WO2000061766A2 - Vaccin anticancereux specifique de la telomerase - Google Patents

Vaccin anticancereux specifique de la telomerase Download PDF

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Publication number
WO2000061766A2
WO2000061766A2 PCT/IB2000/000610 IB0000610W WO0061766A2 WO 2000061766 A2 WO2000061766 A2 WO 2000061766A2 IB 0000610 W IB0000610 W IB 0000610W WO 0061766 A2 WO0061766 A2 WO 0061766A2
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Prior art keywords
telomerase
peptide
antigen
amino acids
length
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PCT/IB2000/000610
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English (en)
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WO2000061766A3 (fr
Inventor
Babita Agrawal
Bryan Michael Longenecker
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Biomira, Inc.
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Priority to AU41394/00A priority Critical patent/AU781376B2/en
Priority to EP00920996A priority patent/EP1171612A2/fr
Priority to CA002368967A priority patent/CA2368967A1/fr
Priority to JP2000611689A priority patent/JP2002541811A/ja
Publication of WO2000061766A2 publication Critical patent/WO2000061766A2/fr
Publication of WO2000061766A3 publication Critical patent/WO2000061766A3/fr

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    • 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
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • C12N9/12—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
    • C12N9/1241—Nucleotidyltransferases (2.7.7)
    • 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
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • 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
    • A61K39/46—Cellular immunotherapy
    • A61K39/462—Cellular immunotherapy characterized by the effect or the function of the cells
    • A61K39/4622—Antigen presenting cells
    • 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
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/4644—Cancer antigens
    • A61K39/464454—Enzymes
    • A61K39/464457—Telomerase or [telomerase reverse transcriptase [TERT]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y207/00—Transferases transferring phosphorus-containing groups (2.7)
    • C12Y207/07—Nucleotidyltransferases (2.7.7)
    • C12Y207/07049—RNA-directed DNA polymerase (2.7.7.49), i.e. telomerase or reverse-transcriptase
    • 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

