IP Library › Granted Patent US 12,453,777
Granted Patent B2
US 12,453,777 · App. 16/825,482 · Granted Oct 28, 2025

Uses of amphiphiles in immune cell therapy and compositions therefor

Inventors: Darrell J. Irvine (Arlington, MA); Peter C. Demuth (Medford, MA)
Assignee: Massachusetts Institute of Technology
A61K47/543A61K39/39A61K40/11A61K40/31A61K40/32A61K40/4202C07K14/705C07K14/7051C07K14/70521C07K16/2803C07K16/2866C07K2317/622C07K2317/76C07K2319/02C07K2319/03C07K2319/30C07K2319/33
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Quick Facts
Patent No.
US 12,453,777
App. No.
16/825,482
Granted
Oct 28, 2025
Kind
B2
Abstract

Provided herein are methods for stimulating an immune response to a target cell population or a target tissue in a subject by administering to the subject a composition comprising an amphiphilic ligand conjugate. Such an amphiphilic ligand conjugate can comprise a lipid, one or more cargos (e.g., a CAR ligand, a chimeric cytokine receptor target, a chimeric co-stimulation receptor target, a synNotch receptor target), and optionally a linker.

Claims (10)

1. A method of stimulating an immune response to a target cell population or a target tissue in a subject, the method comprising administering a composition to the subject, wherein the composition comprises an amphiphilic ligand conjugate comprising a lipid, a chimeric antigen receptor (CAR) ligand, and a polar block linker that couples the lipid to the CAR ligand,

wherein the lipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), the linker is a polyethylene glycol (PEG) linker, the CAR ligand is fluorescein isothiocyanate (FITC),

wherein the subject comprises an immune cell comprising a CAR,

wherein the CAR comprises an extracellular domain comprising a target-binding domain that binds to FITC,

wherein the immune cell is a B cell, a natural killer (NK) cell, a macrophage, a neutrophil, a dendritic cell, a mast cell, an eosinophil, a basophil, or a tumor infiltrating lymphocyte (TIL), and

wherein the immune cell is not a T cell.

2. The method of claim 1 , wherein the CAR further comprises a transmembrane domain and an intracellular signaling domain.

3. The method of claim 2 , wherein the CAR further comprises one or more co-stimulatory domains.

4. The method of claim 1 , wherein the composition further comprises an adjuvant, wherein the adjuvant is an amphiphilic oligonucleotide conjugate comprising an immunostimulatory oligonucleotide conjugated to a lipid, with or without a linker, and optionally a polar compound.

