CA2363999A1 - Peptides of the at1 receptor and their use for preeclampsia and malign hypertension - Google Patents
Peptides of the at1 receptor and their use for preeclampsia and malign hypertension Download PDFInfo
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- CA2363999A1 CA2363999A1 CA002363999A CA2363999A CA2363999A1 CA 2363999 A1 CA2363999 A1 CA 2363999A1 CA 002363999 A CA002363999 A CA 002363999A CA 2363999 A CA2363999 A CA 2363999A CA 2363999 A1 CA2363999 A1 CA 2363999A1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70571—Receptors; Cell surface antigens; Cell surface determinants for neuromediators, e.g. serotonin receptor, dopamine receptor
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0008—Antigens related to auto-immune diseases; Preparations to induce self-tolerance
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/06—Antiabortive agents; Labour repressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
Abstract
The invention relates to peptides of the AT1 receptor and their use for eliminating specifically binding, cell-physiologically active, pathological antibodies in preeclampsia. The inventive peptides are further used for the diagnosis of preeclampsia. According to the invention, peptides having the sequence AFHYESQ, AVHYQSN, SHFYQTR, GYYFDTN or ENTNIT are preferred.
Description
r .
..
Peptides of the ATE receptor and their use in preeclarnpsia and malign hypertension The invention relates to peptides of the ATE receptor and their use and subsequent products in antigenic and immunogenic agents and test kits, in particular for the elimination of specifically binding, cell-physiologically active, pathological antibodies in preeclampsia and for their diagnostic proof. In addition, the invention relates to a process for the proof of anti-ATi receptor antibodies in biological fluids.
The immune system is an essential component part of all animal life. In mammals, it is particularly used as a defence of micro-organisms, for tissue regeneration and for destruction of tumour cells. In classical immunology, a distinction is made between a cellular and a humoral immune defence. This means two distinguishable systems which nevertheless cooperate with one another, all told portraying the immune sys-tem.
There exist a series of diseases which are termed as auto-immune diseases. In such diseases, the immune system in the persons involved frequently works against itself.
The predominantly cell-mediated auto-immune diseases include Multiple Sclerosis and Type I diabetes. A second groups is formed by the antibody-mediated auto-im-mune diseases. For example, this includes rheumatism or also the less frequent auto-immune diseases such as myasthenia gravis or lupus erymathematodes.
The pathogenesis of most auto-immune diseases is unknown. There are various hy-potheses and models of how to explain the origin of auto-immune diseases. For ex-ample, one explanatory model portrays the antigeniclmolecular mimicry. In this, it is presupposed that micro-organisms, e.g. viruses or parasites, equip themselves with certain molecules which are not recognised by the host's own immune system and avoid it. However, if they are recognised as being external and antibodies are in-duced and produced against them, these antibodies also recognise similar body-in-herent structures.
Part of the nature of auto-immune diseases and auto-antibodies is that they bind onto body-inherent cells and tissue. In this, either the cellular immune system and the complementary system are activated, thus triggering pathogenic reactions in the tissue in situ - e.g. chronic inflammations -, or there is a pathological dysfunction of the cells to which the auto-antibodies have bound.
~ - ' '' ' CA 02363999 2001-08-29 .. ,~ .
A classic example of this is dilatative cardiomyopathy. In this auto-immune disease, the organism incorrectly forms auto-antibodies which bind to a defined epitope of the f~1-adrenergenic receptor. These auto-antibodies generate an increase in the pulsa-tion rate in biological tests on rat cardiomyocytes in a cell culture (these cells have a practically identical f31-adrenergenic receptor on the surface). We speak of a phar-maco-active effect of the auto-antibodies, similar to that of adrenaline.
Dilative cardiomyopathy is an auto-immune disease which, if not treated, leads to major impairment of the cardiac output by reduction of the pumping performance with a simultaneous expansion of the heart muscle tissue by infiltrates. But if the an-tibodies are removed from the blood in the early stages of the disease by blood-washing, there is a regeneration of the heart muscle in the course of a year and a drastic improvement of the heart muscle performance, almost reaching the figures for healthy people again.
Apparently, the regeneration of the heart muscle can thus be initiated by the elimina-tion of the pathological antibodies from the blood's circulation - and that is all that happens in the removal of the overall immunoglobulin.
The situation in preeclampsia is similar.
Preeclampsia is a pregnancy-specific form of high pressure and is one of the most important causes of maternal mortality during pregnancy and in the course of birth.
Preeclampsia has even greater importance for the fate of the fruit, i.e. it is responsi-ble for prematurity, retardation of growth and perinatal mortality.
