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WO1990002187A1 - Proteines de fusion recombinantes modifiant la secretion hormonale - Google Patents

Proteines de fusion recombinantes modifiant la secretion hormonale Download PDF

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Publication number
WO1990002187A1
WO1990002187A1 PCT/EP1989/001013 EP8901013W WO9002187A1 WO 1990002187 A1 WO1990002187 A1 WO 1990002187A1 EP 8901013 W EP8901013 W EP 8901013W WO 9002187 A1 WO9002187 A1 WO 9002187A1
Authority
WO
WIPO (PCT)
Prior art keywords
protein
fusion protein
antigenic
gene
lhrh
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.)
Ceased
Application number
PCT/EP1989/001013
Other languages
English (en)
Inventor
Scott C. Chappel
Noreen P. Nugent
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.)
Applied Research Systems ARS Holding NV
Original Assignee
Applied Research Systems ARS Holding NV
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 Applied Research Systems ARS Holding NV filed Critical Applied Research Systems ARS Holding NV
Priority to FI902151A priority Critical patent/FI902151A7/fi
Publication of WO1990002187A1 publication Critical patent/WO1990002187A1/fr
Priority to NO90901842A priority patent/NO901842L/no
Priority to DK106590A priority patent/DK106590A/da
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/62—DNA sequences coding for fusion proteins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/40—Fusion polypeptide containing a tag for immunodetection, or an epitope for immunisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction
    • C07K2319/74—Fusion polypeptide containing domain for protein-protein interaction containing a fusion for binding to a cell surface receptor
    • C07K2319/75—Fusion polypeptide containing domain for protein-protein interaction containing a fusion for binding to a cell surface receptor containing a fusion for activation of a cell surface receptor, e.g. thrombopoeitin, NPY and other peptide hormones
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2730/00—Reverse transcribing DNA viruses
    • C12N2730/00011—Details
    • C12N2730/10011—Hepadnaviridae
    • C12N2730/10111—Orthohepadnavirus, e.g. hepatitis B virus
    • C12N2730/10122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • This invention relates to the production of fusion proteins produced by recombinant DNA technology and used as active iminunogens against peptides which are not inherently antigenic.
  • a highly antigenic protein such as the hepatitis surface antigen (KBsAg)
  • KBsAg hepatitis surface antigen
  • a fusion protein may be expressed.
  • polyclonal antibodies are produced that are directed against both the highly antigenic protein and the protein of interest.
  • LHRH hypothalamic decapeptide
  • LHRH-pituitary interactions may be elicited through the administration of long-acting competitive antagonists of LHRH.
  • These synthetic peptides bind to the pituitary LHRH receptor but do not stimulate post-receptor intracellular activities. Due to their unusually long receptor occupancy, caused by their resistance to proteolytic inactivation, these peptides induce a state of pituitary insensitivity to LHRH due to down regulation of LHRH receptor number.
  • This pharmacologic reduction in pituitary stimulation by LHRH antagonists results in a reduction in gonadotropin release and infertility (Labrie et al [eds] LHRH and its analogs. Amsterdam: Elsevier Scientific Publishers. 1984).
  • a vaccine that is easily administered is likely to supplant surgical sterilization while providing an effective contraceptive for dogs, cats and other mammals.
  • Pregnant cows typically do not exhibit an attractive feed to meat conversion since the developing fetus requires great nutritional requirements. As a result, feed lot owners generally pay substantially less for a cow in which the pregnancy status is unknown or unconfirmed. A certain percentage of cows enter the feed lot pregnant and the fetus represents waste. Thus, a method to induce an infertile state in cows 6-10 months prior to shipment is considered to be a viable, valuable product. If the farmer could guarantee that his cattle are "barren" he could command a higher price for his animals. It is, therefore, another object to provide a recombinant, injectable product which would result in inhibition of ovulatory cyclicity in feedlot heifers.
  • this method of the present invention employs molecular biology techniques to fuse cDNAs together, and to place them into a eukaryotic expression vector for the production of unique fusion proteins.
  • the majority of this fusion protein is a highly antigenic and potent immunogen. It should have substantial hydrophilicity.
  • Such immunogens are coat proteins such as the hepatitis B surface antigen.
  • An oligonucleotide coding for the peptide of interest, against which it is desired to raise anti-bodies, such as the luteinizing hormone releasing hormone molecule, is placed in one or more regions of the protein, preferably in the one or more regions having the highest hydrophilicity.
  • LHRH-HBsAg fusion protein in therapeutically effective concentration, will result in the development of antibodies against the entire molecule. A portion of these antibodies will be directed against the peptide of interest. Most preferably, when the peptide is LHRH, sufficient titres of antibodies against LHRH will be provided thereby preventing hypothalamic-pituitary communication and inducing an infertile state.
  • This immunogen may also be advantageously employed in a variety of commercial or therapeutic settings including an animal anti-fertility vaccine and treatment for benign prostatic hypertrophy.
  • the fusion proteins of the present invention are sufficiently immunogenic so as to preclude the necessity of use of adjuvants or multiple injection, neither of which are well tolerated by the subject.
  • Figure 1 Illustrates the insertion of gonadotropin releasing
  • HBsAg protein hormone sequences within the exposed hydrophilic region of HBsAg protein.
  • HBsAg protein At the top is a diagram of the HBsAg protein in which the site containing the LHRH decapeptide is stippled. Below that is the Avail site along the cDNA that codes for HBsAg in which the cDNA for LHRH is ideally inserted. The figure at the bottom represents a viral coat particle with LHRH inserted between the coat protein sequences.
  • Figure 2 Illustrates a synthetic DNA linker that will be inserted into the Avail site of the HBsAg (see Fig. 1).
  • This linker provides a flexible insertion site for oligonucleotide sequences after amino acid 119 (glycine) of the HBsAg. It results in the insertion of three amino acids before the resumption of the HBsAg sequence at the proline residue (position 120).
  • the LHRH fragment is preferably inserted between the Smal and Bglll site of the linker. Addition of the linker will maintain the proper reading frame (see Fig. 3).
