Ligands to enhance cellular uptake of biomolecules

• US 20060183886A1
• Filed: 10/21/2005
• Published: 08/17/2006
• Est. Priority Date: 11/22/1995
• Status: Abandoned Application

• Current Assignee: CELLective Dx Corporation
• Original Assignee: Cell Care Therapeutics
• Inventors: Zhou, Yuanzhong, Tso, Paul O.P., Roby, Clinton, Duff, Robert, Deamond, Scott
• Application Number:
  US11/256,476
• Publication Number:
  US 20060183886A1
• Time in Patent Office: Days
• US Class Current: 530/350
• CPC Class Codes: A61K 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• CPC Class Codes: A61K 47/6425 the peptide or protein in the drug conjugate being a receptor, e.g. CD4, a cell surface antigen, i.e. not a peptide ligand targeting the antigen, or a cell surface determinant, i.e. a part of the surface of a cell
• CPC Class Codes: A61K 47/65 Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: C07H 15/18 Acyclic radicals, substituted by carbocyclic rings
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids

Abstract

The present invention relates to the design and synthesis of homogeneous A-L-P constructs, which contain a hepatic ligand to direct an oligomer or “payload” to a hepatocyte intracellularly via a receptor-mediated, ligand-directed pathway.

Claims

1. A construct comprising a homogeneous conjugate of formula A-L-P, wherein

A represents a hepatic ligand that specifically binds to a hepatic receptor, thereby facilitating the entrance of said conjugate into cells having said receptor;

L represents a bifunctional linker that is covalently linked to A in a regiospecific manner to form A-L;

A-L is covalently linked to P in a regiospecific manner to form A-L-P;

P represents a biologically stable oligomer comprising the nucleotide sequence of SEQ ID NO;

27 or SEQ ID NO;

28, wherein P is released from the conjugate following hydrolysis or reduction of at least one specific biochemical linkage, and contains internucleotide linkages resistant to enzymatic hydrolysis of biodegradation upon release from the conjugate.

2. The construct of claim 1, wherein said oligomer is an oligonucleotide, an oligonucleotide analog or an oligonucleoside.

18. The construct of claim 2, wherein said oligomer comprises deoxyribose methylphosphonate internucleotide linkages.

19. The construct of claim 2, wherein said oligomer comprises deoxyribose phosphorothioate internucleotide linkages.

20. The construct of claim 2, wherein said oligomer comprises phosphodiester linkages.

21. The construct of claim 2, wherein said oligomer comprises a combination of deoxyribose methylphosphonate/phosphorothioate internucleotide linkages.

22. The construct of claim 2, wherein said oligomer comprises a combination of deoxyribose methylphosphonate/phosphodiester internucleotide linkages.

23. The construct of claim 2, wherein said oligomer comprises deoxyribose phosphorothioate/phosphodiester internucleotide linkages.

24. The construct of claim 2, wherein said oligomer comprises 2′

-O-methylribose methylphosphonate internucleotide linkages.

25. The construct of claim 2, wherein said oligomer comprises 2′

-O-methylribose phosphorothioate internucleotide linkages.

26. The construct of claim 2, wherein said oligomer comprises 2′

-O-methylribose phosphodiester internucleotide linkages.

27. The construct of claim 2, wherein said oligomer comprises a combination of 2′

-O-methylribose methylphosphonate/2′

-O-methylribose phosphodiester internucleotide linkages.

28. The construct of claim 2, wherein said oligomer comprises a combination of 2′

-O-methylribose methylphosphonate/2′

-O-methylribose phosphorothionate internucleotide linkages.

29. The construct of claim 2, wherein said oligomer comprises a combination of 2′

-O-methylribose phosphorothioate/2′

-O-methylribose phosphodiester internucleotide linkages.

64. A pharmaceutical composition comprising a construct according to claim 1 and at least one pharmaceutically acceptable excipient or carrier.

72. The construct of claim 1, wherein the A-L moiety of said construct is YEE(ahGalNAc)₃-SMCC.

4-17. -17. (canceled)

30-63. -63. (canceled)

65-69. -69. (canceled)

70. The pharmaceutical composition of claim e 64 wherein the A-L moiety of said construct is YEE(ahGalNAc)₃-SMCC.

71. (canceled)

73. (canceled)