WO2005070459A1 - Methode pour soutenir l'expression d'un vecteur administre a plusieurs reprises - Google Patents

Methode pour soutenir l'expression d'un vecteur administre a plusieurs reprises Download PDF

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WO2005070459A1
WO2005070459A1 PCT/JP2005/000777 JP2005000777W WO2005070459A1 WO 2005070459 A1 WO2005070459 A1 WO 2005070459A1 JP 2005000777 W JP2005000777 W JP 2005000777W WO 2005070459 A1 WO2005070459 A1 WO 2005070459A1
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vector
complement
administration
expression
gene
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PCT/JP2005/000777
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Japanese (ja)
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WO2005070459A8 (fr
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Hiroto Hara
Yasuji Ueda
Makoto Inoue
Mamoru Hasegawa
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Dnavec Research Inc.
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/13—Tumour cells, irrespective of tissue of origin

Definitions

  • the present invention relates to a method and a drug for continuing gene expression from a vector with repeated administration, and particularly to a method and a drug using a complement inhibitor.
  • virus vectors There are two main types of virus vectors. One type is incorporated into the chromosome to execute gene expression such as transcription and replication, and the other type is to perform gene expression such as transcription and replication outside the chromosome.
  • the present invention enables repeated administration of a vector within a short period of time. It is an object of the present invention to provide a method capable of continuing gene expression and a drug capable of performing the method.
  • the present invention is based on these findings, and is specifically as follows.
  • a vector expression continuation agent comprising a complement inhibitor as an active ingredient.
  • a drug for gene therapy comprising a complement inhibitor as an active ingredient.
  • a repeated dose vector system comprising a complement inhibitor and a repeated dose vector.
  • FIG. 1 A graph showing a decrease in gene expression by 2 administrations of SeV shown as Reference Example 1.
  • FIG. 2 A graph showing an enhancement of SeV neutralization activity in the presence of complement shown as Reference Example 2. so is there.
  • A Inhibition activity of expression of genes mounted on SeV when complement is added or not added to mouse anti-SeV serum.
  • B As a control experiment, the results using mouse non-immune serum are shown.
  • FIG. 3 Draft showing the result of restoring the GFP gene expression of vector force by the complement inhibitor nafamostat mesilate (may be indicated as “FUT175”) in the in vitro analysis system.
  • A Suppressive activity of GFP expression in the experimental group supplemented with guinea pig complement (final concentration 1%) and complement inhibitor nafamostat mesilate at different concentrations.
  • B SeV-loaded GFP expression-inhibiting activity in experimental groups supplemented with different concentrations of the complement inhibitor nafamostat mesilate without complement.
  • FIG. 5 is a graph showing the anti-SeV antibody titer of the host just before the second administration of SeV vector.
  • FIG. 6 is a graph showing the results of restoring gene expression with vector inhibitor by complement inhibitor C1INH in an in vitro analysis system.
  • A Inhibition activity of SeV-loaded GFP expression in experimental groups supplemented with guinea pig complement (final concentration 1%) and different concentrations of complement inhibitor C1INH.
  • B SeV-loaded GFP expression-inhibiting activity in experimental groups in which complement inhibitors C1INH with different concentrations were added to non-complement-added cells.
  • the present invention firstly provides a method of continuing gene expression of a repetitive administration type vector force using a complement inhibitor.
  • the repetitive administration type vector means a vector that may be repeatedly administered within a short period of time during which the elimination action by the host immune system works for reasons such as high expression of the on-board gene, and such a host. It is a vector that is expected to increase its usefulness, such as the spread of applicable diseases, if repeated administration is possible within a short period of time during which the immune system eliminates.
  • Examples of such vectors that exist outside the chromosome, such as the cytoplasm after introduction into the host are Sendai virus vectors and -Eucastle disease virus (
  • NDV vectors such as Paramyxoinoles vector, Baculoinores vector, Box virus vectors such as wild virus vectors, alphavirus vectors, herpes virus vectors, influenza virus vectors, etc. There is.
  • paramyxovirus vectors are suitable examples of the repeated administration vector of the present invention.
  • Sendai virus vectors belonging to this species can be repeatedly administered at long intervals, but if they can be repeatedly administered within a short period of time, they are one of the vectors that are expected to expand the applicable diseases of gene therapy.
