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Cancer vaccines and methods of using the same

A technology for methylating oligonucleotides and methylating nucleic acids, which can be applied to biochemical equipment and methods, medical preparations without active ingredients, and medical preparations containing active ingredients, etc., and can solve the problem of unobserved dendrites. Cellular immune stimulatory activity, not provided, etc.

Inactive Publication Date: 2005-09-07
INEX PHARMA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Unfortunately, no valid control sequences, such as random sequences or mixtures of sequences of the same length, were provided to confirm the predictive value of this in vitro assay and / or the accuracy of the applicant's conclusions about possible immunostimulatory activity in vivo
Furthermore, no immunostimulatory activity was observed on dendritic cells (an important subtype of antigen-presenting cells)

Method used

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  • Cancer vaccines and methods of using the same
  • Cancer vaccines and methods of using the same
  • Cancer vaccines and methods of using the same

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preparation example Construction

[0156] Preparation of the composition

[0157] Preparation of the compositions of the present invention may be accomplished by any technique, but most preferably alcohol dialysis or detergent dialysis are described in detail in the following publications, patents and applications, all of which are hereby incorporated by reference: U.S. Patent 5,705,385; Patent 5,976,567; US Patent Application 09 / 140,476; US Patent 5,981,501; US ​​Patent 6,287,591; International Publication No. WO96 / 40964 and International Publication No. WO98 / 51278. These manufacturing methods provide for small-scale and large-scale manufacture of therapeutic agent-containing immunostimulatory compositions encapsulated in lipid particles, preferably lipid-nucleic acid particles. These methods also yield particles with excellent pharmaceutical properties.

[0158] Vaccine compositions of the present invention can be prepared by adding the target antigen where a response is desired. Methods for incorporation o...

Embodiment 1

[0205] Comparison of in vitro and in vivo leukocyte activation by exposure to free or encapsulated oligonucleotides in whole blood cells

[0206] To indicate the potency of in vitro assays for predicted immune stimulation in vivo, CD69 expression was compared in figure 1 and figure 2 displayed in . CD69 is a cell activation marker, quantitatively expressing the activity of NK cells, B cells and monocytes. The expression of CD69 in NK cells indicates cell activation and IFN-g production, which is important for the induction of Th-1 immune responses. The ability of free and encapsulated ODN1 and 2 to induce CD69 expression was tested in vitro and in vivo. In vitro, the dose was 0.1 mg / ml ODN2 and 10 mg / ml ODN1, and in vivo, the dose was 10 mg / kg ODN2 and 20 mg / kg ODN1. Each oligonucleotide was encapsulated in lipid particles consisting of POPC:CHOL:DODMA:PEGDMG in a ratio of 20:45:25:10.

[0207] figure 1 showed in vitro stimulation of leukocytes containing the activation...

Embodiment 2

[0211] In vivo, dendritic cell activation with methylated oligonucleotides

[0212] As noted above in the Background section, the prior art teaches that methylated CpG oligonucleotides are generally less effective at stimulating an immune response than unmethylated CpG oligonucleotides, whether measured in vivo or in vitro, or Less potent than unmethylated CpG oligonucleotides. US Patent 6,429,199 discloses that methylated oligonucleotides do not enhance CD40 expression in NK cells or human B cells, and do not exhibit any improved survival of dendritic cells, which are involved in Th-1 responses in body fluids and cells Major antigen-presenting cells in immunity. Furthermore, the disclosed methylated CpG oligonucleotides did not enhance the survival, differentiation, activation or maturation of dendritic cells in vitro. Similarly, the in vitro PBMC results published in WO02 / 069369 also did not show any activity of methylated oligonucleotides on dendritic cells.

[0213] In ...

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Abstract

The present invention has found that by encapsulating nucleotides in lipid particles, methylated nucleic acids, especially methylated oligonucleotides, and more particularly methylated nucleic acids containing methylated cytosine CPG dinucleotide motifs can be made Methylated oligonucleotides possess immunostimulatory activity in vivo. The present inventors also discovered that encapsulated methylated nucleic acids, which are generally not immunostimulatory in vivo, are as effective as or more effective than their encapsulated unmethylated counterparts. The present invention also discovers methods of activating and / or expanding dendritic cells in response to antigenic stimulation using the compositions and methods disclosed herein.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Patent Application Serial No. 60 / 379,343, filed May 10, 2002; U.S. Patent Application Serial No. 10 / 290,545, filed November 7, 2002; and U.S. Patent Application, filed April 4, 2003 Priority to application serial number 60 / 460,646. technical field [0003] The present application relates to lipid-nucleic acid formulations and methods for their use in stimulating an immune response in vivo, in particular liposomal formulations of nucleic acid sequences containing at least one methylated cytosine to synergistically enhance their immunity Stimulatory activity wherein the methylated cytosine preferably forms part of a CpG motif. Background technique [0004] Methylation of cytosine is the only known endogenous modification of DNA in eukaryotes, which is achieved by the enzymatic addition of a methyl or hydroxymethyl group to the C-4 or C-5 position of cytosine. Cost...

Claims

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Application Information

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IPC IPC(8): A61K39/39A61P37/00A61P35/00A61P31/00A61K48/00A61K39/00A61K47/18A61P31/04A61P37/02A61P37/04C12N15/09C12N15/117
CPCA61K2039/541A61K2039/55555A61K39/0011A61K2039/55561C12N15/117C12N2310/315A61K39/39C12N2310/3341A61P31/00A61P31/04A61P35/00A61P37/00A61P37/02A61P37/04A61K39/4644A61K39/461
Inventor 英·K·塔姆肖恩·森普尔桑德拉·克利穆克加尼亚·奇克
Owner INEX PHARMA CORP
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