EP1161550A1 - Target cell-specific, multivalent proteins (mvp) - Google Patents
Target cell-specific, multivalent proteins (mvp)Info
- Publication number
- EP1161550A1 EP1161550A1 EP00910717A EP00910717A EP1161550A1 EP 1161550 A1 EP1161550 A1 EP 1161550A1 EP 00910717 A EP00910717 A EP 00910717A EP 00910717 A EP00910717 A EP 00910717A EP 1161550 A1 EP1161550 A1 EP 1161550A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- binding
- virus
- mvp
- cell
- cells
- 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- Withdrawn
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/081—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from DNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2809—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
Definitions
- MVP Target-cell-specific, multivalent proteins
- monovalent proteins are found in nature. These monovalent proteins bind with their binding partner, e.g. B. a cell membrane receptor, in a stoichiometric ratio of 1: 1. Examples of such monovalent proteins are growth factors, cytokines, chemokines, peptide hormones and complement receptors. Furthermore, bonds also occur in nature in a stoichiometric ratio of> 2: 1. For example, two molecules of the growth factor VEGF bind in the form of a dimer to a cell membrane receptor, the VEGF receptor, in order to activate it, while the binding of monomers cannot bring about activation of this receptor.
- B a cell membrane receptor
- the amount of binding products between such monovalent proteins and, for example, their receptors is determined here by the strength of the binding forces between the two binding partners and their respective concentrations.
- bivalent and multivalent proteins are already produced by nature.
- Such bivalent and multivalent proteins are, for example, dimers or multimers of monovalent proteins.
- antibodies dimers linked to one another via SH groups, of two identical heterodimers linked via SH groups, each consisting of an L chain and an H chain
- T cell receptor consisting of an ⁇ chain and a ß chain.
- the invention now relates to new target-cell-specific, multivalent proteins (MVP) which have at least two binding structures which bind to a molecule of a binding partner or at least to two different binding partners.
- MVP multivalent proteins
- the invention further relates to target-cell-specific, multivalent proteins (MVP) which contain a fusogenic peptide and can penetrate through cell membranes with the aid of this fusogenic peptide.
- MVP target-cell-specific, multivalent proteins
- the invention further relates to target cell-specific multivalent proteins (MVP) which contain a cleavage sequence for a protease.
- MVP target cell-specific multivalent proteins
- the invention also relates to the use of such a target-cell-specific, multivalent protein for the prophylaxis, therapy or diagnosis of a disease.
- Target-cell-specific, multivalent proteins have already been described as ligands for viral or non-viral vectors.
- viruses in particular adenoviruses
- additional peptide sequences for conjugation of the desired ligands are expressed on their surface (WO 95/26412)
- a virus in particular adenovirus
- a fusion protein consisting of the cell-external part of the cellular receptor for the virus, a linker and a ligand for a receptor on the desired target cell
- a virus in particular adenovirus
- a fusion protein consisting of an antibody or antibody fragment specific for a protein on the virus capsid and a ligand specific for the desired target cell (WO 94/10323, WO 98/40508)
- a virus especially adenovirus
- Fusion piotein consisting of an antibody or antibody fragment specific for an epitope in the hexon region of the virus and a cationic peptide
- a plasmid EP A 0 535 576 A1
- cell-specific binding structures such as heregulin (Han et al., PNAS 92, 9747 (1995)), erythropoietin (Kasahara et al., Science 266, 1373 (1994)), antibody fragments such as "single chain Fv” ( Marin et al., J. Virol. 70, 2957 (1996)) or receptors such as the extracellular part of the Fc receptor (Dougherty et al., Transfusion Science 17, 121 (1996)) incorporated into the envelope glycoproteins of retroviral vectors and thereby causes a target cell specificity.
- heregulin Hasahara et al., Science 266, 1373 (1994)
- antibody fragments such as "single chain Fv” ( Marin et al., J. Virol. 70, 2957 (1996)) or receptors such as the extracellular part of the Fc receptor (Dougherty et al., Transfusion Science 17, 121 (1996)) incorporated into the envelope glycoprotein
- non-viral vectors consist of plasmids complexed with cationic molecules, such as, for example, cationic polymers or cationic lipids.
- cationic molecules such as, for example, cationic polymers or cationic lipids.
- cell-specific binding structures such as asialoglycoprotein (Wu et al., J. Biol. Chem. 269, 1152 (1994)) or synthetic derivatives thereof (Merwin et al., Bioconjugate Chem. 5, 612 (1994)) linked with polylysine and this either complexed with the gene construct or chemically bound to coat proteins of adenoviral vectors.
- Another method was to bind cell-specific binding structures to streptavidin, which in turn binds to biotin conjugated to the phospholipid head groups of liposomes, the liposomes being complexed with gene constructs (Redelmeir et al., Drug Deliv. J. Deliv. Targeting Therap. Agents 2 , 98 (1995)).
- a further development consisted in the production of artificial ligand systems consisting of a target cell-specific binding structure, a vector-specific binding structure and possibly a fusogenic peptide. a first such ligand system was presented by Fominaya et al., J. Biol. Chem. 271, 10560 (1996).
- This ligand system consists of an antibody fragment specific for the Erb B2 receptor on tumor cells, the fusogenic peptide of Pseudomonas exotoxin A and the DNA-binding domain of the Gal4 protein of yeast, which is inserted into a transgene containing the corresponding Gal4 binding sequence Plasmid, binds.
- this ligand system leads to target cell-specific transfection, it has the disadvantage of the immunogenicity of the yeast Gal4 protein.
- the invention relates to target cell-specific, multivalent proteins (MVP) for the prophylaxis, therapy or diagnosis of a disease, characterized in that the MVP has at least two identical binding structures which bind to a molecule of a binding partner on the target cell.
- the invention further relates to MVPs which have at least two different binding structures specific to the same or different binding partners on the target cell.
- the molecules according to the invention enable improved binding to, inclusion in or networking with the target cell.
- the present invention is a further development of the invention, disclosed in patent application EP-A 0 846 772, in which multifunctional ligands are described, and a further development of the technology for producing single-chain, double-antigen-binding molecules (DE 198161417, not published).
- Patent applications are expressly referred to with this invention.
- the cell-specific binding structures according to the present invention can be cell membrane-binding active substances, such as, for example, homodimers or homomultimers of an adhesion molecule, a growth factor, a cytokine, a chemokine, a hormone, an antibody or an antibody fragment, or the cell membrane-binding parts of these molecules, which are only one of these substances of a cell membrane receptor.
- cell membrane-binding active substances such as, for example, homodimers or homomultimers of an adhesion molecule, a growth factor, a cytokine, a chemokine, a hormone, an antibody or an antibody fragment, or the cell membrane-binding parts of these molecules, which are only one of these substances of a cell membrane receptor.
- binding structures can furthermore be heterodimers or heteromultimers composed of cell-membrane-binding active substances, such as, for example, from adhesion molecules, growth factors, cytokines, chemokines, hormones, antibodies or antibody fragments, or else the cell-membrane-binding parts of these active substances, which bind to at least two different cell and membrane receptors.
