US-12616712-B2 - Sting agonist comprising exosomes for treating neuroimmunological disorders

Abstract

Provided herein are compositions comprising EV, e.g., exosome, which comprises STING agonists and methods of using such compositions for the treatment of neuroimmunological disorders. Methods of producing the compositions (e.g., EVs comprising a STING agonist) described herein are also provided.

Inventors

• Ajay Verma

Assignees

• LONZA SALES AG

Dates

Publication Date

20260505

Application Date

20200924

Claims (20)

1. 1 . A method of treating a glioblastoma multiforme in a subject in need thereof comprising administering to the subject a composition comprising an extracellular vesicle EV and a stimulator of interferon genes protein STING agonist, wherein the EV overexpresses a Scaffold X protein selected from the group consisting of: prostaglandin F2 receptor negative regulator PTGFRN, basigin BSG, immunoglobulin superfamily member 2 IGSF2, immunoglobulin superfamily member 3 IGSF3, immunoglobulin superfamily member 8 IGSF8, integrin beta-1 ITGB1, integrin alpha-4 ITGA4, 4F2 cell-surface antigen heavy chain SLC3A2, ATP transporter protein, and wherein the Scaffold X protein is a whole protein or a fragment thereof.
2. 2 . The method of claim 1 , wherein the composition is administered intrathecally or intratumorally.
3. 3 . The method of claim 1 , wherein the extracellular vesicle is an exosome.
4. 4 . The method of claim 1 , wherein the STING agonist is associated with the extracellular vesicle.
5. 5 . The method of claim 1 , wherein the Scaffold X protein is prostaglandin F2 receptor negative regulator PTGFRN or a fragment thereof.
6. 6 . The method of claim 5 , wherein the STING agonist is linked to the PTGFRN protein or fragment thereof, optionally by a linker.
7. 7 . The method of claim 1 , wherein the extracellular vesicle is produced by a cell that overexpresses a PTGFRN protein.
8. 8 . The method of claim 1 , wherein the extracellular vesicle further comprises a ligand, a cytokine, or an antibody.
9. 9 . The method of claim 8 , wherein the antibody comprises an antagonistic antibody and/or an agonistic antibody.
10. 10 . The method of claim 1 , wherein the STING agonist is a cyclic dinucleotide or a non-cyclic dinucleotide.
11. 11 . The method of claim 1 , wherein the STING agonist comprises a lipid-binding tag.
12. 12 . The method of claim 1 , wherein the concentration of the STING agonist associated with the extracellular vesicle is about 0.01 μM to 100 μM.
13. 13 . The method of claim 1 , wherein the STING agonist is selected from the group consisting of: and a pharmaceutically acceptable salt thereof.
14. 14 . The method of claim 13 , wherein the STING agonist is in the lumen of the extracellular vesicle and is not linked to a scaffold moiety.
15. 15 . The method of claim 14 , wherein the composition further comprises a pharmaceutically acceptable carrier.
16. 16 . The method of claim 1 , wherein the administering induces or modulates an immune response and/or an inflammatory response in the subject.
17. 17 . The method of claim 1 , further comprising administering an additional therapeutic agent.
18. 18 . The method of claim 17 , wherein the additional therapeutic agent is an antibody or antigen-binding fragment thereof or an IL-12 moiety.
19. 19 . A kit comprising a composition which comprises an extracellular vesicle and a STING agonist and instructions for use according to the method of claim 1 .
20. 20 . The method of claim 1 , wherein the extracellular vesicle further comprises one or more antisense oligonucleotides ASO.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority benefit of U.S. Provisional Application Nos. 62/906,002, filed Sep. 25, 2019; 62/989,528 filed Mar. 13, 2020; and 62/704,986 filed Jun. 5, 2020, each of which is herein incorporated by reference in its entirety. REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY VIA EFS-WEB This application includes an electronically submitted sequence listing in .txt format. The .txt file contains a sequence listing entitled “0132-0276US1_ST25.txt” created on Mar. 9, 2026 and is 223,413 bytes in size. The sequence listing contained in this .txt file is part of the specification and is hereby incorporated by reference herein in