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  • C12Y304/21—Serine endopeptidases (3.4.21)
  • C12Y304/21022—Coagulation factor IXa (3.4.21.22)
• • A—HUMAN NECESSITIES
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  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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  • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
  • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
  • A61K47/6807—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
• • A—HUMAN NECESSITIES
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  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
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  • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
  • A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
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  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
  • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
  • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
  • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
• • A—HUMAN NECESSITIES
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  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
  • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
  • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
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  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• • 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
  • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
• • 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
• • 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
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  • 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
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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  • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
  • C12N9/14—Hydrolases (3)
  • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
  • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
  • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
  • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
  • C12N9/6424—Serine endopeptidases (3.4.21)
  • C12N9/644—Coagulation factor IXa (3.4.21.22)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2319/00—Fusion polypeptide

Definitions

• FIG. 6 In vivo gene transfer using the anti-rat plg-R Fab-poly-L-lysine conjugated DNA complex.
• the Target Cell The Target Cell
• “Targeting” is the administration of the compacted nucleic acid in such a manner that it enters the target cells in amounts effective to achieve the clinical purpose.
• DNA and RNA are capable of replication in the nucleus of the target cell, and in consequence the ultimate level of the nucleic acid in the cell may increase after uptake.
• the clinical effect is mediated by a protein expressed by the nucleic acid, it should be noted that the nucleic acid acts as a template, and thus high levels of protein expression can be achieved even if the number of copies of the nucleic acid in the cell is low. Nonetheless, it is desirable to compact high concentrations of DNA to increase the number of target cells which take up the DNA and the number of DNA molecules taken up by each cell.
• TBM tumor necrosis factor
• receptor an accessible structure of the intended target cells. It is not necessary that it be absolutely specific for those cells. however, it must be sufficiently specific for the conjugate to be therapeutically effective.
• target binding moiety is not strictly necessary in the case of direct injection of the NABM/NA condensed complex.
• the target cell in this case is passively accessible to the NABM/NA condensed complex by the injection of the complex to the vicinity of the target cell.
• the gene may be of synthetic. cDNA or genomic origin, or a combination thereof.
• the gene may be one which occurs in nature, a non-naturally occurring gene which nonetheless encodes a naturally occurring polypeptide. or a gene which encodes a recognizable mutant of such a polypeptide. It may also encode an mRNA which will be "antisense" to a DNA found or an mRNA normally transcribed in the host cell, but which antisense RNA is not itself translatable into a functional protein.
• the coding sequence must be operably linked to a promoter sequence functional in the target cell.
• Two DNA sequences are said to be operably linked if the nature of the linkage between the two DNA sequences does not (1) result in the introduction of a frame- shift mutation in the region sequence to direct the transcription of the desired gene sequence or (3) interfere with the ability of the gene sequence to be transcribed by the promoter region sequence.
• a promoter region would be operably linked to a DNA sequence if the promoter were capable of effecting transcription of that DNA sequence. In order to be operably linked" it is not necessary that two sequences be immediately adjacent to one another.
• the promoter may be an "ubiquitous" promoter active in essentially all cells of the host organism, e.g. , for mammals, the beta-actin promoter, or it may be a promoter whose expression is more or less specific to the target cells. Generally speaking, the latter is preferred.
• a promoter native to a gene which is naturally expressed in the target cell may be used for this purpose, e.g. , the PEPCK (phosphoenol pyruvate carboxykinase) promoter for expression in mammalian liver cells.
• the appropriate host cell would be any eukaryotic cell capable of expressing the cloned sequences.
• the complex has a unaggregated, unimolecular toroid structure condensed to smaller than 23nm in diameter; the degree of compaction may be determined by electron microscopy.
• a complex of the PEPCK-hFIX gene with galactosylated polylysine has been compacted to a unimolecular toroid with a mean diameter of about 12 nm, as shown in Table 106.
• the term "unimolecular toroid" indicates that the toroid contains only one nucleic- acid molecule; the toroid may contain many carrier (e.g. , galactosylated poly-Lys) molecules.
