Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-07-02
2001-08-14
Borin, Michael (Department: 1631)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S330000, C530S317000, C514S002600, C514S009100
Reexamination Certificate
active
06274556
ABSTRACT:
BACKGROUND OF THE INVENTION
Lymphocyte homing from the circulation to the lymphoid tissues and migration to sites of inflammation is regulated by interaction with receptors expressed in postcapillary venules, including high endothelial venules (HEV) found in secondary lymphoid tissues (e.g., mesenteric lymph nodes, Peyer's Patches (PP)) (Bevilacqua, M. P.,
Annu. Rev. Immunol.,
11:767-804 (1993); Butcher, E. C.,
Cell,
67: 1033-1036 (1991); Picker, L. J., et al.,
Annu. Rev. Immunol.,
10:561-591 (1992); and Springer, T. A.,
Cell,
76: 301-314 (1994)). These interactions are tissue specific in nature.
Inflammation (e.g., chronic inflammation) is characterized by infiltration of the affected tissue by leukocytes, such as lymphocytes, lymphoblasts, and mononuclear phagocytes. The remarkable selectivity by which leukocytes preferentially migrate to various tissues during both normal circulation and inflammation results from a series of adhesive and activating events involving multiple receptor-ligand interactions as proposed by Butcher and others (Butcher, E. C.,
Cell,
67: 1033-1036 (1991); vonadrian, U. H., et al.,
Proc. Natl. Acad. Sci. USA,
88:7538 (1991); Mayadas, T. N., et al.,
Cell,
74:541 (1993); (Springer, T. A.,
Cell,
76:301 (1994)). As an initial step, there is a transient, rolling interaction between leukocytes and endothelium, which results from the interaction of selectins (and by &agr;4 integrins in some instances) with their carbohydrate ligands. This interaction, which is characterized by rolling in the direction of flow, can be assessed by known methods (Lawrence, M. B. and T. A. Springer,
Cell,
65:859 (1991); WO 92/21746, Springer et al., (Dec. 10, 1992)). This is followed by activation events mediated by chemoattractants such as chemokines and their receptors, which cause activation of integrin adhesiveness and influence the direction of migration of leukocytes through vascular walls. Such secondary signals in turn trigger the firm adhesion of leukocytes to endothelium via leukocyte integrins and their endothelial ligands (Ig-like receptors and the ECM), and subsequent transendothelial migration from the circulation across the vascular endothelium.
In secondary lymphoid tissues, such as Peyer's patches (PPs) and lymph nodes (e.g., peripheral lymph nodes (PLN)), leukocyte trafficking and homing is regulated by interactions of homing receptors on the surface of leukocytes with endothelial cells lining the post-capillary venules, notably high endothelial venules (HEV) (Gowans, J. L. and E. J. Knight,
Proc. R. Soc. Lond.,
159:257 (1964)). Receptors termed vascular addressing, which are present on the endothelial cell surface and regulate the migration and subsequent extravasation of lymphocyte subsets. The vascular addressins show restricted patterns of expression and this tissue specific expression makes an important contribution to the specificity of leukocyte trafficking (Picker, L. J. and E. C. Butcher,
Annu. Rev. Immunol.,
10:561-591 (1992); Berg, E. L., et al.,
Cellular and molecular mechanisms of inflammation,
2:111 (1991); Butcher, E. C.,
Cell,
67:1033-1036 (1991)).
Mucosal vascular addressin MAdCAM-1 (Mucosal Addressin Cell Adhesion Molecule-1) is an immunoglobulin superfamily adhesion receptor for lymphocytes, which is distinct from VCAM-1 and ICAM-1. MAdCAM-1 was identified in the mouse as a
~
60 kd glycoprotein which is selectively expressed at sites of lymphocyte extravasation. In particular, MAdCAM-1 expression was reported in vascular endothelial cells of mucosal tissues, including gut-associated tissues or lymph of the small and large intestine, and the lactating mammary gland, but not in peripheral lymph nodes. MAdCAM-1 is involved in lymphocyte binding to Peyer's Patches. (Streeter, P. R., et al.,
Nature,
331:41-46 (1988); Nakache, M., et al.,
Nature,
337: 179-181 (1989); Picker, L. J., et al.,
Annu. Rev. Immunol.,
10:561-591 (1992); Briskin, M. J., et al.,
Nature,
363:461 (1993); Berg, E. L., et al.,
Nature,
366:695-698 (1993); Berlin, C., et al.,
Cell,
74:185-195 (1993)). MAdCAM-1 can be induced in vitro by proinflammatory stimuli (Sikorski, E. E., et al.,
J. Immunol.,
151:5239-5250 (1993)). cDNA clones encoding murine and primate (e.g., human) MAdCAM-1 have been isolated and sequenced (Briskin, M. J. et al.,
Nature,
363: 461-464 (1993); Briskin et al., WO 96/24673, published Aug. 15, 1996; and Briskin, M. J. et al., U.S. Ser. No. 08/523,004, filed Sep. 1, 1995, the teachings of each of which is incorporated herein by reference in its entirety).
