EP1135516A1 - Utilisation d'un immuno-complexe pour la preparation d'une composition therapeutique permettant de transfecter un polynucleotide dans une cellule macropinocyte - Google Patents

Utilisation d'un immuno-complexe pour la preparation d'une composition therapeutique permettant de transfecter un polynucleotide dans une cellule macropinocyte

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Publication number
EP1135516A1
EP1135516A1 EP99966907A EP99966907A EP1135516A1 EP 1135516 A1 EP1135516 A1 EP 1135516A1 EP 99966907 A EP99966907 A EP 99966907A EP 99966907 A EP99966907 A EP 99966907A EP 1135516 A1 EP1135516 A1 EP 1135516A1
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EP
European Patent Office
Prior art keywords
antibody
polynucleotide
cells
immuno complex
dna
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.)
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EP99966907A
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German (de)
English (en)
Inventor
Eric Jacobs
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Transgene SA
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Transgene SA
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Publication date
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Priority to EP99966907A priority Critical patent/EP1135516A1/fr
Publication of EP1135516A1 publication Critical patent/EP1135516A1/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
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
    • 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
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the use of an immuno complex for the preparation of a therapeutic composition for targeting transfection of a polynucleotide into a macropinocyte cell.
  • a therapeutic composition for targeting transfection of a polynucleotide into a macropinocyte cell.
  • Such a composition is useful in gene therapy, vaccination, and any therapeutic or prophylactic situation in which a gene- based product is administered to such a cell in vi tro, ex vivo or in vivo .
  • Gene therapy has generally been conceived as principally applicable to heritable deficiency diseases (cystic fibrosis, dystrophies, haemophilias, etc.) where permanent cure may be effected by introducing a functional gene.
  • heritable deficiency diseases cystic fibrosis, dystrophies, haemophilias, etc.
  • a much larger group of diseases notably acquired diseases (cancer, AIDS, multiple sclerosis, etc.) might be treatable by transiently engineering host cells to produce beneficial proteins.
  • Many genes involved in said deficiencies or of therapeutic interest have been identified. Direct expression of these genes within patients should contribute to a significant amelioration of the symptoms by expression of the functional polypeptide in targeted tissues.
  • a specific application of gene therapy is vaccination.
  • the immunogenic product encoded by the polynucleotide introduced in cells of a vertebrate may be produced and/or secreted, and be processed and presented by Antigen Presenting Cells (APC) cells in the context of the major histocompatibility antigens, thereby eliciting an immuno response against the expressed immunogen.
  • the Antigen Presenting Cells (APC) such as macrophages and dendritic cells, especially "sentinel cells", play essential roles in the initiation of the immuno response.
  • MHC class I and/or II genes which encode transmembrane glycoproteins involved in presentation of said processed antigenic peptides to CD8 + and/or CD4 + T-cells, and also produce specific accessory protein, thereby leading to T-cell activation
  • MHC class I and/or II genes which encode transmembrane glycoproteins involved in presentation of said processed antigenic peptides to CD8 + and/or CD4 + T-cells, and also produce specific accessory protein, thereby leading to T-cell activation
  • transient transfection a variety of techniques, resulting in either transient expression of the gene of interest, referred to as transient transfection, or permanent transformation of the host cells resulting from incorporation of the polynucleotide into the host genome, have been proposed in order to introduce functional polynucleotides into cells.
  • Most delivery mechanisms used to date involve viral vectors, especially adeno- and retroviral vectors. Viruses have developed diverse and highly sophisticated mechanisms to achieve this goal including crossing of the cellular membrane, escape from lysosomal degradation, delivery of their genome to the nucleus and, consequently, have been used in many gene delivery applications in vaccination or gene therapy applied to humans.