• RNA-free CMV - ⁇ - galactosidase (A) or phFIX (B,C,D, and E), diluted to a final volume of 150 ⁇ l in 700 mM NaCl were vortexed at medium speed in a VIBRAX apparatus (IKA- VIBRAX-VXR). 19 ⁇ g of ⁇ -galactopyranosyl-phenyl isothiocyanate/poly-L-lysine
• the recognition and uptake of circulating glycoproteins by specific cells are determined by the nature of the exposed sugar residues present on the surface of the molecule.
• the clearance systems of specific glycoproteins are relatively exclusive and are mediated by specific types of cells.
• the mannose receptor recognizes glycoproteins with mannose, glucose, fucose, and N-acetylglucosamine residues in exposed, non-reducing positions.
• Various proteins and glycoprotein conjugates bearing these carbohydrate residues bind to isolated alveolar macrophages, and mannose-terminal glycoproteins infused into the circulation of rats are cleared by Kupffer cells in vivo.
• galactose-terminal glycoproteins which are cleared by the asialoglycoprotein receptor on hepatocytes, are not recognized by these cells.
• Animals Adult, male Sprague-Dawley rats, weighing approximately 250 g. , were anesthetized with ether. Using aseptic technique, 0.3 to 0.6 ml of a solution containing 300 ⁇ g (20.8 - 42.0 pmol) of an expression plasmid complexed to the carrier was injected into the caudal vena cava. The rats were killed at different intervals after infusion of the complexes and the livers, lungs, and spleens of transfected animals were removed for analysis. Furthermore, macrophages were isolated from the alveoli, the bone marrow, and spleen. Bone marrow cells were obtained from the rat's femur.
• the cellular distribution of the transgene expression was examined in sections of spleen and liver three days after the injection of complexes containing pCMV/acZ.
• the tissues were analyzed for ⁇ -galactosidase activity by a cytochemical stain.
• An animal treated with complexes made using an irrelevant plasmid (pCMVIL2r) served as control, ⁇ - galactosidase expression was detected in several small cells in the spleen located in the subcapsular region, which conformed to the distribution of cells that expressed nonspecific esterase activity based on cytochemical staining. No ⁇ - galactosidase activity was found in the corresponding cells of the control spleen.
• Mannose-terminal glycoproteins are introduced into macrophages by receptor-mediated endocytosis. delivered to a pre-lysosomal acidic compartment, and subsequently trafficked to the secondary lysosomes. Hence, a portion of the introduced conjugate avoids destruction since the transferred DNA must escape degradation after the complex has entered the cell in order for the transgene to be expressed.
• the physical state of the DNA transferred into cells by these delivery systems may also contribute to its survival and subsequent expression, and highly compact form of DNA may be more resistant to nuclease digestion.
• the small size of the carrier-DNA complex may also permit the introduction of the plasmid into the cells of the reticuloendothelial system specifically via the mannose receptor and not by phagocytosis.
• Receptor-mediated gene transfer may provide a method for delivering DNA to specific target cells using a non-infectious, non-toxic vector.
• This form of gene transfer allows specific tissue targeting with DNA plasmids of considerable size, allowing for delivery of not only the transgene, but also promoter and enhancer elements.
• the delivery of exogenous DNA is dependent on the stability of the DNA-carrier complex, the presence and number of specific receptors on the surface of the targeted cell, the receptor-ligand affinity and interaction, and efficient internalization of the complex.
• expression of the transferred genes rely on their escape from the endosomal vesicles and trafficking to the target cell's nucleus.
• the disulfide bridges of the modified Fab fragment were cleaved with 25mM dithiothreitol. Both the poly (L-lysine) and SPDP was added in fifteen fold molar excess to the modified Fab fragment, and the reaction was carried out at 22°C for 24 hours.
• the conjugate was dialyzed to remove low molecular weight reaction products, and analyzed by separating the resultant proteins on a 0.1 % SDS- 7.5 % polyacrylamide gel electrophoresis. As described previously, analysis of the conjugate demonstrated a protein that migrated slowly, corresponding to a protein greater than 200 kDa in size.
• plasmids Digestions of the plasmids with restriction endonucleases yielded the appropriate size fragments, and purity was established by 1.0% agarose gel electrophoresis.
