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WO-2026096490-A1 - MHC CLASS I ANTIGEN-PRESENTING NANOPARTICLES AND METHODS OF USING SAME

WO2026096490A1WO 2026096490 A1WO2026096490 A1WO 2026096490A1WO-2026096490-A1

Abstract

Disclosed herein are antigen-presenting nanoparticles (APNs) presenting self-epitopes via MHC class I molecules. The APNs encapsulate one or more encapsulated components which induce cell death which are delivered to autoreactive immune cells (e.g., autoreactive T cells) that recognize the self-epitopes, thereby killing the autoreactive immune cells. These APNs can be used to treat various autoimmune diseases and disorders, including type 1 diabetes.

Inventors

  • KWONG, GABRIEL A.
  • CHAN, Ching Shen
  • SIEBART, Jamison Charles
  • SU, FANG-YI

Assignees

  • GEORGIA TECH RESEARCH CORPORATION

Dates

Publication Date
20260507
Application Date
20251028
Priority Date
20241028

Claims (20)

  1. CLAIMS
  2. 1. An antigen-presenting nanoparticle (APN), comprising:
  3. a major histocompatibility complex (MHC) class I comprising a self-epitope or a mimotope thereof, wherein the MHC class I is presented on a surface of the APN; and one or more encapsulated components which induce cell death.
  4. 2. The APN of claim 1, wherein the one or more encapsulated components comprise a nucleic acid encoding an enzyme or fragment thereof which induces cell death.
  5. 3. The APN of claim 2, wherein the enzyme or fragment thereof is caspase, BIM, BID, granzyme B, PUMA, or gasdermin D.
  6. 4. The APN of claim 3, wherein the nucleic acid encoding an enzyme or fragment thereof which induces cell death comprises about 80% similarity or more to any one of SEQ ID NOS: 6-13.
  7. 5. The APN of any one of claims 1-4, wherein the one or more encapsulated components comprise one or more toxins.
  8. 6. The APN of any one of claims 1-5, wherein the self-epitope or mimotope thereof comprises NRP-V7, IGRP, InsulinA, InsulinB, GAD65, chromogranin A, p31, p79, or any fragments thereof.
  9. 7. The APN of claim 6, wherein the self-epitope or mimotope thereof comprises KYNKANVFL (SEQ ID NO: 14), VYLKTNVFI., (SEQ ID NO: 15), LYLVCGERV (SEQ ID NO: 16), or any variants thereof.
  10. 8. The APN of any one of claims 1-7, wherein the APN is a lipid nanoparticle, a liposome, or a polymeric nanoparticle.
  11. 9. The APN of claim 8, wherein the APN comprises at least one ionizable lipid, cholesterol, phospholipid, PEGylated lipid, or a combination thereof. 10. The APN of claim 9, wherein the at least one ionizable lipid comprises cKK-E12, SM102, MC3, Lipid-5, Alc-0315, LP01, Lipid A9, or any combination thereof.
  12. 11. The APN of any one of claims 9-10, wherein the APN comprises from about 30 mol% to about 60 mol% of the ionizable lipid.
  13. 12. The APN of any one of claims 9-11, wherein the APN comprises from about 35 mol% to about 50 mol% cholesterol.
  14. 13. The APN of any one of claims 9-12, wherein the at least one phospholipid comprises DSPC, DOPE, or any combination thereof.
  15. 14. The APN of any one of claims 9-13, wherein the APN comprises from about 5 mol% to about 20 mol% of the phospholipid.
  16. 15. The APN of any one of claims 9-14, wherein the at least one PEGylated lipid comprises ALC-0159, DMG-PEG, DSPE-PEG, PEG14-2000, or any combination thereof.
  17. 16. The APN of any one of claims 9-15, wherein the APN comprises from about 0.5 mol% to about 5 mol% of the PEGylated lipid.
  18. 17. The APN of any one of claims 9-16, wherein a ratio of PEGylated lipid to total lipids is from about 0.01: 1 to about 0.0: 1.
  19. 18. The APN of any one of claims 9-17, wherein the ratio of MHC class 1 to total lipids is from about 0.3:1 to about 6:1.
  20. 19. A method of killing an autoreactive immune cell, the method comprising exposing the APN of any one of claims 1-18 to said autoreactive immune cell.