Although a great deal of knowledge has been obtained in the past few years, the causes of this clinical picture have yet to be clarified. The only causal therapy is premature termination of the pregnancy. However, if the symptoms of the disease occur at an early stage, i.e. particularly before the 20~" week of pregnancy, this is hardly compatible with a healthy survival of the child. On the other hand, each day of extension of a pregnancy can improve the child's chances of survival in this critical phase. The best preconditions for achieving this objective are provided by early rec-ognition (diagnosis) of the development of a preeclampsia and monitoring and treatment methods on this basis (immunoglobulin adsorption) Therefore, the task of the invention entailed finding substances which enable the proof of pathological antibodies in preeclampsia and malign hypertension and ' ~ ' '' ' CA 02363999 2001-08-29 provide corresponding systems therefor. A further task entails enabling the elimination of such antibodies from the blood.
The invention is implemented according to the claims, the sub-claims being pre-ferred variants.
The invention is based on first-time proof that patients with preeclampsia manifest specific antibodies against blood-pressure-effective angiotensin-ATE-receptors.
These antibodies did not occur in women with normal pregnancies, likewise not with pregnant women with chronic hypertension, i.e. hypertension independent of the pregnancy. The angiotensin-II-ATE-receptor antibodies observed lead to an activation of the ATE-receptor, which is probably also responsible for dangerous increases of blood pressure and an acute deterioration of the supply of blood to vital organs of mother and child.
In patients with this disease, an immunoglobulin fraction can be isolated from the ' plasma, containing auto-antibodies which bind onto the angiotensin-1 receptor and activate the cell via it. If peptides of the ATE receptor portraying the point of binding for the antibodies are added to the cell culture system - in vitro -, the pathological effect of the auto-antibodies can be annulled. Similar things are possible by using peptides with analog functions, preferably with the amino-acid sequence AFHYESQ, AVHYQSN, SHFYQTR, GYYFDTN or ENTNIT.
The surprising thing is that the same epitope structures eliminate the anti-bodies re-sponsible for the pathological effect from the blood plasma of the patients when they are bound to a solid phase.
An essential part of the invention is thus the provision of amino-acid sequences in the form of peptides which recognise, bind and eliminate the pathological auto-anti-bodies from the plasma of patients with preeclampsia.
Serum samples of patients with preeclampsia contain auto-antibodies which are directed against the angiotensin-II-ATE receptor sub-type. In a bioassay, these anti-bodies develop a positively chronotropic effect. This effect is inhibited like that of an-giotensin II by the sub-type-selective AT1 receptor blocker Losastan. Alpha and beta-adrenergenic antagonists and the AT2 receptor blocker PD 123319 had no influence.
, ' '. ' ' ' CA 02363999 2001-08-29 It was surprisingly established that the antibodies recognise an epitope on the sec-ond extra-cellular loop of the ATE receptor and that they can be neutralised and affin-ity-chromatographically cleaned with the help of peptides corresponding to this loop.
The epitope is characterised by the amino-acid sequence AFHYESQ. Further, func-tion-analog peptides with the amino-acid sequence AVHYQ~SN, SHFYQTR, GYYFDTN or ENTNIT are part of the scope of the invention.
Thus, the object of the invention is peptides containing the epitope of the AT1 re-ceptor binding physiologically active auto-antibodies, preferably comprising 5 to 10 amino-acids and their variants, which can form a epitope and bind auto-antibodies occurring in preeclampsia.
Peptides partly or totally containing SEQ ID no. 1 AFHYESQ are preferred.
The peptides are synthesised or produced in gene technology according to methods known per se by the set-up of the amino-acids.
Antibodies according to the invention aimed against the epitope of the ATE
receptor are characterised by the fact that they recognise these peptides. Preferably, they recognise the peptide of SEQ ID no. 1 or its variants. Further antibodies recognise the peptides with the amino-acid sequence AVHYQSN, SHFYQTR, GYYFDTN or ENTNIT. They are produced with methods known per se by immunisation of small mammals or immunisation of spleen cells in vitro with the peptides according to the invention.
The antibodies are used in various bio-assays, immunological detection systems and ELISA test systems.
Further, the invention relates to antigenic agents for detection of preeclampsia, con-taining at least one peptide according to the invention, preferably the peptide of SEQ
ID no. 1, or also peptides with the amino-acid sequence AVHYQSN, SHFYQTR, GYYFDTN or ENTNIT. They react with the specific antibodies against blood-pres-sure-effective angiotensin-ATE receptors occurring in preeclampsia. If need be, the antigenic agents are bound to various carriers, such as activated sepharose, cellu-lose or polystyrene carriers.
A further use of the peptides according to the invention entails immunogenic agents.
