EP1144002A2 - Procede de selection et de fabrication de preparations de vaccination et diagnostiques - Google Patents

Procede de selection et de fabrication de preparations de vaccination et diagnostiques

Info

Publication number
EP1144002A2
EP1144002A2 EP00910621A EP00910621A EP1144002A2 EP 1144002 A2 EP1144002 A2 EP 1144002A2 EP 00910621 A EP00910621 A EP 00910621A EP 00910621 A EP00910621 A EP 00910621A EP 1144002 A2 EP1144002 A2 EP 1144002A2
Authority
EP
European Patent Office
Prior art keywords
pathogen
gene library
polypeptides
preparation
antibody
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Withdrawn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
EP00910621A
Other languages
German (de)
English (en)
Other versions
EP1144002A3 (fr
Inventor
Alexander Von Gabain
Michael Buschle
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.)
CISTEM Biotechnologies GmbH
Original Assignee
CISTEM Biotechnologies GmbH
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 CISTEM Biotechnologies GmbH filed Critical CISTEM Biotechnologies GmbH
Publication of EP1144002A2 publication Critical patent/EP1144002A2/fr
Publication of EP1144002A3 publication Critical patent/EP1144002A3/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/02—Libraries contained in or displayed by microorganisms, e.g. bacteria or animal cells; Libraries contained in or displayed by vectors, e.g. plasmids; Libraries containing only microorganisms or vectors
    • 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
    • C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
    • C12N15/1034—Isolating an individual clone by screening libraries
    • C12N15/1037—Screening libraries presented on the surface of microorganisms, e.g. phage display, E. coli display

