EP1278539A1 - Zusammensetzung aus omp proteinen und autologen und/oder heterologen tumorzelllysaten - Google Patents

Zusammensetzung aus omp proteinen und autologen und/oder heterologen tumorzelllysaten

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Publication number
EP1278539A1
EP1278539A1 EP01931780A EP01931780A EP1278539A1 EP 1278539 A1 EP1278539 A1 EP 1278539A1 EP 01931780 A EP01931780 A EP 01931780A EP 01931780 A EP01931780 A EP 01931780A EP 1278539 A1 EP1278539 A1 EP 1278539A1
Authority
EP
European Patent Office
Prior art keywords
omp
lysate
autologous
composition according
protein
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Withdrawn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
EP01931780A
Other languages
English (en)
French (fr)
Inventor
Toufic Renno
Isabelle Invernizzi
Jean-Yves Bonnefoy
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.)
Pierre Fabre Medicament SA
Original Assignee
Pierre Fabre Medicament SA
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 Pierre Fabre Medicament SA filed Critical Pierre Fabre Medicament SA
Publication of EP1278539A1 publication Critical patent/EP1278539A1/de
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/515—Animal cells
    • A61K2039/5152—Tumor 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55516—Proteins; Peptides

Definitions

  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an Omp membrane protein, in particular an OmpA membrane protein of Klebsiella pneumoniae, associated with a lysate of autologous and / or heterologous tumor cells as well as the use of these compositions for the prevention and treatment cancer.
  • Vaccination is an effective way to prevent or reduce viral or bacterial infections.
  • the success of vaccination campaigns in these fields has made it possible to extend the concept of vaccine previously used in the field of infectious diseases to the fields of cancer and autoimmune diseases.
  • Vaccine antigens administered alone in the host are often not immunogenic enough to induce an immune response, and must therefore be combined with an adjuvant or coupled to a carrier protein to induce (or increase) their immunogenicity. Under these conditions, only a humoral type immune response can be induced.
  • CTL cytotoxic T lymphocytes
  • CTL epitope peptide sequences interacting with Let class molecules presented to CD8 + T lymphocytes
  • the difficulty lies in the generation of CTL in vivo, due to the low immunogenicity of these peptides (Melief, 1992, Adv. Cancer Res., 58, 143-175; Nandaz and Sercaz, 1995, Cell, 82, 13- 17).
  • dendritic cells for example, have been used to generate CTL anticancer responses (Nestlé FO et al., 1998, Nat. Med., 4, 328-332).
  • the approaches consisted of loading the dendritic cells ex vivo with the antigen of interest (peptides or cell lysate) and re-implanting these cells in the patient.
  • Other approaches consist in transfecting the dendritic cells ex vivo with the gene coding for the antigen of interest and in reinjecting these transfected cells (Gilboa E. et al., 1998, Cancer Immunol. Immunother., 46, 82-87 ).
  • an anti-tumor vaccination carried out with peptides corresponding to CTL epitopes and in the presence of such an adjuvant can lead to a specific state of tolerance which can lead in certain cases to the desired opposite effect, that is to say to a decrease in the immune response (Toes et al., Proc. ⁇ at. Acad. Sci., USA, 1996, 93, 7855-7860).
  • the international patent application published on April 5, 1990 under the number WO 90/03183 describes immunotherapeutic vaccines comprising antigens originating from melanoma cell lysates, an adjuvant, called “DETOX” consisting of a detoxified endotoxin of the monophosphoryl lipid A type. (MPL) derived from Sahnonella minnesota and a carrier derived from the cell envelope of Mycobacterium bovis, strain BCG.
  • MPL monophosphoryl lipid A type.
  • MPL monophosphoryl lipid A type.
  • the possible side effects of DETOX and of BCG derivative used in immunotherapeutic vaccines are known to those skilled in the art.
