WO1984004598A1 - Analyse immunologique de la gonadotropine chorionique humaine - Google Patents

Analyse immunologique de la gonadotropine chorionique humaine Download PDF

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Publication number
WO1984004598A1
WO1984004598A1 PCT/US1984/000572 US8400572W WO8404598A1 WO 1984004598 A1 WO1984004598 A1 WO 1984004598A1 US 8400572 W US8400572 W US 8400572W WO 8404598 A1 WO8404598 A1 WO 8404598A1
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WO
WIPO (PCT)
Prior art keywords
hcg
immunoassay
antibody
subunit
terminal portion
Prior art date
Application number
PCT/US1984/000572
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English (en)
Inventor
Robert E Canfield
Elmo G Armstrong
Paul H Ehrlich
Steven Birken
Original Assignee
Univ Columbia
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Univ Columbia filed Critical Univ Columbia
Priority to AU28241/84A priority Critical patent/AU2824184A/en
Publication of WO1984004598A1 publication Critical patent/WO1984004598A1/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
    • G01N33/57476—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving oncofetal proteins

Definitions

  • Immunoassays involving serum-derived antibodies have included antibodies directed to the unique carboxy terminal portion of the ⁇ subunit of hCG (ibid.; and Birken, S. et al., Endocrinology, 110:1555 [1982]).
  • This invention concerns an immunoassay for detecting hCG or measuring the level of hCG in a sample.
  • the assay includes an antibody directed to the carboxy terminal portion of the 8 subunit of hCG and a monoclonal antibody directed to a determinant on hCG at a locus sufficiently remote from the carboxy terminal portion of the 8 subunit of hCG that both antibodies can simultaneously bind to hCG, wherein at least one of the antibodies is detectable when both are bound to hCG.
  • the immunoassay can detect or measure levels of hCG or hCG ⁇ in a urine sample and includes a detectable, purified, serum-derived antibody directed to the carboxy terminal portion of the 3 subunit of hCG and a matrix-bound monoclonal antibody directed to a locus on the S subunit sufficiently remote from the carboxy terminal portion that both antibodies can simultaneously bind to hCG.
  • the assay may be used to detect hCG or to measure hCG levels in urine samples. In this way the presence of hCG- producing neoplasms, subclinical spontaneous abortions and ectopic pregnancies can be diagnosed.
  • Fig. 1 is a standard curve showing use of the assay to measure hCG in buffer ( ⁇ --- ⁇ ) and in urine ( ⁇ --- ⁇ ) and to show extent of cross-reactivity with hLH in urine ( ⁇ -- ⁇ ).
  • Fig. 2 illustrates the sensitivity of a conventional radioimmunoassay (Con A Assay, ⁇ ⁇ ) as compared with the newly developed sandwich assay ( ⁇ --- ⁇ ) in the measurement of hCG levels in an artificially inseminated female patient. Also depicted is the hypothetical pattern of hCG levels occurring as a result of subclinical spontaneous abortion (----).
  • this invention provides an immunoassay for detecting hCG or measuring levels of hCG, or both, in a sample.
  • the immunoassay includes an antibody directed to the carboxy terminal portion of the ⁇ subunit of hCG which is a unique peptide sequence not found in hLH.
  • the immunoassay also includes a monoclonal antibody directed to a determinant on hCG at a locus sufficiently remote from the carboxy terminal portion of the ⁇ subunit that both antibodies can simultaneously bind to hCG.
  • at least one of the antibodies is capable of detection when both antibodies are bound to hCG.
  • any antibody directed to the carboxy terminal portion of the ⁇ subunit of hCG would be effective, the presently available and preferred antibodies are purified, serum-derived antibodies. Examples include R525 and R529 as described more fully hereinafter.
  • the present invention is not limited to serum- derived antibodies and also encompasses monoclonal antibodies directed to the carboxy terminal portion of the ⁇ subunit if and when efforts to produce such monoclonal antibodies are successful. Either antibody or both antibodies are capable of detection when the antibodies are bound to hCG. Various means for rendering an antibody detectable are known to those skilled in the art.
  • suitable means include radioactive labeling, e.g., 125 I labeling, fluorescent labeling or linkage to an enzyme which catalyzes a detectable reaction, that is, an ELISA approach, e.g., linkage of an antibody to horseradish peroxidase.
  • An additional approach involves the use of a third anti- body directed to one of the antibodies of the assay where the third antibody, either serum-derived or monoclonal, is detectable, e.g., labeled with a radioactive isotope or a fluorescent moiety.
  • the immunoassay of the present invention may be carried out totally in liquid phase, totally in solid phase or in a mixed liquid/solid system.
  • one of the antibodies, preferably the monoclonal antibody directed to a locus remote from the carboxy terminal portion of the ⁇ subunit be attached to a solid matrix, e.g., agarose or Sepharose.
  • the immunoassay may be used with either urine, plasma, serum or other samples, it is particularly desirable to employ the immunoassay on urine samples because of the greater ease and convenience of obtaining such samples. This is, in fact, one of the substantial advantages provided by the present invention since most presently available immunoassays for hCG are not suitable for use with urine samples.
  • the presently preferred embodiment of the invention involves an immunoassay for detecting hCG ⁇ or measuring levels of hCG ⁇ , and thereby detecting or measuring hCG.
  • This immunoassay includes a purified, serum-derived anti- body directed to the carboxy terminal portion of the ⁇ subunit of hCG and a monoclonal antibody directed to a locus on the ⁇ subunit sufficiently remote from the carboxy terminal portion that both antibodies can simultaneously bind to hCG.
  • the purified, serum-derived antibody is detectable when both antibodies are bound to hCG ⁇ , alone or as hCG, and the monoclonal antibody is attached to a solid matrix.
  • This invention also concerns a purified antibody to the carboxy terminal portion of the ⁇ subunit of hCG, preferably labeled or otherwise detectable, e.g., 125 I-labeled.
