US20110165596A1 - Use of Carbamoyl Phosphate Synthetase 1 (Cps) as a Humoral Biomarker For the Diagnosis of Tumour Diseases and Chronic Inflammatory Intestinal Diseases - Google Patents

Use of Carbamoyl Phosphate Synthetase 1 (Cps) as a Humoral Biomarker For the Diagnosis of Tumour Diseases and Chronic Inflammatory Intestinal Diseases Download PDF

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US20110165596A1
US20110165596A1 US11/575,603 US57560305A US2011165596A1 US 20110165596 A1 US20110165596 A1 US 20110165596A1 US 57560305 A US57560305 A US 57560305A US 2011165596 A1 US2011165596 A1 US 2011165596A1
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cps
tumour
diseases
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patients
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Andreas Bergmann
Joachim Struck
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BRAHMS GmbH
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • G01N33/57488—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds identifable in body fluids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
    • C12Q1/42—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase involving phosphatase
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/573—Immunoassay; Biospecific binding assay; Materials therefor for enzymes or isoenzymes

Definitions

  • the present invention relates to novel uses of the enzyme carbamoyl phosphate synthetase 1 (E.C. 6.3.4.16, always abbreviated below to CPS 1) and/or physiologically occurring CPS 1 fragments having CPS 1 immunoreactivity as a humoral biomarker for medical diagnosis for the detection of tumour diseases (as a humoral tumour marker), i.e.
  • tumour diseases for the diagnosis of tumour diseases, and for the detection and for the progress monitoring of chronic inflammatory intestinal diseases (Crohn's disease; Colitis ulcerosa), by detection of CPS 1 or CPS 1 immunoreactivity in the circulation, in particular in serum or plasma of patients on whom a routine examination to the possible presence of tumours/chronic inflammatory intestinal diseases is carried out, for whom there are grounds for suspecting tumours or chronic inflammatory intestinal diseases or in whom a tumour or a chronic inflammatory intestinal disease has already been detected and who are being monitored or subjected to a treatment.
  • CPS 1 or CPS 1 immunoreactivity in the circulation in particular in serum or plasma of patients on whom a routine examination to the possible presence of tumours/chronic inflammatory intestinal diseases is carried out, for whom there are grounds for suspecting tumours or chronic inflammatory intestinal diseases or in whom a tumour or a chronic inflammatory intestinal disease has already been detected and who are being monitored or subjected to a treatment.
  • tumour is used as an overall term or synonym for neoplasms, in particular malignant neoplasms, as are typical of cancer diseases (carcinomas).
  • malignant tumours i.e. cancer
  • Malignant tumours may occur in virtually any tissue or organ, and, depending on the organ affected, a distinction is made between numerous cancer diseases which may differ considerably from one another with regard to their statistical frequency, prognosis and treatability.
  • Chronic inflammatory intestinal diseases i.e. substantially Crohn's disease (also, Enteritis regionalis; abbreviated to C.D. in this Application) and Colitis ulcerosa (abbreviated to C.U. in this Application), which are intermittent chronic severe diseases with an aetiology not yet definitively explained, are closely related to tumour diagnosis in that it is known that these diseases exhibit malignant degeneration with a high percentage probability and lead to intestinal cancer.
  • tumour markers are determined in biological samples, in particular blood samples and body secretions, of patients examined. Tumour markers are substances which either are formed directly by malignant tumour cells or form as a result of tumour cells inducing the synthesis of the respective marker in non-tumour cells. Because tumour markers are detected in elevated concentration in fluid biological samples (humoral tumour markers) or locally in tissue (cellular tumour markers), they permit, depending on the given circumstances of the individual case, early diagnosis of malignant tumours in risk groups, they are used for primary tumour diagnosis and they permit prognosis and/or monitoring of a tumour treatment and optionally early diagnosis of recurrence of a tumour.
  • tumour is used as an overall term for all more special potential uses (indications) mentioned.
  • An overview of the tumour markers currently used in clinical diagnosis is to be found in Lothar Thomas (editor), Labor und Diagnose, 5th extended edition, section 34, cf. in particular overview 34.1 “Maligne aen [Malignant Diseases]/” on pages 956-961, and the articles on individual clinically used tumour markers under 34.2-34.17 on pages 916-1019.
