EP0544898A1 - Diagnostic precoce du cancer du poumon grace a des combinaisons d'anticorps anti-hydrates de carbone - Google Patents

Diagnostic precoce du cancer du poumon grace a des combinaisons d'anticorps anti-hydrates de carbone

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Publication number
EP0544898A1
EP0544898A1 EP19920915038 EP92915038A EP0544898A1 EP 0544898 A1 EP0544898 A1 EP 0544898A1 EP 19920915038 EP19920915038 EP 19920915038 EP 92915038 A EP92915038 A EP 92915038A EP 0544898 A1 EP0544898 A1 EP 0544898A1
Authority
EP
European Patent Office
Prior art keywords
antibody
lung cancer
antibody specific
antibodies
sialosyl
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.)
Withdrawn
Application number
EP19920915038
Other languages
German (de)
English (en)
Inventor
Daizo Saito
Sen-Itiroh Hakomori
Satoshi c/o Showa Univ. School of Med. KIMURA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biomembrane Institute
Original Assignee
Biomembrane Institute
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 Biomembrane Institute filed Critical Biomembrane Institute
Publication of EP0544898A1 publication Critical patent/EP0544898A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • G01N33/57469—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving tumor associated glycolinkage, i.e. TAG
    • 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
    • G01N33/57407—Specifically defined cancers
    • G01N33/57423—Specifically defined cancers of lung
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present invention is generally directed toward the detection of lung cancer, and more specifically, toward such detection through the use of combinations of anti-carbohydrate antibodies.
  • Lung cancer is a leading cause of cancer deaths in the United States.
  • small cell carcinoma of the lung SCLC
  • SCLC small cell carcinoma of the lung
  • chemo- and radiation therapy has successfully increased the two-year survival of patients with limited stage disease from 1% to 30%, the two-year survival of patients with extensive disease has not been improved by current therapies.
  • the disease metastasizes early and widely, generally rendering it inoperable.
  • the present invention provides methods for the early diagnosis of lung cancer using combinations of anti-carbohydrate antibodies.
  • the method comprises contacting a sputum specimen with a panel of three or more antibodies, wherein there is at least one antibody specific for each of three antigens selected from the group consisting of Le x , sialosyl Le x , Le y , Tn, sialosyl Tn and Le a ; and detecting the presence or absence of immunocomplex formation by each of the antibodies, whereby the presence of immunocomplex formation by any one antibody is indicative of the presence of lung cancer.
  • the method comprises the steps of: (a) contacting one or more aliquots of a sputum specimen, taken from a warm-blooded animal, with an antibody specific for Le x under conditions and for a time sufficient to allow immunocomplexes to form therefrom; (b) detecting the presence or absence of immunocomplexes formed between the antibody and the aliguot; (c) repeating steps (a) and (b) with an antibody specific for sialosyl Le x ; (d) repeating steps (a) and (b) with an antibody specific for Le y ; (e) repeating steps (a) and (b) with an antibody specific for Tn; (f) repeating steps (a) and (b) with an antibody specific for sialosyl Tn; and (g) repeating steps (a) and (b) with an antibody specific for Le a ; wherein the presence of immunocomplexes generated in any of steps (a) - (g) is indicative of the presence of lung cancer.
  • the method comprises contacting a first sputum specimen, taken from the warm-blooded animal prior to initiation of therapy, with a panel of three or more antibodies, wherein there is at least one antibody specific for each of three antigens selected from the group consisting of Le x , sialosyl Le x , Le y , Tn, sialosyl Tn and Le a ; detecting the presence or absence of immunocomplex formation by each of the antibodies, wherein the presence of immunocomplex formation by any one antibody is indicative of the presence of lung cancer; and repeating the contacting and the detecting steps on a second sputum specimen taken from the animal subsequent to the initiation of therapy, thereby monitoring the effectiveness of the therapy in the animal.
  • the method comprises the steps of: (a) contacting one or more aliquots of a first sputum specimen, taken from the warm-blooded animal prior to initiation of therapy, with an antibody specific for Le x under conditions and for a time sufficient to allow immunocomplexes to form therefrom; (b) detecting the presence or absence of immunocomplexes formed between the antibody and the aliquot; (c) repeating steps (a) and (b) with an antibody specific for sialosyl Le x ; (d) repeating steps (a) and (b) with an antibody specific for Le y ; (e) repeating steps (a) and (b) with an antibody specific for Tn; (f) repeating steps (a) and (b) with an antibody specific for sialosyl Tn; (g) repeating steps (a) and (b) with an antibody specific for Le a ; wherein the presence of immunocomplexes generated in any of steps (a) - (g) is indicative of the presence of lung cancer;