  • the paramyxovirus vector may be, for example, a complex of paramyxovirus genomic RNA and viral protein, ie, ribonucleoprotein (RNP).
  • RNP can be introduced into cells in combination with, for example, a desired transfection reagent.
  • Such an RNP is specifically a complex containing the paramyxovirus genomic RNA, N protein, P protein, and L protein.
  • the viral protein functions to transcribe the cistron that encodes the viral protein from the genomic RNA, and the genome itself replicates to form a daughter RNP.
  • the paramyxovirus vector may be a gene lacking any of the genes of the wild-type paramyxovirus.
  • a paramyxovirus vector containing a M, F, or HN gene, or a combination thereof can be suitably used as the paramyxovirus vector of the present invention.
  • Such reconstitution of a viral vector can be performed, for example, by supplying a defective gene product exogenously.
  • the virus vector produced in this way adheres to the host cell in the same way as the wild type virus and is then introduced into the cell by fusing the cell membrane and the vector envelope.
  • the vector genome introduced into the cell is the virus.
  • Daughter virus particles with infectivity similar to the wild type are not formed because of the gene defect.
  • genes that also lack genomic power include the F gene and the Z or HN gene.
  • Viral vectors can be reconstituted by transfecting cells (International Publication Nos. WO00 / 70055 and WO00 / 70070; Li, H.-0. Et al., J. Virol. 74 (14)
  • a virus can be produced using a host cell in which the F gene is integrated into the chromosome.
  • the amino acid sequence is not the virus-derived sequence as it is, but if the activity in introducing the nucleic acid is equal to or higher than that of the wild type, a mutation is introduced or other Substituting with the homologous gene of the virus.
  • the vectors are heterogeneous, they may be repeatedly administered between vectors having the same cross-reactivity. As long as both can be recognized as the same antigen by the host immune system, the method of the present invention is effective.
  • the method for administering these vectors to the host is not particularly limited, and is administered by a method suitable for the type of vector.
  • the administration route can be selected as appropriate, but it can be performed, for example, transdermally, intranasally, transbronchially, intramuscularly, intraperitoneally, intravenously, intraarticularly, intrathecally, or subcutaneously, but is not limited thereto. . It can also be administered locally or systemically.
  • the amount of vector administered is generally about 10 5 ClU / ml to about 10 11 CIU / mU, preferably about 10 7 CIU / ml to about 10 9 CIU / ml, more preferably about 1 X 10 8 CIU.
  • an amount in the range of from / ml to about 5 ⁇ 10 8 CIU / ml is administered in a pharmaceutically acceptable carrier.
  • the dose per dose is 2 X 10 5 CIU — 2 X 10 10 CIU is preferred, and can be given once or multiple times within the range of clinically acceptable side effects. The same applies to the number of administrations.
  • a complement inhibitor is used in order to continuously express a gene introduced into a host via a repeated administration type vector as described above.
  • Complement is a group of proteins belonging to a natural immune system that recognizes and eliminates foreign substances such as pathogens that have invaded a living body.
  • the antigen-antibody conjugate formed by capturing the foreign body with the antibody is complemented by the antigen-antibody conjugate formed by a part of the complement system.
  • a series of systems This enhances the elimination of foreign substances by antibodies.
  • complement system components There are about 20 types of complement system components, of which nine are called complement components, C1 to C9.
  • complement inhibitors also inhibit the classical pathway, alternative pathway, or both pathways (Makrides SC, Pharmacol Reviews 1998 50 (l: 59-87, bahu A et al. Immunopharmacology 2000 49: 133-148).
  • the complement inhibitor that can be used in the invention is not particularly limited as long as it can continuously express a gene introduced into a host via a repeated administration vector.