  • tumour markers determined at present Common to all tumour markers determined at present is that the sensitivity of their determination is relatively limited and they have a relatively high organ specificity.
  • the relatively high organ specificity of tumour markers determined at present has on the one hand the advantage that their detection simultaneously provides information about the organ in which the causative cancer disease has occurred with high probability.
  • a high specificity is a disadvantage in that cancer diseases of other organs are not diagnosable in the determination of organ-specific tumour markers or the simultaneous determination of numerous different tumour markers is required for comprehensive early cancer diagnosis.
  • tumour markers in the case of a high sensitivity of a determination, most or all patients are correctly diagnosed, which is between 20 and 80% depending on cancer disease and tumour marker, results in the danger of non-diagnosis of cancer diseases still being very high in spite of the determination of the tumour markers suitable per se for this purpose.
  • the present invention relates to the identification of a humoral biomarker which can serve as a novel humoral tumour marker and a novel biomarker for chronic inflammatory intestinal diseases, and all possible uses arising from its identification in the area of tumour diagnosis and the diagnosis of chronic inflammatory intestinal diseases.
  • the Claims are intended to provide protection under patent law for these uses or in vitro diagnosis methods with determination of the novel humoral tumour marker or humoral biomarker for chronic inflammatory intestinal diseases.
  • the present invention is based on the surprising finding that substantially elevated concentrations of the enzyme carbamoyl phosphate synthetase 1 (CPS 1) or strong CPS 1 immunoreactivity were detectable with in some cases outstanding sensitivity in the circulation, i.e. in particular in plasmas or sera, of patients in whom clinically different tumours, in particular of internal organs or soft tissues, had been identified, and of patients with C.D or C.U., in clear contrast to healthy control persons, which makes CPS 1 or CPS 1 immunoreactivity a novel humoral tumour marker or biomarker for chronic inflammatory intestinal diseases.
  • CPS 1 or CPS 1 immunoreactivity a novel humoral tumour marker or biomarker for chronic inflammatory intestinal diseases.
  • C.D chronic inflammatory intestinal diseases
  • CPS 1 has as yet never been discussed as a possible humoral tumour marker.
  • the enzyme CPS 1 (E.C. 6.3.4.16) itself has, however, long been well known. It catalyzes the conversion of ammonia, bicarbonate and 2 ATP with formation of carbamoyl phosphate in the first step of the urea cycle. It also plays a role in the biosynthesis of arginine, which in turn is a substrate for the biosynthesis of NO, e.g. in the case of an endotoxin shock (c.f. Shoko Tabuchi et al., Regulation of Genes for Inducible Nitric Oxide Synthase and Urea Cycle Enzymes in Rat Liver in Endotoxin Shock, Biochemical and Biophysical Research Communications 268, 221-224 (2000)).
  • endotoxin shock c.f. Shoko Tabuchi et al., Regulation of Genes for Inducible Nitric Oxide Synthase and Urea Cycle Enzymes in Rat Liver in Endotoxin Shock, Biochemical and Biophysical Research Communications 268, 221-224
  • CPS 1 should be distinguished from the cytosolic enzyme CPS 2 (E.C. 2.7.2.5.), which likewise plays a role in the urea cycle but processes the substrate glutamine. It is known that CPS 1 is localized in mitochondria and occurs in this form in large amounts in liver tissue (it accounts for 2-6% of total liver protein). Its amino acid sequence and genetic localization have long been known (c.f. Haraguchi Y. et al., Cloning and sequence of a cDNA encoding human carbamyl phosphate synthetase I: molecular analysis of hyperammonemia, Gene 1991, Nov. 1; 107 (2); 335-340; cf. also the publication WO 03/089933 A1 of the Applicant).
  • CPS 1 fragments having molar masses of about 140 and 125 kDa were also increasingly detectable during the acute hepatitis, without other more detailed characterization (sequence assignment), whereas no CPS 1 fragments with CPS 1 immunoreactivity could be observed in human autopsy samples in an accompanying immunoblotting analysis (Mikiko Ozaki et al., loc. cit.).
  • CPS 1 has been determined only in serum or plasma of sepsis patients, and also only in investigations by the Applicant (cf. WO 03/089933 A1).
