WO2002019960A2 - Purification, caracterisation et utilisation de structures antigeniques protectrices contre des trypanosomes et des parasites apparentes - Google Patents

Purification, caracterisation et utilisation de structures antigeniques protectrices contre des trypanosomes et des parasites apparentes Download PDF

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Publication number
WO2002019960A2
WO2002019960A2 PCT/BE2001/000146 BE0100146W WO0219960A2 WO 2002019960 A2 WO2002019960 A2 WO 2002019960A2 BE 0100146 W BE0100146 W BE 0100146W WO 0219960 A2 WO0219960 A2 WO 0219960A2
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Prior art keywords
trypanosome
glycoproteins
antigenic structure
proteins
trypanosomes
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PCT/BE2001/000146
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English (en)
Inventor
Libre De Bruxelles Universite
Samuel J. Black
Noel Murphy
Terry Pearson
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Pays, Etienne
Nolan, Derek
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Priority to AU87377/01A priority Critical patent/AU8737701A/en
Publication of WO2002019960A2 publication Critical patent/WO2002019960A2/fr

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    • 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
    • A61K39/002—Protozoa antigens
    • A61K39/005—Trypanosoma antigens
    • 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
    • C07K16/20—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans from protozoa
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • H—ELECTRICITY
    • H04—ELECTRIC COMMUNICATION TECHNIQUE
    • H04L—TRANSMISSION OF DIGITAL INFORMATION, e.g. TELEGRAPHIC COMMUNICATION
    • H04L69/00—Network arrangements, protocols or services independent of the application payload and not provided for in the other groups of this subclass
    • H04L69/16—Implementation or adaptation of Internet protocol [IP], of transmission control protocol [TCP] or of user datagram protocol [UDP]
    • H—ELECTRICITY
    • H04—ELECTRIC COMMUNICATION TECHNIQUE
    • H04L—TRANSMISSION OF DIGITAL INFORMATION, e.g. TELEGRAPHIC COMMUNICATION
    • H04L69/00—Network arrangements, protocols or services independent of the application payload and not provided for in the other groups of this subclass
    • H04L69/30—Definitions, standards or architectural aspects of layered protocol stacks
    • H04L69/32—Architecture of open systems interconnection [OSI] 7-layer type protocol stacks, e.g. the interfaces between the data link level and the physical level
    • H04L69/322—Intralayer communication protocols among peer entities or protocol data unit [PDU] definitions
    • H04L69/329—Intralayer communication protocols among peer entities or protocol data unit [PDU] definitions in the application layer [OSI layer 7]

