Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
2000-02-18
2003-08-26
Ceperley, Mary E. (Department: 1641)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S345000, C530S388900, C530S389800, C536S017300
Reexamination Certificate
active
06610502
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel endogenous compound 2-amino-3-[2-(&agr;-mannopyranosyl)indole-3-yl]propionic acid which is useful for testing a biological function, to an antibody specifically reactive with the novel endogenous compound 2-amino-3-[2-(&agr;-mannopyranosyl)indole-3-yl]propionic acid, to a hybridoma that produces the antibody, to a method for testing a biological function comprising quantitating the novel compound 2-amino-3-[2-(&agr;-mannopyranosyl)indole-3-yl]propionic acid in a biological sample and determining the biological function based on the quantitated value, to a method for immunologically quantitating 2-amino-3-[2-(&agr;-mannopyranosyl)indole-3-yl]propionic acid by using the antibody, and to a process for synthesizing 2-amino-3-[2-(&agr;-mannopyranosyl)indole-3-yl]propionic acid.
BACKGROUND ART
Test of biological functions is very important, for example, for diagnosing diseases or for confirming therapeutic effects. For such test of biological function, various endogenous compound have been used as markers heretofore. Diseases are diagnosed or therapeutic effects are confirmed, based on the presence or concentration of the marker contained in a collected biological sample.
There have been demands for further detailed diagnosis of biological functions such as renal function, central nervous function and developmental function of fetus, and development of novel markers suitable for such diagnosis and development of uses thereof have been strongly demanded.
For example, glomerular filtration rate (hereinafter, abbreviated as “GFR”) is one of the best indexes for testing renal functions. Accurate GFR can be measured by inulin clearance method. However, this measurement method is quite hard for the subject to bear, requiring patience and restraint of the subject. An alternative method is a creatinine clearance method which tests GFR based on creatinine levels in blood and creatinine excretion levels in urine. Creatinine can be easily quantitated by chemical or enzymatic methods. However, it is difficult to obtain accurate GFR by the creatinine clearance method since creatinine is secreted from uriniferous tubule; since its in vivo synthesis level is dependent on physiological parameters such as age, sex, body weight, obesity and the like; and since creatinine levels in blood and urine are increased due to intestine absorption of creatinine after ingestion of cooked meat or the like containing creatinine. Therefore, a novel index as an alternative to inulin and creatinine is strongly demanded.
DISCLOSURE OF THE INVENTION
The objects of the present invention are to provide a method for testing biological functions such as renal function, central nervous function and developmental function of fetus by quantitating a level of a novel endogenous compound; to provide a method for immunologically quantitating the novel endogenous compound; and to provide an antibody used therefor. Furthermore, the objects of the invention are to provide a process for producing the antibody used in the method for immunologically quantitating the novel endogenous compound; to provide a novel compound that can be used as an immunogen or as a hapten in the antibody production process; and to provide a process for synthesizing the novel compound. Moreover, the object of the present invention is to provide a novel intermediate for synthesis of the novel compound. The further object of the invention is to provide a hybridoma that produces an antibody to the novel endogenous compound.
The present inventors have analyzed various substances contained in biological samples by high-performance liquid chromatography, and found the existence of a novel fluorescent substance that appears at a high in vivo level in patients suffering from biological dysfunctions, for example, patients with renal dysfunction, pregnant patients with uremic syndrome and patients with central nervous dysfunction, thereby accomplishing the present invention.
The present invention relates to a method for testing a biological function, comprising: quantitating 2-amino-3-[2-(&agr;-mannopyranosyl)indole-3-yl]propionic acid in a collected biological sample; and determining the biological function based on the quantitated value.
Examples of the above-mentioned biological function include a renal function, a central nervous function, and a developmental function of fetus. The biological sample is, for example, urine, serum, cerebrospinal fluid or amniotic fluid.
The present invention also relates to a method for immunologically quantitating 2-amino-3-[2-(&agr;-mannopyranosyl)indole-3-yl]propionic acid, comprising immunologically quantitating 2-amino-3-[2-(&agr;-mannopyranosyl)indole-3-yl]propionic acid in a sample by using an antibody specifically reactive with 2-amino-3-[2-(&agr;-mannopyranosyl)indole-3-yl]propionic acid.
The present invention further relates to an antibody specifically reactive with 2-amino-3-[2-(&agr;-mannopyranosyl)indole-3-yl]propionic acid. The antibody is, for example, a monoclonal antibody. The monoclonal antibody is, for example, monoclonal antibody KTM-250.
The present invention also relates to a hybridoma which produces a monoclonal antibody specifically reactive with 2-amino-3-[2-(&agr;-mannopyranosyl)indole-3-yl]propionic acid. Examples of the hybridoma include hybridome KTM-250 (FERM BP-6432).
The present invention also relates to a 2-amino-3-[2-(&agr;-D-mannopyranosyl)indole-3-yl]propionic acid derivative represented by general formula (XV):
wherein R
1a
to R
4a
, which may be the same or different, independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted aryl group; R
5a
represents a hydrogen atom, a substituted or unsubstituted sulfamoyl group, a substituted or unsubstituted arylsulfonyl group, a substituted or unsubstituted alkoxycarbonyl group, or a substituted or unsubstituted alkoxymethyl group; R
6a
represents a hydrogen atom or a substituted or unsubstituted alkyl group; and R
7a
represents a hydrogen atom or a substituted or unsubstituted aralkyloxycarbonyl group, or 2-amino-3-[2-(&agr;-L-mannopyranosyl)indole-3-yl]propionic acid derivative represented by general formula (XV′):
wherein R
1a
to R
4a
, which may be the same or different, independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted aryl group; R
5a
represents a hydrogen atom, a substituted or unsubstituted sulfamoyl group, a substituted or unsubstituted arylsulfonyl group, a substituted or unsubstituted alkoxycarbonyl group, or a substituted or unsubstituted alkoxymethyl group; R
6a
represents a hydrogen atom or a substituted or unsubstituted alkyl group; and R
7a
represents a hydrogen atom or a substituted or unsubstituted aralkyloxycarbonyl group. Examples of the derivative include 2-amino-3-[2-(&agr;-mannopyranosyl)indole-3-yl]propionic acid.
The present invention also relates to a process for producing an antibody to 2-amino-3-[2-(&agr;-mannopyranosyl)indole-3-yl]propionic acid, wherein the process uses, as an immunogen or as a hapten, a 2-amino-3-[2-(&agr;-D-mannopyranosyl)indole-3-yl]propionic acid derivative represented by general formula (XV):
wherein R
1a
to R
4a
, which may be the same or different, independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted aryl group; R
5a
represents a hydrogen atom, a substituted or unsubstituted sulfamoyl group, a substituted or unsubstituted arylsulfonyl group, a substituted or unsubstituted alkoxycarbonyl group, or a substituted or unsubstituted alkoxymethyl group; R
6a
represents a hydrogen atom or a substituted or unsubstituted alkyl group; and R
7a
repres
Adachi Kyoko
Fujise Yutaka
Horiuchi Kentaro
Kohno Hiroaki
Sano Hiroshi
Ceperley Mary E.
Fitzpatrick ,Cella, Harper & Scinto
Kyowa Medex Co., Ltd.
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