Oligonucleotides, compositions and methods thereof
Inventors
Zhang, Jason Jingxin • Iwamoto, Naoki • Francis, Christopher J. • Vargeese, Chandra • Butler, David Charles Donnell • Divakaramenon, Sethumadhavan • Lu, Genliang • Marappan, Subramanian
Assignees
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Publication Number
US-12403156-B2
Publication Date
2025-09-02
Expiration Date
Abstract
The present disclosure pertains to the recognition that immune responses mediated by CpG oligonucleotides can be affected by the stereochemistry of modified internucleotidic linkages such as phosphorothioates. In some embodiments, the present disclosure relates to chirally controlled CpG oligonucleotide compositions comprising CpG oligonucleotides comprising multiple modified internucleotidic linkages such as phosphorothioate linkages, wherein the oligonucleotides comprise one or more CpG region motifs having defined stereochemistry patterns of chiral internucleotidic linkages. In some embodiments, CpG oligonucleotides comprising one or more CpG region motifs are capable of agonizing an immune response. In some embodiments, CpG oligonucleotides comprising one or more CpG region motifs are antagonistic. Methods for making and using chirally controlled CpG oligonucleotide compositions are also described. In some embodiments, no immune modulation is desired, and the present disclosure provides methods of identifying chirally controlled oligonucleotide compositions which have decreased immune modulation.
Core Innovation
The disclosure provides a chirally controlled composition comprising a specified oligonucleotide identified as SEQ ID NO: 1 or a salt thereof, with phosphorothioate linkages in defined Sp and Rp configurations. The composition is enriched for the specified oligonucleotide relative to a substantially racemic preparation. The disclosure defines oligonucleotide architectures by sequence, backbone-linkage stereochemistry, sugar modifications, and wing-core or wing-core-wing structural designs.
Defined phosphorothioate linkage stereochemistry, CpG methylation, and sugar modifications modulate TLR9 immunomodulatory activity in sequence-, position-, and species-dependent manners, exhibiting agonism, antagonism, or reduced stimulation. Internucleotidic modifications encompass cleavable phosphorothioate triesters, lipid conjugates, and modifications including 2′-F, 2′-OMe, and 2′-MOE. Additionally, selected chiral patterns provide target-RNA cleavage selectivity and target transcripts containing mutation- or SNP-bearing alleles.
Claims Coverage
The claim set identifies one independent claim directed to a chirally controlled oligonucleotide composition, comprising one inventive feature.
Chirally controlled oligonucleotide composition
The independent claim covers a composition comprising a specified oligonucleotide of SEQ ID NO: 1 or a salt thereof, with phosphorothioate linkages in defined Sp and Rp configurations, wherein the composition is enriched for the specified oligonucleotide relative to a substantially racemic preparation. Dependent claims specify that at least 50% of the oligonucleotides having the specified base sequence are the modified oligonucleotide or a salt thereof, and identify pharmaceutically acceptable and sodium salt forms.
The claim coverage centers on the chirally controlled oligonucleotide composition defined by SEQ ID NO: 1, Sp and Rp phosphorothioate stereochemistry, and stereochemical enrichment relative to a racemic preparation, with dependent claims specifying minimum proportion thresholds and salt forms.
Stated Advantages
The disclosure identifies potential improvements in toxicity, stability, protein binding, pharmacokinetics, and delivery.
Defined phosphorothioate linkage stereochemistry can substantially alter TLR9 agonist or antagonist activity, allowing modulation of immune activity.
The disclosure reports enhanced TLR9 antagonism and reduced TLR9 agonism, including reducing unwanted immune stimulation.
Selected chiral patterns are associated with controlled or improved target-RNA cleavage and selectivity.
Documented Applications
Immune modulation through TLR9 agonist or antagonist activity tuning via CpG motif selection and phosphorothioate stereochemistry, including use as immunostimulatory agents, vaccines, adjuvants, and therapeutic oligonucleotides.
Combination cancer therapies and transcript-splicing therapies.
Targeting RNA transcripts, including transcripts containing mutation- or SNP-bearing alleles.
Evaluation in mouse and human TLR9 agonist and antagonist reporter assays, and in vivo evaluation in an IBS model and a colitis model.
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