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C-class oligonucleotide analogs with enhanced immunostimulatory potency

An immunostimulatory, nucleotide technology, used in medical preparations containing active ingredients, microorganisms, drug combinations, etc.

Inactive Publication Date: 2009-06-10
科勒制药有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These immunostimulatory effects of bacterial DNA are now known to be due to the presence of unmethylated CpG dinucleotides (CpG motifs) in specific base contexts, which are common in bacterial DNA, but in vertebrate DNA they are Methylation without representation

Method used

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  • C-class oligonucleotide analogs with enhanced immunostimulatory potency
  • C-class oligonucleotide analogs with enhanced immunostimulatory potency
  • C-class oligonucleotide analogs with enhanced immunostimulatory potency

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0341] Class C ODN analogs induce IFN-α secretion and human TLR9 activity in vitro

[0342] In this series of experiments, the class C ODN analogs of the present invention were tested in vitro for their ability to stimulate human peripheral blood mononuclear cells (PBMC) to secrete IFN-α and to stimulate HEK293 cells stably transfected with human TLR9 and NF-KB reporter gene constructs Shows the ability of TLR9 signaling.

[0343] ODN was purchased from Biospring (Frankfurt, Germany) and its identity and purity were controlled by Coley Pharmaceutical GmbH (Langenfeld, Germany). ODN was diluted in phosphate buffer (Sigma, Germany) and stored at -20°C. All dilutions were performed with pyrogen-free reagents. Test ODN includes the following:

[0344] 128T * C_G * T * C * G * T * T * T * T * A * C * G * G * C * G * T * C * G * T * G * C * C * G (SEQ ID NO: 48)

[0345] 611 T * C * G * T * C * G * T * T * T * T * A * C_G * G * C_G * C * C_G ...

Embodiment 2

[0372] Other Class C ODN analogs induce IFN-α secretion in vitro

[0373]In this series of experiments, other Class C ODN analogs of the invention were tested in vitro for their ability to induce IFN-[alpha] secretion. Class C ODN analogs in these assays were characterized in part by the presence of AT-rich interrupted inverted repeats, or by the presence of interrupted inverted repeats containing dSpacer residues without conventional nucleotide residues.

[0374] ODN was obtained as in Example 1. Test ODN includes the following:

[0375] 645T * C * G * T * C_G * T * T * T * T * T * A * A * T * A * T * T * T * A * T * T * A SEQ ID NO: 59

[0376] 646 T * C * G * T * C_G * T * T * T * T * C * A * A * T * A * T * T * T * A * T * T * G SEQ ID NO: 50

[0377] 647 T * C * G * T * C_G * T * T * T * T * T * A * A * T * A * T * C * C * A * T * T * A SEQ ID NO: 58

[0378] 649 T * C * G * T * C_G * T * T * T * T *...

Embodiment 3

[0387] Additional class C ODN analogs induce IFN-α secretion and human TLR9 activity in vitro

[0388] In this series of experiments, the ability of the class C ODN analogs of the present invention to stimulate the secretion of IFN-α from human peripheral blood mononuclear cells (PBMC) and to stimulate HEK293 cells stably transfected with human TLR9 and NF-κB reporter gene constructs was tested in vitro Shows the ability of TLR9 signaling. The basic operation scheme is as described in Example 1, except that the test ODN includes the following:

[0389] 664 T ＊ C ＊ G ＊ A ＊ C ＊ G ＊ T ＊ C ＊ G ＊ A ＊ C ＊ G ＊ T ＊ G ＊ A ＊ C ＊ G ＊ T ＊ G (SEQ ID NO: 62)

[0390] 376T ＊ C ＊ G ＊ A ＊ C ＊ G ＊ T ＊ C ＊ G ＊ A ＊ C ＊ G ＊ T ＊ G ＊ A ＊ C ＊ G (SEQ ID NO: 61)

[0391] 801T ＊ C_G ＊ T ＊ C_G ＊ A ＊ C_G ＊ T ＊ T ＊ C_G ＊ G ＊ C ＊ G ＊ C ＊ C_G ＊ T ＊ G ＊ C ＊ C ＊ G (SEQ ID NO: 65)

[0392] 893 T ＊ C ＊ G ＊ T ＊ C_G ＊ T ＊ A ＊ C_G ＊ G ＊ C ＊ G ＊ C * ...

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Abstract

The invention relates to a class of CpG immunostimulatory oligonucleotides containing a CpG immunostimulatory motif and a second motif which is capable of forming secondary structure, including duplex and higher order structures, in vitro and in vivo. The oligonucleotides of the invention are useful as adjuvants in vaccination. The oligonucleotides are also useful for inducing an immune response, inducing expression of a type I interferon (IFN), inducing expression of gamma interferon (IFN-gamma), and for treating a variety of conditions, including allergy, asthma, infection, and cancer.

Description

Area of invention [0001] The invention is generally involved in immune irritating nucleic acids, its composition, and using immune irritating nucleic acid. Invention background [0002] Bacterial DNA has the immune stimulating effect of activating B cells and natural killing cells, but vertebrate DNA is not good.Tokunaga T et al. (1988) JPN J CANCER Res 79: 682-6; Tokunaga T Et Al.The following summary: Krieg, 1998, in: Applied Oligonucleotide Technology, C.A.Stein anda.m.krieg, (EDS.), John Wiley and Sons, New York, PP.431-448) And Krieg AM (2002222) Annu Rev Immunol 20: 709-60.It is known that these immune stimulus of bacterial DNA is due to the existence of non -methylized CPG dilate (CPG base) in a specific base environment, which is common in bacterial DNA, but in vertebrate DNAMethalosis and no representative.Krieg am et al. (1995) nature374: 546-9; krieg am (1999) biochim biophys acta 1489: 107-16. [0003] The immune stimulus of bacterial DNA can be simulated with synthet...

Claims

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Application Information

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IPC IPC(8): C12N15/11A61K31/7088A61K39/39A61P31/00A61P37/08A61P35/00A61K38/00A61K48/00C07H21/02C12N15/117
CPCC12N15/117C12N2310/53C12N2501/056A61K2039/55561C12N2310/31A61K38/00C12N2310/315C12N2310/17C12N2310/33A61K39/39A61P11/06A61P31/00A61P31/04A61P31/10A61P31/12A61P31/18A61P31/20A61P33/00A61P35/00A61P35/02A61P37/04A61P37/08Y02A50/30A61K31/7088
Inventor 欧根·乌尔曼约尔格·福尔默阿瑟·M·克里格伯恩哈德·O·诺尔
Owner 科勒制药有限公司
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