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
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Publication Number
US-10434064-B2
Publication Date
2019-10-08
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 provides a nanostructure comprising a liposomal core having a lipid bilayer. A nucleic acid immune stimulant that stimulates toll like receptors is associated with the lipid bilayer, and oligonucleotides are positioned on the exterior of the liposomal core in the form of an oligonucleotide shell.
The oligonucleotide shell includes CpG-motif containing oligonucleotides, and the CpG-motif containing oligonucleotides are B-class CpG oligonucleotides. The oligonucleotides are indirectly linked to the liposomal core through a linker, and the linker is cholesterol.
All of the oligonucleotides have their 5′-termini exposed to the outside surface of the nanostructure. The document also describes multivalent presentation of nucleic acid immune modulators to immune receptors, including physical co-association of multiple immune modulators in one construct.
Claims Coverage
The document lists one independent claim. The independent claim is directed to a nanostructure architecture combining a liposomal lipid bilayer core with an exterior B-class CpG oligonucleotide shell that is cholesterol-linked and has 5′-termini exposed, with a nucleic acid immune stimulant associated with the lipid bilayer.
Liposomal core with lipid bilayer and nucleic acid immune stimulant associated
A nanostructure comprising a liposomal core having a lipid bilayer, wherein a nucleic acid immune stimulant that stimulates toll like receptors is associated with the lipid bilayer.
Exterior oligonucleotide shell of B-class CpG
Oligonucleotides positioned on the exterior of the liposomal core in the form of an oligonucleotide shell, wherein the oligonucleotides comprise CpG-motif containing oligonucleotides and wherein the CpG-motif containing oligonucleotides are B-class CpG oligonucleotides.
Indirect cholesterol linking with outward 5′ termini
The oligonucleotides are indirectly linked to the liposomal core through a linker, wherein all of the oligonucleotides have their 5′-termini exposed to the outside surface of the nanostructure, and wherein the linker is cholesterol.
Overall, the independent claim coverage centers on the combined liposomal-core association of a toll-like-receptor nucleic acid immune stimulant with an exterior shell of B-class CpG oligonucleotides that are indirectly linked via a cholesterol linker and present 5′-termini externally.
Stated Advantages
Unexpected synergy when multiple immune modulators are physically co-associated in one construct.
Enhanced NF-κB activation when CpG and MPLA are co-delivered in the same SNA.
Elevated TNF and IFN-α upon co-delivery of CpG and MPLA in the same SNA.
Improved antigen-specific cellular responses.
~95% tumor burden reduction in a mouse model.
Documented Applications
Prophylactic and therapeutic use, including treating disease, using the disclosed nanostructure.
Research and diagnostic uses.
Regulatory tolerance applications using immune suppressor variants.
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