Classifications

• • 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
  • C07K16/205—Plasmodium
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • C07K14/44—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from protozoa
  • C07K14/445—Plasmodium
• • 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
• • 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
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• the subject of the invention is new antigens of Plasmodium falciparum and their application in particular with a view to protection against malaria.
• the parasites responsible for malaria in humans including Plasmodium falciparum or Plasmodium vivax to name only the main ones, present in the human host different morphologies and express different antigens, depending on the stage of their development and their location in the organism of the infected host.
• the morphological and antigenic differences of these parasites during their life cycle in humans make it possible to define at least four distinct stages of development.
• the very first stage of development of the parasite in humans corresponds to the sporozoite form introduced into the host's blood, by bites from insects carrying the parasite.
• the second stage corresponds to the passage of the parasite in the liver and to the infection of the hepatic cells in which the parasites develop to form the hepatic schizonts which, when they are mature (for example for P. falciparum on the 6th day after penetration of the sporozoites), release by bursting hepatic merozoites.
• the third stage is characterized by the infection of blood erythrocytes by the asexual forms (merozoites) of the parasite; this erythrocyte stage of development corresponds to the pathogenic phase of the disease.
• the fourth stage corresponds to the formation of forms with sexual potential (or gametocytes) which will become sexual forms or extra-cellular gametes in the mosquito.
• antigens 11.1 Pf11-1) and (Pf155 / RESA) which themselves contained immunogenic determinants leading to cross-reactions as was observed using a human monoclonal antibody ( 20). More recently Udomsangtepch et al (36) described a human monoclonal antibody mAb 33G2 capable of inhibiting the cytoadherence of parasitized red blood cells, whether or not having protuberances with cells of the C32 melanoma cell line cells. It has also been found that this monoclonal antibody effectively inhibits the invasion of erythrocytes by merozoites in an in vitro test (38).
• this monoclonal antibody initially selected because of its reactivity with the molecule Pf155 / RESA (38), lacks specificity. It also reacts with other antigens that appear in the bloodstream stage of infection with the parasite, including the antigens Ag11-1 and Ag332 (20,37).
• the Ag 332 antigen presents undoubtedly a significant potential interest with regard to its ability to induce protective immunity.
• a recombinant polypeptide including the expression product of a fragment of 303 base pairs derived from Pf332 genes has been found to constitute a particularly effective inhibitor of the monoclonal antibody mAb33G2, as was demonstrated in a test of inhibition of the invasion of red blood cells by merozoites (37).
• the characterization of Ag332 has so far been inhibited by the cross-reactions to which antibodies which recognize it give rise, with various other antigens of the parasite (20).
• the present invention results from the identification and characterization of a new gene sequence within the Pf332 gene, of the antigen encoded by this gene sequence and of antibodies inducible in vivo by this antigen and specific for the antigen.
• the gene sequence in question has been located in the subtelomeric region of chromosome 11.
• the antigen expressed by this gene sequence has been shown to have a monospecific character allowing it to specifically detect a mega-colortonic protein of the parasite or asexual parasites in the blood stage by immunoblotting and immunoprecipitation reactions, unlike antibodies induced by other antigens, either derived from Ag332 or related to sequences thereof, such as the synthetic dimer Y (SVTEEIAEEDK) 2 (24) or a fusion protein with beta-galactosidase (20). These antibodies also react with various other molecules of the parasite. Antibodies formed against the EB200 antigen also lead to surface reactions with red blood cells infected with Plasmodium falciparum with an efficiency having the same order of magnitude as that of the monoclonal antibody mAb33G2.
• the peptide sequence of the EB200 antigen, one of the antigens according to the present invention has a characteristic peptide sequence corresponding to that which is framed in the sequence of the clone G9 (FIG. 1 (c)), this sequence having been deduced from the clone G9 resulting from the amplification of one of the fragments of the Pf332 gene under the conditions which will be recalled later.