  • the immunoassay of this invention provides a method of detecting hCG or measuring the level of hCG, or both, in a urine sample.
  • the sample to be tested is placed in the immunoassay under suitable conditions permitting formation of a detectable or measurable complex with hCG.
  • the resulting complex may then be detected if present or the level of hCG present determined by reference to a standard containing a known amount of hCG.
  • Measurements of hCG levels in turn can be used in the diagnosis or identification of disorders which involve production, or elevated levels, of hCG.
  • disorders include certain neoplasms, e.g., male testicular cancer, subclinical spontaneous abortions and ectopic pregnancies.
  • the antibodies used in this experiment were R525 and R529, Birken, S. et al., Endocrinology, 110:1555 (1982), rabbit antisera directed against the hCG ⁇ - CTP determinants, and B101, Ehrlich, P.H. et al.. Journal of Immunology, 128:2709 (1982), a mouse monoclonal antibody directed against an hCG ⁇ ⁇ onformational determinant.
  • the methods of preparation and characteristics of these antibodies were as published in the preceding two cited references.
  • Cyanogen bromide (CnBr) activated Sepharose 4B was obtained from Pharmacia Fine Chemicals and DEAE Affi-Gel Blue from Bio-Rad Laboratories. The preceding purchased materials were used in accordance with the manufacturers' instructions.
  • Electrophoresis of the preparation on nonreducing SDS polyacrylamide gels Weber, K. and Osborn, M., J. Biol. Chem., 244:4406 (1969), indicated that at least 80% of the protein content was ⁇ -globulin.
  • hCG ⁇ Ten mgs of hCG ⁇ was coupled to two grams of CnBr activated Sepharose 4B.
  • the hCG ⁇ coupled Sepharose 4B was used to form an 0.9 x 10 cm column which was used for affinity purification of R525.
  • a 54 ml pool of R525 from several different bleeds between boostings was recycled over the column continuously for 30 hours at 4°C using a peristaltic pump.
  • the column was washed extensively with saline to remove loosely adhering material.
  • the column was then eluted successively with 20 ml of 3M guanidine-HCl, pH 3.0, and 20 ml of 6 M guanidine-HCl, pH 3.0.
  • the effluent was collected in one ml fractions and the absorbance at 280 nm determined.
  • the absorbance profile had two discrete protein peaks corresponding in position to the areas of elution with 3 M and 6 M guanidine-HCl.
  • the fractions having the peak absorbance at 280 nm were pooled and then dialysed extensively against 10 mM sodium acetate, pH 5.5, followed by 0.3 M NaPO 4 , pH 7.5, at 4°C.
  • the dialysed preparations, an aliquot of the unpurified R525 pool and also the R525 pool which had been circulated over the hCG ⁇ affinity column were tested for their ability to bind 125 I-hCG.
  • Buffer B containing 50,000 CPM 125 I-R525 was added to each tube.
  • the samples were incubated vertically for 48-72 hours at 4°C with shaking on the Labquake Shaker.
  • the tubes were then washed three times with 2 ml of Buffer B + 1% Tween 20 to reduce nonspecific binding.
  • the hCG radioimmunoassay was conducted using the R529 antiserum to the hCG ⁇ CTP determinants to measure hCG extracted from urine with ⁇ oncanavalin A as described by Wehmann,et al. Wehmann, R.E., et al.. Clinical Chemistry, 27:1997 (1981).
  • urinary hCG concentration was normalized to creatinine concentration.
  • FIG. 1 A typical standard curve generated for hCG binding in the sandwich assay is shown in Fig. 1.
  • the hCG dosages which give binding equivalent to 10% and 90% of Bmax (ED 10 and ED 90 ) have been tentatively accepted as the limits of the usable range of the standard curve.
  • EDio and ED 90 correspond to 0.01 and 0.50 ng hCG/ml, giving a fiftyfold usable range.
  • the Nonspecific Binding (NSB) in the assay is reduced to an acceptable level by extensive washing of the pellet with buffer containing Tween 20 and bovine ⁇ -globulin. In the assay represented NSB was 2.5% of the total counts added.
  • Fig. 1 also shows the dose response curve of hCG extracted from normal male urine which had been spiked with dosages identical to those used in the standards.
  • the dose response curve for hCG in urine is essentially identical to that for hCG in Buffer B.
  • the slope and ED 50 of the dose response curve were 1.173 and 0.066 ng/ml for hCG in urine, compared to 1.098 and 0.072 ng/ml for hCG in buffer.
  • the dose response curve for hLH added to normal male urine is also shown in Fig. 1. It should be noted that the units for hLH concentration are ⁇ g/ml as opposed to ng/ml for hCG concentration. A concentration of 2 ⁇ g hLH/ml is required to obtain a dose response equivalent to 0.01 ng hCG/ml. Thus, the cross-reactivity of this concentration of hLH in the sandwich assay is 0.0005% on the basis of mass. This level of hLH is approximately fifty fold higher than those present in urine from women at the mid-cycle hLH surge. Saxena, B.B. et al.. Fertility and Sterility, 28:163 (1977). Therefore, physiologic concentrations of hLH are incapable of interfering in the sandwich assay.
  • Fig. 1 shows that the assay is equally effective for the measurement of hCG in buffer and in urine, highly sensitive, i.e., capable of detecting hCG at levels down to 0.004 ng/ml and that cross-reactivity with hLH is exceptionally low, i.e., about 0.0005%, thereby rendering the assay absolutely specific for hCG.
  • Fig. 2 shows the use of the assay to measure hCG levels in the urine of an artificially inseminated female patient at various days after insemination.
  • Fig. 2 also shows the use of a standard radioimmunoassay to measure hCG levels in the same patient's urine.
  • the assay of the present invention is capable of detecting elevated hCG levels after the sixth day following insemination.
  • the standard RIA is less sensitive and cannot detect hCG until the tenth day following insemination.
  • Fig. 2 also illustrates the application of the assay in the diagnosis of subclinical spontaneous abortion.
  • the hypothetical pattern illustrated in Fig. 2 shows that the standard RIA is incapable of detecting either the rise or the fall of hCG as the result of subclinical spontaneous abortion while the assay of the present invention will be able to do so because of its much greater sensitivity.

