WO2005103231A2 - Cellules dendritiques chargees de substances toxiques destinees au traitement de carcinomes de cellules hepatiques - Google Patents

Cellules dendritiques chargees de substances toxiques destinees au traitement de carcinomes de cellules hepatiques Download PDF

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Publication number
WO2005103231A2
WO2005103231A2 PCT/DE2005/000719 DE2005000719W WO2005103231A2 WO 2005103231 A2 WO2005103231 A2 WO 2005103231A2 DE 2005000719 W DE2005000719 W DE 2005000719W WO 2005103231 A2 WO2005103231 A2 WO 2005103231A2
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Prior art keywords
substance
substances
active
antagonistic
toxins
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PCT/DE2005/000719
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German (de)
English (en)
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WO2005103231A3 (fr
Inventor
Dirk Weickmann
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Toximed Gmbh
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Priority to DE112005001476T priority Critical patent/DE112005001476A5/de
Publication of WO2005103231A2 publication Critical patent/WO2005103231A2/fr
Publication of WO2005103231A3 publication Critical patent/WO2005103231A3/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
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0639—Dendritic cells, e.g. Langherhans cells in the epidermis
    • 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
    • A61K39/4615—Dendritic 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
    • A61K39/462—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6901—Conjugates being cells, cell fragments, viruses, ghosts, red blood cells or viral vectors
    • 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
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K2035/124—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells the cells being hematopoietic, bone marrow derived or blood cells