  • Sepsis patients whose highly acute potentially life-threatening disease is typically monitored and treated in intensive care wards represent a patient population which clearly differs from tumour patients, tumour risk patients or patients with chronic inflammatory intestinal diseases, i.e. patients who are suffering from a disease developing over long periods or chronic disease.
  • CPS 1 or CPS 1 immunoreactivity as a humoral biomarker/tumour marker in patient sera according to the present invention
  • the assay method which is described in the experimental section of the present Application and which was used for the testing of sera or plasmas of tumour patients for the presence of CPS 1 or CPS 1 immunoreactivity is the same method as that already described in the above-mentioned Application WO 03/089933 A1 of the Applicant.
  • use is to be regarded as not only the direct immunological determination of CPS 1 in in vitro samples in tumour diagnosis and diagnosis of chronic inflammatory intestinal diseases but also a use of CPS 1 or CPS 1 fragments, or of antibodies to the selective determination thereof, for the preparation of assay kits, or a use for the production of assay components, e.g. of polyclonal or monoclonal antibodies which are provided, for example, in immobilized and/or marked form, as a rule likewise in assay kits for said diseases, or of standard and reference substances.
  • CPS 1 or CPS 1 immunoreactivity it should be possible, for diagnostic purposes, optionally also to effect the CPS 1 determination indirectly as a determination of an enzyme activity which corresponds to the CPS 1 activity or the residual activity of the CPS 1 fragments in the blood. Since CPS 1 in healthy persons does not occur in the circulation, a measurable CPS 1 enzyme activity in the blood of a patient may be a diagnostically significant indication of a serious disturbance of the unimpaired health of the patient. It should also be pointed out here that the activity of an enzyme which is normally localized in the interior of the cell and displays its proper function only there is to be rated as negative per se in the circulation and as such can therefore also contribute to a worsening of the condition.
  • CPS 1 and CPS 1 immunoreactivity detectable in plasma and serum are suitable, on the basis of the results described below, as specific marker peptides (tumour markers) for the diagnosis of tumours (neoplasms) and for the detection and for the monitoring of progress and treatment of C.D. or C.U.
  • CPS 1 and/or CPS 1 fragments are furthermore intended to carry out the determination of CPS 1 and/or CPS 1 fragments as prognosis markers and markers for the monitoring of the progress of tumour diseases as part of a combination measurement with other markers.
  • the actual CPS 1 determination can be effected in any suitable manner known per se, immunoassays of a suitable assay design being preferred.
  • the method for determining CPS 1-immunoreactivity in a biological sample may be any desired known methods of immunodiagnosis which are used for the detection and for the measurement of antigens.
  • CPS 1 is determined with the aid of a ligand binding assay in which specific antibodies suitable for binding and marking are used in immobilized form or marked or markable form.
  • the assay method can be adapted to chip technology or can be designed as an accelerated test (point-of-care test).
  • the immunodiagnostic determination is carried out as a heterogeneous sandwich immunoassay in which one of the antibodies is immobilized on any desired solid phase, for example the walls of coated test tubes (e.g. of polystyrene; “coated tubes”; CT) or on microtitre plates, for example of polystyrene, or on particles, for example magnetic particles, while the other antibody carries a residue which represents a directly detectable label or permits a selective link to a label and serves for the detection of the sandwich structures formed. Delayed or subsequent immobilization with the use of suitable solid phases is also possible.
  • coated test tubes e.g. of polystyrene; “coated tubes”; CT
  • microtitre plates for example of polystyrene
  • particles for example magnetic particles
  • marking techniques which can be used in assays of the described type and which comprise markings with radio isotopes, enzymes or fluorescent, chemiluminescent or bioluminescent labels and directly optically detectable colour markings, such as, for example, gold atoms and dye particles, as used in particular for so-called point-of-care (POC) or accelerated tests.
  • the two antibodies may also have parts of a detection system of the type described below in relation to homogeneous assays.
  • the method according to the invention can furthermore be designed as a homogeneous method in which the sandwich complex formed from the two antibodies and the CPS 1 to be detected remain suspended in the liquid phase.
  • it is preferably to mark both antibodies with parts of a detection system, which permits signal generation or signal triggering when both antibodies are integrated into a single sandwich.
  • detection techniques can be designed in particular as fluorescence amplification or fluorescence extinction detection methods.