• the EB200 antigen more generally belongs to the family of polypeptides having a common amino acid motif or sequence containing all or part of the polypeptide sequence below defined by its amino acid sequence:
• a peptide which contains only part of this sequence is part of the invention when this peptide is capable, if necessary when it is incorporated into a fusion protein, oligomerizes or conjugated to a carrier protein, in vivo a protective immune response in the squirrel monkey Saimiri sciureus.
• the distribution of the successive motifs of the amino acid sequence of a preferred polypeptide in accordance with the invention, as presented above, has no other objective than that of revealing the existence of motifs successive repetitions, within the protein, this repetitiveness is not however devoid of degenerations.
• the blanks (actually direct links) that appear at the end of some of the lines or within some of the lines have no particular meaning. Their only aim is to visually highlight the homologs of partial sequences of these successive repeating patterns. We can notice the frequency of the VTEEV motif within these partially repetitive or "degenerate" motifs.
• FIG. 2 The same amino acid sequence (using the three-letter representation by amino acids, instead of the one-letter representation in the above definition) is shown in Figure 2.
• Figure 2 shows the coding sequence of the recombinant clone , named PfEB200, containing an insert of 411 base pairs isolated from the Pf332 gene. It is recalled that this clone had already been isolated from a bank of expression sequences constructed in an ⁇ Amp3 vector with a batch (pool) of immune human sera (20).
• the present invention derives from the demonstration of the existence within the Ag332 antigen of amino acid sequences which are both specific for this antigen and exposed on the surface of the merozoites of P. falciparum and / or of the globules infected reds.
• the initial P. falciparum genomic library in the vector ⁇ gtWES had itself been constructed by digestion using DNasel and addition of adapters (linkers) containing EcoRI sites as previously described in (21).
• the sequenced parts are represented in FIG. 1 by thickening of the line.
• the enzymes used for the production of the restriction map were: BamH1 (B), Cla1 (C), Dra1 (D), EcoR1 (E) and Hind3 (H).
• EB200 soluble fusion protein expressed in the form of a soluble fusion protein PfEB200 with a glutathione-S-transferase
• the expression of the soluble polypeptide was carried out in E.coli Dh5 ⁇ (F end A1 hsdr 17 (rkmk-) sup E44 thi-1, ⁇ -, rec A1 gyr A96 rel A1 f80d lac Z ⁇ M15).
• the protein was purified by affinity chromatography on agarose beads carrying glutathione groups (32).
• the degree of purification of the fusion protein was analyzed by electrophoresis on polyacrylamide gel containing 10% SDS and by staining with Coomassie blue. Any conventional technique can be used to produce antibodies specific for the EB200 protein (in the form of a fusion or not). However, in this case, the antibodies tested in the tests referred to below were produced under the following conditions: Balb / c mice were immunized by subcutaneous injection of the recombinant protein EB200 (20 ⁇ g) in presence of Freund's complete adjuvant. Two booster injections, each of 15 ⁇ g of antigen, in incomplete Freund's adjuvant were given 3 weeks and 5 weeks respectively after the first injection.
• Antibody titers were determined by immunofluorescence on parasitized red blood cells spread in thin layers. It is the antibodies of such a serum that have been found to be monospecific. Tested in immunoprecipitation and by Westerm Blot on parasitic extracts, the anti-PfEB200 antibodies have been shown to be able to react with a protein of apparent molecular weight of approximately 1000 kDa belonging to the parasite Plasmodium falciparum.
• the antibodies directed against the recombinant protein expressed by the clone EB200 were tested according to their capacity to inhibit, in vitro, the reinvasion of red blood cells by merozoites, in particular in the test described by R. Udomsangpetch et al (37) which itself refers to a publication by Wâhlin, B. et al., entitled "Human antibodies to a M r 155,000 Plasmodium falciparum efficiently inhibit merozo ⁇ te invasion" (human antibodies against a M r 155,000 of Plasmodium falciparum effectively an invasion to merozoites) (1984) Proc. Nat. Acad. Sci. USA 81: 7912.