  • retroviral vectors cannot accommodate large- sized DNA (for example, the dystrophin gene which is around 13 Kb) , the retroviral genome is integrated into host cell DNA and may thus cause genetic changes in the recipient cell and infectious viral particles could disseminate in the organism or in the environment and adenoviral vectors can induce a strong immuno response in treated patients (Mc Coy et al . , Human Gene Therapy 6 (1995), 1553-1560; Yang et al . , Immunity 1 (1996), 433-442). Nevertheless, despite these drawbacks, viral vectors are currently the most useful delivery systems because of their efficiency.
  • lipid-mediated transfection compounds examples include DOTMA (Feigner et al., PNAS 84 (1987), 7413-7417), DOGS or TransfectamTM (Behr et al., PNAS 86 (1989), 6982-6986), DMRIE or DORIE (Feigner et al., Methods 5 (1993), 67-75), DC-CHO (Gao et Huang, BBRC 179 (1991), 280-285), DOTAPTM (McLachlan et al . , Gene Therapy 2 (1995), 674-622) or LipofectamineTM.
  • Non-viral delivery systems have been developed which are based on polymer-mediated transfection.
  • anionic polymers such as, for example, polyamidoamine (Haensler et Szoka, Bioconjugate Chem. 4 (1993), 372-379), dendritic polymer (WO 95/24221), polyethylene imine or polypropylene imine (WO 96/02655), polylysine (US-A-5 , 595 , 897 or FR-A-2 719 316).
  • WO 97/02840 describes a product coupling a nucleic acid and an immunovector using p-benzoquinone as a linker, characterized in that said immunovector is capable of enabling the nucleic acid to be internalised into cells and in that said immunovector has an affinity for the cellular DNA to such an extent that it can transfer the coupled nucleic acid into or to the immediate vicinity of the cell nucleus.
  • p-benzoquinone as a linker
  • Receptor-mediated gene transfer makes use of the ability of receptors on the surface of a variety of differenciated cells to efficiently bind and internalize a ligand and permits the targeting of DNA uptake into specific tissues.
  • Said systems include DNA of interest, a protein containing the receptor- targeting ligand, and in most cases a linking polycation.
  • receptor/targeting ligand systems asialoglycoprotein / asialooromucoid-poly (L-lysine) , transferrin/transferrin-poly (L-lysine) , insulin/albulin- insulin conjugate, and particularly mannose/mannosylated poly (L-lysine) for targeting the macrophages (for a review, Perales et al . , European J. Bioch. 226 (1994), 255-266).
  • L-lysine transferrin/transferrin-poly
  • insulin/albulin- insulin conjugate and particularly mannose/mannosylated poly
  • the technical problem underlying the present invention is to provide means and methods for a targeted delivery of nucleic acid molecules into specific cells, in particular into macropinocyte cells .
  • the present invention relates to the use of an immuno complex which comprises at least one antibody or a reactive part thereof and at least one polynucleotide, for the preparation of a therapeutic composition for the introduction of a polynucleotide into a macropinocyte target cell wherein said immuno complex has a particle size selected between 0.5 ⁇ m and 6 ⁇ m, and preferably has a particle size of at least 1 ⁇ m.
  • nucleic acid molecules in particular advantageous because it allows to specifically direct nucleic acid sequences into, e.g., macrophages and dendritic cells, which are also known as "sentinel" APCs involved in active immunoprotection of mammals against pathogenic agents.
  • sentinel APCs involved in active immunoprotection of mammals against pathogenic agents.
  • MHC glycoproteins leading to T-cell activation and a specific immune response directed against a pathogenic agent or cell expressing said antigenic peptide.
  • Possible applications are, e.g., anti-tumoral vaccination, anti-viral vaccination etc .
  • the size of the immuno complex of the use according to the invention may be selected for optimal use in a particular application. Measurements of the complex size can be achieved by a number of techniques including, but not limited to, dynamic laser light scattering (photon correlation spectroscopy, PCS) , electronic microscopy, freeze fracture electronic microscopy as well as other techniques known to those skilled in the art (see, Washington, Particle Size Analysis in Pharmaceutics and other Industries, Ellis Horwood, New York (1992), 135-169).
  • PCS photon correlation spectroscopy