  • telomeres the DNA at the chromosome ends, are made up of simple tandem repeats. In most somatic cells, telomere sequences are lost during DNA replication due to the need of DNA-dependent DNA polymerases for an RNA primer annealed to the template strand. Because the RNA primer cannot anneal beyond the 5' end of the DNA strand, each time a cell's DNA replicates, short bits of telomeric DNA are lost with each generation. Cells displaying such telomeric shortening go into senescence after a fixed number of population doublings, and senescence correlates directly with the erosion of telomeres to a critical minimum length.
  • telomerase enzyme presents an attractive therapeutic target. Due to the fact that telomerase is a normal "self antigen, however, conventional vaccination strategies are unavailable. Thus, the focus of telomerase- based therapeutics has been enzyme inhibitors of various sorts, rather than vaccine-based approaches.
  • telomerase antigens are provided that are capable of marshalling the immune system against telomerase-expressing cells.
  • telomerase antigens are provided, which are based on peptide sequences of the protein portion of telomerase.
  • telomerase antigens are provided as nucleic acids that are capable of being used to express peptide-based telomerase antigens.
  • the invention provides vaccine compositions which include at least one telomerase antigen.
  • the invention provides vaccine compositions containing telomerase peptide antigens.
  • polynucleotides are provided, which encode protein-based telomerase antigens.
  • the present invention relates to a telomerase-specific vaccines, which are useful generating telomerase-directed activated T-cells. More particularly the inventive vaccines are useful in generating antigen-specific major histocompatability- (MHC-) restricted T-cell responses against telomerase presented by antigen presenting cells. It is believed that the present vaccines act to relieve the tolerance or anergy induced through self- tolerance mechanisms to telomerase in normal individuals. Since telomerase represents a cancer-specific therapeutic target, in one embodiment, the vaccines of the invention are useful in the treatment or prevention of a variety of cancers.
  • MHC- major histocompatability-
  • an "activated T-cell” is one that is in the following phases of the cell cycle: the G, phase, the S phase, the G 2 phase or the M (mitosis) phase.
  • an “activated T-cell” is undergoing mitosis and/or cell division.
  • An activated T- cell may be a T helper (T H ) cell or a cytotoxic T-cell (cytotoxic T lymphocyte (CTL or T c )).
  • Activation of a naive T-cell may be initiated by exposure of such a cell to an antigen- presenting cell (APC) (which contains antigen/MHC complexes) and to a molecule such as IL-1, IL-2, IL-12, IL-13, ⁇ -IFN, and similar lymphokines.
  • APC antigen- presenting cell
  • the antigen/MHC complex interacts with a receptor on the surface of the T-cell (T-cell receptor (TCR)).
  • T-cell receptor TCR
  • CD4 and CDS " T-cell responses against a target antigen are usually dependent upon in vivo priming, either through natural infection or through deliberate immunization.
  • a “naive" T-cell is one that has not been exposed to foreign antigen (non-autologous) antigen or one that has not been exposed to cryptic autologous antigen.
  • a “naive” T-cell is sometimes referred to as an "unprimed” T-cell.
  • a “resting” cell is in the G 0 phase of the cell cycle and hence is not dividing or undergoing mitosis.
  • an "anergic" T-cell is one that is unable to function properly; i.e.. such as a cell that lacks the ability to mediate the normal immune response.
  • T-cells from diseased patients may contain T-cells that have been primed, but are anergic.
  • memory T-cells also known as “memory phenotype” T-cells, is used to designate a class of T-cells that have previously encountered a peptide antigen but are now resting and are capable of being activated.
  • Memory T-cells are T- cells which have been exposed to antigen and then survive for extended periods in the body without the presence of stimulating antigen. However, these memory T-cells respond to
  • memory T-cells are more responsive to a "recall” antigen, when compared with the naive T-cell response to peptide antigen.
  • Memory cells can be recognized by the presence of certain cell-surface antigens, such as CD45R0, CD58, CD1 l ⁇ , CD29, CD44 and CD26, which are markers for differentiated T-cells.
  • an "telomerase-specific" T-cell response is a T- cell response (for example, proliferative, cytotoxic and/or cytokine secretion) to telomerase antigenic stimulus, for example a peptide. which is not evident with other stimuli, such as peptides with different amino acid sequences (control peptides).
  • the responsiveness of the T- cell is measured by assessing the appearance of cell surface molecules that are characteristic of T-cell activation, including, but not limited to CD25 and CD69. Such assays are known in the art.
  • treating in its various grammatical forms in relation to the present invention refers to preventing, curing, reversing, attenuating, alleviating, minimizing, suppressing or halting the deleterious effects of a disease state, disease progression, disease causative agent or other abnormal condition.
  • Telomerase antigens share the characteristic ability to generate a specific T-cell response.
  • This response may be either class I- or class ll-specific.
  • this response is MHC class l-specific, and will comprise antigen- and MHC- restricted cytotoxicity.
  • Class I molecules include HLA-A, HLA-B and HLA-C.
  • preferred antigens bind class I molecules, e.g., HLA-A1, HLA-A2, HLA-A3 or HLA-A11. More preferred antigens bind all class I molecules.
  • class ll-specific (e.g., helper functions) responses are desired, class-II-binding antigens will be used.
  • Class II molecules include HLA-DR, HLA-DQ and HLA-DP. Useful antigens can be determined as set out below.
  • Telomerase antigens are typically derived from the sequence of the protein portion of telomerase, which is disclosed in U.S. Patent No. 5,837,857 (1998) and at GenBank Accession Nos. AF015950 and AF018167, which sequences are hereby incorporated by reference. They may be made, for example, by proteolytic digestions of the telomerase protein and/or by recombinant DNA means. Generally, the relatively short peptide versions will be prepared by synthetic means.