- active substances such as, for example, from adhesion molecules, growth factors, cytokines, chemokines, hormones, antibodies or antibody fragments, or else the cell-membrane-binding parts of these active substances, which bind to at least two different cell and membrane receptors.
- the increased binding to or cross-linking of the same or different cell membrane receptors has the consequence, for example, that the MVP according to the invention bind more strongly to the target cell and / or are taken up in the target cell (for example by pinocytosis, endocytosis or phagocytosis).
- the increased binding to target structures other than cell membrane receptors can, for example, result in increased complex formation with the target structure.
- the MVP can be constructed from the following components: a) from at least one active ingredient [component (a) n ] b) from one or more linkers which may contain a fusogenic peptide and / or a cleavage sequence for a protease [component b ) m ] c) from at least two binding structures, [component c) 0 ],
- components a) n , b) m and c) 0 are to be joined together here by any peptide sequence with a length of preferably 0-30 amino acids in such a way that the resulting MVP represents a single protein strand and the function or Effect of each individual component a) n , b) m and c) 0 is completely retained. 7
- the invention further relates to target-cell-specific, multivalent proteins in which at least two MVPs are linked to one another.
- This connection can take place between components a) n , b) m and / or c) 0 and can be non-covalent or covalent, for example in the sense of a peptide bond or an -SS bond.
- FIGS. 1 and 2 Examples of the possibilities resulting from this invention are shown schematically in FIGS. 1 and 2 (a-c).
- component a) n may be the same or different from component c) 0 .
- Component a or component c can be selected from a group comprising, for example:
- a binding structure for a virus such as for AdV, AAV, a lentivirus, an RTV, vaccinia virus, HSV, influenza virus, HIV - a recombinant antibody specific for a virus protein, for a non-viral vector or for a nucleic acid, such as an IgG, F (from ') 2 , Fab, rec. Fv, diabody or single chain, double antigen binding protein
- a peptide with binding affinity to a defined nucleic acid sequence such as LexA, Gal4 or the DNA binding domain of a transcription factor or an antibody
- An active ingredient such as the part of a receptor that binds the ligand, the ligand for a receptor or the part that binds the receptor
- a recombinant antibody specific for a membrane structure on the target cell for example IgG, F (ab ') 2 , Fab, rec. Fc, diabody or single chain, double antigen binding proteins
- component b) m can contain one or more linkers selected from a group, for example comprising
- Another object of the present invention is a nucleic acid coding for a molecule according to the invention.
- the nucleic acid is generally a DNA or RNA, preferably a double-stranded DNA.
- Expression product contains the nucleic acid of the invention at the 5 'end
- Nucleotide sequence coding for a signal or transmembrane sequence (see e.g. EP-A 0 848 063 or EP-A 0848 061).
- An example of suitable signal or transmembrane sequences is the signal sequence for the immunoglobulin (DNA position ⁇ 63 to> 107, the signal sequence for the CEA (DNA position ⁇ 33 to> 134) or the signal sequence of the Human Respiratory Syncytial Virus Glycoproteins (cDNA the amino acid sequences ⁇ 38 to> 50 or 48 to 65).
- the nucleic acid according to the invention contains a promoter and / or activator at the 5 'end.
- the activator is preferably cell-specific, cell cycle-specific, metabolically specific and / or can be activated or suppressed by an active ingredient.
- activator sequences including their combinations, are described in EP-A 0 790 313, EP-A 0 805 209, EP-A 0 848 063, EP-A 0 848 061, EP-A 0 857 781, EP-A 0 860 445 and EP-A 0 864 651.
- the nucleic acid according to the invention contains the sequence GCCACC or GCCGCC at the 5 'end of the start codon, which sequence can increase the translation.
- the vector can be a viral or non-viral vector.
- a non-viral vector is preferably selected from a group comprising a cationic lipid, a cationic polymer, a cationic peptide or a cationic porphyrin.
- a viral vector is preferably selected from a group comprising RTV, AV, AAV, HSV, vaccinia virus, lenti virus, infiuenza virus.
- the nucleic acid described is cloned into an expression vector, for example a suitable plasmid, into a suitable cell, for example into a bacterial, yeast, insect or mammalian cell, the cultivated or transfected cell is cultivated and the expression product is isolated if necessary.
- these cells express a molecule according to the invention with a binding structure [component a) n or c) 0 ], this binding structure preferably being a transmembrane domain.
- the DNA sequence coding for the transmembrane sequence of the human macrophage colony-stimulating factor (DNA position ⁇ 1485 to> 1554) or the DNA sequence coding for the signal and transmembrane region of the human respiratory syncytical virus (RSV) - glycoprotein G (Amino acids 1 to 63 or their partial sequence amino acids 38 to 63) or the DNA sequence coding for the signal and transmembrane region of the influenza virus neuraminidase (amino acids 7 to 35 or the partial sequence
- Amino acids 7 to 27 are inserted between the promoter sequence and the DNA sequence of the molecule according to the invention or at the 3 'end of the gene.
- nucleic acid construct a nucleotide sequence coding for a glycophospholipid anchor can also be inserted into the nucleic acid construct.
- a glycophospholipid anchor is generally inserted at the 3 'end of the nucleotide sequence coding for the molecule according to the invention and can also be used to insert a signal sequence.
- Glycophospholipid anchors have been described, for example, for the CEA, for the N-CAM and for other membrane proteins, such as Thy-1.
- the respective cell expresses the molecule according to the invention on the cell membrane and thus receives a "receptor" which is specific for those target or effector structures which are recognized by the antigen-binding parts of the molecule according to the invention.
- Another preferred binding structure is the transmembrane or signal transducing domain of a receptor, for example the T cell receptor or the M-CSF receptor.
- the cell expressing the molecule according to the invention on the cell membrane can be activated by binding the target structures to specific functions.
- Such specific functions can be, for example, a cytotoxic reaction of T lymphocytes, phagocytosis reactions of macrophages and granulocytes or exocytosis reactions of granulocytes, monocytes and macrophages.
- Another object of the present invention is therefore a cell containing a nucleic acid according to the invention or a vector according to the invention, in particular a bacterial, insect, yeast or mammalian cell.
- a nucleic acid according to the invention or a vector according to the invention in particular a bacterial, insect, yeast or mammalian cell.
- nucleic acids such as e.g. CHO or BHK cells
- a lymphocyte, a macrophage, a glial cell, an epithelial cell, a liver cell, a kidney cell, a bone marrow cell, an endothelial cell, a smooth or striated muscle cell or a fibroblast are suitable.
- the last-mentioned cells are particularly suitable for gene therapy use, since these cells, which contain the nucleic acid construct according to the invention, are administered to a patient locally or parenterally, e.g. can be injected intravenously, intraarterially, into a body cavity, into an organ or subcutaneously, in order to serve as prophylaxis or therapy for a disease.
- nucleic acid constructs according to the invention can also be administered directly to the patient in a Body cavity, into an organ, into the blood vessel system, subcutaneously or intramuscularly.
