Spherical nucleic acid-based constructs as immunostimulatory agents for prophylactic and therapeutic use
Inventors
Radovic-Moreno, Aleksandar Filip • Mader, Christopher C. • Nallagatla, Subbarao • Hasan, Warefta • Love, Aaron • Gryaznov, Sergei
Assignees
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Publication Number
US-10894963-B2
Publication Date
2021-01-19
Expiration Date
Abstract
Aspects of the invention relate to spherical nucleic acid-based constructs and related methods and compositions thereof. The compositions of the invention are useful for activating agonists of nucleic acid interacting complexes, such as TLRs, stimulating an immune response, and treating diseases such as infectious disease, cancer, allergies, allergic diseases, and autoimmune disease
Core Innovation
The invention relates to nanoscale constructs that stimulate an immune response by presenting CpG oligonucleotides as a spherical corona arranged in a geometrical position around a nanoparticle core. The corona has an exterior shell composed of nucleic acid molecules with a surface density of at least 0.3 pmol/cm2, and the nucleic acid molecules contain a spacer comprising an oligoethylene. The nanoparticle core is about 1 nm to about 40 nm in mean diameter.
The described constructs can be implemented with or without nanoparticle cores and can optionally include metallic nanoparticle cores, such as gold. The nucleic acid agonists include nucleic-acid interacting complexes, notably TLR3, TLR7/8, and TLR9, with CpG oligonucleotides emphasized for immune stimulation. Internucleotide linkage options include phosphodiester and phosphorothioate, and the constructs may include or omit a nanoparticle core depending on the corona architecture.
The document frames the constructs as prophylactic and therapeutic immune stimulators across infectious diseases, cancer, allergies/asthma, and autoimmune disease. Construct examples include AST-008 and compare against free CpG and alum, with results described as enhanced macrophage potency and TLR9 activation, improved in vivo tumor control, increased cytokine secretion including TNF and IL-12, modulation of Th1/Th2 balance and IgG2a increases, and longer survival in a lymphoma model.
Claims Coverage
The independent claim requires a method of treating a subject using a nanoscale construct to stimulate an immune response. The inventive features are organized around the corona geometry and composition, the specified minimum nucleic-acid surface density, the identity of the nucleic-acid agonist, inclusion of an oligoethylene spacer, and a defined nanoparticle core size range.
Nucleic-acid corona around nanoparticle core to stimulate immune response
A nanoscale construct comprises a corona having an exterior shell composed of nucleic acid molecules arranged in a geometrical position around a nanoparticle core, administered in an effective amount to stimulate an immune response.
Minimum nucleic-acid surface density
The nucleic acid molecules have a surface density of at least 0.3 pmol/cm2.
CpG oligonucleotides as the nucleic acid molecules
The nucleic acid molecules are CpG oligonucleotides.
Oligoethylene spacer in nucleic acid molecules
The corona nucleic acid molecules contain a spacer which comprises an oligoethylene.
Nanoparticle core mean diameter range
The nanoparticle core is about 1 nm to about 40 nm in mean diameter.
Overall, the claim coverage centers on administering an immune-stimulating nanoscale construct with a nucleic-acid corona arranged around a nanoparticle core, using CpG oligonucleotides at a specified minimum surface density, with an oligoethylene spacer and a defined nanoparticle core mean diameter.
Stated Advantages
Enhanced macrophage potency.
Improved in vivo tumor control.
TLR9 activation and increased cytokine secretion including TNF and IL-12.
Modulation of immune response parameters including Th1/Th2 balance and IgG2a increases.
Longer survival in a lymphoma model.
Documented Applications
Treating cancer, including lymphoma.
Treating infectious diseases, cancer, allergies/asthma, and autoimmune disease as prophylactic and therapeutic immune stimulation use cases described in the document.
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