Lipid nanoparticle compositions for delivering circular polynucleotides
Inventors
Horhota, Allen T. • Yang, JungHoon • KAUFFMAN, Kevin J. • Barnes, Thomas • Wesselhoeft, Robert Alexander • Becker, Amy M. • Motz, Gregory
Assignees
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Publication Number
US-12077485-B2
Publication Date
2024-09-03
Expiration Date
Abstract
Disclosed herein are novel lipids that can be used in combination with other lipid components, such as helper lipids, structural lipids, and cholesterols, to form lipid nanoparticles for delivery of therapeutic agents, such as nucleic acids (e.g., circular polynucleotides), both in vitro and in vivo.
Core Innovation
The invention relates to ionizable lipids represented by Formula (13*) and Formula (13), or pharmaceutically acceptable salts thereof. The structures are defined by substituent parameters including n, R_a, R_b, R1, and R2, together with the framework (CH2)qC(O)O(CH2)rCH(R8)(R9). For Formula (13*), n is an integer from 2 to 7, R_a is hydrogen, R_b is hydrogen or C1-C6 alkyl, q is an integer from 0 to 12, and r is 0; for Formula (13), n is 2, 3, or 4, q is 3, 4, 5, or 6, and r is 0.
In the defined scaffolds, R8 is H or R10, with one R8 being hydrogen, and R9 and R10 are independently unsubstituted linear C1-C12 alkyl or unsubstituted linear C2-C12 alkenyl for Formula (13*) and unsubstituted linear C2-C12 alkyl for Formula (13). The disclosure includes specific chemical embodiments and formula variants that vary substituent relationships and tail-chain architecture. The described lipids are further positioned for use in transfer vehicles or lipid nanoparticle formulations with helper lipids, cholesterol, and PEG-modified lipids.
The disclosure also describes pharmaceutical compositions and lipid nanoparticle transfer vehicles containing the ionizable lipids together with RNA polynucleotides, including linear RNA polynucleotide and circular RNA (circRNA). The circRNA embodiments are configured with translation initiation element, UTR, IRES, and enhanced exon elements, and are described in the context of target payload protein expression. The lipid nanoparticle context also includes structural lipid-mediated uptake, endosomal release, and formulation features associated with aggregation control and particle properties.
Claims Coverage
The consolidated claim coverage includes two independent formula-based ionizable-lipid claims, one for Formula (13*) and one for Formula (13), together with dependent claims that refine substituent ranges and extend to pharmaceutical compositions. Overall, the claims center on the structural definition of the ionizable lipids and selected formulation combinations with RNA polynucleotides and lipid nanoparticle components.
Ionizable lipid defined by Formula (13*)
An ionizable lipid represented by Formula (13*) or a pharmaceutically acceptable salt thereof, wherein n is an integer from 2 to 7, R_a is hydrogen, R_b is hydrogen or C1-C6 alkyl, and R1 and R2 are each independently (CH2)qC(O)O(CH2)rCH(R8)(R9), with q an integer from 0 to 12 and r equal to 0, where R8 is H or R10 with one R8 being hydrogen, and R9 and R10 are independently unsubstituted linear C1-C12 alkyl or unsubstituted linear C2-C12 alkenyl.
Ionizable lipid defined by Formula (13)
An ionizable lipid represented by Formula (13) or a pharmaceutically acceptable salt thereof, wherein n is 2, 3, or 4, R_a is hydrogen, and R1 and R2 are each independently (CH2)qC(O)O(CH2)rCH(R8)(R9), with q 3, 4, 5, or 6, r 0, R8 H or R10 with one R8 being hydrogen, and R9 and R10 each independently unsubstituted linear C2-C12 alkyl.
Pharmaceutical composition with linear RNA polynucleotide
A pharmaceutical composition in which the RNA polynucleotide is a linear RNA polynucleotide.
Pharmaceutical composition including helper lipid, cholesterol, and PEG-lipid
A pharmaceutical composition further includes a helper lipid (DOPE or DSPC), cholesterol, and a PEG-lipid (DSPE-PEG(2000) or DMG-PEG(2000)).
Circular RNA lipid nanoparticle transfer vehicle
A lipid nanoparticle transfer vehicle containing the ionizable lipid and circular RNA configured to express a target payload protein.
The claims collectively cover ionizable lipids defined by Formula (13*) and Formula (13) with constrained values for n, q, r, R_a, R_b, and the R8/R9/R10 substituent relationships. Dependent coverage extends to pharmaceutical compositions and lipid nanoparticle transfer vehicles containing RNA polynucleotides, including linear RNA polynucleotide and circular RNA, together with helper lipid, cholesterol, and PEG-lipid components.
Stated Advantages
Enhanced uptake into immune cells.
Structural lipid-mediated C1q binding.
Endosomal release.
APOE/LDLR-dependent or APOE/LDLR-independent uptake.
Reduced linear RNA.
Low dsRNA/protein contaminants.
Provides circular RNA with comparisons favoring functional half-life and expression duration relative to linear RNA.
Improves stability of circular RNA polynucleotides.
Reduces immune activation.
Documented Applications
Pharmaceutical compositions for delivering circular RNA in lipid nanoparticles to express a target payload protein, including CARs, cytokines, or immunomodulators.
Methods of treating or preventing disease by administering lipid nanoparticle compositions that encapsulate circular RNA.
In vivo evaluation of circRNA-loaded lipid nanoparticles after IV, IM, intraarterial, intratumoral, and inhalation administration.
In vitro evaluation including T-cell targeting with antibody-conjugated lipid nanoparticles and downstream expression outcomes such as CAR expression and cytotoxicity.
Tumor delivery evaluation and tumor growth effects using circRNA-loaded lipid nanoparticles.
B-cell depletion evaluation as a downstream biological outcome described in examples.
Delivery of RNA polynucleotides, including circular RNA polynucleotide and linear RNA polynucleotide, using pharmaceutical compositions including an ionizable lipid and transfer vehicle/nanoparticle or lipid nanoparticle components.
Delivery of immune-relevant payloads such as cytokines, transcription factors, immune checkpoint inhibitors, CARs, and TCR chain payloads using RNA expression-sequence elements including IRES and ribosomal skipping/protease sites.
Therapeutic use of engineered RNA constructs to express therapeutic proteins, cytokines, interferons, and immune-regulatory payloads, including CAR and TCR-related payload concepts.
Pharmaceutical compositions and transfer vehicles that include an RNA polynucleotide with ionizable lipid and optionally helper lipid, cholesterol, and PEG-lipids.
Immune cell delivery involving binding to C1q, either by an immune-cell delivery potentiating lipid binding to C1q or by promoting transfer-vehicle binding to C1q for immune cell delivery.
Targeting and/or immune-cell-associated formulations using optional targeting moieties and immune-cell antigen selection including C1qR and macrophage antigens such as mannose receptor (CD206) and C1q.
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