- Another object of the present invention is therefore also a medicament containing an MVP according to the invention, a nucleic acid according to the invention coding for an MVP or a cell according to the invention, which expresses an MVP.
- Another object of the present invention is a diagnostic agent containing a molecule according to the invention, which is directed against an analyte with its binding structure [component a) n or c) 0 ].
- the MVP according to the invention, the nucleic acid according to the invention, the vector according to the invention or the cell according to the invention are therefore suitable for therapy, prophylaxis or diagnosis of, for example, tumor diseases, autoimmune diseases, inflammatory diseases, diseases of the blood, in particular of the blood coagulation and / or blood circulation system, diseases of the nervous system and / or infectious diseases.
- component a and / or component c) 0 preferably contains at least one whole antibody molecule or at least one epitope-binding fragment of an antibody.
- These antibodies are preferably of completely human origin.
- the murine monoclonal antibodies are preferably used in humanized form. Humanization takes place in the method described by Winter et al. (Nature 349, 293 (1991)) and Hoogenboom et al. (Rev. Tr. Transfus. Hemobiol. 36, 19 (1993)).
- Antibody fragments and recombinant Fv fragments are made according to the prior art and as described below.
- the specificity of the antibody can be directed against one or more identical or different epitopes on the coat proteins of the virus.
- Antibodies against the envelope proteins of viruses that can be used as vectors are, for example, antibodies against the
- component a) n and / or c) 0 contains at least one cell-specific part of an Fc receptor.
- Fc receptor One of the antibodies already mentioned binds to this Fc receptor via its Fc part, which binds directly or indirectly to the gene construct with its antigen-binding part.
- component a) n and / or c) 0 contains the receptor for the coat protein of a virus.
- the choice of this active ingredient depends on the disease which is to be prevented (prophylactic use) or treated (therapeutic use) by administering the MVP or the gene coding for the MVP.
- the promoter sequences for the nucleotide sequence which codes the active substance are to be selected with regard to the type of therapy for the disease and taking into account the target cell to be transduced.
- the retinoblastoma protein (pRb / p110) and the related p107 and p130 proteins are inactivated by phosphorylation.
- Those genes of these cell cycle inhibitors which are preferred are to be used Have mutations for the inactivation sites of the expressed proteins without their function being impaired thereby. Examples of these mutations have been described for p110.
- the DNA sequence for the p107 protein or the p130 protein is mutated in an analogous manner.
- the protein p53 is inactivated in the cell either by binding to special proteins, such as MDM2, or by oligomerizing the p53 via the dephosphorylated C-terminal serine.
- a DNA sequence is therefore preferably used for a p53 protein which is shortened at the C-terminal by the serine 392.
- coagulation inducing factors and angiogenesis inhibitors for example:
- PAI-1 Plasminogen activator inhibitor-1
- IFN ⁇ endostatin - interferons
- LIF Leukemia inhibitory factor
- TF Tissue Factor
- coagulation-active fragments cytostatic and cytotoxic proteins
- Interferons such as IFN- ⁇ , IFNß or IFN ⁇
- TNF such as TNF ⁇ or TNFß
- cytostatic or cytotoxic antibodies and fusion proteins between antigen-binding antibody fragments with cytostatic, cytotoxic or inflammation-causing proteins or enzymes d) cytostatic or cytotoxic antibodies and fusion proteins between antigen-binding antibody fragments with cytostatic, cytotoxic or inflammation-causing proteins or enzymes.
- the cytostatic or cytotoxic antibodies include those directed against membrane structures of endothelial cells, as described, for example, by Burrows et al. (Pharmac. Ther. 64, 155 (1994)), Hughes et al., (Cancer Res. 49, 6214 (1989)) and Maruyama et al., (PNAS USA 87, 5744 (1990)).
- these include antibodies against the VEGF receptors.
- This also includes cytostatic or cytotoxic antibodies directed against membrane structures on tumor cells.
- cytostatic or cytotoxic antibodies directed against membrane structures on tumor cells.
- Such antibodies have been described, for example, by Sedlacek et al., Contrib. to Oncol. 32, Karger Verlag, Kunststoff (1988) and Contrib. to Oncol. 43, Karger
- Suitable ligands are, for example, monoclonal antibodies or their antigen-binding antibody fragments directed against the following membrane antigens:
- MCP-2 - IL-2 - RANTES
- MCAF monocyte chemotactic and activating factor
- MIP-1 ⁇ , -ß macrophage inflammatory protein-1
- NAP-2 neutrophil activating protein-2
- LIF human leukemia inhibitory factor
- Cobra venom factor or partial sequences from the CVF which functionally correspond to the human complement factor C3b, i.e. which can bind to the complement factor B and, after cleavage by the factor D, represent a C3 convertase
- bacterial proteins which activate complement or trigger inflammation such as, for example, porins from salmonella typhimurium, "clumping" factors from staphylococcus aureus, modulins especially from gram-negative bacteria, "major outer membrane protein” from Legionella or from haemophilus influenzae type B or from stickies or M-molecules from streptococcal group G.
- Enzymes for the activation of precursors of cytostatics for example for enzymes which cleave inactive pre-substances (prodrugs) into active cytostatics (drugs).
- CB human carboxypeptidase
- - Phosphatase in particular human alkaline phosphatase, human acidic prostate phosphatase or type 5 acidic phosphatase - oxidase, in particular human lysyl oxidase or human D-amino acid oxidase - Peroxidase, in particular human glutathione peroxidase, human eosinophil peroxidase or human thyroid peroxidase
- Target cells - proliferating endothelial cells or
- Immunosuppressive antibodies are, for example, antibodies specific for the T cell receptor or its CD3 complex, against CD4 or CD8 furthermore against the IL-2 receptor, IL-1 receptor or IL-4 receptor or against the adhesion molecules CD2, LFA-1, CD28 or CD40
- active substances can be used for the purposes of the invention, which fusion proteins from antibodies or Fab or rec. Fv fragments of these antibodies or other ligands specific for the target cell and the above.
- Cytokines
- active substances or their nucleic acid sequences are selected which directly or indirectly inhibit inflammation in the joint, for example, and / or promote the reconstitution of extracellular matrix (cartilage, connective tissue) in the joint.
- IL-1-RA - IL-1 receptor antagonist
- soluble IL-1 receptor binds and inactivates IL-1
- IL-6 increases the secretion of TIMP and superoxides and decreases the secretion of IL-1 and TNF ⁇ by synovial cells and chondrocytes - soluble TNF receptor soluble TNF receptor binds and inactivates TNF.
- IL-4 inhibits the formation and secretion of IL-1, TNF ⁇ and MMP - IL-10
- IL-10 inhibits the formation and secretion of IL-1, TNF ⁇ and MMP and increases the secretion of TIMP
- IGF-1 insulin-like growth factor
- IGF-1 stimulates the synthesis of extracellular matrix.
- TGFß especially TGFßl and TGFß2
- TGFß stimulates the synthesis of extracellular matrix.