• the sizes of plasmids are as follows: pGEM/uc , 6.0; pCMV/acZ, 10.9; and pCMVIL2r, 5.4 kB. No contamination with bacterial genomic DNA or RNA was present in the plasmid preparations.
• Luciferase activity persisted in the liver and lung, tissues which have plgR, achieving maximum values of 13795 ⁇ 4431 and 461402 ⁇ 230078 integrated light units (ILU) per milligram of protein extract, respectively, at four to six days after injection. Tissues that failed to express the receptor did not have significant transgene expression.
• WHHL Watanabe Heritable Hyperlipidemic
• the DNA complex used in this project is targeted to the hepatic asialoglycoprotein receptor using galactose as a ligand. It is known that macrophages have a similar receptor which is able to clear galactosylated particles larger than 15 nm from the bloodstream.
• the present invention addresses two of the problems associated with effective gene therapy: the immunogenicity (i.e. , antigenicity) and molecular heterogeneity of the gene transfer complex.
• the immunogenicity of the gene transfer complex is minimized or abolished by constructing chimeric monoclonal antibodies and single-chain antibodies.
• the heterologous sequences in the Fabs are the most likely cause of the immune response, most of the heterologous sequences in the Fabs are replaced with same-species sequences (i.e. , for use in humans, chimeric rodent-human monoclonals are generated).
• single chain antibodies were generated.
• the Fv portion of the fusion protein may be separated by a linker or spacer from the portion comprising the therapeutic protein
• the spacer may vary from 0 to 30 amino acid residues in length.
• CsCl-purified pGL3 an expression vector encoding luciferase.
• the protein will be added dropwise to the DNA, with constant vortexing, and then 1 M NaCl added until turbidity disappears.
• the complex is used immediately, after an aliquot is removed for electron microscopy to confirm production of a tight toroid structure.
• Increased expression of the mouse/human chimeric MAbs may be achieved, if necessary or desirable, as follows.
• Cell lines that have been cotransfected with mouse variable heavy and light chain genes and with human constant genes as described above and that are producing chimeric antibody are secondarily transfected with the cytomegalovirus immediate-early gene (CMV iel) that also contains the hygromycin B resistance gene (Hy R ).
• CMV iel cytomegalovirus immediate-early gene
• Hy R hygromycin B resistance gene
• Single-chain Fv and single chain Fv fusion proteins may be achieved in eukaryotic cells [e.g. , COS-7 (ATCC CRL 1651), myeloma cell lines, and HEK293 cells (ATCC CRL 1573)] .
• eukaryotic cells e.g. , COS-7 (ATCC CRL 1651), myeloma cell lines, and HEK293 cells (ATCC CRL 1573)
• leader sequences are added to the proteins to assure that the proteins are secreted (thereby improving ease of purification).
• the leader sequences may be added, or the immunoglobulin sequences upstream of the Nicholls primers may simply be included.
• Synthetic peptides based in sequence on amino acids 359-374 of ⁇ 1 antiprotease, bind in a specific and saturable fashion to the receptor on HepG2 cells and mediate a functional response [Perimutter, et al. (1990)
• Figure 21A shows the spectrum obtained from unmodified polylysine
• Figure 21B shows the spectrum obtained from LC sulfo SPDP-conjugated polylysine
• Figure 21C shows the spectrum obtained from LC sulfo SPDP-conjugated polylysine following treatment with DTT
• Figure 21D shows the spectrum obtained from LC sulfo SPDP-conjugated polylysine complexed with the C1315 peptide.
• Binding assays were performed on all three cell lines [HuH7, HepG2 (high), and HepG2 (low)] simultaneously with the same batch of iodinated C105Y peptide so that the proper comparisons could be made. c) Determination Of Surface SEC Receptor Binding In
• SEC-R has been found in lung, liver, and brain [reviewed in Perimutter (1994) Pediatric Res. , supra]; all of which exhibit severe disease in disorders for which the methods and compositions of the preset invention may be used for therapeutic treatment.
• Cells affected in ⁇ -1-antiprotease deficiency, the most common genetic cause of liver disease in children, and Alzheimer's disease express the SEC-R.
• Specific targeting of these cells using the methods and compositions of the present invention provides a means for gene therapy of these diseases.

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