  • Antigen Presenting Cells possess different mechanisms of antigen uptake: (a) capture of antigens by surface receptors such as receptors for immunoglobulins (Fc) or for complement, available on granulocytes , monocytes or macrophages, allows efficient delivery of the antigen to the processing compartment after receptor-mediated phagocytosis; and (b) antigens that fail to bind to cell surface receptors can still be taken up by fluid phase pinocytosis. Fluid phase uptake can occur via distinct mechanism: micropinocytosis, i.e.
  • macrophage cells refers to cells which are capable of macropinocytosis events as previously defined, and to take up macromolecules , preferably ranging in size from about 0.5 ⁇ m to about 6 ⁇ m, into the cytoplasm. Preferably they are selected from the group consisting of macrophages and dendritic cells.
  • immuno complex in the scope of the present invention means a complex formed between at least one antibody and at least one antigen.
  • the antibody involved in said immuno complex is specific for said antigen and therefore is able to recognize and to bind to its specific antigen.
  • the antibody included in the immuno complex can specifically recognize and bind to the polynucleotide present in said immuno complex or to at least one antigenic compound formulated with said polynucleotide. Furthermore, the antibody may only recognize the polynucleotide and not said antigenic compound formulated with said polynucleotide or, vice versa, only the antigenic compound formulated with the polynucleotide and not the polynucleotide (monoreactive antibody) . In another embodiment the antibody is able to recognize and bind to said polynucleotide and to said antigenic compound formulated with the polynucleotide (polyreactive antibody) .
  • antigenic compound with which the polynucleotide may be formulated are polypeptides, preferably viral polypeptides, cationic lipids and/or cationic polymers, eventually substituted with an immunogenic element.
  • polypeptides preferably viral polypeptides, cationic lipids and/or cationic polymers, eventually substituted with an immunogenic element.
  • Candidate compunds are widely described in the literature related .to synthetic vectors for gene therapy, the immunogenic (or antigenic) properties of which can be easily tested, for example, by direct administration to mammals.
  • These antigenic compounds preferably are selected among compounds comprising at least one peptide, one sugar part or any other suitable immunogenic part.
  • the antibody is an anti- polynucleotide antibody, more preferably an anti-DNA antibody.
  • Anti-polynucleotide antibody” or “anti-DNA antibody” designates an antibody which is able to recognize and to bind with a single stranded or/and double stranded polynucleotide or a DNA molecule, respectively.
  • said antibody can be a polyclonal, or preferably, a monoclonal antibody.
  • said antibody is an autoantibody obtained from serum of a mammal with an autoimmuno disease (see for example Yanase et al . , J. Clin. Invest. 100 (1997), 25-31).
  • Such an anti-polynucleotide antibody can be obtained, e.g., by immunization of mammals with all or part of a polynucleotide as previously described in Marion et al . (Methods 11 (1997), 3-11) and by production in hybridoma cells according to methods wellknown in the art (see for example Avraemas et al . , PNAS 95 (1998), 5601-5606). Moreover, anti-polynucleotide antibodies and more specifically anti-DNA antibodies are already commercially available (Interchim) .
  • antibody encompasses whole i munoglobulins of any class (mono- and multimeric ) , preferably IgG or IgM, chimeric antibodies and hybrid antibodies with dual or multiple epitope specificities, and "reactive parts thereof” which means antibody fragments derived from said antibodies which can be selected from the group consisting of F(ab')2' F(ab)2 Fab', Fab, Fv, sFv and minimal recognition units, including hybrid fragments and anti-idiotypes (US 4,699,880) which pertain the ability to recognize and to bind specifically to polynucleotides or to DNA.
  • polynucleotide as used in the scope of the present invention means a DNA and/or RNA fragment, single or double- stranded, linear or circular, natural or synthetic, modified or not (see US 5525711, US 4711955, US 5792608 or EP 302 175 for modification examples) defining a fragment or a portion of a nucleic acid, without size limitation. It may be, inter alia, a geno ic DNA, a cDNA, an mRNA, an antisense RNA, a ribozyme, or DNA encoding such RNAs . "Polynucleotides” and “nucleic acids” are synonyms with regard to the present invention.
  • the polynucleotide may be in the form of a linear polynucleotide, and preferably in the form of a plasmid.