These contain at least one peptide, preferably the peptide of SEQ ID no. 1, or also r .
peptides with the amino-acid sequence AVHYQSN, SHFYQTR, GYYFDTN or ENTNIT, which induce the production of antibodies capable of recognising auto-anti-gens in preeclampsia.
In addition, a test kit for detection of anti-AT, receptor antibodies to prove pre-eclampsia is provided by the invention.
The test kit entails - at least one peptide according to the invention, if need be bound to a solid phase - a buffer - a specific conjugate plus enzyme - a washing solution - the substrate solution for detection of the enzyme reaction - and a stop solution The bio-assay entails - spontaneously pulsing neo-natal cardiomyocytes in primary culture or - cardiomyocytes differentiated from undifferentiated embryonal stem cells - in one culture medium Thanks to the development of the new test kits on the basis of the peptides accord-ing to the invention, the proof of preeclampsia and assessments of the sequence can be done quickly and simply.
The invention further relates to a process of detection of anti-ATE receptor antibodies in biological fluids. The sample to be examined is put into contact with at least one peptide according to the invention or with a combination of these peptides with a car-rier material under conditions permitting an antigen-antibody reaction.
Detection is then done by means of chemical or physical methods known per se.
The anti-ATE receptor antibodies were detected in all serums of patients with pre-eclampsia examined up to now. The antibodies appear after the 20t" week of preg-nancy and disappear relatively quickly after labour. The anti-ATE receptor antibodies were not detected in normal pregnancies or in pregnant sufferers from hypertension.
As the antibodies behave like the agonist angiotensin II in in vitro tests, these anti-bodies play a role in pathogenesis or preeclampsia. As they can be detected in all . ' '. ' ' ' CA 02363999 2001-08-29 preeclampsia serums examined, they are of importance as diagnostic markers.
Cultivated neo-natal rat heart cells were used as a bioassay. These cells develop a rhythmic spontaneous pulsation and react to an angiotensin-II stimulation with an in-crease of the beat frequency.
Detection of these AT, receptor antibodies according to the invention is used both for early recognition of preeclampsia and also as a basis for new therapeutic methods.
Thus, the object of the invention is also therapeutic agents against preeclampsia containing these peptides, as the removal of the angiotensin-ATE receptor antibodies from maternal blood (for example by means of specific or inspecific immuno-adsorp-tion) leads to an improvement of the clinical image or can at least prevent a progres-sion, which is connected with a reduction of the maternal risk and in particular with a distinct improvement of the chances of the child surviving.
The specific immunoglobulin adsorption is done on a column on which there are peptides in which at least the antibody-binding sequence AFHYESQ is contained (preferably containing the second extra-cellular loop of the ATE receptor or sequence I D no. 1 ).
The inspecific immunoglobulin adsorption is done on a column preferably containing sheep's or chicken's antibodies against the human immunoglobulin or protein A
or C1q.
With this adsorber, all the Ig of the blood plasma, also the auto-antibodies directed against the ATE receptor, are bound and eliminated, making use of a suitable appa-ratus known to experts.
The invention described with the example of preeclampsia can equally be used for some cases of malign hypertension in which an auto-antibody recognising the same epitope (the same sequence) is also found.
The invention is to be explained below in more detail with some examples of em-bodiments.
Fig. 1:
Effect of loops I - III of the ATE receptor on the cell-contracting activity of the auto-antibodies (contained in the y-globulin fraction isolated from the serum of preeclamp-sia patients) The Y-globulin fraction of the serum of preeclampsia patients increases the beat fre-quency of the heart muscle cells by 22 ~ x beats per minute (fictive). If the y-globulin fractions are pre-incubated with peptides portraying these parts of the ATE
receptor corresponding to loops I - III and the antibodies are subsequently added to the cell test system, the loop II peptides inhibit the antibody effect on the cells.
Fig. 2:
Epitope analysis of loop II of the ATE receptor - effect of amino-acid sequences from loop II on the auto-antibody-mediated cell stimulations The y-globulin fraction of the serum of preeclampsia patients increases the beat fre-quency of the heart muscle cells. The amino acid sequence AFHYESQ from loop II
inhibits the effect of the auto-antibodies, but not, on the other hand, the sequence areas from other parts of loop II.
. ' ' ' CA 02363999 2001-08-29 3. Bioassay to detect the antibodies To identify and characterise the ATE receptor antibodies, a sensitive bioassay was used. Spontaneously pulsing cardiomyocytes reacting to an angiotensin-II
stimula-tion with an increase of the beat frequency were used. This positively chronotropic effect was blocked by the selective antagonist Losartan. The incubation of these cells with the anti-ATE receptor auto-antibody also led to an increase of the pulsation rate, which was stopped by Losartan. Further, this agonistic effect was neutralised by a peptide corresponding to the second extra-cellular loop of the ATE
receptor.
