Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,...
Reexamination Certificate
2001-01-12
2004-07-27
Chan, Christina (Department: 1644)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
C424S134100, C424S141100, C424S146100, C424S184100, C530S387100, C530S388100, C530S388200, C530S383000, C530S389200
Reexamination Certificate
active
06767540
ABSTRACT:
BACKGROUND OF THE INVENTION
The mechanisms responsible for the development of asthma in atopic patients include genetic predisposition and the effects of environmental exposures to inflammatory stimuli in the airways of susceptible individuals (Bleecker, E. R., and D. A. Meyers in
Genetics of Allergy and Asthma
. M. N. Blumenthal, and B. Bjorksten, (eds. Marcel Dekker, New York, p. 307 1997). Asthma represents a chronic inflammatory process of the airways. The consequences of chronic inflammation in the asthmatic airways include increased numbers of fibroblasts and the deposition of extracellular matrix (ECM) such as collagen, fibronectin, and laminin within the airway wall (Altraja, A., et al.
Am. J. Respir. Cell. Mol. Biol.
15: 482, 1996; Roche, W. R., et al.
Lancet.
1:520, 1989). The plasminogen activator (PA) system has an important role in controlling endogenous fibrosis and regulating ECM proteolysis relevant to tissue remodeling (Gabazza, E. C., et al.
Lung.
177: 253, 1999). The tissue-type PA (tPA) and urokinase-type PA (uPA) converts plasminogen to plasmin, which enhances proteolytic degradation of the ECM. An important mechanism in the regulation of PA activity is inhibition of uPA or tPA by three major inhibitors, which are PAI-1, PAI-2, and PAI-3 (Kruitoff, E. K.
Enzyme
40: 113, 1988). Among these three inhibitors, PAI-1 is the most important in controlling lung fibrosis (Geiger, M., et al,
Immunopharmacology
32: 53, 1996; Lardot, C., et al.
Eur. Respir. J.
11: 912, 1988; Kruitoff E. K., et al.
J. Biol. Chem.
261: 11207, 1986). PAI-1 overexpressing mice suffered severe lung injury and deposition of ECM after bleomycin challenge (Eitzman, D. T., et al.
J. Clin. Invest.
97: 232, 1996) or hyperoxia (Barazzone, C., et al.
J. Clin. Invest.
98: 2666, 1996), whereas PAI-1 deficient mice were protected against such a fibrotic reaction. These findings show that PAI-1 is closely associated with fibrosis and ECM accumulation after lung injury or inflammation. Recently, the induction of PAI-1 was demonstrated in mast cells of the asthmatic airway (Cho, S. H., et al.
J. Immunol.
165: 3154-3161, 2000).
The human PAI-1 gene is located on chromosome 7 (q21.3-q22) and contains eight introns and nine exons distributed over about 12.3 kb (Klinger, K. W., et al.
Proc. Natl. Acad. Sci. U.S.A.
84: 8548, 1987). Eight polymorphisms of the PAI-1 gene have been discovered up to now, but only a few genotypes seem to influence the synthesis and both concentration and activity of the inhibitor in plasma (Dawson, S. J., et al.
J. Biol. Chem.
268: 10739, 1993; Hermans, P. W., et al.
Lancet.
354: 556, 1999; Dawson, S., et al.
Arteriosclero. Thromb.
11: 183, 1991; Mansfield, M. et al.
Thromb. Haemost.
71: 731, 1994). The most important of these is a single guanosine insertion/deletion variation (5G or 4G) in the promoter region (4G deletion polymorphism), situated 675 bp upstream from the transcriptional start site of the PAI-1 gene (Dawson, S. J., et al.
J. Biol Chem.
268: 10739, 1993; Eriksson, P., et al,.
Proc. Natl. Acad. Sci USA
92: 1851, 1995). The 4G allele is correlated with increased plasma PAI-1 levels. In vitro experiments have initially shown that the 5G allele contains an additional binding site for a protein likely related to the NF-&kgr;B group of transcription factors, and this binding site is absent in the 4G allele (Dawson, S. J., et al.
J. Biol. Chem.
268: 10739, 1993). After stimulation with IL-1, HepG2 cells transfected with the 4G allele produce six times more PAI-1 mRNA than those with the 5G allele. These data suggest a functional role of the 4G/5G polymorphism in response to cytokines, the 4G allele being associated with enhanced gene expression (Dawson, S. J., et al.