Definitions

  • the invention relates to a method for selecting and producing vaccine and diagnostic preparations against pathogens of the most varying types.
  • infectious diseases are highly increasing again. On the one hand, this is caused by the fact that ever new, more complex infectious diseases occur, such as, e.g., hepatitis C, AIDS, hemorrhagic intestinal diseases etc., and, on the other hand, by the fact that some pathogens have become resistant to the established vaccines. At the same time, many pathogens which so far could successfully be treated with medicaments, have become resistant to these medicaments.
  • many pathogens which so far could successfully be treated with medicaments, have become resistant to these medicaments.
  • intestinal infections or diseases like tuberculosis or malaria have to be pointed out.
  • the increasing resistance of bacterial pathogens to antibiotics poses great problems for world-wide health policies.
  • the production of recombinant vaccines is simple, primarily with a view to producing large amounts as are required for a world-wide vaccination campaign, yet the efficiency of the recombinantly prepared vaccine often does not compare to the efficiency of the biogenic vaccine.
  • the reasons for this often reside in the non-nativity of the recombinant vaccines, so that in the vaccinated person not quite exactly those antibodies will be formed which would be required for efficiently combatting an attack by the pathogen.
  • the object of the present invention to provide a method for producing vaccines against pathogens with which efficient vaccines can be developed quickly and at low costs. In doing so, the knowledge about the genetic information of the pathogens is to be optimally utilized. Furthermore, vaccines are to be created which can easily be transformed by the immune system of the vaccinated subject into a safe protection against the respective pathogen.
  • this object is achieved by a method for selecting and producing vaccine and diagnostic preparations against a certain pathogenic organism, which is characterized by the following steps: immunizing a non-human vertebrate with a preparation of the pathogenic organism, taking samples containing the antibodies to the pathogen- preparation from immunized vertebrates and, optionally, working up these samples, producing a gene library of the genome of the pathogenic organism, which gene library is capable of being expressed in host cells, the pathogen polypeptide sequences-expressing gene library-host cells being selectable as regards their binding to an antibody, identifying antigenic polypeptides by contacting the gene library with the antibody-containing sample taken, and selecting the gene library for those clones whose expressed polypeptides bind to an antibody, isolating and finishing the identified antigenic polypeptides to a vaccine or diagnostic preparation.
  • the method according to the invention it is rapidly and efficiently possible to develop a vaccine or a diagnostic agent against any desired pathogen which optimally leads to a reliable immunization of an organism to be vaccinated.
  • the vaccines or diagnostic agents according to the invention can be employed for immunization of or diagnosis in any animal types, yet the preferred application is in humans.
  • Preferred animal pathogens are pathogens for agriculturally useful animals or for pets.
  • a reliable detection system for infections with a certain pathogen can be provided which - provided with a suitable marker - can be employed for routinely testing organisms potentially infected with this pathogen.
  • polypeptides are obtained with the method according to the invention which are capable of producing antibodies in a vertebrate.
  • the polypeptides immediately selected from the gene library can be used, e.g. by purifying them directly by amplification of the host cells and subsequent recovery of the polypeptide from these cells.
  • the selected polypeptides or their genetic information, respectively, which is part of the host cells and thus can be obtained directly
  • pathogens of which there exists only a rough mapping these pathogen proteins may be employed either in their entirety or in truncated form for vaccine production.
  • the parts of the proteins which optionally can be truncated will depend on the polypeptides selected according to the invention which, in the vaccine produced, preferably should remain as complete as possible in their antigenic form. If two or more antigenic polypeptides can be associated with a pathogen protein, the combination of at least these polypeptides frequently can lead to a particularly advantageous vaccine. If the antigenic polypeptides in the pathogen protein are not adjacent, it may also be advisable to provide a spacer between the polypeptides before the vaccine is finished.
  • the inventive isolation and finishing of the vaccines or diagnostic agents may thus include the above steps of design adaptation. Isolation may also be effected exclusively on DNA level, which means that the genetic information regarding the antigenic polypeptides from the selected host cells is, e.g., taken over into a further expression vector, is expressed in pharmaceutically suitable expression cells and worked up to a pharmaceutical preparation. Also the vaccine or the diagnostic agent itself can be provided on DNA level; the technology for DNA vaccines is known in principle, and corresponding carrier or administration systems, such as, e.g., by powder-ject injections, have been described.
  • vaccines or diagnostic agents against all infectious pathogens can be developed, i.e., e.g., against bacteria, viruses, fungi, protozoa etc..
  • the method according to the invention is, however, particularly well suited for pathogens which have a comparatively small genome, which either is easy to sequence or which has already been completely sequenced. Therefore, according to the invention primarily vaccines or diagnostic agents against bacterial or viral pathogens are preferred.
  • non-human vertebrates which according to the invention are infected with the pathogen preparation
  • all animals are suitable which exhibit sufficient generation of antibodies upon infection with a pathogen, i.e., e.g., amphibians, reptiles, birds or mammals.
  • a pathogen i.e., e.g., amphibians, reptiles, birds or mammals.
  • animals are used which have already been established in the immunological laboratory, such as frogs (e.g. Xenopus laevis), chickens or rodents, in particular rabbits, rats or mice.
  • a non-human mammal is immunized with a preparation of the pathogenic organism.
  • a non-human vertebrate is given a preparation of the selected pathogen so that an immune reaction is triggered in the vertebrate.
  • an immune reaction which will be termed "immunization" for the purposes of the present invention for the sake of simplicity, antibodies to the pathogen are formed in the vertebrate.
  • these antibodies are taken from the vertebrate and optionally are purified by common methods to a purified antibody preparation.
  • serum may be taken from the vertebrate from which the antibody preparation used for selection of the gene library will be produced.
  • Immunization of the vertebrates may be carried out with subletal or with letal doses; taking of the antibodies may be effected once, e.g. upon sacrificing the animals, or in several charges, e.g. after several administrations of the pathogen preparation.