In order to identify the epitopes of the auto-antibodies on the second extra-cellular loops of the angiotensin II ATE receptor, an attempt was made to neutralise the anti-AT~ receptor auto-antibodies with short overlapping peptides. It was seen that two epitopes existed on this extra-cellular loop of the ATE receptor of hypertension suffer-ers, these being in a position to annul the effect of the antibody. These were the epitopes ENTNIT and AFHYESQ. In preeclampsia patients, the agonistic effect of the antibodies achieved via the AT, receptor was only neutralised by the peptide AFHYESQ. This epitope has a special importance in this disease, as it was identified in all the patients examined. The function-analog peptides SHFYQTR and GYYFDTN were also in a position to neutralise the antibodies, Tab. I.
Tab. I Patients' antibodies, pre-treated with peptide Patient Antibody + Peptide No. 1:40 AFHYESQ SHFYQTR GYYFDTN
1 19.6~1.90 1.2~0.84 0.811.16 2.410.72 2 20.0~1.90 1.611.24 0.810.80 2.811.20
..
Peptides of the ATE receptor and their use in preeclarnpsia and malign hypertension The invention relates to peptides of the ATE receptor and their use and subsequent products in antigenic and immunogenic agents and test kits, in particular for the elimination of specifically binding, cell-physiologically active, pathological antibodies in preeclampsia and for their diagnostic proof. In addition, the invention relates to a process for the proof of anti-ATi receptor antibodies in biological fluids.
The immune system is an essential component part of all animal life. In mammals, it is particularly used as a defence of micro-organisms, for tissue regeneration and for destruction of tumour cells. In classical immunology, a distinction is made between a cellular and a humoral immune defence. This means two distinguishable systems which nevertheless cooperate with one another, all told portraying the immune sys-tem.
There exist a series of diseases which are termed as auto-immune diseases. In such diseases, the immune system in the persons involved frequently works against itself.
The predominantly cell-mediated auto-immune diseases include Multiple Sclerosis and Type I diabetes. A second groups is formed by the antibody-mediated auto-im-mune diseases. For example, this includes rheumatism or also the less frequent auto-immune diseases such as myasthenia gravis or lupus erymathematodes.
The pathogenesis of most auto-immune diseases is unknown. There are various hy-potheses and models of how to explain the origin of auto-immune diseases. For ex-ample, one explanatory model portrays the antigeniclmolecular mimicry. In this, it is presupposed that micro-organisms, e.g. viruses or parasites, equip themselves with certain molecules which are not recognised by the host's own immune system and avoid it. However, if they are recognised as being external and antibodies are in-duced and produced against them, these antibodies also recognise similar body-in-herent structures.
Part of the nature of auto-immune diseases and auto-antibodies is that they bind onto body-inherent cells and tissue. In this, either the cellular immune system and the complementary system are activated, thus triggering pathogenic reactions in the tissue in situ - e.g. chronic inflammations -, or there is a pathological dysfunction of the cells to which the auto-antibodies have bound.
~ - ' '' ' CA 02363999 2001-08-29 .. ,~ .
A classic example of this is dilatative cardiomyopathy. In this auto-immune disease, the organism incorrectly forms auto-antibodies which bind to a defined epitope of the f~1-adrenergenic receptor. These auto-antibodies generate an increase in the pulsa-tion rate in biological tests on rat cardiomyocytes in a cell culture (these cells have a practically identical f31-adrenergenic receptor on the surface). We speak of a phar-maco-active effect of the auto-antibodies, similar to that of adrenaline.
Dilative cardiomyopathy is an auto-immune disease which, if not treated, leads to major impairment of the cardiac output by reduction of the pumping performance with a simultaneous expansion of the heart muscle tissue by infiltrates. But if the an-tibodies are removed from the blood in the early stages of the disease by blood-washing, there is a regeneration of the heart muscle in the course of a year and a drastic improvement of the heart muscle performance, almost reaching the figures for healthy people again.
Apparently, the regeneration of the heart muscle can thus be initiated by the elimina-tion of the pathological antibodies from the blood's circulation - and that is all that happens in the removal of the overall immunoglobulin.
The situation in preeclampsia is similar.
Preeclampsia is a pregnancy-specific form of high pressure and is one of the most important causes of maternal mortality during pregnancy and in the course of birth.
Preeclampsia has even greater importance for the fate of the fruit, i.e. it is responsi-ble for prematurity, retardation of growth and perinatal mortality.