- TIMP-1 TIMP-1
- TIMP-2 TIMP-3
- Target cells - proliferating, immature cells of the hematopoietic system or
- LIF Leukemia Inhibitory Factor
- Target cells Target cells
- NGF Nerve growth factor
- BDNF Brain-derived neurotrophic factor
- CNTF - Ciliary neurotrophic factor
- Enzymes for example - tyrosine hydroxylase - dopadecarboxylase 3c) cytokines and their inhibitors, which inhibit or neutralize the neurotoxic effect of TNF ⁇ , for example
- IL-10 inhibits the formation of IFN ⁇ , TNF ⁇ , IL-2 and IL-4
- Active substances for inhibiting coagulation or for promoting fibrinolysis for example - Tissue plasminogen activator (tPA)
- Urokinase-type plasminogen activator uPA
- Serine proteinase inhibitors such as C-1S inhibitor, ⁇ 1-antitrypsin or antithrombin III
- TFPI Tissue Factor Pathway Inhibitor
- Angiogenesis factors for example - VEGF (1-4)
- Active substances for inhibiting the proliferation of smooth muscle cells after injuries to the endothelial layer for example - an antiproliferative, cytostatic or cytotoxic protein or
- cytostatics an enzyme for splitting precursors of cytostatics into cytostatics as already listed above (under tumor) or a fusion protein of one of these active ingredients with a ligand, for example an antibody or antibody fragments specific for muscle cells
- the MVP according to the invention containing a protein for the prophylaxis of
- a protein formed by the infectious agent (or the nucleic acid sequence encoding this protein) is to be selected as the active substance, which can be produced by triggering an immune reaction, i.e. leads to neutralization and / or killing of the pathogen by antibody binding and / or by cytotoxic T lymphocytes.
- Such neutralization antigens are already used as vaccine antigens (see
- the neutralization antigens (or their nucleic acid sequences) of the following pathogens are preferably selected as active ingredients:
- HSV Herpes Simplex Virus
- RSV Respiratory Syncytial Virus
- VZV Varizella Zoster Virus
- Such active substances within the meaning of the invention also include an anti-idiotype antibody or its antigen-binding Fragments whose antigen binding structures (the "complementarity determining regions") represent copies of the protein or carbohydrate structure of the neutralizing antigen of the infectious agent.
- anti-idiotype antibodies can replace carbohydrate antigens in particular in bacterial infectious agents.
- antigens on tumor cells have been described, for example, by Sedlacek et al., Contrib. to Oncol. 32, Karger Verlag,
- genes for the following antigens and for the following anti-idiotype antibodies are further examples:
- - a protein that has cytostatic, apoptotic or cytotoxic effects.
- an enzyme which is a precursor of an antiviral or cytotoxic
- IFN ⁇ , IFNß, IFN- ⁇ , TNFß, TNF ⁇ , IL-1 or TGFß include, for example, IFN ⁇ , IFNß, IFN- ⁇ , TNFß, TNF ⁇ , IL-1 or TGFß
- Antibodies against virus antigens include:
- Rev binding proteins bind to the Rev-RNA and inhibit Rev-dependent post-transcriptional stages of retrovirus gene expression.
- Rev binding proteins are:
- Ribozymes that digest the mRNA of genes for cell cycle control proteins or the mRNA of viruses have been clearly described, for example, by Christoffersen et al., J. Med. Chem. 38, 2033 (1995).
- Antibacterial Active Ingredients include, for example, antibodies that neutralize bacterial toxins or opsonize bacteria. For example, antibodies against
- component a) n and / or c) 0 can contain an active ingredient, part of the active ingredient or an analog of the active ingredient which binds to a receptor of the target cell.
- Such active ingredients are, for example:
- VEGF vascular endothelial growth factor
- PDGF EGF
- TGF ⁇ TGFß
- KGF EGF
- SDGF EGF
- FGF IGF
- HGF HGF
- NGF NGF
- BDNF Neurotrophine
- BMF Bombesin
- M-CSF Thrombopoietin
- Erythropoietin SCF
- SDGF Oncostatin
- PDEGF Endothelin -1 - cytokines such as IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL -12, IL- 13, IL-14, IL-15
- - Chemokines such as RANTES, MCAF, MIP-1 ⁇ or -ß, NAP, ß-thromboglobulin - Peptide hormones such as SRH, SIH or STH, MRH or MSH, PRH, PIH or prolactin, GnRH, LH-RH, FSH-RH, LH / ICSH or FSH, TRH or TSH, CRH or ACTH
- angiotensin kinins, histamine, homologues or analogues thereof
- steroid hormones such as estrogens, gestagens, androgens, glucocorticoids, Mineralokortiko.de, homologues or analogues thereof
- component a) n and / or c) 0 can also be an adhesion molecule, part of the adhesion molecule or an analogue of an adhesion molecule which is attached to a corresponding adhesion molecule on the cell membrane or to another specific binding structure for an adhesion molecule on the target cell binds.
- adhesion molecules that function as component a) n and / or c) 0 are, for example
- Vitronectin for the Vitronectin receptor
- GMP-140 for lewis X
- ICAM-1 for LFA-1, MAC-1
- component a) n and / or c) 0 can also be the extracellular part of an Fc receptor (Dougherty et al., Transfusion Science 17, 121 (1996)), on which an antibody is specific for the target cell is bound via its Fc part.
- component c) 0 can also be an antibody molecule or the epitope-binding part of an antibody molecule.
- the murine monoclonal antibodies are preferably used in humanized form. Humanization takes place in the method described by Winter et al. (Nature 349, 293 (1991) and Hoogenboom et al. (Rev. Tr. Transfus. Hemobiol. 36, 19 1993)). Antibody fragments are prepared according to the prior art, for example in the by Winter et al., Nature 349, 293 (1991), Hoogenboom et al., Rev. Tr. Transfus. Hemobiol. 36, 19 (1993), Girol, Mol. Immunol. 28, 1379 (1991) or Huston et al., Int. Rev. Immunol. 10, 195 (1993).
- Recombinant antibody fragments are produced directly from existing hybridomas or are isolated from libraries of murine or human antibody fragments using "phage display” technology. These antibody fragments are then used directly on the genetic level for further manipulations (e.g. fusion with other proteins).
- the genetic information which codes for the antigen-binding domains (VH, VL) of the antibodies is obtained by isolating the mRNA and reverse transcribing the RNA in cDNA and the subsequent amplification by means of polymerase chain reaction and oligonucleotides complementary to the 5 'and 3' ends of the variable fragments.
- the VH and VL fragments are then cloned into bacterial expression vectors, for example in the form of Fv fragments, single-chain Fv fragments (scFv) or as Fab fragments.
- New antibody fragments can also be isolated directly from antibody libraries (immune libraries, naive libraries) of murine or human origin using the "phage dispiay” technology.
- the antigen-binding domains are cloned as fusion proteins with the coat protein g3P of filamentous bacteriophages either in the phage genome or in phagemid vectors in the form of scFv fragments or as Fab fragments.