  • the vertebrates are selected such that besides the formation of antibodies, also a formation of antigen- recognizing cells of the cellular system of the immune system is caused by the administration of the pathogen preparation.
  • these cells can then be used for further selection of the polypeptides identified according to the inveniton, e.g. by assaying these peptides or the pathogen proteins associated with these peptides for their binding capacity relative to these cells.
  • antigen-recognizing cells of the cellular system of the immune system are additionally taken from the immunized vertebrate, with which cells the identified antigenic polypeptides are further selected in that the identified antigenic polypeptides or the complete proteins of the pathogen to be associated with the identified antigenic polypeptides are tested for their capacity of binding to the antigen-recognizing cells, and those polypeptides or proteins are selected for finishing which exhibit a binding capacity to the cells.
  • vertebrates are provided in which the cellular components of the immune system are simple to remove and to handle.
  • T cells are removed as antigen-recognizing cells of the cellular system of the immune system from the immunized vertebrate.
  • spleen and lymphatic nodes can be removed from the immunized vertebrate, from which an antigen- recognizing cell-containing suspension is prepared with which the binding capacity of the identified polypeptides or of the associated proteins relative to the antigen-recognizing cells is tested. Removal of T cells or PBMC from peripheral blood is preferred with respect to humans.
  • the binding capacity of the polypeptides themselves relative to these cells can be assayed, or it may be tested whether certain other regions of the pathogen protein with which the polypeptide can be associated, have a binding capacity relative to these cells. For frequently those regions of the pathogen protein which may trigger a humoral immune response, are not identical with the ones that have a binding capacity for cellular immune response. In doing so, thus parts thereof or the entire pathogen protein with which one or several identified antigenic polypeptides can be associated, may be used as a basis for the binding test relative to antigen-recognizing cells.
  • the selection of the partial sequences thus conveniently is made by means of the known or predicted protein structure such that antigenic motifs will remain as complete as possible.
  • a preferred method thus is characterized in that a combination of partial sequences of the complete pathogen proteins associated with the antigenic polypeptides are used as a basis for the selection regarding the binding capacity.
  • a pathogen preparation containing the complete pathogen is used for the introductory infection of the vertebrate.
  • the vertebrate can produce an immune response which is completely directed to the native pathogen and thus ensures that the vaccines found according to the invention confer a reliable vaccine protection against the native pathogen.
  • the infection of the vertebrate with the entire pathogen is not possible, e.g. if it kills the vertebrate, before a sufficient cellular and humoral immune response has occurred, so that a further procedure according to the invention cannot take place. In that case, an inactivated preparation of the pathogen must be started from.
  • fixed pathogenic material e.g. inactivated or cross-linked material
  • This mode of procedure may be recommendable e.g. for highly infectious pathogens the handling of which is cumbersome and dangerous .
  • a particularly efficient immune response can be triggered in vertebrates if the pathogen preparation employed for immunizing comprises and adjuvant.
  • organic polycations or a mixture of organic cations is used as adjuvants.
  • Particularly preferred adjuvants are basic polypeptides, in particular polyarginine or polylysine.
  • vaccines and diagnostic agents against a plurality of pathogens it is possible to produce vaccines and diagnostic agents against a plurality of pathogens.
  • vaccines against human pathogens are provided for which there exists no or only an insufficient immunization alternative and/or which have developed resistances to available chemical or immunological treatments.
  • Preferred pathogens which are to be fought within the scope of the present invention may thus be selected from the group of Borrelia burgdorferi, Chlamydia spp., group A streptococci, non- typifyable haemophilus influenzae, Legionella pneumophila, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Staphylococcus aureus, Pseudomonas aeruginosa, Rickettsia rickettsii, Shigella spp., Toxoplasma gondi or Treponema pallidum.
  • preferred pathogens are pathogenic Aspergillus, Candida, Mycobacterium, Rhizopus, Trichophyton, Microsporum, Trypanosoma, Pneumocystis, Plasmodium, Meningococcus and Chlostridia strains as well as retroviruses or hematogenic viruses .
  • polypeptides which have been produced with a polypeptide sequencer are preferably used as a basis for testing the binding capacity relative to the antigen-recongizing cells.
  • the choice of the gene library or of the host cells may be arbitrary; what is essential is that the gene library host cells are selected on the basis of the binding of the expressed polypeptides to the antibodies taken from the vertebrates. Accordingly, for the sake of simplicity, the expressed polypeptides should be presented on the outer side of the cells, e.g. as a portion of the outer domain of a membrane protein.
  • the length of the expressed polypeptides is then chosen by way of the respective requiremetns of the gene library/host cell system, yet frequently it ranges between 10 and 200 amino acids, in particular between 20 and 100 amino acids.
  • the selection of the cells may be effected e.g.
  • the expressed polypeptides are outwardly presented as a part of the membrane protein of the gene library host cells.
  • a selection system is preferred in which the gene library host cells become resistant to a selection agent because of the binding of an antibody to the expressed polypeptide.
  • virus receptor in the cells may be constructed such that the former is blocked by the binding of the antibody to the expressed polypeptide, e.g. by intermolecular interaction or by steric blocking.
  • gene library host cells comprise an OmpA, LamB or FhuA selection system.
  • the former can be localized in the genome of the pathogen and associated with certain pathogen proteins (or ORFs). It is, of course, a prerequisite that at least a rough gene mapping of the pathogens is already available. It is, however, particularly advantageous if the complete gene sequence of the pathogen is already available. Accordingly, by using a genomic analysis of the pathogenic organism as a basis, preferably the selected antigenic polypeptides are associated to defined proteins of this pathogenic organism, and those antigenic polypeptides which have been associated with the same protein, are combined.
  • polypeptide combinations can then be used as a basis for the binding test relative to antigen-recognizing cells, optionally in combination with further partial sequences of the associated pathogen protein (or also as entire protein).
  • Determination of the binding properties may be effected with a plurality of assays.