Although a great deal of knowledge has been obtained in the past few years, the causes of this clinical picture have yet to be clarified. The only causal therapy is premature termination of the pregnancy. However, if the symptoms of the disease occur at an early stage, i.e. particularly before the 20~" week of pregnancy, this is hardly compatible with a healthy survival of the child. On the other hand, each day of extension of a pregnancy can improve the child's chances of survival in this critical phase. The best preconditions for achieving this objective are provided by early rec-ognition (diagnosis) of the development of a preeclampsia and monitoring and treatment methods on this basis (immunoglobulin adsorption) Therefore, the task of the invention entailed finding substances which enable the proof of pathological antibodies in preeclampsia and malign hypertension and ' ~ ' '' ' CA 02363999 2001-08-29 provide corresponding systems therefor. A further task entails enabling the elimination of such antibodies from the blood.
The invention is implemented according to the claims, the sub-claims being pre-ferred variants.
The invention is based on first-time proof that patients with preeclampsia manifest specific antibodies against blood-pressure-effective angiotensin-ATE-receptors.
These antibodies did not occur in women with normal pregnancies, likewise not with pregnant women with chronic hypertension, i.e. hypertension independent of the pregnancy. The angiotensin-II-ATE-receptor antibodies observed lead to an activation of the ATE-receptor, which is probably also responsible for dangerous increases of blood pressure and an acute deterioration of the supply of blood to vital organs of mother and child.
In patients with this disease, an immunoglobulin fraction can be isolated from the ' plasma, containing auto-antibodies which bind onto the angiotensin-1 receptor and activate the cell via it. If peptides of the ATE receptor portraying the point of binding for the antibodies are added to the cell culture system - in vitro -, the pathological effect of the auto-antibodies can be annulled. Similar things are possible by using peptides with analog functions, preferably with the amino-acid sequence AFHYESQ, AVHYQSN, SHFYQTR, GYYFDTN or ENTNIT.
The surprising thing is that the same epitope structures eliminate the anti-bodies re-sponsible for the pathological effect from the blood plasma of the patients when they are bound to a solid phase.
An essential part of the invention is thus the provision of amino-acid sequences in the form of peptides which recognise, bind and eliminate the pathological auto-anti-bodies from the plasma of patients with preeclampsia.
Serum samples of patients with preeclampsia contain auto-antibodies which are directed against the angiotensin-II-ATE receptor sub-type. In a bioassay, these anti-bodies develop a positively chronotropic effect. This effect is inhibited like that of an-giotensin II by the sub-type-selective AT1 receptor blocker Losastan. Alpha and beta-adrenergenic antagonists and the AT2 receptor blocker PD 123319 had no influence.
, ' '. ' ' ' CA 02363999 2001-08-29 It was surprisingly established that the antibodies recognise an epitope on the sec-ond extra-cellular loop of the ATE receptor and that they can be neutralised and affin-ity-chromatographically cleaned with the help of peptides corresponding to this loop.
The epitope is characterised by the amino-acid sequence AFHYESQ. Further, func-tion-analog peptides with the amino-acid sequence AVHYQ~SN, SHFYQTR, GYYFDTN or ENTNIT are part of the scope of the invention.
Thus, the object of the invention is peptides containing the epitope of the AT1 re-ceptor binding physiologically active auto-antibodies, preferably comprising 5 to 10 amino-acids and their variants, which can form a epitope and bind auto-antibodies occurring in preeclampsia.
Peptides partly or totally containing SEQ ID no. 1 AFHYESQ are preferred.
The peptides are synthesised or produced in gene technology according to methods known per se by the set-up of the amino-acids.
Antibodies according to the invention aimed against the epitope of the ATE
receptor are characterised by the fact that they recognise these peptides. Preferably, they recognise the peptide of SEQ ID no. 1 or its variants. Further antibodies recognise the peptides with the amino-acid sequence AVHYQSN, SHFYQTR, GYYFDTN or ENTNIT. They are produced with methods known per se by immunisation of small mammals or immunisation of spleen cells in vitro with the peptides according to the invention.
The antibodies are used in various bio-assays, immunological detection systems and ELISA test systems.
Further, the invention relates to antigenic agents for detection of preeclampsia, con-taining at least one peptide according to the invention, preferably the peptide of SEQ
ID no. 1, or also peptides with the amino-acid sequence AVHYQSN, SHFYQTR, GYYFDTN or ENTNIT. They react with the specific antibodies against blood-pres-sure-effective angiotensin-ATE receptors occurring in preeclampsia. If need be, the antigenic agents are bound to various carriers, such as activated sepharose, cellu-lose or polystyrene carriers.
A further use of the peptides according to the invention entails immunogenic agents.
