EP1272214A1 - Vaccin contre des maladies cancereuses, a base de mimotopes d'antigenes exprimes sur des cellules tumorales - Google Patents

Vaccin contre des maladies cancereuses, a base de mimotopes d'antigenes exprimes sur des cellules tumorales

Info

Publication number
EP1272214A1
EP1272214A1 EP01925550A EP01925550A EP1272214A1 EP 1272214 A1 EP1272214 A1 EP 1272214A1 EP 01925550 A EP01925550 A EP 01925550A EP 01925550 A EP01925550 A EP 01925550A EP 1272214 A1 EP1272214 A1 EP 1272214A1
Authority
EP
European Patent Office
Prior art keywords
mimotopes
antibodies
tumor cells
antibody
vaccine
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
EP01925550A
Other languages
German (de)
English (en)
Inventor
Christoph Zielinski
Otto Scheiner
Erika Jensen-Jarolim
Heimo Breiteneder
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.)
Bio Life Science Forschungs- und Entwicklungsgesmbh
Original Assignee
Bio Life Science Forschungs- und Entwicklungsgesmbh
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 DE10018403A external-priority patent/DE10018403A1/de
Priority claimed from DE10041342A external-priority patent/DE10041342A1/de
Application filed by Bio Life Science Forschungs- und Entwicklungsgesmbh filed Critical Bio Life Science Forschungs- und Entwicklungsgesmbh
Publication of EP1272214A1 publication Critical patent/EP1272214A1/fr
Ceased legal-status Critical Current

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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
    • A61K39/0011—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • 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