  • the ones most commonly used at present are described in Romero et al (Mol. Med. Today 4, (1998), pp. 305- 312), among them also the Elisspot assay by which T cells which bind to an (MHC-II-presented ) antigen due to their cytokine secretion (mostly interferon- ⁇ ) can be identified.
  • This assay not only is established, standardizable and simple to handle, it is also extremely sensitive for the purposes of the present invention, particularly since for this assay no cellular in vitro proliferation is required. According to a preferred embodiment of the method according to the invention, thus the binding capacity relative to the withdrawn antigen-recognizing cells is determined by using the Elisspot assay.
  • the finishing of the vaccines and diagnostic agents of the invention comprises admixing a pharmaceutically acceptable carrier as well as further auxiliary components.
  • initial immunization is not restricted to non-human vertebrates.
  • both the antibodies and also optionally the antigen-recognizing cells are recovered from humans and are subjected to the selection and production methods according to the invention.
  • primary immunization is, however, either left up to nature, i.e. antibodies and T cells are taken from already immunized patients, or it is worked with non-infectious pathogen preparations.
  • the withdrawal of antibodies and T cells from humans who have already successfully overcome an infection with this pathogen and have built up a sufficient cellular and humoral protection is a particularly preferred variant of the present invention.
  • the present invention thus also relates to a method variant in which the step of "immunizing a non-human vertebrate", is replaced by the method step "selecting a person who has overcome an infection with that particular pathogen and has formed antibodies as well as antigen-recognizing cells".
  • the step of "immunizing a non-human vertebrate” is replaced by the method step "selecting a person who has overcome an infection with that particular pathogen and has formed antibodies as well as antigen-recognizing cells”.
  • the present invention relates to a vaccine preparation comprising a selected polypeptide or a protein containing this polypeptide or the DNA thereof, produced or obtainable by the method according to the invention.
  • the present invention relates to a diagnostic preparation comprising a selected polypeptide, prepared or obtainable by the method of the invention, which comprises a marker for detecting the polypeptide.
  • markers which can be used for detecting the polypeptide all those usable for detecting the binding of two substances are under consideration, preferably, however, radioactive, fluorescent, chromogenic or amplifyable markers are coupled to the diagnostic agent according to the invention. Just like vaccination, diagnosis may take place on nucleic acid level.
  • a further aspect of the present invention thus relates to a diagnosis kit, comprising a diagnostic preparation according to the invention and detection reagents for the marker.
  • the present invention relates to a kit for carrying out the method of the invention, comprising a gene library of the genome of the pathogenic organism, host cells in which the gene library can be expressed, wherein the pathogen polypeptide sequences-expressing gene library host cells are selectable with a view to their binding to an antibody, and a selection agent.
  • the potential of the antigen selection of the present invention is, however, not restricted to vaccines and diagnostic agents against certain pathogens. It has been shown that the method according to the invention is also suitable for preparing efficient tumor antigens. Particularly with the combination of humoral and cellular selection which is preferred according to the invention, particularly suitable tumor antigens can be found. With the tumor antigens found according to the invention, particularly effetive tumor vaccinations can be carried out. However, instead of immunizing the non-human vertebrate with the pathogen preparation, the vertebrate is immunized with a preparation of the respective tumor cell, or antibodies and optionally antigen-recognizing cells are taken from a human tumor patient.
  • Fig. 1 shows the method according to the invention for identifying antigens
  • Fig. 2 shows the construction of a gene library for a microbial genome
  • Figs. 3 and 4 show the selection of the antibody-binding cells by OmpA or LamB selection
  • Figs. 5 and 6 show the association of the identified polypeptides with the pathogen proteins via genomics
  • Fig. 7 shows the generation of overlapping peptide fragments for further characterization by means of T cell binding assay
  • Fig. 8 shows the screening of the antigen-binding polypeptide by means of Elisspot assay.
  • a mouse is immunized with a homogenized pathogenic microbe, polyarginine having been admixed to the homogenisate. After immunization has taken place, serum is taken from the mouse, and spleen and lymphatic nodes are removed. The serum is used for identifying antigens which are recognized by the antibodies in the serum; from spleen and lymphatic nodes, a suspensioin of T cells is prepared (Fig. 1).
  • An expression gene library is prepared according to
  • WO 99/30151 A wherein the microbial genome is digested to fragments of a length of approximately 150 bp and is inserted into suitable selection/expression vectors. With these expression vectors, host cells are transformed, a selectable gene library being generated (Fig. 2).
  • Fig. 3 The antibodies withdrawn from the mouse are admixed with the genetic library host cells, the antibodies being able to bind to suitable expressed structures (Fig. 3).
  • Fig. 4 shows a system in which selection is effected with phages. Binding of the antibody to the expressed polypeptide at the outside of the cell results in a steric blocking of the phage binding site. By this, the cell cannot be infected with the normally letal phage and is positively selected, resulting in an enrichment (e.g. by the factor 10 3 to 10 6 ; higher or lower enrichments depending on the selection system) of those clones which comprise antigenic microbial peptides.
  • an enrichment e.g. by the factor 10 3 to 10 6 ; higher or lower enrichments depending on the selection system
  • the localization of the polypeptide in the pathogen genome is carried out via a genomic data library of the microbial pathogen, and the polypeptide is associated with a certain protein or ORF (Fig. 5). Since humoral and cellular antigens often are separate structures on a protein (Fig. 6), overlapping peptide fragments of the total protein sequence found via the genomic data library are generated, e.g. by automated peptide synthesizers (Fig. 7).
  • the identified antigenic polypeptides and the generated samples are assayed for their binding to T cells by means of an Elisspot assay.
  • the polypeptide samples are provided in a suitable reaction vessel, e.g. a microtiter plate coated with a cytokine-specific antibody, and admixed with the spleen and lymphatic node suspension from the mouse.
  • T cells which bind to an antigen (which, e.g., is presented to them by MHC-II-carrying antigen presenting cells) produce - upon binding to the antigen - cytokines, e.g. interferon- ⁇ .
  • the latter binds to the immobilized antibody and may be detected e.g. by a marked depoty antibody.

