Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Fusion protein or fusion polypeptide
Reexamination Certificate
1995-01-06
2003-03-25
Spector, Lorraine (Department: 1647)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Fusion protein or fusion polypeptide
C530S350000, C530S387300, C530S387500, C530S395000, C435S069700
Reexamination Certificate
active
06537553
ABSTRACT:
BACKGROUND OF THE INVENTION
Cells recruited to a site of inflammation represent pivotal components of the human inflammatory response. These cells include a large array of immune cells which may exert a beneficial effect due to their combined ability to combat infection and promote the restoration of normal tissue integrity. However, these immune cells may also contribute to undesirable effects such as tissue damage arising from autoimmune diseases or as a consequence of excessive cell recruitment.
The pathological consequences of inflammation are largely mediated by immune cells such as neutrophils and monocytes, and the molecules they elaborate. These circulating cells must first exit the circulatory system in order to participate in the inflammatory processes at extravascular locations. Initial events in this process involve adhesion between myeloid cells and vascular endothelial cells. During inflammation, endothelial cells are activated by cytokines, resulting in the expression of E-selectin on the endothelial cell surfaces. Consequently, leukocytes are slowed down through the interaction of their cell surface carbohydrates with E-selectin, a process referred to as “rolling”. This interaction results in the capturing of chemoattractants by leukocytes and the activation of integrins in granualocytes and monocytes, resulting in a stronger adhesion of the leukocytes to endothelial cells and extravasation of leukocytes.
E-selectin is a selectin that is transiently expressed on endothelial cells 2 to 8 hours after stimulation of IL-1 and other inflammatory agents, and mediates a neutrophil adhesion pathway distinct from that mediated by ICAMS and leukocyte integrins. The neutrophil chemoattractant IL-8, which is secreted by activated endothelial cells, acts on neutrophils as a feedback inhibitor to attenuate the hyperadhesive interaction between neutrophils and E-selectin receptors. P-selectin is located in a-granules of platelets and Weibel-Palade bodies of endothelial cells, and is rapidly mobilized to the surface of these cells after stimulation by products of the clotting cascade such as thrombin, where it mediates adhesion of neutrophils and monocytes. Selectins function in a wide range of cell interactions in the vasculature and are expressed both on leukocytes and endothelial cells. Selectins mediate adhesion events within the blood vascular compartment through calcium-dependent recognition of specific carbohydrates.
Tumor metastasis resembles the inflammation process. During metastasis tumor cells adhere to endothelial cells and then extravasculate from the blood stream into the surrounding tissue. In addition, it has been shown that the amount of sialyl Le
x
and sialyl Le
a
structures are increased in carcinoma cells and that some tumor cells can adhere to endothelial cells by selectin-mediated interactions. Since metastasis is the major cause of death for cancer patients, there is a need to control the process of metastasis.
The present invention provides a means for controlling both the adverse effects of the inflammatory response and the spread of tumor metastasis, and provides related advantages as well.
SUMMARY OF THE INVENTION
The present invention provides antagonists to cell adhesion which are useful in controlling the negative effects of inflammation, and the metastasis of cancer cells. These antagonists are molecules capable of mediating cell adhesion to endothelial cells. The antagonists are ligands to E-selectin containing the sialyl Le
x
structure, and antibodies to sialyl Le
x
-determinants. Ligands to E-selectin according to the present invention are sialyl Le
x
-containing molecules such as sialyl Le
x
glycoproteins, sialyl Le
x
glycolipids, and sialyl Le
x
oligosaccharides, and other related sialyl Le
x
-containing molecules capable of inhibiting E-selectin mediated cell adhesion to endothelial cells.
The present invention also provides methods of using the antagonists of the present invention to reduce inflammation, and methods to inhibit the process of metastasis by carcinogenic cells. The present invention also provides nucleic acid molecules encoding soluble glycoprotein antagonists, in particular nucleic acid sequences encoding soluble leukosialin, and vectors and cells capable of expressing soluble sialyl Le
x
containing antagonists. The present invention further provides a method of determining metastatic potential by comparing the efficiency of E-selectin-mediated adhesion of the cells to be tested. In addition the present invention provides a method of producing a preferred antagonist of the present invention, soluble sialyl Le
x
positive glycoproteins, in particular soluble chimeric sialyl Le
x
positive leukosialin.
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Fukuda Minoru
Sawada Ritsuko
Tsuboi Shigeru
La Jolla Cancer Research Foundation
Lazar-Wesley Eliane
Spector Lorraine
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