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US-20260124311-A1 - POLYMER-DRUG CONJUGATES FOR STING PATHWAY ACTIVATION

US20260124311A1US 20260124311 A1US20260124311 A1US 20260124311A1US-20260124311-A1

Abstract

Disclosed herein are conjugates that can effectively deliver a STING agonist. An example conjugate includes a hydrophilic polymer, a diamidobenzimidazole (diABZI), and a linker attaching the diABZI to the hydrophilic polymer. Also disclosed are modified diABZI compounds and methods of making and using the conjugates.

Inventors

  • John T. Wilson
  • Karan Arora
  • Taylor L. Sheehy
  • Jacob Schulman

Assignees

  • VANDERBILT UNIVERSITY

Dates

Publication Date
20260507
Application Date
20231012

Claims (20)

  1. 1 . A conjugate, or a pharmaceutically acceptable salt thereof, comprising: a hydrophilic polymer; a diamidobenzimidazole (diABZI); and a linker attaching the diABZI to the hydrophilic polymer.
  2. 2 . The conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the hydrophilic polymer comprises polyethylene glycol (PEG), a copolymer comprising a recurring hydrophilic unit and a recurring linking unit, poly(dimethylacrylamide) (PDMA), dextran, poly(lysine), poly(arginine), poly(glutamic acid), poly(aspartic acid), polyethylenimine (PEI), poly(mannose MA), poly(glucose MA), poly(galactose MA), poly(methacrylic acid), poly(propyl acrylic acid), zwitterionic polymer, poly(phosphorylcholine), poly(sulfobetaine), poly(carboxylbetaine), poly(2-methacryloyloxyethyl phosphorylcholine), or a combination thereof.
  3. 3 . The conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the hydrophilic polymer comprises PEG, a copolymer comprising a recurring hydrophilic unit and a recurring linking unit, or PDMA.
  4. 4 . The conjugate of claim 3 , or a pharmaceutically acceptable salt thereof, wherein the hydrophilic polymer comprises PEG, the PEG having a number average molecular weight of about 1 kDa to about 50 kDa as measured by gel permeation chromatography.
  5. 5 . The conjugate of claim 3 , or a pharmaceutically acceptable salt thereof, wherein the hydrophilic polymer comprises the copolymer, the copolymer having a number average molecular weight of about 15 kDa to about 150 kDa as measured by gel permeation chromatography.
  6. 6 . The conjugate of claim 3 , or a pharmaceutically acceptable salt thereof, wherein the recurring hydrophilic unit of the copolymer comprises a dimethylacrylamide unit, a (2-diethylamino) ethyl methacrylate (DEAEMA) unit, a (2-dimethylamino) ethyl methacrylate (DMAEMA) unit, a N-(2-hydroxypropyl)methacrylamide unit, a 2-amino methacrylate hydrochloride unit, a polyethylene glycol methacrylate (PEGMA) unit, or a combination thereof; and at least one of the recurring linking units of the copolymer comprises the linker.
  7. 7 . The conjugate of claim 3 , or a pharmaceutically acceptable salt thereof, wherein the hydrophilic polymer comprises PDMA, the PDMA having a number average molecular weight of about 15 kDa to about 185 kDa as measured by gel permeation chromatography.
  8. 8 . The conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the diABZI has formula (III)
  9. 9 . The conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the linker is non-cleavable.
  10. 10 . The conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the linker is cleavable.
  11. 11 . The conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the linker comprises a hypoxia sensitive linker, a reactive oxygen species (ROS) sensitive linker, a pH sensitive linker, a redox sensitive linker, an enzyme sensitive linker, a light sensitive linker, or a combination thereof.
  12. 12 . The conjugate of claim 11 , or a pharmaceutically acceptable salt thereof, wherein the enzyme sensitive linker is a matrix metalloproteinase sensitive linker, a p-aminobenzyl alcohol system linker, a cathepsin sensitive linker, a beta-glucuronidase sensitive linker, an esterase sensitive linker, or a combination thereof.
  13. 13 . The conjugate of claim 11 , or a pharmaceutically acceptable salt thereof, wherein the redox sensitive linker is a glutathione sensitive linker, a nitroreductase/NADH sensitive linker, or a combination thereof.
  14. 14 . The conjugate of claim 11 , or a pharmaceutically acceptable salt thereof, wherein the pH sensitive linker is a hydrazone, a silyl ether, a low pH sensitive linker, or a combination thereof.
  15. 15 . The conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, comprising 1 to 15 diABZI per hydrophilic polymer.
  16. 16 . The conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the hydrophilic polymer has a number average molecular weight of about 1 kDa to about 200 kDa as measured by gel permeation chromatography.
  17. 17 . The conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the conjugate has an aqueous solubility of greater than or equal to 1 mg/ml.