Definitions

  • the present invention is related to a method for the recovering, the purification and the characterization of one or more protective antigenic structures against trypanosomes and related parasites, as well as to said protective antigenic structures obtained and to their use as diagnostic tools and for the prevention and/or the treatment of diseases induced by trypanosomes and related parasites.
  • African animal trypanosomiases are diseases caused by flagelled protozoans, parasites of the blood, which induce upon sensitive animals a more or less severe anemia which may affect various organs, especially cardiac organs. Left untreated animals often die of the disease.
  • Trypanosoma brucei Trypanozoon
  • Trypanosoma gambiense species as well as their sub-species and nosodemes .
  • VSG surface coat proteins
  • glycans are involved in the sorting of membrane proteins in polarized cells. It has been described that N-linked glycans containing linear poly-N-acetyllactosamine (pNAL) were only associated with proteins of the flagellar pocket/endocytic pathway in Trypanosoma brucei and are present only in bloodstream forms of the parasite [4] . The authors show that these glycoproteins bind to tomato lectin (TL) , a property that unexpectedly allowed their single-step isolation.
  • pNAL linear poly-N-acetyllactosamine
  • the present invention aims to provide a new method for the recovering and the characterization of an antigenic structure which protects against trypanosomes and related parasites, which does not present the drawbacks of the state of the art and which could be used as a diagnostic tool for identifying infections by said trypanosomes and related parasites or could be used for the prevention and/or the treatment of diseases induced by trypanosomes and related parasites.
  • the present invention is related to a method for the isolation, purification and characterization of a surface immunogenic or antigenic structure of a trypanosome
  • glycoproteins located on the surface of the flagellar pocket (fp) of said trypanosome preferably glycoproteins containing linear poly-N- acetyllactosamine (pNAL) , from a biological extract comprising said trypanosome,
  • immunogenic or antigenic structure a structure made of one or more epitopes, either topographically assembled or linear, which are able to produce an effective immune response against trypanosome or other related human or animal parasites infections, as well as nucleotide sequences (cDNA, RNA sequences) , encoding said antigenic structure or said epitopes .
  • antibody able to inhibit trypanosome growth trypanosome activity in vi tro
  • amino acid sequence or the nucleotide sequence of the antigenic structure according to the invention obtaining by methods well known by the person skilled in the art, the amino acid sequence of the antigenic structure when said antigenic structure has been purified and when at least a portion of said antigenic structure is characterized. Said identification is preferably correlated with genetic sequences already sequenced for trypanosomes or related parasites .
  • the step of purifying the glycoproteins located at the surface of the flagellar pocket of the trypanosome according to the method of the invention is made by passing the biological extract containing said trypanosome on a support upon which tomato lectin molecules have been preliminary immobilized in order to retain by binding said glycoproteins to tomato lectin molecules and to obtain affinity complexes between said tomato lectin molecules and said glycoproteins, and by recovering said glycoproteins from said complex, preferably, according to the method described elsewhere [4] .
  • the purification of said glycoproteins is obtained by applying to said column a solution containing a competitive binder in order to obtain affinity complexes between said tomato lectin molecules and said competitive binder.
  • the competitive binder is a solution containing chito-oligosaccharides , preferably tri- N-acetyl chitotriose and tetra-N-acetyl chitotetraose .
  • Another aspect of the present invention is related to the antigenic structure recovered, purified and characterized by the method according to the invention, an inhibitor directed against said antigenic structure and their use as a medicament.
  • an inhibitor directed against said antigenic structure is any natural or synthetic molecule able to interact specifically with said antigenic structure in order to block the expression of said antigenic structure, such as a RNA antisense or a ribozyme able to interact with a RNA or a genomic nucleotide sequence encoding said antigenic structure, or an hypervariable portion of an antibody (monoclonal or polyclonal) able to interact with said antigenic structure
  • said antigenic structure is able to induce an immune response, preferably a cellular humoral and/or local immune response against trypanosomes and related parasites .
  • Another aspect of the present invention is related to a diagnostic kit comprising said antigenic structure, nucleotide sequences encoding said antigenic structure or its epitopes, and/or inhibitors directed against said antigenic structure for the detection, the quantification and/or the monitoring of trypanosomes and related parasites inside a patient (cattle or human) and the possible evolution of an infection by said parasites, especially by trypanosomes, through the analysis of biological fluids obtained from said patient .
  • Another aspect of the present invention is related to a pharmaceutical composition (preferably a vaccine) comprising an adequate pharmaceutically acceptable carrier or diluent, the antigenic structure according to the invention, the nucleotide sequences encoding said antigenic structure or its epitopes and/or inhibitors directed against said antigenic structure according to the invention, and possibly adjuvants for inducing the immune response (preferably a humoral cellular and/or local immune response) against trypanosomes and related parasites.
  • Said vaccine could comprise these elements that can be administrated in vivo or ex vivo to a patient (a cattle animal and/or a human) suffering from said parasites, especially from said trypanosomes.
  • nucleotide sequences comprising the information for encoding the antigenic structure or the epitopes according to the invention could be introduced as a naked vaccine in a cell or directly in a patient .
  • a further aspect of the invention is also related to cells transformed by the nucleotide sequences encoding the antigenic structure according to the invention or one or more of its epitopes, such cells could be used for the industrial production of said antigenic structure or could be administrated to the patients when they present said antigenic structure at their surface.
