IP Library › Granted Patent US 12,246,097
Granted Patent B2
US 12,246,097 · App. 18/151,182 · Granted Mar 11, 2025

Nanoparticle vaccine adjuvant and methods of use thereof

Inventors: Darrell J. Irvine (Arlington, MA); Murillo Silva (Lancaster, MA); Shane Crotty (San Diego, CA); Yu Kato (San Diego, CA)
Assignees: MASSACHUSETTS INSTITUTE OF TECHNOLOGY; LA JOLLA INSTITUTE FOR IMMUNOLOGY
A61K9/51A61K9/0019A61K9/141A61K9/19A61K39/02A61K39/39A61K39/4611A61K39/4612A61K39/4622A61K39/464402A61K39/464838A61K2039/55555A61K2039/55572A61K2239/31B82Y5/00B82Y40/00
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,246,097
App. No.
18/151,182
Granted
Mar 11, 2025
Kind
B2
Abstract

Non-liposome, non-micelle particles formed of a lipid, an additional adjuvant such as a TLR4 agonist, a sterol, and a saponin are provided. The particles are porous, cage-like nanoparticles, also referred to as nanocages, and are typically between about 30 nm and about 60 nm. In some embodiments, the nanocages include or are administered in combination with an antigen. The particles can increase immune responses and are particularly useful as adjuvants in vaccine applications and related methods of treatment. Preferred lipids, additional adjuvants including TLR4 agonists, sterols, and saponins, methods of making the nanocages, and method of using them are also provided.

Claims (20)

1. A porous or perforated non-liposome, non-micelle nanoparticle comprising a phospholipid, a sterol, a saponin, and a TLR4 agonist lipopolysaccharide (LPS) or a lipid A derivative thereof.

2. The particle of claim 1 , wherein the saponin comprises Quil A or QS-21.

3. The particle of claim 1 , wherein the nanoparticle is about 30 nm to about 60 nm.

4. The particle of claim 1 , wherein the phospholipid is 2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC).

5. The particle of claim 1 , wherein the lipopolysaccharide (LPS) or lipid A derivative thereof is a natural or synthetic monophosphoryl lipid A (MPLA).

6. The particle of claim 5 comprising lipid: MPLA: sterol: saponin molar ratio of 2.5:1:10:10, or a variation thereof wherein the molar ratio of lipid, MPLA, sterol, saponin or any combination thereof is increased or decreased by any value between about 0 and about 3.

7. The particle of claim 5 , wherein the MPLA is natural or synthetic 4′-monophosporyl lipid A (MPLA) or 3-O-deacylated monophosphoryl lipid A (3D-MPLA).

8. The particle of claim 1 , wherein the sterol is cholesterol or a derivative thereof.

9. The particle of claim 1 , wherein the saponin is a natural or synthetic saponin.

10. A method of making the particle of claim 1 , comprising mixing the phospholipid, sterol, saponin, and lipopolysaccharide (LPS) or a lipid A derivative thereof in an aqueous carrier comprising detergent to form a solution and removing the detergent until the phospholipid, sterol, saponin, and lipopolysaccharide (LPS) or a lipid A derivative thereof self-assemble into porous or perforated nanoparticles.

11. A pharmaceutical composition comprising a plurality of the particle of claim 1 and a pharmaceutical carrier.

12. A method of treating a subject in need thereof comprising administering the subject the pharmaceutical composition of claim 11 in an effective amount to induce an immune response against an antigen.

13. A kit comprising a plurality of the particles of claim 1 in a lyophilized or dried form, or suspended in a pharmaceutically acceptable carrier.

14. The particle of claim 1 , wherein the saponin is Quil A.

15. The particle of claim 14 , wherein the sterol is cholesterol, the lipopolysaccharide (LPS) or a lipid A derivative thereof is MPLA, and the phospholipid is DPPC.

16. The particle of claim 1 , the saponin is QS-21.

17. The particle of claim 16 , wherein the sterol is cholesterol, the lipopolysaccharide (LPS) or a lipid A derivative thereof is MPLA, and the phospholipid is DPPC.

18. A porous or perforated non-liposome, non-micelle, cage-like nanoparticle comprising a phospholipid, cholesterol, QS-21, and MPLA.

19. The pharmaceutical composition of claim 11 , further comprising an antigen.

20. The pharmaceutical composition of claim 19 , wherein the antigen is derived from a source selected from the group consisting of a virus, bacterium, parasite, plant, protozoan, fungus, tissue and transformed cell.