  • the polynucleotide can also be an oligonucleotide which is to be delivered to the cell, e.g., for antisense or ribozyme functions.
  • the polynucleotide is preferably a naked polynucleotide (Wolff et al .
  • the polynucleotide contains at least one coding sequence that can be transcribed and translated to generate a polypeptide of interest.
  • the genetic information necessary for expression by a target cell comprises all the elements required for transcription of DNA into RNA and, if necessary, for translation of mRNA into a polypeptide.
  • Transcriptional promoters suitable for use in various vertebrate systems are well known.
  • suitable promoters include viral promoters like RSV, MPSV, SV40, CMV or 7.5k, vaccinia promoter, inducible promoters, etc.
  • the polynucleotide can also include intron sequences, targeting sequences, transport sequences, sequences involved in replication or integration. Said sequences have been reported in the literature and can be readily obtained by those skilled in the art.
  • the polynucleotide can also be modified in order to be stabilized with specific components as spermine . According to the invention, the polynucleotide can be homologous or heterologous to the target cells into which it is introduced.
  • polypeptides encoded by the polynucleotide are enzymes, hormones, cytokines, membrane receptors, structural polypeptides, transport polypeptides, tumoral, viral or infectious antigens, adhesines, ligands, transcription factors, translation factors, replication factors, stabilization factors, antibodies, E6 or E7 from HPV, MUC1, BRCA1, interferons, interleukin (IL-2, IL-4, IL-6, IL-7, IL- 12, GM-CSF (Granulocyte Macrophage Colony Stimulating Factor), the tk gene from Herpes Simplex type 1 virus (HSV-1) , p53 or VEGF.
  • the polynucleotide can also code for an antibody.
  • the term “antibody” encompasses whole immunoglobulins of any class, chimeric antibodies and hybrid antibodies with dual or multiple antigen or epitope specificities, and fragments, such as F(ab)'2# Fab', Fab including hybrid fragments and anti-idiotypes (US 4,699,880).
  • said DNA encodes all or part of a polypeptide which is an immunity conferring polypeptide and acts as endogenous immunogens to provoke a humoral or cellular response, or both, against infectious agents, including intracellular viruses, and also against tumor cells.
  • An "immunity conferring polypeptide” means that said polypeptide when it is expressed in the transfected cells will participate in an immune response in the treated patient. More specifically, said polypeptide expressed in macropinocyte cells such as APCs will be processed and the resulting fragments will be presented on the surface of these cells by MHC class I and/or II molecules in order to elicit a specific immune response.
  • the anti-polynucleotide antibody and the polynucleotide comprised in the immuno complex are an anti-DNA antibody and DNA, respectively.
  • the antibody included in the immuno complex shows a dissociation rate constant (K ⁇ ) which is at the most equal to 8xl0 ⁇ 7 , preferably at the most equal to lOxlO "7 .
  • the dissociation rate constant (K ⁇ ) values of the antibodies can be calculated by using for example the inhibition assay described in Friquet et al . (J. Immunol. Methods 77 (1985), 305-319).
  • This constant and its determination for an antibody used in the present invention are well known by those skilled in the art.
  • This skilled person can furthermore determine, without undue experimentation, for such an antibody, characterized by a certain dissociation rate constant, and for an antigen, the ratio of antibody to polynucleotide which allows to generate an immuno complex according to the present invention.
  • the skilled man can test antibody dilution ranges combined with a fixed quantity of polynucleotide, measure the complex sizes by known methods and finally determine the ratio of said antibody to said polynucleotide for producing immuno complexes of suitable size.
  • This ratio may be adapted according to the nature (complete antibody or fragment of an antibody) or the properties (dissociation rate constant) of the antibody.
  • the weight ratio can be 50:1.
  • a skilled person is capable of handling these minor adjustments. It is also possible to use a mixture of different anti-polynucleotide antibodies, with different dissociation constant, different epitopes specificities, etc .
  • the immuno complex further comprises a targeting element which can mediate attachment of said immuno complex to the surface of the target cell.