  • Anti-C5 antibody formulation Antibody formulation against necrotic components such as pexelizumab (Alexion Pharmaceuticals Inc)
  • Solubilized protein factors Solubilized Clq receptors such as TP10, TP20 (Clq inhibition, Marsh H and Ryan Ub, 1997, Xenotransplantation: The Transplantation of Organs ana Tissues Between Species (Cooper DKC, Kemp E, Piatt JL and White DJG, eds) 2nd ed, pp 437-455, Springer, Berlin), solubilized CD59 (Suppression of MAC complex formation, Suzuki H, et al. 1996 FEBS Lett 399: 272-276), solubilized DAF (C3 / C5Convertase Inhibition, Moran P et al. 1992 J Immunol 149: 1736-1743) and solubilized MCP (C3 / C5 Convertase inhibition, Christiansen D et al. 1996 Eur J Immunol 26: 578-585)
  • Peptide inhibitors C089 (C5 receptor antagonist, Konteatis ZD et al. 1994 J Immunol 153: 4200-4205), Compstatin (C3 inhibitor, Sahu A, et al. J Immunol 1996 157 (2): 884-91)
  • a complement inhibitor can be used as a complement inhibitor of the present invention as long as it suppresses complement that enhances neutralizing activity against a repetitive administration type vector and can continue expression of vector force.
  • Preferable examples include complement inhibitors that can suppress C or C5 among complements.
  • Complement inhibitors that can suppress C1 include those listed as “C1 suppression” in the complement inhibitors listed above, as well as anti-C1 antibodies and C1 receptor antagonists.
  • Complement inhibitors that can suppress C5 are described as “C5 suppression”, “anti-C5 antibody”, “C5 receptor antagonist”, “C3 / C5 convertase inhibition” among the complement inhibitors listed above. Or those having functions equivalent to these.
  • the timing of the use of a complement suppressor to continue gene expression from a repeated dose vector is at the time of vector administration, preferably at the repeated dose where the vector is administered again after the first administration of the vector. .
  • the beta be administered repeatedly after the second dose.
  • “during administration” in “vector administration” or “repetitive administration” means mixing into a vector solution and administering it to the host at the same time, or separately from the vector solution and before and after vector administration. Or administration by different routes.
  • the method of administration of the complement inhibitor is not necessarily the same as the method of administration of the vector and the administration site, and as an example, the complement inhibitor is administered orally to the intravenous administration of the vector. Another route or form of administration Any administration method capable of continuing gene expression from the vector is included in the present invention.
  • the complement inhibitor is not limited to one type of use, and a plurality of types may be used in combination. Alternatively, the type may be changed for each vector administration. Further, the dosage of the complement inhibitor may be constant or may be changed for each vector administration.
  • continuation of expression means enabling or facilitating gene expression from repeatedly administered vectors.
  • the expression level after repeated administration as a result of this continuation of expression may be the same level or higher than the expression level after the first vector introduction, or less. Even in this case, it is possible to include a deviation in the case where a significantly higher expression can be maintained as compared with the case where a conventional complement inhibitor is not administered.
  • the use of a complement suppressor enables gene expression from a repeatedly administered vector in a repeat-administration vector, thereby complement suppression. Significantly higher gene expression can be maintained than when no agent is used. Therefore, it is possible to continuously impart the gene function loaded on the vector to the host. Therefore, according to the present invention, the therapeutic effect of gene therapy is improved when used in the medical field such as gene therapy, and more stable when used in the research field such as the creation of transgenic animals. To provide a representation.
  • Another aspect of the present invention relates to a vector expression continuation agent comprising a complement inhibitor as an active ingredient.
  • the complement suppressor can be used in the repeated administration of a repeated administration type vector to continue the expression of the gene loaded on the vector. Therefore, this complement inhibitor can be used as a vector expression continuation agent.
  • the vector expression continuation agent means a reagent for suppressing the second and subsequent expression reduction generally observed in vectors repeatedly administered and continuing the expression.
  • This vector expression continuation agent contains a complement inhibitor capable of continuing gene expression from the vector.
  • Whether or not the expression of the gene of complement inhibitory vector power can be continued is described in the Examples. It can be evaluated using the method shown. That is, after introducing the first vector into a laboratory animal such as a mouse, a candidate complement inhibitor is administered when the second vector is introduced. Evaluate the expression of the loaded gene after the second and subsequent vector introductions based on the expression of the reporter gene. Then, the expression level of the loaded gene in the host to which the drug is not administered is compared with the expression level of the loaded gene in the host to which the complement inhibitor has been administered. When the expression level is high, it is evaluated that the complement inhibitor can be used as a vector expression continuation agent.
  • this complement inhibitor when used as a vector expression continuation agent, it may be composed of one type of complement inhibitor force or a mixture of plural types of complement inhibitors. Note that complement inhibitors that can be used as a vector expression continuation agent are as described above, and a description thereof is omitted here. Moreover, other components can be contained in addition to the complement inhibitor.
