Lipid nanoparticle formulations and compositions
Inventors
Karmali, Priya Prakash • Tanis, Steven • Bao, Yanjie
Assignees
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Publication Number
US-12311033-B2
Publication Date
2025-05-27
Expiration Date
Abstract
Disclosed are compositions of lipid nanoparticles (LNP) comprising an ionizable cationic lipid, a phospholipid, a sterol, and a PEG-lipid (non-functionalized and optionally functionalized). The functionalized PEG-lipid can be conjugated with a binding moiety to create a targeted LNP (tLNP). The disclosed tLNP preferentially deliver a nucleic acid molecule or other negatively charged payload to cells expressing a cell surface antigen recognized by the binding moiety of the tLNP, and are better tolerated, as compared to LNPs and tLNPs comprising ionizable cationic lipids found in marketed pharmaceuticals comprising LNPs.
Core Innovation
The disclosure defines targeted lipid nanoparticle compositions that include an ionizable cationic lipid, a phospholipid, a sterol, and PEG-lipids. The PEG-lipids include functionalized PEG-lipids prepared for conjugating binding moieties, together with non-functionalized PEG-lipids, and the targeting moiety is configured to direct preferential delivery of nucleic acids and negatively charged payloads to cells expressing a corresponding antigen.
The disclosed tLNPs are described as providing improved detargeting and tolerability compared with prior commercial LNPs. The disclosure also reports a branched ionizable cationic lipid class, including CICL1 and CICL-IE/CICL250.4, and characterizes conical lipid nanoparticles associated with improved endosomolytic activity and payload release.
The document further reports targeted lipid nanoparticle characterization and optimization, including hydrodynamic size, polydispersity index, encapsulation efficiency, binder density, N/P ratio, ionizable cationic lipid content, PEG-lipid anchor carbon length or scaffold, and functional versus non-functional PEG combinations. It also includes antibody decoration, PEG anchor length/scaffold S1–S4, PEG molecular weight ranges, conjugation concepts, and extensive context on nucleic acid payloads, binding moieties, delivery, toxicity, and biodistribution.
Claims Coverage
The provided claim set includes independent coverage for LNP compositions defined by molar percentages of an ionizable cationic lipid, PEG-lipid, phospholipid, and sterol. Across the claims, two core inventive features are emphasized: the structured lipid-composition framework and the targeted payload or immune-cell context using functionalized PEG-lipid conjugation.
LNP lipid composition defined by ionizable cationic lipid, PEG-lipid, phospholipid, and sterol mol %
A lipid nanoparticle comprising about 35 to about 65 mol % an ionizable cationic lipid; about 0.5 to about 3 mol % PEG-lipid comprising functionalized PEG-lipid and non-functionalized PEG-lipid; about 7 to about 13 mol % a phospholipid; and about 27 to about 50 mol % a sterol.
Targeted mRNA payload with covalently attached binding moiety
The lipid nanoparticle includes an mRNA payload encoding a chimeric antigen receptor and a binding moiety comprising an antibody or an antigen-binding fragment specific for human CD5, human CD8, or human CD2 covalently attached to the functionalized PEG-lipid via a lysine or cysteine residue.
Functionalized PEG-lipid maleimide moiety
The PEG moiety in the functionalized PEG-lipid includes a terminal maleimide moiety.
Claim coverage centers on an LNP composition defined by quantified molar ranges for an ionizable cationic lipid, PEG-lipid, phospholipid, and sterol, with dependent coverage extending to functionalized PEG-lipid conjugation, a terminal maleimide PEG moiety, and a targeted CAR-encoding payload in a CAR-T context.
Stated Advantages
Improved T cell transfection while reducing liver uptake through formulation changes.
Minimizing liver expression while supporting performance through optimization of binder density, N/P ratio, and ionizable cationic lipid content.
Antibody decoration alters delivery locus to favor targeted delivery.
Improved detargeting and tolerability versus prior commercial LNPs.
Improved endosomolytic activity and payload release associated with conical LNP formation by the branched ionizable cationic lipid class.
CICL1 shows greater tolerance and clears faster than ALC-0315, supported by LC-MS/MS lipid biodistribution/biodegradability results.
Documented Applications
In vivo mouse transfection reporting via splenic T cell mCherry expression to demonstrate targeted delivery performance of tLNPs.
Tumor-model delivery comparing CD5 versus CD8 targeting, with reported CAR expression and tumor burden reduction.
Tolerability assessment in rats and non-human primates for the tLNPs.
CRISPR delivery using SpCas9 and sgRNA with described effects of dosing and redosing.
Delivery to CD117+ HSCs.
Extension of targeting to other T-cell antigens including CD2/CD4/CD8.
Dual conjugation using azide/DBCO click to attach CD5 antibody plus CD47 peptide while preserving LNP properties.
The disclosure connects PEG-lipid functionality to targeting (tLNP) and includes context on nucleic acid payloads including mRNA and other nucleic acids (DNA/siRNA/miRNA/ASO).
An LNP application includes an mRNA payload encoding a chimeric antigen receptor and a binding moiety comprising an antibody or antigen-binding fragment specific for human CD5, human CD8, or human CD2, covalently attached to the functionalized PEG-lipid via a lysine or cysteine residue.
A dependent context characterizes a reprogrammed immune cell as a CAR-T cell.
Example study frameworks using CICL1-based tLNPs are described, including physicochemical characterization and in vivo/in vitro evaluation [procedural detail omitted for safety].
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