its entirety. BACKGROUND OF THE DISCLOSURE Neuroimmunological disorders are some of the most devastating and difficult to treat. Examples of such diseases include gliomas, peripheral tumors that have metastasized to the brain or meninges (neoplastic meningitis), and chronic infectious meningitis. Gliomas are the most common type of tumors to affect the central nervous system. Ostrom, Q. T., et al., Neuro Oncol 16(7): 896-913 (2014). Gliomas comprise about 30 percent of all brain tumors and central nervous system tumors, and 80 percent of all malignant brain tumors. Gliomas typically begin in the glial cells that surround and support neurons in the brain, including astrocytes, oligodendrocytes, and ependymal cells. Hanif, F., et al., Asian Pac J Cancer Prev 18(1): 3-9 (2017). Of the gliomas, glioblastoma (also known as glioblastoma multiforme (GBM)) is the most common and the most aggressive. Despite the aggressive standard of care currently used (e.g., surgery, radiation therapy, chemotherapy, and electric field therapy), there remains a need for more effective and comprehensive treatment options for neuroimmunological disorders, e.g., gliomas, e.g., glioblastoma multiforme (GBM). GBM is rarely curable. For instance, the current survival rate for GBM is 14-15 months after diagnosis with less than 3-5% of people surviving longer than five years. Without treatment, most patients succumb to the disease within just a few months. Omuro, A., et al., JAMA 310:1842-1850 (2013). Prognosis generally worsens with age. Extracellular vesicles (EVs) (e.g., exosomes) are important mediators of intercellular communication. They are also important biomarkers in the diagnosis and prognosis of many diseases, such as cancer. As drug delivery vehicles, EVs (e.g., exosomes) offer many advantages over traditional drug delivery methods (e.g., peptide immunization, DNA vaccines) as a new treatment modality in many therapeutic areas. However, despite its advantages, EVs (e.g., exosomes) have had limited clinical efficacy. For example, dendritic-cell derived exosomes (DEX) were investigated in a Phase II clinical trial as maintenance immunotherapy after first line chemotherapy in patients with inoperable non-small cell lung cancer (NSCLC). However, the trial was terminated because the primary endpoint (at least 50% of patients with progression-free survival (PFS) at 4 months after chemotherapy cessation) was not reached. Besse, B., et al., Oncoimmunology 5(4):e1071008 (2015). Accordingly, new and more effective engineered EVs (e.g., exosomes) are required, particularly those that can be used to better treat neuroimmunological disorders, such as gliomas, peripheral tumors that have metastasized to the brain or meninges (neoplastic meningitis), and chronic infectious meningitis. SUMMARY OF THE DISCLOSURE Provided herein is a method of treating a neuroimmunological disorder in a subject in need thereof comprising administering to the subject a composition comprising an extracellular vesicle and a stimulator of interferon genes protein (STING) agonist (“exoSTING”). In some aspects, the composition is administered intrathecally or intratumorally. In some aspects, the neuroimmunological disorder is a brain tumor. In some aspects, the brain tumor is a glioma. In some aspects, the glioma is a low grade glioma or a high grade glioma. In certain aspects, the glioma is oligodendroglioma, anaplastic astrocytomas, glioblastoma multiforme, diffuse intrinsic pontine glioma, IDH1 and IDH2-mutated glioma, or any combination thereof. In further aspects, the glioma is glioblastoma multiforme. In some aspects, the neuroimmunological disorder is a neoplastic meningitis. In some aspects, the neuroimmunological disorder is chronic infectious meningitis. In some aspects, the extracellular vesicle is an exosome, a nanovesicle, an apoptotic body, a microvesicle, a lysosome, an endosome, a liposome, a lipid nanoparticle, a micelle, a multilamellar structure, a revesiculated vesicle, an extruded cell, or any combination thereof. In certain aspects, the extracellular vesicle is an exosome. In some aspects, the STING agonist is associated with the extracellular vesicle. In certain aspects, the STING agonist is encapsulated within the extracellular vesicle. In further aspects, the