EP0553301A1 - Procedes de detection et de suivi de l'evolution d'un cancer, de la grossesse ou d'une maladie trophoblastique - Google Patents

Procedes de detection et de suivi de l'evolution d'un cancer, de la grossesse ou d'une maladie trophoblastique

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Publication number
EP0553301A1
EP0553301A1 EP19920902062 EP92902062A EP0553301A1 EP 0553301 A1 EP0553301 A1 EP 0553301A1 EP 19920902062 EP19920902062 EP 19920902062 EP 92902062 A EP92902062 A EP 92902062A EP 0553301 A1 EP0553301 A1 EP 0553301A1
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EP
European Patent Office
Prior art keywords
cancer
serum
whole blood
component
peptide complex
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP19920902062
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German (de)
English (en)
Inventor
Laurence A. Cole
Andrew Kardana
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Yale University
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Yale University
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Publication date
Application filed by Yale University filed Critical Yale University
Publication of EP0553301A1 publication Critical patent/EP0553301A1/fr
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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
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • G01N33/76—Human chorionic gonadotropin including luteinising hormone, follicle stimulating hormone, thyroid stimulating hormone or their receptors
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/575—Hormones
    • G01N2333/59—Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g. HCG; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]

Definitions

  • the present invention concerns methods for detecting and following the course of cancer, pregnancy and trophoblastic disease by analyzing whole blood, plasma or serum for the presence of serum gonadotropin peptide complex or a component thereof.
  • BCF beta- core fragment
  • the ⁇ -core fragment is composed of segments of hCG ⁇ -subunit (residues 6-40 disulfide-linked to residues 55-92), and is about half the molecular weight (10,300).
  • Two N-linked sugar chains are linked to the ⁇ -core fragment at Asn 13 and Asn 30; these are devoid of sialic acid and are of different structures to those at analogous positions on the hCG ⁇ -subunit (Birken, S., Armstrong E.G., Gawinowi ⁇ z-Kolks, M.A. , Cole, L.A., Agosto, G.M.
  • ⁇ -core fragment has been detected in trophoblast tissue and in 93% (77/83) of
  • Pregnancy serum ⁇ -core fragment levels have been reported to be extremely low, 0.02 -0.3% of hCG level (Wehmann et al supra and Alfthan et al, supra) . This has led to a conclusion that serum levels cannot account for the high levels found in urine, and that ⁇ -core fragment must therefore be the result of renal degradation of circulating hCG or the ⁇ -subunit. As such, there was controversy as to whether the ⁇ -core fragment is a secretory product of the cells versus a degradation product by the kidney of circulating hCG or its ⁇ -subunit.
  • ⁇ -core fragment levels in urine are highest at 12-16 weeks of pregnancy, when serum hCG and ⁇ -subunit levels are continuously declining (Cole et al, Mol. Endocrinol, 1988; 2:825-30 and Kato, Y., Braunstein, G.D., " ⁇ -Core Fragment is a Major Form of Immunoreactive Urinary Chorionic Gonadotropin in Human
  • ⁇ -core fragment has been detected in trophoblast tissue and in 93% (77/83) of an assortment of tumor sections (Kardana et al, Br. J. Cancer, 1988, 58:281-6).
  • Forms of ⁇ -core fragment have also been detected in cultures of the DoT and CaSki cervical cancer cell lines (Hussa, R.O., Fein, H.G. , Pattillo, R.A. , Nagellberg, S.B., Rosen, S.W., Weintraub, B.D., Perini, F. , Ruddon, R.W. , Cole, L.A.
  • urinary ⁇ -core fragment injected into humans has a very rapid metabolic clearance rate (Wehmann, R.E., Blithe, D.L., Flack, M.R., Nisula, B.C., "Metabolic Clearance Rate and Urinary Clearance of Purified ⁇ -core", J. Clin Endocrinol Metab. (1989) 69:510- 17) .
  • These studies had two major limitations. Firstly, they recovered only 8% of the injected material. Secondly, purified urinary ⁇ -core fragment may have already been processed for excretion. A more accurate assessment of clearance rate would be obtained by measuring the postpartum disappearance of serum ⁇ -core fragment complex, which represents the major form found in serum.
  • Cervical cancer is one of the most common malignancies afflicting women (E. Silverberg, "Cancer Statistics", CA-A Cancer J. Clinicians. 6, 9-26, (1986)).
