Search

US-12622922-B2 - Compositions and methods for metal containing formulations capable of modulating immune response

US12622922B2US 12622922 B2US12622922 B2US 12622922B2US-12622922-B2

Abstract

This disclosure provides compositions and methods for stimulating the innate immune response in a subject with agents capable of stimulating an innate immune response in a subject upon administration to the subject (e.g., damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs)). In particular, the present invention is directed to compositions of DAMPs/PAMPs and metals ions, as well as systems and methods utilizing such nanoparticles (e.g., in diagnostic and/or therapeutic settings).

Inventors

  • James J. Moon
  • Xiaoqi SUN

Assignees

  • THE REGENTS OF THE UNIVERSITY OF MICHIGAN

Dates

Publication Date
20260512
Application Date
20190712

Claims (19)

  1. 1 . A composition comprising a nanoparticle comprising one or more stimulator of interferon genes (STING) agonists and/or Toll-Like receptor (TLR) agonists, and one or more cations selected from the group consisting of Zn 2+ , Mn 2+ , Fe 2+ , Fe 3+ , Cu 2+ , Ni 2+ , Co 2+ , Pb 2+ , Sn 2+ , Ru 2+ , Au 2+ , Mg 2+ , VO 2+ , Al 3+ , Co 3+ , Cr 3+ , Ga 3+ , Tl 3+ , Ln 3+ , MoO 3+ , Cu + , Au + , Tl + , Ag + , Hg 2+ , Pt 2+ , Pb 2+ , Hg 2+ , Cd 2+ , Pd 2+ , Pt 4+ , Na + , and K + , wherein the nanoparticle further comprises poly (histidine)-polyethylene glycol (PH-PEG) or lipid-poly-histidine.
  2. 2 . The composition of claim 1 , wherein the one or more STING agonists, is selected from the group consisting of cGAMP, cdiAMP, cdiGMP, cAIMP, 2′3′-cGAMP, 3′3′-cGAMP, c-di-AMP, c-di-GMP, cAIMP Difluor, cAIM(PS)2, Difluor (Rp/Sp), 2′2′-cGAMP, 2′3′-cGAM(PS)2 (Rp/Sp), 3′3′-cGAMP Fluorinated, c-di-AMP Fluorinated, 2′3′-c-di-AMP, 2′3′-c-di-AM(PS)2 (Rp,Rp), c-di-GMP Fluorinated, 2′3′-c-di-GMP, c-di-IMP, eGAM(PS)2, 2′2′-cGAM(PS)2,2′3′-cGAM(PS)2, cGAMP Fluorinated, 2′3′-cGAMP Fluorinated, 2′2′-cGAMP Fluorinated, 2′3′-cdAMP, 2′2′-cdAMP, 3′3′-cdAMP, c-di-AM(PS)2, 2′2′-c-di-AM(PS)2,3′3′-c-di-AM(PS)2, 2′3′-cdAMP Fluorinated, 2′2′-cdAMP Fluorinated, 3′3′-cdAMP Fluorinated, cdGMP, 2′3′-cdGMP, 2′2′-cdGMP, 3′3′-cdGMP, c-di-GM(PS)2,2′3′-c-di-GM(PS)2,2′2′-c-di-GM(PS)2,3′3′-c-di-GM(PS)2, cdGMP Fluorinated, 2′3′-cdGMP Fluorinated, 2′2′-cdGMP Fluorinated, 3′3′-cdGMP Fluorinated, 2′3′-cAIMP, 2′2′-cAIMP, 3′3′-cAIMP, cAIMP Difluor (3′3′-cAIMP Fluorinated, 2′3′-cAIMP Fluorinated, 2′2′-cAIMP Fluorinated, cAIM(PS)2 Difluor, 3′3′-cAIM(PS)2 Difluor (Rp/Sp), 2′3′-cAIM(PS)2 Difluor, 2′2′-cAIM(PS)2 Difluor, 2′3′-cdIMP, 2′2′-cdIMP, 3′3′-cdIMP, c-di-IM(PS)2,2′3′-c-di-IM(PS)2,2′2′-c-di-IM(PS)2,3′3′-c-di-IM(PS)2, c-di-IMP Fluorinated, 2′3′-cdIMP Fluorinated, 2′2′-cdIMP Fluorinated, 3′3′-cdIMP Fluorinated, and amidobenzimidazole (ABZI)-based compounds; wherein the one or more TLR agonists are selected from TLR-3 agonists, TLR-4 agonists, TLR-5 agonists, TLR-7 agonists, TLR-8 agonists, TLR-9 agonists.
