Lipid nanoparticles for delivery of nucleic acids and methods of use thereof
Inventors
Drummond, Daryl C. • Kirpotin, Dmitri B. • Hayes, Mark E. • Koshkaryev, Alexander • Fulton, Ross B.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12331264-B2
Publication Date
2025-06-17
Expiration Date
Abstract
The present disclosure provides for improved compositions of ionizable lipid nanoparticles for the delivery of therapeutic nucleic acids to cells. Cationic ionizable lipids are engineered with improved stability to oxidative degradation while in storage, while retaining high transfection activity or potency in cells. These lipids are designed to be biodegradable, thus improving the tolerability of nanoparticles formed with them in vivo. In addition, targeting of these nanoparticles in a highly specific manner to dendritic cells is provided for through inclusion of antibody conjugates directed against cell surface receptors.
Core Innovation
The invention relates to improved ionizable cationic lipid nanoparticles for nucleic acid delivery, and to lipid nanoparticle and particle compositions comprising an ionizable cationic lipid and an anionic phospholipid. The disclosed lipid structures include engineered polyene or polyunsaturated hydrocarbon tails with cis-oriented olefin double bonds and defined separation by methylene groups or unsaturated linear ethylene, n-propylene, or n-butylene alkyl chains, together with dialkyl amino alkyl or dialkyl aminoalkyl headgroup attachment.
The disclosure further describes branched ionizable lipid embodiments defined by structural formulas including Formula VIII, with substituents such as Z1 and Z2 as ester or ether linkages and additional variables including d, e, f, and related substituent relationships. It also includes anionic phospholipids defined by Formula V and Formula V-A, PEG-containing and/or alkylene glycol-containing lipids defined by Formula VII, and named examples including ALC-0315 and SM-102, with phosphatidylserine, phosphatidylglycerol, N-glutaryl-PE, and N-succinyl-PE among the listed phospholipid classes.
The document also provides exemplar ionizable cationic lipids and bioreducible cationic lipids, including structures having disulfide linkages, and describes LNP compositions that encapsulate nucleic acids, including siRNA, mRNA, and DNA. Comparative data and characterization are described in relation to oxidation byproducts and oxidative degradation product limits versus reference formulations, while maintaining transfection potency, biodegradability, and bioreducibility in the disclosed embodiments.
Claims Coverage
The independent claims center on ionizable cationic lipid compounds defined by R22 hydrocarbon lipid tail geometry and dialkyl amino alkyl or dialkyl aminoalkyl headgroup attachment. Across the claims, the inventive features focus on linear polyunsaturated C16-C18 tails with cis-oriented olefin double bonds, specified separation by unsaturated linear ethylene, n-propylene, or n-butylene chains or by at least two methylene groups, and selected headgroup attachment options.
Linear polyunsaturated cis-olefin tail with defined separation
Each R22 is independently a linear polyunsaturated C16-C18 hydrocarbon lipid tail consisting of saturated alkyl groups on both ends of a pair of cis-oriented olefin double bonds separated by an unsaturated linear ethylene, n-propylene or n-butylene alkyl chain between the olefins within each R22 hydrocarbon chain.
Dialkyl amino alkyl headgroup attachment selection
Attachment to a dialkyl amino alkyl group selected from the group consisting of dimethylaminoethyl, diethylaminoethyl, and dimethylaminopropyl.
Identical R22 tails with methylene separation
Each R22 is an identical linear polyunsaturated C16-C18 hydrocarbon lipid tail consisting of saturated alkyl groups on both ends of a pair of cis-oriented olefin double bonds separated by at least two methylene groups between the two olefin double bonds within each R22 hydrocarbon chain.
Identical R22 tails with n-butylene separation
Each R22 is an identical, linear polyunsaturated C16-C18 hydrocarbon lipid tail consisting of saturated alkyl groups on both ends of a pair of cis-oriented olefin double bonds separated by an unsaturated linear n-butylene alkyl chain between the olefins within each R22 hydrocarbon chain.
Dialkyl aminoalkyl attachment
Indicates attachment to a dialkyl aminoalkyl group.
Dialkyl amino alkyl headgroup selection
Attachment to a dialkyl amino alkyl group selected from the group consisting of a dimethylaminoalkyl, diethylaminoalkyl, dialkylaminoethyl, or dialkylaminopropyl group.
The independent claims define ionizable cationic lipid compounds primarily by the R22 tail structure, including cis-oriented olefin double bonds in linear polyunsaturated C16-C18 hydrocarbon lipid tails with defined separation, and by attachment to dialkyl amino alkyl or dialkyl aminoalkyl groups selected from listed options. Dependent constraints further narrow tail identity, symmetry, and separation geometry.
Stated Advantages
Surprisingly enhances targeting of encapsulated nucleic acids by adding phosphatidyl-L-serine below 20 mol%.
Improved dendritic-cell targeting and dendritic-cell transfection efficiency is described for the LNP formulations.
Immunogenicity effects are described as influenced by PEG-lipid inclusion.
Oxidative degradation behavior and lipid ester oxidative mechanisms are analyzed to motivate more oxidation-resistant lipid structures.
Increased oxidative stability during storage.
Reduced oxidation byproducts versus reference formulations.
Maintaining transfection potency and biodegradability.
Unexpected inclusion of anionic phospholipids with condensed nucleic acids.
Documented Applications
Targeting of encapsulated nucleic acids using lipid nanoparticle formulations including an ionizable cationic lipid, sterol-containing lipid, phosphatidylserine, and PEG-lipid.
LNP vaccine compositions for targeting dendritic cells and achieving dendritic-cell transfection.
LNPs containing lipids and nucleic acids.
An LNP ionizable lipid having Formula (IV).
Lipid nanoparticle and particle compositions.
Encapsulation of siRNA, mRNA, and DNA.
Interested in licensing this patent?