Drug – bio-affecting and body treating compositions – Lymphokine
Reexamination Certificate
1999-04-05
2002-09-24
Mertz, Prema (Department: 1646)
Drug, bio-affecting and body treating compositions
Lymphokine
C514S002600, C514S008100, C514S012200, C514S885000
Reexamination Certificate
active
06455035
ABSTRACT:
FIELD OF THE INVENTION
The invention generally relates to angiogenic factors and more particularly to the angiopoietin family of growth factors and to methods of decreasing or inhibiting vascular permeability and/or plasma leakage.
BACKGROUND OF THE INVENTION
Plasma leakage, a key component of inflammation, occurs in a distinct subset of the microvessels. In particular, in most organs plasma leakage occurs specifically in the venules. Unlike arterioles and capillaries, venules become leaky in response to numerous inflammatory mediators including histamine, bradykinin, and serotonin.
One characteristic of inflammation is the plasma leakage that results from intercellular gaps that form in the endothelium of venules. Most experimental models of inflammation indicate that these intercellular gaps occur between the endothelial cells of postcapillary and collecting venules (Baluk, P., et al., Am. J. Pathol. 1998 152:1463-76). It has been shown that certain lectins may be used to reveal features of focal sites of plasma leakage, endothelial gaps, and finger-like processes at endothelial cell borders in inflamed venules (Thurston, G., et al., Am. J. Physiol, 1996, 271: H2547-62). In particular, plant lectins have been used to visualize morphological changes at endothelial cell borders in inflamed venules of, for example, the rat trachea. Lectins, such as conconavalin A and ricin, that bind focally to inflamed venules reveal regions of the subendothelial vessel wall exposed by gaps that correspond to sites of plasma leakage (Thurston, G., et al., Am J Physiol, 1996, 271: H2547-62).
The properties of the microvessels are dynamic. Chronic inflammatory diseases, for example, are associated with microvascular remodeling, including angiogenesis and microvessel enlargement. Microvessels can also remodel by acquiring abnormal phenotypic properties. In a murine model of chronic airway inflammation, we found that airway capillaries acquire properties of venules, including widened vessel diameter, increased immunoreactivity for von Willebrand factor, and increased immunoreactivity for P-selectin. In addition, these remodeled vessels leak in response to inflammatory mediators, whereas vessels in the same position in the airways of normal mice do not.
Certain substances have been shown to decrease or inhibit vascular permeability and/or plasma leakage. For example, mystixins are synthetic peptides that have been reported to inhibit plasma leakage without blocking endothelial gap formation (Baluk, P., et al., J. Pharmacol. Exp. Ther., 1998, 284: 693-9). Also, the beta 2-adrenergic receptor agonist formoterol reduces microvascular leakage by inhibiting endothelial gap formation (Baluk, P. and McDonald, D. M., Am. J. Physiol., 1994, 266:L461-8).
What factors determine whether a vessel will acquire phenotypic features of venules? One apparent clue came from studies of angiopoietin-1 (Ang1), a ligand for the endothelial cell-specific receptor Tie2. In mice that transgenically overexpress Ang1 in the skin under the keratin-14 promoter (K14-Ang1 mice), microvessels in the position of capillaries have widened vessel diameter, immunoreactivity for P-selectin, and immunoreactivity for von Willebrand factor. Thus, these vessels have phenotypic features of venules.
Chronic inflammation is associated with blood vessel formation and enlargement and changes in vessel phenotype. In mice with chronic airway inflammation, strain dependent differences to the same stimulus have been shown to result in either blood vessel proliferation or enlargement, depending on the host response (Thurston, G., et al., Am. J. Pathol., 1998, 153: 1099-112). Analyses of mouse embryos deficient in the TIE-2 receptor illustrate its importance in angiogenesis, particularly for vascular network formation in endothelial cells. Sato, T. N., et al., Nature 376:70-74 (1995). In the mature vascular system, the TIEs could function in endothelial cell survival, maintenance and response to pathogenic influences.