These contain at least one peptide, preferably the peptide of SEQ ID no. 1, or also r .
peptides with the amino-acid sequence AVHYQSN, SHFYQTR, GYYFDTN or ENTNIT, which induce the production of antibodies capable of recognising auto-anti-gens in preeclampsia.
In addition, a test kit for detection of anti-AT, receptor antibodies to prove pre-eclampsia is provided by the invention.
The test kit entails - at least one peptide according to the invention, if need be bound to a solid phase - a buffer - a specific conjugate plus enzyme - a washing solution - the substrate solution for detection of the enzyme reaction - and a stop solution The bio-assay entails - spontaneously pulsing neo-natal cardiomyocytes in primary culture or - cardiomyocytes differentiated from undifferentiated embryonal stem cells - in one culture medium Thanks to the development of the new test kits on the basis of the peptides accord-ing to the invention, the proof of preeclampsia and assessments of the sequence can be done quickly and simply.
The invention further relates to a process of detection of anti-ATE receptor antibodies in biological fluids. The sample to be examined is put into contact with at least one peptide according to the invention or with a combination of these peptides with a car-rier material under conditions permitting an antigen-antibody reaction.
Detection is then done by means of chemical or physical methods known per se.
The anti-ATE receptor antibodies were detected in all serums of patients with pre-eclampsia examined up to now. The antibodies appear after the 20t" week of preg-nancy and disappear relatively quickly after labour. The anti-ATE receptor antibodies were not detected in normal pregnancies or in pregnant sufferers from hypertension.
As the antibodies behave like the agonist angiotensin II in in vitro tests, these anti-bodies play a role in pathogenesis or preeclampsia. As they can be detected in all . ' '. ' ' ' CA 02363999 2001-08-29 preeclampsia serums examined, they are of importance as diagnostic markers.
Cultivated neo-natal rat heart cells were used as a bioassay. These cells develop a rhythmic spontaneous pulsation and react to an angiotensin-II stimulation with an in-crease of the beat frequency.
Detection of these AT, receptor antibodies according to the invention is used both for early recognition of preeclampsia and also as a basis for new therapeutic methods.
Thus, the object of the invention is also therapeutic agents against preeclampsia containing these peptides, as the removal of the angiotensin-ATE receptor antibodies from maternal blood (for example by means of specific or inspecific immuno-adsorp-tion) leads to an improvement of the clinical image or can at least prevent a progres-sion, which is connected with a reduction of the maternal risk and in particular with a distinct improvement of the chances of the child surviving.
The specific immunoglobulin adsorption is done on a column on which there are peptides in which at least the antibody-binding sequence AFHYESQ is contained (preferably containing the second extra-cellular loop of the ATE receptor or sequence I D no. 1 ).
The inspecific immunoglobulin adsorption is done on a column preferably containing sheep's or chicken's antibodies against the human immunoglobulin or protein A
or C1q.
With this adsorber, all the Ig of the blood plasma, also the auto-antibodies directed against the ATE receptor, are bound and eliminated, making use of a suitable appa-ratus known to experts.
The invention described with the example of preeclampsia can equally be used for some cases of malign hypertension in which an auto-antibody recognising the same epitope (the same sequence) is also found.
The invention is to be explained below in more detail with some examples of em-bodiments.
Fig. 1:
Effect of loops I - III of the ATE receptor on the cell-contracting activity of the auto-antibodies (contained in the y-globulin fraction isolated from the serum of preeclamp-sia patients) The Y-globulin fraction of the serum of preeclampsia patients increases the beat fre-quency of the heart muscle cells by 22 ~ x beats per minute (fictive). If the y-globulin fractions are pre-incubated with peptides portraying these parts of the ATE
receptor corresponding to loops I - III and the antibodies are subsequently added to the cell test system, the loop II peptides inhibit the antibody effect on the cells.
Fig. 2:
Epitope analysis of loop II of the ATE receptor - effect of amino-acid sequences from loop II on the auto-antibody-mediated cell stimulations The y-globulin fraction of the serum of preeclampsia patients increases the beat fre-quency of the heart muscle cells. The amino acid sequence AFHYESQ from loop II
inhibits the effect of the auto-antibodies, but not, on the other hand, the sequence areas from other parts of loop II.
. ' ' ' CA 02363999 2001-08-29 3. Bioassay to detect the antibodies To identify and characterise the ATE receptor antibodies, a sensitive bioassay was used. Spontaneously pulsing cardiomyocytes reacting to an angiotensin-II
stimula-tion with an increase of the beat frequency were used. This positively chronotropic effect was blocked by the selective antagonist Losartan. The incubation of these cells with the anti-ATE receptor auto-antibody also led to an increase of the pulsation rate, which was stopped by Losartan. Further, this agonistic effect was neutralised by a peptide corresponding to the second extra-cellular loop of the ATE
receptor.
