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EP0688432A1 - Diagnose sätze für einen hcg oder hcg-fragmente sekretierenden krebs und mittel für die immunotherapie eines solchen krebs - Google Patents

Diagnose sätze für einen hcg oder hcg-fragmente sekretierenden krebs und mittel für die immunotherapie eines solchen krebs

Info

Publication number
EP0688432A1
EP0688432A1 EP94909172A EP94909172A EP0688432A1 EP 0688432 A1 EP0688432 A1 EP 0688432A1 EP 94909172 A EP94909172 A EP 94909172A EP 94909172 A EP94909172 A EP 94909172A EP 0688432 A1 EP0688432 A1 EP 0688432A1
Authority
EP
European Patent Office
Prior art keywords
hcg
polypeptides
polypeptide
primary sequence
fragments
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Withdrawn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
EP94909172A
Other languages
English (en)
French (fr)
Inventor
Dominique Bellet
Frédéric TROALEN
Nathalie Rouas-Freiss
Jean-Michel Bidart
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.)
Cephalon France SAS
Original Assignee
Laboratoire L Lafon SA
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
Priority claimed from FR9302820A external-priority patent/FR2702494B1/fr
Priority claimed from FR9312039A external-priority patent/FR2710845B1/fr
Application filed by Laboratoire L Lafon SA filed Critical Laboratoire L Lafon SA
Publication of EP0688432A1 publication Critical patent/EP0688432A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0006—Contraceptive vaccins; Vaccines against sex hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • 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
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/59—Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g.hCG [human chorionic gonadotropin]; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]
    • 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

