 424/145.1; 424/158.1; 424/484; 424/486; 424/810; 530/388.15; 530/388.23; 530/389.2; 530/868 |
| International Class: |
A61K 39/395; C07K 16/24 |
| U.S Patent Documents: |
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| Foreign Patent Documents: |
186833; 366043; 212489; 101681; 659766; 351789; 492448; 614984; 2279077; WO-91/02078; WO-91/09967; WO-92/11383; WO-92/16553; WO-93/06213; WO-94/29347; WO-95/23813 |
| Other References: |
Abraham, Edward et al, "Efficacy and Safety of Monoclonal Antibody to Human Tumor Necrosis Factor .alpha. in Patients With Sepsis Syndrome,"JAMA, vol. 273(12):934-941 (1995). cited by other.
Barbuto, J.A.M. et al. "Production of Neutralizing Antibodies to Tumor Necrosis Factor by Human Tumor-Infiltrating B Lymphocytes" Proc. Am. Assoc. Cancer Res. 34:487, Abstract No. 2904 (Mar. 1993). cited by other.
Bendtzen, K. et al. "Auto-antibodies to IL-1.alpha. and TNF.alpha. in Normal Individuals and in Infectious and Immunoinflammatory Disorders" in The Physiological and Pathological Effects of Cytokines (Wiely-Liss, Inc., 1990) 447-52. cited by other.
Boekstegers, P. et al, "Repeated administration of F(ab')2 fragment of an anti-tumor necrosis factor alpha monoclonal antibody in patients with severe sepsis: effects on the cardiovascular system and cytokine levels," Shock, vol. 1(4):237-245 (1994)(abstract from Pub Med). cited by other.
Boyle, P. et al. "A Novel Monoclonal Human IgM Autoantibody which Binds Recombinant Human and Mouse Tumor Necrosis Factor- .alpha." Cell. Immunol. 152:556-68 (1993). cited by other.
Boyle, P. et al. "The B5 Monoclonal Human Autoantibody Binds to Cell Surface TNF.alpha. on Human Lymphoid Cells and Cell Lines and Appears to Recognize a Novel Epitope" Cell. Immunol. 152:569-81 (1993). cited by other.
Brekke, Ole Henrik et al, "Therapeutic Antibodies for Human Diseases at the Dawn of the Twenty-First Century," Nature, vol. 2:52-62 (2003). cited by other.
Chow, A.W. et al. "Effect of monoclonal antibody on human tumor necrosis factor (TNF MAb) on TNF.alpha., IL-1.beta., and IL-6 levels in patients with sepsis syndrome" Clinical Research 42:2 299A (1994). cited by other.
Cohen, Jonathan et al, "INTERSEPT: An international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-alpha in patients with sepsis," Critical Care Medicine, vol. 24(9):1431-1440 (1996). cited by other.
Cox, J.P.L. et al. "A directory of human germ-line V.sub.ksegments reveals a strong bias in their usage" Eur. J. Immunol. 24(2):827-36 (1994). cited by other.
Department of Surgery, University of Toronto Annual Report, Jul. 1, 1998-Jun. 30, 1999--found online at http://www.surg.med.utoronto.ca/AnnRep/AR98.sub.--99/index.html. cited by other.
Elliot, M.J. et al. "Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor .alpha." Arthritis & Rheumatism 36(12):1681-90 (1993). cited by other.
Feldmann, Marc et al, "Anti-TNF.alpha. Therapy of Rheumatoid ARthritis: What Have We Learned?" Annu. Rev. Immunol., vol. 19:163-196 (2001). cited by other.
Figini, Mariangela et al, "In Vitro assembly of Repertoires of Antibody Chains on the Surface of Phage by Renaturation," J. Mol. Biol., vol. 239:68-78 (1994). cited by other.
Fomsguaard, A. et al. "Auto-antibodies to Tumor Necrosis Factor .alpha. in Healthy Humans and Patients with Inflammatory Diseases and Gram-Negative Bacterial Infections" Scand. J. Immunol. 30:219-23 (1989). cited by other.