  • a further aspect of the present invention is related to a method of prevention and/or treatment of a patient (preferably cattle, but also including the human) suffering from trypanosomes and/or related parasite infections, comprising the administration of a sufficient amount of an antigenic structure, a nucleotide sequence encoding said antigenic structure or its epitopes, inhibitors directed against said antigenic structure or the pharmaceutical composition according to the invention to said patient for inducing a protective immune response against said trypanosomes and related parasites (especially African animal trypanosomiasis, for which the patient is a livestock animal) .
  • a protective immune response against said trypanosomes and related parasites especially African animal trypanosomiasis, for which the patient is a livestock animal
  • a last aspect of the present invention is related to the use of the antigenic structure according to the invention or the pharmaceutical composition according to the invention for the preparation of a medicament in the prevention and/or the treatment of diseases and infections induced by trypanosomes and related parasites, especially African animal trypanosomiasis, the patient being a cattle animal .
  • the trypanosome is a pathogenic trypanosome for human and/or animal, preferably selected from the group consisting of Trypanosoma (Nannomonas) congolense, Trypanosoma vivax (Duttonella) , Trypanosoma brucei (Trypanozoon) , Trypanosoma gambiense, Trypanosoma evansi , Trypanosoma equiperdum species and sub-species, and the nosodemes of said species.
  • Other related parasites are Trypanosoma cruzi and various species of Leishmania .
  • the pharmaceutically acceptable carrier can be any compatible non-toxic substance suitable for administering the composition (vaccine) according to the invention.
  • the pharmaceutically acceptable carriers according to the invention are the ones well known by the person skilled in the art such as tablets, coated or non- coated pills, capsules, solutions or syrups.
  • the pharmaceutically acceptable carrier may vary according to the mode of administration (intravenous, intramuscular, parenteral, etc.).
  • the vaccine according to the invention may also comprise adjuvants well known by the person skilled in the art, which may increase or regulate the humoral, local and/or cellular response of the immune system against trypanosomes or other related parasites or pathogenic agents .
  • the vaccine according to the invention is prepared by the methods generally applied by the person skilled in the art for the preparation of a vaccine, wherein the percentage of active compound / pharmaceutically acceptable carrier can vary within very large ranges, only limited by the tolerance and the level of acquaintance of the patient to the vaccine. The limits are in particular determined by the frequency of administration.
  • Fig. la shows an elution profile of proteins of T. brucei after tomato lectin chromatograph .
  • Fig. lb represents results obtained after SDS-PAGE and silver staining of the corresponding tomato lectin chromatography fractions.
  • Fig.lc represents results obtained after SDS-PAGE and autoradiography of the corresponding tomato lectin chromatography fractions.
  • Fig. Id represents a Western blot of the corresponding tomato lectin chromatography fractions using different antibodies.
  • Fig. le represents the results obtained after SDS-PAGE and autoradiography of precipitated proteins from SDS and CHAPS lysates of T. brucei cells metabolically labelled with 35 S .
  • Figs. 2a-c show labeling experiments performed on ultrathin sections of bloodstream forms of T. brucei using biotinylated tomato lectin.
  • Fig. 2d shows labeling experiments performed on procyclic forms of T. brucei using biotinylated tomato lectin.
  • Fig. 2e shows labeling experiments performed on bloodstream forms of T. brucei in the presence of chito-oligosaccharides using biotinylated tomato lectin.
  • Fig. 2f shows a direct fluorescence microscopy analysis on T. brucei cells using Texas-Red- conjugated tomato lectin.
  • Fig. 2g shows a direct fluorescence microscopy analysis on T. brucei cells using FITC- conjugated concanavalin A.
  • Fig.3 shows antibody responses of infection sera from susceptible Boran, trypanotolerant N'Dama and Cape buffalo to different proteins from T. congolense IL 3000.
  • Fig. 4a represents an immunization challenge profile of mice after infection with T. brucei (each curve shows the average parasite number in a group containing seven mice at day 0) .
  • Fig. 4b represents an immunization challenge profile of mice after infection with T. congolense (each curve shows the average parasite number in a group containing seven mice at day 0) .
  • Fig. 5 represents the screening of a
  • glycoproteins present in the flagellar pocket of T. brucei were isolated by lectin chromatography of CHAPS lysates of cellular suspensions that contained cells metabolically labelled with 35 S or surface-labelled with
  • the protocol was the following.
  • a tomato lectin was coupled to Affigel 10 (BioRad) - 2.0 mg lectin/ml of gel.
  • Cells (10 7 ) previously surface-labelled with 125 I or metabolically labelled with 35 S were added to a suspension of unlabelled cells (2.0 X 10 10 ) and the combined pellet was extracted by resuspension in 20 ml of TSC (25 M Tris-Cl pH 7.5, 150 mM NaCl, 0.1 M CaCl 2 , 1% CHAPS) and protease inhibitors.
  • the extract was centrifuged (50,000 X g for 1 h) and the supernatant was dialyzed overnight against 10 volumes of TSC and then applied to a tomato lectin column (-2.2 ml bed volume) equilibrated with TSC.
  • the column was washed before reversing the flow and eluting bound proteins using a mixture of chito-oligosaccharides (20 mg/ml of tri-JM- acetyl-chitotriose and tetra-JY-acetyl-chitotetraose in TSC; Seikagaku corporation) that specifically compete with linear pNAL for binding to tomato lectin.
  • Results are presented on Fig. lb.
  • the positions of molecular mass markers are shown on the left (St; BenchMarkTM protein ladder, GibcoBRL) .
  • Silver staining demonstrated a significant enrichment in the binding fraction of a group of proteins ranging in molecular weight from 30 to over 100 kDa.
  • the tomato lectin binding fraction was further characterized using antibodies against flagellar pocket and lysosomal proteins (Figure 4c) , for example, the expression-site-associated genes (ESAGs) 6 and 7, which encode subunits of the transferrin receptor [7-9] , the 145 kDa LDL-binding protein [10] and invariant glycoproteins ISG 100 and CBl-gp [11] .
