Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2000-07-19
2003-02-18
Chang, Ceila (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C562S445000
Reexamination Certificate
active
06521666
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to pharmaceutical compositions comprising molecules that are inhibitors of &agr;4 mediated (including &agr;4&bgr;7) adhesion and which could be useful in treating conditions such as asthma, diabetes, rheumatoid arthritis, inflammatory bowel disease and other diseases involving leukocyte infiltration of the gastrointestinal tract or other epithelial lined tissues; such as, skin, urinary tract, respiratory airway and joint synovium.
The inhibitors of the present invention could also be useful in treating conditions involving leukocyte infiltration of other tissues including lung, blood vessels, heart and nervous system as well as transplanted organs such as kidney, liver, pancreas and heart.
2. Description of the Related Art
The adhesion of leukocyte to endothelial cells or extracellular matrix proteins is a fundamental process for immunity and inflammation and involves multiple adhesive interactions. The earliest events in this process include leukocyte rolling followed by changes in integrin avidity, which leads to subsequent firm adhesion (for reviews see Butcher,
Cell
67:1033-1036 (1991); Harlan,
Blood
3:513-525 (1985); Hemler,
Annu. Rev. Immunol.
8:365-400 (1990);
Osborn,
Cell
62:3-6 (1990); Shimizu et al.,
Immunol. Rev.
114:109-143 (1990); Springer,
Nature
346:425-434 (1990); Springer,
Cell
76:301-314 (1994)). In response to chemotactic factors, the leukocytes must migrate through two adjacent endothelial cells and into tissues that are composed, in part, of the extracellular matrix protein fibronectin (FN) (see Wayner et al.,
J. Cell Biol.
105:1873-1884 (1987)) and collagen (CN) (see Bornstein et al.,
Ann. Rev. Biochem.
49:957-1003 (1980) and Miller, Chemistry of the collagens and their distribution. In Connective Tissue Biochemistry. K. A. Piez and A. H. Reddi, editors. Elsevier, Amsterdam. 41-78. (1983)) Important recognition molecules that participate in these reactions belong to the integrin gene superfamily (for reviews see Hemler,
Annu. Rev. Immunol.
8:365-400 (1990); Hynes,
Cell
48:549-554 (1987); Shimizu et al.,
Immunol. Rev.
114:109-143 (1990); and Springer,
Nature
346:425-434 (1990)).
Integrins are composed of non-covalently associated subunits, referred to as the alpha (&agr;) and beta (&bgr;) subunits (for reviews see Hemler,
Annu. Rev. Immunol.
8:365-400 (1990); Hynes,
Cell
48:549-554 (1987); Shimizu et al.,
Immunol. Rev.
114:109-143 (1990); and Springer,
Nature
346:425-434 (1990)). To date, 8 integrin &bgr; subunits have been identified which can associate with 16 distinct &agr; subunits to form 22 distinct integrins. The &bgr;7 integrin subunit, first cloned by Erle et al., (Erle et al.,
J. Biol. Chem.
266:11009-11016 (1991)) is expressed only on leukocytes and is known to associate with two distinct &agr; subunits, &agr;4 (Ruegg et al.,
J. Cell Biol.
117:179-189 (1992)) and &agr;E (Cerf-Bensussan et al.,
Eur. J. Immunol.
22:273-277 (1992) and Kilshaw et al.,
Eur. J. Immunol. as its sole ligand.
The &agr;4&bgr;7 complex has three known ligands (VCAM, CS-1, MAdCAM). One ligand which shows unique specificity for &agr;4&bgr;7 is Mucosal Addressing Cell Adhesion Molecule (MAdCAM) (see Andrew et al.,
J. Immunol
153:3847-3861 (1994); Briskin et al.,
Nature
363:461-464 (1993); and Shyjan et al.,
J. Immunol
156:2851-2857 (1996)). MAdCAM is highly expressed on Peyer's patch high endothelial venules, in mesenteric lymph nodes, and on gut lamina propria and mammary gland venules (Berg et al.,
Immunol. Rev.
105:5 (1989)). Integrin &agr;4&bgr;7 and MAdCAM have been shown to be important in regulating lymphocyte trafficking to normal intestine (Holzmann et al.,
Cell
56:37 (1989)).
The second ligand for &agr;4&bgr;7 is connecting segment 1 (CS-1), an alternatively spliced region of the FN A chain (see Guan et al.,
Cell
60:53-61 (1990) and Wayner et al.,
J. Cell Biol.
109:1321-1330 (1989)). The cell-binding site within this alternatively spliced region is composed of 25 amino acids where the carboxy terminal amino acid residues, EILDVPST, form the recognition motif (see Komoriya et al.,
J. Biol. Chem.
266:15075-15079 (1991) and Wayner et al.,
J. Cell Biol.
116:489-497 (1992)).
