Multivalent delivery of immune modulators by liposomal spherical nucleic acids for prophylactic or therapeutic applications
Inventors
Radovic-Moreno, Aleksandar Filip • Kang, Richard • Nallagatla, Subbarao • Mader, Christopher C. • Gryaznov, Sergei
Assignees
Flashpoint Therapeutics Inc • Northwestern University • Exicure Operating Co
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Publication Number
US-11957788-B2
Publication Date
2024-04-16
Expiration Date
Abstract
Liposomal spherical nucleic acids that function as multivalent immune modulators are provided according to the invention. The liposomal spherical nucleic acids of the invention are useful prophylactic and therapeutic applications as well as research and diagnostic indications.
Core Innovation
The invention relates to liposomal spherical nucleic acids (SNAs) as multivalent immune modulators. The disclosed nanostructure includes a liposomal core having a lipid bilayer and an oligonucleotide shell positioned on the exterior of the liposomal core with an orientation radially outwards.
The nanostructure encapsulates an antigen within the liposomal core and presents immune-stimulatory or immune-suppressive nucleic acids in the external oligonucleotide shell. The oligonucleotide shell comprises at least one CpG-motif containing oligonucleotide and can be enriched for pattern-recognition receptor (PRR) modulating nucleic acids including TLR agonists/antagonists and RIG-I agonists/antagonists.
The CpG-motif containing oligonucleotide is indirectly linked to the liposomal core through a lipid anchor, and antigen can be co-delivered by encapsulation in the core or by conjugation/association with the oligonucleotide shell. The described configurations aim to bridge innate and adaptive immunity or induce tolerance/regulatory effects.
The disclosure further describes immune activation and functional dependence on PRR signaling, including MyD88-dependent and MyD88-independent pathway effects, NF-baB, TNF, and IFN-b1. In the provided tumor-related examples, the constructs are described as reducing tumor burden and producing stronger antigen-specific cellular responses than free oligonucleotide and alum.
Claims Coverage
The independent claim set is centered on a nanostructure comprising an antigen-encapsulating liposomal core with an outward-oriented oligonucleotide shell containing at least one CpG-motif containing oligonucleotide indirectly linked via a lipid anchor. Dependent claims refine the oligonucleotide shell composition and presentation and also include a treatment method for promoting an immune response.
Antigen-encapsulating liposomal core with radially outward oligonucleotide shell
A nanostructure comprising a liposomal core having a lipid bilayer and an oligonucleotide shell oriented radially outwards positioned on the exterior of the liposomal core; wherein an antigen is encapsulated within the liposomal core.
CpG-motif containing oligonucleotide shell
The oligonucleotide shell comprises at least one CpG-motif containing oligonucleotide.
Indirect CpG-motif linkage via lipid anchor
The CpG-motif containing oligonucleotide is indirectly linked to the liposomal core through a lipid anchor.
CpG-motif-containing oligonucleotides with 5′-terminus exposure
CpG-motif containing oligonucleotides in an oligonucleotide shell have their 5′ termini exposed on the nanostructure’s outside surface.
Specific CpG-motif oligonucleotide sequences
The CpG-motif containing oligonucleotide includes or consists of a sequence corresponding to SEQ ID NO: 1 or SEQ ID NO: 21.
Lipid anchor comprising cholesterol
The nanostructure uses a lipid anchor comprising cholesterol.
Oligonucleotide shell size range
The oligonucleotide shell includes 50–300 oligonucleotides.
Administering the nanostructure to promote an immune response
A method for treating a disorder by administering the nanostructure of claim 1 in an effective amount to the subject to promote an immune response.
Overall, the claim coverage is directed to outward-oriented, antigen-encapsulating liposomal spherical-nucleic-acid nanostructures in which CpG-motif containing oligonucleotides are indirectly linked to the core via a lipid anchor, with dependent claims specifying oligonucleotide shell presentation, selected CpG-motif sequences, lipid anchor identity, oligonucleotide shell size, and a treatment method context for promoting an immune response.
Stated Advantages
Reduces tumor burden.
Produces stronger antigen-specific cellular responses compared with free oligonucleotide and alum.
Described as enabling synergistic immune activation when TLR4 and TLR9 agonists are physically associated in one construct.
Can be configured to bridge innate and adaptive immunity or to induce tolerance/regulatory effects.
Documented Applications
Prophylactic and therapeutic applications using liposomal SNAs as multivalent immune modulators.
Treating a disorder by administering the nanostructure in an effective amount to promote an immune response.
Cancer/tumor-related use cases are described, including an E.G7-OVA tumor model and C57BL/6 mice with tumor burden reduction and antigen-specific cellular responses.
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