  • Figure 1 depicts a flowchart illustrating a procedure for preparing sputum specimens for staining, i.e., immunohistochemical or otherwise.
  • Figure 2 graphically illustrates the reactivity of various anti-carbohydrate antibodies with sputum specimens.
  • the scores presented represent averages from immunohistochemical stainings of malignant or borderline cells in sputa. A total of 38 cases were collected; 11 Class C or B and 26 Class D or E.
  • the present invention is generally directed towards methods for early diagnosis of lung cancer or for monitoring the effectiveness of cancer therapy in a warm- blooded animal with lung cancer. More specifically, the disclosure of the present invention shows that combinations of anti-carbohydrate antibodies may be used to detect lung cancer.
  • a traditional method for detecting lung cancer has been Papanicolaou's stain.
  • a problem with this method is that it does not detect cancer cells sufficiently early for therapeutic purposes.
  • lung cancer may be detected prior to clinical manifestations by the use of combinations of antibodies to certain antigens. Further it is easier to find malignant cells by the methods of the present invention than by Papanicolaou's staining.
  • the antigens found to be useful within the methods of the present invention include Le x , dimeric Le x , sialosyl Le x , Le y , sialosyl Tn, fucosyl GMl, Tn and Le a .
  • the structures of these antigens are depicted in Table 1.
  • Gal represents galactose
  • GlcNAc represents N-acetylglucoseamine
  • Glc glucose
  • Fuc represents fucose
  • NeuAc represents N-acetylneuraminic acid
  • GalNAc represents N-acetylgalactoseamine
  • Ser represents serine
  • Thr represents threonine
  • Cer Ceramide. Ceramides are sphingolipid bases which are acylated on the amine with a fatty acid.
  • Antibodies employed in the present invention selectively bind (i.e., with an affinity of about 10 7 liters/mol or higher) to the antigens listed above.
  • the term "antibody,” as used herein, includes both monoclonal and polyclonal antibodies and may be an intact molecule, a fragment thereof, or a functional equivalent thereof. The antibody may be genetically engineered. Examples of antibody fragments include F(ab') 2 , Fab', Fab and Fv.
  • polyclonal antibodies may be produced by immunization of an animal and subsequent collection of its sera. Immunization is accomplished, for example, by a systemic administration, such as by subcutaneous. intrasplenic or intramuscular injection, into a rabbit, rat or mouse. It is generally preferred to follow the initial immunization with one or more booster immunizations prior to sera collection. Such methodology is well known and described in a number of references.
  • MAbs monoclonal antibodies
  • MAbs suitable within the present invention include those of murine or human origin, or chimeric antibodies such as those which combine portions of both human and murine antibodies (i.e., antigen binding region of murine antibody plus constant regions of human antibody).
  • Human and chimeric antibodies may be produced using methods known by those skilled in the art. Human antibodies and chimeric human-mouse antibodies are advantageous when administered clinically because they are less likely than murine antibodies to cause the production of anti-antibodies.
  • MAbs may be generally produced by the method of Kohler and Milstein (Nature 256:495-497, 1975; Eur. J. Immunol. 6:511-519, 1976). Briefly, the lymph nodes and/or spleens of an animal immunized with one of the antigens listed in Table 1 are fused with myeloma cells to form hybrid cell lines ("hybridomas" or "clones"). Each hybridoma secretes a single type of immunoglobulin and, like the myeloma cells, has the potential for indefinite cell division. It may be desirable to couple such molecules to a carrier to increase their immunogenicity.
  • Suitable carriers include keyhole limpet hemocyanin, thyroglobulin, bovine serum albumin and derivatives thereof.
  • An alternative to the production of MAbs via hybridomas is the creation of MAb expression libraries using bacteriophage and bacteria (e.g., Sastry et al., Proc. Natl. Acad. Sci USA 86:5728, 1989; Huse et al., Science 246:1275, 1989). Selection of antibodies exhibiting appropriate specificity may be performed in a variety of ways which will be evident to those skilled in the art.
  • MAbs suitable within the present invention include SH1, SH2, SNH3, AH6, TKH2, TKH6, and CA3F4.
  • SH1 is an IgG 3 directed against Le x (Singhal et al.. Cancer Res. 50: 1375-1380, 1990).
  • SH2 is an IgG directed against SH2 (Singhal et al., ibid.).
  • SNH3 is an IgM directed against sialosyl Le x and has a specificity similar to that of CS-LEX (Fukushima et al., Cancer Res. 44:5279-5285, 1984).
  • AH6 is an IgM directed against Le y (Abe et al., Cancer Res. 46:2639-2644, 1986).
  • TKH2 is an IgG 1 directed against sialosyl Tn (Kjeldsen et al., Cancer Res. 48:2214-2220, 1988).
  • TKH5 is an IgG 3 directed against fucosyl GM1 (Kjeldsen et al., ibid.).