  • telomerase antigens Nine-mers are typical of class I antigens, since they usually retain the requisite functional character; they include Ile-Leu-Ala-Lys-Phe-Leu-His-Trp-Leu (ILAKFLHWL) as a preferred species. Variants of telomerase antigens are also contemplated. It is only important that any variants retain the functional characteristics of a telomerase antigen: (1) the ability to bind an MHC molecule, e.g., HLA-A2, and (2) the ability to induce a telomerase specific T-cell response. Amino acid substitutions, i.e.
  • “conservative substitutions” that yield “conservative variants,” may be made, for instance, on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues involved.
  • nonpolar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, proline. phenylalanine, tryptophan, and methionine;
  • polar neutral amino acids include glycine, serine, threonine, cysteine. tyrosine, asparagine, and glutamine;
  • positively charged (basic) amino acids include arginine. lysine. and histidine;
  • negatively charged (acidic) amino acids include aspartic acid and glutamic acid. Substitutions typically may be made within groups (a)-(d).
  • glycine and proline may be substituted for one another based on their relatively small sizes and lack of side-chains.
  • amino acids such as alanine, cysteine, leucine, methionine, glutamic acid, glutamine, histidine and lysine are more commonly found in ⁇ -helices, while valine, isoleucine, phenylalanine, tyrosine. tryptophan and threonine are more commonly found in ⁇ -pleated sheets.
  • Glycine, serine. aspartic acid, asparagine, and proline are commonly found in turns. The importance of substitution groups based on structure, of course, increases with the length of the antigen.
  • Some preferred conservative substitutions may be made among the following groups: (i) S and T; (ii) P and G; and (iii) A. V, L and I.
  • S and T S and T
  • P and G P and G
  • A. V, L and I A preferred conservative substitutions
  • the skilled scientist readily can construct DNAs encoding the conservative amino acid variants. Of course, smaller variants may be synthesized.
  • One such genus of conservative HLA-A2-binding variants includes peptides of the structure: (A/V/L/I)(A/V/L/I)(A/V/L/I)(A/V L/I)KF(A/V/L/I)HW(A/V/L/I).
  • some preferred conservative va ⁇ ants include LLAKFLHWL, ILAKFLHWI, IIAKFLHWL, IIA FLHWI, ILARFLHWL, and ILVKFLHWL, and permutations thereof, so long as the requisite functional characteristics are retained.
  • GLFGGGGGV can bind HLA-A2.
  • the only real conservation observed in 9-mer HLA-A2- binding peptides was an He or a Leu at about position 2 (counting N- to C-terminal) and a Val or a Leu at about position 9.
  • Some simple variants therefore, include GLAKFLHWL, ILAGFLHWL, ILAKGLHWL, ILAKFGHWL.
  • ILAKFLGWL and ILAKFLHGL subject to the presence of the requisite functional characteristics.
  • the anisan will appreciate that, while the anchor residues and auxiliary residues are relatively conserved in HLA binding, the remainder of the antigen can vary widely, and is probably responsible for the particular antigenic character of the antigen, i.e., it differentiates telomerase from non-telomerase.
  • substitutions include replacing L-amino acids with the corresponding D-amino acids.
  • This rationale moreover can be combined with the foregoing conservative substitution rationales.
  • D-leucine may be substituted for L-isoleucine.
  • these D- amino acid-containing peptides may be prepared which have an inverse sequence, relative to the native sequence.
  • ILAKFLHWL becomes LWHLFKALI.
  • Such "retro-inverso" peptides are expected to have improved properties, such as increased in vivo half-life. This translates into smaller doses and more economically viable production.
  • Multimers can contain multiple copies of the same peptide, or they can be mixed and matched.
  • the multimers can be direct tandem repeats, and may contain short spacers sequences of amino acids (e.g., 2-5 residues) like Gly and/or Pro, or other suitable spacers.
  • Multimers may be any length, but typically will be less than about 100 amino acids.
  • Preferred multimers are less than about 60 amino acids and have between about 2 and 5 copies of peptides of about 8 to about 12 amino acids long. Multimers may also comprise several different telomerase antigens.
  • telomerase antigens may be glycosylated or partially glycosylated according to methods known in the art. They also can be modified with large molecular weight polymers, such as polyethylene glycols. In addition, lipid modifications are preferred because they may facilitate the encapsulation or interaction of the derivative with liposomes. Exemplary lipid moieties useful for this purpose include, but are not limited to, palmitoyl, myristoyl, stearoyl and decanoyl groups or. more generally, any C 2 to C 30 saturated, monounsaturated or polyunsaturated fatty acyl group.
  • telomerase antigen For convenience in making chemical modifications, it is sometimes useful to include in a telomerase antigen one or more amino acids having a side chain amenable to modification.
  • a preferred amino acid is lysine. which may readily be modified at the ⁇ -amino group.
  • Side-chain carboxyls of aspartate and glutamate are readily modified, as are serine, threonine and tyrosine hydroxyl groups, the cysteine sulfhydryl group and the histidine amino group.
  • the introduction of two cysteine residues, at spaced locations in a peptide antigen, may serve to form a structural constraint through a disulfide bridge, which may improve binding to MHC molecules.
  • telomerase antigen within the present invention is a non- peptide "mimetic," i.e., a compound that mimics one or more functional characteristics of the telomerase antigen.
  • Mimetics are generally water-soluble, resistant to proteolysis, and non- immunogenic. Conformationally restricted, cyclic organic peptides which mimic telomerase antigens can be produced in accordance with known methods described, for example, by Saragovi, et al. Science 253: 792 (1991).
  • Telomerase antigens may also be constructed as hybrids (and/or formulated as distinct molecules together in liposomes, as described below) with immune-stimulatory molecules, like cytokines and adjuvants.
  • Interleukin-2 IL-2
  • Other cytokines include GM-CSF, IL-12 and flt-3 ligand.