Definitions

  • Diagnostic kit for a cancer secreting hCG or hCG fragments and means intended for the therapy of such cancer.
  • the present invention relates to a method for the treatment of cancer secreting hCG or fragments of hCG and means for implementing this method.
  • Human gonadotropic chorionic hormone Human gonadotropic chorionic hormone
  • hCG is an oligomeric glycoprotein consisting of the non-covalent association of two subunits ⁇ (hCG- ⁇ ) and ⁇ (hCG- ⁇ ). It belongs to the family of gonadothyreotropic hormones also comprising folliculotropic hormone (FSH), luteotropic hormone (LH) and thyreotropic hormone (TSH). HCG is secreted physiologically by the trophoblast from the start of pregnancy and stimulates the corpus luteum to maintain the synthesis of steroid hormones essential for implantation of the embryo.
  • FSH folliculotropic hormone
  • LH luteotropic hormone
  • TSH thyreotropic hormone
  • hCG and / or its subunits are also secreted by a majority of trophoblastic tumors and certain non-trophoblastic tumors, thus constituting biological markers which can help in the diagnosis or prognosis and in the monitoring of these tumors (Bellet and al. Rev. Prat. 40: 1677-1990).
  • hCG- ⁇ is detectable in healthy men ( ⁇ 1 ng / ml) and women over 45 years of age without menopause ( ⁇ 3 ng / ml). In contrast, hCG- ⁇ is not detectable in the normal population.
  • trophoblastic tumors In the case of trophoblastic tumors, it has been shown that benign (hydatidiform moles) and malignant (choriocarcinomas) placental tumors are characterized by an important serum hCG / hCG- ⁇ ratio: the percentage of free hCG which is 0.05 to 1% during normal pregnancies amounts to 1-5% in the case of moles and exceeds 5% in choriocarcinomas.
  • This serum hCG / hCG- ⁇ ratio is used as a control for the development of testicular tumors: a percentage of hCG- ⁇ becoming less than 5% is often characteristic of a favorable development of the tumor during treatment. This ratio will rise quickly in the event of an unfavorable development or a relapse.
  • hCG- ⁇ not detectable in healthy individuals, is found in many patients with certain non-trophoblastic tumors (tumors of the bladder, pancreas, cervix, tumors without primitive found, endometrial and lung tumors).
  • the subject of the present invention is a method of treating cancer secreting hCG or fragments of hCG which consists in
  • the polypeptides are formed by a chain of 9 to 40 amino acids corresponding to a part of the primary sequence of hCG. They may in particular be polypeptides comprising from 15 to 40 amino acids or, in the case of polypeptides capable of being recognized by cytotoxic T lymphocytes, shorter polypeptides having in particular from 9 to 11 amino acids.
  • set of polypeptides covering at least part of the primary sequence of hCG denotes a set of polypeptides as defined above which correspond to successive sequences of hCG or of its fragments or better which correspond to sequences overlapping.
  • At least one set of polypeptides will be used which covers the primary sequence of the ⁇ subunit of hCG or at least part of this sequence.
  • the synthesis of the ⁇ subunit is dependent on an ultigenic group comprising 7 genes (Talmadge et al., Nucl. Acids Res. 12, 8415, 1984). Analysis of the nucleotic sequences shows that three of these genes (1, 3, 5) have an identical structure, four others of these genes (2, 6, 7 and 8) encode a variant at codon 117 with substitution. alanine instead of an aspartic acid.
  • a study of gene expression shows that genes 1, 3 and 5 are expressed by the normal placenta.
  • tumourogenesis processes involving non-trophoblastic cells the expression of several genes leads to both the secretion of the normal protein and of a protein mutated to 117.
  • ⁇ subunit denotes both the normal protein and the protein mutated at 117.
  • polypeptide corresponding to the antigen responsible for the state of immunization means a polypeptide which has the same sequence as one of the polypep ⁇ tides responsible for the state of immunization or a sequence resulting from the combination of sequences at least partial of the polypeptides responsible for the state of immunization.
  • the state of immunization with respect to one of the polypeptides can be identified by a test for stimulating the proliferation of T lymphocytes by the polypeptides, or also by a test for cytotoxicity of T lymphocytes against vis the polypeptides.
  • the recognized polypeptides are formed by a sequence of at least 9 amino acids corresponding to a part of the primary sequence of 1'hCG.
  • the polypeptides interact with the class I molecules of the major histocompatibility complex of the patient. Each class I molecule interacts with peptides with specific motifs.
  • the present invention also relates to a diagnostic kit for a cancer secreting hCG or hCG fragments comprising a set of polypeptides covering at least part of the primary sequence of 1'hCG.
  • the subject of the present invention is also a composition intended for the immunotherapy of cancers secreting hCG or hCG fragments comprising an effective dose of a polypeptide corresponding to at least part of the primary sequence of hCG and in particular a polypeptide corresponding to at least part of the primary sequence of the hCG ⁇ subunit and a pharmaceutically acceptable vehicle.
  • the present invention also relates to the use of a polypeptide corresponding to at least a part of the primary sequence of 1'hCG and in particular of a polypeptide corresponding to at least a part of the primary sequence of the ⁇ subunit hCG for the manufacture of a composition for the immunotherapy of cancers secreting hCG or fragments of hCG.