In order to identify the epitopes of the auto-antibodies on the second extra-cellular loops of the angiotensin II ATE receptor, an attempt was made to neutralise the anti-AT~ receptor auto-antibodies with short overlapping peptides. It was seen that two epitopes existed on this extra-cellular loop of the ATE receptor of hypertension suffer-ers, these being in a position to annul the effect of the antibody. These were the epitopes ENTNIT and AFHYESQ. In preeclampsia patients, the agonistic effect of the antibodies achieved via the AT, receptor was only neutralised by the peptide AFHYESQ. This epitope has a special importance in this disease, as it was identified in all the patients examined. The function-analog peptides SHFYQTR and GYYFDTN were also in a position to neutralise the antibodies, Tab. I.
Tab. I Patients' antibodies, pre-treated with peptide Patient Antibody + Peptide No. 1:40 AFHYESQ SHFYQTR GYYFDTN
1 19.6~1.90 1.2~0.84 0.811.16 2.410.72 2 20.0~1.90 1.611.24 0.810.80 2.811.20
Claims (19)
1. Peptides of the ATE receptor, preferably comprising 5 to 30, preferably 5 to amino acids as well as their variants, which can form an epitope and bind auto-antibodies occurring in preeclampsia and malign hypertension.
2. Peptides according to Claim 1, wherein they comprise SEQ ID no. 1 AFHYESQ or contain this sequence in an identical or slightly modified form.
3. Peptides according to Claim 1, wherein they are comprise at least one of the amino acid sequences AVHYQSN, SHFYQTR, GYYFDTN or ENTNIT or contain at least one of these sequences in an identical or slightly modified form.
4. Antibodies aimed against the epitope of the ATE receptor, wherein they recognise the peptides according to Claims 1 to 3.
5. Antibodies according to Claim 4, wherein they recognise the peptides of SEQ ID no. 1 or peptides with the amino acid sequence AVHYQSN, SHFYQTR, GYYFDTN or ENTNIT.
6. Use of the human ATE receptor, preferably of the peptides according to Claims 1 to 3, for the production of agents for diagnostic and therapeutic purposes in diseases with a positive antibody status, in particular preeclampsia.
7. Use according to Claim 6, wherein auto-antibody binding peptides according to Claims 1 to 3 are used.
8. Use according to Claims 6 and 7, wherein recombinantly produced, auto-antibody binding receptor parts of the ATE receptor as well as of the peptides according to Claims 1 to 3 are used.
9. Use according to Claims 6 to 8, wherein peptides according to Claims 1 to 3 and/or molecules containing these peptides are used soluble or bound to a solid phase for direct or indirect (competitive) detection of antibodies in body fluids, in particular blood.
10. Use according to Claims 6 to 9, wherein peptides according to Claims 1 to and/or molecules containing these peptides are used bound to a solid phase for binding and elimination of the pathological, functionally active auto-antibodies in body fluids, in particular blood, i.e. for immunoglobulin adsorption.
11. Use according to Claims 6 to 10, wherein the amino acid sequences and/or molecules containing these sequences are used bound to a solid phase for binding and elimination of the pathological, functionally active auto-antibodies in body fluids, in particular blood, i.e. for immunoglobulin adsorption in combination with unspecific (overall immunoglobulin binding ligands).
12. Binding and elimination of the pathological, functionally active auto-antibodies according to Claims 4 and 5 in body fluids, in particular blood, by use of inspecific adsorber molecules such as protein A, protein G, anti-human immunoglobulin as well as overall immunoglobulin binding ligands such as amino acids, in particular L-tryptophane or peptides.
13. Use of peptides at least containing at least one of the amino acid sequences according to Claims 1 to 3 for the immunisation of mammals for the purpose of obtaining polyclonal and monoclonal antibodies.
14. Use of antibodies aimed against the amino acid sequences according to Claims 1 to 3 for immunisation of mammals for the purpose of obtaining anti-idiotypical antibodies.
15. Antigenic agent for detection of preeclampsia and malign hypertension, wherein it contains at least one peptide according to Claims 1 to 3, preferably SEQ ID no.1.
16. Immunogenic agent, wherein it contains at least one peptide according to Claims 1 to 3, preferably SEQ ID no. 1, which induces the production of antibodies capable of recognising auto-antigens in preeclampsia or malign hypertension.
17. Test kit to determine anti-AT1 receptor antibodies for proof of preeclampsia or malign hypertension, containing at least one peptide according to Claims 1 to 3.