- Antigen-binding phages are selected on antigen-loaded plastic vessels (panning), on antigen-conjugated, paramagnetic "beads" or by binding to cell surfaces.
- Immune libraries are prepared by PCR amplification of the variable antibody fragments from B lymphocytes of immunized animals or patients. Combinations of oligonucleotides that are specific for murine or human immunoglobulin genes or for the human immunoglobulin gene families are used for this purpose.
- Naive libraries can be made using non-immunized donors as the source of the immunoglobulin genes.
- immunoglobulin germline genes can be used for the production of semisynthetic antibody repertoire, the complementarity-determining region 3 of the variable fragments being supplemented by PCR using degenerate primers.
- single pot libraries have the advantage over immune libraries that antibody fragments against a large number of antigens can be isolated from a single library.
- antibody fragments can be further increased by means of the "phage display” technology, whereby new libraries from existing ones Antibody fragments can be produced by random, codon-based or targeted mutagenesis, by "chain shuffling" individual domains with fragments from naive repertoires or with the help of bacterial mutator strains and antibody fragments with improved properties can be isolated by reselection under stringent conditions.
- murine murine
- Antibody fragments are humanized by gradually replacing one of the variable domains with a human repertoire and subsequent selection with the original antigen ("guided selection").
- the humanization of murine antibodies takes place by targeted exchange of the hypervariable regions of human antibodies by the corresponding regions of the original murine antibody.
- At least two identical or different binding structures for the target cell [component c) 0 ] should be contained in the ligand according to the invention.
- a special form of bispecific or multispecific, recombinant antibodies are single-chain, double or multiple antigen-binding molecules. The preparation of these molecules was described in patent application DE 198161417 (not published). This patent application is expressly referred to, for example, for the production of component c) 0 .
- component c) o can also represent the coat protein or a part of the coat protein of viruses which specifically bind to selected cells via their coat protein.
- the choice of the binding structure for a target cell depends on the target cell to which the MVP is to bind.
- Examples include:
- this includes antibodies or antibody fragments, directed against membrane structures of endothelial cells, as described, for example, by Burrows et al. (Pharmac. Ther. 64, 155 (1994), Hughes et al. (Cancer Res. 49, 6214 (1989) and Maruyama et al. (PNAS-USA 87, 5744 (1990)).
- these include antibodies against the VEGF receptors.
- the binding structures also include all active substances which bind to membrane structures or membrane receptors on endothelial cells.
- active substances include substances that contain mannose in addition, 1L-1 or growth factors or their fragments or
- Partial sequences of them that bind to receptors expressed by endothelial cells such as for example PDGF, bFGF, VEGF, TGFß (Pusztai et al., J. Pathol. 169, 191 (1993)).
- adhesion molecules that bind to activated and / or proliferating endothelial cells.
- adhesion molecules such as Slex, LFA-1, MAC-1, LECAM-1, VLA-4, vitronectin or RGD peptides have already been described (reviews by Augustin-Voss et al., J. Cell Biol. 119, 483 ( 1992), Pauli et al., Cancer Metast. Rev. 9, 175 (1990), Honn et al., Cancer Metast. Rev. H, 353 (1992)).
- the binding structures in the sense of this invention include, in particular, glycoproteins of the envelope of viruses which have a tropism for endothelial cells.
- viruses include, for example:
- Alpha viruses such as Semliki Forest virus - the virus of epidemic, hemorrhagic fever
- binding structures in the sense of the invention also include
- Substances that bind specifically to the surface of immune cells include antibodies or antibody fragments directed against membrane structures of immune cells, as described, for example, by Powelson et al., Biotech. Adv. U, 725 (1993).
- binding structures also include monoclonal or polyclonal antibodies or antibody fragments which, with their antigen-binding variable part, bind to Fc- ⁇ - or Fc- ⁇ - or Fc- ⁇ receptors of immune cells (Rojanasakul et al., Pharm. Res. H, 1731 (1994)).
- Fc fragment of human monoclonal or polyclonal immunoglobulin This also includes the Fc fragment of human monoclonal or polyclonal immunoglobulin.
- Fc fragments are, for example, genetically engineered using recombinant DNA or according to the methods of Haupt et al., Klin. Wschr. 47: 270 (1969), Kranz et al., Dev. Biol. Standard 44, 19 (1979); Fehr et al., Adv. Clin. Pharmac. 6, 64 (1974),
- the binding structures also include all substances that bind to membrane receptors on the surface of immune cells. These include cytokines such as IL-1, IL-2, IL-3, IL-4, IL-6, IL-10, TNF ⁇ ,
- GM-CSF, M-CSF of further growth factors such as EGF, TGF, FGF, IGF or PDGF or their fragments or partial sequences of them that bind to receptors expressed by immune cells.
- adhesion molecules and other ligands that bind to cell membrane structures such as the mannose 6-phosphate receptor on macrophages in the spleen, liver, lungs and other tissues.
- binding structures within the meaning of this invention also include glycoproteins of the envelope of those viruses which have a tropism for lymphocytes and / or macrophages.
- Viruses that infect macrophages include, for example:
- HIV-1 particularly those strains with mutations in the V3 region of gp120 which lead to an increased binding to macrophages - HIV-2
- Viruses that infect lymphocytes include, for example:
- VZV varicella zoster virus
- HHV-6 Herpes virus 6
- HHV-6 particularly infects T cells - Rabies virus; the Rabies virus coat protein binds particularly to TH2 cells
- glycoprotein gp120 preferentially binds to the CD4 molecule of T cells - HTLV-II;
- HTLV-II particularly infects B cells
- HTLV-I particularly infects T cells
- Influenza C viruses bind via the haemagglutinin esterase fusion (HEF) -
- Influenza C viruses with a mutation in nucleotide position 872 (which encodes position 284 of the HEF of the amino acid sequence), for example a
- the surface protein HEF with this mutation has a significantly stronger affinity for the N-acetyl-9-O-acetylneuraminic acid receptor than the wild virus
- binding structure for N-acetyl-9-O-acetylneuraminic acid.
- This binding structure is defined by the catalytic triad serine-71, histidine 368 or - 369 and aspartic acid 261
- EBV particularly infects B cells - herpes simplex virus 2;
- HSV-2 particularly infects T cells
- Binding structures for muscle cells include, for example, antibodies or antibody fragments directed against membrane structures of muscle cells, in particular of smooth muscle cells.
- Such antibodies are, for example - the antibody 10F3
- the binding structures also include all active substances which bind to membrane structures or membrane receptors on muscle cells (review by Pusztai et al., J. Pathol. 169, 191 (1993), Harris, Curr. Opin. Biotechnol. 2, 260 (1991) ).
- this includes growth factors or their fragments or partial sequences of them, which bind to receptors expressed by smooth muscle cells, for example
- the binding structures in the sense of this invention also include glycoproteins of the envelope of viruses which have a tropism for muscle cells.
- viruses include, for example, the cytomegalovirus.
- the binding structures include antibodies or antibody fragments directed against receptors expressed on poorly differentiated blood cells.
