Drug – bio-affecting and body treating compositions – Nonspecific immunoeffector – per se ; or nonspecific...
Reexamination Certificate
1999-06-01
2002-06-04
Eyler, Yvonne (Department: 1646)
Drug, bio-affecting and body treating compositions
Nonspecific immunoeffector, per se ; or nonspecific...
C424S185100, C424S279100, C514S002600, C514S056000, C514S059000, C514S885000
Reexamination Certificate
active
06399078
ABSTRACT:
1. BACKGROUND OF THE INVENTION
Cell surface receptors play an important role in biology by relaying extracellular messages into intracellular signaling pathways, thereby allowing individual cells to appropriately respond to their surroundings. Such receptors play critical roles in processes including growth control, developmental patterning, hormonal signaling and the immune response. The function of such receptors is thus frequently involved in diseases and conditions involving these processes such as cancer, developmental defects, endocrine disorders, tissue rejection, and autoimmune dysfunctions. These same receptors are also frequently involved in the infection of a host by a pathogenic organism. In particular, many viruses utilize such receptors to facilitate entry into a host cell. These diseases, conditions, and infections are thus amenable to treatment by compounds which are capable of blocking a receptor's function as a mediator of signal transduction or pathogenic intrusion.
Ultimately, there are widespread medical applications for such receptor blocking functions owing to this correspondingly widespread involvement of receptors in organismal function. For example, the recruitment of leukocytes from the circulation to sites of injury and infection is a key process in the physiological response to wound healing and the clearance of pathogenic organisms (Springer (1994) Cell 76: 301-14). Recent advances in the understanding of the molecular mechanisms that regulate leukocyte recruitment have identified a complex interplay between leukocyte, cytokines, chemokines, adhesion molecules, and extracellular matrix components that is essential for directed leukocyte migration. Chemokines comprise an ever enlarging family of small molecular weight cytokines that play a key role as effector molecules which stimulate leukocytes to leave the circulation and migrate to the sites of inflammation and injury. This superfamily of cytokines has well over thirty distinct member, which bind to subsets of G-protein coupled serpentine receptors. Despite the beneficial properties that chemokines have in the wound healing process and for the clearance of infectious organisms, they also can have pathophysiological consequences. Continued expression of chemokines stimulates the accumulation of leukocytes which, when appropriately activated, release injurious enzymes and oxidative radicals. Many inflammatory and immunological disorders, such as arthritis, asthma, reperfusion injury, and atherosclerosis, are characterized by increased levels of specific sets of chemokines. Therefore, a likely target for suppression of inflammatory or immunological disorders is to inhibit chemokine expression or function, thereby limiting the degree of leukocyte infiltration.
Complement activation also plays a fundamental role in inflammation. Inappropriate or excessive activation of the complement system can lead to harmful, potentially life-threatening consequences due to severe inflammatory tissue destruction. These consequences are clinically manifested in various disorders, including septic shock, multiple organ failure and hyperacute graft rejection. In addition, inappropriate activation of the inflammatory response is associated with immune complex and/or autoimmune diseases such as glomerulonephritis and systemic lupus erythematosus (SLE). Such diseases may be triggered by deficiencies in the ability to solubilize and clear circulating immune complexes, leading to the accumulation and deposition of such complexes in blood vessel walls and tissues where they activate the complement cascade and produce local inflammation. Furthermore, such undesirable inflammatory reactions may subsequently augment the antigen presenting functions of mononuclear phagocytes, leading to the abnormal presentation of self antigens—a condition known as autoimmunity. Thus strategies to antagonize components of the complement system would potentially have far ranging applications in the treatment of inflammatory and autoimmune dysfunctions. Indeed, genetic complement deficiencies or complement depletion have been proven to be beneficial in reducing tissue injury in a number of animal models of severe complement- dependent inflammation (Kirschfink M (1997) Immunopharmacology (Netherlands) 38: 51-62).
The complement system relies upon the function of a number of cell surface receptors. These include complement receptor 1 (CR1, also known as C3b Receptor and CD35), complement receptor type 2 (CR2, also known as C3d Receptor and CD21), and complement receptor type 3 (CR3, also known as CR3. MAC-1 and CD11bCD18). Each of these receptors serves a unique function in complement mediated immune response, and so agents designed to antagonize each of these receptors have unique therapeutic benefits. Indeed, a genetically engineered, soluble form of CR1, lacking transmembrane and cytoplasmic domains, has been tested as an anti-inflammatory agent and found to limit tissue injury in an in vivo model of acute inflammation. Another strategy for treating inflammatory disorders is to interfere with complement receptor 3 (CR3, CD18/11b)—mediated adhesion of inflammatory cells to the vascular endothelium. Experimental therapies which target complement receptor function also include the administration of CR3-specific antibodies which interfere with receptor-mediated adhesion of inflammatory cells to the vascular endothelium (Kirschfink, M. et al. (1997) Immunopharmacology (Netherlands) 38: 51-62). Such studies have demonstrated that protection against complement-mediated inflammatory tissue damage can be achieved using complement receptor antagonists in various animal models of sepsis, myocardial as well as intestinal ischemia/reperfusion injury, adult respiratory distress syndrome, nephritis and graft rejection. Thus complement receptor antagonists are suitable therapeutic agents to control inflammatory diseases and inflammatory related conditions.
Cell surface receptors have also been implicated in the genesis of cancer through the molecular analysis of the etiology of this group of related diseases characterized by a loss of cellular growth control. Indeed, cell surface receptors play multiple roles in oncogenic transformation including: serving as portholes for cellular infection by known and suspected human tumor viruses including Epstein-Barr virus, human T-cell leukemia virus (HTLV), Hepatitis B virus, and Papilloma viruses; serving as mediators of growth factor and transforming growth factor dependent stimulation of cancer cell growth through autocrine or paracrine mechanisms; and, finally, by indirectly facilitating the progression of cancer by potentiating the vascularization of tumor tissue and thus allowing for the continued growth of a mass of oncogenically transformed cells. Therapeutic agents capable of blocking any or all of these receptor functions thus have great utility in the treatment and prevention of human cancers. For example, the mitogenic action of epidermal growth factor (EGF) is mediated by ligand-induced autophosphorylation of the EGF receptor (EGFR), and EGFR is commonly overexpressed in solid human tumors. Compounds designed to block receptor tyrosine kinase activity by serving as competitive inhibitors of ATP binding to the intracellular kinase catalytic domain of the EGFR, have been shown in cell culture studies to be capable of blocking EGF-stimulated growth in a concentration dependent manner without affecting basal growth (Wakeling et al. (1996) Breast Cancer Res. Treat. (Netherlands) 38: 67-73; see also Rewcastle et al. (1998) J. Med. Chem. 41:742-51). Furthermore, a broad spectrum neuropeptide receptor antagonist has been shown to inhibit tyrosine kinase activation, block cell growth and increase apoptosis in in vitro and in vivo studies of a small cell lung cancer in which cell growth is sustained by multiple autocrine and paracrine growth loops involving bombesin-like neuropeptide growth factors (Tallett, et al. (1996) Cancer Res. 56: 4255-63). Indeed, for certain cancers generally unaffected by conventiona
Burns Jennifer M.
Devico Anthony L.
Gallo Robert
Lewis George K.
Andres Janet L.
Eyler Yvonne
Fuierer Marianne
Hultquist Steven J.
University of Maryland Biotechnology Institute
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