  • poly ⁇ peptides can be used in free form or in a more immunogenic form, in particular a form in which the peptide is coupled to a polylysine matrix according to the MAP technique (Posnett et al. J. Biol. Chem. 263, 17, 1988).
  • the polypeptide is advantageously administered with an adjuvanting immunity.
  • adjuvants of immunity we may cite muramyldipeptide and SAF-1 (Allison et al., J. Immunol. Methods 45, 157, 1986).
  • polypeptide can be protected at its NH 2 and COOH terminal ends in order to reduce the risks of degradation.
  • the BCG vaccine (Bacillus Calmette Guérin) constituted by living attenuated strains of tuberculous bacillus (see in particular D. Lamm et al, New England Journal of Medicine 325, 17, 1205, 1991).
  • the present invention therefore further relates to a composition intended for the immunotherapy of cancers secreting hCG or hCG fragments comprising an effective dose of a polypeptide corresponding to at least part of the primary sequence of hCG and an effective dose of BCG in a pharmaceutically acceptable vehicle.
  • immunotherapy can be carried out with doses of polypeptides from 1 to 100 mg administered in particular at the level of the tumor.
  • the polypeptides can be administered in the case of bladder cancer, as is already practiced in the case of immunotherapy with BCG, that is to say by intravesical instillation one week after resection. tumor, then this administration is repeated every week for 6 weeks and additional intravesical administration is performed 3, 6, 12, 18 and 24 months later.
  • Percutaneous or general administrations are also possible. Description of the figures.
  • Fig. 1 shows the proliferation of lymphocytes from a patient with bladder cancer in the presence of hCG, free ⁇ and ⁇ subunits and various polypeptides.
  • Fig. 2 shows the proliferation of lymphocytes from another patient with bladder cancer in the presence of free ⁇ and ⁇ subunits and different polypeptides.
  • Fig. 3A shows the proliferation of lymphocytes from a patient with bladder cancer in the presence of different polypeptides.
  • Fig. 3B shows the proliferation of lymphocytes from a patient with testicular cancer in the presence of different polypeptides.
  • PBMC mononuclear cells
  • the PBMCs are cultured (2 ⁇ 10 5 cells per well) in RPMI 1640 supplemented with 10% human AB serum, 2 mM L-glutamine, 100 IU / ml of penicillin and 100 ⁇ g / ml of streptomycin, in the presence of polypeptide at different concentrations.
  • the cells are then incubated at 37 ° C with 5% C0 2 for 5 days.
  • a ⁇ Ci of tritiated thymidine is then added to each well.
  • the cells are collected 18 hours later and The incorporation of the radioactivity is analyzed by spectrometry in a scintillation liquid using a ⁇ counter.
  • FIG. 1 We have given in FIG. 1 the results of proliferation of lymphocytes from a patient with bladder cancer in the presence
  • results demonstrate a significant proliferation with the polypeptide corresponding to the sequence 95-115 of the ⁇ subunit of hCG as well as with the polypeptide corresponding to the sequence 25-59 of the ⁇ subunit of the hCG.
  • the 95-115 hCG- ⁇ and 25-59 hCG- ⁇ polypeptides can be used for immunotherapy in the patient tested.
  • FIG. 2 results of the same type on lymphocytes from another patient with bladder cancer.
  • the results demonstrate a significant proliferation with the polypeptide corresponding to the sequence 31 - 50 of the ⁇ subunit of hCG as well as with the polypeptide corresponding to the sequence 41 - 61 of the ⁇ subunit of the hCG.
  • hCG- ⁇ and 41-61 hCG- ⁇ polypeptides 31 - 50 can be used for immunotherapy.
  • FIG. 3A We have given in FIG. 3A the results of PBMC proliferation tests of another patient with bladder cancer secreting the ⁇ subunit of hCG in the presence of different polypeptides covering the entire ⁇ subunit of hCG (50 ⁇ m).
  • T cells from a patient with testicular cancer secreting hCG- ⁇ , proliferated in the presence of the peptide hCG- ⁇ (20-47) (Fig. 3B).
  • PBMCs isolated by Ficoll gradient are tested for their cytotoxic action against autologous targets (patient B lymphocytes immortalized by Epstein-Barr virus) labeled with chromium 51 and serving as cells presenting the hCG polypeptides. . Cytotoxicity is evaluated by counting the radioactivity due to the release of 51 Cr from the lysed target.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Endocrinology (AREA)
  • Public Health (AREA)
  • Microbiology (AREA)
  • Veterinary Medicine (AREA)
  • Mycology (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Reproductive Health (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Urology & Nephrology (AREA)
  • Biochemistry (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • General Physics & Mathematics (AREA)
  • Toxicology (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Zoology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pathology (AREA)
  • Analytical Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Virology (AREA)
  • Food Science & Technology (AREA)
  • Cell Biology (AREA)
  • Biotechnology (AREA)
EP94909172A 1993-03-11 1994-03-10 Diagnose sätze für einen hcg oder hcg-fragmente sekretierenden krebs und mittel für die immunotherapie eines solchen krebs Withdrawn EP0688432A1 (de)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
FR9302820 1993-03-11
FR9302820A FR2702494B1 (fr) 1993-03-11 1993-03-11 Trousse de diagnostic d'un cancer secrétant l'hCG ou des fragments d'hCG et vaccin destiné à l'immunothérapie d'un tel cancer.
FR9312039A FR2710845B1 (fr) 1993-10-08 1993-10-08 Composition destinée à l'immunothérapie d'un cancer sécrétant l'hCG ou des fragments d'hCG.
FR9312039 1993-10-08
PCT/FR1994/000265 WO1994020859A1 (fr) 1993-03-11 1994-03-10 TROUSSE DE DIAGNOSTIC D'UN CANCER SECRETANT L'hCG OU DES FRAGMENTS D'hCG ET MOYENS DESTINES A L'IMMUNOTHERAPIE D'UN TEL CANCER