- binding structures also include monoclonal ⁇ or polyclonal antibodies or antibody fragments which bind with their constant domains to Fc- ⁇ receptors of immune cells.
- the binding structures also include all substances which
- Bind membrane structures or membrane receptors on the surface of poorly differentiated blood cells includes growth factors, such as SCF, IL-1, IL-3, IL-6, GM-CSF or their fragments or partial sequences thereof, which bind to receptors expressed by blood cells.
- growth factors such as SCF, IL-1, IL-3, IL-6, GM-CSF or their fragments or partial sequences thereof, which bind to receptors expressed by blood cells.
- Binding structures for svnovial cells and inflammatory cells include monoclonal or polyclonal antibodies or antibody fragments that bind with their variable domains to membrane structures of synovial cells or inflammatory cells.
- membrane structures are, for example
- This also includes monoclonal or polyclonal antibodies or antibody fragments that bind to the Fc receptor with their constant domains.
- Cytokines or growth factors or their fragments or partial sequences of them that bind to receptors expressed by synovial cells such as IL-1-RA, TNF ⁇ , IL-4, IL-6, IL-10, IGF, TGFß.
- the binding structures include antibodies or antibody fragments directed against the virus antigens expressed on the cell membrane of virus-infected cells.
- the binding structures include all substances that bind to membrane structures or membrane receptors on the surface of liver cells.
- this includes growth factors, such as cytokines, EGF, TGF, FGF or PDGF, or their fragments or partial sequences thereof, which bind to receptors expressed by such cells.
- growth factors such as cytokines, EGF, TGF, FGF or PDGF, or their fragments or partial sequences thereof, which bind to receptors expressed by such cells.
- binding structures that bind to cell membrane structures that are selective for certain tissues. These include, for example:
- Transferrin receptor transferrin liver, other tissue cells
- Insulin receptor insulin liver other tissue cells
- Fc- ⁇ receptors immunoglobulin G reticuloendothelial system, other tissues
- binding structures in the sense of the invention particularly include glycoproteins of the envelope of viruses which have a tropism for selected cells, such as for example
- liver cells e.g. the Marburg virus via the asialoglycoprotein
- HBV is bound via fibronectin.
- glial cells include antibodies or antibody fragments directed against membrane structures of glial cells, as described, for example, by Mirsky et al. (Cell and Tissue Res. 240, 723 (1985)), Coakham et al. (Prog. Exp. Tumor Res. 29, 57 (1985)) and McKeever et al. (Neurobiol. 6, 119 (1991)).
- membrane structures also include neural adhesion molecules such as
- N-CAM especially its polypeptide chain C.
- This also includes all active substances that bind to membrane structures or membrane receptors on glial cells.
- active substances that bind to membrane structures or membrane receptors on glial cells.
- these include substances that carry mannose at the end and are attached to the mannose-6
- binding structures in the sense of the invention include in particular
- Glycoproteins of the envelope of those viruses which have tropism for glial cells are Glycoproteins of the envelope of those viruses which have tropism for glial cells.
- viruses include, for example:
- Suitable ligands are, for example, monoclonal antibodies or their antigen-binding antibody fragments with specificity for the following antigens:
- the binding structures also include all of the active ingredients
- Bind membrane structures or membrane receptors of leukemia cells Bind membrane structures or membrane receptors of leukemia cells. For example, this includes growth factors or their fragments or partial sequences of them that bind to receptors expressed by leukemia cells.
- Retinoids e.g. "Retinoic acid” in acute promyelocytic leukemia.
- linker depends on the chemical nature of components a) n and c) 0 and on the method by which these components are connected to one another via the linker. If the binding structures are peptides or proteins, a peptide or protein is preferably used as the linker and the linker is preferably connected to components a) n and c) 0 via a peptide bond.
- Such molecules are preferably produced as fusion proteins with the aid of recombined DNA technology.
- linker represents a structure which connects component a) n to component c) 0 .
- Such structures result from the various chemical conjugation methods with the help of which molecules
- linker [component a) n and component b) m ] can also each be a peptide or protein.
- the connection between the two is preferably via a peptide bond and to component c) o via one of the chemical conjugation methods.
- the linker contains a fusogenic peptide or a translocalization peptide depends on the use of the molecule according to the invention. If the molecule according to the invention is to have its effect extravascularly in the connective tissue or in the cell, the linker is preferably a molecule with a fusogenic property. This fusoge ⁇ e property facilitates the passage of the molecule according to the invention through the cell membrane.
- viral or bacterial peptides or proteins as well as synthetic peptides are used as linkers with a fusogenic property.
- Molecules with a fusogenic property are, for example (for details see patent application EP-A 0 846 772): * Peptides containing the translocation domain (domain II) of exotoxin A from Pseudomonas
- LAEA LAAAAGC (SEQ. ID NO .: 2)
- FAG V-VLAG AALG VAAAAQ I (SEQ ID NO .: 3) of the fusion protein of the measles virus
- proteins of viruses which have fusogenic properties are also used.
- viruses have fusogenic and / or translocating coat proteins, for example paramyxoviruses, Retroviruses and herpesviruses. These include, for example, the TAT protein from HIV or its translocalizing amino acid sequence or the VP22 protein from HSV.
- viruses also have glycoproteins which are responsible both for virus attachment and subsequently for cell membrane fusion (Gaudin et al., J. Gen. Viro. 76, 1541 (1995)).
- Such proteins are formed, for example, by alpha, rhabdo and orthomyxoviruses.
- Fusogenic proteins in the sense of this invention are, for example:
- the hemagglutinin from influenza A or B viruses in particular the HA2 component - the M2 protein from influenza A viruses used alone or in combination with the hemagglutinin from influenza or with mutants of neuraminidase from influenza A which the Enzyme activity is absent, but this causes hemagglutination.
- the fusion activity of the HEF protein is activated by cleaving the HEFo into the subunits HEF1 and HEF2.
- transmembrane glycoprotein of filoviruses such as * the Marburg virus * the Ebola virus
- the fusion protein of the Sendai virus especially the amino-terminal 33 amino acids of the F1 component - the transmembrane glycoprotein of the semliki forest virus, especially the egg component
- Viral fusogenic proteins are either obtained by dissolving the coat proteins from a virus enrichment with the aid of detergents (such as, for example, ⁇ -D-octylglucopyranoside) and separation by centrifugation (review by Mannio et al., BioTechniques 6, 682 (1988)) or else with the aid from molecular biological methods known to the person skilled in the art.
- detergents such as, for example, ⁇ -D-octylglucopyranoside
- Components a) n , b) m and c) 0 are preferably linked to form an MVP via peptide bonds.
- an arbitrarily long peptide sequence is inserted between these components, preferably a peptide sequence of 0-30 amino acids.
- Such compounds are produced in such a way that the naturally occurring dimerization (or multimerization) of proteins is used or that connecting parts are inserted into components a, b and / or c and these connecting parts enable the linkages.