Definitions

  • biogenic poisons Needs coordinated, so-called biogenic, poisons. These biogenic poisons have found their place in the interplay of different types of life in the course of long development periods.
  • Plants or animals can have a primarily toxic effect through the production of toxins or can only acquire secondary toxicity by ingesting toxic substances from the living or inanimate environment.
  • Tumors the most dangerous and feared diseases of our time, are currently being combated in a very radical and less environmentally friendly way.
  • the following can be used as simple, characteristic keywords: steel, radiation and chemotherapy.
  • a pharmaceutical active ingredient is known from DE 199 61 141 A1, in which it has been found that components of the spider venom from spiders of the Sicaridae family can be used for the treatment of tumor diseases. Mainly, a peptide toxin from the poison of this type of spider, a further antagonistic substance obtained from the poison and / or a combination of these components are used medically.
  • This active ingredient can be used for the treatment of tumor diseases and in parallel or in support of tumor operations and residual tumor tissue can be destroyed.
  • genetically modified body cells tumor cells
  • the active ingredient in question recognizes the changed surface structure of such cells and kills them without complications. cannot be used pharmaceutically.
  • dendritic cells loaded with toxic substances for the treatment of cancer.
  • the toxic substances are selected here from the venom of scolopenders of the genera Scolopendra and Herriscolopendra, snakes of the genera Bitis and Naja, spiders of the genera Loxosceles, Sicarius and Pholcus, as well as scorpions of the genus Parabuthus and a combination of one or more of these toxins.
  • Dendritic cells are cells of the immune system that are differentiated from stem cells and provided with dendrites, which detect and destroy genetically degenerate cells. The destruction can take place, for example, by pumping immunopeptide toxins into the genetically degenerate cell by means of the dendrites after docking onto them.
  • the dendritic cell takes on the function of a transport cell.
  • the immunopeptide toxin lyses the degenerated cell.
  • the number of dendritic cells present in the body in interaction with the rest of the immune system is no longer sufficient to effectively fight degenerate cells.
  • the patient's own dendritic cells produced in vitro can be injected into the patient or around the tumor.
  • Stem cells from the spinal cord are preferably used for this.
  • the method according to the invention is based on human or animal stem cells, with human spinal cord stem cells being preferred. Own (autologous) stem cells are preferably used here.
  • the spinal cord stem cells are isolated from the spinal cord by methods known per se. Spinal puncture procedures are most frequently used here. The tissue thus obtained can be taken directly into cell culture, but in general the removed spinal cord is treated in such a way that the cells remain viable for a longer period of time. For this purpose, shock freeze treatment has proven its worth. The cells treated in this way are then stored in liquid nitrogen. The removal and storage are of course carried out under the greatest possible sterility.
  • the spinal cord stem cells are placed in conventional cell culture vessels in a medium suitable for growth.
  • DMEM-HarrTs F12 - Medium in combination with RPMI has proven particularly successful.
  • antibiotics preferably mixtures of antibiotics, are added.
  • Antibiotics that can be used include penicillin and streptomycin.
  • Amino acids, such as glutamine, and fetal calf serum or substitutes therefor can be considered as further additives.
  • the cells are cultivated in the incubator at a suitable temperature, the body temperature of approximately 37 ° C. being preferred.
  • Renal cell carcinoma also called kidney carcinoma or adenocarcinoma of the kidney
  • Kidney cancer is one of the rarer cancers. It occurs more frequently in men than in women.
  • the kidneys are two organs of the same type, each lying next to the backbone.
  • the kidneys of an adult are about 13 cm long and 8 cm wide and have one typical bean-shaped shape.
  • There are small tubes in each kidney through which the blood is filtered and cleaned of waste materials. These are excreted in the urine.
  • the urine produced in the kidneys is passed through the ureter into the bladder, which collects the urine and keeps it in the body until urination.
  • Renal cell carcinoma is a cancer of the cell layer that lines these tubules of the kidney.
  • kidney pelvis If it is part of the kidney in which the urine is collected and transported to the ureter, the so-called kidney pelvis, or if the ureter is directly affected by cancer, it is called urothelial carcinoma (carcinoma of the transitional epithelium) of the renal pelvis and ureter.
  • the active compounds according to the invention are obtained from the poison of the following animal species: a) Loxosceles spp. (Hermit spiders) b) Scytodiae spp (food spiders) and c) the Drymusa spider species
  • Spiders of the genus Loxosceles occur in around 50 species in the warmer to the tropical regions of North America, Central America, South America and the Caribbean. About 20 species can be found in Africa as far as the Mediterranean region and southern Europe.
  • the animals usually colored in brown tones, reach a body length (without legs) of 8 to 15 millimeters. These spiders are especially active at night and are very shy. Your network is irregular. As a shelter, they look for dark spots under stones, in their cracks, or under leaves.
  • Spiders of the genus Scytodidae have only six eyes. They owe their name to their hunting method. These spiders catch their prey with ejected threads of glue and then bind them with other glue threads attached in a zigzag fashion.
  • the genus Drymusa is systematically classified together with the genera Loxosceles, Scytodiae and Sicarius among the six-eyed spiders.
  • the active substance according to the invention can optionally contain a substance antagonistic or synergistic with the respective toxin or peptide toxin and / or penetrating substance from the total poison cocktail of the animal species in question.
  • the antagonistic or synergistic substance is preferably a phospholipase or a hyaluronidase or a combination of both substances. It is further preferred that the antagonistic or synergistic substance is a mixture of the phospholipases and hyaluronidases and / or toxins present in other species.