Description

MHC CLASS I ANTIGEN-PRESENTING NANOPARTICLES AND METHODS OF USING SAME CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of priority to U.S. Provisional Application No. 63/712,845, filed October 28, 2024, which is incorporated by reference herein in its entirety. GOVERNMENT SUPPORT CLAUSE [0002] This invention was made with government support under CA280832 awarded by the National Institutes of Health. The Government has certain rights in the invention. REFERENCE TO SEQUENCE LISTING [0003] The sequence listing submitted on October 28, 2025, as an. XML file entitled “10034-398W01._ST26.xml” created on October 28, 2025, and having a file size of 31,345 bytes is hereby incorporated by reference pursuant to 37 C. F. R. § 1.52(e)(5). BACKGROUND [0004] Autoreactive T cells are a subset of T cells that recognize self-antigens due to a failure in central or peripheral tolerance mechanisms. During thymic development, T cells undergo positive and negative selection; however, incomplete deletion or inadequate anergy induction can result in the escape of autoreactive T cells. These autoreactive T cells can contribute to autoimmune disorders by targeting host tissues through antigen-specific cytotoxicity or proinflammatory cytokine secretion. Regulatory T cell dysfunction or impaired checkpoint signaling (e.g., CTLA-4, PD-1 pathways) further exacerbates their activity, underscoring their role in the etiology of diseases like type 1 diabetes, multiple sclerosis, and systemic lupus erythematosus. [0005] Type 1 diabetes (T1D) is an autoimmune disease in which autoreactive cytotoxic T cells attack and destroy the insulin-producing cells within the pancreatic islets of Langerhans. As of 2024, the only FDA-approved disease-modifying therapy for T1D is an Fc receptornonbinding «CD3 monoclonal antibody (teplizumab) to delay the onset of clinical T1D by modifying the phenotype and activity of CD8 T cells, including autoreactive CD8+ T cells. While effective, aCD3 monoclonal antibodies broadly modulate T cell immunity, thereby making subjects vulnerable to serious side effects, such as cytokine release syndrome, and opportunistic infections. [0006] Accordingly, there exists a need for improved treatments for eliminating autoreactive T cells, particularly for the treatment of autoimmune disorders like type 1 diabetes. These needs and others are at least partially satisfied by the present disclosure. SUMMARY [0007] Disclosed herein are antigen-presenting nanoparticles (APNs) which target and destroy autoreactive T cells. The APNs present self-epitopes on their surface, which would be recognized and bound only by autoreactive T cells (i.e., thereby preventing off target delivery of the APNs to normal T cells). Upon binding to an autoreactive T cell, the APN delivers to the cell one or more encapsulated components which induce cell death, which kills the cell. These APNs enable targeted and efficient elimination of autoreactive T cells, which can be particularly useful for the treatment, prevention, and/or management of autoimmune diseases such as type 1 diabetes. [0008] In one aspect, disclosed herein are antigen-presenting nanoparticles (APNs) (such as, for example, a lipid nanoparticle, a liposome, or a polymeric nanoparticle), comprising: a major histocompatibility complex (MHC) class I comprising a self-epitope or a mimotope thereof (such, as, for example, self-epitope or mimotope thereof comprising NRP-V7, IGRP, InsulinA, InsulinB, GAD65, chromogranin A, p31, p79, or any fragments thereof, including, but not limited to KYNKANVFL (SEQ ID NO: 14), VYLKTNVFL (SEQ ID NO: 15), LYLVCGERV (SEQ ID NO: 16), or any variants thereof), wherein the MHC class I is presented on a surface of the APN; one or more encapsulated components which induce cell death. In some aspects, the one or more encapsulated components comprise a nucleic acid encoding an enzyme or fragment thereof which induces cell death (such as, for example, caspase, BIM, BID, granzyme B, PUMA, or gasdermin D). In some aspects, the one or more encapsulated components comprise one or more toxins (such as, for example, diphtheria toxin, pseudomonas exotoxin A, ricin, shiga toxin, or ribosome-inactivating proteins). [0009] Also disclosed herein are APNs of any preceding aspect wherein the APN comprises at least one ionizable lipid (including, but not limited to cKK-E12, SM102, MC3, Lipid-5, Alc-0315, LP01, Lipid A9, or any combination thereof), cholesterol, phospholipid (including, but not limited to DSPC, DOPE, or any combination thereof), PEGylated lipid (including, but not limited to ALC-0159, DMG-PEG, DSPE-PEG, PEG14-2000), or a combination thereof. In some aspects, the APN comprises from about 30 mol% to about 60 mol% of the ionizable lipid; from about 35 mol% to about 50 mol% cholesterol; from about 5 mol% to about 20 mol% of the phospholipid; and/or from about 0.5 mol% to about 5 mol% of the PEGylated lipid. In some aspects, the rati