  • Figure 4 Diagrams the scheme used to insert HBsAg-LHRH fusion
  • the plasmid BPV-HL is advantageously used to transform C127 cells.
  • This gene is advantageously expressed in our mammalian expression system.
  • the DNA encoding the coat protein was cloned into the mouse metallothionein gene, just a few base pairs from the site of transcription initiation. All of the signals that regulate the expression of the inserted gene (for coat protein) in mammalian cells are supplied by the mouse gene, whose coding sequences and poly A addition signals lie downstream from the insert.
  • the surface antigen protein is secreted into the medium where it is found in the form of particles.
  • the recombinant product i.e., surface antigen without nuclear material
  • the amino acid sequence of the hepatitis antigen was determined. This sequence was analyzed for the region of the molecule that would be expected to have the most hydrophilic properties. Into that region (identified by the Avail site in Figure 1) was cloned a short oligonucleotide sequence that provides unique cloning sites ( Figure 2). Into this region, cDNA sequences encoding for specific proteins may be inserted either by blunt end ligation at a unique Smal site or at the Bglll site (see Figure 2).
  • the oligonucleotide encoding LHRH was synthesized on an Applied Biosystems 380-A automated DNA synthesizer using the solid phase synthetic methods developed by Caruthers et al (Genetic Engineering 4:1-17, 1982).
  • the oligonucleotide was cleaved from the solid support using concentrated ammonium hydroxide. Purification was achieved using preparative gel electrophoresis. The purified oligonucleotide was polynucleotide kinase and analyzed by gel electrophoresis for size and purity.
  • the LHRH oligonucleotide was inserted into the Smal and Bglll cloning site by the following method: The LHRH oligonucleotide was synthesized (as shown in Figure 3) to contain a 3' blunt end and a 5' CTAG overhang. Following digestion of the HBsAg DNA (containing the synthetic insert) with S ⁇ ia I and Bglll, the LHRH DNA was inserted. The resultant construction was named HBsAg-LHRH. Synthetic BamHI linkers were added to each terminus of the HBsAg-LHRH cDNA and inserted into the vector CL28/Bam in the proper orientation. CL28/Bam obtained from Dr. Dean Hamer (at the NIH) contains a 3.8 kbp mouse DNA fragment that includes the entire metallothionein gene, including upstream control elements, inserted into the EcoRI site of the bacterial vector pBR322.
  • CL28/Bam is a derivative of pJYMMT (E) (Hamer, Dean et al , J . Mol . Appl . Genet. 1, 4 , 273-288 (1982)) which is identical to pJYMMT(E) except for the removal of the SV40 sequences.
  • E pJYMMT
  • a unique Bglll site located just after the transcriptional initiation region of the mouse gene allows the insertion of foreign genes as BamHI fragments which have the same 5' overhang (GATC) as the cut Bglll site.
  • the resultant hepatitis B surface protein contained an LHRH sequence within a hydrophilic region of the molecule.
  • HBsAg/LHRH protein 10 ⁇ g of the purified BPV-HBsAg-LHRH cDNA was added to 0.5 ml of a 250mm CaCl 2 solution containing 10 ⁇ g salmon sperm DNA as a carrier. The mixture was bubbled into 0.5ml of 28mM NaCl, 50mM HEPES and 1.5mM sodium phosphate. The calcium phosphate precipitate was allowed to form for 30-40 minutes at room temperature.
  • Medium obtained from the cell lines was tested for presence of HBsAg and LHRH immunoactivity.
  • Tissue culture medium was clarified by low speed centrifugation and HBsAg particles were sedimented at 42,000 rpm (200,000 xg) for 4 hours.
  • Pellets were resuspended in a small volume of phosphate-buffered saline and assayed along with starting material and supernatants for HBsAg activity with a commercial radioimmunoassay (RIA) purchased from Clinical Assays, Inc.
  • RIA radioimmunoassay
  • the culture medium supernatants and resuspended pellets were analyzed for LHRH immunoactivity with a radioimmunoassay utilizing LHRH antiserum purchased from Arnel Antibodies, Inc.
  • LHRH for iodination and the reference preparation were purchased from Sigma Fine Chemicals, Inc., and the insoluble protein A (to pellet antigenantibody complexes) was obtained from Sigma Fine Chemicals, Inc.
  • cell lines expressing the fusion protein were produced and readily identified by standard screening methods.
  • the appropriate dose to elicit an infertile state in male rabbits or other animals may be determined with a titration type procedure.
  • male rabbits injected with 0.5, 1 or 5 mg of the protein coupled with blood sample collection will allow determination of serum gonadotropin and testicular steroid levels as well as anti-LHRH antibody titres.
  • appropriate boosting intervals may also be determined.
  • fusion genes and gene products such as the selection of the antigenic gene or the protein gene whose activity is to be immunologically suppressed, without departing from either the spirit or scope of the present invention.
  • highly immunogenic proteins other than HBsAg may be used, such as other hydrophilic coat proteins or the hepatitis B core antigen.
  • peptides other than LHRH may be used. While a similar method has been reported for presenting antigenic epitopes to the immune system, in Australian patent 69792/87, antigenic epitopes are always used, such as viral, bacterial or protozoan epitopes. It has not before been suggested to use non-antigenic peptides in such a fusion protein in order to be able to induce the production of antibodies against such peptides without the disadvantages of prior art haptenization techniques.
  • substantially non-antigenic peptides are peptides which do not substantially differ in structure across species or any other peptide or protein which, when injected into a foreign animal, does not cause any substantial titre of anti ⁇ bodies to be raised against it.
  • LHRH growth hormone releasing hormone, adrenocorticotropin hormone, parathyroid hormone, inhibin, and subunits of gonadotropins. Portions of or slightly modified versions of such peptides may also be used.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • Zoology (AREA)
  • Biophysics (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Biomedical Technology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Wood Science & Technology (AREA)
  • General Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Veterinary Medicine (AREA)
  • Reproductive Health (AREA)
  • Diabetes (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Plant Pathology (AREA)
  • Microbiology (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Physics & Mathematics (AREA)
  • Toxicology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Virology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