Definitions

  • the present invention relates to a method for producing a vaccine against cancer, and this vaccine itself.
  • the invention is based on the finding that such a vaccine can be obtained by a process which uses antibodies which are active against an antigen formed by the tumor cells in order to obtain mimotopes of this antigen, by means of which a body's immune response can be stimulated.
  • the present invention relates to a method for producing a vaccine against cancer, which is characterized in that first of all using one or more of the body's own or synthetic antibodies, which are specifically active against one or more antigens specifically expressed by the tumor cells, from a phage. Peptide library one or more mimotopes of these antigens are selected and these mimotopes are then conjugated to a macromolecular carrier.
  • the present invention furthermore relates to a vaccine against cancer which can be produced by this method.
  • Vaccines against cancer diseases are obtained by the method according to the invention, even if the nature or structure of the corresponding antigen is not known or is not known in detail.
  • the vaccines obtained are phage-free and therefore ideally suited for vaccination in the human system.
  • the vaccine in particular also enables prophylaxis against cancer, i.e. the vaccine according to the invention is able to protect against a potential cancer by active immunization, that is to say not to let it arise in the first place.
  • the vaccine can also be used to treat an existing cancer.
  • antibodies are used in the method according to the invention which have already proven effective as such in clinical tests against cancer.
  • the vaccine when the vaccine is administered, the formation of the body's own antibodies against those antigens of the cancer cells against which the clinically tested antibodies are also effective is induced. This increases the effectiveness of the vaccine.
  • the mimotopes obtained in the process according to the invention can be conjugated to the macromolecular carrier in any manner, for example by genetic engineering or chemical means which the mimotopes are bound to the carrier by means of a chemical reaction.
  • the mimotopes are preferably provided with a linker such as, for example, a short-chain oligopeptide before the conjugation with the carrier.
  • the conjugation to the carrier then takes place via the linker.
  • the mimotopes are conjugated to the carrier by genetic engineering, i.e. the vaccine is prepared so that a DNA or RNA sequence coding for the vaccine is incorporated into an expression system so that the entire vaccine, i.e. the carrier with the mimotopes bound to it is expressed.
  • the mimotopes found with the help of the antibodies can be conjugated as mono-, di-, tri- or oligomers with a macromolecular carrier.
  • Such conjugations are described, for example, in the publication by Th.H. Turpen, S.J. Reinl, Y. Charoenvit, S.L. Hoffman, V. Fallarme in Bio / Technology 1995, Volume 13, pages 53 to 57 using the example of conjugation of epitopes with macromolecular carriers.
  • the described procedures can be transferred analogously to the conjugation of the mimotopes used in the method according to the invention with the macromolecular carrier. Reference is hereby made to the disclosure content of this publication.
  • RNA sections coding for the epitopes are integrated either individually or one or more times in succession into the RNA sequence of the carrier.
  • the expression of mono-, di- or oligomeric epitope conjugates is thereby achieved.
  • the RNA or DNA sections coding for the mimotopes are integrated as mono-, di-, tri- or oligomeric mimotope sequences into the RNA or DNA sequence of the carrier.
  • the mono-, di-, tri, or oligomeric mimotopes can be bound to the macromolecular carrier either simply or in multiple form.
  • the present invention provides a method for producing a vaccine against adenocarcinomas of the gastrointestinal tract, prostate carcinoma, breast cancer (breast carcinoma), multiple myeloma, B-lymphoproliferative post-graft syndrome, B-cell malignancy and chronic lymphatic leukemia available.
  • the vaccine produced by the process can counteract the development of these cancers.
  • the antibodies used for the production of the vaccine against cancer diseases according to the invention are specifically effective against antigens which are specifically expressed by tumor cells.
  • these antibodies can be the body's own, as are present in the blood serum of sick patients as a result of the humoral immune response to the antigen or antigens.
  • These antibodies are produced or isolated using known, conventional methods.
  • monoclonal antibodies but also polyclonal antibodies can be used in the method according to the invention.
  • the body's own or synthetic antibodies used in the method according to the invention include those antibodies which trigger an antibody-dependent cellular cytotoxicity (ADCC reaction) or which recognize a receptor acting as an antigen for a growth factor of the tumor cells.
  • ADCC reaction antibody-dependent cellular cytotoxicity
  • the use of such antibodies ensures a particularly pronounced effect of the vaccine obtainable by the process according to the invention.
  • the body's own or synthetic antibodies used in this embodiment preferably comprise those antibodies which are directed against the HER-2 / neu protein expressed by the tumor cells or the epithelial glycoprotein antigen, C017-1A, or the phosphoprotein surface antigen on lymphocytes, CD20, or the Epidermal Growth Factor (EGF) - receptor are specifically effective.
  • EGF Epidermal Growth Factor
  • the HER-2 / neu protein is a receptor for a growth factor, under whose control the tumor cells grow.
  • Antibodies against the HER-2 / neu protein are described for example in US 5,772,997. Reference is hereby made to the disclosure content of this patent.
  • Herceptin is a humanized monoclonal antibody derived from mice. Herceptin is active against the HER-2 / neu antigen, which is often overexpressed as a growth factor receptor on tumor cells. Especially in breast cancer tumors, the HER-2 / neu antigen is specifically expressed on the cell surface in about 20 - 30% of cases.