  • TKH6 is an IgM directed against Tn (Kjeldsen et al., ibid.).
  • CA3F4 is an IgG directed against Le a (Young et al., J. Biol. Chem. 258:4890-4894. 1983). Numerous other MAbs to these antigens have been described (see Hakomori, Advances in Cancer Research 52:257-331, 1989 and the references cited within).
  • antibodies against combinations of the above antigens may be used to detect lung cancer in a sample of lung cells, such as a sputum specimen. More than one antibody against a particular antigen may be employed, so long as there is at least one antibody for each of the other antigens selected.
  • a panel of at least one antibody for each of the antigens Le x , sialosyl Le x , Le y , sialosyl Tn, Tn and Le a is used.
  • Particularly preferred antibodies for these antigens are, respectively, the MAbs SH1, SNH3, AH6, TKH2 , TKH6 and CA3F4.
  • panels of at least one antibody for each of two or three antigens selected from Le x , sialosyl Le x , Le y , sialosyl Tn, Tn and Le a may be used.
  • one or more antibodies for each of the antigens Le x , Le y and Le a may form a panel. Given the teachings provided herein, it will be evident to those of ordinary skill in the art that other combinations of antibodies may be utilized.
  • antibodies for a combination of antigens are reacted individually with separate aliquots from a sputum specimen.
  • a single aliquot may be analyzed either sequentially or simultaneously. The order in which testing of multiple aliquots (or testing of a single aliquot sequentially) by different antibodies is performed may be varied.
  • Detection of the presence of immunocomplexes formed between an antigen described above and an antibody specific for the antigen may be accomplished by a variety of known techniques, such as radioimmunoassays (RIA) and enzyme-linked immunosorbent assays (ELISA).
  • Suitable immunoassays include the double monoclonal antibody sandwich immunoassay technique of David et al. (U.S. Patent 4,376,110); monoclonal-polyclonal antibody sandwich assays (Wide et al., in Kirkham and Hunter, eds., Radioimmunoassay Methods, E. and S. Livingstone, Edinburgh, 1970); the "western blot" method of Gordon et al. (U.S.
  • Patent 4,452,901 immunoprecipitation of labeled ligand (Brown et al., J. Biol. Chem. 255:4980-4983, 1980); enzyme-linked immunosorbent assays as described by, for example, Raines and Ross (J. Biol. Chem. 257:5154-5160. 1982); immunocytochemical techniques, including the use of fluorochromes (Brooks et al., Clin. Exp. Immunol. 39: 477, 1980); and neutralization of activity (Bowen-Pope et al., Proc. Natl. Acad. Sci. USA 81:2396-2400, 1984).
  • the antibodies may either be labeled or unlabeled.
  • unlabeled antibodies find use in agglutination assays.
  • unlabeled antibodies can be used in combination with labeled molecules that are reactive with immunocomplexes, or in combination with labeled antibodies (second antibodies) that are reactive with the antibody directed against the compound, such as antibodies specific for immunoglobulin.
  • the antibodies can be directly labeled.
  • the reporter group can include radioisotopes, fluorophores, enzymes, luminescers, or dye particles.
  • a reporter group is bound to the antibody.
  • the step of detecting immunocomplexes involves removing substantially any unbound antibody and then detecting the presence of the reporter group. Unbound antibody is antibody which has not bound to the antigen.
  • a reporter group is bound to a second antibody capable of binding to the antibodies specific for the antigen.
  • the step of detecting immunocomplexes involves (a) removing substantially any unbound antibody (i.e., antibody not bound to the antigen), (b) adding the second antibody, (c) removing substantially any unbound second antibody and then (d) detecting the presence of the reporter group.
  • the antibody specific for the antigen is derived from a mouse
  • the second antibody is an anti-murine antibody.
  • a reporter group is bound to a molecule capable of binding to the immunocomplexes.
  • the step of detecting involves (a) adding the molecule, (b) removing substantially any unbound molecule, and then (c) detecting the presence of the reporter group.
  • An example of a molecule capable of binding to the immunocomplexes is protein A.
  • Reporter groups suitable for use in any of the methods include radioisotopes, fluorosphores, enzymes, luminescers, and dye particles.
  • detection of immunocomplexes may be used to monitor the effectiveness of lung cancer therapy.
  • Sputum specimens taken from a warm-blooded animal, such as a human, prior to and subsequent to initiation of therapy may be analyzed by the methods of the present invention described above.
  • the absence of specific immunocomplexes in the subsequent sample (post-therapy initiation) reflects successful therapy.
  • Sputum was collected from subjects every morning for three days and stored in "Sacomano's solution” (2% polyethylene glycol in 50% ethanol) at room temperature. "High-risk" subjects were heavy smokers, i.e., at least one pack of cigarettes per day for 20 years. Staining of sputum specimens is preferably done within a few days after collection. However, specimens may be stored for six months at 4°C.