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  • Health & Medical Sciences (AREA)
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  • Engineering & Computer Science (AREA)
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  • Immunology (AREA)
  • Urology & Nephrology (AREA)
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Abstract

Une analyse immunologique pour détecter et mesurer la gonadotropine chorionique humaine (hCG) dans un échantillon comporte l'orientation d'un anticorps vers la partie terminale carboxy de la sous-unité beta de la hCG et l'orientation d'un anticorps monoclonal vers un déterminant sur la hCG en un emplacement suffisamment éloigné de la partie terminale carboxy de la sous-unité beta de la hCG pour que les deux anticorps puissent se lier simultanément à la hCG, où au moins l'un des anticorps peut être détecté lorsque les deux sont liés à la hCG. Dans un mode préférentiel de réalisation, une analyse immunologique de la hCG ou de la hCG beta dans l'urine comporte l'orientation d'un anticorps dérivé de sérum, purifié, marqué ou détectable vers la partie terminale carboxy de la sous-unité beta de la hCG et l'orientation d'un anticorps monoclonal lié à la matrice vers un emplacement de la sous-unité beta suffisamment éloigné de la partie terminale carboxy pour que les deux anticorps puissent se lier simultanément à la hCG ou à la hCG beta.
PCT/US1984/000572 1983-05-06 1984-04-13 Analyse immunologique de la gonadotropine chorionique humaine WO1984004598A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU28241/84A AU2824184A (en) 1983-05-06 1984-04-13 Immunoassay for human chorionic gonadotropin