L'invention concerne une protéine de fusion recombinante résultant de l'expression de deux gènes régulée par un seul promoteur, ayant pour effet de modifier la sécrétion hormonale lorsqu'on l'administre dans une dose thérapeutiquement efficace. Un gène code pour la production d'une protéine hydrophile hautement antigénique telle que l'antigène de surface de l'hépatite B, et l'autre gène code pour un peptide qui seul n'est pas sensiblement antigénique, tel que l'hormone de libération de la lutéostimuline.
PCT/EP1989/001013 1988-08-30 1989-08-29 Proteines de fusion recombinantes modifiant la secretion hormonale Ceased WO1990002187A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
FI902151A FI902151A7 (fi) 1988-08-30 1989-08-29 Yhdistelmä-DNA-fuusioproteiineja hormonierityksen muuttamiseksi
NO90901842A NO901842L (no) 1988-08-30 1990-04-25 Rekombinante fusjonsproteiner for endring av hormonutskillelse.
DK106590A DK106590A (da) 1988-08-30 1990-04-30 Rekombinant-fusionsproteiner til aendring af hormon sekretion

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US24655888A 1988-08-30 1988-08-30
US246,558 1988-08-30

Publications (1)

Publication Number Publication Date
WO1990002187A1 true WO1990002187A1 (fr) 1990-03-08

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ID=22931196

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1989/001013 Ceased WO1990002187A1 (fr) 1988-08-30 1989-08-29 Proteines de fusion recombinantes modifiant la secretion hormonale

Country Status (9)