J. Biol. Chem.
268: 10739, 1993). Both alleles bind a transcriptional activator, whereas the 5G allele also binds a repressor protein to an overlapping binding site, which decreases the binding of the activator by interference due to steric hindrance. A relationship between increased PAI-1 levels in plasma and the 4G polymorphism has been described in patients with cardiovascular and metabolic diseases (Dawson, S. J., et al.
J. Biol. Chem.
268: 10739, 1993; 16-20).
Treatment of bronchial asthma patients with prednisone resulted in an increase of PAI-1 activity (Banach-Wawrzenczyk, E. et al.,
Pol. Merkuriusz Lek
7(43): 9-11, 2000; Dziedzicko, A. et al.,
Pneumonol. Alergol Pol
66(3-4): 173-177, 1998). No statistical difference were found with other fibrinolysis factors after the treatment.
Bleomycin-induced lung injury was reported to result in increased PAI-1 activity levels (Olman, M. A. et al.
J. Clin. Invest.
96(3): 1621-1630, 1995). In situ hybridization showed mRNA induction. The observations suggested that PAI-1 expression plays an important role in the formation and persistence of extracellular fibrin in injured lung tissue.
There exists a need for asthma treatments and chronic obstructive pulmonary discase treatments. These treatments may be able to take advantage of the observed PAI-1 activity levels.
SUMMARY OF THE INVENTION
Antagonists to plasminogen activator inhibitor type-1 (PAI-1) can be used for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Antagonists can be antibodies, peptides, proteins, nucleic acids, small organic molecules, or polymers.
DESCRIPTION OF THE SEQUENCE LISTINGS
The following sequence listings form part of the present specification and are include to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these sequences in combination with the detailed description of specific embodiments presented herein.
SEQ ID NO:
Description
Sequence
1
Murine PAI-1 sense
AGCAGAGTGGAGGGCACA
2
Murine PAI-1 antisense
GATGCCGTATGCCACGGT
3
Murine GAPDH sense
GAGTCTACTGGTGTCTTCACC
4
Murine GAPDH antisense
GTCATGAGCCCTTCCACAATGC
5
5G alternative forward primer
GTCTGGACACGTGGGGG
6
4G alternative forward primer
GTCTGGAGACGTGGGGA
7
Reverse primer
GCTGTCCACCCGGTGCTCTG
8
Control reverse upstream
AAGCTTTTACCATGGTAACCCCTGGT
primer
DEFINITIONS
The following definitions are provided in order to aid those skilled in the art in understanding the detailed description of the present invention.
“Antibodies” refers to whole antibodies and antibody fragments or molecules including antibody fragments, including, but not limited to, single chain antibodies, humanized antibodies, DEIMMUNISED™ antibodies, and Fab, F(ab′)
2
, V
H
, V
L
, F
d
, and single or double chain Fv fragments.
“PAI” refers to plasminogen activator inhibitor; “PAI-1” refers to plasminogen activator inhibitor type-1.
“TDT” refers to transmission disequilibrium test.
“ECM” refers to extracellular matrix.
“tPA” refers to tissue-type plasminogen activator.
“uPA” refers to urokinase-type plasminogen activator.
“FITC” refers to fluorescein-isothiocyanate.
DETAILED DESCRIPTION OF THE INVENTION
PAI-1 is shown to be highly expressed in the airways of a murine asthma model. Additionally, the 4G allele was shown to be preferentially transmitted to asthmatic children. These results suggest a possible role of PAI-1 gene and the 4G polymorphism in the pathophysiology of asthma. Antagonists of PAI-1 can be used to reduce or eliminate asthma or chronic obstructive pulmonary disease.
The induction of the PAI-1 gene in the lung tissue of a murine asthma model was shown using both a RT-PCR and an immunofluorescence approach. Although many cell types are capable of synthesizing PAI-1 (Loskutoff, D. J., M. Sawdey, and J. Mimuro.
Prog. Hemost. Thromb.
9: 87, 1995), endothelial cells may be the major source of PAI-1 under basal conditions (Yamamoto, C., et al.
Thromb. Res.
74: 163, 1994). Prinsky et al. demonstrated that macrophages appeared to be the principal cell type secreting PAI-1 in lung tissue under hypoxic conditions (
J. Clin. Invest.
102: 919, 1998). Mast cells have been shown to be one of the important sources of PAI-1 in the asthmatic airways (Cho, S. H., et al.
J. Immunol.
165: 3154, 2000). T
Cho Seong H.
Demissie-Sanders Sossiena
Oh Chad K.
Tan Sunny
Thomas David W.
Belyavskyi Michail A
Chan Christina
Liljestrand Cheryl A.
Tanox, Inc.
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