Cell adhesion ihibiting compounds

Details Cell adhesion ihibiting compounds Cell adhesion ihibiting compounds

1998-12-21

2001-05-22

Carlson, Karen Cochrane (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S016700, C514S017400, C514S863000, C530S317000, C530S328000, C530S329000, C530S333000

Reexamination Certificate

active

06235711

ABSTRACT:

Many of the cell-cell and cell-extracellular matrix interactions are mediated by protein ligands (e.g. fibronectin, vitronfectin and VCAM-1) and their integrin receptors [e.g. VLA-4 (&agr;4&bgr;1)]. Recent studies have shown these interactions to play an important role in many physiological (e.g. embryonic development and wound healing) and pathological (e.g. tumour-cell invasion and metastasis, inflammation, atherosclerosis and autoimmune diseases) conditions. Agents which can selectively inhibit some of these interactions are predictably useful for the treatment of a number of diseases.
Integrins are heterodimeric cell surface receptors that are composed of noncovalently associated &agr; and &bgr; subunits. Using molecular biology and protein chemistry, a number of &agr; and &bgr; subunits have been identified. The integrin family can be subdivided into classes based on the &bgr; subunits, which can be associated with one or more &agr; subunits. The most widely distributed integrins belong to the &bgr;1 class, also known as the very late antigens (VLA). The second class of integrins are leukocyte-specific receptors and consist of one of three a subunits (&agr;L, &agr;M, or &agr;X) complexed with the &bgr;2 protein. The cytoadhesins &agr;IIb&bgr;3 and &agr;v&bgr;3, constitute a third class of integrins. A fourth class of integrins includes &agr;4&bgr;7.
A wide variety of proteins serve as ligands for integrin receptors. In general, the proteins recognised by integrins fall into one of three classes: extracellular matrix proteins, plasma proteins, and cell surface molecules. Extracellular matrix proteins such as collagen, fibronectin, fibrinogen, laminin, thrombospondin, and vitronectin bind to a number of integrins. Many of these adhesive proteins also circulate in plasma and bind to activated blood cells. Additional components in plasma that are ligands for integrins include fibrinogen and factor X. Cell-bound complement C3bi and several transmembrane proteins, such as Ig-like cell adhesion molecule (ICAM-1,2,3) and vascular cell adhesion molecule (VCAM-1), which are members of the Ig superfamily, also serve as cell-surface ligands for some integrins. Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is another member of the Ig superfamily and is bound by the integrin &agr;4&bgr;7.
The target amino acid sequences for many integrins have been identified. For example, the target sequence in &agr;5&bgr;1, &agr;II&bgr;3, and &agr;v&bgr;3, is the Arg-Gly-Asp tripeptide found in proteins such as fibronectin, fibrinogen, thrombospondin, type 1 collagen, vitronectin and vWF. However, the Arg-Gly-Asp sequence is not the only integrin recognition motif used by adhesive ligands. Another integrin &agr;4&bgr;1 binds the variable region (CS1) of fibronectin via the sequence Leu-Asp-Val and the platelet integrin &agr;IIb&bgr;3 also recognises the sequence His-His-Leu-Gly-Gly-Ala-Lys-Gln-Ala-Gly-Asp-Val at the carboxy-terminus of the gamma chain of fibrinogen.
The present invention principally relates to agents which block the interaction of the ligand VCAM-1 to its integrin receptor VLA-4 (&agr;4&bgr;1). [Reference for a review on VLA-4: Structure of the Integrin VLA-4 and Its Cell—Cell and Cell Matrix Adhesion Functions, M. E. Hemler, M. J. Elices, C. Parker and Y. Takada, Immunological Reviews, 114 (1990) 45-65.] Integrin &agr;4&bgr;1 is expressed on numerous hematopoietic cells and established cell lines, including hematopoietic precursors, peripheral and cytotoxic T lymphocytes, B lymphocytes, monocytes, thymocytes and eosinophils. Unlike other &bgr;1 integrins that are involved only in cell-extracellular matrix interactions, &agr;4&bgr;1 mediates both cell—cell and cell-extracellular matrix interactions. Cells expressing activated &agr;4&bgr;1 bind to the carboxy-terminal cell binding domain of fibronectin (non Arg-Gly-Asp mediated), to VCAM-1 expressed on endothelial cells, and to each other to promote homotypic aggregation. The expression of VCAM-1 by endothelial cells is upregulated by proinflammatory cytokines such as INF-&ggr;, TNF-&agr;and IL-1&bgr;.