Griffiths, A.D. et al, "Human anti-self antibodies with high specificity from phage display libraries" The EMBO J. 12(2):725-34 (1993). cited by other.
Hawkins, Robert E. et al, "Selection of Phage Antibodies by Binding Affinity Mimicking Affinity Maturation," J. Mol. Biol., vol. 226:889-896 (1992). cited by other.
Holler, E. et al, "Modulation of Acute Graft-Versus-Host Disease After Allogeneic Bone Marrow Transplantation by Tumor Necrosis Factor .alpha. (TNF.alpha.) Release in the Course of Pretransplant Conditioning: Role of Conditioning Regimens andProphylactic Application of a Monoclonal Antibody Neutralizing Human TNF.alpha. (MAK 195F)," Blood, vol. 86(3):890-899 (1995). cited by other.
Hoogenboom, Hennie R. et al, "converting rodent into human antibodies by guided selection," Antibody Engineering, Oxford University Press, pp. 169-185 (1996). cited by other.
Huse, W.D. et al. "Generation of a large combinatorial library of the immunoglobulin repertoire in phage lambda" Science 246:1275-81 (1989). cited by other.
Jespers, Laurent S. et al, "Guiding the Selection of Human Antibodies from Phage Display Repertoires to a Single Epitope of an Antigen," Bio/Technology, vol. 12:899-903 (1994). cited by other.
Kempeni, Joachim, "Update on D2E7: a fully human anti-tumour necrosis factor .alpha. monoclonal antibody," Ann. Rheum. Dis., vol. 59(Suppl. I):144-145 (2000). cited by other.
Lerner, R.A. et al. "Antibodies without immunization" Science 258:1313-14 (1992). cited by other.
Leusch, H-G. et al. Failure to demonstrate TNF.alpha.-specific autoantibodies in human sera by ELISA and Western blot J. Immunol. Methods 139:145-47 (1991). cited by other.
Lewis, Craig M. et al, "Use of alanine scanning mutagenesis to improve the affinity of an anti gp120 (HIV) antibody," J. Cell. Biochem., vol. 18D, p. 215 (1994). cited by other.
Low, Nigel, thesis extract, Cambridge University (1996). cited by other.
Low, Nigel et al, "Mimicking Somatic Hypermutation: Affinity Maturation of Antibodies Displayed on Bacteriophage Using a Bacterial Mutator Strain," J. Mol. Biol., vol. 260:359-368 (1996). cited by other.
Marks, J.D. et al. "By-passing immunization: Human antibodies from V-gene libraries displayed on phage" J. Mol. Biol. 222:581-97 (1991). cited by other.
Medynski, Dan, "Phage Display: All Dressed Up and Ready to Role," Bio/Technology, vol. 12:1134-1136 (1994). cited by other.
Moller et al. "Monoclonal antibodies to human tumor necrosis factor .alpha.: in vitro and vivo application" Cytokine 2(3):162-69 (1990). cited by other.
Nilsson, Bjorn, "Antibody engineering," Current Opinion in Structural Biology, vol. 5:450-456 (1995). cited by other.
Reinhart, K. et al, "Assessment of the safety and efficacy of the monoclonal anti-tumor necrosis factor antibody-fragment, MAK 195F, in patients with sepsis and septic shock: a multicenter, randomized, placebo-controlled, dose-ranging study," Crit.Care Med., vol. 24(5):733-742 (1996) (abstract from Pub Med). cited by other.
Reichmann, L. et al, "Phage display and selection of a site-directed randomized single-chain antibody Fv fragment for its affinity improvement," Biochemistry, vol. 32(34):8848-8855 (1993) (abstract from Pub Med). cited by other.
Santora, L.C. et al, "Characterization of Noncovalent Complexes of Recombinant Human Monoclonal Antibody and Antigen Using Cation Exchange, Size Exclusion Chromatography, and BIAcore," Analytical Biochemistry, vol. 299:199-129 (2001). cited by other.