  • the peptide toxin and the substance which is antagonistic and / or synergistically active for this purpose are preferably obtained from the total poison cocktail by a fractionation process, and it is further preferred that the pharmaceutical active substance contains a peptide toxin and a substance which has an antagonistic or synergistic effect and which consists of different fractions come.
  • the effect of the pharmaceutical active ingredient can advantageously be tailored to the type and / or size of tumor to be treated.
  • the peptide toxin, and the substance having an antagonistic and / or synergistic effect can be obtained by fractionation methods known per se for the separation of proteins from the total poison raw mixture. It is preferred that the peptide toxin and the antagonistic or synergistic acting therefor Substance can be obtained by gel chromatography, HPC, affinity chromatography and / or ion exchange chromatography.
  • the peptide toxin is present as an active pharmaceutical ingredient in such an amount that the active ingredient has a destructive effect on tumor cells.
  • the required proportions are chosen so that the active ingredient according to the invention has no or only a slight toxic effect in the patient to be treated.
  • the amounts of the active pharmaceutical ingredients must also be matched to the type of tumor to be treated and the physical, possibly also psychological, circumstances of the respective patient.
  • the preliminary tests required for such coordination are to be carried out by the person skilled in the art in the context of animal tests and / or ethically justifiable tests on the patient on the basis of his technical knowledge and ability.
  • a pharmaceutical active ingredient in which the amount of peptide toxin and the substance having an antagonistic or synergistic effect thereon comprises an amount of peptide toxin and antagonistic or synergistic substance which is selected as a function of the tumor to be treated.
  • the pharmaceutical active ingredient according to the invention contains conventional carriers and auxiliary substances, such as antibiotics, antifungals, antituberculotics, agents against parasites, cytostatics, amino acids, enzymes which promote wound healing and / or mitotic inhibitors. Preference is given to penicillin / streptomycin, poiymyxin / genetic mycin (5%), mitopodocide, vinca rosea alkaloids, bromelaina or bromelains.
  • auxiliary substances such as antibiotics, antifungals, antituberculotics, agents against parasites, cytostatics, amino acids, enzymes which promote wound healing and / or mitotic inhibitors.
  • auxiliary substances such as antibiotics, antifungals, antituberculotics, agents against parasites, cytostatics, amino acids, enzymes which promote wound healing and / or mitotic inhibitors. Preference is given to penicillin / streptomycin, poiymyxin / genetic mycin (5%), mitopodocide, vinca rosea alkaloids
  • the peptide toxin and the antagonistic or synergistic substance are used in combination with one another in the pharmaceutical active ingredient according to the invention.
  • the present invention also includes derivatives and salts of the substances provided according to the invention.
  • the peptide toxin can comprise one or more additions, substitutions and / or deletions of amino acids, it naturally having to be ensured that the medicinal effect according to the invention is retained.
  • the active ingredient described is obtained by methods customary in chemical process engineering. This includes in particular fractionation processes; however, other methods can also be used, for example immunological methods, in order to get the desired substances out of the total poison cocktail.
  • a preferred process for the preparation of an active ingredient according to the invention comprising at least one peptide toxin and / or at least one substance having an antagonistic or synergistic effect, at least one peptide toxin and / or at least one antagonistic or synergistic substance from the poison of animals of the above under a) to c). mentioned species, has the following steps:
  • the poisons in question contain various peptide toxins and various substances which have an antagonistic or synergistic effect thereon, and other active substances which are also of medical and therapeutic relevance. All of these substances can be found in a certain ratio to be determined by a person skilled in the art can be used therapeutically in a medical active substance.
  • fractionation process shows, by way of example only, a possibility of obtaining the peptide toxins and the substances having an antagonistic or synergistic effect. Further configurations are possible.
  • the raw poison mixture is homogenized before the fractionation, and it is further preferred that the fractions are deep-frozen before further processing and more preferably lyophilized.
  • peptide toxins contained in the animal venom and counter-directed (to this end antagonistic or synergistic) enzymes, or peptide toxins in combination with enzymes, in appropriate concentrations and proportions for the treatment of tumor diseases and in parallel or supportive to tumor operations can be used and it can (residual) tumor tissue be destroyed.
  • at least one peptide toxin or at least one substance acting antagonistically or synergistically comes from the poison of animals of the species mentioned.
  • the destruction of tumor tissue not detected during the operation and the prevention of local tumor metastasis in the organism can be achieved.
  • genetically defective body cells tumor cells
  • the phospholipases used according to the invention can recognize or selectively bind tumor cells whose surface structure has been changed, and can lyse.
  • tissue in desired, locally delimited areas - here tumor tissue-predestined tissue areas - can be killed without complications.
  • the mode of operation is based on native, mutually influencing modes of action of the peptide toxins and the antagonistic or synergistic substances present in the animal venom as follows:
  • Phospholipases are also known as hyaluronidases Penetration enzymes described. It is the case that the enzymes mentioned make tissue more permeable to the active substance according to the invention via digestive functions. In addition, they can recognize genetically defective body cells (tumor cells) and these themselves or by infiltration of necrotic or cytotoxic peptides that are coupled to them are killing.