  3. 3 . The composition of claim 1 , wherein the nanoparticle is encapsulated within a liposome.
  4. 4 . The composition of claim 3 , wherein the nanoparticle is further associated with an antigen, wherein associated is selected from complexed, conjugated, encapsulated, absorbed, adsorbed, and admixed; wherein the antigen is derived from a self-antigen and/or is selected from the group consisting of alpha-actinin-4, Bcr-Abl fusion protein, Casp-8, beta-catenin, cdc27, cdk4, cdkn2a, coa-1, dek-can fusion protein, EF2, ETV6-AML1 fusion protein, LDLR-fucosyltransferaseAS fusion protein, HLA-A2, HLA-A11, hsp70-2, KIAAO205, Mart2, Mum-1, 2, and 3, neo-PAP, myosin class I, OS-9, pml-RARα fusion protein, PTPRK, K-ras, N-ras, Triosephosphate isomerase, Bage-1, Gage 3,4,5,6,7, GnTV, Herv-K-mel, Lage-1, Mage-A1,2,3,4,6, 10,12, Mage-C2, NA-88, NY-Eso-1/Lage-2, SP17, SSX-2, and TRP2-Int2, MelanA, gp100, tyrosinase, TRP-1, TRP-2, MAGE-1, MAGE-3, BAGE, GAGE-1, GAGE-2, p15 (58), CEA, RAGE, NY-ESO, SCP-1, Hom/Mel-40, PRAME, p53, H-Ras, HER-2/neu, BCR-ABL, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, Epstein Barr virus antigens, EBNA, human papillomavirus (HPV) antigens E6 and E7, TSP-180, MAGE-4, MAGE-5, MAGE-6, p185erbB2, p180erbB-3, c-met, nm-23H1, PSA, TAG-72-4, CA 19-9, CA 72-4, CAM 17.1, NuMa, K-ras, β-Catenin, CDK4, Mum-1, p16, TAGE, PSMA, PSCA, CT7, telomerase, 43-9F, 5T4, 791Tgp72, α-fetoprotein, 13HCG, BCA225, BTAA, CA 125, CA 15-3, CA 195, CA 242, CA-50, CAM43, CD68\KP1, CO-029, FGF-5, G250, Ga733, human EGFR protein or its fragments, HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB\70K, NY-CO-1, RCAS1, SDCCAG16, TA-90, TAAL6, TAG72, TLP, TPS, WT1 (and WT1-derived peptide sequences: WT1 126-134 (RMFP NAPYL (SEQ ID NO:376)), WT1 122-140 (SGQARMFPNAPYLPSCLES (SEQ ID NO:377)), and WT1 122-144 (SGQARMFPNAPYLPSCLESQPTI (SEQ ID NO:378)), MUC1, LMP2, EGFRVIII, Idiotype, GD2, Ras mutant, p53 mutant, Proteinase3, Survivin, hTERT, Sarcoma translocation breakpoints, EphA2, EphA4, LMW-PTP, PAP, ML-IAP, AFP, ERG, NA17, PAX3, ALK, Androgen receptor, Cyclin B1, Polysialic acid, MYCN, RhoC, TRP-2, GD3, Fucosyl GM1, Mesothelin, sLe, CYP1B1, PLAC1, GM3, BORIS, Tn, GloboH, NY-BR-1, RGS5, SART3, STn, Carbonic anhydrase IX, PAX5, OY-TES1, Sperm protein 17, LCK, HMWMAA, AKAP-4, XAGE 1, B7H3, Legumain, Tie 2, Page4, VEGFR2, MAD-CT-1, FAP, PDGFR-alpha, PDGFR-β, MAD-CT-2, Fos-related antigen 1, ERBB2, Folate receptor 1, IDH1, IDO, LY6K, fms-related tyro-sine kinase 1, KDR, PADRE, TA-CIN, SOX2, neoantigens, and aldehyde dehydrogenase.
