Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or...
Reexamination Certificate
2001-09-20
2004-06-22
Nolan, Patrick J. (Department: 1644)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Reexamination Certificate
active
06753135
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to treatment of disease in humans and other mammals. More particularly, it relates to biological markers such as cell populations, cell surface antigen expression levels, and soluble factor concentrations that are indicative of the efficacy of treatment of atopic asthma and other inflammatory disorders.
BACKGROUND OF THE INVENTION
Prednisone is a corticosteroid used to treat a wide variety of inflammatory disorders, including asthma, atopy, arthritis, multiple sclerosis, ulcerative colitis, and Crohn's disease. While a comprehensive understanding of the action of prednisone and other glucocorticoids (a class of corticosteroids) is lacking, the drugs are known to have broad-ranging anti-inflammatory and immunosuppressive effects, including inhibition of pro-inflammatory mediators and activation of anti-inflammatory mediators. They affect the growth, differentiation, and function of monocytes and lymphocytes; the distribution of cellular subsets; and the production of cytokines, cellular proteins that are secreted and affect the behavior of other cells. Because the disorders treated by glucocorticoids themselves involve unknown immunological mechanisms, it is unclear which of the many effects of prednisone are most important in inhibiting the inflammatory response.
In addition, because of their broad-ranging systemic effects, prednisone and other glucocorticoids have a large number of side effects, some of them quite serious, which restrict their applicability in many patients, particularly for long-term use. These side effects include weight gain, hyperglycemia, bone thinning, digestive problems, cataracts, susceptibility to infection, hypertension, mood swings, and insomnia. It would be beneficial to have a drug that could provide the desired anti-inflammatory and immunosuppressive effects of prednisone without the detrimental side effects. Additionally, localizing the effects to the region of inflammation (e.g., the lungs) would minimize the systemic side effects. In order to do so, however, more information must be obtained about the mechanism of action of glucocorticoids in treating inflammatory disorders.
One very common inflammatory disease that has long been treated with prednisone is asthma, a chronic respiratory syndrome of uncertain etiology. Typical asthma symptoms include coughing, wheezing, chest tightness, and shortness of breath. These clinical symptoms are thought to result from hyper-responsiveness of the airways and a long-term inflammatory process that causes reversible obstruction of the airways. Many asthma sufferers also suffer from atopy, a hypersensitive allergic response to airborne antigens. The clinical manifestations of atopic asthma arise from the superposition of environmental factors on genetic predispositions that increase the probability of developing the syndrome.
Atopic asthma is an immunologic disease mediated by IgE antibodies and characterized by infiltration of the airways with mast cells, lymphocytes, and eosinophils.
The allergic response results from a hyperactivity of T
H
2 (type 2 helper) T lymphocytes, triggering the production of cytokines such as interleukin (IL)-4, IL-5, IL-6, IL-10, and IL-13, which enhance antibody production from B cells and induce essential aspects of the allergic response, such as mucosal tissue injury by eosinophils. T cells also support IgE-mediated responses to airborne allergens and orchestrate the recruitment and activation of primary effector cells. Products released by the inflammatory cells accumulated in the airways contribute to the tissue destruction characteristic of asthma.
A large number of studies have been performed, mostly in vitro, to elucidate the anti-inflammatory mechanism of glucocorticoids in diseases such as asthma. One hypothesis is that glucocorticoids suppress the activation of cells that produce cytokines to prime eosinophils and induce the migration of lymphocytes, eosinophils, and basophils into the airway. Upon entering a cell, glucocorticoids bind with intracellular glucocorticoid receptors (GR), which are widely distributed among different cell types. The glucocorticoid-receptor complex then enters the cell nucleus and turns on specific genes by binding with DNA and directing the transcription process. In particular, glucocorticoids interact with two transcription factors, activating protein 1 (AP-1) and nuclear factor NF-&kgr;B. AP-1 is involved in the regulation of several genes, including those that express adhesion molecules and cytokines, while NF-&kgr;B regulates the transcription of genes involved in the inflammatory response. It is estimated that each cell type has ten or more target genes per cell, although they may not all be expressed. It would be highly desirable to develop new glucocorticoids or other drugs that would be more selective moderators of gene expression, leading to a reduction in toxic effects and localization of effects to disease regions.
Current studies on the effect of glucocorticoids on asthma and other inflammatory disorders are performed by measuring the effect of the drug on quantities of cell types, cell surface antigen expression, and soluble factors, both in vivo and in vitro. A number of factors have been shown to be correlated with glucocorticoid use, such as an increase in circulating granulocytes or decrease in number of eosinophils, which are responsible for many of the inflammatory tissue damage effects of asthma. However, while many studies examine IgE levels and related factors, there are few data available with respect to other measurements in vivo, such as cell surface marker expression on granulocytes and lymphocytes, or soluble factors in serum. Available data are also conflicting. For example, variable effects of glucocorticoids on T cell counts have been shown, while B cells are believed to be only minimally affected by glucocorticoids, with redistribution from peripheral blood to other lymphoid compartments being of main importance. There have also been conflicting reports on immunoglobulin levels post glucocorticoid treatment. As is well known to those of skill in the art, the correlation between in vitro and in vivo measurements is tenuous at best, and in vivo measurements must be performed to obtain information that can be used for treatment or diagnostic purposes.
Methods and compositions are currently being developed for alternative treatments of asthma and other inflammatory disorders that minimize side effects. Much of this work is devoted to regulation of the various interleukins. For example, U.S. Pat. No. 5,908,839, issued to Levitt et al., discloses methods for treating asthma by regulating the function of the IL-9 receptor. U.S. Pat. No. 5,683,983, issued to Barrett et al., discloses compounds that bind to the IL-5 receptor. U.S. Pat. No. 5,874,080, issued to Hebert et al., provides anti-IL-8 monoclonal antibodies for treatment of asthma.
In general, much more information must be obtained before less broad ranging but sufficiently effective anti-inflammatory drugs can be developed for treatment of autoimmune or inflammatory diseases such as asthma. In addition, accurate but simple methods for evaluating drug efficacy are lacking. One of the problems in elucidating both drug action and disease pathogenesis is that appropriate tools are lacking to measure a broad range of applicable immunological components in vivo from a large number of subjects. Thus many studies on the effects of glucocorticoids on cellular responses are performed in vitro or in animal models, neither of which is directly applicable to humans. In addition, the studies tend to examine factors that are already known to be implicated in glucocorticoid action, rather than searching for novel factors that may be useful for indicating the disease progression or treatment efficacy.
There is a need, therefore, for a simple but effective method of gauging the anti-inflammatory or immunosuppressive response of candidate drugs for treating asthma, atopy, and other inflammatory diseases. The
Alters Susan E.
Cheal Karen L.
Kantor Aaron B.
Nolan Patrick J.
SurroMed, Inc.
Swanson & Bratschun LLC
LandOfFree
Biological markers for evaluating therapeutic treatment of... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Biological markers for evaluating therapeutic treatment of..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Biological markers for evaluating therapeutic treatment of... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3364421