  • the anti CBl-gp antibody was obtained from Cedar lane Laboratories Hornby, Ontario, Canada; antibodies against LDL-binding protein were a gift from P. Courtoy (ICP, Brussels) .
  • CBl-gp initially appeared as a 100 kDa glycoform, which then underwent elongation of N- glycans to generate the larger sized ( ⁇ 150 - 180 kDa) mature form of the protein [11] .
  • This elongation does not occur in procyclic forms and it was proposed that the enzymes responsible are not active during this stage of the parasite life cycle [11] .
  • tomato lectin precipitations were performed using denatured (SDS) or native (CHAPS) lysates of cells metabolically labelled with 35 S ( Figure le) . More precisely, biotinylated tomato lectin (40 ⁇ g) and streptavidin-agarose were used to precipitate proteins from SDS and CHAPS lysates (4 X 10 7 cell equivalents) of cells metabolically labelled with 35 S [5] . After extensive washing, the precipitated proteins were eluted using the chito-oligosaccharide mixture and subjected to SDS-PAGE and autobiography.
  • SDS denatured
  • CHAPS lysates 4 X 10 7 cell equivalents
  • Biotinylated tomato lectin was used to investigate the localization of tomato lectin binding sites in trypanosomes. More precisely, ultra thin sections of bloodstream forms of T. brucei (Fig. 2a-c) , of procyclic forms of T. brucei (Fig. 2d) and of bloodstream forms of T. brucei in the presence of chito-oligosaccharides (20 mg/ l) (Fig. 2e) were incubated with biotinylated tomato lectin followed by gold (10 nm) -conjugated goat antibiotin antibody. In these figures, scale bars represent 0,5 ⁇ m.
  • Adsorptions were carried out for 1 hour at 4°C using 1 ml post-infection serum per 200 ⁇ l Sepharose 4B bearing 250 ⁇ g covalently-associated TL-purified trypanosome material.
  • Adsorption on immobilized TL-purified proteins depleted serum of binding antibodies as determined by Western blotting on TL-purified proteins after SDS-PAGE.
  • Results presented in Table 2 show that the T. brucei growth-supporting capacity of post-infection Cape buffalo serum was largely restored by adsorption on immobilized TL-purified trypanosome material. It has been demonstrated that residual trypanosome growth-inhibitory activity of the absorbed serum is due to antibodies against other trypanosome components.
  • mice Immunization of mice with deglycosylated tomato lectin binding trypanosome material induces trypanosome growth- inhibitory antibodies.
  • Mice (BALB/c) were immunized by intraperitoneal injection of 25 ⁇ g tomato lectin purified T. brucei ILTat 1.1 protein that was deglycosylated using IV-glycosidase F as described [4] and emulsified in Freund's complete adjuvant (0.2 ml/mouse) . The mice were boosted twice with 20 ⁇ g protein in Freund's incomplete adjuvant with 2 weeks between each immunization.
  • mice One group of control mice was immunized with ovalbumin using the same immunization protocol as the tomato lectin immunized group, and a second control group was not treated. Blood for serum preparation was collected 2 weeks after the second boost and screened for antibodies against the deglycosylated tomato lectin purified trypanosome material by Western blotting after SDS-PAGE. [0089] Between 5 and 12 bands could be detected, dependent on the percentage of gel used (data not shown) .
  • mice were challenged by intraperitoneal injection of 5 x 10 2 T. brucei GUTat 3.1, a different serodeme to the one from which the receptors were purified, or the same number of T. congolense IL 1180 which are of a different species.
  • mice All control mice became parasitemic. Those infected with T. congolense IL 1180 were all dead by day 20 post-infection, whereas those infected with T. brucei GUTat 3.1 developed an undulating parasitemia and survived up to 80 days post-infection.
  • T. congolense resides solely within the vascular system, whereas T. brucei also invades lymph, tissue fluids and the central nervous system. As a result of their tissue location it may be necessary to induce production of higher concentrations of antibody, or different classes of antibody, or both, to fully protect against infection with T. brucei .
  • Tomato lectin protein immunized mice that did not develop patent parasitemia were euthanized by C0 2 on day 80 post-infection and sera collected.
  • Mouse serum has low xanthine oxidase activity and there is no need for its depletion prior to testing for any impact of the serum on trypanosome growth in vi tro .
  • Results are presented in Table 3 and show that there was complete inhibition of trypanosome growth in the presence of 20% immune, but not control mouse serum. [0098] Some variation in growth inhibition of the different clones was observed at the lower concentrations of immune sera, with T. congolense 3338 displaying complete inhibition down to 2.5%. This may be due to variation between tomato lectin binding proteins of the different clones, levels of expression of these proteins, binding efficiency of the antibodies or a combination of these.
  • Fig. 4a-b Immunization challenge profiles corresponding to these experiments are presented on Fig. 4a-b.
  • the profiles show the survival of challenged animals for the duration of the infection.
  • T. brucei and T. congolense challenges two non-immunized control mouse strains were used, Balb/c and Swiss. Whereas Balb/c mice are inbred, Swiss mice are out bred and are thought to be somewhat more resilient to infection.
  • T. brucei challenge Fig. 4a
  • all ovalbumin-immunized animals were dead by day 80 post -infection and there was one survivor in the non- immunized control group, although this animal was weak and was euthanized on day 85 post-infection.
  • the supernatants were also tested for their effects on growth of T. brucei brucei clone 1-bloodstream forms, in vi tro .
  • the supernatants were tested on T. brucei brucei clone 22, which expresses a different variant surface glycoprotein (VSG) than that expressed by clone 1.
  • VSG surface glycoprotein
  • Two different individuals repeated the growth inhibitory experiments.
  • Supernatants were also tested independently on the clone 1 bloodstream form parasites.
  • Positive clones are analyzed to identify duplicates and grouped according to whether they are recognized by one or both sera. Similar screening of T. brucei cDNA expression libraries are being undertaken to identify positive clones .
  • the sequence obtained by microsequencing is searched in the current T. brucei genome database, which is estimated to be about 50% complete (http://www.tigr.org/tdb/mdb/tbdb/) . [0110] Once identified these genes are used for the construction of a recombinant vaccine against trypanosomes.