  • the Pap (Papanicolaou) smear has led to early diagnosis and has mainly been responsible for the overall improvement in survival reported for this disease (Yajima, A., Mori, T. , Sato, S., Wakisaka, T., and Suzuki, M. , "Effect of Cytologic Screening on the Detection of Cervical Carcinoma", Obstet. Gynecol. , 59., 565-568 (1982)).
  • the ovary is the second most common site of gynecologic cancer (E. Silverberg, supra) .
  • the common epithelial ovarian cancers lack early warning symptoms and there are no routine tests, like the Pap smear,
  • a readily available blood test that would aid in the detection of women at increased risk for having gynecologic malignancies, particularly cervix and ovarian cancer would be a major step forward for patients in whom advanced stage disease is almost always fatal. Such a test may obviate the need for pelvic examination and Pap smears. Furthermore, blood tests do not require the need for a trained physician as required for pelvic examinations and Pap smears.
  • the efficacy of treatment for patients with recurrent gynecologic cancer is reflected in the volume of cancer at the time recurrence is documented and the sites of recurrent disease. Therapy may be of limited value when recurrent disease is not identified until the patient has clinical signs or symptoms. Early recognition of persistent or recurrent cancer may lead to more effective therapeutic intervention.
  • Surgical intervention in the form of radical surgery may cure patients with central recurrence of cervical cancer. Diagnosis of persistent or recurrent central disease in a radiation field may be difficult to confirm by cytologic or biopsy techniques. An accurate tumor marker for cervical cancer may lead to earlier recognition and a more rapid diagnosis and treatment.
  • LASA lipid-associated sialic acid
  • SCC squamous cell carcinoma antigen
  • Human chorionic gonadotropin is a glycoprotein hormone composed of the following two dissimilar subunits: alpha 92 amino acids long and beta 145 amino acids long, joined non-covalently. It is normally produced by trophoblast tissue and can be detected in the blood and urine of women in pregnancy or trophoblast disease. Free forms of hCG alpha and beta subunits, which can account for 90% of the total produced, are also found in blood and urine in pregnancy and trophoblast disease (Cole, L. A., Kroll, T. G. , Ruddon, R. W.
  • Free beta-subunit, asialo free beta and the core fragment of asialo beta-subunit, together called “UGF”, are rapidly cleared from the circulation and are more-readily detected in urine than in serum samples (Schroeder, H.R. , and Halter, CM., "Specificity of Human beta- Choriogonadotropin Assays for the Hormone and for an Immunoreactive Fragment Present in Urine During Normal Pregnancy", Clin. Chem..
  • Ectopic hCG has been detected in the blood and tissues of patients with non-trophoblastic cancers, most notably gynecologic malignancies (R.O. Hussa, "Human Chorionic Gonadotropin, a Clinical Marker: Review of its Biosynthesis", Ligand Rev.. 3. . 1-43, (1981)).
  • hCG free beta-subunit and core fragment, UGF have also been detected in patients with non-trophoblastic cancers (Papapetrou, P.D., and Nicopoulou, S.C., "The Origin of a Human Chorionic Gonadotropin beta-subunit Core Fragment in the Urine of Patients with Cancer", Endocrinologica, 112 , 415-422 (1986); Vaitukaitis, J.L., "Characterization of a Small Molecular Size Urinary Immunoreactive Human Chorionic Gonadotropin (hCG)-like Substance Produced by Normal Placenta and by hCG-secreting Neoplasms", J. Clin. Endocrinol. Metab.. 53., 1014-20 (1981)).
  • Tumor marker - a molecule that specifically identifies a specific tumor
  • SGPC or "SGP complex” or "serum gonadotropin peptide complex” - a complex of one or two molecules, namely ⁇ -core fragment (intracellular post-translatonal processing product of pre- ⁇ -subunit of hCG, which cannot be made from the complete ⁇ -subunit of hCG) or onomeric ⁇ -core fragment (same origin as the ⁇ -core fragment) with a carrier protein;
  • SUBSTITUTE SHEET the molecules are present in differing quantities in culture fluids in an assortment of cancer cell lines; the carrier protein masks the epitopes of these two molecules so that they cannot be detected by conventional methods, i.e, the molecules cannot be detected by current immunoassays for (1) hCG, for (2) hCG beta subunit (also called “beta subunit”) , for (3) hCG beta subunit core fragment (also called “beta core fragment”) or for (4) hCG beta subunit C terminal peptide or other hCG antigens, by presently existing methods; the physical characteristics of these two molecules (such physical characteristics being based on dissociated molecules) indicate that the ⁇ -core fragment is similar to hCG beta subunit residues 6 to 40 disulfide linked to hCG beta subunit residues 55 to 92 and having a distinctly different oligosaccharide structure compared to hCG or its beta subunit; the monomeric ⁇ -core fragment appears to be similar to and possibly represents beta subunit residues 1 to
  • SGP serum gonadotropin peptides
  • ⁇ -core fragment a peptide of amino acids 6 to 40 bonded by disulfide bridges to a peptide of amino acids 55 to 92 of the 1 to 145 amino acid sequence of human chorionic gonadotropin beta-subunit and (2) monomeric ⁇ -core fragment, a peptide of amino acids 6 to 92 or 1 to 92 of the 1 to 145 amino acid sequence of human chorionic gonadotropin beta- subunit, each having different attached oligosaccharides to hCG or its ⁇ -subunit.