  18. 18 . A pharmaceutical composition comprising the conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  19. 19 . The pharmaceutical composition of claim 18 , wherein the pharmaceutically acceptable excipient comprises saline, trehalose, sucrose, or a combination thereof.
  20. 20 . A method of modulating a stimulator of interferon genes (STING) pathway in a subject in need thereof, the method comprising administering to the subject an effective amount of the conjugate according to claim 1 , or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable excipient.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63/415,570 filed on Oct. 12, 2022, which is incorporated fully herein by reference. FEDERALLY SPONSORED RESEARCH This invention was made with government support under Grant No. R01 CA245134 awarded by the National Institutes of Health. The government has certain rights in the invention. TECHNICAL FIELD This disclosure relates to polymer-STING agonist conjugates and their use in biomedical applications, such as drug delivery. INTRODUCTION Stimulator of interferon genes (STING) is a receptor in the endoplasmic reticulum that propagates innate immune sensing of cytosolic pathogen-derived and self DNA. Compounds that can modulate STING (e.g., STING agonists) can be beneficial for numerous diseases, such as cancer. However, efficacy of STING agonists can be impeded by barriers to its delivery. SUMMARY In one aspect, disclosed are conjugates, or a pharmaceutically acceptable salt thereof, comprising: a hydrophilic polymer; a diamidobenzimidazole (diABZI); and a linker attaching the diABZI to the hydrophilic polymer. In another aspect, disclosed are pharmaceutical compositions comprising the disclosed conjugate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In another aspect, disclosed are methods of modulating a STING pathway in a subject in need thereof, the method comprising administering to the subject an effective amount of the disclosed conjugate, or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable excipient. In another aspect, disclosed are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of the disclosed conjugate, or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable excipient, wherein the subject has melanoma, breast cancer, neuroblastoma, renal cell carcinoma, colon cancer, lung cancer, glioma, glioblastoma, pancreatic cancer, osteosarcoma, ovarian cancer, cervical cancer, bladder cancer, T and B cell lymphomas, medulloblastoma, head and neck cancer (HNSCC), liver cancer, or prostate cancer. In another aspect, disclosed are compounds of formula (VI), or a pharmaceutically acceptable salt thereof, wherein: L3 is C3-8alkylene or C3-8alkenylene; L4 is C1-6alkylene or C1-6alkenylene; L5 is or a combination thereof; G3 is combination thereof; m is 0-4; and n is 1-2. In another aspect, disclosed are pharmaceutical compositions comprising the disclosed compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another aspect, disclosed are methods for treating a disease or disorder associated with STING dysfunction comprising administering to a subject in need thereof, a therapeutically effective amount of the disclosed compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. BRIEF DESCRIPTION OF THE DRAWINGS The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawings will be provided by the Office upon request and payment of the necessary fee. FIG. 1A shows the isothermal calorimetry performed to determine KD of binding of diamidobenzimidazole (diABZI)-amine (1) to human recombinant STING, using cyclic dinucleotides and commercially available diABZI as controls. FIG. 1B shows the isothermal calorimetry performed to determine KD of binding of diABZI-V/C-Mal (3) to human recombinant STING, using cyclic dinucleotides and commercially available diABZI as controls. FIG. 2 shows the results from a Cathepsin-B release assay in conjunction with MALDI-MS analysis to determine cathepsin sensitivity of V/C linker compared to a non-cleavable conjugate. FIG. 3A shows the dose-response curves from a THP1-Dual™ reporter assay comparing relative interferon production between diABZI-amine (1), diABZI-Mal (2), and diABZI-V/C-Mal (3). FIG. 3B shows the dose-response curves from an Interferon-β sandwich ELISA performed on isolated splenocytes comparing relative interferon-β production between diABZI-Amine (1), diABZI-Mal (2) and diABZI-V/C-Mal (3). FIG. 4A shows a comparison of STING activation between diABZI-amine (1) and diABZI-V/C-DBCO (9) in THP1 Dual™ reporter cells. FIG. 4B shows a comparison of STING activation between diABZI-V/C-DBCO (9) and diABZI-DBCO (8) in THP1 Dual™ reporter cells. FIG. 5 shows the dose-response curves for diABZI-ECT (10) and diABZI-SS-ECT (11) inducing IRF signaling in THP-1 Dual™ reporter cells at 24 hours. FIG. 6 shows the dose-response curves diABZI-ECT (10), diABZI-Methacrylate (14), and diABZI-SS-methacrylate (15) inducing IRF signaling in THP-1 Dual Reporter cells at 24 hours. FIG. 7A shows the isothermal calorimetry performed to determine KD of binding of diABZI-20kPEG