  • a particularly preferred method of this type relates to the use of detection reagents to be used in pairs, as described, for example, in U.S. Pat. No. 4,822,733, EP-B1-180 492 or EP-B1-539 477 and the prior art cited therein.
  • FIG. 1 shows the results of the measurement of the CPS 1 immunoreactivity in plasmas of healthy normal persons and of patients with various, clinically diagnosed tumour diseases indicated in the figure by the immunoassay described in more detail in the experimental section, the dashed line indicating the lower limit of detection of the test (0.5 ng/ml).
  • FIG. 2 shows corresponding results in plasmas of patients who are suffering from an acute episode of their chronic inflammatory intestinal disease (C.D. or C.U.).
  • Peptide PCEN17 CEFEGQPVDFVDPNKQN SEQ ID NO: 1
  • Peptide PCVD14 CVPWNHDFTKMEYD SEQ ID NO: 2
  • Recombinant standard material was obtained from InVivo GmbH (Henningsdorf, Germany). This was a crude cell extract of an E. coli strain which expressed the recombinant N-terminal region of human CPS 1, supplemented by an N-terminal strip of strep tag. An arbitrary concentration of CPS 1 was attributed to the extract.
  • the peptide-specific antibodies were prepared in a 1-step method from the antisera which had been obtained beginning with the fourth month after immunisation.
  • the peptides PCEN17 and PCVD14 were first coupled with Sulfo-Link gel (cf. operating procedure “SulfoLink Kit” from PIERCE, Rockford, Ill., USA). In each case 5 mg of peptide were offered per 5 ml of gel for coupling.
  • the peptide columns were first washed three times alternately with 10 ml each of elution buffer (50 mM citric acid, pH 2.2) and binding buffer (100 mM sodium phosphate, 0.1% Tween, pH 6.8). 100 ml of the antisera were filtered over 0.2 ⁇ m and the column material present was added. For this purpose, the gel was quantitatively rinsed with 10 ml of binding buffer from the column. The incubation was effected overnight at room temperature with tilting. The batches were transferred quantitatively into empty columns (NAP 25, Pharmacia, emptied). The run-throughs were discarded. Washing was then carried out with 250 ml of binding buffer until protein-free (protein content of the wash eluate ⁇ 0.02 A280 nm).
  • Elution buffer was added to the washed columns, and 1 ml fractions were collected.
  • the protein content of each fraction was determined by means of the BCA method (cf. operating procedure of PIERCE, Rockford, Ill., USA). Fractions having protein concentrations>0.8 mg/ml were pooled. Protein determination of the pools by means of the BCA method gave yields of 27 mg for the anti-PCEN17 antibody and 33 mg for the anti-PCVD14 antibody.
  • chemiluminescence marking of the antibody 10 ⁇ l of MA70 acridinium NHS ester (1 mg/ml; from HOECHST Behring) were added to 67 ⁇ l of the antibody solution and incubation was effected for 15 minutes at room temperature. 423 ⁇ l of 1 M glycine were then added and incubation was effected for a further 10 minutes. Thereafter, the marking batch was rebuffered via an NAP-5 gel filtration column (Pharmacia) with 1 ml of mobile phase A (50 mM potassium phosphate, 100 mM NaCl, pH 7.4) according to the operating procedure and was freed from low molecular weight constituents.
  • mobile phase A 50 mM potassium phosphate, 100 mM NaCl, pH 7.4
  • a gel filtration HPLC was carried out for separating off final residues of labels not bound to antibodies (column: Waters Protein Pak SW300).
  • the sample was applied and was chromatographed at a flow rate of 1 ml/min with mobile phase A.
  • the wavelengths 280 nm and 368 nm were measured using a flow photometer.
  • the absorption ratio 368 nm/280 nm as a measure of the degree of marking of the antibody was 0.10 at the peak.
  • the monomeric fractions containing antibodies (retention time 8-10 min) were collected and were collected in 3 ml of 100 mM sodium phosphate, 150 mM NaCl, 5% bovine serum albumin, 0.1% sodium azide, pH 7.4.