• the recombinant antigen PfEB200 is capable of inhibiting the phagocytosis of opsonized parasitized red blood cells (technique described in (ii) by monocytes of monkeys.
• the EB200 protein or fractions of it still have the following characteristics:
• polypeptide EB200 In the above, reference was made above all to the polypeptide EB200. It goes without saying that the invention also relates to any part of this polypeptide which is able, if necessary after incorporation into a fusion protein, oligomerization or conjugation to a carrier protein, to induce in vivo a protective immune response on the squirrel monkey Saimiri sciureus.
• the invention extends to all equivalent peptides resulting from the expression of the corresponding sequences of DNAs originating from infectious Plasmodiae for humans, other than P. falciparum, for example strains 7G8 (Brazil), T9- 96 (Thailand), FcBR (South America), 37D (derived from NF54, Netherlands) and Banjul (Gambia) which are all recognized in immunoprecipitation tests with the serum ⁇ EB200. It also recognizes erythrocytes infected with these parasites.
• all peptides are structurally differentiating from the previous ones by substitutions, deletions or additions of one or more amino acids is part of the invention since it is recognized by antibodies previously formed against EB200 and, preferably, if necessary after oligomerization, incorporation into a fusion protein, conjugation to a carrier molecule, since it induces in the squirrel monkey Saimiri sciureus antibodies active against parasites of human malaria, in particular P. falciparum.
• any polypeptide or fragment of polypeptide comprising in common a part of amino acid sequence with EB200 and which is capable of inducing in vivo antibodies capable of inhibiting the invasion of globules red in a proportion at least equal to 50% compared to those observable in preparations of control erythrocytes placed under the same conditions in the presence of the same concentrations of merozoites, but in the absence of the polypeptides or part of polypeptides of the genus in question .
• the invention naturally relates to any polypeptide containing a part of a sequence extending beyond the ends of the EB200 sequence, since the polypeptide concerned would exhibit protective immunogenic properties. of the same nature.
• Part beyond the ends of EB200 is meant, for example, the amino acid sequences which adjoin the amino acid structure of EB200 in the larger peptide sequence deduced from the nucleotide sequence of the G9 fragment, from which EB200 is derived (FIG. 1C ).
• the invention extends its effects to all peptides derived from the preceding ones, except that certain aminoacyl residues of their amino acid sequences would be substituted by others, even deleted or on the contrary intercalated in the represented sequences , without the modified peptides obtained losing the biological properties characteristic of the EB200 polypeptide.
• the invention relates more particularly to the monomer sequences corresponding to the degenerate repeating units present in EB200, in particular the peptides whose sequences correspond to the sequences (a to o) which follow:
• the peptides of the genus in question are capable of inducing in vivo a protective immune response in the squirrel monkey Saimiri sciureus or else of inhibiting the invasion of erythrocytes by merozoites.
• part of the invention is also any peptide equivalent containing motifs which can be represented by the formula:
• each of the groups X represents, according to the index which follows the signs of parenthesis which surrounds the group considered, a dipeptide or tripeptide each containing , at least one hydrophobic amino-acyl residue, this peptide equivalent being capable of inducing a protective immune response in the squirrel monkey Saimiri sciureus or of inhibiting an in vitro invasion of erythrocytes by P. falciparum.
• the invention relates to any fusion protein, oligomer or conjugate involving the peptides according to the invention.
• These peptides can be produced by chemical synthesis. It can also be the same for oligomers of these peptides or peptides conjugated to carrier molecules. Techniques allowing these syntheses to be carried out are recalled in the following, of course without limitation.