  • the object of the present invention consists of new and improved immunotherapeutic compositions which in particular have the advantage of:
  • an Omp protein such as the P40 protein of Klebsiella pneumoniae
  • a lysate of autologous and / or heterologous tumor cells preferably without recourse to the addition of an adjuvant or a carrier, had the advantages mentioned above.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising in an acceptable pharmaceutical medium at least one Omp protein, or one of its fragments, associated with a lysate of autologous and / or heterologous tumor cells.
  • Proteins derived from said Omp protein whose amino acid sequence exhibits homology, as defined below, of at least 80%, preferably 85%, 90%, 95% and 99%, after optimal alignment with the sequence of the reference Omp protein and which are capable of generating or increasing a CTL and / or anti-tumor response can also be used as Omp protein in the pharmaceutical compositions according to the present invention.
  • the term “protein” will also be understood to denote the peptides or polypeptides and the term “Omp” (for “Outer Membrane Protein”), the proteins of the outer membrane.
  • Omp the OmpA, the porines (in particular the OmpC and F) and the OmpX of E. coli.
  • the Omp is chosen from among. OMP of Enterobacteriaceae.
  • the Omp is chosen from OmpA, namely the proteins of the external membrane of type A, and more particularly those of Klebsiella pneumoniae. Even more preferably, the one called P40 will be used as described in patents WO 95/27787 and WO 96/14415.
  • the term “fragment of an Omp protein” is intended to denote in particular any fragment of the amino acid sequence included in the amino acid sequence of the Omp protein which is capable of generating or increasing a CTL and / or anti-tumor response, said fragment Omp protein comprising at least 5 amino acids, preferably at least 10 amino acids or more preferably at least 15, 20, 25, 30, 40, 50, 75 and 100 consecutive amino acids of the sequence of said Omp protein .
  • composition according to the invention comprises an Omp protein or one of its fragments according to the invention, characterized in that said Omp protein, or one of its fragments, is obtained by a process extraction from a culture of said enterobacterium.
  • the composition according to the invention comprises an Omp protein or one of its fragments, characterized in that said Omp protein or one of its fragments, is obtained by recombinant route.
  • Omp protein or one of its fragments is obtained by recombinant route.
  • Omp proteins obtained by the recombinant route are particularly well defined, and can thus be used and marketed for administration in humans more easily and quickly, in particular for reasons of marketing authorization.
  • the Omp protein used in the compositions according to the invention is the OmpA protein from Klebsiella pneumoniae.
  • the invention relates to the use in the compositions according to the invention, of the amino acid sequence of said OmpA protein of Klebsiella pneumoniae, or one of its fragments, which comprises: a) the sequence of amino acids of sequence SEQ ID ⁇ ° 1; b) the amino acid sequence of a sequence having a homology of at least 80%, preferably 85%, 90%, 95% and 99%, after optimal alignment with the sequence SEQ ID No. 1; or c) the amino acid sequence of a fragment of at least 5 amino acids, preferably 10, 15, 20, 25, 30, 40, 50, 75 and 100 amino acids, of a sequence as defined in a).
  • nucleic acid or amino acid sequence having a homology of at least 80% after optimal alignment with a determined nucleic acid or amino acid sequence is meant a sequence which after optimal alignment with said determined sequence includes a percentage identity of at least 80% with said determined sequence.
  • percentage of identity between two nucleic acid or amino acid sequences within the meaning of the present invention is meant a percentage of identical nucleotides or amino acid residues between the two sequences to be compared, obtained after the best alignment, this percentage being purely statistical and the differences between the two sequences being distributed randomly and over their entire length.
  • Sequence comparisons between two nucleic acid or amino acid sequences are traditionally carried out by comparing these sequences after having optimally aligned them, said comparison being carried out by segment or by "comparison window” to identify and compare the regions. sequence similarity locale.
  • Optimal alignment of sequences for comparison can be carried out, in addition to manually, using the local homology algorithm of Smith and Waterman (1981) [Ad. App.