- connecting parts can be, for example:
- Multimerization has occurred through a non-covalent or covending connection (e.g. through S-S bridges, peptide compounds)
- MVP multivalent protein
- binding sites The functionality of the binding sites is verified immunologically (ELISA, immunocytology, flow cytometry) or in proliferation assays with primary human endothelial cells. Targeted transduction is performed using adenoviruses that express the lacZ gene under the control of the CMV promoter.
- PSecTagA (Invitrogen, expression vector with Igk leader sequence) was used as the vector for the cloning of all expression constructs.
- the PCR products were purified with QIAquick TM spin columns (Qiagen) according to the manufacturer's instructions, digested with the restriction enzymes BamHI and EcoRI and, after separation by agarose gel electrophoresis, purified again with QIAquick TM spin columns.
- the digested PCR products were then ligated into the correspondingly cut and purified vector pSeqTagA (T4 ligase, promega).
- a plasmid preparation was carried out using qiagen tip 500 columns according to the manufacturer's instructions. The correctness of the construct was confirmed by sequencing.
- the sc Fv (anti AV) -VEGF construct was cloned by 2-fragment ligation.
- the sc Fv (anti AV) fragment was produced by means of PCR (see above) using the following oligonucleotides: PelB Metminus
- a A Q P A T A Q V (SEQ ID NO .: 23) 5 'TAA CTC GCG GCC CAG CCG GCC ACG GCC CAG GT 3' (SEQ ID NO .: 24)
- the plasmid anti AV-pUC119mycHis (R. Hawkins in: Watkins et al., Gene Therapy 4, 1104 (1997)) served as a template.
- the PCR product was purified with QIAquick TM spin columns (Qiagen) according to the manufacturer's instructions and digested with the restriction enzymes Sfil and Notl.
- the 2nd fragment, VEGF was obtained by restriction digestion of the VEGF plasmid with the restriction enzymes Not1 and EcoRI.
- the vector, pSecTagA was digested with Sfil and EcoRI. After the restriction digestion products had been separated by agarose gel electrophoresis, they were purified again with QIAquick TM spin columns. Fragments 1 and 2 were then ligated into the cut and purified vector (T4 ligase, promega).
- a plasmid preparation was carried out using qiagen tip 500 columns according to the manufacturer's instructions. The correctness of the construct was confirmed by sequencing.
- the nucleotide and protein sequence of the s.c. construct Fv anti AV-VEGF is shown in Figure 3.
- s.c. anti AV-VEGF The expression of s.c. anti AV-VEGF is also carried out by stably transfected HEK293 cells. Like VEGF, this fragment can also be purified using IMAC.
- This molecule is thus present as a monomer and has one binding site for the adenoviral "fiber” protein and two binding sites for the VEGF receptors. The functionality of these binding sites is verified immunologically (ELISA, immunocytology, flow cytometry) or in proliferation assays with primary human endothelial cells. Targeted transduction is performed using adenoviruses that express the lacZ gene under the control of the CMV promoter.
- an scVEGF2 construct (amino acids 1-109, GGGSGGGRASG-GGS linker (SEQ ID NO .: 26) and amino acids 6-114) was cloned and expressed.
- 2 PCR reactions (see under 1) were carried out with the following oligonucleotides: - with VEGF back 1 (see under 1) and VEGF for 2 (see below)
- CAC GAA GTG GTG AAG (SEQ ID NO .: 28)
- the PCR products were purified with QIAquick TM spin columns (Qiagen) according to the manufacturer's instructions, digested with the restriction enzymes BamHI and Ascl (1) or Ascl and EcoRI (2) and, after separation by agarose gel electrophoresis, again with QIAquick TM spin columns cleaned up.
- the digested PCR products (1) and (2) were then ligated into the correspondingly cut and purified vector pSeqTagA (T4 ligase, Promega).
- a plasmid preparation was carried out with Qiagen tip 500 columns according to the manufacturer's instructions. The correctness of the construct was confirmed by sequencing.
- the scVEGF2 plasmid was digested with the restriction enzyme EcoRI and the single-stranded overhang was filled in using klenow fragment (Boehringer Mannheim). Then it was digested with Notl.
- the S11-VEGF plasmid was digested with the restriction enzyme Xhol as a vector, the single-stranded overhang was filled in and then digested with NotI.
- the products were purified and ligated with QIAquick TM spin columns.
- a plasmid preparation was carried out using Qiagen tip 500 columns according to the manufacturer's instructions.
- the nucleotide and protein sequence of the construct S11-scVEGF2 is shown in FIG. 4.
- scVEGF2 construct In vitro transcription and translation (promega, according to the manufacturer) of the scVEGF2 construct resulted in a protein that ran in the SDS polyacrylamide gel with the expected size of about 34 kd.
- the plasmid was transfected into HEK293 cells as described in Example 1. Transiently transfected cells showed a clear signal in immunofluorescence (see Example 1). Here were mainly the compartments of the cellular secretion path are shown. Stable clones were obtained by selection in 200 ⁇ g / ⁇ l zeocin. The cell culture supernatant was purified by immobilized metal affinity chromatography (IMAC) using six C-terminal histidine residues.
- IMAC immobilized metal affinity chromatography
- Sc Fv anti AV (S11) - scVEGF2 is also expressed by stably transfected HEK293 cells. Like scVEGF2, this fragment is also purified using IMAC.
- target cell-specific multivalent proteins for systemic therapy of cancer were developed.
- the aim is to selectively bind the MVP to tumor or tumor endothelial cells. This is a prerequisite for the use of toxic proteins or prodrug-activating systems for the targeted destruction of tumors without toxic effects on healthy tissue.
- the active ingredient contained in the MVP acts on the tumor endothelial cells. Their destruction leads to an obstruction of the blood supply to the tumor and to its death.
- VEGF vascular endothelial growth factor
- VEGF vascular endothelial growth factor
- KDR kinase insert domain-containing receptor
- flt-1 fms-like tyrosine kinase
- VEGF binds to its receptors as a disulfide-linked dimer.
- the recombinant scFv fragment of a selected antibody was used as the active ingredient. This antibody binds to the CD3 molecule of the human T cell receptor.
- scFv-VEGF polypeptide chain leads to the formation of a homodimer which has two binding sites for CD3 and two binding sites for VEGF receptors.
- VEGF Cell binding structure
- disulfide bridges formation of disulfide bridges.
- the receptor-binding domain of VEGF amino acids 1-114 was first cloned into a eukaryotic expression vector and expressed in mammalian cells.
- a VEGF fragment from amino acid 11 to 109 is sufficient for binding to Flk-1 (Sieffle et al., J. Biol. Chem. 273, 11115 (1998)).
- This VEGF fragment was fused N-terminally to the single chain Fv fragment (scFv) anti CD3 by a short linker.
- Anti CD3 binds to the CD3 subunit of the T cell receptor. Expression was also in mammalian cells. The functionality of the binding sites is verified immunologically (ELISA, immunocytology, flow cytometry) or in proliferation assays with primary human endothelial cells. Furthermore, by binding T cells to endothelial cells via the MVP according to the invention.