  • This targeting element may be a part of the antibody or of the polynucleotide of said immuno complex.
  • this targeting element may be capable of mediating attachment of the immuno complex to a receptor selected from the group consisting of Fc , FcRI, FcRII, FcRIII, complement receptors, immunoglogulin A or E receptors and macrophage mannose receptor.
  • This attachment to the surface of the cell although not necessary, may facilitate the macropinocytosis event since the immuno complex would be located in close proximity to the target cell.
  • the macropinocyte target cell is a macrophage or a dentritic cell.
  • composition prepared according to the use of the invention can be used in a method for the therapeutic treatment of humans or animals, preferably in a vaccination method.
  • the composition may also comprise a pharmaceutically acceptable injectable carrier (for examples, see Remington's Pharmaceutical Sciences, 16 ⁇ ed. (1980), Mack Publishing Co).
  • the carrier is preferably isotonic, hypotonic or weakly hypertonic and has a relatively low ionic strength, such as provided by a sucrose solution.
  • aqueous or partly aqueous liquid carriers comprising sterile, pyrogen-free water, dispersion media, coatings, and equivalents, or diluents (e.g;, Tris-HCl, acetate, phosphate), emulsifiers, solubilizers or adjuvants.
  • diluents e.g;, Tris-HCl, acetate, phosphate
  • emulsifiers emulsifiers
  • solubilizers or adjuvants e.g., solubilizers or adjuvants.
  • the pH of the pharmaceutical preparation is suitably adjusted and buffered in order to be useful in in vivo applications.
  • the composition prepared in accordance with the use of the present invention is in a form for administration into a vertebrate tissue.
  • tissues include those of muscle, skin, nose, lung, liver, spleen, bone marrow, thymus , heart, lymph, bone, cartilage, pancreas, kidney, gall bladder, stomach, intestine, testis, ovary, uterus, rectum, nervous system, eye, gland, connective tissue, blood, tumor etc.
  • Cells where the transfection of a foreign polynucleotide would be obtained are those found in each of the listed target tissues ( hematopo ⁇ etic cells, etc.).
  • the administration may, for example, be made by subdermal , intravenous, intramuscular, intracerebral , intratracheal , intraarterial , intraperitoneal , intravesical , intrapleural , intracoronary or intratumoral injection, preferably intradermal or intranasal, with a syringe or other devices.
  • the present invention also relates to a process for introducing a polynucleotide into a macropinocyte target cell wherein said process comprises contacting said cell with at least one composition prepared according to the use of the present invention.
  • This process may be applied by direct administration of said composition to the cell in vivo, or by in vi tro treatment of the cell which may have been extracted from the subject to be treated and by then re- introducing it into the subject (ex vivo process) .
  • This process can also be implemented on cultured cells ( in vi tro) .
  • the plasmid/antibody complexes are obtained by adding appropriate amounts of antibody to the plasmid in water or in Tris-buffered saline.
  • the plasmid comprises a reporter gene such as a gene coding for, e.g., luciferase or beta-galactosidase .
  • the plasmid pTG11033 (European patent application 98 11 2151.0) encoding the Photinus pyralis luciferase gene under the control of the cytomegalovirus enhancer/promoter and containing the intron HMG1 is preferably used.
  • Many anti-DNA antibodies are commercially available.
  • mice IgG2b anti-DNA intercolated
  • H55402M purified mice IgGl,k anti-DNA
  • H55124M purified mice IgG2a anti-DNA (single and double stranded)
  • M11025M purified sheep anti-DNA
  • Plasmid preparations at various concentrations are used: 10 ⁇ g/ml, 1 ⁇ g/ml, 0.10 ⁇ g/ml and 0.010 ⁇ g/ml . These plasmid preparations are incubated with various amounts of antibody in order to obtain an antibody concentration in the preparation of: 40 ⁇ g/ ⁇ g DNA, 4 ⁇ g/ ⁇ g DNA, 0.40 ⁇ g/ ⁇ g DNA 0.040 ⁇ g/ ⁇ g DNA, in PBS for 15 minutes at room temperature.
  • the particle size of the formed complexes is determined by dynamic laser light scattering.
  • the concentration of the DNA or preferably of the added antibody, can then be adjusted in order to obtain a suitable complex particle size (0.5 - 6 ⁇ m) .
  • reaction mixtures are then added to wells of 24 well plates that comprise mouse dendritic cells cultured according to published methods in conventional culture medium.