18. Method to detect anti-AT1 receptor antibodies in biological fluids, wherein the sample to be examined is brought into contact with at least one peptide of Claims 1 to 3 or with a combination of these peptides with a carrier material under conditions permitting an antigen-antibody reaction and rendering proof by means of physical or chemical methods known per se.
19. Use of the peptides according to Claims 1 to 3 for production of therapeutic agents against preeclampsia or malign hypertension.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19860320 | 1998-12-24 | ||
| DE19954305A DE19954305A1 (en) | 1998-12-24 | 1999-11-11 | Peptides of the AT¶1¶ receptor and their use, in particular for the diagnosis of preeclampsia |
| DE19954305.4 | 1999-11-11 | ||
| DE19860320.7 | 1999-11-11 | ||
| PCT/DE1999/004112 WO2000039154A2 (en) | 1998-12-24 | 1999-12-22 | Peptides of the at1 receptor and their use for preeclampsia and malign hypertension |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2363999A1 true CA2363999A1 (en) | 2000-07-06 |
Family
ID=26051071
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002363999A Abandoned CA2363999A1 (en) | 1998-12-24 | 1999-12-22 | Peptides of the at1 receptor and their use for preeclampsia and malign hypertension |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1141018A2 (en) |
| JP (1) | JP2002539075A (en) |
| AU (1) | AU2429100A (en) |
| CA (1) | CA2363999A1 (en) |
| WO (1) | WO2000039154A2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8110374B2 (en) | 2001-05-11 | 2012-02-07 | Cell Trend GmbH | Method for predicting the risk of transplant rejection and immunological testkit |
| US8425877B2 (en) | 2006-08-04 | 2013-04-23 | Celltrend Gmbh | Method for diagnosis of systemic sclerosis involving an anti-AT1-receptor antibody |
| CN109467599A (en) * | 2017-09-08 | 2019-03-15 | 武汉华纪元生物技术开发有限公司 | Small peptide ATR001 and the monoclonal antibody and application that by small peptide preparation there is skewed popularity to adjust AT1R function |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2314811A1 (en) * | 2000-08-02 | 2002-02-02 | Brian Archibald Macvicar | Autoimmunity to angiotensin at1 receptors in schizophrenia |
| DE10327066A1 (en) * | 2002-11-29 | 2004-09-16 | Max-Delbrück-Centrum für Molekulare Medizin | Determination of agonistic autoantibodies |
| US7741050B2 (en) | 2002-11-29 | 2010-06-22 | Max-Delbrueck-Centrum fuer Molkulare Medizin | Identification of agonistic autoantibodies |
| EP1884776A1 (en) | 2006-08-04 | 2008-02-06 | Celltrend GmbH | Method for diagnosis of a disease involving an anti-endothelin-receptor antibody |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU6770794A (en) * | 1993-04-23 | 1994-11-21 | Herbert J. Evans | Polypeptides that include conformation-constraining groups which flank a protein-protein interaction site |
| DE19826442A1 (en) * | 1998-06-02 | 1999-12-09 | Affina Immuntechnik Gmbh | Rationally designed peptides, their production and their use |
-
1999
- 1999-12-22 EP EP99967916A patent/EP1141018A2/en not_active Withdrawn
- 1999-12-22 AU AU24291/00A patent/AU2429100A/en not_active Abandoned
- 1999-12-22 CA CA002363999A patent/CA2363999A1/en not_active Abandoned
- 1999-12-22 JP JP2000591065A patent/JP2002539075A/en active Pending
- 1999-12-22 WO PCT/DE1999/004112 patent/WO2000039154A2/en active Application Filing
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8110374B2 (en) | 2001-05-11 | 2012-02-07 | Cell Trend GmbH | Method for predicting the risk of transplant rejection and immunological testkit |
| US8425877B2 (en) | 2006-08-04 | 2013-04-23 | Celltrend Gmbh | Method for diagnosis of systemic sclerosis involving an anti-AT1-receptor antibody |
| CN109467599A (en) * | 2017-09-08 | 2019-03-15 | 武汉华纪元生物技术开发有限公司 | Small peptide ATR001 and the monoclonal antibody and application that by small peptide preparation there is skewed popularity to adjust AT1R function |
| CN109467599B (en) * | 2017-09-08 | 2021-06-04 | 武汉华纪元生物技术开发有限公司 | Short peptide ATR001, monoclonal antibody prepared from short peptide and having function of preferentially regulating AT1R, and application of monoclonal antibody |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2429100A (en) | 2000-07-31 |
| EP1141018A2 (en) | 2001-10-10 |
| WO2000039154A2 (en) | 2000-07-06 |
| WO2000039154A8 (en) | 2001-02-15 |
| JP2002539075A (en) | 2002-11-19 |
| WO2000039154A3 (en) | 2000-09-21 |
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