  • Telomerase antigens may be made as fusion proteins with IL-2, for example, by recombinant DNA or chemical synthetic means, or they may made as chemical conjugates using bi-functional chemical linkers. It is anticipated that such chimeric proteins would possess an increased ability to generate a T-cell-specif ⁇ c response against telomerase.
  • Adjuvants include monophosphoryl lipid A (MPLA), and derivatives thereof, which also may be attached to a telomerase antigen by conventional linkers.
  • Other conventional immune stimulatory molecules include keyhole limpet hemocyanin (KLH).
  • telomerase antigens which would be expected to generate a more specific response, associated with a particular epitope for example. Moreover, these small antigens may be more economically produced.
  • telomerase antigen it is advantageous to identify additional telomerase antigen and further to refine the T-cell antigenicity of telomerase. even down to the epitopic level.
  • One classic method involves proteolytic treatment of the large antigen to derive smaller antigens.
  • fragments of protein antigens can be produced by recombinant DNA techniques and assayed to identify particular epitopes.
  • small peptides can be produced by in vitro synthetic methods and assayed.
  • phagocytic antigen presenting cells or any APC
  • macrophages may be fed large antigens (or portions thereof) and thus act as the starting material for these methods.
  • the MHC class I or class II molecules can be isolated from these starting cells using known methods, such as antibody affinity (MHC-specific antibodies) and chromatographic techniques.
  • sequences structures of the most prevalent peptide epitopes associated with class I and/or class II molecules may be determined. Supplied with this sequence/structural information, permutations of the determined sequence can be made, as detailed above, and assayed using known T-cell assays. Rammensee et al., supra, provides extensive methods and guidance related to identifying both class I and class II motifs.
  • telomerase-specific antigen as described above, will be useful in formulating telomerase-specific vaccines.
  • Preferred antigens may be associated with lipids, usually either by direct lipid modification of the antigen and/or by liposomal association, as described below.
  • the antigens may be administered as peptides or peptide mimetics, or they may be administered in nucleic acid form.
  • the telomerase antigen is associated with a liposome.
  • Techniques for preparation of liposomes and the formulation of various molecules, including peptides, with liposomes ⁇ e.g., encapsulation or complex formation) are well known to the skilled artisan.
  • Liposomes are microscopic vesicles that consist of one or more lipid bilayers surrounding aqueous compartments. See, generally, Bakker-Woudenberg et al, Eur. J. Clin. Microbiol. Infect. Dis. 12 (Suppl. 1): S61 (1993) and Kim, Drugs 46: 618 (1993).
  • Liposomes are similar in composition to cellular membranes and as a result, liposomes generally can be administered safely and are biodegradable.
  • Liposomes can adsorb to virtually any type of cell and then release the encapsulated agent.
  • the liposome fuses with the target cell, whereby the contents of the liposome empty into the target cell.
  • an absorbed liposome may be endocytosed by cells that are phagocytic. Endocytosis is followed by intralysosomal degradation of liposomal lipids and release of the encapsulated agents. Scherphof et al., (1985) Ann. N Y. Acad. Sci. 446: 368.
  • Anionic liposomal vectors have also been examined. These include pH sensitive liposomes which disrupt or fuse with the endosomal membrane following endocytosis and endosome acidification. Among liposome vectors, however, cationic liposomes are the most studied, due to their effectiveness in mediating mammalian cell transfection in vitro.
  • Cationic lipids are not found in nature and can be cytotoxic, as these complexes appear incompatible with the physiological environment in vivo which is rich in anionic molecules. Liposomes are preferentially phagocytosed into the reticuloendothelial system. However, the reticuloendothelial system can be circumvented by several methods including saturation with large doses of liposome particles, or selective macrophage inactivation by pharmacological means. Classen et al, (1984) Biochim. Biophys. Acta 802: 428.
  • Suitable liposomes that are used in the methods of the invention include multilamellar vesicles (MLV), oligolamellar vesicles (OLV), unilamellar vesicles (UV), small unilamellar vesicles (SUN), medium-sized unilamellar vesicles (MUN), large unilamellar vesicles (LUV), giant unilamellar vesicles ( GUV), multivesicular vesicles (MW), single or oligolamellar vesicles made by reverse-phase evaporation method (REV), multilamellar vesicles made by the reverse-phase evaporation method (MLV-REV), stable plurilamellar vesicles (SPLV), frozen and thawed MLV (FATMLV), vesicles prepared by extrusion methods (VET), vesicles prepared by French press (FPV), vesicles prepared by fusion
  • the present vaccine formulations may be formulated advantageously with some type of adjuvant.
  • adjuvants are substances that act in conjunction with specific antigenic stimuli to enhance the specific response to the antigen.
  • MPLA for example, has been shown to serve as an effective adjuvant to cause increased presentation of liposomal antigen by the APCs to specific T Lymphocytes. Alving, C.R. 1993. Immunobiol. 187:430-446.
  • adjuvants such as Detox, alum, QS21, complete and/or incomplete Freund's adjuvant, MDP, LipidA and derivatives thereof, are also suitable.
  • Another class of adjuvants include stimulatory cytokines, such as IL-2.
  • the present vaccines may be formulated with IL-2 or IL-2 may be administered separately for optimal antigenic response.
  • IL-2 is beneficially formulated with liposomes.
  • Vaccines may be formulated for multiple routes of administration. Specifically preferred routes include intramuscular, percutaneous, subcutaneous, or intradermal injection, aerosol, oral or by a combination of these routes, at one time, or in a plurality of unit dosages. Administration of vaccines is well known and ultimately will depend upon the particular formulation and the judgement of the attending physician.
  • Vaccine formulations can be maintained as a suspension, or they may be lyophilized and hydrated later to generate a useable vaccine.

