Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Structurally-modified antibody – immunoglobulin – or fragment...
Reexamination Certificate
1998-09-21
2002-11-19
Gambel, Phillip (Department: 1644)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Structurally-modified antibody, immunoglobulin, or fragment...
C424S192100, C530S350000, C530S387300
Reexamination Certificate
active
06482409
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a treatment for inflammatory bowel disease (IBD). More particularly, this invention relates to the use of antibodies recognizing the integrin VLA-4 (very late antigen-4) in the treatment of IBD.
BACKGROUND OF THE INVENTION
Inflammatory bowel disease, or IBD, is a collective term encompassing ulcerative colitis and Crohn's disease (ileitis), which are chronic inflammatory disorders of the gastrointestinal tract. Ulcerative colitis is confined to the large intestine (colon) and rectum, and involves only the inner lining of the intestinal wall. Crohn's disease may affect any section of the gastrointestinal tract (i.e., mouth, esophagus, stomach, small intestine, large intestine, rectum and anus) and may involve all layers of the intestinal wall. Both diseases are characterized by abdominal pain and cramping, diarrhea, rectal bleeding and fever. The symptoms of these diseases are usually progressive, and sufferers typically experience periods of remission followed by severe flareups.
IBD affects an estimated two million people in the United States alone. Although IBD is not considered a fatal illness, prolonged disease can lead to severe malnutrition affecting growth or to the formation of abscesses or intestinal scar tissue, leading in turn to infection or bowel obstruction.
IBD has no cure, and the exact causes of IBD are not yet understood. Conventional treatments for IBD have involved anti-inflammatory drugs, immunosuppressive drugs and surgery. Sulfasalazine and related drugs having the bioactive 5-amino-salicylic acid (5-ASA) moiety are widely used to control moderate IBD symptoms and to maintain remission. Severe inflammation is often treated with powerful corticosteroids and sometimesACTH or with immunosuppressants such as 6-mercaptopurine and azathioprine. The most common surgical treatments for severe chronic IBD are intestinal resections and, ultimately, colectomy, which is a complete cure only for ulcerative colitis.
Severe side effects are associated with the drugs commonly prescribed for IBD, including nausea, dizziness, changes in blood chemistry (including anemia and leukopenia), skin rashes and drug dependence; and the surgical treatments are radical procedures that often profoundly alter the everyday life of the patient. Accordingly, there is a great need for treatments for IBD that are effective yet less severe in their side effects and are less invasive of the IBD sufferer's body and quality of life.
The search for the causes of IBD and more effective treatments has led several investigators to study diseased and normal tissue on a cellular level. This has led to observations of variations in the normal content of intestinal mucin (Podolsky, 1988 [1]) and to the observation of colonic glycoproteins that emerge only in diseased tissue (Podolsky and Fournier, 1988a [2], 1988b [3]). Researchers have observed that the cell adhesion molecule ICAM-1 is expressed at elevated levels in IBD tissue (Malizia et al., 1991 [4]). This molecule is thought to mediate leukocyte recruitment to sites of inflammation through adhesion to leukocyte surface ligands, i.e., LFA-1 (CD11a/CD18 complex) on all leukocytes and Mac-1 (CD11b/CD18) on phagocytes. (See, e.g., Springer, 1990 [5].) Because flareups of IBD are often accompanied by increased concentrations of neutrophils and lymphocytes in the intestinal submucosa, blocking of interactions between endothelial cell receptors (such as ICAM-1) and their leukocyte ligands (such as LFA-1, Mac-1) has been proposed as a treatment for IBD.
Another cell adhesion molecule, VCAM-I (vascular cell adhesion molecule-1) is expressed on inflamed endothelium and has been shown to recognize the &agr;
4
&bgr;
1
integrin, VLA-4, expressed on the surface of all leukocytes except neutrophils (Springer, 1990 [5]). VCAM-1 also has been found to be expressed constitutively in noninflamed tissue, including Peyer's patch follicular dendritic cells (Freedman et al., 1990 [6]; Rice et al., 1991 [7]). Additionally, besides mediating cell adhesion events, VCAM-1 also has recently been determined to play a costimulatory role, through VLA-4, in T cell activation (Burkly et al., 1991 [8]; Damle and Arrufo, 1991 [9]; van Seventer et al., 1991 [10]). Accordingly, further study of VCAM-1 has been taken up to investigate whether it plays a role as a regulator of the immune response as well as a mediator of adhesion in vivo.
