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WO-2026096393-A1 - LIPID ANTIBODY OLIGONUCLEOTIDE CONJUGATES COMPOSITIONS AND USES THEREOF

WO2026096393A1WO 2026096393 A1WO2026096393 A1WO 2026096393A1WO-2026096393-A1

Abstract

Disclosed herein are compositions and pharmaceutical formulations that comprise a binding moiety conjugated to a polynucleic acid molecule linked to a lipophilic moiety. Also described herein include methods for treating a disease or disorder which utilize a composition or a pharmaceutical formulation comprising a binding moiety conjugated to a polynucleic acid molecule linked to a lipophilic moiety.

Inventors

  • DOPPALAPUDI, VENKATA RAMANA
  • COCHRAN, Michael Caramian
  • NALLAGATLA, Subbarao
  • ALBIN, Tyler
  • MARKS, Isaac
  • GOEL, VARUN
  • HARTMANN, Marc Andrew

Assignees

  • Atrium Therapeutics, Inc.

Dates

Publication Date
20260507
Application Date
20251027
Priority Date
20241028

Claims (20)

  1. 1. A polynucleotide conjugate comprising a binding moiety conjugated to a polynucleotide molecule, wherein the polynucleotide conjugate further comprises a lipophilic moiety.
  2. 2. The polynucleotide conjugate of claim 1, wherein the lipophilic moiety is a linear or branched alkyl group.
  3. 3. The polynucleotide conjugate of claim 2, wherein the linear alkyl group is selected from the group consisting of C6, C8, CIO, C12, C14, C16, C18, C20, C22, C24 and C26 hydrocarbon chain.
  4. 4. The polynucleotide conjugate of claim 2 or 3, wherein the linear alkyl group is a C16 or C22 hydrocarbon chain.
  5. 5. The polynucleotide conjugate of any one of claims 1-4, wherein the lipophilic moiety is conjugated to a nucleotide of the polynucleotide molecule.
  6. 6. The polynucleotide conjugate of any one of claims 1-5, wherein the lipophilic moiety is conjugated to a sugar moiety of the nucleotide of the polynucleotide molecule at the 2’- or 3’ - carbon or a modification made thereof.
  7. 7. The polynucleotide conjugate of any one of claims 1-6, wherein the polynucleotide molecule is a single-stranded or a double-stranded polynucleotide.
  8. 8. The polynucleotide conjugate of claim 7, wherein the double-stranded polynucleotide is an siRNA comprising a guide strand and a passenger strand.
  9. 9. The polynucleotide conjugate of claim 7 or 8, wherein the double-stranded polynucleotide comprises a passenger strand comprising a PMO molecule and a guide strand comprising an RNA molecule, forming a heteroduplex structure.
  10. 10. The polynucleotide conjugate of claim 8 or 9, wherein the lipophilic moiety is conjugated to the passenger strand.
  11. 11. The polynucleotide conjugate of any one of claims 8-10, wherein the lipophilic moiety is conjugated to a nucleotide of the passenger strand at one of the positions 2-8 from the 5’ end.
  12. 12. The polynucleotide conjugate of any one of claims 8-11, wherein the lipophilic moiety is conjugated to a nucleotide of the passenger strand at position 2, 3, or 6 from the 5’ end.
  13. 13. The polynucleotide conjugate of any one of claims 8-12, wherein the lipophilic moiety is conjugated to the guide strand. Attorney Docket No. 45532-790.601
  14. 14. The polynucleotide conjugate of any one of claims 8-13, wherein the lipophilic moiety is conjugated to a nucleotide of the guide strand at one of the positions 16-21 from the 5’ end.
  15. 15. The polynucleotide conjugate of any one of claims 1-14, wherein the lipophilic moiety is conjugated to the nucleotide via a first linker.
  16. 16. The polynucleotide conjugate of claim 15, wherein the first linker is selected from the compound of Formula (A) or Formula (B): Formula (A) wherein n is 1-20; and x is 1-30; or Formula (B) wherein n is 1-10; and x is 1-30.
  17. 17. The polynucleotide conjugate of claim 15 or 16, wherein the first linker is selected from the compounds listed in Table 1 and Table 2.
  18. 18. The polynucleotide conjugate of any one of claims 1-17, wherein the lipophilic moiety is further modified with a triazole (tz), an oleyl, a carboxylic acid, or a combination thereof.
  19. 19. The polynucleotide conjugate of any one of claims 1-18, wherein the lipophilic moiety further modified with tzC14, tzC16, tzC18, tzC20, tzC18-oleyl, or 2’-O-C16.
  20. 20. The polynucleotide conjugate of any one of claims 1-19, wherein the lipophilic moiety is further modified with a triazole (tz) by click chemistry.