  • the administration of Herceptin leads to the initiation of the natural cell death of the tumor cells which re-express the HER-2 /.
  • the vaccine produced according to the invention is particularly effective against the types of cancer in which HER-2 / neu is expressed on the tumor cells, i.e. e.g. against breast cancer.
  • the body's own or synthetic antibodies used in the method according to the invention comprise the clinically proven antibody preparation Panorex from GlaxoWellcome. This antibody preparation is also known as edrecolamab.
  • Panorex is a monoclonal antibody derived from mice. As by Riethmüller et al., Lancet 343 (1994) 1177-83 Panorex is directed against the epithelial glycoprotein antigen C017-1A. Reference is hereby made to the disclosure content of this publication. Panorex is particularly effective against adenocarcinomas of the gestrointestinal tract (Punt, Cancer 83 (1998) 679-89; Martin et al., J. Clin. Pathol.
  • the body's own or synthetic antibodies used in the method according to the invention comprise the clinically proven antibody preparation MabThera from Genentech Inc.
  • This antibody preparation is also referred to as Rituxan (IDEC Pharmaceuticals) or Rituximab (Hoffmann-LaRoche).
  • MabThera is a humanized, monoclonal antibody that is obtained from mice and is directed against the phosphoprotein surface antigen on lymphocytes, CD20. MabThera is particularly effective against multiple myeloma (Treon et al., Ann. Oncol. 1 1 (2000) 107-1 1), against B-lymphoproliferative post-graft syndrome (Milpied et al., Ann. Oncol.
  • the vaccine produced according to the invention is particularly effective against these types of cancer.
  • the body's own or synthetic antibodies used in the method according to the invention include the antibody preparation IMC-C225 (cetuximab) from ImClone, which is in clinical studies.
  • IMC-C225 (cetuximab) is a chimerized monoclonal antibody that targets the Epidermal Growth Factor (EGF) receptor.
  • EGF Epidermal Growth Factor
  • IMC-C225 (cetuximab) is particularly effective against head and neck tumors (Hueng et al., Cancer Res. 59 (1999), 1935-40; Baselga et al., J. Clin. Oncol. 18 (2000) 904-14). Reference is hereby made to the disclosure content of these publications.
  • the vaccine produced in the method according to the invention is particularly effective against these types of cancer.
  • the representation of the mimotopes or the mimotope conjugates selected from the phage peptide libraries preferably takes place using a plant expression system, such as the tobacco mosaic virus system.
  • a plant expression system such as the tobacco mosaic virus system.
  • the expression of the mimotopes or the mimotope conjugates can take place by transient infection of the host plants with tobacco mosaic viruses.
  • the mimotopes and mimotope conjugates expressed in this way are free of endotoxins and phages and are therefore particularly suitable for use in the process according to the invention for producing a vaccine or as a vaccine itself.
  • This expression system is also particularly suitable for the production of the mimotopes or mimotope conjugates in large quantities.
  • the body's own or synthetic antibodies are used in the method according to the invention to select suitable peptide mimotopes of the antigens against which antibodies are specifically active from phage peptide libraries.
  • An overview of phage peptide libraries and related literature is given by M. B. Zwick, J. Shen and J. K. Scott in Current Opinion in Biotechnologie 1998, 9: 427-436. Reference is hereby made to the disclosure content of this publication.
  • Phage-peptide libraries consist of parliamentary phages that express different peptides on their surface in a very wide range of variations.
  • the appropriate peptide mimotopes are found by conventional selection methods using the antibodies against the specific antigen from these libraries. It should be noted that the chemical nature of the mimotopes found does not have to match the corresponding epitope of the antigen.
  • the mimotopes selected in this way are characterized by DNA sequencing. Following the pattern of the sequences found, mimotopes are produced or synthesized as a fusion protein with a macromolecular carrier and chemically conjugated to the macromolecular carrier.
  • This conjugation can take place, for example, in such a way that an albumin-binding protein (ABP), as is expressed, for example, by streptococci, is linked to the mimotope protein.
  • ABP albumin-binding protein
  • the connection of ABP and proteins is described by S. Baumann, P. Grob, F. Stuart, D. Pertlik, M. Ackermann and M. Suter in the Journal of Immunological Methods 221 (1998) 95-106. Reference is hereby made to the disclosure content of this publication.
  • the step of conjugating the mimotopes with the macromolecular carrier ensures that when the vaccine is administered, an immune response of the body is induced, i.e. this step is done to make the mimotopes immunogenic.
  • the expression of the mimotope proteins or mimotope conjugate proteins found can be determined by systemic transient infection of plant expression systems (host plants), such as Nicotiana Tabacum or Nicotina benthamiana, using the genomic and infectious RNA from recombinant tobacco mosaic viruses (TMV) or by completely recombinant TMV -Particles are made.
  • host plants such as Nicotiana Tabacum or Nicotina benthamiana
  • TMV tobacco mosaic viruses
  • the DNA sequence coding for the foreign protein is first ligated into a cDNA copy of the TMV located in a plasmid, so that this sequence comes under the control of the subgenomic promoter for the original coat protein of the TMV.
  • the fusion to the ABP takes place first.
  • the cDNA coding for the mimotope is added to the 3 'end of the cDNA coding for the ABP in the same reading frame.
  • the resulting cDNA of the ABP-mimotope fusion protein is inserted into a cDNA copy of the TMV genome. This sequence comes under the control of the subgenomic promoter for the original coat protein of the TMV.
