Methods related to immunostimulatory nucleic acid-induced interferon

• US 20060286070A1
• Filed: 07/08/2005
• Published: 12/21/2006
• Est. Priority Date: 09/27/1999
• Status: Active Grant

• Current Assignee: Coley Pharmaceutical GmbH (Pfizer Inc.), University of Iowa Research Foundation
• Original Assignee: Coley Pharmaceutical GmbH (Pfizer Inc.), Coley Pharmaceutical Group, Inc. (Pfizer Inc.), University of Iowa Research Foundation
• Inventors: Hartmann, Gunther, Krieg, Arthur M., Bratzler, Robert L.
• Granted Patent: US 7,776,344 B2
• Time in Patent Office: Days
• US Class Current: 424/85.700
• CPC Class Codes: A61K 2039/5154 Antigen presenting cells [APCs], e.g. dendritic cells or macrophages
• CPC Class Codes: A61K 2039/5158 Antigen-pulsed cells, e.g. T-cells
• CPC Class Codes: A61K 2039/55561 CpG containing adjuvants; Oligonucleotide containing adjuvants
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/21 Interferons [IFN]
• CPC Class Codes: A61K 39/461 characterised by the cell type used
• CPC Class Codes: A61K 39/464411 Immunoglobulin superfamily
• CPC Class Codes: A61K 39/464419 Receptors for interleukins [IL]
• CPC Class Codes: A61K 39/464463 Phosphatases
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C12N 15/117 Nucleic acids having immunomodulatory properties, e.g. containing CpG-motifs
• CPC Class Codes: C12N 2501/056 Immunostimulating oligonucleotides, e.g. CpG
• CPC Class Codes: C12N 2501/22 Colony stimulating factors (G-CSF, GM-CSF)
• CPC Class Codes: C12N 2501/23 Interleukins [IL]
• CPC Class Codes: C12N 5/0639 Dendritic cells, e.g. Langherhans cells in the epidermis

Abstract

Methods and compositions are provided for extending the clinical utility of IFN-α in the treatment of a variety of viral and proliferative disorders. Among other aspects, the invention provides methods which increase the efficacy of IFN-α treatment and reduce IFN-α treatment-related side effects. In addition, methods are provided for supporting the survival and for activating natural interferon producing cells (IPCs) in vitro without exogenous IL-3 or GM-CSF. The invention is based on the discovery that certain CpG and non-CpG ISNAs promote survival and stimulation of IPCs.

Claims

1-203. -203. (canceled)

204. A chimeric nucleic acid comprising at least two types of immunostimulatory nucleic acids selected from the group consisting of CpG nucleic acids, T-rich nucleic acids, and poly-G nucleic acids, wherein at least one immunostimulatory nucleic acid induces production of interferon alpha (IFN-α

) from human peripheral blood mononuclear cells and has a formula 5′

Y₁N₁CGN₂Y₂ 3′

wherein Y₁ and Y₂ are, independent of one another, nucleic acid molecules comprising between 1 and 10 nucleotides, and wherein Y₁ comprises at least one modified internucleotide linkage and Y₂ comprises at least one modified internucleotide linkage and wherein N₁ and N₂ are nucleic acid molecules, each independent of one another, comprising between 0 and 20 nucleotides, wherein N₁CGN₂ comprises at least 6 nucleotides in total and wherein the nucleotides of N₁CGN₂ have a phosphodiester backbone, and wherein at least one immunostimulatory nucleic acid is an oligonucleotide comprising a diol at either or both termini.

205. The chimeric nucleic acid of claim 204, wherein the immunostimulatory nucleic acid that induces IFN-α

and has a formula 5′

Y₁N₁CGN₂Y₂ 3′

is selected from the group consisting of

206. The chimeric nucleic acid of claim 205, wherein the immunostimulatory nucleic acid that induces IFN-α

and has a formula 5′

Y₁N₁CGN₂Y₂ 3′

is selected from the group consisting of

207. The chimeric nucleic acid of claim 206, wherein the diol is hexaethyleneglycol (HEG).

208. The chimeric nucleic acid of claim 206, wherein the diol is tetraethyleneglycol (TEG).

209. The chimeric nucleic acid of claim 206, wherein the chimeric nucleic acid induces production of type I IFN from human peripheral blood mononuclear cells but has minimal effects activating B cells.

210. The chimeric nucleic acid of claim 209, wherein the immunostimulatory nucleic acid that induces IFN-α

and has a formula 5′

Y₁N₁CGN₂Y₂ 3′

is selected from the group consisting of

211. The chimeric nucleic acid of claim 210, wherein the immunostimulatory nucleic acid that induces IFN-α

and has a formula 5′

Y₁N₁CGN₂Y₂ 3′

is selected from the group consisting of

212. The chimeric nucleic acid of claim 211, wherein the immunostimulatory nucleic acid that induces IFN-α

and has a formula 5′

Y₁N₁CGN₂Y₂ 3′

is selected from the group consisting of

213. A composition comprising the chimeric nucleic acid of claim 209 and a pharmaceutically acceptable excipient.

214. The composition of claim 213, further comprising an antigen.

215. The composition of claim 213, further comprising a microsphere.

216. A method of inducing an immune response in a subject, the method comprising administering to the subject a chimeric nucleic acid of claim 206 in an amount sufficient to induce an immune response in the subject.

217. A method of inducing an immune response in a subject, the method comprising administering to the subject a chimeric nucleic acid of claim 209 in an amount sufficient to induce an immune response in the subject.