• This synthetic method consists in successively condensing, in the required order, the amino acids or peptides previously formed with other amino acids or peptides previously formed chosen so as to allow the production of a polypeptide having the final sequence chosen as amino acids, being it is understood that care will have been taken, if necessary, to protect beforehand all the reactive functions carried by these amino acids or peptides, with the exception of those of their amine and carboxyl functions which must intervene in the formation of peptide bonds, in particular after activation of said carboxyl functions.
• aminoacyl used has an additional acid function (in particular in the case of glutamic acid), these functions are protected, for example by t-butylester groups.
• the synthesis preferably begins with the condensation of the C-terminal amino acid with the amino acid which corresponds to the neighboring amino acid in the desired sequence and, closely in close proximity, with the other amino acids chosen in an appropriate manner, the synthesis ends with the fixing of the N-terminal amino acid.
• the first C-terminal amino acid in the chain to be produced is attached to a porous polymer resin, acting as an insoluble support through its carboxylic group.
• the amino function of this first amino acid will normally have been protected beforehand with an appropriate protective group, for example by a t-butyloxycarbonyl group.
• the oligomerization of the monomer blocks obtained can be carried out in any case as is known. These oligomers contain, for example from 2 to 20 monomer units. There is moreover no limit to the maximum number of monomer units capable of being included in the oligomer, except for the capacity of the oligomer finally obtained to be water-soluble or easily soluble in l 'water.
• a first method of oligomerization or polymerization of the monomer consists in the reaction of the latter with a crosslinking agent, such as glutaraldehyde.
• a crosslinking agent such as glutaraldehyde.
• Another preferred oligomerization process uses the techniques described by Richman and Reese, RT. (1988) Proc. Nat. Acad. a5: 1662-1666 or Posnett, DN. (1988) The Journal of Biological Chemistry Vol. 283, No. 4. These methods involve a small "central peptide matrix" (peptidyl core matrix) formed from a limited number of trifunctional amino acids, in particular lysines, interconnected so as to contain a large number of free functions vis with respect to the molecular weight of this central matrix and forming as many arms or dendrites which can then be conjugated with distinct amino acids or with C-terminal ends.
• central peptide matrix peptidyl core matrix
• central matrix based on heptalysins comprising sites for the attachment of 9-16 peptide chains.
• Cys - SS - C— Peptide Cys - SS - C— Peptide
• oligomer also includes the conjugates obtained by covalent coupling of several monomer units to a carrier molecule (natural or synthetic), physiologically acceptable and non-toxic, by means of complementary reactive groups respectively carried by the carrier molecule and / or the monomer units. Examples of suitable groupings are illustrated in the following.
• polylysines or poly (D-L-alanine) -poly (L-lysine) or immunologically inert proteins.
• Any coupling process can be used which involves, on the one hand, one or more reactive functions of the peptide and, on the other hand, one or more reactive functions of support molecules.
• these are the carboxyl and amino functions, which can give rise to a coupling reaction in the presence of a coupling agent of the type of those used.
• a coupling agent of the type of those used.
• proteins for example, 1- ethyl-3- (3-dimethylaminopropyl) - carbodiimide, N-hydroxybenzotriazole, etc.
• glutaraldehyde especially when it comes to link together amino groups respectively carried by the peptide and the support molecule.
• the invention also relates to a variant of the process for producing the oligomers according to the invention, this variant consisting in the transformation of cells of a culture of competent cells with a vector containing a nucleotide sequence coding for an oligomeric polypeptide containing the above-mentioned units. monomers under the control of a promoter recognized by said competent cells, under conditions allowing the expression in these cells of said oligomeric nucleotide sequence, and the recovery of the expression product of said nucleotide sequence.
• This is also part of the invention. There is no need to insist on the techniques that can be used, except that, preferably, the elements of the vector are preferably such that the expression product is transported outside the cells. competent, even excreted in their culture medium.
• the invention naturally relates to the corresponding acid fragments, more particularly to all or part of those which follow from FIG. 1 (c) with regard to the sequence G9.
