Method for identifying biologically active oligonucleotides capable of modulating the immune system
Inventors
Zargari, Arezou • Kouznetzov, Nicolai • Admyre, Charlotte • Von Stein, Petra • Von Stein, Oliver
Assignees
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Publication Number
US-9157919-B2
Publication Date
2015-10-13
Expiration Date
Abstract
The present invention relates to methods of identifying oligonucleotides capable of modulating the immune system in a mammalian subject, comprising analysis of which tertiary structural type said oligonucleotide adopts, in phosphate-buffered saline solution. Further, the invention provides oligonucleotides identifiable by the methods of the invention and to their use in methods of treating diseases, such as inflammatory diseases, autoimmune diseases, infectious diseases, neurodegenerative diseases and cancer.
Core Innovation
The invention relates to identifying immunomodulatory oligonucleotides by analyzing which tertiary structure type an oligonucleotide adopts in phosphate-buffered saline (PBS) solution. Functional effects are linked to specific tertiary-structure compositions independently of primary sequence, using circular dichroism (CD) spectroscopy for identifying the adopted tertiary structure type.
Tertiary-structure compositions are defined so that oligonucleotides forming ≥40% telomeric G-quadruplex tetramer in PBS preferentially induce interferon cytokines, including interferon-α, interferon-β, and interferon-γ. In contrast, oligonucleotides forming ≥45% non-G-quadruplex dimer preferentially induce IL-6 and/or IL-10, with non-G-quadruplex dimer types including Fragile X G-quadruplex dimer and G-quadruplex dimer forms 1 and 2.
The document describes reference oligonucleotides for CD fitting and provides active and non-active oligonucleotides, including tables listing oligonucleotides and cytokine induction data. The tertiary-structure types include telomeric G-quadruplex tetramer, G-quadruplex basket monomer, G-quadruplex chair monomer, non-G-quadruplex dimer types, and random coil type.
Based on the identified immunomodulatory oligonucleotides, the document also outlines therapeutic uses for treating inflammatory/autoimmune/infectious/neurodegenerative diseases and cancer using medicaments and pharmaceutical compositions, including combination therapy concepts. The document further provides examples of combination therapy with rituximab (anti-CD20) and glucocorticosteroids.
Claims Coverage
The independent claims cover oligonucleotides identifiable by tertiary structure analysis in PBS, selected oligonucleotide sets, and methods of treating disease by administering such oligonucleotides where cytokine level changes are beneficial. Across the independent claims, inventive features center on PBS tertiary-structure-type identification by CD analysis and on defining specific oligonucleotides from enumerated SEQ ID NO sets for cytokine modulation therapy.
Tertiary structure type identification in PBS for an enumerated oligonucleotide set
An oligonucleotide identifiable by analyzing which tertiary structure type said oligonucleotide adopts in phosphate-buffered saline solution, wherein the oligonucleotide is selected from the group consisting of SEQ ID NOs: 13-16, 68, 70 and 79.
Selected oligonucleotide set for cytokine modulation
An oligonucleotide selected from the group consisting of SEQ ID NOs 13-16.
Selected oligonucleotide set defined by SEQ ID NO enumeration
An oligonucleotide selected from the group consisting of SEQ ID NOs 68, 70, and 79.
Treating disease by administering a selected oligonucleotide to balance cytokines
A method for treating a disease, comprising administering an effective amount of an oligonucleotide selected from the group consisting of SEQ ID NOs: 13-16, 68, 70 and 79, to a subject in need thereof, wherein an increase or balancing the levels of cytokines is beneficial to said disease.
Claim coverage is grounded in the use of enumerated SEQ ID NO oligonucleotides and, for one independent claim, identification via determining the tertiary structure type adopted in PBS. The therapeutic independent claim ties administration of these selected oligonucleotides to increasing or balancing cytokine levels as beneficial for treating disease.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating a disease by administering an effective amount of an immunomodulatory oligonucleotide selected from the enumerated SEQ ID NO sets where cytokine level increase or balancing is beneficial.
The document further specifies diseases/indications including inflammatory bowel disease, meningitis, allergy/atopic eczema/asthma/COPD, infectious and inflammatory diseases, neurodegenerative diseases, multiple sclerosis, various cancers and malignancies, and hepatitis/cirrhosis-related diseases, including combinations.
Combination therapy using immunomodulatory oligonucleotides together with rituximab (anti-CD20) and glucocorticosteroids is outlined.
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