  • Irradiated 5 ml polystyrene tubes (from Greiner) were coated with purified anti-PCVD14 antibody as follows: the antibody was diluted in 50 mM Tris, 100 mM NaCl, pH 7.8 to a concentration of 6.6 ⁇ g/ml. 300 ⁇ l of solution were pipetted into each cube. The tubes were incubated for 20 hours at 22° C. The solution was filtered with suction. Each tube was then filled with 4.2 ml of 10 mM sodium phosphate, 2% Karion FP, 0.3% bovine serum albumin, pH 6.5. After 20 hours, the solution was filtered with suction. Finally, the tubes were dried in a vacuum dryer.
  • the standard material used was recombinant human CPS 1 expressed in E. coli , in the form of a crude E. coli extract, containing the total soluble intracellular protein. This extract was diluted serially in horse normal serum (from SIGMA). Arbitrary concentrations were attributed to the standards thus prepared, according to their dilution.
  • Test sera used for the CPS 1 determinations were firstly 557 plasmas of various patients with clinically diagnosed tumours of various organs/tissues. For each test plasma there existed exact clinical documentation which permitted an itemisation of the patient plasmas used in the measurement according to the tumour type found in them.
  • FIG. 1 94 plasmas of patients with cancer of the large intestine (in FIG. 1 : Colon-Ca), 97 plasmas of patients with liver cancer (Liver-Ca), 26 plasmas of patients with kidney cancer (Kidney-Ca), 152 plasmas of patients with pancreatic cancer (Pancreas-Ca), 48 plasmas of patients with lung cancer (Lung-Ca) and 140 plasmas of patients with breast cancer (Breast-Ca).
  • Control sera used were 128 sera of apparently healthy persons.
  • washing was then effected 4 times with 1 ml of wash solution (0.1% Tween 20) per tube each time, the tubes were allowed to drip and the chemiluminescence bound to the tube was measured in a luminometer (from BERTHOLD, LB952T; base reagents from BRAHMS AG).
  • the concentration of CPS 1 immunoreactivity was read using the MultiCalc (spline fit) software.
  • the results for tumour patients are shown in FIG. 1 and the results for patients with chronic inflammatory intestinal diseases (C.D.; C.U.) are shown in FIG. 2 .
  • C.D.; C.U. chronic inflammatory intestinal diseases
  • FIG. 2 a clear difference is found between healthy persons, in whom no concentrations of CPS 1 above the limit of detection (0.5 ng/ml) were found, and patients, the sensitivity of the detection of CPS 1 being entirely different for different tumour types.
  • CPS 1 inhibitors include in particular Ca ions and other metal ions and substances of the steroid type. They furthermore include antibodies or other specific binders which, as CPS 1 inhibitors, can eliminate or reduce the activity of CPS 1 in the circulation by binding to CPS 1.
  • CPS 1 inhibitors are administered to patients in whom CPS 1 is detectable in the blood is a means of therapeutically influencing the pathological process and significantly improving the condition and/or the wellbeing of a cancer patient.
  • a further teaching based on the fundamental discoveries of the present invention is therefore to provide CPS 1 inhibitors as active constituents of therapeutic agents which are intended for the treatment of cancer patients and of patients who are suffering from an acute episode of C.D. or C.U.

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DE102004045705A DE102004045705A1 (de) 2004-09-21 2004-09-21 Verwendungen der Carbamoylphosphat Synthetase 1(CPS) als humoraler Biomarker für die Diagnose von Tumorerkrankungen und chronisch entzündlichen Darmerkrankungen
DE102004045705.0 2004-09-21
PCT/EP2005/009827 WO2006032392A2 (de) 2004-09-21 2005-09-13 Verwendungen der carbamoylphosphat sythetase 1 (cps 1) als humoraler biomarker für die diagnose von tumorerkrankungen und chronisch entzündlichen darmerkrankungen

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US10260111B1 (en) 2014-01-20 2019-04-16 Brett Eric Etchebarne Method of detecting sepsis-related microorganisms and detecting antibiotic-resistant sepsis-related microorganisms in a fluid sample

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US8426180B2 (en) 2013-04-23
WO2006032392A3 (de) 2006-09-08
US20120077208A1 (en) 2012-03-29
JP2008513744A (ja) 2008-05-01
EP1792186A2 (de) 2007-06-06
EP1792186B1 (de) 2009-07-15
DE102004045705A1 (de) 2006-04-06
JP4795353B2 (ja) 2011-10-19
DE502005007715D1 (de) 2009-08-27

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