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US49221083A 1983-05-06 1983-05-06

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JP (1) JPS60501271A (fr)
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0212522A2 (fr) * 1985-08-12 1987-03-04 Juridical Foundation The Chemo-Sero-Therapeutic Research Institute Procédé pour mesurer la HST
EP0219870A2 (fr) * 1985-10-24 1987-04-29 The General Hospital Corporation Méthode de détection d'une sous-unité de polypeptide en présence d'une protéine quaternaire contenant cette sous-unité
EP0254081A2 (fr) * 1986-06-30 1988-01-27 Yuko Yoneda Procédé pour détecter une protéine spécifique
EP0293779A1 (fr) * 1987-06-05 1988-12-07 Daiichi Pure Chemicals Co. Ltd. Essai immunologique utilisant l'agglutination de latex

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2040664A1 (fr) * 1990-05-11 1991-11-12 Harold C. Warren, Iii Composition immunoreactive, necessaire d'essai et test rapide pour la gonadotrophine chorionique
AU5136100A (en) * 1999-05-17 2000-12-05 Avi Biopharma, Inc. Combined approach to treatment of cancer with hcg vaccines
GB201402668D0 (en) * 2014-02-14 2014-04-02 Concepta Diagnostics Ltd Fertility and pregnancy monitoring device and method

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US4048298A (en) * 1975-02-25 1977-09-13 Rohm And Haas Company Solid phase double-antibody radioimmunoassay procedure
US4098876A (en) * 1976-10-26 1978-07-04 Corning Glass Works Reverse sandwich immunoassay
US4244940A (en) * 1978-09-05 1981-01-13 Bio-Rad Laboratories, Inc. Single-incubation two-site immunoassay
US4248965A (en) * 1976-10-07 1981-02-03 Mochida Seiyaku Kabushiki Kaisha Immunochemical process of measuring physiologically active substances
US4376110A (en) * 1980-08-04 1983-03-08 Hybritech, Incorporated Immunometric assays using monoclonal antibodies

Family Cites Families (2)

* Cited by examiner, † Cited by third party
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CH642458A5 (en) * 1980-04-25 1984-04-13 Hoffmann La Roche Immunological method
ES8307897A1 (es) * 1981-04-13 1983-08-01 Hoechst Co American Un metodo de determinar la presencia de un antigeno en un medio liquido sospechoso de contenerlo.

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4048298A (en) * 1975-02-25 1977-09-13 Rohm And Haas Company Solid phase double-antibody radioimmunoassay procedure
US4248965A (en) * 1976-10-07 1981-02-03 Mochida Seiyaku Kabushiki Kaisha Immunochemical process of measuring physiologically active substances
US4098876A (en) * 1976-10-26 1978-07-04 Corning Glass Works Reverse sandwich immunoassay
US4244940A (en) * 1978-09-05 1981-01-13 Bio-Rad Laboratories, Inc. Single-incubation two-site immunoassay
US4376110A (en) * 1980-08-04 1983-03-08 Hybritech, Incorporated Immunometric assays using monoclonal antibodies