  • anti-inflammatory drugs cortisol, dexamethasone, prednisolone, triamcinolone, etc.
  • immunosuppressants cyclophosphamide, azathioprine, 6-mercaptopurine, methotrexate, mizoribine, cyclosporine, tacrolimus, OKT-3, Baslliximab, Zenapax, Remicade
  • it may be diluted with a physiological saline or a buffer that may contain a preservative or the like.
  • the vector expression continuation agent of the present invention can be used as a reagent for producing a transgenic animal.
  • a vector expression continuation agent is used for the production of a transgenic animal, the expression of a foreign gene introduced through the vector can be continued, so that a stable phenotype can be imparted.
  • Yet another embodiment of the present invention is a gene therapy drug comprising a complement inhibitor as an active ingredient.
  • the complement suppressor can be used for repeated administration of a repeated-dose vector, so that the expression of the gene loaded on the vector can be continued. It can be used as a drug used in combination with gene therapy. That is, the drug for gene therapy comprising the complement suppressant of the present invention as an active ingredient is a repetitive administration vector carrying a gene having a function desired to be given to a patient that does not itself exert the effect of gene therapy. In combination with the agent of the present invention, the expression of the gene loaded on the vector is continued. It has an effect.
  • a pharmaceutical in order to prepare a complement inhibitor as an auxiliary drug for the above gene therapy, a pharmaceutical can be combined with a desired pharmacologically acceptable carrier or vehicle as necessary.
  • this carrier or medium is a suspending agent, surfactant, stabilizer, killing agent as long as it is within the range of materials that do not significantly inhibit the activity that can continue the expression of the onboard gene on the vector by the complement inhibitor.
  • Biological agents, preservatives, and other additives can be added.
  • the gene therapy drug can be used for the treatment of humans and animals other than humans as an adjunct to gene therapy using a repetitive administration type vector.
  • gene expression from the repeated administration vector can be continued and the therapeutic effect can be improved.
  • This drug can be used at the time of the first administration of the vector. For example, if you are naturally infected with a virus that can induce neutralizing activity that is the same or different from the vector but crossed before gene therapy with a repeated dose vector, Even at the time of vector administration, gene expression from the vector may be suppressed. Therefore, if neutralization activity that crosses the vector used for treatment is detected in the patient's serum, this gene therapy drug can be used at the first vector introduction to allow expression of the on-board gene. It ’s good.
  • the present invention can also be provided as a repeated administration vector system comprising a complement inhibitor and a repeated administration vector.
  • a complement inhibitor for continuing expression from this vector is provided, so that research fields such as the production of transgenic animals, medical fields such as gene therapy, etc.
  • the present invention can be made easier to use.
  • the expression level of the vector-borne gene was examined when the second administration of the SeV vector was performed.
  • the Ffly-deficient SeV vector was loaded with the firefly luciferase gene as a reporter gene.
  • This SeV vector (5xl0 6 CIU / mouse) was intranasally administered to Balb / cA mice as the first, and eight days later, the same vector lxlO 8 CIU was administered into the thigh muscle.
  • muscles were collected and homogenized, and luciferase activity in the homogenate was determined for the Luciferase Assay System (Promega).
  • the luciferase activity at the second administration was almost reduced to the background level as compared with the first time. This indicates that the host has acquired the neutralizing activity of the SeV vector by multiple administrations.
  • SeV neutralization activity was enhanced by complement.
  • anti-SeV serum Seb vector (2xl0 7 CIU / mouse) was intraperitoneally administered to Balb / cA mice (60 mice), and the same amount of vector was additionally administered on days 14 and 21. .
  • whole blood was collected from all the heads and pooled to obtain anti-SeV serum.
  • the non-immune serum used as a control was pooled from the serum of 30 untreated mice.
  • the serum was previously heated at 56 ° C for 30 minutes.
  • Guinea pig complement (CedarLane CL5000-1) was used as the complement, and was used at a final concentration of 1% in the experimental system.
  • Neutralization activity was measured by modifying a known method (neutralization test, pp261-274, revised second edition, Virus Experimental Studies, General Review, National Institute of Preventive Hygiene, Alumni Association, 1973 Maruzen).
