Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Binds antigen or epitope whose amino acid sequence is...
Reexamination Certificate
2001-05-04
2003-11-11
Mertz, Prema (Department: 1646)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Binds antigen or epitope whose amino acid sequence is...
C424S141100, C424S143100, C424S144100, C514S885000, C514S826000, CD24S110000
Reexamination Certificate
active
06645492
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to regulating IL-9 activity and treating atopic allergies and related disorders like asthma, based upon the relationship between IL-9 and its receptor.
BACKGROUND OF THE INVENTION
Inflammation is a complex process in which the body's defense system combats foreign entities. While the battle against foreign entities may be necessary for the body's survival, some defense systems improperly respond to foreign entities, even innocuous ones, as dangerous and thereby damage surrounding tissue in the ensuing battle.
Atopic allergy is an ecogenetic disorder, where genetic background dictates the response to environmental stimuli. The disorder is generally characterized by an increased ability of lymphocytes to produce IgE antibodies in response to ubiquitous antigens. Activation of the immune system by these antigens leads to allergic inflammation and may occur after ingestion, penetration through the skin, or after inhalation. When this immune activation occurs and pulmonary inflammation ensues this disorder is broadly characterized as asthma. Certain cells are critical to this inflammatory reaction and they include T cells and antigen presenting cells, B cells that produce IgE, and mast cells/basophils and eosinophils that bind IgE. These inflammatory cells accumulate at the site of allergic inflammation and the toxic products they release contribute to the tissue destruction related to the disorder.
While asthma is generally defined as an inflammatory disorder of the airways, clinical symptoms arise from intermittent air flow obstruction. It is a chronic disabling disorder that appears to be increasing in prevalence and severity
1
. It is estimated that 30-40% of the population suffer with atopic allergy, and 15% of children and 5% of adults in the population suffer from asthma.
1
Thus, an enormous burden is placed on our health care resources.
The mechanism of susceptibility to atopy and asthma remains unknown. Interestingly, while most individuals experience similar environmental exposures, only certain individuals develop atopic allergy and asthma. This hypersensitivity to environmental allergens known as “atopy” is often indicated by elevated serum IgE levels or abnormally great skin test response to allergens in atopic individuals as compared to nonatopics.
10
Strong evidence for a close relationship between atopic allergy and asthma is derived from the fact that most asthmatics have clinical and serologic evidence of atopy.
4-9
In particular, younger asthmatics have a high incidence of atopy.
10
In addition, immunologic factors associated with an increase in serum total IgE levels are very closely related to impaired pulmonary function.
3
Both the diagnosis and treatment of these disorders are problematic.
1
The assessment of inflamed lung tissue is often difficult, and frequently the source of the inflammation cannot be determined. Without knowledge of the source of the airway inflammation and protection from the inciting foreign environmental agent or agents, the inflammatory process cannot be interrupted. It is now generally accepted that failure to control the pulmonary inflammation leads to significant loss of lung function over time.
Current treatments suffer their own set of disadvantages. The main therapeutic agents, &bgr; agonists, reduce the symptoms, i.e., transiently improve pulmonary functions, but do not affect the underlying inflammation so that lung tissue remains in jeopardy. In addition, constant use of &bgr; agonists results in desensitization which reduces their efficacy and safety.
2
The agents that can diminish the underlying inflammation, the anti-inflammatory steroids, have their own known list of disadvantages that range from immunosuppression to bone loss.
2
Because of the problems associated with conventional therapies, alternative treatment strategies have been evaluated.
65-66
Glycophorin A,
64
cyclosporin,
65
and a nonapeptide fragment of IL-2,
63
all inhibit interleukin-2 dependent T lymphocyte proliferation and therefore, IL-9 production,
51
however, they are known to have many other effects.
2
For example, cyclosporin is used as a immunosuppressant after organ transplantation. While these agents may represent alternatives to steroids in the treatment of asthmatics,
63-66
they inhibit interleukin-2 dependent T lymphocyte proliferation and potentially critical immune functions associated with homeostasis. What is needed in the art is the identification of a pathway critical to the development of asthma that explains the episodic nature of the disorder and the close association with allergy that is downstream of these critical immune functions. Nature demonstrated that this pathway is the appropriate target for therapy since biologic variability normally exists at this pathway and these individuals are otherwise generally not immunocompromised or ill except for their symptoms of atopy.
Because of the difficulties related to the diagnosis and treatment of asthma, the complex pathophysiology of this disorder is under intensive study. Although this disorder is heterogeneous and may be difficult to define because it can take many forms, certain features are found in common among asthmatics. Examples of such traits include elevated serum IgE levels, abnormal skin test response to allergen challenge, bronchial hyperresponsiveness (BHR), bronchodilator reversibility, and airflow obstruction.
3-10
These expressions of these asthma related phenotypes may be studied as quantitative or qualitative measures.
Elevated IgE levels are also closely correlated with BHR, a heightened bronchoconstrictor response to a variety of stimuli.
4, 6, 8, 9
BHR is believed to reflect the presence of airway inflammation,
6, 8
and is considered a risk factor for asthma.
11-12
BHR is accompanied by bronchial inflammation and an allergic diathesis in asthmatic individuals.
13-21
Even in children with no symptoms of atopy and asthma, BHR is strongly associated with elevated IgE levels.
19
A number of studies document a heritable component to atopy and asthma.
4, 10, 21
However, family studies have been difficult to interpret since these disorders are significantly influenced by age and gender, as well as many environmental factors such as allergens, viral infections, and pollutants.
22-24
Moreover, because there is no known biochemical defect associated with susceptibility to these disorders, the mutant genes and their abnormal gene products can only be recognized by the anomalous phenotypes they produce. Thus, an important first step in isolating and characterizing a heritable component is identifying the chromosomal locations of the genes.
Cookson et al. provided the first description of a genetic localization for inherited atopy.
25
These investigators described evidence for genetic linkage between atopy and a single marker on a specific chromosomal region designated 11q13.1. Later, they suggested evidence of maternal inheritance for atopy at this locus.
26
Although maternal inheritance genetic imprinting had been observed for atopy, it had never been explained previously. However, efforts to confirm this linkage have not been generally successful.
27-31
Recently, the &bgr; subunit of the high-affinity IgE receptor was mapped to chromosome 11q, and a putative mutation associated with atopy has been described in this gene.
32, 33
However, because of the difficulties by others of replicating this linkage, the significance of this gene and polymorphism remains unclear. While additional studies will be required to confirm whether this putative mutation causes atopy in the general population, data collected so far suggests this polymorphism is unlikely to represent a frequent cause of atopy.
Because serum IgE levels are so closely associated with the onset and severity of allergy and asthma as clinical disorders, attention has focused on studies of the genetic regulation of serum total IgE levels. While past studies have provided evidence for Mendelian inheritance for serum total IgE levels,
34-38
Kari U. Prasad
Levitt Roy Clifford
Maloy W. Lee
Nicolaides Nicholas C.
Genaera Corporation
Mertz Prema
Morgan & Lewis & Bockius, LLP
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