  • antagonistic or synergistic substances are understood to mean, for example, phospholipases and hyaluronidases or peptide toxins from animals of the aforementioned genera, although it is not excluded that other antagonistic or synergistic substances are present in the animal venom, which can also be used according to the invention.
  • a comparison can be made with respect to absolute and relative amounts of the components of the active ingredient according to the invention in vitro on living human cells (healthy and tumorous) of the tissue type to be treated. Attention to the tendency to spread is of the greatest importance. This can be clarified in preliminary tests in comparison of the tumor tissue strength to the tissue surrounding the tumor.
  • the mode of action of total poison or individual substances, separated therefrom by column chromatography and characterized by their molecular weight, can take place by testing them in corresponding healthy and tumorous human cell lines.
  • the peptide toxins preferably originate from the same organism as those which have an antagonistic or synergistic effect Substances and / or other active substances optionally contained. In this way, the effective interaction or counterplay of these substances developed by nature can be exploited.
  • the pharmaceutical active substances according to the invention can be produced in such a way that first a crude poison mixture is obtained by methods known per se and fractionation of the crude poison mixture is carried out by fractionation methods, likewise known per se, for the separation of proteins. This serves the purpose of the peptide toxins and to obtain the antagonistic or synergistic substances for this purpose in as separate a form as possible or in separate fractions. Subsequently, different fractions can be combined to produce a pharmaceutical active ingredient, or individual fractions can be combined with peptide toxins originating from other organisms or substances having an antagonistic or synergistic effect. Individual fractions can also be used to produce an active pharmaceutical ingredient. Hyaluronidases from snake venoms, for example from cobra venoms, can preferably be used as antagonistic substances. This can be combined with one or more fractions from substances obtained from animals of the types mentioned under a) to c).
  • the dendritic cells loaded with the active substances from the animal species mentioned under a) to c) can be used for the therapy of tumor diseases, especially renal cell carcinomas.
  • the dendritic cells can be used as sole therapy, but also as accompanying therapy, without the risk of the disadvantages of conventional therapy.
  • the dendritic cells are loaded with one and / or more toxic substances from the poison of the animal species mentioned under a) to c). However, it is also possible to use a combination of at least two of these toxic substances from the poisons mentioned.
  • the poison of the animals mentioned above contains a whole cocktail of compounds, which include not only peptide toxins, but also toxins with an amido group, which, however, have no protein structure and have, for example, a molecular weight of 30 to 55 kDa.
  • the poison cocktail also includes substances with an antagonistic effect, which ensure the spatially and temporally controlled spread of the toxins released by the animal.
  • the toxins are preferably peptide toxins.
  • the toxins generally have necrotic, cytotoxic and / or apoptotic properties.
  • the toxins can be isolated from the poison cocktails of the animals by methods known per se.
  • peptide toxins derivatives are to be understood to mean, inter alia, toxins in which one or more amino acids have been added, deleted and / or replaced by other amino acids, the toxic properties of which are of course retained in each case. It should be noted that a toxin can combine not only cytotoxic, but also necrotic and / or apoptotic properties.
  • the dendritic cells loaded with the toxic substances can be used for the targeted therapy of tumors. Since the dendritic cells actively search for and find tumor cells and attack them with cell-destroying substances, the toxic substances are selected so that they have cytotoxic, necrotic and / or apoptotic properties. Such substances are present in the poison cocktails of the animal species mentioned.
  • Interleukin has proven to be particularly suitable here according to the invention.
  • the cells are cultivated in the presence of pure interleukin.
  • Interleukin 6, interleukin 12 and interleukin 14 are preferred.
  • interleukin differs from case to case and can be determined and optimized by a person skilled in the art through experiments.
  • the interleukins are substances belonging to the cytokines that act as signal substances of the immune system. As mediators, you are responsible for Induction and course of the T-cell mediated cytotoxic immune response and the B-cell activation (antibody production)
  • Interleukin 6 is formed by activated T cells, macrophages, fibroblasts and endothelial cells. It is a glycoprotein with an MG of 21000 D. Its main function is its effect as a “colony stimulating factor (CSF). It is also a growth factor for plasma cells, keratinocytes and mesangium cells. It induces the synthesis of acute phase proteins.
  • CSF colony stimulating factor
  • Interleukin 12 is a factor that stimulates natural killer cells.
  • Interleukin 14 is formed by T cells and B cells and causes a further proliferation of already activated B cells.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Cell Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Microbiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Mycology (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Wood Science & Technology (AREA)
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  • Hematology (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • General Engineering & Computer Science (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne un agent pharmaceutique destiné au traitement de carcinomes de cellules hépatiques à l'aide de cellules dendritiques cultivées en présence de leukine, et chargées de toxines provenant du venin des araignées du type Loxosceles, Scytodiae ou Drymusa. L'invention concerne également des procédés de fabrication desdites cellules dendritiques.
PCT/DE2005/000719 2004-04-21 2005-04-20 Cellules dendritiques chargees de substances toxiques destinees au traitement de carcinomes de cellules hepatiques WO2005103231A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DE112005001476T DE112005001476A5 (de) 2004-04-21 2005-04-20 Mit toxischen Substanzen beladene dendritische Zellen zur Behandlung von Nierenzellkarzinomen