  • a dilution series of anti-SeV serum or non-immune serum was prepared. Complement was added to this serum dilution series as necessary, and then mixed with a certain amount of the GFP gene-loaded F gene-deficient SeV betater. This mixed solution was kept at 37 ° C. for 1 hour. After incubation the mixture was added LLC-MK cells (about 2xl0 5 cells / well) ⁇ this in 96 well, cells were infected with SeV.
  • the horizontal axis represents the serum dilution rate
  • the vertical axis represents the neutralizing activity.
  • Neutralizing activity was shown relative to 0% of the fluorescence in wells without vector addition and 100% of the fluorescence in wells without vector addition-antiserum. In the graph, the more the curve is shifted to the right, the stronger the neutralization activity.
  • Neutralization activity was measured in the same manner as described in Reference Example 2 except that a complement inhibitor was added.
  • nafamostat mesilate (Core Inhibitor for Injection 10, Shimizu Pharmaceutical) is a mixture of antiserum and complement (or antiserum) in Reference Example 2 above so that the final concentration is 0.1 mg / m or O.Olmg / ml. Only) and then the vector solution was added to this mixture.
  • Complement suppression 2J administration increases SeV vector expression at the second administration
  • a peptide-type complement inhibitor 2J (Roos A, et al. J Immunol. 2001 167 (12): 7052-9) that suppresses C1 of the classical pathway was used as a complement inhibitor.
  • the 2J peptide used in this example was synthesized based on the amino acid sequence published in the literature of Roos A et al.
  • the GFP gene-loaded F gene-deficient SeV vector was first administered intranasally at 5xl0 6 CIU per Balb / cA mouse.
  • 250 g of each 2J peptide dissolved in 100 1 DPBS (-) was intravenously injected into the tail.
  • Type SeV vector (5xl0 6 CIU / mouse) was mixed with 2J peptide (1.25 / zg) and administered by auricle.
  • the pinna was cut and collected, and the Luciferase activity in the homogenate was measured using the Luciferase Assay System (Promega).
  • the single-dose group was prepared in the same manner as the double-dose group except that the first administration of GFP-loaded SeV / dF vector was not performed.
  • DPBS ( ⁇ ) was administered in place of 2J in each of the twice-administered group and the once-administered group was performed in parallel.
  • Example 2 the anti-SeV antibody titer in the plasma collected just before the second administration on the 14th day was measured by ELISA (Presym Seika HVJ, Denka Seken). In the single dose group, the antibody titer is measured before the first vector introduction.
  • C1INH complement inhibitory action of C1INH was determined in Example 1, except that instead of nafamostat mesilate, the complement inhibitor C1INH “Belinaito! 3 ” (Aventis Pharma) was used. It carried out similarly by activity measurement. “Berinaito! 3 ” was added so that the final concentration was equivalent to 0, 3, 6, 12-fold concentrated plasma.
  • Figure 5 (A) shows the experimental group with guinea pig complement added at a final concentration of 1%, and (b) shows the experimental group with no complement added.

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Abstract

On a découvert qu'un complément renforce la fonction d'élimination d'un vecteur du système immunitaire d'une personne hôte. On peut soutenir de manière significative l'expression d'un vecteur génétique par administration d'un complément inhibiteur lors de la deuxième administration du vecteur et des administrations suivantes. Selon la méthode fondée sur cette découverte, on administre un complément inhibiteur pendant la deuxième administration d'un vecteur et pendant les administrations suivantes afin de soutenir l'expression d'un vecteur du gène à administrer à plusieurs reprises. En outre, le complément inhibiteur sert de réactif pour un médicament et permet de soutenir l'expression du vecteur à administrer à plusieurs reprises.
PCT/JP2005/000777 2004-01-22 2005-01-21 Methode pour soutenir l'expression d'un vecteur administre a plusieurs reprises WO2005070459A1 (fr)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
WO2021007111A1 (fr) * 2019-07-05 2021-01-14 Apellis Pharmaceuticals, Inc. Thérapie par vecteurs viraux

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021007111A1 (fr) * 2019-07-05 2021-01-14 Apellis Pharmaceuticals, Inc. Thérapie par vecteurs viraux
EP3996744A4 (fr) * 2019-07-05 2023-07-12 Apellis Pharmaceuticals, Inc. Thérapie par vecteurs viraux

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