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WO-2026096840-A2 - MANGANESE GLYCEROPHOSPHATE GELS AND METHODS OF USE THEREOF

WO2026096840A2WO 2026096840 A2WO2026096840 A2WO 2026096840A2WO-2026096840-A2

Abstract

This invention relates to compositions comprising an immunogen and a manganese glycerophosphate (MnGp) gel useful in raising an immune response in a subject, vaccinating a subject, and/or immunotherapy, such as cancer immunotherapy, in a subject. In addition, this invention relates to MnGp gels and methods of synthesizing the same using mechanical shear stress and/or synthesis of nanoparticles.

Inventors

  • BACHELDER, Eric
  • AINSLIE, KRISTY
  • ROQUE, John
  • ISLAM, Md Jahirul
  • EHRENZELLER, Stephen

Assignees

  • THE UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL

Dates

Publication Date
20260507
Application Date
20251031
Priority Date
20241031

Claims (20)

  1. 1. A composition comprising an immunogen and a manganese glycerophosphate (MnGp) gel.
  2. 2. The composition of claim 1, wherein the immunogen is a protein (e.g., a subunit vaccine), a nucleic acid (e.g., an immunostimulatory nucleic acid and/or a nucleic acid encoding an immunogenic protein), and/or a whole-pathogen immunogen (e.g., a live attenuated pathogen, a dead pathogen, and/or an inactivated pathogen).
  3. 3. The composition of claim 2, wherein the whole-pathogen immunogen is a virus, a bacterium, a prion, a parasite, and/or a fungus.
  4. 4. The composition of any preceding claim, wherein the MnGp gel is comprised of MnGp particles.
  5. 5. The composition of claim 4, wherein the MnGp particles have an average particle size from about 25 to 10000 nanometers (e.g., about 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 4000, 5000, 6000, 7000, 8000, 9000, or 10000 nanometers).
  6. 6. The composition of any preceding claim, wherein the MnGp gel has an average pore size from about 0.1 to about 15 pm (e.g., about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 pm).
  7. 7. The composition of any preceding claim, wherein the immunogen is present from about 0.01 to about 500 weight percent of the composition, and the MnGp particles are present in a concentration from about 1 to about 400 mg/mL (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 75, 100, 125, 150, 200, 250, 300, 350, or 400 mg/mL).
  8. 8. The composition of any preceding claim, wherein the composition further comprises a cryoprotectant.
  9. 9. The composition of claim 8, wherein the cryoprotectant is sucrose. Attorney Docket No. 5470.985.WO
  10. 10. The composition of claim 9, wherein the sucrose is present in a concentration from about 10 to about 1000 mg/mL (e.g., about 10, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 400, 500, 600, 700, 800, 900, or 1000 mg/mL).
  11. 11. The composition of any one of claims 8-10, wherein the composition is lyophilized.
  12. 12. The composition of any preceding claim, wherein the composition further comprises at least one additional adjuvant.
  13. 13. The composition of claim 12, wherein the at least one additional adjuvant is an oil-in- water emulsion (e.g., a squalene in water emulsion (e.g., AS03 or MF59)), an aluminum salt (e.g., aluminum hydroxide, aluminum phosphate, and/or aluminum potassium sulfate), cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), a sponin adjuvant (e.g., Quil-A®), QS-21, and/or a toll-like receptor (TLR) agonist (e.g., monophosphoryl lipid A (MPLA), CpG, flagellin, polyinosinic:polycytidylic acid, Pam3CKS4, resiquimod (R848), and/or imiquimod).
  14. 14. The composition of claim 13, wherein the at least one additional adjuvant is cGAMP and the cGAMP is present in an amount from about 0.001 pg to about 5 pg (e.g., about 0.001, 0.005, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 pg).
  15. 15. The composition of claim 13, wherein the at least one additional adjuvant is a CpG adjuvant, optionally CpG 1018, CpG 1826, CpG 2006, and/or CpG 2395.
  16. 16. The composition of any preceding claim, which is a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
  17. 17. The composition of claim 16, wherein the pharmaceutically acceptable carrier is a physiological buffer (e.g., phosphate buffered saline (PBS), 4-(2 -hydroxy ethyl)- 1- piperazineethanesulfonic acid (HEPES), water, saline, and the like).
  18. 18. The composition of any preceding claim, wherein the composition is suitable for intravenous administration, mucosal administration, intradermal administration, intramuscular Attorney Docket No. 5470.985.WO administration, vaginal administration, rectal administration, subcutaneous administration, transdermal administration, oral administration, sublingual administration, buccal administration, intranasal administration, and/or intratumoral administration.
  19. 19. The composition of claim 18, wherein the composition persists in vivo from about 1 day to about 365 days (e.g., about 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 40, 50, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, or 365 days) after administration.
  20. 20. The composition of any preceding claim, wherein the immunogen is present within the structure of the MnGp gel.