5. The method of claim 1 , wherein the amphiphilic ligand conjugate binds albumin under physiological conditions.

Assignments (5)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 14, 2020
From: HOWARD HUGHES MEDICAL INSTITUTE
To: IRVINE, DARRELL
Reel/Frame 052391/0149 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 14, 2020
From: IRVINE, DARRELL J.
To: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Reel/Frame 052391/0166 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 14, 2020
From: DEMUTH, PETER C.
To: ELICIO THERAPEUTICS, INC.
Reel/Frame 052391/0200 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 14, 2020
From: ELICIO THERAPEUTICS, INC.
To: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Reel/Frame 052391/0239 →
CONFIRMATION OF ASSIGNMENT Recorded Apr 14, 2020
From: IRVINE, DARRELL
To: HOWARD HUGHES MEDICAL INSTITUTE
Reel/Frame 052392/0054 →
Continuity (2)
Provisional Application 62821248 · Mar 20, 2019
Related Publication 20200345853A1 · Nov 5, 2020
References Cited (145)
US 7615539B2 · Uhlmann et al. · 2009 [cited by applicant]
US 7741297B2 · Jiang et al. · 2010 [cited by applicant]
US 9426778B2 · Onozawa et al. · 2016 [cited by applicant]
US 10029016B2 · Irvine et al. · 2018 [cited by applicant]
US 10953105B2 · Irvine et al. · 2021 [cited by applicant]
US 20060246126A1 · Allen et al. · 2006 [cited by applicant]
US 20070104654A1 · Hsieh et al. · 2007 [cited by applicant]
US 20070154398A1 · Wang et al. · 2007 [cited by applicant]
US 20080139262A1 · Lin · 2008 [cited by applicant]
US 20100183639A1 · Uhlmann et al. · 2010 [cited by applicant]
US 20110300163A1 · Champion et al. · 2011 [cited by applicant]
US 20120087949A1 · Tan et al. · 2012 [cited by applicant]
US 20120121606A1 · Ruben et al. · 2012 [cited by applicant]
US 20120129199A1 · Daftarian et al. · 2012 [cited by applicant]
US 20120294931A1 · Kim et al. · 2012 [cited by applicant]
US 20130295129A1 · Irvine et al. · 2013 [cited by applicant]
US 20140099337A1 · Davis et al. · 2014 [cited by applicant]
US 20140162944A1 · Tiberg et al. · 2014 [cited by applicant]
US 20140255378A1 · Watkins et al. · 2014 [cited by applicant]
US 20140294932A1 · Kim et al. · 2014 [cited by applicant]
US 20150044208A1 · Castanheira Aires da Silva et al. · 2015 [cited by applicant]
US 20150232514A1 · Dockal et al. · 2015 [cited by applicant]
US 20150283205A1 · Phipps et al. · 2015 [cited by applicant]
US 20160228573A1 · Niyikiza et al. · 2016 [cited by applicant]
US 20160361360A1 · Chang et al. · 2016 [cited by applicant]
US 20170224797A1 · Popescu et al. · 2017 [cited by applicant]
US 20180028634A1 · Chen · 2018 [cited by applicant]
US 20190062457A1 · Elias · 2019 [cited by examiner]
US 20200230221A1 · Irvine et al. · 2020 [cited by applicant]
US 20210187112A1 · Irvine et al. · 2021 [cited by applicant]
US 20230372395A1 · Irvine · 2023 [cited by examiner]
US 20240082373A1 · Irvine et al. · 2024 [cited by applicant]
EP 0491628A2 · 1992 [cited by applicant]
JP 8510255A · 1996 [cited by applicant]
JP 2010507386A · 2010 [cited by applicant]
JP 2014504294A · 2014 [cited by applicant]
JP 2015514108A · 2015 [cited by applicant]
KR 1020150030724A · 2015 [cited by applicant]
WO 1994001138A1 · 1994 [cited by applicant]
WO 1994026778A1 · 1994 [cited by applicant]
WO 2003066649A1 · 2003 [cited by applicant]
WO 2004029277A2 · 2004 [cited by applicant]
WO 2005117984A2 · 2005 [cited by applicant]
WO 2008115319A2 · 2008 [cited by applicant]
WO 2008121949A1 · 2008 [cited by applicant]
WO 2008139262A2 · 2008 [cited by applicant]
WO 2010071852A2 · 2010 [cited by applicant]
WO 2012082841A2 · 2012 [cited by applicant]
WO 2013151771A1 · 2013 [cited by applicant]
WO 2014011987A1 · 2014 [cited by applicant]
WO 2014204762A1 · 2014 [cited by applicant]
WO 2015057834A1 · 2015 [cited by applicant]
WO 2016069647A1 · 2016 [cited by applicant]
WO 2017035009A1 · 2017 [cited by applicant]
WO 2017137477A1 · 2017 [cited by applicant]
WO 2017141243A1 · 2017 [cited by applicant]
WO 2019060425A1 · 2019 [cited by applicant]