Country Link
EP (1) EP0396653A1 (fr)
JP (1) JPH03502584A (fr)
AU (1) AU629237B2 (fr)
DK (1) DK106590A (fr)
FI (1) FI902151A7 (fr)
GR (1) GR1000321B (fr)
IL (1) IL91462A0 (fr)
WO (1) WO1990002187A1 (fr)
ZA (1) ZA896628B (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0448513A3 (en) * 1990-03-21 1991-12-27 Japat Ltd Process for production of peptidylglycine alpha-hydroxylating monooxygenase and use thereof
WO1992013081A1 (fr) * 1991-01-24 1992-08-06 British Technology Group Ltd. Capside presentant un antigene, avec une proteine enveloppe de ms2 de fusion
US5688506A (en) * 1994-01-27 1997-11-18 Aphton Corp. Immunogens against gonadotropin releasing hormone
EP1035133A3 (fr) * 1999-02-17 2002-09-25 Pfizer Products Inc. Protéines de fusion comprenant des supports capables d' induire une double réponse immunitaire
US6783761B2 (en) 2000-05-05 2004-08-31 Aphton Corporation Chimeric peptide immunogens

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05339295A (ja) * 1991-12-05 1993-12-21 Agency Of Ind Science & Technol 抗体の作成方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3963691A (en) * 1974-10-07 1976-06-15 Merck & Co., Inc. Synthetic antigens of luteinizing hormone releasing hormone
EP0131363A1 (fr) * 1983-05-24 1985-01-16 Celltech Limited Produits polypeptidiques et protéiniques et procédés pour leur production et utilisation
EP0175261A2 (fr) * 1984-09-12 1986-03-26 Chiron Corporation Immunogènes à base de particule hybride
EP0219106A2 (fr) * 1985-10-17 1987-04-22 F. Hoffmann-La Roche Ag Polypeptides induisant des anticorps contre le virus du SIDA

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL78775A (en) * 1985-05-15 1992-06-21 Biotech Australia Pty Ltd Oral vaccines
EP0224574A4 (fr) * 1985-06-04 1988-04-26 Biotech Res Partners Ltd Vaccins auto-antigenes.

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3963691A (en) * 1974-10-07 1976-06-15 Merck & Co., Inc. Synthetic antigens of luteinizing hormone releasing hormone
EP0131363A1 (fr) * 1983-05-24 1985-01-16 Celltech Limited Produits polypeptidiques et protéiniques et procédés pour leur production et utilisation
EP0175261A2 (fr) * 1984-09-12 1986-03-26 Chiron Corporation Immunogènes à base de particule hybride
EP0219106A2 (fr) * 1985-10-17 1987-04-22 F. Hoffmann-La Roche Ag Polypeptides induisant des anticorps contre le virus du SIDA

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0448513A3 (en) * 1990-03-21 1991-12-27 Japat Ltd Process for production of peptidylglycine alpha-hydroxylating monooxygenase and use thereof
WO1992013081A1 (fr) * 1991-01-24 1992-08-06 British Technology Group Ltd. Capside presentant un antigene, avec une proteine enveloppe de ms2 de fusion
US5534257A (en) * 1991-01-24 1996-07-09 British Technology Group Limited Antigen-presenting capsid with fusion MS2-coat protein
US5688506A (en) * 1994-01-27 1997-11-18 Aphton Corp. Immunogens against gonadotropin releasing hormone
US6132720A (en) * 1994-01-27 2000-10-17 Aphton Corp. Immunogens against gonadotropin releasing hormone
US6303123B1 (en) 1994-01-27 2001-10-16 Aphton Corporation Methods for the treatment of hormone-dependent tumors with immunogens against gonadotropin releasing hormone
EP1035133A3 (fr) * 1999-02-17 2002-09-25 Pfizer Products Inc. Protéines de fusion comprenant des supports capables d' induire une double réponse immunitaire
US6911206B1 (en) * 1999-02-17 2005-06-28 Pfizer Inc. Fusion proteins comprising carriers that can induce a dual immune response
US6783761B2 (en) 2000-05-05 2004-08-31 Aphton Corporation Chimeric peptide immunogens

Also Published As

Publication number Publication date
AU4076189A (en) 1990-03-23
JPH03502584A (ja) 1991-06-13
IL91462A0 (en) 1990-04-29
FI902151A0 (fi) 1990-04-27
FI902151A7 (fi) 1990-04-27
GR1000321B (el) 1992-06-25
AU629237B2 (en) 1992-10-01
EP0396653A1 (fr) 1990-11-14
DK106590D0 (da) 1990-04-30
DK106590A (da) 1990-04-30
GR890100540A (en) 1990-08-22
ZA896628B (en) 1991-04-24

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