Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1999-08-19
2004-12-14
Nolan, Patrick J. (Department: 1644)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S007310, C424S009100, C424S009810
Reexamination Certificate
active
06830891
ABSTRACT:
TECHNICAL FIELD
The present invention relates to methods for the diagnosis of allergic bronchopulmonary aspergillosis (ABPA) and recombinant allergens to be used in the methods. During the priority year the recombinant allergen that in the priority application was called rAsp f2 has officially been named rAsp f6. The official name is used in this text.
TECHNICAL BACKGROUND
Allergic bronchopulmonary aspergillosis (ABPA). Allergic bronchopulmonary aspergillosis is the most severe allergic complication caused by
Aspergillus
species, mainly
A. fumigatus
. ABPA is the result of hypersensitivity to
Aspergillus
-antigens mainly in patients suffering from long-standing atopic asthma (8-12) or cystic fibrosis (16-19). Although originally considered as a rare disease (13), ABPA is currently recognized with much greater frequency. ABPA with varied clinical presentations has been reported to occur in about 15% of the asthmatic patients sensitized to
A. fumigatus
(14,15), while in patients with cystic fibrosis the reported incidence varies from 10 to 35% (16,17). ABPA has been described as an immune disease that ranges from asthma to fatal destructive lung disease with defined clinical, serological, radiological and pathological features (8,18-22). Because of its severity ABPA should be ruled out in patients with chronic asthma or cystic fibrosis exhibiting immediate cutaneous reactivity to
A. fumigatus
(8). The diagnostic criteria for ABPA are asthma or cystic fibrosis, history of roentgenographic infiltrates (in most cases), immediate cutaneous reactivity to
A. fumigatus
extracts, elevated total serum IgE, precipitating antibodies to
A. fumigatus
, peripheral blood eosinophilia, elevated specific serum IgE and IgG to
A. fumigatus
as compared to sera from patients with asthma and cutaneous reactivity to
Aspergillus
, but without ABPA, and proximal (central) bronchiectasis with normal tapering of distal bronchi (23-25). In cases where all criteria are present, diagnosis is readily made (26). However, all of the eight criteria are rarely present at the same time even in classic ABPA-patients with central bronchiectasis. With exception of bronchiectasis and to some extent elevated specific serum IgE and IgG to
A. fumigatus
, none of the diagnostic criteria are specific for ABPA (26). Furthermore, pulmonary infiltrates and central bronchiectasis are commonly detected in patients suffering from cystic fibrosis also in the absence of sensitization to
A. fumigatus
, which makes a diagnosis of ABPA in patients with cystic fibrosis even more difficult (16). Therefore, serologic identification of ABPA has a greater diagnostic potential, but is, however, hampered by the lack of standardized, reliable fungal extracts (5,7,27-29).
Aspergillus fumigatus
antigens. The major problem in the immunodiagnosis of diseases related to
A. fumigatus
stems from the antigenic complexity of the fungus. Antigen/allergen extracts of
A. fumigatus
contain hundreds of different proteins (6,30,31), of which a limited subset are able to let bind human serum IgE (6,32,33,35). The fungus has been reported to produce more than 40 IgE-binding components which generate complex IgE-binding patterns when extracts are examined by Western blot analysis using sera from allergic individuals (32,33). To make the picture even more complicated, serum IgE from different patients recognize highly variable patterns of fungal proteins (6,36). In the case of patients suffering from ABPA, depending on the stage of the disease, different allergenic “fingerprints” may be obtained with serum of the same patient taken at different times, even if fungal extract from the same batch is used (36,37).
It has been suggested to use purified native allergenic components instead of crude allergen extracts for diagnosing ABPA (79). Recombinant
A. fumigatus
allergens with connections to ABPA have been described earlier (71,83).
The inventors are named authors in a number of articles about recombinant allergens from
A. fumigatus
(cloning and expression: 39,43,49,51,52,82, and diagnostic use: 59,66,32,71,76,81).
Result of International-Type Search During the Priority Year.
The references 66, 79 and 84 have been categorised as being of particular relevance.
Banerjee et al., (84) describes antigens that cannot be intracellular. The described antigens are shown to react with sera of patients with ABPA, but there are no data suggesting that the antigens will not react with sera of
A. fumigatus
-sensitised patients not having ABPA.
Moser et al (66) and Little et al., (79) describe secreted proteins/antigens that do not allow for differential diagnosis of ABPA because they frequently reacts with sera of
A. fumigatus
-sensitised patients without ABPA and sera of ABPA patients.
THE OBJECTIVES OF THE INVENTION
The main objective of the invention is to provide improved methods for diagnosis of ABPA.
One subobjective is to provide in vitro diagnostic methods that have the sufficient specificity and sensitivity for diagnosis of ABPA.
A second subobjective is to provide well-defined allergen preparations that can be used for the diagnosis of ABPA both in vitro and in vivo, including immunoassay and skin reactivity measurement methods, respectively.
REFERENCES:
Colman et al. Research in Immunology, vol. 145 pp. 33-36, 1994.*
Banerjee et al., Asian Pacific Journal of Allergy and Immunology, (1990) 8:13-18.
Moser et al., The Journal of Allergy and Clinical Immunology, (1994) 93(1(1)):1-11.
Little et al., The Journal of Allergy and Clinical Immunology, (1996) 98(1):55-63.
Blaser Kurt
Crameri Reto
Hemmann Stefanie
Dinsmore & Shohl LLP
Nolan Patrick J.
Pharmacia Diagnostics AB
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