Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
2000-05-01
2002-10-08
Chan, Christina (Department: 1644)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S007920, C435S069600, C435S335000, C530S388230, C530S809000
Reexamination Certificate
active
06461821
ABSTRACT:
TECHNICAL FIELD
This invention relates to a smooth muscle growth inhibitory composition comprising apM1 (adipose most abundant gene transcript 1) as an active ingredient, a method for diagnosis of arteriosclerosis (atherosclerosis) which comprises assaying said apM1 in a sample, and a diagnostic kit for arteriosclerosis which comprises an antibody against said apM1 as an active component.
BACKGROUND ART
It is well known that, in modern society, obesity or an excessive accumulation of body fat is involved in the development of diabetes mellitus, hyperlipidemia, hypertension, and atherosclerotic diseases inclusive of angina pectoris and myocardial infarction. With obesity, not only genetic factors but also environmental factors are associated.
Recently, leptin and many other obesity-related genes have been isolated from animal models. While the group of these genes thus isolated is suspected to be involved in the establishment of obesity in man, various environmental factors such as the excessive food intake and insufficient physical exercise by contemporary man are also considered to be playing a crucial role in the development of diabetes mellitus and atherosclerosis via fat storage.
Not only the search for obesity-related genes but also the approach toward elucidation of the specific genes expressed in adipose tissues under overnutrition and of the influences of such gene transcripts on the individual seem to be of remarkable significance for expatiation of the etiologies of said diseases and establishment of relevant therapeutic modalities.
The object of this invention is to cast light on the obesity-related genes and their expression products which should be useful for elucidation of the pathogenesis of various obesity-related diseases, particularly atherosclerotic diseases such as angina pectoris, myocardial infarction, etc., and establishment of pertinent therapeutic modalities and to establish therapeutic and diagnostic methods for the diseases by utilizing such genes and expression products.
The inventors have conducted intensive studies for accomplishing the above object and made it clear previously that accumulation of fat, particularly visceral fat in the abdominal cavity, is closely associated with abnormal glucose tolerance, hyperlipidemia and hypertension. Furthermore, through large-scale sequencing analyses of the genes expressed in adipose tissue, they elucidated that many secretory protein genes have been expressed in adipose tissue and that, particularly in visceral fat, the expression of various bioactive substance genes can be observed. In addition to the cloning of those known genes, the inventors succeeded in cloning an adipose tissue-specific collagen-like protein apM1 gene [Biochem. Biophys. Res. Commun., 221, 286-289 (1996)].
This apM1 gene was found to be coding for the secretory protein (apM1) consisting of 244 amino acid residues, contain a 66-residue collagen-like motif (G-X-Y), and have homology with the Clq subcomponent of the complement system and collagen X and VII. However, the physiological function of this gene and its expression product apM1 remained to be known.
In the ensuring research, the inventors made a series of investigations in regard to the expression of said apM1 gene by the genetic engineering technique, preparation of an antibody against the expression product apM1, establishment of an apM1 assay system utilizing said antibody, and relationship of the blood apM1 concentration determined by using said assay system to the body fat distribution or various diseases. The research led to the novel finding, inter alia, that apM1 has smooth muscle growth inhibitory activity and that the blood apM1 concentration faithfully reflects the atherosclerotic change.
Furthermore, the inventors obtained the novel finding that apM1 is effective in the prevention and treatment of post-angioplasty restenoses, such as restenosis after percutaneous transluminal coronary angioplasty (PTCA) using a stent, and for that matter, in the prophylaxis and therapy of atherosclerotic diseases accompanied by angiopathy, such as angina pectoris and myocardial infarction. This invention has been developed on the basis of the above finding.
DISCLOSURE OF INVENTION
In accordance with the invention, there is provided a smooth muscle growth inhibitory composition comprising a pharmacologically effective amount of at least one member selected from the group consisting of apM1 and its salt in combination with a pharmaceutically acceptable carrier.
Furthermore, in accordance with the invention, there is provided a therapeutic and prophylactic composition for post-angioplasty restenoses which comprises a pharmacologically effective amount of at least one member selected from the group consisting of apM1 and its salt in combination with a pharmaceutically acceptable carrier.
There is also provided in accordance with the invention a prophylactic and therapeutic composition for arteriosclerosis which comprises a pharmacologically effective amount of at least one member selected from the group consisting of apM1 and its salt in combination with a pharmaceutically acceptable carrier.
There is also provided in accordance with the invention a method for diagnosis of arteriosclerosis which comprises quantitating apM1 in a sample with an anti-apM1 antibody and comparing the value thus found with the values measured in healthy subjects and in patients with arteriosclerosis.
In addition, the present invention provides a diagnostic kit for arteriosclerosis, which comprises an anti-apM1 antibody as an active component, and a monoclonal anti-apM1 antibody which is effective in diagnosing the arteriosclerosis.
The smooth muscle growth inhibitory composition according to the invention is effective, through its smooth muscle growth inhibitory activity, in the prophylaxis and therapy of atherosclerotic diseases accompanied by angiopathy, such as angina pectoris, myocardial infarction inclusive of thrombosis, brain infarction, etc. and in the arrest of progression of such atherosclerotic diseases. In fact, apM1 as the active ingredient of the composition of the invention has an ability to inhibit expression of the cell adhesion molecules governing the onset of arteriosclerosis, namely VCAM-1 (vascular cell adhesion molecule-1), ELAM (endothelial leukocyte adhesion molecule), ICAM-1 (intercellular adhesion molecule-1), and so on. It is because of this action that the composition of the invention antagonizes the onset of various atherosclerotic diseases.
Consequently, the invention further provides a pharmaceutical composition for inhibiting the expression of adhesion molecules in vascular endothelial cells.
The fact that apM1 inhibits expression of said cell adhesion molecules indicates that the composition of the invention can be indicated for the prophylaxis and therapy of bronchial asthma which is a disease related to type I allergy accompanying eosinophilic infiltration and also known to be a disease associated with an enhanced expression of VCAM-1, for instance.
Furthermore, in view of the fact that said ICAM-1 and ELAM are known to be inflammation-related adhesion molecules, the composition of the invention comprising apM1 as an active ingredient may be indicated as an antiinflammatory agent or a therapeutic drug for rheumatoid arthritis, for instance, by taking advantage of said inhibitory effect on the expression of adhesion molecules.
Furthermore, the composition of the invention is effective in the prevention and treatment of post-angioplasty restenoses, for example in stent PTCA cases. Thus, after an operation for neovascularization against the coronary artery stenosis in angina pectoris or myocardial infarction, the post-ischemic reperfusion and injury of vascular endothelial cells evoke expression of adhesion molecules in vascular endothelial cells and consequent proliferation of smooth muscle cells to induce a restenosis. The composition of the invention inhibits such expression of adhesion molecules and growth of smooth muscle cells to thereby contribute to the preve
Matsuzawa Yuji
Ohmoto Yasukazu
Chan Christina
Huynh Phuong N.
Otsuka Pharmaceutical Co. Ltd.
Sughrue & Mion, PLLC
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