  • the percentage of identity between two nucleic acid or amino acid sequences is determined by comparing these two optimally aligned sequences per comparison window in which the region of the nucleic acid or amino acid sequence to be compared. may include additions or deletions with respect to the reference sequence for optimal alignment between these two sequences.
  • the percentage of identity is calculated by determining the number of identical positions for which the nucleotide or the amino acid residue is identical between the two sequences, by dividing this number of identical positions by the total number of positions in the comparison window. and multiplying the result obtained by 100 to obtain the percentage of identity between these two sequences.
  • BLAST 2 sequences available on the site http://www.ncbi.nlm.nih.gov/gorf/bl2.html, the parameters used being those given by default (in particular for the parameters “open gap penaltie”: 5, and “extension gap penaltie”: 2; the chosen matrix being for example the “BLOSUM 62” matrix proposed by the program), the percentage of identity between the two sequences to be compared being calculated directly by the program.
  • sequences having a homology of at least 80% with the reference Omp sequence, or among the amino acid sequences of fragment of reference Omp sequence it is preferred:
  • - the peptide sequences capable of inducing CTL activity (Cytotoxic T Lymphocytes), as it can be evaluated with a standard method for measuring CTL activity based for example on the measurement of percentage of specific lysis of co- incubated with effector lymphocytes from animals immunized with a peptide derived from the reference Omp sequence associated with a relevant peptide; and or
  • said homologous peptides or said Omp fragments will be capable of inducing a CTL activity and / or of generating or increasing an antitumor activity at least equal to 10%, preferably 20%, 30%, 50% and 75% of the activity measured under the same conditions for the reference Omp sequence.
  • the other essential element of the pharmaceutical compositions according to the invention relates to a lysate of autologous and / or heterologous tumor cells.
  • autologous tumor cells means tumor cells belonging to the subject who will receive the compositions according to the invention.
  • heterologous tumor cells should be understood to mean cells originating from tumors originating from an individual different from that for which the composition according to the invention is intended.
  • the use of heterologous cells makes it possible to obtain pharmaceutical compositions which make it possible in particular to treat patients suffering from cancer from whom the removal of tumor cells is not possible.
  • the use of heterologous cells also makes it possible to obtain standardized compositions according to the invention comprising antigens found in many types of cancer and thus usable in a majority of patients.
  • Tumor cells can be obtained from a sample of cancerous tissue, for example following a biopsy or surgical resection.
  • a cell lysate can be defined within the meaning of the present invention as a mixture of intracellular and / or membrane antigens, preferably intracellular and membrane.
  • lysates of tumor cells forming part of the pharmaceutical composition according to the invention
  • tumor cells expressing an associated tumor antigen particular preference is given to tumor tumor cells originating from cancers with tumor cells expressing an associated tumor antigen, as mentioned below.
  • Said autologous and / or heterologous tumor cell lysate according to the invention can be obtained by mechanical, chemical or enzymatic lysis of tumor cells.
  • freeze / thaw In order to lyse the cells mechanically, mention may in particular be made of the techniques known to those skilled in the art, namely in particular sonication, ultrasonication or freezing / thawing. Particularly preferred is freeze / thaw, and most particularly the use of multiple freeze / thaw cycles.
  • the cells can also be lysed using chemical compounds or enzymes, such as for example digitonin lysis buffer, triton X-100 or Nonidet P40. Any method of breaking the cell membrane of tumor cells can be used to obtain a lysate.
  • chemical compounds or enzymes such as for example digitonin lysis buffer, triton X-100 or Nonidet P40. Any method of breaking the cell membrane of tumor cells can be used to obtain a lysate.