Assignments (7)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 23, 2024
From: IRVINE, DARRELL
To: HOWARD HUGHES MEDICAL INSTITUTE
Reel/Frame 068983/0822 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 23, 2024
From: HOWARD HUGHES MEDICAL INSTITUTE
To: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Reel/Frame 068983/0840 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 23, 2024
From: CROTTY, SHANE; KATO, YU
To: LA JOLLA INSTITUTE FOR ALLERGY AND IMMUNOLOGY
Reel/Frame 068982/0334 →
CHANGE OF NAME Recorded Oct 23, 2024
From: LA JOLLA INSTITUTE FOR ALLERGY AND IMMUNOLOGY
To: LA JOLLA INSTITUTE FOR IMMUNOLOGY.
Reel/Frame 068982/0362 →
CHANGE OF NAME Recorded Oct 23, 2024
From: LA JOLLA INSTITUTE FOR IMMUNOLOGY.
To: LA JOLLA INSTITUTE FOR IMMUNOLOGY
Reel/Frame 068982/0367 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 23, 2024
From: CROTTY, SHANE; KATO, YU
To: LA JOLLA INSTITUTE FOR IMMUNOLOGY
Reel/Frame 068982/0594 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 23, 2024
From: SILVA, MURILLO
To: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Reel/Frame 068982/0793 →
Continuity (3)
Continuation 16510463 · Jul 12, 2019
Provisional Application 62731214 · Sep 14, 2018
Related Publication 20230157967A1 · May 25, 2023
References Cited (60)
US 3238190A · Erbring · 1966 [cited by applicant]
US 4912094A · Myers · 1990 [cited by applicant]
US 5057540A · Kensil · 1991 [cited by applicant]
US 8283456B2 · Gin · 2012 [cited by applicant]
US 9107904B2 · Irvine · 2015 [cited by applicant]
US 9149520B2 · Walker · 2015 [cited by applicant]
US 9241988B2 · Shaw · 2016 [cited by applicant]
US 20050220814A1 · Dominowski · 2005 [cited by applicant]
US 20110206758A1 · Vandepapeliere · 2011 [cited by applicant]
US 20110300177A1 · Gin · 2011 [cited by applicant]
US 20140356384A1 · Hubbell · 2014 [cited by applicant]
US 20160045595A1 · Morein · 2016 [cited by applicant]
EP 0362278 · 1990 [cited by applicant]
EP 0362279 · 1990 [cited by applicant]
WO 9414454 · 1994 [cited by applicant]
WO 9633739 · 1996 [cited by applicant]
WO 9836772 · 1998 [cited by applicant]
WO 2009156960 · 2009 [cited by applicant]
WO 2018104313 · 2018 [cited by applicant]
WO 2019051149 · 2019 [cited by applicant]
Fox et al. A nanoliposome delivery system to synergistically trigger TLR4 and TLR7. Journal of Nanobiotechnology 2014, 12:17. [cited by examiner]
Bach, et al., “The effect of infections on susceptibility to autoimmune and allergic diseases”, N. Eng. J. Med., 347:911-20 (2002). [cited by applicant]
Bodera, “Immunostimulatory oligonucleotides”, Recent Pat. Inflamm. Allergy Drug Discov., 5(1):87-93 (2011). [cited by applicant]
Carrasco, et al., “B cells acquire particulate antigen in a macrophage-rich area at the boundary between the follicle and the subcapsular sinus of the lymph node”, Immunity, 27(1):160-171 (2007). [cited by applicant]
Dalpke, “Phosphodiester CpG oligonucleotides as adjuvants: polyguanosine runs enhance cellular uptake and improve immunostimulative activity of phosphodiester CpG oligonucleotides in vitro and in vivo”, Immunology, 106(… [cited by applicant]
Dalsgaard, et al. “Saponin adjuvants. 3. Isolation of a substance from Quillaja saponaria Molina with adjuvant activity in food-and-mouth disease vaccines,” Archiv. Gesamte Virusforsch, 44:243-54 (1974). [cited by applicant]
Deuwell, et al., “ISCOMATRIX adjuvant combines immune activation with antigen delivery to dendritic cells in vivo leading to effective cross-priming of CD8+ T cells”, J Immunology. 187(1):55-63 (2011). [cited by applicant]
Ersching, et al., “Germinal Center Selection and Affinity Maturation Require Dynamic Regulation of mTORC1 Kinase”, Immunity, 46(6):1045-58 (2017). [cited by applicant]
Fiedler, “Further constituents of Crataegus; paper-chromatographic determination of chlorogenic and caffeic acid”, Arzneimittel-Forsch. 4:41-5 (1954). [cited by applicant]
Fousteri, et al., “Subcutaneous insulin B: 9-23/IFA immunisation induces Tregs that control late-stage prediabetes in NOD mice through IL-10 and IFNgamma”, Diabetologia, 53:1958-70 (2010). [cited by applicant]
Gitlin, et al, “Humoral Immunity. T cell help controls the speed of the cell cycle in germinal center B cells”, Science, 349(6248):643-6 (2015). [cited by applicant]
Gitlin, et al., “Clonal selection in the germinal center by regulated proliferation and hypermutation”, Nature, 509(7502):637-40 (2014). [cited by applicant]
