METHODS RELATED TO IMMUNOSTIMULATORY NUCLEIC ACID-INDUCED INTERFERON

• US 20110033421A1
• Filed: 07/13/2010
• Published: 02/10/2011
• Est. Priority Date: 09/27/1999
• Status: Abandoned Application

• 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: Krieg, Arthur M., Hartmann, Gunther, Bratzler, Robert L.
• Application Number:
  US12/835,000
• Publication Number:
  US 20110033421A1
• Time in Patent Office: Days
• US Class Current: 424/85.7
• 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

1-46. -46. (canceled)

47. A method of treating a subject to activate interferon-producing cells (IPCs) of the subject comprising

isolating IPCs from a subject in need of such treatment,

culturing the IPCs in vitro,

contacting the IPCs in vitro with an effective amount of an isolated immunostimulatory nucleic acid, and

returning the contacted IPCs to the subject.

48. The method of claim 47, further comprising contacting the IPCs in vitro with a growth factor.

49. The method of claim 47, further comprising contacting the IPCs in vitro with IL-3.

50. The method of claim 47, further comprising contacting the IPCs in vitro with GM-CSF.

51. The method of claim 47, wherein the IPCs are cultured in vitro in the absence of IL-3.

52. The method of claim 47, wherein the IPCs are cultured in vitro in the absence of GMCSF.

53. The method of claim 47, wherein the immunostimulatory nucleic acid is modified.

54. The method of claim 47, wherein the immunostimulatory nucleic acid comprises a backbone with at least one nuclease-resistant internucleotide linkage selected from the group consisting of:

phosphorothioate, phosphorodithioate, methylphosphonate, and peptide.

55-121. -121. (canceled)

122. A method of enhancing efficacy of IFN-α

treatment in a subject in need of such treatment, comprising

administering to a subject in need of such treatment an amount of a pharmaceutical composition comprising IFN-α

effective for treating a condition of the subject;

isolating natural interferon-producing cells (IPCs) from a donor;

contacting the isolated IPCs ex vivo with an amount of a pharmaceutical composition comprising an immunostimulatory nucleic acid effective for inducing the IPCs-to release IFN-α

; and

administering the contacted cells to the subject.

123. The method of claim 122, wherein the donor is the subject.

124. The method of claim 122 further comprising contacting the isolated IPCs with an antigen.

125. The method of claim 122, wherein the administering the contacted cells comprises local injection.

126. The method of claim 125, wherein the local injection is via a blood vessel supplying a target tissue.

127. The method of claim 126, wherein the blood vessel is selected from the group consisting of a hepatic artery, a portal vein, a celiac artery, and a splenic artery.

128. The method of claim 122, wherein the immunostimulatory nucleic acid is modified.

129. The method of claim 122, wherein the immunostimulatory nucleic acid comprises a backbone with at least one nuclease-resistant internucleotide linkage selected from the group consisting of:

phosphorothioate, phosphorodithioate, methylphosphonate, and peptide.

140. The method of claim 122, wherein the subject has a condition selected from the group consisting of a proliferative disorder and a viral infection.

141. The method of claim 122, wherein the subject has a proliferative disorder selected from the group consisting of:

hairy cell leukemia, chronic myelogenous leukemia, cutaneous T-cell leukemia, multiple myeloma, follicular lymphoma, malignant melanoma, squamous cell carcinoma, AIDS-related Kaposi'"'"'s sarcoma, renal cell carcinoma, prostate carcinoma, bladder cell carcinoma, cervical dysplasia, and colon carcinoma.

142. The method of claim 122, wherein the subject has a viral infection selected from the group consisting of:

hepatitis B, hepatitis C, condyloma acuminatum, human immunodeficiency virus, herpes, cytomegalovirus, Epstein-Barr virus, and papillomavirus.

130-139. -139. (canceled)

143. A method of supporting survival of natural interferon-producing cells (IPCs) in vitro, comprising

isolating IPCs from a subject;

culturing the IPCs in a sterile medium suitable for tissue culture; and

contacting the IPCs in vitro with an amount of immunostimulatory nucleic acid effective to support the growth of the IPCs in the absence of interleukin 3 (IL-3).

144-200. -200. (canceled)

201. An isolated nucleic acid having a sequence selected from the group consisting of:

202. A pharmaceutical composition comprising

an isolated nucleic acid having a sequence selected from the group consisting of:

203. The pharmaceutical composition of claim 202, further comprising IFN-α

.