  • An RNA transcript of the recombinant TMV is then in vitro Genome synthesized. This RNA is infectious and is applied to wounded leaves of the above host plants.
  • the viral proteins and the desired foreign protein are synthesized in the cytoplasm of the host cells.
  • the mimotope proteins can also be obtained on a larger scale without problems in endotoxin-free form.
  • the expression or production of the mimotope proteins found can also be carried out by conventional methods, such as expression in E. coli bacteria.
  • ABP ABP conjugation protein
  • mimotope protein a single-stranded DNA sequence of the selected mimotopes is first obtained and double-stranded DNA is generated therefrom. This DNA is ligated into the expression vector pSB 51 1. The resulting construct of information for mimotope and ABP is used to transform competent E. coli XL-1 cells. After the cells have been amplified and harvested, the recombined protein can be purified using NiNTA agarose.
  • Herceptin antibody was bound to the monoclonal mouse antibody using its Fc part. Herceptin was incubated in a concentration of 10 ⁇ g / ml PBS for two hours.
  • This library contained filamentous Ml 3 phages, in the pVIII gene, which codes for a phage coat protein, inserted nucleotide sequences which code for peptides with a length of 9 amino acid residues.
  • This library contained 10 9 individual phage clones, which differed in the sequence of their inserts.
  • Phages which bound to the Herceptin using these peptides were detached from the Herceptin again by means of pH reduction. Suitable E. coli host cells were infected with the phage eluted in this way and amplified by the growth of the bacterial cells. This process from the binding to the antibody to the amplification of specifically bound phages is called the panning round. Three rounds of panning were performed and DNA was isolated and sequenced from the resulting phage clones. The most frequently identified sequence coding for an inserted peptide was used as the basis for the synthesis of the vaccine conjugates.
  • the peptide fused to the pVIII surface on the phage is not entirely terminal, but 5 amino acid residues of the pVIII protein are still present at its N-terminus. These were in the solid phase synthesis of the Peptides included. Furthermore, the peptide was provided with a linker of the type GlyGlyGlyGlyGly at the C-terminus in order to enable the formation of the native 3D structure also on the conjugation partner. A C-terminal Cys was also added to allow the organic chemical coupling reaction to the carrier proteins.
  • the mimotope was provided with the linker GGGGGC at its C-terminus. Accordingly, the amino acid sequence coupled to the coupling partner was AEGEFATLMQIISQGGGGGC (sequence 2).
  • Two routes of immunization were used. 15 ⁇ g or 150 ⁇ g of the respective conjugate was used subcutaneously, 150 ⁇ g each intraperitoneally.
  • the Gerbu adjuvant was used as adjuvant.
  • In the subcutaneously immunized groups there were 5 mice each, in the i. p. immunized groups of 3 mice each.
  • the control groups (3 mice each) were given only the conjugation partner with the Gerbu adjuvant.
  • Sera from the mouse groups which had been immunized with tetanus toxoid plus sequence 2 were tested for KLH plus sequence 2 alone.
  • Sera from the mouse groups that had been immunized with KLH plus sequence 2 were tested for TT plus sequence 2 and TT alone.
  • Appropriate rat anti-mouse IgGl and anti-mouse IgG2a were used to determine the isotype of the mimotope-specific antibodies.
  • HRP Horseraddish Peroxidase conjugated anti-rat IgG antibody was used to detect the binding. HRP undergoes a color reaction with a substrate. The result of this color reaction can be quantified with the photometer. The absorption coefficient is measured (OD value).
  • the titre control was carried out after the third immunization.
  • the sera were pooled.
  • the dilution was 1: 2500.
  • Figures 1 and 2 show the results given in Tables 1 and 2 of immunizations with sequence 2 coupled to KLH.
  • the bar groups 1 to 4 correspond as follows:
  • Figures 3 and 4 show the results of immunizations with sequence 2 coupled to TT. The meaning of the bars is the same as for Figures 1 and 2.
  • Mimotope peptides CWAEMLLPLAC (sequence number 3); RSRLWAVME (sequence number 4); CLADPFIPHGC (sequence number 5) and ATLMQI-ISQ (sequence number 1) were synthesized, chemically coupled to KLH using succinimide-thiopyridine linkers and purified by gel filtration. 200 microg conjugate or 10 10 phage particles (with the mimotope ATLMQIISQ) per dose were used to immunize rabbits. The immunizations were carried out subcutaneously once with complete Freund's adjuvant, followed by five further doses of the antigen in incomplete Freund's adjuvant at 14-day intervals. Blood samples were taken before (preimmune serum) and one week after the last dose.
  • mice IgG directed specifically against mimotopes could also be achieved in rabbits.
  • the following example shows this:
  • Her-2 / neu is recognized in the cell membranes of the SKBR3 cell line in the ELISA by the humanized monoclonal antibody Herceptin.
  • this binding is sought to be prevented by preincubation with mimotopes on phages or KLH as a carrier.
  • the wells of a 96-well ELISA plate (Nunc) were coated with membrane fractions of the Her-2 / newly overexpressing cell line SKBR3 and as a control for unspecific antibody binding with membrane fractions of the Her-2 / newly negative cell line HTB 132 in PBS overnight.
  • Herceptin anti-Her-2 / neu antibody was also treated overnight by preincubation with various antigens: mimotopes, control mimotopes or buffers.
  • ELISA was carried out to test the rabbit sera for specific anti-Her 2 / neu antibodies. As already described under point 3.B.), ELISA plates were coated with SKBR3 membranes, blocked and then tested in this case with sera from the immunized rabbits (preimmune serum versus immune serum) in a 1:10 dilution. Bound rabbit IgG was detected with a peroxidase-labeled anti-rabbit IgG antibody and a color reaction was developed and read again by adding substrate.
  • This example shows that immunizations with Mimotop-KLH are suitable for inducing antibodies against the natural Her2 / neu on SKBR3 cells.