Thompson, J. et al, "Affinity maturation of a high-affinity human monoclonal antibody against the third hypervariable loop of human immunodeficiency virus: use of phage display to improve affinity and broaden strain reactivity," J. Mol. Biol., vol.256(1):77-88 (1996) (abstract from Pub Med). cited by other.
Tomlinson, I.M. et al. "The structural repertoire of the human V.sub.k domain" The EMBO J. 14(18):4628-38 (1995). cited by other.
Tomlinson, I.M. et al. "The repertoire of human germline V.sub.H sequences reveals about fifty groups of V.sub.H segments with different hypervariable loops" J. Mol. Biol. 227:776-98 (1992). cited by other.
Tracey, K.J. et al. "Tumor necrosis factor: A pleiotropic cytokine and therapeutic target" Annu. Rev. Med. 45:491-503 (1994). cited by other.
Van Der Poll, T. et al, "Effect of postponed treatment with an anti-tumour necrosis factor (TNF) F(ab')2 fragment on endotoxin-induced cytokine and neutrophil responses in chimpanzees," Clin. Exp. Immunol., vol. 100:21-25 (1995). cited by other.
Vaughan, Tristan J. et al, "Human antibodies by design," Nature Biotechnology, vol. 16:535-539 (1998). cited by other.
Ward, E. Sally et al, "Binding activities of a repertoire of single immunoglobulin variable domains secreted from Escherichia coli," Nature, vol. 341:544-546 (1989). cited by other.
Winter, Greg et al, "Making antibodies by phage display technology," Annu. Rev. Immunol., vol. 12:433-455 (1994). cited by other.
Foote et al, "Antibody Framework Residues Affecting the Conformation of the Hypervariable Loops," J. Mol. Biol., vol. 224:487-490 (1992). cited by other.
Osborn, Jane et al., "From rodent reagents to human therapeutics using antibody guided selection," Methods, vol. 36:61-68 (2005). cited by other.
Queen, Cary et al., "A humanized antibody that binds to the interleukin 2 receptor," Proc. Natl. Acad. Sci. USA, vol. 86:10029-10033 (1989). cited by other.
Winter et al. (1993) "Humanized antibodies" Immunol Today 14(6):243-246. cited by other.
Marks et al. (1992) "By-Passing Immunization: Building High Affinity Human Antibodies By Chain Shuffling" Bio/Technology 10:779. cited by other. |
|
| Abstract: |
Human antibodies, preferably recombinant human antibodies, that specifically bind to human tumor necrosis factor .alpha. (hTNF.alpha.) are disclosed. These antibodies have high affinity for hTNF.alpha. (e.g., K.sub.d=10.sup.-8 M or less), a slow off rate for hTNF.alpha. dissociation (e.g., K.sub.off=10.sup.-3 sec.sup.-1 or less) and neutralize hTNF.alpha. activity in vitro and in vivo. An antibody of the invention can be a full-length antibody or an antigen-binding portion thereof. The antibodies, or antibody portions, of the invention are useful for detecting hTNF.alpha. and for inhibiting hTNF.alpha. activity, e.g., in a human subject suffering from a disorder in which hTNF.alpha. activity is detrimental. Nucleic acids, vectors and host cells for expressing the recombinant human antibodies of the invention, and methods of synthesizing the recombinant human antibodies, are also encompassed by the invention. |
| Claim: |
The invention claimed is:
1. A composition comprising a biodegradable, biocompatible polymer and a human antibody, or an antigen-binding portion thereof, that dissociates from human TNF.alpha. with a K.sub.d of 1.times.10.sup.-8 M or less and a K.sub.off rate constant of 1.times.10.sup.-3s.sup.-1 or less, both determined by surface plasmon resonance, and neutralizes human TNF.alpha. cytotoxicity in a standard in vitro L929 assay with anIC.sub.50 of 1.times.10.sup.-7 M or less, wherein the biodegradable, biocompatible polymer provides controlled release.