The third ligand for &agr;4&bgr;7 is vascular cell adhesion molecule 1 (VCAM-1), a cytokine inducible protein expressed on endothelial cells (see Elices et al.,
Cell
60:577-584 (1990) and Ruegg et al.,
J. Cell Biol.
117:179-189 (1992)). VCAM and CS-1 (see Elices et al.,
Cell
60:577-584 (1990)) are two ligands which are shared by &agr;4&bgr;7 and &agr;4&bgr;1. It remains to be unequivocally shown whether MAdCAM, VCAM and CS-1 bind to the same site on &agr;4&bgr;7. Using a panel of monoclonal antibodies, Andrew et al., showed that &agr;4&bgr;7 interaction with its three ligands involve distinct but overlapping epitopes (Andrew et al.,
J. Immunol
153:3847-3861 (1994)).
UTILITY OF THE INVENTION
A number of in vitro and in vivo studies indicate that &agr;4 plays a critical role in the pathogenesis of a variety of diseases. Monoclonal antibodies directed against &agr;4 have been tested in a variety of disease models. Efficacy of anti-&agr;4 antibody was demonstrated in a rat and mouse model of experimental autoimmune encephalomyelitis (see Baron et al.,
J. Exp. Med.
177:57-68 (1993) and Yednock et al.,
Nature
356
:
63
-
66
(1992)). A significant number of studies have been done to evaluate the role of &agr;4 in allergic airways (see Abraham et al.,
J. Clin. Invest.
93:776-787 (1994); Bochner et al.,
J. Exp. Med.
173:1553-1556 (1991); Walsh et al.,
J. Immunol
146:3419-3423 (1991); and Weg et al.,
J. Exp. Med.
177:561-566 (1993)). For example, monoclonal antibodies to &agr;4 were effective in several lung antigen challenge models (see Abraham et al.,
J. Clin. Invest.
93:776-787 (1994) and Weg et al.,
J. Exp. Med.
177:561-566 (1993)). Interestingly, blockade of cellular recruitment is not seen in certain lung models even though there is abrogation of the late phase response (see Abraham et al.,
J. Clin. Invest.
93:776-787 (1994)). The cotton-top tamarin, which experiences spontaneous chronic colitis, showed a significant attenuation of colitis when anti-&agr;4 antibody was administered (see Bell et al.,
J. Immunol.
151:4790-4802 (1993) and Podolsky et al.,
J. Clin. Invest.
92:372-380 (1993)). Monoclonal antibody to &agr;4 inhibits insulitis and delays the onset of diabetes in the non-obese diabetic mouse (see Baron et al.,
J. Clin. Invest.
93:1700-1708 (1994); Burkly et al., i Diabetes 43:529-534 (1994); and Yang et al.,
Proc. Natl. Acad. Sci. USA
90:10494-10498 (1993)). Other diseases where &agr;4 has been implicated include rheumatoid arthritis (see Laffon et al.,
J. Clin. Invest.
88:546-552 (1991) and Morales-Ducret et al.,
J. Immunol.
149:1424-1431 (1992)) and atherosclerosis (see Cybulsky et al.,
Science
251:788-791 (1991)). Delayed type hypersensitivity reaction (see Issekutz,
J. Immunol.
147:4178-4184 (1991)) and contact hypersensitivity response (see Chisholm et al.,
Eur. J. Immunol.
23:682-688 (1993) and Ferguson et al.,
J. Immunol.
150:1172-1182 (1993)) are also blocked by anti-&agr;4 antibodies. For an excellent review of in vivo studies implicating &agr;4 in disease (see Lobb et al.,
J. Clin. Invest.
94:1722-1728 (1995)).
Although these studies clearly implicate &agr;4 in a variety of diseases, it is not clear whether the inhibition seen was due to blocking &agr;4&bgr;1, &agr;4&bgr;7, or both. Recently, several studies have addressed this issue using an antibody which recognizes the &agr;4&bgr;7 complex (see Hesterberg et al.,
Gastroenterology
(1997)), antibodies against &bgr;7 or antibodies directed against MAdCAM (see Picarella et al.,
J. Immunol.
158:2099-2106 (1997)), for which &agr;4&bgr;1 does not bind. In the primate model of inflammatory bowel disease, it was shown that antibodies to the &agr;4&bgr;7 complex ameliorated inflammation and decreased diarrhea (see Hesterberg et al., Gastroentero
Gudmundsson Kristjan S.
Martin Richard
Sircar Ila
Birch & Stewart Kolasch & Birch, LLP
Chang Ceila
Small Andrea D.
Tanabe Seiyaku Co. Ltd.
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