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Abstract

La présente invention concerne l'utilisation d'un immuno-complexe comprenant au moins un anticorps ou une partie réactive de cet anticorps et au moins un polynucléotide, pour la préparation d'une composition thérapeutique permettant l'introduction d'un polynucléotide dans une cellule cible macropinocyte, ledit immuno-complexe ayant une dimension des particules sélectionnée entre 0,5 νm et 6 νm.
EP99966907A 1998-12-04 1999-11-26 Utilisation d'un immuno-complexe pour la preparation d'une composition therapeutique permettant de transfecter un polynucleotide dans une cellule macropinocyte Withdrawn EP1135516A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP99966907A EP1135516A1 (fr) 1998-12-04 1999-11-26 Utilisation d'un immuno-complexe pour la preparation d'une composition therapeutique permettant de transfecter un polynucleotide dans une cellule macropinocyte

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP98403057 1998-12-04
EP98403057A EP1006197A1 (fr) 1998-12-04 1998-12-04 L'utilisation d'un complexe immunologique pour la préparation d'une composition thérapeutique, utile pour la transfection des polynucléotides dans des cellules macropinocyte
EP99966907A EP1135516A1 (fr) 1998-12-04 1999-11-26 Utilisation d'un immuno-complexe pour la preparation d'une composition therapeutique permettant de transfecter un polynucleotide dans une cellule macropinocyte
PCT/EP1999/009219 WO2000034499A1 (fr) 1998-12-04 1999-11-26 Utilisation d'un immuno-complexe pour la preparation d'une composition therapeutique permettant de transfecter un polynucleotide dans une cellule macropinocyte

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EP1135516A1 true EP1135516A1 (fr) 2001-09-26

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EP98403057A Withdrawn EP1006197A1 (fr) 1998-12-04 1998-12-04 L'utilisation d'un complexe immunologique pour la préparation d'une composition thérapeutique, utile pour la transfection des polynucléotides dans des cellules macropinocyte
EP99966907A Withdrawn EP1135516A1 (fr) 1998-12-04 1999-11-26 Utilisation d'un immuno-complexe pour la preparation d'une composition therapeutique permettant de transfecter un polynucleotide dans une cellule macropinocyte

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EP98403057A Withdrawn EP1006197A1 (fr) 1998-12-04 1998-12-04 L'utilisation d'un complexe immunologique pour la préparation d'une composition thérapeutique, utile pour la transfection des polynucléotides dans des cellules macropinocyte

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EP (2) EP1006197A1 (fr)
JP (1) JP2002531585A (fr)
AU (1) AU2280200A (fr)
CA (1) CA2349404A1 (fr)
WO (1) WO2000034499A1 (fr)

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Publication number Priority date Publication date Assignee Title
AU2002309567A1 (en) * 2001-05-16 2002-12-03 The Children's Hospital Of Philadelphia Dna-antibody complexes to enhance gene transfer
WO2016168711A1 (fr) * 2015-04-17 2016-10-20 The Regents Of The University Of California Procédés de détection d'une agglutination et compositions destinées à être utilisées dans la pratique de ceux-ci

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Publication number Priority date Publication date Assignee Title
FR2736642B1 (fr) * 1995-07-10 1997-09-12 Pasteur Institut Immunovecteurs, notamment anticorps et fragments d'anticorps utilisables pour le transport intracellulaire et intranucleaire de principes biologiquement actifs notamment d'haptenes, de proteines et d'acides nucleiques
AU707186B2 (en) * 1997-07-01 1999-07-01 Transgene S.A. Compositions useful for transferring therapeutically active substances into a target cell, and their use in gene therapy

Non-Patent Citations (1)

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Title
See references of WO0034499A1 *

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EP1006197A1 (fr) 2000-06-07
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CA2349404A1 (fr) 2000-06-15
WO2000034499A1 (fr) 2000-06-15

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