Description

Attomey Docket No. 45532-790.601 LIPID ANTIBODY OLIGONUCLEOTIDE CONJUGATES COMPOSITIONS AND USES THEREOF CROSS REFERENCE [0001] This application claims the benefit of U.S. Provisional Application No. 63/712,997 filed October 28, 2024, which is incorporated herein by reference in its entirety. BACKGROUND OF THE DISCLOSURE [0002] Gene suppression by RNA-induced gene silencing provides several levels of control: transcription inactivation, small interfering RNA (siRNA)-induced mRNA degradation, and siRNA-induced transcriptional attenuation. In some instances, RNA interference (RNAi) provides long lasting effect over multiple cell divisions. As such, RNAi represents a viable method useful for drug target validation, gene function analysis, pathway analysis, and disease therapeutics. Although the in vivo delivery of RNAi therapeutics in the liver has been successful, the delivery of RNAi agent to other tissues beside liver remains difficult. Therefore, there is a need for new methods for efficient delivery of siRNA in tissues other than the liver. SUMMARY OF THE DISCLOSURE [0003] Disclosed herein is a polynucleotide conjugate comprising a binding moiety conjugated to a polynucleotide molecule. In some embodiments, the polynucleotide conjugate further comprises a lipophilic moiety. In some embodiments, the lipophilic moiety is a linear or branched alkyl group. In some embodiments, the linear alkyl group is selected from the group consisting of C6, C8, CIO, C12, C14, C16, C18, C20, C22, C24 and C26 hydrocarbon chain. In some embodiments, the linear alkyl group is a C16 or C22 hydrocarbon chain. In some embodiments, the lipophilic moiety is conjugated to a nucleotide of the polynucleotide molecule. In some embodiments, the lipophilic moiety is conjugated to a sugar moiety of the nucleotide of the polynucleotide molecule at the 2’- or 3’ - carbon or a modification made thereof. In some embodiments, the polynucleotide molecule is a single-stranded or doublestranded polynucleotide. In some embodiments, the double- stranded polynucleotide is an siRNA comprising a guide strand and a passenger strand. In some embodiments, the double-stranded polynucleotide comprises a passenger strand comprising a PMO molecule and a guide strand comprising an RNA molecule, forming a heteroduplex structure. In some embodiments, the lipophilic moiety is conjugated to the passenger strand. In some embodiments, the lipophilic moiety is conjugated to a nucleotide of the passenger strand at one of the positions 2-8 from the 5’ end. In some embodiments, the lipophilic moiety is conjugated to a nucleotide of the Attorney Docket No. 45532-790.601 passenger strand at position 2, 3, or 6 from the 5’ end. In some embodiments, the lipophilic moiety is conjugated to the guide strand. In some embodiments, 16-21 from the 5’ end. In some embodiments, the lipophilic moiety is conjugated to the nucleotide via a first linker. In some embodiments, the first linker is selected from the compound of Formula (A) or Formula (B): Formula (A) wherein n is 1-20; and x is 1-30; or Formula (B) wherein n is 1-10; and x is 1-30. [0004] In some embodiments, the first linker is selected from the compounds listed in Table 1 and Table 2. In some embodiments, the lipophilic moiety is further modified with a triazole (tz), an oleyl, a carboxylic acid, or a combination thereof. In some embodiments, the lipophilic moiety further modified with tzC14, tzC16, tzC18, tzC20, tzC18-oleyl, or 2’-O-C16. In some embodiments, the lipophilic moiety is further modified with a triazole (tz) by click chemistry. In some embodiments, the polynucleotide molecule comprises a blunt end, an unmatched end or an overhang. In some embodiments, the polynucleotide molecule comprises a blunt end, an unmatched end or an overhang at 5’ terminus, 3’ terminus, or both at the guide strand. In some embodiments, the overhang is stable or degradable by a nuclease. In some embodiments, the lipophilic moiety is conjugated to a second linker coupling the binding moiety to the polynucleotide molecule. In some embodiments, the second linker is a cleavable linker or a non- cleavable linker. In some embodiments, the second linker is a bond, C1-C30 alkyl group, a homobifunctional linker or a heterobifunctional linker, optionally conjugated to a C1-C6 alkyl group. In some embodiments, the second linker is a Bismal linker, SMCC linker, MBS linker, C16 linker, or C22 linker. In some embodiments, the lipophilic moiety is conjugated to the Attomey Docket No. 45532-790.601 binding moiety. In some embodiments, the binding moiety is selected from the group consisting of peptides, toxins, sugars, carbohydrates, and polymers. In some embodiments, the binding moiety is selected from the group consisting of hormones, steroids, phospholipids, di -and triacylglycerols, fatty acids, hydrocarbons, enzyme substrates, biotin, digoxigenin, and polysaccharides. In some embodiments, the peptide is a bicyclic peptide or a tricyclic pept