Abstract

L'invention concerne des antigènes des lymphocytes T spécifiques de la télomerase utiles dans la génération de réponses des lymphocytes T à la télomérase. Les formulations d'antigènes de la télomérase comme vaccins servent à traiter et prévenir le cancer grâce à des techniques in vivo ou ex vivo.
PCT/IB2000/000610 1999-04-09 2000-04-07 Vaccin anticancereux specifique de la telomerase WO2000061766A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU41394/00A AU781376B2 (en) 1999-04-09 2000-04-07 Telomerase-specific cancer vaccine
EP00920996A EP1171612A2 (fr) 1999-04-09 2000-04-07 Vaccin anticancereux specifique de la telomerase
CA002368967A CA2368967A1 (fr) 1999-04-09 2000-04-07 Vaccin anticancereux specifique de la telomerase
JP2000611689A JP2002541811A (ja) 1999-04-09 2000-04-07 テロメラーゼ特異的癌ワクチン

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US12853999P 1999-04-09 1999-04-09
US60/128,539 1999-04-09

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WO2000061766A2 true WO2000061766A2 (fr) 2000-10-19
WO2000061766A3 WO2000061766A3 (fr) 2001-03-08

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JP (1) JP2002541811A (fr)
AU (1) AU781376B2 (fr)
CA (1) CA2368967A1 (fr)
WO (1) WO2000061766A2 (fr)