  • a cancer e.g., a non-trophoblastic cancer
  • beta gonadotropin peptide complex the regular and monomeric beta core fragments which together are one part of what is herein called "serum gonadotropin peptide complex" are in fact present at high levels in blood/serum/plasma, but are bound tightly to a much larger, unrelated, molecule, in such a way that they loose all recognition by hCG, hCG ⁇ - subunit and ⁇ -core fragment tests. Applicants have discovered methods to break up this complex, expose it and thus quantitate this important molecule.
  • the present invention concerns a method for detecting and following the course of a cancer, e.g., a non- trophoblastic cancer, comprising analyzing whole blood or a
  • SUBSTITUTESHEET fluid of whole blood for the presence of serum gonadotropin peptide complex or a component of serum gonadotropin peptide complex wherein the presence of serum gonadotropin peptide complex or a component thereof is an indication of the presence of a cancer, e.g., a non-trophoblastic cancer, pregnancy or a trophoblastic disease in a patient from which the blood or fluid of whole blood was obtained.
  • a cancer e.g., a non-trophoblastic cancer, pregnancy or a trophoblastic disease in a patient from which the blood or fluid of whole blood was obtained.
  • the present invention is also directed to a method of breaking up serum gonadotropin peptide complex to expose one or more epitopes thereof comprising contacting serum gonadotropin peptide complex or a fluid containing the same with a dissociation agent or by dissociation by heating at a temperature above 60"C. More particularly, this aspect of the invention relates to contacting blood, serum or plasma with a dissociation agent, i.e, a detergent, a chaotropic agent, an acid having a pH of 2 to 3 or an organic acid, or by heating the blood, serum as plasma to a temperature above and then conducting a separation to remove the dissociation agent or to separate out the serum gonadotropin peptide complex or a component thereof.
  • a dissociation agent i.e, a detergent, a chaotropic agent, an acid having a pH of 2 to 3 or an organic acid
  • the present invention is further directed to a composition
  • a composition comprising a serum gonadotropin peptide free from serum gonadotropin peptide complex in blood or a fluid thereof, e.g., plasma or serum.
  • the present invention further relates to a substantially pure (or purified) serum gonadotropin peptide complex comprising at least one ⁇ -core fragment selected from the group consisting of a regular ⁇ -core fragment and a monomeric ⁇ -core fragment, in association with a higher molecular weight carrier molecule which immunologically masks at least a substantial portion of the contained ⁇ -core fragments, said complex being further characterized by: (a) a molecular weight about 70,000 in serum as measured by gel filtration and
  • Figs. 1A to IE are graphs which represent the results for gel filtration of serum.
  • Figs. IF to IJ are graphs which represent gel filtration of serum fractions (according to an embodiment of the present invention) .
  • results are depicted for fractions tested for hCG
  • Figs. 1A, IB, 1C and ID depict results for early, mid-and term pregnancy, and choriocarcinoma serum, respectively.
  • Figs. IF to II are repeat chromatography of the POOLS marked A, B, C and D (after dissociation with ammonium thiocyanate, NH 4 SCN) .
  • Fig. IE depicts the results for pregnancy serum, untreated and
  • Fig. IJ depicts the results for pregnancy serum directly treated with NH 4 SCN (right) .
  • the present invention is based on the finding that the regular and monomeric ⁇ -core fragments in serum is associated with other molecules, to form a high molecular weight complex, which denies recognition by existing antibodies to the ⁇ -subunit and ⁇ -core fragment epitopes.
  • This complex can be dissociated with, for example, 3M ammonium thiocyanate to release the ⁇ -core fragment.