MAdCAM-1 specifically binds the lymphocyte integrin &agr;4&bgr;7 (also referred to as LPAM-1 (mouse), &agr;4&bgr;p (mouse)), which is a lymphocyte homing receptor involved in homing to Peyer's patches (Berlin, C., et al.,
Cell,
80:413-422 (1994); Berlin, C., et al.,
Cell,
74:185-195 (1993); and Erle, D. J., et al.,
J. Immunol.,
153: 517-528 (1994)). In contrast to VCAM-1 and fibronectin, which interact with both &agr;4&bgr;1 and &agr;4&bgr;7 (Berlin, C., et al.,
Cell,
74: 185-195 (1993); Strauch, U.S., et al.,
Int. Immunol.,
6:263 (1994)), MAdCAM-1 is a selective ligand for &agr;4&bgr;7 receptor.
Inflammatory bowel disease (IBD), such as ulcerative colitis and Crohn's disease, for example, can be a debilitating and progressive disease involving inflammation of the gastrointestinal tract. Affecting an estimated two million people in the United States alone, symptoms include abdominal pain, cramping, diarrhea and rectal bleeding. IBD treatments have included anti-inflammatory drugs (such as corticosteroids and sulfasalazine), immunosuppressive drugs (such as 6-mercaptopurine, cyclosporine and azathioprine) and surgery (such as, colectomy). Podolsky,
New Engl. J. Med.,
325:928-937 (1991) and Podolsky,
New Engl. J. Med.,
325:1008-1016 (1991). There is a need for inhibitors of MAdCAM-1 function to provide new therapies useful in the treatment of IBD and other diseases involving leukocyte infiltration of the gastrointestinal tract or other mucosal tissues.
SUMMARY OF THE INVENTION
As shown herein, the conserved amino acid motif LDTSL (SEQ ID NO: 1) is involved in Mucosal Addressin Cell Adhesion Molecule-1 (hereinafter “MAdCAM-1”) binding to MAdCAM-1 ligands, such as human &agr;4&bgr;7. In addition, compounds containing this peptide sequence or truncated versions thereof, e.g., Asp-Thr and Leu-Asp-Thr, bind to &agr;4&bgr;7 and can inhibit adhesion of leukocytes expressing &agr;4&bgr;7 on the cell surface to MAdCAM-1. It has also been discovered that groups on the N- and C-termini of the peptide sequences enhance the binding of these compounds to &agr;4&bgr;7 and are more potent inhibitors of interaction between MAdCAM-1 and its ligands. Accordingly, the present invention provides novel compounds comprising peptide sequences which mimic the conserved amino acid motif LDTSL and which have groups bonded to the N- and C-termini.
Also provided are methods of inhibiting the interaction of a cell bearing a ligand of MAdCAM-1, including &agr;4&bgr;7 integrins, with MAdCAM-1 or a portion thereof (e.g., the extracellular domain), comprising contacting the cell with a compound of the present invention. In one embodiment, the invention relates to a method of inhibiting the MAdCAM-mediated interaction of a first cell bearing an &agr;4&bgr;7 integrin with MAdCAM, for example with a second cell bearing MAdCAM, comprising contacting the first cell with a compound of the present invention. In another embodiment, the invention relates to a method of treating an individual suffering from a disease associated with leukocyte recruitment to tissues (e.g., endothelium) expressing the molecule MAdCAM-1.
One embodiment of the present invention is a method of inhibiting the binding of a cell such as a leukocyte expressing a ligand for MAdCAM-1 on the cell surface (e.g., &agr;4&bgr;7) to MAdCAM-1, for example to endothelial cells expressing MAdCAM-1 on the cell surface. The method comprises contacting the leukocytes with an effective amount of an inhibitor repr
Schwender Charles F.
Shroff Hitesh N.
Borin Michael
Hamilton Brook Smith & Reynolds P.C.
Millennium Pharmaceuticals Inc.
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