2. The composition of claim 1, wherein the human antibody, or antigen-binding portion thereof, is a recombinant antibody, or antigen-binding portion thereof.
3. The composition of claim 1, wherein the human antibody, or antigen-binding portion thereof, dissociates from human TNF.alpha. with a K.sub.off rate constant of 5.times.10.sup.-4s.sup.-1 or less.
4. The composition of claim 1, wherein the human antibody, or antigen-binding portion thereof, dissociates from human TNF.alpha. with a K.sub.off rate constant of 1.times.10.sup.-4s.sup.-1 or less.
5. The composition of claim 1, wherein the human antibody, or antigen-binding portion thereof, neutralizes human TNF.alpha. cytotoxicity in a standard in vitro L929 assay with an IC.sub.50 of 1.times.10.sup.-8 M or less.
6. The composition of claim 1, wherein the human antibody, or antigen-binding portion thereof, neutralizes human TNF.alpha. cytotoxicity in a standard in vitro L929 assay with an IC.sub.50 of 1.times.10.sup.-9 M or less.
7. The composition of claim 1, wherein the human antibody, or antigen-binding portion thereof, neutralizes human TNF.alpha. cytotoxicity in a standard in vitro L929 assay with an IC.sub.50 of 1.times.10.sup.-10 M or less.
8. The composition of claim 1, wherein the human antibody, or antigen-binding portions thereof, comprises a light chain variable region (LCVR) having a CDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ IDNO: 3, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26 andcomprises a heavy chain variable region (HCVR) having a CDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO:33 and SEQ ID NO: 34.
9. The composition of claim 1, wherein the biodegradable, biocompatible polymer is ethylene vinyl acetate.
10. The composition of claim 1, wherein the biodegradable, biocompatible polymer is a polyanhydride.
11. The composition of claim 1, wherein the biodegradable, biocompatible polymer is polyglycolic acid.
12. The composition of claim 1, wherein the biodegradable, biocompatible polymer is collagen.
13. The composition of claim 1, wherein the biodegradable, biocompatible polymer is a polyorthoester.
14. The composition of claim 1, wherein the biodegradable, biocompatible polymer is polylactic acid.
15. A pharmaceutical composition comprising the antibody, or antigen-binding portion thereof, of claim 1, and a pharmaceutically acceptable carrier.
16. A method for treating a subject suffering from a disorder in which TNF.alpha. activity is detrimental comprising administering to the subject the pharmaceutical composition of claim 15.
17. The method of claim 16, wherein the disorder is an autoimmune disorder.
18. The method of claim 17, wherein the autoimmune disorder is rheumatoid arthritis.
19. The method of claim 17, wherein the autoimmune disorder is rheumatoid spondylitis.
20. The method of claim 16, wherein the disorder is an intestinal disorder.
21. The method of claim 20, wherein the intestinal disorder is inflammatory bowel disorder.
22. The method of claim 20, wherein the intestinal disorder is idiopathic inflammatory bowel disease.
23. The method of claim 20, wherein the intestinal disorder is Crohn's disease.
24. The method of claim 20, wherein the intestinal disorder is ulcerative colitis.
25. The method of claim 16, wherein the disorder is osteoarthritis or gouty arthritis.
26. The method of claim 16, wherein the pharmaceutical composition is administered in combination with at least one additional therapeutic agent.
27. A composition comprising a biodegradable, biocompatible polymer and a human antibody, or antigen-binding portion thereof, with a light chain variable region (LCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, ormodified from SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or 8 or by one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9; and a heavy chain variable region (HCVR) having a CDR3 domaincomprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or by one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9, 10, 11and/or 12, wherein the biodegradable, biocompatible polymer provides controlled release.
28. The composition of claim 27, wherein the antibody, or antigen-binding portion thereof, further comprises a light chain CDR2 domain comprising the amino acid sequence of SEQ ID NO: 5 and a heavy chain CDR2 domain comprising the amino acidsequence of SEQ ID NO: 6.
