Immunostimulatory oligonucleotides with modified bases and methods of use thereof

Abstract

Immunomodulatory oligonucleotide compositions are disclosed. These oligonucleotides comprise an immunostimulatory hexanucleotide sequence comprising a modified cytosine. These oligonucleotides can be administered in conjunction with an immunomodulatory peptide or antigen. Methods of modulating an immune response upon administration of the oligonucleotide comprising a modified immunostimulatory sequence are also disclosed.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. patent application Ser. No. 10 / 365,678, filed on Feb. 10, 2003, which is a continuation of U.S. application Ser. No. 09 / 324,191, filed Jun. 1, 1999, allowed, which claims the priority benefit of U.S. Provisional Patent Application No. 60 / 088,310 filed Jun. 5, 1998. The aforementioned applications are hereby incorporated herein by reference in their entirety.STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH[0002]Not ApplicableTECHNICAL FIELD[0003]The present invention relates to immunomodulatory compositions comprising an immunostimulatory oligonucleotide sequence (ISS) in which at least one base has been substituted with a base modified by the addition to C-5 and / or C-6 on cytosine with an electron-withdrawing moiety. It also relates to the administration of said ISS to modulate an immune response.BACKGROUND ART[0004]The type of immune response generated to infection or ot...

AI Technical Summary

Problems solved by technology

While most current vaccines elicit effective humoral (antibody, or “Th2-type”) responses, they fail to elicit cellular responses (in particular, major histocompatibility complex (MHC) class I-restricted CTL, or “Th1-type” responses) which are generally absent or weak.

Moreover, antibody responses are inappropriate in certain indications, most notably in allergy where an antibody response can result in anaphylactic shock.

Proposed vaccines using small peptides derived from the target antigen and other currently used antigenic agents that avoid use of potentially infective intact viral particles, do not always elicit the immune response necessary to achieve a therapeutic effect.

The lack of a therapeutically effective human immunodeficiency virus (HIV) vaccine is an unfortunate example of this failure.

A recent study which examined induction of NK activity in response to CpG containing-oligonucleotides suggested that the unmethylated CpG motif was necessary but not sufficient for oligonucleotide induction of NK lytic activity.

These cytokines appear to play a significant role in recruiting eosinophils into site of allergen exposure, where tissue damage and dysfunction result.

Such immunization treatments present the risk of inducing IgE-mediated anaphylaxis and do not address the cytokine-mediated events of the allergic late phase response.

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