  • the pharmaceutical composition according to the invention can also comprise a cytokine or a growth factor, in particular alpha or gamma interferon, TNF, GM-CSF (Granulocyte Macrophage Colony Stimulating Factor), IL-2, IL-4, IL-6 and IL-18, an HSP (Heat Shock Protein) such as for example hs ⁇ 70, hs ⁇ 90, hs ⁇ 96, which makes it possible to potentiate the immune response, and / or fibroblasts genetically engineered to release a cytokine or growth factor. Mention may be made of fibroblasts expressing GM-CSF sold by the company Immune Response Corporation.
  • the compositions according to the invention can also contain antigen presenting cells. The latter can be chosen in particular from macrophages, B lymphocytes or dendritic cells and preferably from macrophages.
  • Antigen presenting cells can be obtained by in vitro production from stem cells from human blood or spinal cord (see
  • macrophages humans obtained from blood mononuclear cells preferably isolated from the patient to be treated.
  • the number of macrophages can be increased using M-CSF (Macrophage Colony Stimulating Factor).
  • the use of antigen presenting cells is optional in the present invention.
  • the invention also relates to compositions according to the invention without antigen presenting cells allowing a therapeutic treatment which does not require ex vivo manipulation of antigen presenting cells and whose implementation is thus easier and more simplified and not having the possible disadvantages of those using antigen presenting cells.
  • compositions according to the invention can also comprise an adjuvant making it possible to increase the immune response, in particular chosen from the group of adjuvant comprising Qs21 (mixture of saponins marketed by the company
  • Leif Leishmania major Initiation Factor marketed by the company Corixa
  • CT cholera toxin
  • LT LT for “Heat labile enterotoxin”, just like the detoxified versions of CT or the LT.
  • composition according to the invention is characterized in that it contains no other adjuvant making it possible to increase the immune response such as those mentioned above, apart from said Omp protein, in particular said enterobacterium OmpA protein , or one of its fragments.
  • the pharmaceutically acceptable medium is the medium in which the compounds of the invention are administered, preferably a medium injectable into humans. It can for example consist of water, an aqueous saline solution or an aqueous solution based on dextrose and or glycerol.
  • composition according to the invention also contains a detergent.
  • compositions according to the invention can also contain a detergent, and in particular any type of pharmaceutically acceptable surfactant, such as for example anionic, cationic, nonionic or amphoteric surfactants.
  • a detergent such as for example anionic, cationic, nonionic or amphoteric surfactants.
  • the invention also relates to the compositions according to the invention, characterized in that they are conveyed in a form which makes it possible to ensure and / or improve their stability, and thus also comprise, for example, vectors making it possible to ensure and / or to improve the stability of the Omp protein association or one of its fragments and of the lysate of autologous and / or heterologous tumor cells, in particular the vectors chosen from liposomes, virosomes, nanospheres, microspheres or microcapsules.
  • the invention also includes the use of an Omp protein or a fragment thereof associated with a lysate of autologous and / or heterologous tumor cells for the preparation of a pharmaceutical composition intended to generate or enhance an immune response against a tumor cell.
  • the Omp protein or one of its fragments is used in combination with a lysate of autologous tumor cells for the preparation of a pharmaceutical composition intended to generate or increase an immune response against said cell autologous tumor.
  • the use according to the invention relates to the preparation of a pharmaceutical composition intended for preventing or treating cancers, preferably cancers associated with a tumor antigen.
  • pancreatic adenocarcinoma (Hammel et al., 1998, Eur. J. Gastroenterol. Hepatol., 10: 345-8);
  • Another subject of the invention is the use of an Omp protein or of a fragment thereof associated with a lysate of autologous and / or heterologous tumor cells for the preparation of a pharmaceutical composition intended for inhibiting the growth of tumors .
  • compositions according to the invention consist in particular in:
  • tumor cells - optionally and not preferably to carry out primary or secondary cultures of said tumor cells;
  • compositions according to the invention with adequate concentrations of protein Omp or one of its fragments and lysate of tumor cells;
  • compositions comprising for example from 0.01 to 50 mg, and preferably from 0.1 to 25 mg of cell lysate, and from 0.1 to 50 mg, and preferably from 1 to 25 mg of Omp.