29. The composition of claim 28, wherein the antibody, or antigen-binding portion thereof, further comprises a light chain CDR1 domain comprising the amino acid sequence of SEQ ID NO: 7 and a heavy chain CDR1 domain comprising the amino acidsequence of SEQ ID NO: 8.
30. A composition comprising a biodegradable, biocompatible polymer and a human antibody, or antigen-binding portion thereof, with a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chainvariable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2, wherein the biodegradable, biocompatible polymer provides controlled release.
31. The composition of claim 30, wherein the antibody has an IgG1 heavy chain constant region.
32. The composition of claim 30, wherein the antigen-binding portion of the antibody is a Fab fragment or a single chain Fv fragment.
33. A composition comprising a biodegradable, biocompatible polymer and, a human antibody that binds TNF.alpha. and is the antibody D2E7, or an antigen-binding portion thereof, wherein the biodegradable, biocompatible polymer providescontrolled release.
34. The composition of claim 33, wherein the biodegradable, biocompatible polymer is ethylene vinyl acetate.
35. The composition of claim 33, wherein the biodegradable, biocompatible polymer is a polyanhydride.
36. The composition of claim 33, wherein the biodegradable, biocompatible polymer is polyglycolic acid.
37. The composition of claim 33, wherein the biodegradable, biocompatible polymer is collagen.
38. The composition of claim 33, wherein the biodegradable, biocompatible polymer is a polyorthoester.
39. The composition of claim 33, wherein the biodegradable, biocompatible polymer is polylactic acid.
40. A pharmaceutical composition comprising the antibody, or antigen-binding portion thereof, of claim 33, and a pharmaceutically acceptable carrier.
41. A method for treating a subject suffering from a disorder in which TNF.alpha. activity is detrimental comprising administering to the subject the pharmaceutical composition of claim 40.
42. The method of claim 41, wherein the disorder is an autoimmune disorder.
43. The method of claim 42, wherein the autoimmune disorder is rheumatoid arthritis.
44. The method of claim 42, wherein the autoimmune disorder is rheumatoid spondylitis.
45. The method of claim 41, wherein the disorder is an intestinal disorder.
46. The method of claim 45, wherein the intestinal disorder is inflammatory bowel disorder.
47. The method of claim 45, wherein the intestinal disorder is idiopathic inflammatory bowel disease.
48. The method of claim 45, wherein the intestinal disorder is Crohn's disease.
49. The method of claim 45, wherein the intestinal disorder is ulcerative colitis.
50. The method of claim 41, wherein the disorder is osteoarthritis or gouty arthritis.
51. The method of claim 41, wherein the pharmaceutical composition is administered in combination with at least one additional therapeutic agent.
52. A composition comprising an absorption delaying agent and a human antibody, or an antigen-binding portion thereof, that dissociates from human TNF.alpha. with a K.sub.d of 1.times.10.sup.-8 M or less and a K.sub.off rate constant of1.times.10.sup.-3s.sup.-1 or less, both determined by surface plasmon resonance, and neutralizes human TNF.alpha. cytotoxicity in a standard in vitro L929 assay with an IC.sub.50 of 1.times.10.sup.-7 M or less.
53. The composition of claim 52, wherein the human antibody, or antigen-binding portion thereof, is a recombinant antibody, or antigen-binding portion thereof.
54. The composition of claim 52, wherein the human antibody, or antigen-binding portion thereof, dissociates from human TNF.alpha. with a K.sub.off rate constant of 5.times.10.sup.-4s.sup.-1 or less.
55. The composition of claim 52, wherein the human antibody, or antigen-binding portion thereof, dissociates from human TNF.alpha. with a K.sub.off rate constant of 1.times.10.sup.-4s.sup.-1 or less.
56. The composition of claim 52, wherein the human antibody, or antigen-binding portion thereof, neutralizes human TNF.alpha. cytotoxicity in a standard in vitro L929 assay with an IC.sub.50 of 1.times.10.sup.-8 M or less.
