Integrin targeting ligands and uses thereof
Inventors
Li, Zhen • Carlson, Jeffrey • Nicholas, Anthony • Li, Xiaokai • Shu, Dongxu • Fowler-Watters, Matthew
Assignees
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Publication Number
US-12667619-B2
Publication Date
2026-06-30
Expiration Date
Abstract
Compounds having affinity for integrins, the synthesis of these compounds, and the use of these compounds as ligands to facilitate the delivery of cargo molecules to cells expressing integrins are described. The described integrin targeting ligands have serum stability and affinity for αvβ3 integrin and/or αvβ5 integrin, and are suitable for conjugation to cargo molecules, such as such as oligonucleotide-based therapeutic agents (e.g., RNAi agents), to facilitate delivery of the cargo molecules to cells and tissues, such as tumor cells, that express integrin αvβ3, integrin αvβ5, or both integrin αvβ3 and integrin αvβ5. Compositions that include integrin targeting ligands and methods of use are also described.
Core Innovation
The invention provides an integrin targeting group comprising a scaffold or linker configured to bind a ligand to an RNAi agent, wherein the ligand is an avb3 ligand selected from a specified group of ligands or a pharmaceutically acceptable salt thereof. The disclosure describes multiple chemical structures and variants, including scaffold or linker attachment points, common core architecture, stereochemical marking, and reactive handles for conjugation to cargo molecules, including RNAi agents.
The disclosed structures include azide or N3-labeled structures, protected reactive groups, and internal-linking or attachment of integrin targeting ligands to the RNA sense strand. The integrin-targeting ligands are linked to cargo molecules through defined scaffold or linker attachment points, and the disclosure includes pharmaceutical composition context and administration routes.
The disclosure further describes serum-stable integrin-targeting ligand compounds with affinity for integrins avb3 and/or avb5, and states targeting to integrin-expressing cells and tissues, including tumor cells and clear cell renal carcinoma. The overall framework is presented as a conjugation platform for RNAi cargo and related integrin-targeting ligand precursors bearing reactive groups such as azide.
Claims Coverage
The consolidated claim coverage centers on one independent inventive concept: an integrin targeting group that links an avb3 ligand to an RNAi agent via a scaffold or linker. Dependent claims further add a composition with a pharmaceutically acceptable excipient and in vivo delivery and target gene inhibition in integrin avb3-expressing cells, including a specific EPAS1 (HIF2 alpha) example.
Integrin targeting group with avb3 ligand bound to an RNAi agent
An integrin targeting group comprising a scaffold or linker that binds a ligand to an RNAi agent, wherein the avb3 ligand is selected from specified ligands or a pharmaceutically acceptable salt thereof.
Composition with pharmaceutically acceptable excipient
A composition including the integrin targeting group together with a pharmaceutically acceptable excipient.
In vivo delivery of RNAi to integrin avb3-expressing cells
A method for delivering one or more RNAi agents to a cell expressing integrin avb3 in a subject by administering the composition.
In vivo inhibition of target gene expression in integrin avb3-expressing cells
An in vivo method for inhibiting expression of a target gene in a cell expressing integrin avb3 by administering to a subject an effective amount of the composition.
Target gene EPAS1 (HIF2 alpha)
The method wherein the target gene is EPAS1 (HIF2 alpha).
Overall, the claims are directed to an integrin targeting group that links an avb3 ligand to an RNAi agent, together with compositions and in vivo methods for RNAi delivery and target gene inhibition in integrin avb3-expressing cells.
Stated Advantages
Improved RNAi knockdown is described as ligand-dependent and PEG-dependent in kidney tumor mouse data.
Knockdown improvements are described across multiple examples with comparisons to no-ligand and an RGD-mimetic peptide ligand.
Reduced efficacy in avb3 KO tumors is described, supporting contributions from avb3 and avb5 integrins.
Serum stability.
Affinity for integrins avb3 and/or avb5.
Enables in vivo delivery of RNAi agents to cells expressing integrin avb3 in a subject.
Provides a method for inhibiting expression of a target gene in integrin avb3-expressing cells.
Provides a specific target gene example for inhibition, EPAS1 (HIF2 alpha).
Documented Applications
In vivo kidney tumor mouse studies in which RT-qPCR of normalized human HIF2b1 mRNA is used to measure knockdown after treatment with the disclosed integrin-targeting RNAi constructs across multiple examples.
Applications in delivering RNAi agents to cells expressing integrin avb3 in a subject, as part of in vivo delivery and inhibition of target gene expression.
Inhibiting target gene expression in a cell expressing integrin avb3 by administering a composition comprising the integrin targeting group and a pharmaceutically acceptable excipient, including inhibition of EPAS1 (HIF2 alpha).
Conjugation to cargo molecules including oligonucleotide therapeutics such as RNAi agents for targeted delivery to integrin-expressing cells and tissues.
Targeted delivery to tumor cells, including clear cell renal carcinoma.
In vivo delivery of one or more RNAi agents to a cell or tissue of a subject by administering a composition.
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