• This DNA fragment can either be in the state individualized, or recombined within a larger recombinant DNA.
• these DNAs of larger sizes it is understood that the invention relates to:
• DNAs coding for fusion proteins involving a DNA sequence coding for a peptide according to the invention with DNA sequences coding themselves for heterologous peptide sequences which do not interfere with the induction properties by the polypeptide sequence according to the invention of a protective immunity against P. falciparum;
• Any vector containing this polypeptide sequence placed under the control of a promoter authorizing its expression in a competent cellular host and whose polymerases are capable of recognizing said promoter.
• the invention extends its effects to cell cultures thus transformed by such recombinant vectors or DNA which allow the expression of the polypeptide or fragment of the polypeptide according to the invention.
• part of the invention forms the specific antibodies of the sequences contained in EB200 or of peptides or fragments of peptides having the same biological properties as defined above.
• This protection extends its effects to all monoclonal antibodies specific for the same polypeptide sequences, as well as to secretory hybridomas of these monoclonal antibodies. It will be understood that the skilled person is able to produce these monoclonal antibodies and to select them in sorting operations involving the specific recognition by the monoclonal antibodies to be selected, amino acid sequences of peptides characteristic of the invention.
• the invention likewise relates to any pharmaceutical composition using these polypeptides, if appropriate associated with pharmaceutically acceptable vehicles facilitating their use in vaccination operations in order to induce the production in vivo, in particular in humans, of a protective immune response against infectious malarial parasites.
• the invention also relates to the antibody preparations, induced by EB200 or the equivalent peptides of the invention, whether these antibodies are polyclonal (sera containing them or immunoglobulin fraction purified from these sera) or monoclonal antibodies obtained as indicated below. -above.
• the invention relates to pharmaceutical compositions containing such antibodies for the purpose of entering into competition in vivo with the human parasite, in particular in individuals infected or threatened with infection by this parasite, in particular of the P. falciparum type, in order to protect them from the pathogenic effects due to this infection.
• the antibodies according to the invention are also more particularly characterized by the fact that they do not give rise to crossed immune reactions with the expression products of the Pf11-1 gene (27) and of the Pf155 / RESA gene (38).
• the clone containing the nucleotide sequence coding for EB200, contained in Escherichia coli DH5 was deposited on July 25 under number I-1128 at the National Collection of Cultures of Microorganisms of the Institut Pasteur de Paris (CNCM). The bibliography to which reference has been made in this description by references to publication numbers supplements this description.
• the invention also relates to the other applications of these antibodies, in particular their use for the in vitro diagnosis, for example carried out on a serum sample, of an infection by malarial parasites, in particular at the stage of infection of blood erythrocytes, for example by means of a conventional antigen-antibody reaction.
• the invention finally relates to the application of the peptides themselves to the in vitro detection of the presence of antibodies characteristic of infection by malarial parasites, in particular of the P. falciparum type or the like, and more particularly still at the erythrocyte stage of these parasites, in the form of merozoites.
• Anti-PfEB200 antibodies have also been used to locate the Pf332 antigen in the parasite.
• Indirect immunofluorescence on parasites fixed in air and analyzed by confocal microscopy, shows an image formed by structures similar to vesicles of about 0.5-1 ⁇ m. These vesicles were located in the cytoplasm of the parasitized red blood cell, dissociated from the parasite, and transported to the membrane of the erythrocyte.
• the Pf332 antigen appears to be associated with the membrane of red blood cells. Indeed, immunoelectromicroscopy shows that the Pf332 antigen is transported towards the membrane of the erythrocyte in association with "Maurer's clefts".
• the anti-PfEB200 serum reacts with the surface of the parasitized monkey red blood cells.
• the presence of epitopes of Pf332 on the surface of red blood cells confirms that this antigen may be the target of host immunological reactions and therefore be of interest for the development of a vaccine.