57. The composition of claim 52, wherein the human antibody, or antigen-binding portion thereof, neutralizes human TNF.alpha. cytotoxicity in a standard in vitro L929 assay with an IC.sub.50 of 1.times.10.sup.-9 M or less.
58. The composition of claim 52, wherein the human antibody, or antigen-binding portion thereof, neutralizes human TNF.alpha. cytotoxicity in a standard in vitro L929 assay with an IC.sub.50 of 1.times.10.sup.-10 M or less.
59. The composition of claim 52, wherein the human antibody, or antigen-binding portions thereof, comprises a light chain variable region (LCVR) having a CDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ IDNO: 3, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26 andcomprises a heavy chain variable region (HCVR) having a CDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO:33 and SEQ ID NO: 34.
60. A pharmaceutical composition comprising the antibody, or antigen-binding portion thereof, of claim 52, and a pharmaceutically acceptable carrier.
61. A method for treating a subject suffering from a disorder in which TNF.alpha. activity is detrimental comprising administering to the subject the pharmaceutical composition of claim 60.
62. The method of claim 61, wherein the disorder is an autoimmune disorder.
63. The method of claim 62, wherein the autoimmune disorder is rheumatoid arthritis.
64. The method of claim 62, wherein the autoimmune disorder is rheumatoid spondylitis.
65. The method of claim 61, wherein the disorder is osteoarthritis or gouty arthritis.
66. The method of claim 61, wherein the pharmaceutical composition is administered in combination with at least one additional therapeutic agent.
67. The method of claim 61, wherein the disorder is an intestinal disorder.
68. The method of claim 67, wherein the intestinal disorder is inflammatory bowel disorder.
69. The method of claim 67, wherein the intestinal disorder is idiopathic inflammatory bowel disease.
70. The method of claim 67, wherein the intestinal disorder is Crohn's disease.
71. The method of claim 67, wherein the intestinal disorder is ulcerative colitis.
72. A composition comprising an absorption delaying agent and a human antibody, or antigen-binding portion thereof, with a light chain variable region (LCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, or modifiedfrom SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or 8 or by one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9; and a heavy chain variable region (HCVR) having a CDR3 domain comprising theamino acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or by one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12.
73. The composition of claim 72, wherein the antibody, or antigen-binding portion thereof, further comprises a light chain CDR2 domain comprising the amino acid sequence of SEQ ID NO: 5 and a heavy chain CDR2 domain comprising the amino acidsequence of SEQ ID NO: 6.
74. The composition of claim 73, wherein the antibody, or antigen-binding portion thereof, further comprises a light chain CDR1 domain comprising the amino acid sequence of SEQ ID NO: 7 and a heavy chain CDR1 domain comprising the amino acidsequence of SEQ ID NO: 8.
75. A composition comprising an absorption delaying agent and a human antibody, or antigen-binding portion thereof, with a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region(HCVR) comprising the amino acid sequence of SEQ ID NO: 2.
76. The composition of claim 75, wherein the antibody, has an IgG1 heavy chain constant region.
77. The composition of claim 75, wherein the antigen-binding portion of the antibody is a Fab fragment or a single chain Fv fragment.
78. A composition comprising an absorption delaying agent and a human antibody that binds TNF.alpha. and is the antibody D2E7, or an antigen-binding portion thereof.
79. A pharmaceutical composition comprising the antibody, or antigen-binding portion thereof, of claim 78, and a pharmaceutically acceptable carrier.
80. A method for treating a subject suffering from a disorder in which TNF.alpha. activity is detrimental comprising administering to the subject the pharmaceutical composition of claim 79.