  • the Lysat / Omp ratio can be between 1/2 and 1/10, and preferably between 1/5 and 1/8.
  • antigen presenting cells When antigen presenting cells are used, these are incubated in vitro with the Omp protein, or a fragment thereof, associated with a lysate of autologous and / or heterologous tumor cells. They could for example be incubated at 37 ° C for a period of between 5 minutes and 24 hours.
  • the amounts and concentrations of antigen presenting cells to be used are those described in the prior art. We can thus use for example 10 7 antigen presenting cells per ml.
  • the antigen presenting cells brought into contact with the Omp protein, or a fragment thereof, associated with a lysate of autologous and / or heterologous tumor cells are then injected into the patient, preferably the patient from which they originated. Depending on the patient's physical condition, for example, 10 6 to 10 12 antigen presenting cells may be injected.
  • the subject of the invention is also a device suitable for implementing the above-mentioned therapeutic method, such as for example a kit, comprising at least the Omp and the means necessary to prepare the compositions according to the invention, such as for example a protocol, a pharmaceutically acceptable medium or a lysis buffer.
  • this device may also contain these cells, preferably purified.
  • the subject of the invention is a method for detecting tumor antigens, characterized in that it consists in:
  • the first step of this process consists in mixing the tumor extracts with proteins or fragments of Omp, in particular in the quantities and proportions mentioned above. Prior to this step, it is possible to modify the Omp or their fragment so as to make them suitable for the step of isolating the Omp-antigen complexes, it is for example possible to biotinylate the Omp.
  • an affinity chromatography column can be used, then by carrying out successive elutions, the tumor antigens will be separated and isolated.
  • Conventional techniques are then used to identify said antigens, such as, for example, the sequencing of said antigens by techniques known to those skilled in the art using mass spectrometry, a Maldi-Tof and bioinformatics.
  • the legends of the figures and examples which follow are intended to illustrate the invention without in any way limiting its scope.
  • Figure 1 Measurement of tumor volume following immunization with a B16.F10 lysate with or without P40.
  • Figures 2A and 2B Measurement of the percentage of eyes with pathology (Figure 2A) and the degree of pathology (Figure 2B) in TRP / Tag mice following immunization with an eye lysate with or without P40. Degree 0: no visible pathology; Degree 1: moderate pathology; Degree 2: severe pathology.
  • Figures 3A and 3B SDS-PAGE gel showing the fractions of the mixtures of the lysate of B16.F10 with P40-biotin ( Figure 3 A) or TT-biotin ( Figure 3B) eluted with detergent from a streptavidin-sepharose column (' TT 'for Tetanus Toxoid).
  • 2,500 melanoma B16.F10 cells were implanted subcutaneously on day 0 in C57BL / 6 mice, from which the B16.F10 cells were originally derived. Also on day 0, the C57BL / 6 mice were immunized subcutaneously at the base of the tail with P40 (350 ⁇ g) mixed with a lysate of 10 B16.F10 cells (ground with a Dounce homogenizer, sonicated and passed over nylon screen) or with lysate alone. A second immunization 10 days apart from the first was also done using the same injection method. From day 18 post-implantation, the volume of the subcutaneous tumor was measured.
  • TRP / Tag mice develop tumors in the eyes, which can therefore be easily seen.
  • a mixture of P40 (350 ⁇ g) and tumor eye lysate (ground with a Dounce homogenizer, sonicated and passed through a nylon sieve) or lysate alone were injected subcutaneously at the base of the tail in TRP / Tag mice at 4 weeks of age. The frequency and severity of eye tumors were measured daily.
  • the biotinylation of the P40 or TT proteins is carried out in a mixture containing 340 ⁇ l of P40 or TT at 6 milligrams (mg) / ml, 100 ⁇ l of NaHCO3, 0.5 Mole / liter (M), pH 8.5, 100 ⁇ l of S-NHS biotin (2 mg / ml) and 460 ⁇ l of ultra pure water.
