Targeting ligands for therapeutic compounds
Inventors
Rozema, David B. • Wakefield, Darren H. • Blokhin, Andrei V. • Benson, Jonathan D. • Li, Zhen • Pei, Tao • Fleitz, Fred
Assignees
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Publication Number
US-12116573-B2
Publication Date
2024-10-15
Expiration Date
Abstract
Described are novel targeting ligands that may be linked to compounds, such therapeutic compounds, that are useful in directing the compounds to the target in vivo. The targeting ligands disclosed herein can serve to target expression-inhibiting oligomeric compounds, such as RNAi agents, to liver cells to modulate gene expression. The targeting ligands disclosed herein, when conjugated to an expression-inhibiting oligomeric compound, may be used in a variety of applications, including use in therapeutic, diagnostic, target validation, and genomic discovery applications. Compositions including the targeting ligands disclosed herein when linked to expression-inhibiting oligomeric compounds are capable of mediating expression of target nucleic acid sequences in liver cells, such as hepatocytes, which may be useful in the treatment of diseases or conditions that respond to inhibition of gene expression or activity in a cell, tissue, or organism.
Core Innovation
The disclosure relates to targeting ligand structures for conjugation to an expression-inhibiting oligomeric compound designated by Z. The Targeting Moiety is selected from the group consisting of carbohydrates, glycans, haptens, vitamins, folate, biotin, aptamers, peptides, insulin, EGF and transferrin, with examples including GalNAc and related galactose derivatives intended to recognize the asialoglycoprotein receptor.
The described targeting-ligand compositions include structures identified as Formula A and Formula B, Structure 1, Structure 1a through Structure 1d, Structure 4 and 4b/4d, and additional structures 101a through 101d, 102 through 102d, and 103. Each structure includes a targeting moiety and a tether/branch point/linker arrangement, including PEG-based tethers, cleavable moieties, and variable repeat index n, and the attachment can be provided in optional phosphoramidite forms for coupling to the 5′ end of a sense strand using phosphate/phosphonate/phosphorothioate-type linkages.
The disclosure further includes galactose cluster concepts for asialoglycoprotein receptor affinity, with embodiments using up to three or four terminal GalNAc/galactosamine derivatives. The resulting conjugates are stated to deliver RNAi to liver/hepatocytes to modulate gene expression, and the document frames the conjugates as suitable for therapeutic, diagnostic, target-validation, and genomic-discovery applications.
Claims Coverage
The independent claim coverage centers on a targeting ligand defined by selection from a listed group of Targeting Moiety types, with dependent refinements to carbohydrate targeting moieties and to ligands shown by provided structures. Across the provided claim summaries, three inventive features are identified.
Targeting ligand selected from targeting moiety group
A targeting ligand selected from a group consisting of Targeting Moieties comprising carbohydrates, glycans, haptens, vitamins, folate, biotin, aptamers, peptides, insulin, EGF and transferrin.
Carbohydrate targeting moiety
The targeting ligand has a Targeting Moiety where the Targeting Moiety is a carbohydrate.
Selected from provided structures
The targeting ligand is selected from a group of targeting ligands shown by provided structure images.
Overall, the claim coverage is directed to a targeting ligand defined by a selectable Targeting Moiety from a defined list, with dependent limitations specifying a carbohydrate Targeting Moiety and ligands represented by particular provided structures.
Stated Advantages
Provides flexibility and length to the linkage between the targeting ligand and the therapeutic cargo.
Structure 101d is reported to provide markedly higher conjugation efficiency than Structure 102d.
Greater knockdown is stated for 5′-end attachment than for 3′-end attachment in F12 RNAi agents.
Not explicitly described in patent.
Documented Applications
Targets therapeutic cargo using targeting ligands that include tether-linked targeting moieties.
Attaching GalNAc ligands to RNAi oligonucleotides using targeting-ligand phosphoramidite intermediates.
Constructing targeting-ligand-modified RNAi oligonucleotides.
Lp(a) targeting and F12 examples in apo(a) transgenic mice and cynomolgus monkeys.
Therapeutic use via delivery of RNAi to liver/hepatocytes to modulate gene expression.
Diagnostic use.
Target-validation use.
Genomic-discovery use.
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