The present invention also relates to agents which block the interaction of the ligand MAdCAM-1 and the integrin &agr;4&bgr;7.
Regulation of &agr;4&bgr;1-mediated cell adhesion is important in numerous physiologic processes, including T-cell proliferation, B-cell localisation to germinal centres, and adhesion of activated T cells and eosinophils to endothelial cells. In addition, integrin &agr;4&bgr;1-mediated processes have been implicated in tumour cell metastasis and diseases involving lymphocyte, monocyte or eosinophil recruitment such as multiple sclerosis, rheumatoid arthritis, asthma, psoriasis, insulin-dependent diabetes, glomerulonephritis, inflammatory bowel disease, ischaemic heart disease, myocarditis, peripheral vascular disease, transplant rejection, for example chronic allograft rejection, and allergic disorders. Evidence for the involvement of VLA-4VCAM-1 interaction in the above disease processes has been accumulated by investigating the role of the peptide CS-1 and antibodies specific for VLA-4 or VCAM-1 in various in vitro and in vivo experimental models of inflammation (e.g. contact cutaneous hypersensitivity response in mice), experimental autoimmune encephalomyelitis, lung antigen challenge, diabetes, ulcerative colitis, nephritis and allograft rejection. Additionally, integrin &agr;4&bgr;7-mediated processes have been implicated in lymphocyte recruitment in diseases such as inflammatory bowel disease and insulin-dependent diabetes.
For example, in an experimental model of arthritis (arthritis induced in inbred female Lewis rats with a single intraperitoneal injection of peptidoglycan-polysaccharide fragments from group A streptococcal cell walls), intravenous administration of CS-1 at the initiation of arthritis (days 0-4; 300 &mgr;g/day) or on days 11 to 16 in animals with established arthritis, was shown to suppress both acute and chronic inflammation. [Reference: Synthetic Fibronectin Peptides Suppress Arthritis in Rats by Interrupting Leukocyte Adhesion and Recruitment, S. M. Wahl, J. B. Allen, K. L. Hines, T. Imamichi, A. M. Wahl, L. T. Furcht and J. B. McCarthy, J. Clin. Invest, 94 (1994) 655-662].
In another model of inflammation (contact hypersensitivity response in oxazalone or 2.4-dinitrofluorobenzene-sensitised mice), intravenous administration of the anti-&agr;-4 specific monoclonal antibodies R1-2 or PS/2 (4 to 6 hours prior to challenge) significantly inhibited (50-60% reduction in the ear swelling response) the efferent response. [Reference:
Monoclonal Antibodies to the Integrin &agr;-4 Subunit Inhibit the Murine Contact Hypersensitivity Response, P. L. Chisholm, C. A. Williams and R. R. Lobb, Eur. J. Immunol., 23 (1993) 682-688]. In an intestinal inflammation model (acute colitis in Cotton-top tamarin), anti-&agr;4 integrin monoclonal antibody HP1/2 that binds VLA4 resulted in significant attenuation of acute colitis. In contrast, two anti-E-selectin monoclonal antibodies (BB11 and EH8) slightly diminished colitis after the 10-day treatment period in Cotton-top tamarin [Reference: Attenuation of Colitis in the Cotton-top Tamarin by Anti-&agr; 4 Integrin Monoclonal Antibody, D. K. Podolsky, R. Lobb, N. King, C. D. Benjamin, B. Pepinsky, P. Sehgal and M. deBeaumont, J. Clin. Invest., 92 (1993) 372-380].
The antibodies have also been shown to be effective in a model of autoimmune encephalomyelitis (EAE). EAE is an inflammatory condition of the central nervous system with similarities to multiple sclerosis. In the model the inflammation is induced experimentally. In both EAE and multiple sclerosis, circulating leukocytes penetrate the blood-brain barrier and damage myelin, resulting in impaired nerve conduction and paralysis. EAE can be induced actively by priming an animal to CNS proteins like myelin basic protein (MBP), or adoptively by injection of activated lymphocytes that are specific for these CNS antigens. Various monoclonal antibodies,

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