  • Levels of released ⁇ -core fragment (relative to hCG) are comparable to those reported for tissue and urine.
  • the level of "free" ⁇ -core fragment in serum, as conventionally detected by immunoassay/gel filtration is extremely low (beyond detection by conventional immunoassays) .
  • the proportion of ⁇ -core fragment found in early pregnancy serum was 18% of the hCG level, that in mid- pregnancy was 91% and in term pregnancy 50% of the hCG level.
  • urine ⁇ -core fragment levels are 35%, 490% and 250% of hCG levels, respectively, for equivalent stages of pregnancy.
  • Levels of masked ⁇ -core fragment (untreated SGPC) in serum are approximately one quarter ⁇ - core fragment levels in urine. Considering that serum creatinine levels are 1/20-1/40th of urine levels, such levels of masked ⁇ -core fragment in serum are more than ample to account for urine levels.
  • One embodiment of the present invention involves the breaking up of serum gonadotropin peptide complex to expose one or more epitopes thereof. This is accomplished by exposing SGPC for a sufficient period of time to a dissociation agent.
  • a dissociation agent such as a detergent, e.g., sodium lauryl sulfate, "TRITON X100" ("TRITON” is a surfactant based on alkylaryl polyether alcohols, sulfonates and sulfates; nonionic, cationic and anionic types, oil-soluble and water-soluble types) or NP40 (octylphenylethylene oxide) ; a chaotropic agent, e.g.
  • guanidine ammonium thiocyanate or urea
  • the dissociating agent is any agent which serves to dissociate non-covalently linked proteins.
  • blood, plasma or serum is heated to greater than 60°C. The treated blood, plasma or serum is then subjected to a separation step to remove precipitates and/or separate out the SGPC or component thereof or to separate out the dissociation agent.
  • the SGP can be detected by any convenient hCG ⁇ -subunit or ⁇ -core fragment assay, for example, ELISA, RIA, dyes, fluorometric assays or EIMA (enzyme immunometric assay) .
  • hCG ⁇ -subunit or ⁇ -core fragment assay for example, ELISA, RIA, dyes, fluorometric assays or EIMA (enzyme immunometric assay) .
  • T TESHEET The SGPC and SGP can also be detected in a non- dissociated state by the use of polyclonal antibodies or monoclonal antibodies, said antibodies specific to SGPC.
  • the two steps of dissociation and separation may be combined in a single operation by using, for example, reverse phase high pressure liquid chromatography (HPLC) , wherein the solvent utilized therein may act as the dissociation agent.
  • HPLC reverse phase high pressure liquid chromatography
  • the following of the course of a cancer, pregnancy or a trophoblastic disease involves the detecting of the progression or regression of the non-trophoblastic cancer or trophoblastic disease or the progression of a pregnancy comprising
  • step (b) subsequent to step (a) , taking one or more further measurements of SGPC or a component thereof, e.g., SGP, in blood or a fluid component thereof, e.g., serum or plasma from said patient, and
  • kits comprising in one or more containers, means to detect SGP or SGPC, e.g., an antibody, in blood or a fluid thereof and optionally means to dissociate SGPC, e.g., a dissociation agent as described herein.
  • Non-limiting examples of uses for the present invention are as follows:
  • IVF in vitro fertilization Programs: hCG is given during the IVF procedure. Administered hCG has to completely leave the circulation system (takes 2-3 weeks) before endogenous hCG can be detected and pregnancy demonstrated. With the development of sensitive methods, detection of a separate molecule beta core fragment - carrier complex, could establish pregnancy after just 7-10 days.
  • hCG is useful for monitoring only the first 8-10 weeks of pregnancy, after this time levels indiscriminately fall. Levels of SGP and SGPC do not fall until approximately 16 weeks of pregnancy and thus have an advantage over hCG in monitoring pregnancy/placental health.
  • Urine measurement of beta core fragment (the urine form of SGP) have proven to be useful in the detection and management of ovarian, uterine and endometrial cancers. There has, however, been some reluctance to break away from the traditional serum/blood measurement of tumor markers and start examining urines. Further reluctance has come from the 2-3-fold variation in urine concentrations at different times of the day. The discovery of SGPC and means to expose epitopes thereon provides a means of measuring this useful marker in the blood/serum.
  • SUBSTITUTESHEET 4 Detection and following the course of cancers, e.g., ovarian cancer, cervical cancer, endometrial cancer, breast cancer, vaginal cancer, vulvar cancer, lung cancer, colon cancer, bladder cancer and pancreatic cancer.