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Abstract

L'invention concerne un procédé de récupération et de caractérisation d'une structure antigénique de surface d'une poche flagellaire de trypanosome (fp), caractérisé en ce qu'il consiste à purifier des glycoprotéines de membrane situées sur la surface de la poche flagellaire (fp) du trypanosome, de préférence des glycoprotéines contenant une poly-N-acétyllactosamine linéaire (pNAL), à partir d'un extrait biologique contenant le trypanosome, à déglycosyler ces glycoprotéines en protéines, à obtenir des hybridomes sécrétant des anticorps monoclonaux dirigés centre ces protéines, à cribler les hybridomes résultants afin de sélectionner un hybridome positif qui secrète un anticorps capable d'inhiber la croissance du trypanosome (activité du trypanosome in vitro), à obtenir cet anticorps à partir de cet hybridome, à sélectionner et à purifier une structure antigénique parmi les protéines de la poche flagellaire du trypanosome (fp) par liaison de ces protéines à l'anticorps monoclonal, et à éventuellement identifier la séquence des acides aminés de la structure antigénique ainsi que la séquence nucléotidique codant pour cette structure antigénique.
PCT/BE2001/000146 2000-09-06 2001-09-06 Purification, caracterisation et utilisation de structures antigeniques protectrices contre des trypanosomes et des parasites apparentes WO2002019960A2 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010000849A3 (fr) * 2008-07-04 2010-03-04 Institut De Recherche Pour Le Developpement (I.R.D.) Procédé de criblage de protéines secrétées conservées
WO2011058055A1 (fr) 2009-11-13 2011-05-19 Universite Victor Segalen Bordeaux 2 Applications therapeutiques et diagnostics contre les trypanosomoses
WO2011058080A1 (fr) 2009-11-10 2011-05-19 Universite Victor Segalen Bordeaux 2 Vaccins et diagnostics contre les trypanosomoses

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010000849A3 (fr) * 2008-07-04 2010-03-04 Institut De Recherche Pour Le Developpement (I.R.D.) Procédé de criblage de protéines secrétées conservées
US8865419B2 (en) 2008-07-04 2014-10-21 Institut De Recherche Pour Le Developpement (I.R.D.) Method for the screening of conserved secreted proteins
WO2011058080A1 (fr) 2009-11-10 2011-05-19 Universite Victor Segalen Bordeaux 2 Vaccins et diagnostics contre les trypanosomoses
WO2011058055A1 (fr) 2009-11-13 2011-05-19 Universite Victor Segalen Bordeaux 2 Applications therapeutiques et diagnostics contre les trypanosomoses
FR2952649A1 (fr) * 2009-11-13 2011-05-20 Univ Victor Segalen Bordeaux 2 Applications therapeutiques et diagnostiques contre les trypanosomoses animales africaines

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