- PSecTagA (Invitrogen, expression vector with Igk leader sequence) was used as the vector for the cloning of all expression constructs.
- the VEGF cDNA cloned into this vector was amplified by PCR from genomic DNA of the human tumor cell line LNCaP with Taq polymerase (Pharmacia) (30 cycles, annealing temperature: 58 ° C.). For this, oligonucleotides published by Leung et al., Science 246, 1306 (1989) were used.
- the PCR products were purified with QIAquick TM spin columns (Qiagen) according to the manufacturer's instructions, digested with the restriction enzymes BamHI and EcoRI and, after separation by agarose gel electrophoresis, purified again with QIAquick TM spin columns.
- the digested PCR products were then ligated into the correspondingly cut and purified vector pSeqTagA (T4 ligase, Promega).
- a plasmid preparation was carried out using Qiagen tip 500 columns according to the manufacturer's instructions. The correctness of the construct was confirmed by sequencing.
- the sc Fv anti CD3-VEGF construct was cloned by 2-fragment ligation.
- the 2nd fragment, VEGF was obtained by restriction digestion of the VEGF plasmid with the restriction enzymes Not1 and EcoRI.
- the vector, pSecTagA was digested with Sfil and EcoRI. After the restriction digestion products had been separated by agarose gel electrophoresis, they were purified again with QIAquick TM spin columns. Fragments 1 and 2 were then ligated into the cut and purified vector (T4 ligase, Promega).
- a plasmid preparation was carried out using Qiagen tip 500 columns according to the manufacturer's instructions. The correctness of the construct was confirmed by sequencing.
- VEGF construct In vitro transcription and translation (Promega, according to the manufacturer) of the VEGF construct resulted in a protein that ran in the SDS polyacrylamide gel with the expected size of about 20 kd.
- Transiently transfected cells showed a clear signal in immunofluorescence (1st antibody: monoclonal anti-His-Tag, Dianova; 2nd antibody: goat anti-mouse Cy3, Dianova). Here were mainly the compartments of the cellular secretion path are shown. Stable clones were obtained by selection in 200 ug / ul Zeozin. The cell culture supernatant was purified by immobilized metal affinity chromatography (IMAC) using six C-terminal histidine residues.
- IMAC immobilized metal affinity chromatography
- Sc Fv anti CD3-VEGF is also expressed by stably transfected HEK293 cells. Like VEGF, this fragment can also be purified using IMAC. Production of a monomeric scFv-scVEGF2 molecule according to the invention
- an scFv fragment is fused with two VEGF units which are connected via an additional peptide linker.
- This molecule is thus present as a monomer and has one binding site for the CD3 molecule of the T cell receptor and two binding sites for a VEGF receptor. The functionality of these binding sites is verified immunologically (ELISA, immunocytology, flow cytometry) or in proliferation assays with primary human endothelial cells. Targeted binding of T cells is measured based on their cytotoxicity for the endothelial cell.
- scVEGF2 construct (amino acids 1-109, GGGSGGGRASG-GGS linker and amino acids 6-114) was cloned and expressed.
- 2 PCR reactions (see under 1) were carried out with the following oligonucleotides:
- CAC GAA GTG GTG AAG (SEQ ID NO .: 33)
- the PCR products were purified with QIAquick TM spin columns (Qiagen) according to the manufacturer's instructions, digested with the restriction enzymes BamHI and Ascl (1) or Ascl and EcoRI (2) and, after separation by agarose gel electrophoresis, again with QIAquick TM spin columns cleaned up.
- the digested PCR products (1) and (2) were then ligated into the correspondingly cut and purified vector pSeqTagA (T4 ligase, Promega).
- a plasmid preparation was carried out using Qiagen tip 500 columns according to the manufacturer's instructions. The correctness of the construct was confirmed by sequencing.
- the scVEGF2 plasmid was digested with the restriction enzyme EcoRI and the single-stranded overhang was filled in using Klenow fragment (Boehringer Mannheim). Then it was digested with Notl.
- the products were purified and ligated with QIAquick TM spin columns.
- a plasmid preparation was carried out using Qiagen tip 500 columns according to the manufacturer's instructions.
- the nucleotide and protein sequence of the construct BMA031-scVEGF2 is shown in FIG. 4.
- s.c. Fv anti CD3-scVEGF2 also occurs through stably transfected HEK293 cells. Like scVEGF2, this fragment is also purified using IMAC.
- MVL-Illb1 MVL which is formed by dimerization or multimerization of the cell binding structure, this assembly being stabilized by the formation of disulfide bridges.
- MVPs according to the invention containing at least one binding structure for the vector, at least two binding structures for the target cell and at least one linker.
- MVPs according to the invention containing several ligands; A. at least simply connected via the same or different binding structures for the vector; B. at least simply connected via the same or different linkers; C. at least simply connected via the same or different binding structures for the target cell.
- Table 1
- GCT GTA CTG GTG AGG CCT GGG TCC TCA GTG AAG ATT TCC TGC AAG GCT TCT GGC TAT GTA A V L V R P G S S V K I S C K A S G Y V
- GCT GTA CTG GTG AGG CCT GGG TCC TCA GTG AAG ATT TCC TGC AAG GCT TCT GGC TAT GTA A V L V R P G S S V K I S C K A S G Y V
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DE19910419A DE19910419A1 (en) | 1999-03-10 | 1999-03-10 | Target Cell-Specific Multivalent Proteins (MVP) |
DE19910419 | 1999-03-10 | ||
PCT/EP2000/001612 WO2000053790A1 (en) | 1999-03-10 | 2000-02-26 | Target cell-specific, multivalent proteins (mvp) |
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EP (1) | EP1161550A1 (en) |
JP (1) | JP2002537847A (en) |
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PL195457B1 (en) * | 2002-08-05 | 2007-09-28 | Zaklady Farm Polpharma Sa | Expression cassette, bi-cistron plasmide vector, pharmaceutical composition and their application |
DE10259713A1 (en) * | 2002-12-19 | 2004-07-08 | Johannes-Gutenberg-Universität Mainz | Process for the stabilization of expression and improvement of the specific effector function of single chain antigen-recognizing genetic constructs (scARC) and corresponding mutated MDM2 protein specific scT cell receptors |
JP2008537752A (en) | 2005-04-12 | 2008-09-25 | イントラディグム コーポレイション | RNAi therapeutic compositions and methods for treating cancer and other neovascular diseases |
US7893244B2 (en) | 2005-04-12 | 2011-02-22 | Intradigm Corporation | Composition and methods of RNAi therapeutics for treatment of cancer and other neovascularization diseases |
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DE19649645A1 (en) * | 1996-11-29 | 1998-06-04 | Hoechst Ag | Multiple functional ligand system for target cell-specific transfer of nucleotide sequences |
HUP9900956A2 (en) * | 1998-04-09 | 2002-04-29 | Aventis Pharma Deutschland Gmbh. | Single-chain multiple antigen-binding molecules, their preparation and use |
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- 2000-02-26 WO PCT/EP2000/001612 patent/WO2000053790A1/en not_active Application Discontinuation
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