  5. 5 . The composition of claim 4 , wherein the antigen is conjugated to the outer surface of the nanoparticle.
  6. 6 . The composition of claim 1 , wherein the nanoparticle is further associated with an adjuvant, wherein associated is selected from complexed, conjugated, encapsulated, absorbed, adsorbed, and admixed, wherein the adjuvant is selected from the group consisting of CPG, polyIC, poly-ICLC, 1018 ISS, aluminum salts, BCG, CP-870,893, CpG7909, CyaA, dSLIM, Cytokines, IC30, IC31, Imiquimod, IS Patch, ISS, MF59, monophosphoryl lipid A, OK-432, OM-174, OM-197-MP-EC, vector system, PLGA microparticles, imiquimod, resiquimod, gardiquimod, 3M-052, SRL172, Virosomes, YF-17D, VEGF trap, beta-glucan, Pam3Cys, vadimezan, AsA404, glucopyranosyl lipid adjuvant, GLA-SE, CD1d ligands, STING agonists, CL401, CL413, CL429, Flagellin, RC529, E6020, imidazoquinoline-based small molecule TLR-7/8a, AS01, AS02, AS03, AS04, AS15, IC31, CAF01, ISCOM, Cytokines, bacterial toxins, and any combination of adjuvant.
  7. 7 . The composition of claim 3 , wherein the average particle size of the nanoparticle is between 6 to 500 nm.
  8. 8 . The composition of claim 1 , wherein the nanoparticle comprises (i) one or more STING agonists and/or TLR agonists, (ii) Zn 2+ , and (iii) PH-PEG or lipid-poly-histidine.
  9. 9 . The composition of claim 8 , wherein the nanoparticle comprises (i) c-di-AMP, Zn 2+ , and PH-PEG or lipid-poly-histidine.
  10. 10 . The composition of claim 9 , wherein the nanoparticle comprises PH-PEG.
  11. 11 . The composition of claim 9 , wherein the nanoparticle comprises lipid-poly-histidine.
  12. 12 . The composition of claim 11 , wherein the lipid-poly-histidine comprises 11 histidine residues.
  13. 13 . The composition of claim 11 , wherein the lipid of the lipid-poly-histidine is dioleoylphosphatidylethanolamine (DOPE).
  14. 14 . The composition of claim 1 , wherein the nanoparticle comprises (i) one or more STING agonists and/or TLR agonists, (ii) Mn 2+ , and (iii) PH-PEG or lipid-poly-histidine.
  15. 15 . The composition of claim 14 , wherein the nanoparticle comprises (i) c-di-AMP, (ii) Mn 2+ , and (iii) PH-PEG or lipid-poly-histidine.
  16. 16 . The composition of claim 15 , wherein the nanoparticle comprises PH-PEG.
  17. 17 . The composition of claim 15 , wherein the nanoparticle comprises lipid-poly-histidine.
  18. 18 . The composition of claim 17 , wherein the lipid-poly-histidine comprises 11 histidine residues.
  19. 19 . The composition of claim 17 , wherein the lipid of the lipid-poly-histidine is dioleoylphosphatidylethanolamine.

