Alpha-v beta-6 integrin ligands and uses thereof
Inventors
Almeida, Aaron • Li, Zhen • Bush, Erik W. • Pei, Tao • Glebocka, Agnieszka • Nicholas, Anthony • Carlson, Jeffrey • Fowler-Watters, Matthew
Assignees
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Publication Number
US-12173086-B2
Publication Date
2024-12-24
Expiration Date
Abstract
Integrin ligands having serum stability and affinity for αvβ6 integrins are described. Compositions comprising αvβ6 integrin ligands having serum stability and having affinity for αvβ6 integrins and methods of using them are also described.
Core Innovation
The patent discloses engineered, non-naturally occurring peptide-based αvβ6 integrin ligands comprising a defined peptide structure, including the RGDLXaa1Xaa2L-Xaa3Xaa4L-R motif and SEQ ID NO: 96, or a pharmaceutically acceptable salt thereof. The ligands include an optional R1 region in which PEG and/or a linking group is present, and the disclosure further includes amine-terminal capping and defined side-chain features.
The ligands are designed to provide improved serum stability while retaining αvβ6 binding. The disclosure reports serum-stability comparisons relative to the natural αvβ6-binding peptide RGDLATLRQL and describes serum/protease resistance considerations using an amine-terminal cap (Z) and non-standard residues.
The patent further discloses pharmaceutical compositions containing the αvβ6 ligands with pharmaceutically acceptable excipients. The ligand framework supports conjugation to cargo molecules, including PEG/cargo polymer constructs, labeled polymer conjugates, and oligomeric compounds such as RNAi agents, and the document includes targeting evidence and gene-expression inhibition use cases involving αvβ6-expressing epithelial cells and epithelial tumors.
Claims Coverage
The provided claim coverage identifies two related independent claim themes: an αvβ6 integrin ligand with defined peptide positions and optional PEG/linking, and in vivo inhibition of target gene expression using an oligomeric RNAi agent conjugated to the ligand. Across the claims, the inventive features center on a specific peptide architecture, optional R1 PEG/linking, conjugation to cargo, and targeted epithelial cell and epithelial tumor contexts.
Engineered αvβ6 integrin ligand peptide with defined amino-acid positions
An αvβ6 integrin ligand comprising a defined peptide structure corresponding to Formula VIII or SEQ ID NO: 96, with specified residue identities including L-arginine, L-glycine or N-methyl glycine, L-aspartic acid, L-leucine, L-alanine, L-α-amino-butyric acid, L-citrulline, and α-amino-isobutyric acid, or a pharmaceutically acceptable salt thereof.
Optional PEG and/or linking group in the R1 region
R1 is optional and, if present, includes PEG and/or a linking group.
Conjugation of αvβ6 ligand to a cargo molecule
The αvβ6 integrin ligand is conjugated to a cargo molecule selected from small molecules, biologics, nucleic acids or polynucleotides, peptides, aptamers, polymers, proteins, toxins, vitamins, polyethylene glycol, haptens including digoxigenin and biotin, radioactive atoms or molecules, and fluorophores.
Oligomeric cargo as an RNAi agent
The oligomeric compound is an RNAi agent.
In vivo inhibition of target gene expression using ligand-conjugated RNAi
An in vivo method inhibits expression of a target gene in a cell by administering an oligomeric RNAi agent conjugated to the αvβ6 integrin ligand.
Targeting epithelial cells and epithelial tumors
The method uses a cell selected from type I and II alveolar epithelial cell, goblet cell, secretory epithelial cell, ciliated epithelial cell, corneal and conjunctival epithelial cell, dermal epithelial cell, cholangiocyte, enterocyte, ductal epithelial cell, glandular epithelial cell, renal tubule, and epithelial tumors (carcinomas).
The claim coverage centers on an engineered αvβ6 integrin ligand with a defined peptide sequence architecture and optional PEG/linking via an R1 region, together with conjugation to cargo molecules and specifically oligomeric RNAi agents. It further covers in vivo inhibition of target gene expression using ligand-conjugated RNAi directed to selected epithelial cell types and epithelial tumors (carcinomas).
Stated Advantages
Improved serum stability while retaining αvβ6 binding.
Documented Applications
Pharmaceutical compositions containing the αvβ6 ligands.
Binding studies and targeting evidence using cargo/polymer conjugates linked to αvβ6 ligands, including labeled polymer conjugates.
In vivo gene-knockdown by inhibiting expression of a target gene in a cell through administration of an oligomeric RNAi agent conjugated to the αvβ6 integrin ligand, including α-ENaC (SCNN1A) mRNA knockdown in rats.
Targeting of epithelial cell types and epithelial tumors (carcinomas) as part of the in vivo method using αvβ6 ligand–RNAi conjugates.
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