81. The method of claim 80, wherein the disorder is an autoimmune disorder.
82. The method of claim 81, wherein the autoimmune disorder is rheumatoid arthritis.
83. The method of claim 81, wherein the autoimmune disorder is rheumatoid spondylitis.
84. The method of claim 80, wherein the disorder is an intestinal disorder.
85. The method of claim 84, wherein the intestinal disorder is inflammatory bowel disorder.
86. The method of claim 84, wherein the intestinal disorder is idiopathic inflammatory bowel disease.
87. The method of claim 84, wherein the intestinal disorder is Crohn's disease.
88. The method of claim 84, wherein the intestinal disorder is ulcerative colitis.
89. The method of claim 80, wherein the disorder is osteoarthritis or gouty arthritis.
90. The method of claim 80, wherein the pharmaceutical composition is administered in combination with at least one additional therapeutic agent.
91. A composition comprising a carrier which prevents rapid release and a human antibody, or an antigen-binding portion thereof, that dissociates from human TNF.alpha. with a K.sub.d of 1.times.10.sup.-8 M or less and a K.sub.off rate constantof 1.times.10.sup.-3s.sup.-1 or less, both determined by surface plasmon resonance, and neutralizes human TNF.alpha. cytotoxicity in a standard in vitro L929 assay with an IC.sub.50 of 1.times.10.sup.-7 M or less.
92. The composition of claim 91, wherein the human antibody, or antigen-binding portion thereof, is a recombinant antibody, or antigen-binding portion thereof.
93. The composition of claim 91, wherein the human antibody, or antigen-binding portion thereof, dissociates from human TNF.alpha. with a K.sub.off rate constant of 5.times.10.sup.-4s.sup.-1 or less.
94. The composition of claim 91, wherein the human antibody, or antigen-binding portion thereof, dissociates from human TNF.alpha. with a K.sub.off rate constant of 1.times.10.sup.-4s.sup.-1 or less.
95. The composition of claim 91, wherein the human antibody, or antigen-binding portion thereof, neutralizes human TNF.alpha. cytotoxicity in a standard in vitro L929 assay with an IC.sub.50 of 1.times.10.sup.-8 M or less.
96. The composition of claim 91, wherein the human antibody, or antigen-binding portion thereof, neutralizes human TNF.alpha. cytotoxicity in a standard in vitro L929 assay with an IC.sub.50 of 1.times.10.sup.-9 M or less.
97. The composition of claim 91, wherein the human antibody, or antigen-binding portion thereof, neutralizes human TNF.alpha. cytotoxicity in a standard in vitro L929 assay with an IC.sub.50 of 1.times.10.sup.-10 M or less.
98. The composition of claim 91, wherein the human antibody, or antigen-binding portions thereof, comprises a light chain variable region (LCVR) having a CDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ IDNO: 3, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26 andcomprises a heavy chain variable region (HCVR) having a CDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO:33 and SEQ ID NO: 34.
99. A pharmaceutical composition comprising the antibody, or antigen-binding portion thereof, of claim 91, and a pharmaceutically acceptable carrier.
100. A method for treating a subject suffering from a disorder in which TNF.alpha. activity is detrimental comprising administering to the subject the pharmaceutical composition of claim 99.
101. The method of claim 100, wherein the disorder is an autoimmune disorder.
102. The method of claim 101, wherein the autoimmune disorder is rheumatoid arthritis.
103. The method of claim 101, wherein the autoimmune disorder is rheumatoid spondylitis.
104. The method of claim 100, wherein the disorder is an intestinal disorder.
105. The method of claim 104, wherein the intestinal disorder is inflammatory bowel disorder.
106. The method of claim 104, wherein the intestinal disorder is idiopathic inflammatory bowel disease.
107. The method of claim 104, wherein the intestinal disorder is Crohn's disease.
108. The method of claim 104, wherein the intestinal disorder is ulcerative colitis.
109. The method of claim 100, wherein the disorder is osteoarthritis or gouty arthritis.
110. The method of claim 100, wherein the pharmaceutical composition is administered in combination with at least one additional therapeutic agent.
111. A composition comprising a carrier which prevents rapid release and a human antibody, or antigen-binding portion thereof, with a light chain variable region (LCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, ormodified from SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or 8 or by one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9; and a heavy chain variable region (HCVR) having a CDR3 domaincomprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or by one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9, 10, 11and/or 12.