Description

CROSS REFERENCE TO RELATED APPLICATIONS The application is a national stage of International (PCT) Patent Application Serial No. PCT/US2019/041659, filed Jul. 12, 2019, which claims priority to U.S. Provisional Patent Application 62/697,092, filed Jul. 12, 2018 the entire contents of which are incorporated herein by reference. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under CA210273 awarded by the National Institutes of Health. The government has certain rights in the invention. FIELD OF THE INVENTION This disclosure provides compositions and methods for stimulating the innate immune response in a subject with agents capable of stimulating an innate immune response in a subject upon administration to the subject (e.g., damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs)). In particular, the present invention is directed to compositions of DAMPs/PAMPs and metals ions, as well as systems and methods utilizing such nanoparticles (e.g., in diagnostic and/or therapeutic settings). BACKGROUND OF THE INVENTION The innate immune system is humans' first line of defense, and activation of which can induce pro-inflammation cytokines secretion and orchestrate adaptive immune systems. DAMPs and PAMPs represent two major innate immune stimulators. DAMPs are endogenous host biomolecules released upon tissue damage and include heat-shock proteins and HMGB1 (high-mobility group box 1), ATP, uric acid, hyaluronan fragments, heparin sulfate and tumor-derived DNA. PAMPs are conserved pathogen components recognized by various pathogen recognition receptors (PRRs) and induce anti-pathogen inflammation. PAMPs include ligands of Toll-Like receptors (TLRs), NOD-Like receptors (NLRs), RIG-I-Like receptors (RLRs), cytosolic DNA sensors (CDS), stimulator of IFN genes (STING) agonists, purine containing or purine derived agents, and C-type lectin receptors (CLRs). DAMPs and PAMPs can induce pro-inflammatory cytokines production and immune cell pro-inflammation phenotypic change, which are critical for both cancer and autoimmune disease. On one hand, the pro-inflammation phenotypic change could break the immune-suppressive tumor microenvironment, tuning “cold tumor” to “hot tumor”. Therefore, TLR-3, TLR4, TLR7, TLR9, NLRP3 and STING agonists are currently in clinical trials for cancer immunotherapy. Especially, tumor-derived DNA-cGAS-STING pathway has been recently found to be critical for tumor immune surveillance and shown dramatic cancer immunotherapy effect in preclinical studies, which led to a number of phase I clinical trials of STING agonists. On the other hand, DAMPs and PAMPs are extensively involved in occurrence and progress of autoimmune diseases. Inhibition of abnormal innate immune activation is emerging to be effective therapy for many uncurable autoimmune diseases. Modulating DAMP and PAMP mediated immune responses will provide new therapeutic approaches for diverse human diseases, including cancer and autoimmune diseases. This present invention addresses this need. SUMMARY Immune checkpoint blockades can allow patients' own immune system to fight against cancer. However, the current average response rate to immune check point blockades is only around 30%. This may be attributed to that some tumors, characterized as “cold tumors”, are less visible to the immune system. The characters of such tumors include low inflammatory responses, less mutation burden, and deficient tumoral-infiltration of T cells and other pro-inflammatory immune cells. In contrast, “hot tumors”, with more inflammatory signatures available for immune system recognize, have better therapeutic response rate to cancer immunotherapy. Therefore, it is critical to understand how to turn “cold tumors” into “hot tumors”. Accumulating evidence indicates that immune surveillance of tumors, mediated by the innate immune system, recognizes the presence of tumor by sensing tumor cell-derived DNA by STING pathway. The activation of STING pathway could elicit innate immune cascade, such as type-I interferon response and other pro-inflammation phenotypic change, which further elicit adaptive antitumor reaction. Therefore, STING is regarded as the “trigger” of the reversion from “cold tumor” to “hot tumor”. For example, intra-tumoral administration of STING agonists could elicit antitumor immune response to both local and metastatic tumors. In a clinical setting, type-1 interferon response is found to be a signature of better cancer therapy prognosis similar to antigen-specific T cells infiltration. Therefore, developing STING agonists with great in-vivo stability, favorable pharmacokinetics properties and acceptable safety profiles is of great significance and high translational value. However, most human STING agonists under current evaluations are based on cyclic dinucleotides and their derivates. Their small molecular weight, poor pharmacokinetics pa