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-11123294-B2
Publication Date
2021-09-21
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 multivalent immune modulator includes a liposomal core having a lipid bilayer and an exterior oligonucleotide shell formed by immune stimulant or immune suppressor oligonucleotides that are structured on the liposomal surface.
In the claimed nanostructure, all oligonucleotides are single-stranded B-class CpG oligonucleotides positioned on the exterior of the liposomal core. Each oligonucleotide is indirectly linked to the liposomal core through a lipid anchor, and embodiments include specific oligonucleotide shell compositions, orientation, and linker chemistries.
The immune modulatory liposomal SNAs are used to treat or prophylaxis disorders, including cancer, infectious diseases, allergy/asthma, and autoimmune disease. Antigen co-delivery formats are described, including mixed, linked to the shell, linked via a linker, linked to the core, and encapsulated.
The document also discusses comparative results showing enhanced immune activation when pattern recognition receptor agonists are co-assembled in the same construct versus separate delivery, and in vivo tumor reduction in a mouse model using antigen-loaded liposomal SNAs.
Claims Coverage
The document includes two independent claims, one directed to a nanostructure and one directed to a method of treating a disease or disorder by administering the nanostructure. Across the independent claims, the coverage centers on the same structural immune-modulating liposomal SNA architecture with specific B-class CpG oligonucleotides positioned on the exterior and indirectly linked via a lipid anchor.
Exterior single-stranded B-class CpG oligonucleotide shell on a liposomal core
A nanostructure comprising a liposomal core having a lipid bilayer and oligonucleotides, wherein all the oligonucleotides are single-stranded B-class CpG oligonucleotides positioned on the exterior of the liposomal core in the form of an oligonucleotide shell.
Indirect lipid-anchor linkage of each oligonucleotide
Each oligonucleotide is indirectly linked to the liposomal core through a lipid anchor.
Administering liposomal B-class CpG shell nanostructure to stimulate immune system
A method for treating a disease or disorder in a subject, comprising administering a nanostructure comprising a liposomal core having a lipid bilayer and oligonucleotides to stimulate the immune system of a subject to treat a disease or disorder in the subject.
Overall, the claim set protects liposomal spherical nucleic acid nanostructures where single-stranded B-class CpG oligonucleotides are displayed as an exterior oligonucleotide shell and are indirectly linked via a lipid anchor, and also protects methods of treating diseases or disorders by administering that nanostructure to stimulate the immune system.
Stated Advantages
Enhanced immune activation when agonists are co-assembled in the same construct versus separate delivery.
Antigen-conjugated constructs increase immune-cell activation.
Tumor burden reduction is described in an in vivo mouse model using antigen-loaded liposomal SNAs.
Documented Applications
Treating or prophylaxis of disorders including cancer.
Treating or prophylaxis of disorders including infectious diseases.
Treating or prophylaxis of disorders including allergy/asthma.
Treating or prophylaxis of disorders including autoimmune disease.
Treatment of cancer in a subject by administering the described nanostructure.
Treatment targets for cancer include biliary tract cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, lymphoma, liver cancer, lung cancer, skin cancer, oral cancer, ovarian cancer, pancreas cancer, prostate cancer, rectal cancer, testicular cancer, thyroid cancer, and renal cancer.
Additional cancer targets include small cell lung cancer, non-small cell lung cancer, melanoma, hairy cell leukemia, chronic myelogenous leukemia, cutaneous T-cell leukemia, multiple myeloma, follicular lymphoma, squamous cell carcinoma, and bladder cell carcinoma.
Additional cancer targets include neuroblastoma, sarcoma, or an intraepithelial neoplasm.
Specifically treating skin cancer.
Regulatory/tolerance-inducing use via immune suppressors, including TLR antagonists, is discussed.
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