Description

Attorney Docket No. 5470.985.WO MANGANESE GLYCEROPHOSPHATE GELS AND METHODS OF USE THEREOF STATEMENT OF PRIORITY [0001] This application claims the benefit of U.S. Provisional Application Serial No. 63/714,626, filed October 31, 2024, the entire contents of which are incorporated by reference herein. STATEMENT OF GOVERNMENT SUPPORT [0002] This invention was made with government support under Grant No. 75N93019C00052 awarded by the National Institutes of Health. The government has certain rights in the invention. FIELD OF THE INVENTION [0003] This invention relates to compositions comprising an immunogen and manganese glycerophosphate (MnGp) gel, and methods of use of the same in raising an immune response, vaccinating a subject, and/or providing an immunotherapy to a subject. BACKGROUND OF THE INVENTION [0004] Vaccination stands as one of the most successful public health measures to date. In the United States alone, extensive childhood vaccination programs have achieved the full eradication of smallpox and polio, as well as significant reductions (>90%) in other previous high morbidity and mortality infectious diseases such as diphtheria, measles, and mumps (Rodrigues and Plotkin, 2020; Roush, 2007). More recently, the SARS-CoV-2 mRNA vaccines demonstrated profound efficacy in preventing severe illness and improving disease outcomes, especially in aged, immunocompromised, and high-risk comorbidity populations (Kelly et al., 2022; Lin et al., 2022; Polack et al., 2020). Nevertheless, complications observed with the vaccine rollout and global distribution - namely, poor stability outside of cold-chain storage (Uddin and Roni, 2021) and carrier-mediated reactogenicity (Sutton et al., 2022) - highlight the continual need to develop novel vaccine formulations. [0005] Traditional vaccine development is largely focused on the production of live attenuated pathogens, but the capacity for vaccine strains to replicate in and cause illness to the host prompts safety concerns for immunocompromised populations (Minor, 2015; Plotkin, 2014). In contrast, subunit vaccines, which are comprised of purified protein(s), peptide(s), or Attorney Docket No. 5470.985.WO polysaccharide(s) of a pathogen (i.e., antigen) and are therefore non-infectious, represent a promising alternative vaccination strategy that circumvents these safety concerns (Kyriakidis et al., 2021). Subunit antigens are often weakly immunogenic on their own, typically eliciting modest humoral immunity with little to no cellular immunity (Reed et al., 2013). Therefore, subunit vaccines often incorporate adjuvants, or immunostimulatory molecules, to enhance and prolong the immune response. Aluminum-containing adjuvants (i.e., “alum”) are perhaps the most widely used subunit vaccine adjuvants, largely due to their potency, safety profile, and relatively accessible cost (Lindblad, 2004). However, despite proven efficacy in several licensed vaccines, alum primarily elicits a T helper 2 (Th2) cell-biased response (i.e., antibody- mediated, or humoral, immunity) with a marginal T helper 1 (Thl) cell response (i.e., cell- mediated immunity) (Pulendran et al., 2021). Thus, for diseases where a robust Thl response is critical, such as influenza (Aleebrahim-Dehkordi et al., 2022) and certain cancers (Knutson and Disis, 2005), candidate vaccines require more effective adjuvant systems. As such, significant progress has been made in the exploration of adjuvants MF59 (Ko and Kang, 2018), AS04 (Didierlaurent et al., 2009)), toll-like receptor (TLR) agonists (e.g., polyinosinic:polycytidylic acid (poly(I:C)) (Martins et al., 2015), cytosine-phosphate-guanine (CpG) oligodeoxynucleotides (ODNs) (Bode et al., 2011)), and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) agonists (e.g., cGAMP (Li et al., 2013)) to improve the Thl/Th2 balance of vaccine responses. [0006] Current limitations in conventional adjuvants, like alum described above, require improved design and delivery. Thus, new adjuvants for vaccine and immunotherapy methodologies are desired. SUMMARY OF THE INVENTION [0007] The present invention is based on the finding that applying mechanical shear stress to a MnGp powder allows the formation of an MnGp gel, and the beneficial functions of said gel as an adjuvant. [0008] Thus, one aspect of the invention relates to a composition comprising an immunogen and an MnGp gel. In some embodiments, the composition further comprises a cryoprotectant. In some embodiments, the composition is a pharmaceutical composition comprising a pharmaceutically acceptable carrier. [0009] Another aspect of the invention relates to a method of raising an immune response in a subject, said method comprising administering to the subject an effective amount of a composition as described herein, thereby raising an immune response in the subject. Attorney Docket No. 5470.985.WO [0010] Another aspect of the invention relates to a method of vaccinating a subject against a pa