It has been suggested that the TIE receptors play roles in endothelial cell determination, proliferation, differentiation and cell migration and patterning into vascular elements. The predominant expression of the TIE receptors in vascular endothelia suggests that TIE plays a role in the development and maintenance of the vascular system. The TIE receptors are also expressed in primitive hematopoietic stem cells, B cells and a subset of megakaryocytic cells, thus suggesting the role of ligands which bind these receptors in early hematopoiesis, in the differentiation and/or proliferation of B cells, and in the megakaryocytic differentiation pathway. Iwama, et al. Biochem. Biophys. Research Communications 195:301-309 (1993); Hashiyama, et al. Blood 87:93-101 (1996), Batard, et al. Blood 87:2212-2220 (1996).
An angiogenic factor, which was originally called TIE-2 ligand-1 (TL1) but is also referred to as angiopoietin-1 (Ang1), has been identified that signals through the TIE-2 receptor and is essential for normal vascular development in the mouse. By homology screening, an Ang1 relative has been identified and called TIE-2 ligand-2 (TL2) or angiopoietin-2 (Ang2). Ang2 is a naturally occurring antagonist for Ang1 and the TIE2 receptor. For a description of the cloning and sequencing of TL1 (Ang1) and TL2 (Ang2) as well as for methods of making and uses thereof, reference is hereby made to PCT International Publication No. WO 96/11269 published Apr. 18, 1996 and PCT International Publication No. WO 96/31598 published Oct. 10, 1996 both in the name of Regeneron Pharmaceuticals, Inc.; and S. Davis, et al., Cell 87: 1161-1169 (1996) each of which is hereby incorporated by reference. Ang1* is a mutant form of angiopoietin-1 that comprises the N-terminal domain of angiopoietin-2 fused to the coiled-coil domain and the fibrinogen domain of angiopoietin-1 and that has a Cys to Ser mutation at amino acid 245 (See PCT International Publication No. WO 98/05779 published Feb. 12, 1998 in the name of Regeneron Pharmaceuticals, Inc. which is hereby incorporated by reference). Ang1* has been shown to be a potent agonist for the Tie-2 receptor.
Including the above-described angiopoietins, applicants have identified a family of several related angiogenic factors. These have been designated TIE-2 ligand-1 (TL1) also referred to as angiopoietin-1 (Ang1); TIE-2 ligand-2 (TL2) or angiopoietin-2 (Ang2); Tie ligand-3 (TL3) and Tie ligand-4 (TL4). For descriptions of the structure and functional properties of these four related factors, reference is hereby made to the following publications, each of which is hereby incorporated by reference: U.S. Pat. No. 5,643,755, issued Jul. 1, 1997 to Davis, et al.; U.S. Pat. No. 5,521,073, issued May 28, 1996 to Davis, et al.; U.S. Pat. No. 5,650,490, issued Jul. 22, 1997 to Davis, et al.; U.S. Ser. No. 08/348,492, filed Dec. 2, 1994, now allowed, date of allowance Aug. 29, 1997; U.S. Ser. No. 08/418,595, filed Apr. 6, 1995, now allowed, date of allowance Nov. 26, 1996; U.S. Ser. No. 08/665,926, filed Jun. 19, 1996, now allowed, date of allowance Dec. 9, 1997; PCT International Application No. PCT/US95/12935, filed Oct. 6, 1995, published on Apr. 18, 1996, with Publication No. WO 96/11269; and PCT International Application No. PCT/US96/04806, filed Apr. 5, 1996, published on Oct. 10, 1996, with Publication No. WO96/31598, both PCT applications in the name of Regeneron Pharmaceuticals, Inc.
The angiopoietins can be structurally divided into three domains: an N terminal region lacking in homology to any known structures; an alpha-helical rich coil-coil segment similar to motifs found in many proteins that seem to promote multimerization; and a “fibrinogen-like domain” thus dubbed because it is distantly related to a domain first found in fibrinogen but now noted to be in many other proteins (Davis, S. et al., (1996) Cell 87: 1161-1169). The fibrinogen-like domain represents the most conserved region of the angiopoietins, and recent studies indicate that it comprises the receptor-binding portion of an angiopoietin. In addi
Mc Donald Donald
Suri Chitra
Thurston Gavin
Yancopoulos George D.
Cobert Robert J.
Mertz Prema
Palladino Linda O.
Regeneron Pharmaceuticals Inc.
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