  • the mixture is then placed for 2 hours (h) at 4 ° C in order to stop the biotinylation reaction and is then dialyzed overnight against PB S in dialysis cassettes at room temperature with magnetic stirring in order to remove the biotin in excess.
  • the P40 biotin (2 mg / ml) + lysate (0.9 x 10 6 cells per ml) or TT biotin (2 mg / ml) + lysate (0.9 x 10 6 cells per ml) mixture is dialyzed in a cassette dialysis against ultra pure water overnight, at room temperature, with magnetic stirring. This step makes it possible to promote the hydrophobic interactions between P40 and the lysate. TT serves as a negative control.
  • the support used for this chromatography low pressure affinity is an analytical column with a stationary phase of high performance sepharose-streptavidin previously saturated with BSA in order to eliminate all artefactual interactions.
  • the samples used are either P40 biotin + lysate or TT biotin + lysate obtained after the dialysis step and are incubated with the resin for half an hour at room temperature so that the biotin streptavidin interactions take place correctly.
  • the washing step is carried out with five column volumes of PBS IX and the elution of the proteins and peptides retained by P40 is carried out with five column volumes of PBS IX + 0.1% of chaps.
  • the resin is then washed with 2 column volumes of PBS IX.
  • the samples are lyophilized and taken up in Tris Glycine / SDS buffer, heated at 99 ° C for 5 min and centrifuged for 1 min at 13,000 rpm ("rpm" for revolutions per minute).
  • the proteins are analyzed by denaturing electrophoresis on polyacrylamide gel.
  • the proteins are visualized by staining with silver nitrate. As shown in FIGS. 3 A and 3B, several proteins are eluted with the detergent in the case of the P40-lysate mixture (FIG. 3 A), but not in the case of the TT-lysate mixture (FIG. 3B), demonstrating the existence of specific hydrophobic interactions of Omp.
  • Omp proteins unlike the carrier proteins conventionally used such as TT, make it possible to specifically retain antigens and thereby isolate and analyze them. OMPs therefore make it possible to isolate a larger number of tumor antigens compared to conventional carriers.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Microbiology (AREA)
  • Oncology (AREA)
  • Immunology (AREA)
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  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
EP01931780A 2000-05-04 2001-05-03 Zusammensetzung aus omp proteinen und autologen und/oder heterologen tumorzelllysaten Withdrawn EP1278539A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0005702 2000-05-04
FR0005702A FR2808445A1 (fr) 2000-05-04 2000-05-04 Proteine omp associee a un lysat de cellules tumorales autologues et/ou heterologues
PCT/FR2001/001348 WO2001082959A1 (fr) 2000-05-04 2001-05-03 Proteine omp associee a un lysat de cellules tumorales autologues et/ou heterologues

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US20050037437A1 (en) * 2001-09-14 2005-02-17 Reinhard Zeidler Identification of antigen by xenogenic, allogenic or autologous antibody-mediated precipitation

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FR2726472B1 (fr) * 1994-11-07 1997-01-31 Pf Medicament Proteine porteuse a effet adjuvant, complexe immunogene la contenant, leur procede de preparation, sequence nucleotidique et vaccin
FR2789588B1 (fr) * 1999-02-17 2001-05-04 Pf Medicament Utilisation d'une proteine ompa d'enterobacterie associee a un antigene dans une composition pharmaceutique destinee a generer ou accroitre une reponse cytotoxique antivirale, antiparasitaire ou antitumorale
FR2790960B1 (fr) * 1999-03-15 2002-10-31 Pf Medicament Utilisation de fractions membranaires bacteriennes a activite immunostimulante dans le traitement de cancers, leurs procedes de preparation et les compositions pharmaceutiques les contenant

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FR2808445A1 (fr) 2001-11-09
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