Immunotherapeutic constructs and methods of their use
Inventors
Yantasee, Wassana • LUND, Amanda • NGAMCHERDTRAKUL, Worapol • REDA, Moataz
Assignees
Oregon Health and Science University • PDX Pharmaceuticals Inc
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Publication Number
US-11235058-B2
Publication Date
2022-02-01
Expiration Date
Abstract
Disclosed herein are immunotherapeutic constructs comprising a delivery particle, at least one adjuvant, and one or more therapeutic agents/compounds that cause antigen release and/or modulate immunosuppressive tumor microenvironment. These immunotherapeutic constructs create adaptive immunity or anti-cancer immune response(s) that can be used, for instance, to prevent and treat broad types of cancer. Further disclosed are uses of the immunotherapeutic constructs, including to prevent and treat cancer in humans and animals.
Core Innovation
The invention describes an immunotherapeutic construct based on a nanoparticle platform comprising a mesoporous silica nanoparticle (MSNP) having an exterior surface coated with polyethylenimine (PEI), with polyethylene glycol (PEG) bound to the PEI or to the MSNP. The construct provides a vehicle for delivering nucleic acid components that are attached in a non-covalent manner, and includes siRNA that inhibits expression or activity of STAT3 (siSTAT3) and an adjuvant comprising a CpG oligonucleotide non-covalently attached to the PEI.
The construct is characterized by the co-presentation of STAT3-inhibiting siRNA and CpG oligonucleotide adjuvant on the same nanoparticle platform. It expressly does not comprise a tumor-specific antigen or ovalbumin.
The disclosed construct is used in situ for tumor vaccination approaches and supports activation of adaptive immunity, including CD8+ T cells and dendritic cells (APCs/DCs), including cross-presentation. The disclosure also describes anti-cancer use, immune checkpoint synergy, modulation of the tumor microenvironment, and tumor growth inhibition at local and distant tumor sites, including mention of an abscopal systemic immune effect.
Claims Coverage
The document provides at least one independent claim defining the immunotherapeutic construct. The inventive features center on a specific MSNP/PEI/PEG nanoparticle platform, non-covalent attachment of siSTAT3 and a CpG oligonucleotide adjuvant, and exclusion of tumor-specific antigen or ovalbumin.
Mesoporous silica nanoparticle platform with PEI and PEG
A nanoparticle platform comprising a mesoporous silica nanoparticle (MSNP), polyethylenimine (PEI) coating an exterior surface of the MSNP, and polyethylene glycol (PEG) bound to the PEI or to the MSNP.
Non-covalent siRNA targeting STAT3
An siRNA that inhibits expression or an activity of STAT3 (siSTAT3) non-covalently attached to the PEI.
Non-covalent CpG oligonucleotide adjuvant attached to PEI
An adjuvant comprising a CpG oligonucleotide non-covalently attached to the PEI.
Exclusion of tumor-specific antigen and ovalbumin
The immunotherapeutic construct does not comprise a tumor-specific antigen or ovalbumin.
Overall, the independent claim defines an immunotherapeutic construct centered on a PEI-coated MSNP with PEG binding, where siSTAT3 and a CpG oligonucleotide adjuvant are non-covalently attached to the PEI, and where tumor-specific antigen or ovalbumin is excluded.
Stated Advantages
Augmenting immune response and inhibiting suppressive environment of tumors.
Immune-mediated antitumor effects and survival benefits across multiple tumor models.
Supports activation of adaptive immunity, including CD8+ T cells and dendritic cells (APCs/DCs), including cross-presentation.
Provides tumor growth inhibition at local and distant tumor sites, including an abscopal systemic immune effect.
Described immune checkpoint synergy and tumor microenvironment modulation.
Safety observations including testing in cynomolgus monkeys.
Documented Applications
In situ tumor vaccination using nanoparticles carrying CpG and siRNA (including siSTAT3).
Multiple tumor model use cases including B16F10, LLC-JSP, CT26, and 4T1.
Safety testing in cynomolgus monkeys.
Prevention and treatment of cancers in humans and animals using an in situ tumor vaccination approach.
Combination contexts involving immune checkpoint inhibitors and other anti-cancer therapies, with tumor microenvironment modulation and mention of abscopal systemic immune effects.
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