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-10837018-B2
Publication Date
2020-11-17
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 is directed to a nanoscale construct in which a corona comprised of an exterior shell of nucleic acid molecules is arranged in a geometrical position around a nanoparticle core. The nucleic acid molecules are CpG oligonucleotides, with the corona providing an immunostimulatory/adjuvant function. The construct is defined by a nanoparticle core diameter of about 1 nm to about 40 nm.
The construct further specifies that the CpG oligonucleotides contain a spacer that comprises an oligoethylene and do not comprise an oligonucleotide spacer. The corona geometry and spherical nanoscale presentation are described as enabling nucleic-acid interacting complex agonist presentation. Mechanistic support is described for enhanced potency and faster activation in macrophages and improved cytokine induction, including TLR9-dependent activation.
The disclosed constructs are described as producing immunotherapeutic performance, including an example construct AST-008 with increased IL-12, balanced Th1/Th2 response, and tumor-clearing and survival benefit in lymphoma models. The document also describes modulation based on nucleic-acid sequence and chemistry, including phosphodiester (PO) versus phosphorothioate (PS) linkages and internal/5′ PS modifications, as well as effects of core size and loading density.
Claims Coverage
The independent claim recites a nanoscale corona construct with CpG oligonucleotides arranged around a nanoparticle core, including a spacer limitation and a core diameter range, for a total of 1 independent claim in the provided set.
Nucleic-acid corona arranged around a nanoparticle core
A corona comprised of an exterior shell composed of nucleic acid molecules arranged in a geometrical position around a nanoparticle core.
CpG oligonucleotides in the corona
The nucleic acid molecules are CpG oligonucleotides.
Oligoethylene spacer without an oligonucleotide spacer
The nucleic acid molecules contain a spacer which comprises an oligoethylene and do not comprise an oligonucleotide spacer.
Nanoparticle core diameter about 1 nm to about 40 nm
The diameter of the nanoparticle core is about 1 nm to about 40 nm.
The claim coverage centers on a nanoscale construct where CpG oligonucleotides form a nucleic-acid corona exterior shell arranged around a nanoparticle core, with the CpG spacer defined as oligoethylene and the nanoparticle core diameter constrained to about 1–40 nm.
Stated Advantages
Enhanced potency and faster activation in macrophages.
Improved cytokine induction.
TLR9-dependent activation.
Increased IL-12 and balanced Th1/Th2 response.
Tumor-clearing and survival benefit in lymphoma models.
Documented Applications
Immunotherapeutic use in lymphoma models, including tumor-clearing and survival benefit (example construct AST-008).
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