Glienke et al, Frontiers in Pharmacology, Feb. 12, 2015, vol. 6, Article 21, p. 1-7. (Year: 2015). [cited by examiner]
Malia et al, Proteins, 2016, 84:427-434. (Year: 2016). [cited by examiner]
Barthelemy et al, Journal of Biological Chemistry, 2008, 283:3639-3654. (Year: 2008). [cited by examiner]
Beiboer et al, Journal of Molecular Biology, 2000, 296:833-849. (Year: 2000). [cited by examiner]
Choi et al, 2011, Molecular Biosystems, 2011, 7:3327-3334. (Year: 2011). [cited by examiner]
De Genst et al, Developmental and Comparative Immunology, 2006, 30:187-98. (Year: 2006). [cited by examiner]
Griffiths et al, The EMBO Journal, 1993, 12:725-734. (Year: 1993). [cited by examiner]
Klimka et al, British Journal of Cancer, 2000, 83:252-260. (Year: 2000). [cited by examiner]
Ward et al, Nature, 1989, 341:544-546. (Year: 1989). [cited by examiner]
U.S. Appl. No. 16/644,893, filed Mar. 5, 2020, Darrell J. Irvine. [cited by applicant]
International Preliminary Report on Patentability, PCT/US2020/023896, dated Sep. 16, 2021, 12 pages. [cited by applicant]
International Search Report and Written Opinion, PCT/US2020/023896, dated Sep. 16, 2020, 21 pages. [cited by applicant]
Takagi, M. et al., “Chimeric Cytokine Receptor Can Transduce Expansion Signals in Interleukin 6 Receptor alpha (IL-6Ra)-IL-11Ra-, and gp130-low to -negative Primitive Hematopoietic Progenitors,” Molecular Biology of the… [cited by applicant]
Watanabe, N. et al., “Molecular Therapy,” vol. 22, Supplement 1, (2014)Copyright The American Society of Gene & Cell Therapy Cancer-Targeted Gene & Cell Therapy II 772. Conferring CAR T Cells With Resistance to TGF[beta… [cited by applicant]
Wilkie, S. et al., “Selective Expansion of Chimeric Antigen Receptor-targeted T-cells with Potent Effector Function using Interleukin-4” Journal of Biological Chemistry, vol. 285 (33):25538-25544 (2010). [cited by applicant]
Bejestani, E. et al., “Characterization of a switchable chimeric antigen receptor platform in a pre-clinical solid tumor model,” OncoImmunology, 16 pages (2017). [cited by applicant]
Cao, Y. et al., “Design of Switchable Chimeric Antigen Receptor T Cells Targeting Breast Cancer,” Angew. Chem. Int. Ed., vol. 55: 7520-7524 (2016). [cited by applicant]
International Preliminary Report on Patentability, PCT/US2018/051764, dated Mar. 24, 2020, 9 pages. [cited by applicant]
International Search Report and Written Opinion, PCT/US2018/051764, dated Mar. 8, 2019, 13 pages. [cited by applicant]
Invitation to Pay Additional Fees, and, Where Applicable, Protest Fee, PCT/US2020/023896, dated Jun. 19, 2020, 14 pages. [cited by applicant]
Irvine, D. et al. “Enhancing combination immunotherapy and adoptive cell therapy of cancer via lymph node-targeted vaccines,” Synthetic Immunotherapy, Abstract IA06:pp. IA06-IA06 (2018). [cited by applicant]
Irvine, D. et al. “Enhancing the function of CAR T cells via a universal vaccine strategy,”Abstract IA37: Cancer Immunology Research, 4th CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Sci… [cited by applicant]
Kim, M-S., et al., “Redirection of Genetically Engineered CAR-T Cells Using Bifunctional Small Molecules,” J. Am. Chem. Soc, 4 page (2015). [cited by applicant]
Kudo, K. et al., “T Lymphocytes Expressing a CD16 Signaling Receptor Exert Antibody-Dependent Cancer Cell Killing,” Cancer Res., vol. 74(1):93-103 (2013). [cited by applicant]
Liu, H. et al., “Structure-based programming of lymphnode targeting in molecular vaccines,” Nature, vol. 507 (7493):519-522 (2014). [cited by applicant]
Lohmueller, J. et al., “mSA2 affinity-enhanced biotin-binding CAR-T cells for universal tumor targeting,” OncoImmunology, 21 pages (2017). [cited by applicant]
Ma, J. et al., “Versatile strategy for controlling the specificity and activity of engineered T cells,” PNAS, vol. 113(4): E450-E458 (2016). [cited by applicant]
Ma, L. et al., “Enhanced CAR-T cell activity against solid tumors by vaccine boosting through the chimeric receptor,” Science.vol. 365: 162-168 (2019). [cited by applicant]
