Ionizable cationic lipids
Inventors
Drummond, Daryl C. • Kirpotin, Dmitri B. • Hayes, Mark E.
Assignees
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Publication Number
US-12077725-B2
Publication Date
2024-09-03
Expiration Date
Abstract
The present disclosure provides compounds useful as ionizable cationic lipids. The ionizable cationic lipids are useful for preparing lipid nanoparticles for the delivery of therapeutic nucleic acids to cells. Cationic ionizable lipids were engineered with improved stability to oxidative degradation while in storage.
Core Innovation
The invention relates to ionizable cationic lipids and bioreducible cationic lipids for lipid nanoparticle and Stablized Nucleic Acid Lipid Particles delivery of therapeutic nucleic acids. The disclosed compounds are selected from a defined group of named AKG-UO compounds and Compound 17/18/19/23/24/25, and the lipid tails contain at least two C=C olefins with ≤2 methylene spacers, contrasted with one-methylene C=C lipids such as DLin-MC3-DMA and DLin-KC2-DMA.
The structures emphasize a cationic nitrogen center and long unsaturated hydrocarbon chains, and some embodiments include a methylated phosphate head group. The bioreducible character is represented through degradable functional core motifs, including cyclic carbonate/esters and phosphate/ester linkage motifs, with cleavable groups in the presented motifs. The disclosure also includes embodiments that can provide biodegradability and optional targeting ligands, including antibody conjugates targeting dendritic cells.
The patent reports that the stabilized AKG-UO lipid designs substantially reduce oxidation byproducts during storage versus a control LNP and a reference LNP containing DLin-KC2-DMA. Reported improvements include reductions of oxidation byproducts by ≥30% to more than 95%, and the disclosure states that therapeutic nucleic acids including siRNA, mRNA, and DNA can be encapsulated for delivery.
Claims Coverage
The independent claim covers selecting a compound from a specified group consisting of named AKG-UO compounds and several specifically numbered Compound options. Across the supplied claim set, the inventive features are the selected compound identity and dependent narrowing to particular listed members.
Selected ionizable compound from a defined group
A compound selected from the group consisting of AKG-UO-1, AKG-UO-1A, AKG-UO-1B, AKG-UO-2, AKG-UO-4, AKG-UO-4A, AKG-UO-5, AKG-UO-6, AKG-UO-7, AKG-UO-8, AKG-UO-9, AKG-UO-10, Compound 17, Compound 18, Compound 19, Compound 23, Compound 24, and Compound 25.
Specific AKG-UO member selection
The compound of claim 1 is AKG-UO-1A, AKG-UO-1B, or AKG-UO-10.
Specific numbered compound selection
The compound of claim 1 is Compound 23, Compound 24, or Compound 25.
Across the independent claim and its dependent refinements, the inventive scope is determined by selecting one specific ionizable lipid compound from the explicitly enumerated group. Dependent claims narrow this selection to particular named AKG-UO members or specific numbered compounds, defining the protected subject matter by which member of the group is used.
Stated Advantages
Substantial reductions in oxidation byproducts during storage, reported as ≥30% to more than 95% versus a control LNP and versus DLin-KC2-DMA.
Improved oxidative stability for LNP/SNALP delivery of therapeutic nucleic acids.
Enables encapsulation of nucleic acids, including siRNA, mRNA, or DNA.
Prevention of infections such as Mycobacterium tuberculosis.
Targeting of dendritic cells using ligands such as anti-DEC205.
Induction of a CD8+ T-cell response.
Documented Applications
Delivery of therapeutic nucleic acids using lipid nanoparticles and Stablized Nucleic Acid Lipid Particles, including encapsulation of siRNA, mRNA, and DNA.
Vaccine applications and infectious-disease applications, including examples such as Mycobacterium and COVID-19/SARS-CoV-2.
Used in the context of intended vaccine and drug use for infectious diseases.
Vaccine use using LNP-mediated nucleic acid delivery with dendritic-cell targeting.
Prevention of infections such as Mycobacterium tuberculosis.
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