Hartmann, “Delineation of a CpG Phosphorothioate oligodeoxynucleotide for activating primate immune responses in vitro and in vivo”, J. of Immun., 164(3):1617-24 (2000). [cited by applicant]
International Search Report for corresponding PCT application PCT/US2019/041580 dated Dec. 6, 2019. [cited by applicant]
Ito, et al., “Cancer Neoantigens: A Promising Source of Immunogens for Cancer Immunotherapy” J. Clin. Cell Immunol., 6:322 (2015). [cited by applicant]
Johnson, et al., “Characterization of a nontoxic monophosphoryl lipid A”, Rev. Infect. Dis., 9 Suppl: S512-S516 (1987). [cited by applicant]
Kayagaki, et al., “Noncanonical Inflammasome activation by intracellular LPS independent of TLR4”, Science, 241(6151): 1246-1249 (2013). [cited by applicant]
Liu, et al., “Structure-based programming of lymph-node targeting in molecular vaccines”, Nature Letters, 507:519-22 (+ 11 pages of extended data) (2014). [cited by applicant]
Livingston, “Large Scale Synthesis of the Next Generation Synthetic Saponin Adjuvant TiterQuil”, National Institutes of Health, accessed Sep. 11, 2018. [cited by applicant]
Luderitz, et al., “Structural relationship of [cited by applicant]
Mascola, et al., “HIV-1 neutralizing antibodies: understanding nature's pathways”, Immunological reviews, 254(1):225-44 (2013). [cited by applicant]
Morelli, “Development of prophylactic and therapeutic vaccines using the ISCOMATRIX adjuvant”, Immunology and Cell, 87(5):371-6 (2009). [cited by applicant]
Morelli, et al., “ISCOMATRIX: a novel adjuvant for use in prophylactic and therapeutic vaccines against infectious diseases”, J. Med. Microbiol., 61(Pt 7):935-43 (2012). [cited by applicant]
Phan, et al., “Immune complex relay by subcapsular sinus microphages and noncognate B cells drives antibody affinity maturation”, Nat. Immunol., 10(7):786-793 (2009). [cited by applicant]
Phan, et al., “Subcapsular encounter and complement-dependent transport of immune complexes by lymph node B cells”, Nat. Immunol., 8(9):992-1000 (2007). [cited by applicant]
Ragupathi, et al., “Natural and synthetic Saponin adjuvant QS-21 for vaccines against cancer”, Expert Rev. Vaccines, 10(4): 463-70 (2011). [cited by applicant]
Ramirez-Ortiz, Zaida G., et al., “Toll-Like Receptor 9-Dependent Immune Activation by unmethylated CpG Motifs in Aspergillus fumigatus DNA”, Infection and Immunity, 2123-2129 (2008). [cited by applicant]
Schumacher et al., “Neoantigens in cancer immunotherapy”, Science, 348(6230):69-74 (2015). [cited by applicant]
Shi, et al., “Inflammatory caspases are innate immune receptors for intracellular LPS”, Nature, 514(7521): 187-192 (2014). [cited by applicant]
Silva, et al., “The Combination of ISCOMATRIX Adjuvant and TLR Agonists Induces Regression of Established Solid Tumors In Vivo”, J Immunol., 194(5):2199-207 (2015). [cited by applicant]
Silveira, et al., “Quillaja brasiliensis saponins are less toxic than Quil A and have similar properties when used as an adjuvant for a viral antigen preparation”, Vaccine, 29:9177-82 (2011). [cited by applicant]
Sun, et al., “ISCOMs and ISCOMATRIX”, Vaccine, 27(33):4388-401 (2009). [cited by applicant]
Vochten, et al., “Physico-chemical properties of sapoalbin and their relation to the foam stability”, J. Pharm. Belg., 42:213-26 (1968). [cited by applicant]
Vollmer and Krieg, “Immunotherapeutic applications of CpG oligodeoxynucleotide TLR9 agonists”, Adv. Drug Deliv Rev, 61(3): 195-204 (2009). [cited by applicant]
Weiner, “Immunostimulatory oligodeoxynucleotides containing the CpG motif are effective as immune adjuvants in tumor antigen immunization”, PNAS, 94(20): 10833-7 (1997). [cited by applicant]
What are The Differences Between Liposomes And Micelles?, downloaded online Mar. 29, 2022 from Website of Avanti Polar Lipids. [cited by applicant]
Wilson, et al., “Inflammasome-Dependent and -Independent IL-18 Production Mediates Immunity to the ISCOMATRIX Adjuvant”, J. Immunol., 192(7):3259-68 (2014). [cited by applicant]
Yoshikawa, et al., “Bioactive saponins and glycosides. III. Horse chestnut. (1): The structures, inhibitory effects on ethanol absorption, and hypoglycemic activity of escins Ia, Ib, IIa, IIb, and IIIa from the seeds of [cited by applicant]
Zaida, et al., “Toll-like receptor 9-dependent immune activation by unmethylated CpG motifs in Aspergillus fumigatus DNA”, Infect. Immun., 76(5):2123-9, (2008). [cited by applicant]
Zu, et al., “Recent Development in the Synthesis of Natural Saponins and Their Derivatives”, J. Carb. Chem., 33(6):269-97 (2014). [cited by applicant]