Constrained lipids and methods of use thereof
Inventors
Scully, Stephen • Jayaraman, Muthusamy • Sankaran, Ganapathy Subramanian
Assignees
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Publication Number
US-12215068-B2
Publication Date
2025-02-04
Expiration Date
Abstract
The present disclosure details various lipids, compositions, and/or methods of optimized systems and delivery vehicles for the delivery of nucleic acid sequences, polypeptides or peptides for use in vaccinating against infectious agents.
Core Innovation
The invention relates to compounds of Formula IC and pharmaceutically acceptable salts thereof, defined by a highly specified substitution pattern across linker structures, substituent groups, heteroatom-containing linkages, and bridged ring elements. The scaffold includes selections for A, L1 and L2, Q1 and Q2, W1 and W2, X1 and X2, Y1 and Y2, Z1 and Z2, R10, R11, and related R1-R12 substituent options, with explicit integer constraints for m, n, and p and options for heterocyclo formation when selected substituents are taken together with the nitrogen atom.
The structural definitions include carbonyl-, ester-, and amidate-related linkers, optionally substituted branched alkyl or bond connectivity, and optionally substituted C5-C12 bridged cycloalkylenyl at Z1 with Z2 as -(CH2)p-. The substitution pattern also defines R11 as C1-C20 branched alkyl in which one or more methylene linkages are optionally and independently replaced with -O-, -CH=CH-, or -CH≡CH- as stated in the inputs.
The disclosure also describes lipid nanoparticle compositions in which the compound of Formula IC functions as an ionizable lipid. In these compositions, the LNP includes the ionizable lipid and, in the described refinements, the coding RNA is mRNA.
Claims Coverage
The consolidated claim coverage identifies one independent claim directed to a compound of Formula IC (or a pharmaceutically acceptable salt thereof) with a tightly constrained variable substitution pattern. The inventive features cover the scaffold definition and, in dependent refinements, extend to lipid nanoparticle compositions including the ionizable lipid and coding RNA specified as mRNA.
Formula IC compound with constrained substitution pattern
A compound of Formula IC or a pharmaceutically acceptable salt thereof, with A, L1, R1-R8, Q1, W1, R12a, X1, Y1, Z1, R10, Q2, W2, R12b, X2, Y2, Z2, and R11 defined by the stated group selections and constraints, including optional heterocyclo formation and explicit integer ranges for m, n, and p.
Linker and carbonyl-containing W1/W2 selections
W1 and W2 are selected from carbonyl-, ester-, and amidate-related linkages, with Q1 and Q2 as C1-C20 alkylenyl, X1 and X2 as optionally substituted branched C1-C15 alkylenyl or a bond, and Y1 and Y2 as -(CH2)m- / -(CH2)n- or heteroatom-containing options where stated.
Bridged cycloalkylenyl and branched alkyl constraints
Z1 is optionally substituted C5-C12 bridged cycloalkylenyl, Z2 is -(CH2)p- with p being 0 or 1, and R11 is C1-C20 branched alkyl in which one or more methylene linkages are optionally and independently replaced with -O-, -CH=CH-, or -CH≡CH- as stated in the inputs.
Lipid nanoparticle including the ionizable lipid
A lipid nanoparticle (LNP) that includes an ionizable lipid defined by the compound of Formula IC.
LNP coding RNA specified as mRNA
The lipid nanoparticle (LNP) uses a coding RNA that is mRNA.
The claim set centers on a Formula IC compound defined by multi-variable structural constraints across linkers, heteroatom-containing segments, bridged ring elements, and branched alkyl substituents, and extends to LNP compositions containing the ionizable lipid with mRNA as the coding RNA.
Stated Advantages
Reduces aggregation.
Alters clearance from circulation.
Improves mucus traversal.
Alters immune response.
Alters membrane fluidity.
Improves stability.
Elicits immune response.
Documented Applications
Lipid nanoparticle formulations for nucleic acid delivery using the defined ionizable lipid.
Vaccine formulations comprising a polynucleotide encoding a protein of interest and a delivery vehicle containing the disclosed ionizable compounds.
Delivery of nucleic acids to cells, including immune cells such as CD8+ T cells, T regulatory (Treg) cells, B cells, macrophages, dendritic cells, and liver immune cells.
Therapeutic treatment of protein-deficiency disease using an LNP formulation where mRNA encodes a functional protein.
Therapeutic treatment using an LNP formulation where siRNA targets an overexpressed polypeptide.
Use of pharmaceutical compositions containing an LNP with a pharmaceutically acceptable carrier for optional intravenous or intramuscular administration.
Method of vaccinating against infectious agents.
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