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US6440735B1 (en) * 1998-03-31 2002-08-27 Geron Corporation Dendritic cell vaccine containing telomerase reverse transcriptase for the treament of cancer
EP1257284A1 (fr) * 2000-02-15 2002-11-20 The Regents of the University of California Vaccin universel et methode de traitement du cancer utilisant la transcriptase inverse de la telomerase
WO2003000227A2 (fr) * 2001-06-25 2003-01-03 Yissum Research Development Company Of The Hebrew University Of Jerusalem Procede de preparation de vesicules chargees d'un materiau biologique et differentes utilisations desdites vesicules
DE102006025146A1 (de) * 2006-05-30 2007-12-06 Charité - Universitätsmedizin Berlin Peptide zur differentiellen Modulation der proteasomalen Aktivität
WO2008017568A1 (fr) 2006-08-10 2008-02-14 International Investment And Patents Sa Plasmides ayant une action immunologique
US7388071B2 (en) 2000-02-15 2008-06-17 The Regents Of The University Of California Composition and method for inducing and enhancing a telomerase reverse transcriptase-reactive cytotoxic T lymphocyte response
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US7413864B2 (en) 1997-04-18 2008-08-19 Geron Corporation Treating cancer using a telomerase vaccine
US7750121B2 (en) 1997-04-18 2010-07-06 Geron Corporation Antibody to telomerase reverse transcriptive
US8222392B2 (en) 1996-10-01 2012-07-17 Geron Corporation Kit for detection of telomerase reverse transcriptase nucleic acids
US8709995B2 (en) 1997-04-18 2014-04-29 Geron Corporation Method for eliciting an immune response to human telomerase reverse transcriptase
WO2014079464A1 (fr) * 2012-11-21 2014-05-30 Sherif Salah Abdul Aziz Nouvelles compositions enzymatiques pour le traitement d'une infection par le virus de l'immunodéficience humaine (vih)

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US7388071B2 (en) 2000-02-15 2008-06-17 The Regents Of The University Of California Composition and method for inducing and enhancing a telomerase reverse transcriptase-reactive cytotoxic T lymphocyte response
EP1257284A1 (fr) * 2000-02-15 2002-11-20 The Regents of the University of California Vaccin universel et methode de traitement du cancer utilisant la transcriptase inverse de la telomerase
US8697836B2 (en) 2000-02-15 2014-04-15 The Regents Of The University Of California Composition and method for inducing and enhancing a telomerase reverse transcriptase-reactive cytotoxic T lymphocyte response
EP1257284A4 (fr) * 2000-02-15 2005-12-21 Univ California Vaccin universel et methode de traitement du cancer utilisant la transcriptase inverse de la telomerase
US7375117B2 (en) 2000-12-22 2008-05-20 Gemvax As Polypeptides
WO2002051994A2 (fr) * 2000-12-22 2002-07-04 Gemvax As Polypeptides
US7078416B2 (en) 2000-12-22 2006-07-18 Gemvax As Polypeptides
US8193326B2 (en) 2000-12-22 2012-06-05 Gemvax As Nucleic acids encoding novel TERT polypeptides
JP2004522433A (ja) * 2000-12-22 2004-07-29 ゲムヴァックス・アーエス ポリペプチド
WO2002051994A3 (fr) * 2000-12-22 2002-12-27 Gemvax As Polypeptides
AU2002311616B2 (en) * 2001-06-25 2007-11-22 Yissum Research Development Company Of The Hebrew University Of Jerusalem A method for preparation of vesicles loaded with biological material and different uses thereof
WO2003000227A3 (fr) * 2001-06-25 2003-11-13 Yissum Res Dev Co Procede de preparation de vesicules chargees d'un materiau biologique et differentes utilisations desdites vesicules
WO2003000227A2 (fr) * 2001-06-25 2003-01-03 Yissum Research Development Company Of The Hebrew University Of Jerusalem Procede de preparation de vesicules chargees d'un materiau biologique et differentes utilisations desdites vesicules
DE102006025146A1 (de) * 2006-05-30 2007-12-06 Charité - Universitätsmedizin Berlin Peptide zur differentiellen Modulation der proteasomalen Aktivität
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US8691959B2 (en) 2006-08-10 2014-04-08 Cosmo Bio-Technologies Srl Plasmids with immunological action
WO2014079464A1 (fr) * 2012-11-21 2014-05-30 Sherif Salah Abdul Aziz Nouvelles compositions enzymatiques pour le traitement d'une infection par le virus de l'immunodéficience humaine (vih)

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AU4139400A (en) 2000-11-14
EP1171612A2 (fr) 2002-01-16

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