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Abstract

L'invention concerne un procédé de sélection et de fabrication de préparations de vaccination et diagnostiques dirigées contre un organisme pathogène précis. Selon ce procédé, on immunise un vertébré non humain au moyen d'une préparation à base de l'organisme pathogène, on fait sur ce vertébré des prélèvements contenant des anticorps de la préparation à base de l'organisme pathogène, on crée une bibliothèque de gènes du génome de l'organisme pathogène, ladite bibliothèque de gènes pouvant être exprimée dans des cellules hôtes (les séquences polypeptidiques pathogènes qui expriment les cellules hôtes de la bibliothèque de gènes pouvant être sélectionnées en fonction de leur liaison à un anticorps), on identifie les polypeptides antigéniques par la mise en contact de la bibliothèque de gènes avec un prélèvement contenant des anticorps fait sur le vertébré et l'on mène le processus à terme en obtenant un vaccin ou une préparation diagnostique avec les polypeptides antigéniques identifiés.
EP00910621A 1999-02-01 2000-01-28 Procede de selection et de fabrication de preparations de vaccination et diagnostiques Withdrawn EP1144002A3 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
AT0012999A AT407643B (de) 1999-02-01 1999-02-01 Verfahren zur selektion und herstellung von vakzin- und diagnostika-präparationen
AT12999 1999-02-01
PCT/EP2000/000661 WO2000045839A2 (fr) 1999-02-01 2000-01-28 Procede de selection et de fabrication de preparations de vaccination et diagnostiques

Publications (2)

Publication Number Publication Date
EP1144002A2 true EP1144002A2 (fr) 2001-10-17
EP1144002A3 EP1144002A3 (fr) 2001-11-28

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP00910621A Withdrawn EP1144002A3 (fr) 1999-02-01 2000-01-28 Procede de selection et de fabrication de preparations de vaccination et diagnostiques

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Country Link
EP (1) EP1144002A3 (fr)
AT (1) AT407643B (fr)
AU (1) AU3277400A (fr)
WO (1) WO2000045839A2 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT410798B (de) * 2001-01-26 2003-07-25 Cistem Biotechnologies Gmbh Verfahren zur identifizierung, isolierung und herstellung von antigenen gegen ein spezifisches pathogen
AU2003254555A1 (en) * 2002-07-26 2004-02-23 Intercell Ag S. aureus antigene
EP1622933A2 (fr) * 2003-04-22 2006-02-08 Intercell AG Antigenes h. pylori

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4906564A (en) * 1987-03-13 1990-03-06 The United States Of America As Represented By The Secretary Of The Army Antigenic determinants recognized by antibodies obtained using a pathogenic agent or a derivative thereof that presents a restricted set of antigens
WO1999030151A1 (fr) * 1997-12-05 1999-06-17 Intercell Biomedizinische Forschungs- Und Entwicklungs Gmbh Technique de cellules pour criblage de bibliotheques combinatoires

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0045839A3 *

Also Published As

Publication number Publication date
AU3277400A (en) 2000-08-25
AT407643B (de) 2001-05-25
WO2000045839A2 (fr) 2000-08-10
WO2000045839A3 (fr) 2001-10-04
EP1144002A3 (fr) 2001-11-28
ATA12999A (de) 2000-09-15

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