Publications (1)

Publication Number Publication Date
EP0688432A1 true EP0688432A1 (de) 1995-12-27

Family

ID=26230164

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94909172A Withdrawn EP0688432A1 (de) 1993-03-11 1994-03-10 Diagnose sätze für einen hcg oder hcg-fragmente sekretierenden krebs und mittel für die immunotherapie eines solchen krebs

Country Status (6)

Country Link
EP (1) EP0688432A1 (de)
JP (1) JPH08507604A (de)
AU (1) AU6211294A (de)
CA (1) CA2157868A1 (de)
NZ (1) NZ262435A (de)
WO (1) WO1994020859A1 (de)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5677275A (en) * 1994-08-05 1997-10-14 The United States Of America As Represented By The Department Of Health And Human Services Treatment of cancer with human chorionic gonadotropin
FR2745638A1 (fr) 1996-03-04 1997-09-05 Roussy Inst Gustave Procede pour la detection de la transformation maligne de cellules humaines
US5968513A (en) * 1996-06-24 1999-10-19 University Of Maryland Biotechnology Institute Method of promoting hematopoiesis using derivatives of human chorionic gonadotropin
US6319504B1 (en) 1996-06-24 2001-11-20 University Of Maryland Biotechnology Institute Treatment and prevention of HIV infection by administration of derivatives of human chorionic gonadotropin
US5997871A (en) * 1996-06-24 1999-12-07 University Of Maryland Biotechnology Insitute Treatment and prevention of cancer by administration of derivatives of human chorionic gonadotropin
US6583109B1 (en) 1997-06-24 2003-06-24 Robert C. Gallo Therapeutic polypeptides from β-hCG and derivatives
US7994278B1 (en) * 1999-08-06 2011-08-09 Nobel Biosciences Llc Biologically active polypeptides derived from a novel early stage pregnancy factor designated maternin (MA)

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4201770A (en) * 1973-05-07 1980-05-06 The Ohio State University Antigenic modification of polypeptides
US4234561A (en) * 1978-02-06 1980-11-18 Research Corporation Antigen for early pregnancy test and contraceptive vaccine
US4713366A (en) * 1985-12-04 1987-12-15 The Ohio State University Research Foundation Antigenic modification of polypeptides
FR2623715B1 (fr) * 1987-11-26 1990-12-21 Lafon Labor Structures peptidiques, immunogenes les contenant et leurs applications au controle de la fertilite
GB8821507D0 (en) * 1988-09-14 1988-10-12 Cancer Res Campaign Tech Improvements relating to peptides
WO1992007272A1 (en) * 1990-10-17 1992-04-30 Yale University Methods for detecting and following the course of cancer, pregnancy and trophoblastic disease

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9420859A1 *

Also Published As

Publication number Publication date
CA2157868A1 (fr) 1994-09-15
NZ262435A (en) 1997-05-26
WO1994020859A1 (fr) 1994-09-15
AU6211294A (en) 1994-09-26
JPH08507604A (ja) 1996-08-13

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