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Methods and products for stimulating the immune system using immunotherapeutic oligonucleotides and cytokines

Inactive Publication Date: 2005-09-08
UNIV OF IOWA RES FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0018] According to another aspect the invention is a method for treating a subject having a neoplastic disorder. The method includes the step of administering to the tumor of a subject having a neoplastic disorder an immunopotentiating cytokine and an immunostimulatory CpG oligonucleotide having a sequence including at least the following formula: 5′ X1CGX2 3′ wherein the oligonucleotide includes at least 8 nucleotides wherein C and G are unmethylated and wherein X1 and X2 are nucleotides, in an amount effective for synergistically increasing survival time of the subject with respect to a subject administered the immunostimulatory CpG oligonucleotide or the immunopotentiating cytokine alone.

Problems solved by technology

One of the most complex phenomenon in cancer immunology relates to the failure of the immune system to eliminate tumors.
It is possible that the immune system fails to eliminate tumors not because neoantigens are absent, but rather because in vivo the response to antigens is inadequate.
Although bacillus Calmette-Guerin has been tested in many clinical trials, the results have been inconclusive, and the value of this type of bacterial adjuvant therapy remains uncertain (Piessens and David, 1996, supra).

Method used

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  • Methods and products for stimulating the immune system using immunotherapeutic oligonucleotides and cytokines
  • Methods and products for stimulating the immune system using immunotherapeutic oligonucleotides and cytokines
  • Methods and products for stimulating the immune system using immunotherapeutic oligonucleotides and cytokines

Examples

Experimental program
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Effect test

example 1

Materials and Methods

[0145] Tumor Model and Tumor Antigens: The 38C13 murine B cell lymphoma model has been used extensively in studies of antibody-based therapy and active immunization of lymphoma (Kwak, L. W., et al., Proc Natl Acad Sci USA 93:10972-7, 1996). The idiotype (Id) of the 38C13 surface IgM serves as a highly specific tumor-associated antigen (Bergman, Y., and Haimovich, J., Eur Immunol 7:413-7, 1977). Id was obtained from the supernatant of a cell line that secretes 38C13 IgM as described (Eshhar, Z., et al., J Immunol 122:2430, 1979), and purified by protein a affinity chromatography. Purified Id was conjugated to keyhole limpet hemocyanin (KLH) using glutaraldehyde and used as the immunogen. The cell line that produces 38C13 Id / murine GM-CSF fusion protein was kindly provided by Dr. Ronald Levy. This cell line was cultured in a hollow fiber reactor (Unisyn Technologies, Hopkinton, Mass.), and fusion protein obtained by protein a affinity chromatography. The fusion p...

example 2

CpG Oligonucleotide Enhances Development of an Antibody response to Id-KLH immunization when using GM-CSF as an Adjuvant

[0153] CpG oligonucleotide is known to induce production by APCs of a number of cytokines including GM-CSF (Krieg, A. M., Trends in Microbiology 4:73-6, 1996). In order to determine if the addition of CpG oligonucleotide to GM-CSF would further enhance the immune response mice were immunized with a single subcutaneous injection of 50 μg of Id-KLH in PBS mixed in aqueous solution with 50 μg of CpG oligonucleotide, 10 μg of GM-CSF, or a combination of CpG oligonucleotide and GM-CSF. Serum was obtained weekly and evaluated by ELISA for the presence of antigen-specific IgG (anti-Id IgG). As illustrated in FIG. 1, mice immunized using both CpG oligonucleotide and GM-CSF developed the highest levels of anti-Id IgG. The effect of these two adjuvants appeared to be additive.

[0154] The combination of GM-CSF and CpG oligonucleotide could therefore enhance a number of diffe...

example 3

CpG Oligonucleotide enhances production of anti-Id Antibodies following immunization with Id / GM-CSF fusion Protein

[0155] The Id / GM-CSF fusion protein consisting of the 38C13 variable regions, human IgG constant regions, and murine GM-CSF (Id / GM-CSF) has been shown to be an excellent immunogen (Tao, M. H., and Levy, R., Nature 362:755-758, 1993). In order to evaluate if CpG oligonucleotide can further enhance the specific antibody response induced by Id / GM-CSF, mice were immunized with Id-KLH or Id / GM-CSF with and without CpG oligonucleotide as an adjuvant. Serum was obtained weekly and anti-Id IgG levels determined. No toxicity was observed in any mice. As illustrated in FIG. 2, CpG oligonucleotide enhanced production of anti-Id antibodies in response to Id / GM-CSF.

[0156] In a separate experiment, mice were immunized on day 0 and boosted on day 14 with the same antigen and adjuvant. The combination of Id / GM-CSF and CpG oligonucleotide induced remarkably high levels of anti-Id IgG a...

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Abstract

The present invention relates to synergistic combinations of immunostimulatory CpG oligonucleotides and immunopotentiating cytokines. In particular, the invention relates to methods of stimulating an immune response using the synergistic combination of compounds and products related thereto.

Description

FIELD OF THE INVENTION [0001] The present invention relates to synergistic combinations of immunostimulatory CpG oligonucleotides and immunopotenitiating cytokines. In particular, the invention relates to methods of stimulating an immune response using the synergistic combination of compounds and products related thereto. BACKGROUND OF THE INVENTION [0002] The theory of immune surveillance is that a prime function of the immune system is to detect and eliminate neoplastic cells before a tumor forms. A basic principle of this theory is that cancer cells are antigenically different from normal cells and thus elicit immune reactions that are similar to those that cause rejection of immunologically incompatible allografts. Studies have confirmed that tumor cells differ, either qualitatively or quantitatively, in their expression of antigens. For example, “tumor-specific antigens” are antigens that are specifically associated with tumor cells but not normal cells. Examples of tumor speci...

Claims

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Application Information

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IPC IPC(8): A61K38/00A61K31/7088A61K39/00A61K39/39A61P15/00A61P35/00A61P37/04
CPCA61K39/0011A61K39/39A61K2039/55522A61K2039/55527A61K2039/55538A61K2039/55561A61K2300/00A61P15/00A61P15/16A61P15/18A61P31/00A61P31/04A61P31/10A61P31/12A61P35/00A61P35/02A61P37/04A61P37/08A61P43/00
Inventor KRIEG, ARTHURWEINER, GEORGE
Owner UNIV OF IOWA RES FOUND
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