Compounds and compositions including phosphorothioated oligodeoxynucleotide, and methods of use thereof

Inventors

Kortylewski, Marcin Tomasz • SWIDERSKI, Piotr Marek • Marcucci, Guido • Zhang, Bin • Kuo, Ya-Huei

Assignees

City of Hope

Abstract

The present disclosure relates to a compound including a nucleic acid sequence conjugated to an anti-microRNA or a microRNA-mimic or a compound including a modified anti-microRNA sequence, compositions of such a compound, and method of treatment of a disease, and method of suppressing microRNA activity by the disclosed compound or composition.

Core Innovation

The invention concerns a compound comprising a phosphorothioated CpG oligodeoxynucleotide (CpG-ODN) conjugated to a nucleic acid sequence as set forth in SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, or SEQ ID NO: 21. The described conjugates use covalent linker architectures that directly connect the phosphorothioated CpG-ODN to the conjugated nucleic acid sequence, and the conjugated nucleic acid sequence is positioned with specified conjugation linkages.

The linkage chemistries include phosphoramidate linkage, phosphorodiamidate linkage, phosphorodithioate linkage, phosphonocarboxylic acid linkage, phosphonocarboxylate linkage, phosphonoacetic acid linkage, phosphonoformic acid linkage, methyl phosphonate linkage, boron phosphonate linkage, and O-methylphosphoroamidite linkage. The linker architectures further include heteroalkylene linker options and cyclo-heteroalkylene branched linkers having 5-substituted thymidine branch points.

The disclosure also describes phosphorothioate linkages and chemically modified nucleotides within the conjugates, together with activated or protected reactive groups such as azide, NHS, and sulfhydryl or derivatives, additional functional moieties, click-chemistry reactive groups, copper-free azide/alkyne systems such as DBCO, PEG, and bisphosphonate conjugation. The described conjugates are framed for systemic administration and for treatment of diseases, with a focus on cancers such as AML and CML and myelodysplastic syndrome, and the nucleic acid component includes anti-microRNA and microRNA-mimic oligonucleotides including anti-miR126, anti-miR155, anti-miR125b, anti-miR146a, anti-miR9, anti-miR142, anti-miR10b, anti-miR17, anti-miR21, and anti-miR92.

Claims Coverage

The provided claim excerpts cover one compound concept with three inventive features: a phosphorothioated CpG-ODN conjugated to specified nucleic acid sequences, specified CpG-ODN linkage chemistries, and sequence-specific embodiments. The excerpts also indicate use for leukemia treatment and optional combination therapy.

The claimed concept is narrowed by specific CpG-ODN linkage chemistries and by fixing the conjugated nucleic acid sequence to at least one of the listed SEQ ID NO embodiments. The excerpts also indicate downstream use for leukemia treatment and optional combination with additional named therapeutic agents.

Stated Advantages

Documented Applications