112. The composition of claim 111, wherein the antibody, or antigen-binding portion thereof, further comprises a light chain CDR2 domain comprising the amino acid sequence of SEQ ID NO: 5 and a heavy chain CDR2 domain comprising the amino acidsequence of SEQ ID NO: 6.
113. The composition of claim 112, wherein the antibody, or antigen-binding portion thereof, further comprises a light chain CDR1 domain comprising the amino acid sequence of SEQ ID NO: 7 and a heavy chain CDR1 domain comprising the amino acidsequence of SEQ ID NO: 8.
114. A composition comprising a carrier which prevents rapid release and a human antibody, or antigen-binding portion thereof, with a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chainvariable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2.
115. The composition of claim 114, wherein the antibody has an IgG1 heavy chain constant region.
116. The composition of claim 114, wherein the antigen-binding portion of the antibody is a Fab fragment or a single chain Fv fragment.
117. A composition comprising a carrier which prevents rapid release and a human antibody that binds TNF.alpha. and is the antibody D2E7, or an antigen-binding portion thereof.
118. A pharmaceutical composition comprising the antibody, or antigen-binding portion thereof, of claim 117, and a pharmaceutically acceptable carrier.
119. A method for treating a subject suffering from a disorder in which TNF.alpha. activity is detrimental comprising administering to the subject the pharmaceutical composition of claim 118.
120. The method of claim 119, wherein the disorder is an autoimmune disorder.
121. The method of claim 120, wherein the autoimmune disorder is rheumatoid arthritis.
122. The method of claim 120, wherein the autoimmune disorder is rheumatoid spondylitis.
123. The method of claim 119, wherein the disorder is an intestinal disorder.
124. The method of claim 123, wherein the intestinal disorder is inflammatory bowel disorder.
125. The method of claim 123, wherein the intestinal disorder is idiopathic inflammatory bowel disease.
126. The method of claim 123, wherein the intestinal disorder is Crohn's disease.
127. The method of claim 123, wherein the intestinal disorder is ulcerative colitis.
128. The method of claim 119, wherein the disorder is osteoarthritis or gouty arthritis.
129. The method of claim 119, wherein the pharmaceutical composition is administered in combination with at least one additional therapeutic agent.
130. A composition comprising a biodegradable, biocompatible polymer and a human antibody, or antigen-binding portion thereof, with the following characteristics: a) dissociates from human TNF.alpha. with a K.sub.off rate constant of1.times.10.sup.-3s.sup.-1 or less, as determined by surface plasmon resonance; b) has a light chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or8 or by one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9; c) has a heavy chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alanine substitution atposition 2, 3, 4, 5, 6, 8, 9, 10 or 11 or by one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6,8,9,10,11 and/or 12, wherein the biodegradable, biocompatible polymer provides controlled release.
131. A composition comprising an absorption delaying agent and a human antibody, or antigen-binding portion thereof, with the following characteristics: a) dissociates from human TNF.alpha. with a K.sub.off rate constant of1.times.10.sup.-3s.sup.-1 or less, as determined by surface plasmon resonance; b) has a light chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or8 or by one to five conservative amino acid substitutions at positions 1, 3,4, 6, 7, 8 and/or 9; c) has a heavy chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alanine substitution atposition 2, 3, 4, 5, 6, 8, 9, 10 or 11 or by one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6,8,9,10,11 and/or 12.
132. A composition comprising a carrier which prevents rapid release and a human antibody, or antigen-binding portion thereof, with the following characteristics: a) dissociates from human TNF.alpha. with a K.sub.off rate constant of1.times.10.sup.-3s1 or less, as determined by surface plasmon resonance; b) has a light chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or 8 orby one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9; c) has a heavy chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alanine substitution at position2, 3, 4, 5, 6, 8, 9, 10 or 11 or by one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12. |
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