  • Mucus was removed from sputum using a blender (e.g.. Waring ® blender model 31 BL91; 11,000 rpm for 10 seconds). Cells were collected in sediment by centrifugation at 2,000 rpm for 5 minutes. The cells were smeared on glass slides for immunohistological staining, and fixed with 95% ethanol for 10 minutes at room temperature. Papanicolaou's staining was also performed for grading malignancies. Fixed cells on the slides were washed twice with phosphate buffered saline (PBS) for 10 minutes at room temperature.
  • PBS phosphate buffered saline
  • the slides were reacted with biotinylated secondary antibody (Vectastain ® ABC Kit) for 20 minutes at room temperature in a moisture chamber.
  • the slides were washed three times with PBS for 5 minutes at room temperature.
  • a preformed avidin-biotinylated horseradish peroxidase complex (Vectastain ® ABC Kit) was added for 30 minutes at room temperature in a moisture chamber.
  • the slides were again washed three times with PBS for 5 minutes to remove unreacted complex.
  • the slides were dipped in a solution containing diamino benzidine (DAB, a substrate for horseradish peroxidase) and H 2 O 2 (20 mg DAB, 30 ⁇ l H 2 O 2 , 65 mg NaN 3 , 0.05M Tris chloride buffer, pH 7.6, final volume of 100 ml) for 5 minutes at room temperature.
  • the slides were washed with distilled water for 5 minutes and counterstained with Meyer's Hematoxylin (Muto Chemicals, Tokyo, Japan) without dilution for 20 seconds at room temperature.
  • the slides were washed with running water for 10 minutes and then sealed and examined under a microscope ( ⁇ 40x - 200x magnification).
  • MAbs is shown in Figure 2 (cells in sputum) and Table 4 (stained lung cancer tissue sections).
  • AH6, TKH2, TKH6 and CA3F4 exhibited the strongest binding to lung cancer specimens.
  • MAbs may be produced against tumor-associated carbohydrate antigens by immunization of mice with purified glycoplipid antigen coated on Salmonella minnesota (Young et al., J. Exp. Med. 150:1008-19, 1979).
  • the procedure for the preparation of MAb SH-1 is representative.
  • Lewis 3** antigen III 3 Fuc nLc 4
  • the tumor is homogenized three times in isopropanol:hexane:H 2 O and filtered.
  • the organic extract is evaporated to dryness and partitioned three times by the method of Folch (J. Biol. Chem. 191:819, 1951).
  • the combined upper phase is evaporated and dialyzed against distilled water in a spectrapore 3 (3500 mol. wt. cut-off) dialysis tubing.
  • the dialysate is evaporated using excess ethanol and subjected to ion-exchange chromatography on DEAE-Sephadex A-25 column (4 x 50 cm).
  • the sample is applied in chloroform:methanol:water (30:60:8).
  • the nonbinding pass-through fraction is collected which contains Lewis x antigen.
  • the sample is evaporated and subjected to high-pressure liquid chromatography (HPLC) on an iotrobead system consisting of isopropanol:hexane:water (55:40:5 to 55:25:20).
  • the fractions are pooled on the basis of staining with orcinol-sulfuric acid.
  • the glycolipids migrating between standard H 1 and H 2 glycolipids are pooled and acetylated using pyridine-acetic anhydride.
  • the acetylated glycolipids are applied to a preparative TLC plate and developed in dichloroethanol:acetone:water (40:60:0.03). Each isolated band is analyzed by NMR and permethylation analysis, and Le x band is collected.
  • Balb/c mice female, 8-week-olds are immunized with the purified Lewis x antigen (III 3 Fuc nLc4).
  • the antigen (40 ⁇ g/100 ⁇ l ethanol) is injected into 800 ⁇ l phosphate-buffered saline (PBS) at 37oC.
  • PBS phosphate-buffered saline
  • the solution is further mixed with 250 ⁇ g of acid-treated S. minnesota (1 mg/ml PBS).
  • the mixture is incubated at 37oC. for 30 min and lyophilized.
  • the lyophilized powder is resuspended in 1 ml PBS.
  • Mice are immunized every 10 to 14 days apart by tail vein injection of 250 ⁇ l of antigen suspension of PBS.
  • mice Three days after the last injection, animals are killed by cervical dislocation and spleens are aseptically excised. Lymphocytes are fused with mouse myeloma SP 2 cells (5:1) using polyethylene glycol. Clones are screened after 11 days of fusion. The clones at this stage are small. Clones were screened using a Pandex machine, in which antigen is coated on submicron polystyrene particles. Antigen-coated beads are mixed with the antibody supernatants, followed by the addition of FITC-goat anti-mouse IgG and IgM.
  • This assay (“Pandex assay”) is two- to fourfold more sensitive than traditional radioimmunoassay or ELISA assay and requires only 10 ng of antigen/well as opposed to 50 to 100 ng/well in other assays. This screening procedure further facilitates the selection of a high-affinity antibody to Lewis x .
  • the clones that test positive are cloned by single-cell dilution and are also tested by TLC immunostaining. Clones producing MAb SH-1, showing high reactivity in the Pandex assay and in TLC immunostaining, are selected and frozen.