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
Cancer Traetment Reports, Volume 63, Abstract 361, issued July 1979, MIGGIANO, V. et al, Murine Monoclonal Antibodies to Human Chorionic Gonado-Tropin. *
Clincal Chemistry, Volume 28, pages 1862-1866, issued September 1982, WADA, W.G. et al, Enzyme Immunoassay of the Glycoprotein Tropic Hormones-Choriogonadotropin, Lutropin, Thyrotropin-with Solid Phase Monoclonal Antibody for the Alpha-Subunit and Enzyme-Coupled Monoclonal Antibody Specific for the Beta-Subunit. *
Clinical Chemistry, Volume 28, pages 546-547, issued March 1982, SHIMUZU, S.Y. et al, Choriogonadotropin Measured by Use of Monoclonal Antibodies in A Two-Site Immunoradio-Metric Assay. *
Federation Proceedings; American Society of Biological Chemists, Volume 40, page 1595, Abstract 321, issued June 1981, MURALIDHAR, K. et al, Hybridoma Secreting Antibodies Specific to Human Chorionic Gonadoropin. *
Immunobiology, Volume 160, page 5, Abstract 7, issued 1981, BERGER, P. et al, Intra-and Interspecies Cross Reactions of Monoclonal Antibodies Against Human Chorionic Gonadotropin. *
Indian Journal of Experimental Biology, Volume 18, pages 1361-1365, issued December 1980, GUPTA, S.K. et al, Development of Hybridomas Secreting Anti-Human Chorionic Gonadotropin Antibodies. *
Journal of Immunological Methods, Volume 42, pages 11-15, issued 18 April 1981, UOTILLA, M., et al, Two-Site Sandwich Enzyme Immunoassay with Monoclonal Antibodies to Human Alpha-Fetoprotein. *
Journal of Immunological Methods, Volume 45, pages 249-254, issued 1981, HURELL, J.G.R. et al, Monoclonal Antibodies Directed Against Human Myoglobin: Characterization and Application in A Bideterminant Radioimmunoassay. *
Journal of Immunology, Volume 128, pages 2709-2713, issued June 1982, EHRLICH, P.H. et al, Micing Two Monoclonal Antibodies Yeilds Enhanced Affinity for Antigen. *
Molecular Immunology, Volume 19, pages 451-455, isseud March 1982, KATUS, H.A. et al, Increased Specificity in Human Cardiac-Myosin Radioimmunoassay Utilizing Two Monoclonal Antibodies in A Double Sandwich Assay. *
Mount Sinai Journal of Medicine, Volume 47, pages 528-534, issued September 1980, BEERS, P.C., Immunoassay in Reproductive Medicine. *
Proceedings, National Academy of Sciences, U.S.A., Volume 79, pages 2245-2249, isseud April 1982, MOYLE, W.R. et al, Use of Monoclonal Antibodies to Subunits of Human Chorionic Gonadotropin to Examine the Orientation of the Hormone in its Complex with Receptor. *
Protides Biological Fluids, Volume 29, pages 837-842, issued 1982, BOSCH, A.M.G. et al, Characteristics of Monoclonal Antibodies Against Human Chorionic Gonadotropin. *
Reproductive Immunology, ALAN R. LISS, Inc., GLEICHER, N. ED, pages 21-28, published 1981, BEERS, P.C., Immunoassay in Reproductive Medicine. *
See also references of EP0146563A4 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0212522A2 (fr) * 1985-08-12 1987-03-04 Juridical Foundation The Chemo-Sero-Therapeutic Research Institute Procédé pour mesurer la HST
EP0212522A3 (fr) * 1985-08-12 1987-07-15 Juridical Foundation The Chemo-Sero-Therapeutic Research Institute Procédé pour mesurer la HST
EP0219870A2 (fr) * 1985-10-24 1987-04-29 The General Hospital Corporation Méthode de détection d'une sous-unité de polypeptide en présence d'une protéine quaternaire contenant cette sous-unité
EP0219870A3 (fr) * 1985-10-24 1988-11-09 The General Hospital Corporation Méthode de détection d'une sous-unité de polypeptide en présence d'une protéine quaternaire contenant cette sous-unité
EP0254081A2 (fr) * 1986-06-30 1988-01-27 Yuko Yoneda Procédé pour détecter une protéine spécifique
EP0254081A3 (fr) * 1986-06-30 1988-04-20 Yuko Yoneda Procédé pour détecter une protéine spécifique
EP0293779A1 (fr) * 1987-06-05 1988-12-07 Daiichi Pure Chemicals Co. Ltd. Essai immunologique utilisant l'agglutination de latex
US4952520A (en) * 1987-06-05 1990-08-28 Daiichi Pure Chemicals Co., Ltd. Immunoassay making use of latex agglutination

Also Published As

Publication number Publication date
CA1229549A (fr) 1987-11-24
EP0146563A4 (fr) 1988-11-07
JPS60501271A (ja) 1985-08-08
EP0146563A1 (fr) 1985-07-03

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