It has now been surprisingly discovered that administering anti-VLA-4 antibody significantly reduces acute inflammation in a primate model for IBD. Cotton top tamarins suffering from a spontaneous intestinal inflammation comparable to ulcerative colitis in humans that were treated with an anti-VLA-4 antibody (HP1/2) showed significant reduction in inflammation of biopsied intestinal tissue.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides novel methods for the treatment of IBD and further provides new pharmaceutical compositions useful in the treatment of IBD. In particular, the present invention provides a method comprising the step of administering to an IBD sufferer a VLA-4 blocking agent, e.g., an anti-VLA-4 antibody, such as antibody HP1/2 Also contemplated is the use of analogous antibodies, antibody fragments, soluble proteins and small molecules that mimic the action of anti-VLA-4 antibodies in the treatment of IBD.
REFERENCES:
patent: 4816397 (1989-03-01), Boss et al.
patent: 4833092 (1989-05-01), Geysen
patent: 0 314 863 (1989-05-01), None
patent: 0 330 506 (1989-09-01), None
patent: 0 333 517 (1989-09-01), None
patent: 0 346 078 (1989-12-01), None
patent: WO 91/03252 (1991-03-01), None
patent: WO 90/03400 (1990-04-01), None
patent: WO 90/13300 (1990-11-01), None
patent: WO 92/00751 (1992-01-01), None
patent: WO 95/19790 (1995-07-01), None
Edgington et al. Biotechnology 10: 383-389 (1992).*
Ward et al. Therapeutic Immunology 1: 165-171 (1994).*
AlBelda et al. FASEB Journal 8: 504-512 (1994).*
Jones et al. Gut 36: 724-730 (1995).*
Soriano et al. Laboratory investigation 80: 1541-1551 (2000).*
Brown, Jr., P. et al., “Anti-Tac-H, a Humanized Antibody to the Interleukin 2 Receptor, Prolongs Primate Cardiac Allograft Survival”,Proc. Natl. Acad. Sci. USA, 88:2663-2667 (1990).
Burkly, L. et al., “Singalling by Vascular Cell Adhesion Molecule-1 (VCAM-1) Through VLA-4 Promotes CD3-dependent T Cell Proliferation”,Eur. J. Immunol., 21:2871-2875 (1991).
Clackson, T. et al., “Making Antibody Fragments Using Phage Display Libraries”,Nature, 352:624-628 (1991).
Co, M.S. et al., “Humanized Antibodies for Antiviral Therapy”,Proc. Natl. Acad. Aci. USA, 88:2869-2873 (1990).
Damle, N. et al., “Vascular Cell Adhesion Molecule 1 Induces T-cell Antigen Receptor-dependent Activation of CD4+Lymphocytes”,Proc. Natl. Acad. Sci. USA, 88:6403-6407 (1991).
Devlin, J. et al., “Random Peptide Libraries: A Source of Specific Protein Binding Molecules”,Science, 249:400-406 (1990).
Dobrina, A. et al., “Mechanisms of Eosinophil Adherence to Cultured Vascular Endothelial Cells”,J. Clin. Invest., 88:20-26 (1991).
Elices, M.J. et al., “VCAM-1 Activated Endothelium Interacts with the Leukocyte Intergrin VLA-4 at a Site Distinct from the VLA-4/Fibronectin Binding Site”,Cell, 60:577-584 (1990).
Freedman, A. et al., “Adhesion of Human B Cells to Germinal Centers in Vitro Involves VLA-4 and INCAM-110”,Science, 249:1030-1033 (1990).
Harris, W.J. and S. Emery, “Therapeutic antibodies—the coming of age”,TIBTECH,11:42-44 (1993).
Hemler, M.E. et al., “Characterization of the Cell Surface Heterodimer VLA-4 and Related Peptides”,J. Biol. Chem., 262(24):11478-11485 (1987).
Holzmann, B. and I.L. Weissman, “Integrin Molecules Involved in Lymphocyte Homing to Peyer's Patches”,Immunolical Reviews, 0(108):45-61 (1989).
Holzmann, B. et al., “Identification of a Murine Peyer's Patch-Specific Lymphocyte Homing Receptor as an Integrin Molecule with an &agr; Chain Homologous to H
Burkly Linda C.
Lobb Roy R.
Biogen Inc.
Fish & Richardson PC
Gambel Phillip
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