Abstract

Des procédés sont décrits pour la détection du cancer du poumon utilisant des combinaisons d'anticorps dirigés contre des séquences d'hydrates de carbone dans des molécules de lipide ou de protéine résidant à la surface des cellules cancéreuses. La présente invention concerne également les procédés de contrôle de l'efficacité de la thérapie contre le cancer du poumon.
EP19920915038 1991-06-26 1992-06-25 Diagnostic precoce du cancer du poumon grace a des combinaisons d'anticorps anti-hydrates de carbone Withdrawn EP0544898A1 (fr)

Applications Claiming Priority (2)

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US72176091A 1991-06-26 1991-06-26
US721760 1991-06-26

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EP0544898A1 true EP0544898A1 (fr) 1993-06-09

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JP (1) JPH06503177A (fr)
WO (1) WO1993000588A1 (fr)

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CA2548394A1 (fr) * 2003-12-12 2005-06-30 Bayer Pharmaceuticals Corporation Procede de prediction et de pronostic du cancer, et surveillance de traitement anticancereux

Family Cites Families (6)

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Publication number Priority date Publication date Assignee Title
US4865998A (en) * 1983-03-11 1989-09-12 Sloan-Kettering Institute For Cancer Research Monoclonal antibodies to human lung cancers and method
US4752569A (en) * 1984-06-21 1988-06-21 The Regents Of The University Of California Sialylated Lewisx epitope, antibodies and diagnosis
US4873188A (en) * 1985-05-28 1989-10-10 Oncogen Method, monoclonal antibody, and monoclonal antibody fragments for detecting human non-small cell lung carcinomas and cell line for producing such antibodies
NZ222509A (en) * 1986-11-19 1993-03-26 Oncogen Hybridoma cell line producing antibodies binding to tumour-associated mucin antigen
AU632469B2 (en) * 1988-04-04 1993-01-07 Johns Hopkins University, The A method for early detection of lung cancer
AU659808B2 (en) * 1990-08-30 1995-06-01 Biomembrane Institute, The Inhibition of metastasis potential and invasiveness by oligosaccharides or oligosaccharide antigens or antibodies

Non-Patent Citations (1)

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Title
See references of WO9300588A1 *

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WO1993000588A1 (fr) 1993-01-07
JPH06503177A (ja) 1994-04-07

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