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Abstract

L'invention concerne un procédé pour produire un vaccin contre des maladies cancéreuses, ainsi que le vaccin lui-même. Ce procédé consiste à utiliser tout d'abord un ou plusieurs anticorps agissant spécifiquement contre un ou plusieurs d'antigènes exprimés spécialement par les cellules tumorales, pour sélectionner un ou plusieurs mimotopes de ces antigènes dans une bibliothèque de phages-peptides. Pour l'obtention du vaccin, ces mimotopes, sous la forme de leurs monomères, dimères, trimères ou oligomères, sont conjugués une ou plusieurs fois avec un substrat macromoléculaire. Ces vaccins ainsi produits entraînent, lorsqu'ils sont administrés, une réponse immunitaire humorale et par conséquent l'apparition d'une immunité active, consécutive à la vaccination.
EP01925550A 2000-04-13 2001-04-12 Vaccin contre des maladies cancereuses, a base de mimotopes d'antigenes exprimes sur des cellules tumorales Ceased EP1272214A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE10018403A DE10018403A1 (de) 2000-04-13 2000-04-13 Verfahren zur Herstellung einer Vakzine gegen Krebserkrankungen
DE10018403 2000-04-13
DE10041342 2000-08-23
DE10041342A DE10041342A1 (de) 2000-08-23 2000-08-23 Vakzine gegen Krebserkrankungen
PCT/EP2001/004251 WO2001078766A1 (fr) 2000-04-13 2001-04-12 Vaccin contre des maladies cancereuses, a base de mimotopes d'antigenes exprimes sur des cellules tumorales

Publications (1)

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EP1272214A1 true EP1272214A1 (fr) 2003-01-08

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EP01925550A Ceased EP1272214A1 (fr) 2000-04-13 2001-04-12 Vaccin contre des maladies cancereuses, a base de mimotopes d'antigenes exprimes sur des cellules tumorales

Country Status (6)

Country Link
US (1) US7166694B2 (fr)
EP (1) EP1272214A1 (fr)
AU (2) AU2001252262B2 (fr)
CA (1) CA2405290C (fr)
IL (1) IL152054A0 (fr)
WO (1) WO2001078766A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9296803B2 (en) 2010-03-11 2016-03-29 Health Research, Inc. Methods and compositions containing Fc fusion proteins for enhancing immune responses
US20210346484A1 (en) 2017-12-11 2021-11-11 Medizinische Universitaet Wien Method of producing a vaccine composition and uses thereof

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3040121B2 (ja) * 1988-01-12 2000-05-08 ジェネンテク，インコーポレイテッド 増殖因子レセプターの機能を阻害することにより腫瘍細胞を処置する方法
JPH05117165A (ja) 1991-10-24 1993-05-14 Masakazu Ueda 抗癌剤
US5869445A (en) * 1993-03-17 1999-02-09 University Of Washington Methods for eliciting or enhancing reactivity to HER-2/neu protein
US5801005A (en) * 1993-03-17 1998-09-01 University Of Washington Immune reactivity to HER-2/neu protein for diagnosis of malignancies in which the HER-2/neu oncogene is associated
AU712441B2 (en) 1994-12-14 1999-11-04 Scripps Research Institute, The In vivo activation of tumor-specific cytotoxic T cells
ES2190799T5 (es) * 1996-03-01 2008-08-16 Novartis Ag Inmunogenos peptidicos para vacunacion y tratamiento contra la alergia.
EP1051483A1 (fr) 1997-12-31 2000-11-15 Pincus, Seth H. Une methode pour isoler un peptide qui mime immunolgiquement les carbohydrates microbiens, y compris les carbohydrates des streptocoques du group b, et son utilisation dans un vaccin
JP2002514573A (ja) 1998-05-08 2002-05-21 スローン − ケッタリング インスティチュート フォー キャンサー リサーチ 能動的なワクチン接種のための組成物および方法
WO2001008636A2 (fr) 1999-08-03 2001-02-08 The Ohio State University Polypeptides et polynucleotides ameliorant la reactivite immunitaire a la proteine her-2

Non-Patent Citations (1)

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Title
See references of WO0178766A1 *

Also Published As

Publication number Publication date
AU5226201A (en) 2001-10-30
US20050100551A1 (en) 2005-05-12
WO2001078766A1 (fr) 2001-10-25
AU2001252262B2 (en) 2006-02-02
CA2405290C (fr) 2011-06-21
IL152054A0 (en) 2003-05-29
CA2405290A1 (fr) 2001-10-25
US7166694B2 (en) 2007-01-23

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