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102004019323.1 2004-04-21
DE102004019323A DE102004019323A1 (de) 2004-04-21 2004-04-21 Mit toxischen Substanzen beladene dendritische Zellen zur Behandlung von Nierenzellkarzinomen

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WO2005103231A2 true WO2005103231A2 (fr) 2005-11-03
WO2005103231A3 WO2005103231A3 (fr) 2006-12-28

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000001823A2 (fr) * 1998-07-02 2000-01-13 Immunex Corporation Mutants flt3-l et leur utilisation
WO2001043754A2 (fr) * 1999-12-17 2001-06-21 Mack, Gerd, R. Preparation pharmaceutique a base de venin d'araignee, sa preparation et son utilisation pour traiter des affections tumorales
WO2001088105A2 (fr) * 2000-05-17 2001-11-22 Toximed Gmbh Production de cellules dendritiques issues de cellules souches de la moelle osseuse
WO2001087346A2 (fr) * 2000-05-17 2001-11-22 Toximed Gmbh Cellules dendritiques chargees de substances toxiques
WO2003006055A2 (fr) * 2001-05-14 2003-01-23 Duotol Ab Procedes permettant de favoriser la presentation de l'antigene et de la modulation de reponses immunitaires au moyen de toxines du cholera et son sous-unite b
WO2004053095A2 (fr) * 2002-12-10 2004-06-24 Merix Bioscience, Inc. Maturation in situ de cellules dendritiques
WO2004074451A2 (fr) * 2003-02-18 2004-09-02 Maxcyte, Inc. Introduction d'antigenes dans des cellules par electroporation

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000001823A2 (fr) * 1998-07-02 2000-01-13 Immunex Corporation Mutants flt3-l et leur utilisation
WO2001043754A2 (fr) * 1999-12-17 2001-06-21 Mack, Gerd, R. Preparation pharmaceutique a base de venin d'araignee, sa preparation et son utilisation pour traiter des affections tumorales
WO2001088105A2 (fr) * 2000-05-17 2001-11-22 Toximed Gmbh Production de cellules dendritiques issues de cellules souches de la moelle osseuse
WO2001087346A2 (fr) * 2000-05-17 2001-11-22 Toximed Gmbh Cellules dendritiques chargees de substances toxiques
WO2003006055A2 (fr) * 2001-05-14 2003-01-23 Duotol Ab Procedes permettant de favoriser la presentation de l'antigene et de la modulation de reponses immunitaires au moyen de toxines du cholera et son sous-unite b
WO2004053095A2 (fr) * 2002-12-10 2004-06-24 Merix Bioscience, Inc. Maturation in situ de cellules dendritiques
WO2004074451A2 (fr) * 2003-02-18 2004-09-02 Maxcyte, Inc. Introduction d'antigenes dans des cellules par electroporation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MCI MOWAT A ET AL: "ORAL VACCINATION WITH IMMUNE STIMULATING COMPLEXES" IMMUNOLOGY LETTERS, AMSTERDAM, NL, Bd. 65, 1999, Seiten 133-140, XP002906832 ISSN: 0165-2478 *

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WO2005103231A3 (fr) 2006-12-28
DE102004019323A1 (de) 2005-11-10
DE112005001476A5 (de) 2007-05-24

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