• the recombinant polypeptide PfEB200 inhibits phagocytosis, by monocytes, erythrocytes infected in the presence of hyperimmune monkey serum.
• the invention also relates to compositions using the peptides previously defined in association with other peptide constituents having vaccinating properties against malaria, in particular due to Plasmodium falciparum, more particularly the ability to induce a protective immune response in vivo, including the production of immunoprotective antibodies capable of destroying the parasites of the blood stage, responsible for the disease in humans, in a primate model represented by the squirrel monkey SAIMIRI SCIUREUS.
• the "second polypeptide” consists of a polypeptide derived from a major P falciparum antigen, having a molecular weight of the order of 72 kDA, hence the designation "72 kDA antigen” used in the following for the denote, in particular of a polypeptide derived from this 72 kDA antigen having the capacity, like this:
• This "second polypeptide" is itself often recognized by sera from human patients living in regions where malaria is endemic.
• the nucleotide sequence coding for the 72 kDA antigen peptide sequence has been identified by LS MATTEI et al European Journal of Immunology (1989) 19: 1823 - 1828.
• the "second polypeptide” advantageously consists of a polypeptide hereinafter designated “i72" comprising the 153 amino acids of the C - terminal region of the 72 kDA antigen.
• the amino acid sequence, as well as a nucleic acid sequence encoding the i72 polypeptide, are shown below:
• second polypeptide can also be constituted by a recombinant polypeptide containing all or part of the sequence of i72, for example a fusion molecule with the glutatione transferase of Schistosoma japonicum, according to the technique described by DB Smith and KS Johnson (1988) Gene 67, 41-48, by transformation of E. Coli with the plasmid pGEX previously modified with the appropriate insertion nucleotide sequence.
• Coli Escherichia coli DH5 ⁇ transformed by the above plasmid modified by a nucleotide sequence coding for the peptide i72, was deposited on July 24, 1991 with the National Collection of Cultures of Microorganisms of the Institut Pasteur de Paris (CNCM) under number I - 1129.
• third polypeptide (peptide or oligopeptide) as well as a nucleic acid fragment which codes for this third polypeptide, are characterized in that they contain the following respective sequence elements:
• GAA CAA TTA AAT AAA AAT AAG GAT GGA TAT GTT GTT TTG GTT ACT GAA
• TTT TTA AAG TTA TTA ATA AAA TTA CAT AAT GCA GGA TTG GTA CAT CTT
• a strain of E. Coli, transformed by such a nucleic acid was deposited at the CNCM under the number I-987 on July 27, 1990.
• a preferred "third peptide” is the recombinant peptide containing the sequence of the peptide "R 23" - of formula
• a strain of E. Coli containing the corresponding DNA sequence was deposited on July 27, 1990 under number I - 986 at the CNCM.
• the R23 peptide was likewise produced in the form of a recombinant fusion protein with the glutatione transferase from Schistosoma japonicum, according to the technique already mentioned by D.B. Smith and K.S. Johnson.
• these different peptides can be replaced by fragments or fusion proteins meeting the conditions which have also been defined above.
• the invention naturally also relates to the mixtures of specific antibodies which can be obtained from the respective constituents of the above-mentioned mixtures of polypeptides.
• These mixtures antibodies can be administered in vivo, in particular for the purpose of interfering with parasitaemia due to infection by a human parasite, in particular of the P. falciparum type.
• the invention likewise extends its effects to mixtures of the nucleic sequences in which the different corresponding nucleic sequences have been recombined with one another, under conditions permitting their expression in the form of a fusion protein comprising peptide sequences corresponding to the sequences of the three constituents (whole or partial) previously taken into consideration.
• telomere-rclated sequences 39. Veroick, K. D., D. Walliker, and T. F. McCutchan. 1988. Genetic hypervariability of telomere-rclated sequences is associated with meiosis in Plasmodiumfalciparum.

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