  • cancers e.g., ovarian cancer, cervical cancer, endometrial cancer, breast cancer, vaginal cancer, vulvar cancer, lung cancer, colon cancer, bladder cancer and pancreatic cancer.
  • tumor markers presently available are for blood, not urine, and panels containing several of such markers are generally employed. SGP could be one of such markers on such panel. Detection of tumor markers in blood has been found to be more reliable than in urine, since urine sampling is affected, for example, by an individual's intake of fluid prior to testing.
  • SUBSTITUTE SHEET immunoreactivity ( ⁇ 0.1% of hCG level) were pooled (Fig. 1), lyophilized and reconstituted in 4ml 3M ammonium thiocyanate. After 15 minutes at room temperature, samples were centrifuged and re-applied to the S-100 HR column. To avoid instant reassociation, 3ml of 3M ammonium thiocyanate was put on the column prior to sample application. Alternatively, solid ammonium thiocyanate was added directly to the serum pool (to 3M) , left 15 minutes at room temperature, centrifuged then applied to the S-100 HR column.
  • HCG dimer was measured using a modification of the Tandem-E kit from Hybritech (San Diego, CA) .
  • This assay which requires the presence of an ⁇ and a ⁇ -subunit, has 0% (wt/wt) cross-reactivity with free ⁇ - subunit and ⁇ -core fragment.
  • Free ⁇ -subunit was measured in an assay using monoclonal 1E5 coated onto microtitre plates (Hybritech) .
  • This assay has 3% cross-reactivity with hCG and 0% with ⁇ -core fragment, ⁇ -core fragment was measured using monoclonal B204 (Columbia College of Physicians and Surgeons) coated onto microtitre plates.
  • This assay has 0.6% cross-reactivity with hCG and 9% cross-reactivity with free ⁇ -subunit (Cole et al, Cancer Res. , (1983) 48:1356-60;
  • Serum was taken from three women with ovarian cancer, including one woman who was (falsely) negative for the beta core fragment (human chorionic gonadotropin beta-subunit core fragment) in urine and who had a markedly elevated level of CA 125 in serum, consistent with advanced disease and clinical manifestations of advanced disease. All three women, including the "false negative" woman, had relatively high serum levels (2.5 to 32.1 picomoles/ml or 2.5 to 32.1 x 10 "12 moles/ml) of SGPC versus 3 to 100 femtomoles per ml or 3 to 100 x 10 '15 moles/ml of beta core fragment in urine.
  • JAR trophoblastic
  • SGPC ovarian cancer

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Abstract

Procédé de détection et de suivi de l'évolution d'un cancer, de la grossesse ou d'une maladie trophoblastique, comprenant l'analyse de sang total ou d'un fluide de sang total pour y détecter la présence d'un complexe peptidique de gonadotrophine sérique ou d'un constituant du complexe peptidique de gonadotrophine sérique, la présence d'un complexe peptidique de gonadotrophine sérique ou d'un de ses constituants étant l'indication de la présence d'un cancer, de la grossesse ou d'une maladie trophoblastique chez un malade dont on a prélevé le sang ou un liquide de sang total.
EP19920902062 1990-10-17 1991-10-04 Procedes de detection et de suivi de l'evolution d'un cancer, de la grossesse ou d'une maladie trophoblastique Withdrawn EP0553301A1 (fr)

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JP (1) JPH06502494A (fr)
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FR2702494B1 (fr) * 1993-03-11 1995-06-09 Lafon Labor Trousse de diagnostic d'un cancer secrétant l'hCG ou des fragments d'hCG et vaccin destiné à l'immunothérapie d'un tel cancer.
JPH08507604A (ja) * 1993-03-11 1996-08-13 ラボラトル エル．ラフォン ｈＣＧまたはｈＣＧのフラグメントを分泌する癌に対する診断用キットおよびかような癌の免疫療法用手段
US6927034B2 (en) 1998-02-03 2005-08-09 The Trustees Of Columbia University In The City Of New York Methods for detecting trophoblast malignancy by HCG assay
US6500627B1 (en) 1998-02-03 2002-12-31 The Trustees Of Columbia University In The City Of New York Methods for predicting pregnancy outcome in a subject by HCG assay
CN109564223A (zh) * 2016-09-06 2019-04-02 富士瑞必欧株式会社 肿瘤标记物的测定方法及测定试剂

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WO1992007272A1 (fr) 1992-04-30
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