Rodgers, D. et al., “Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies,” PNAS, 113(4): E459-E468 (2016). [cited by applicant]
Urbanska, K. et al., “A Universal Strategy for Adoptive Immunotherapy of Cancer through Use of a Novel T-cell Antigen Receptor,” Cancer Research, vol. 72:1844-1852 (2012). [cited by applicant]
Aldwell et al., Oral delivery of lipid-encapsulated Mycobacterium bovis BCG extends survival of the bacillus in vivo and induces a long-term protective immune response against tuberculosis. Vaccine. Mar. 15, 2006;24(12)… [cited by applicant]
Andrews et al., Conjugation of lipid and CpG-containing oligonucleotide yields an efficient method for liposome Incorporation. Bioconjug Chem. Jul. 20, 2011;22(7):1279-86. [cited by applicant]
Bachmann et al., Vaccine delivery: a matter of size, geometry, kinetics and molecular patterns. Nat Rev Immunol. Nov. 2010;10(11):787-96. [cited by applicant]
Bagby et al., Impact of molecular weight on lymphatic drainage of a biopolymer-based imaging agent. Pharmaceutics. May 23, 2012;4(2):276-95. [cited by applicant]
Ballas et al., Divergent therapeutic and immunologic effects of oligodeoxynucleotides with distinct CpG motifs. J Immunol. Nov. 1, 2001;167(9):4878-86. [cited by applicant]
Bedoui et al., Cross-presentation of viral and self antigens by skin-derived CD103+ dendritic cells. Nat Immunol. May 2009;10(5):488-95. [cited by applicant]
Bourquin et al., Targeting CpG oligonucleotides to the lymph node by nanoparticles elicits efficient antitumoral Immunity. J Immunol. Sep. 1, 2008;181(5):2990-8. [cited by applicant]
Cai et al., Lymphatic drug delivery using engineered liposomes and solid lipid nanoparticles. Adv Drug Deliv Rev. Sep. 10, 2011;63(10-11):901-8. [cited by applicant]
Cuomo et al., Oligonucleotides and polynucleotides condensation onto liposome surface: effects of the base and of the nucleotide length. Colloids Surf B Biointerfaces. Apr. 1, 2013;104:239-44. [cited by applicant]
Dass. Lipoplex-mediated delivery of nucleic acids: factors affecting in vivo transfection. J Mol Med (Berl). Sep. 2004;82 (9):579-91. [cited by applicant]
Davis. G-quartets 40 years later: from 5′-GMP to molecular biology and supramolecular chemistry. Angew Chem Int Ed Engl. Jan. 30, 2004;43(6):668-98. [cited by applicant]
Fujita et al., Overview and outlook of Toll-like receptor ligand-antigen conjugate vaccines. Ther Deliv. Jun. 2012;3 (6):749-60. [cited by applicant]
Goldblatt. Conjugate vaccines. Clin Exp Immunol. Jan. 2000;119(1):1-3. [cited by applicant]
Heegaard et al., Dendrimers for vaccine and immunostimulatory uses. A review. Bioconjug Chem. Mar. 17, 2010;21 (3):405-18. [cited by applicant]
Hubbell et al., Materials engineering for immunomodulation. Nature. Nov. 26, 2009;462(7272):449-60. [cited by applicant]
Johansen et al., Lympho-geographical concepts in vaccine delivery. J Control Release. Nov. 20, 2010;148(1):56-62. [cited by applicant]
Kaminskas et al., PEGylation of polylysine dendrimers improves absorption and lymphatic targeting following SC administration in rats. J Control Release. Dec. 3, 2009;140(2):108-16. [cited by applicant]
Kaminskas et al., Targeting the lymphatics using dendritic polymers (dendrimers). Adv Drug Deliv Rev. Sep. 10, 2011;63(10-11):890-900. [cited by applicant]
Keler et al., Antibody-targeted vaccines. Oncogene. May 28, 2007;26(25):3758-67. [cited by applicant]
Klinman. Immunotherapeutic uses of CpG oligodeoxynucleotides. Nat Rev Immunol. Apr. 2004;4(4):249-58. [cited by applicant]
Kobayashi et al., Delivery of gadolinium-labeled nanoparticles to the sentinel lymph node: comparison of the sentinel hode visualization and estimations of intra-nodal gadolinium concentration by the magnetic resonance … [cited by applicant]
Kobayashi et al., Multimodal nanoprobes for radionuclide and five-color near-infrared optical lymphatic imaging. ACS Nano. Nov. 2007;1(4):258-64. [cited by applicant]
Kwong et al., Induction of potent anti-tumor responses while eliminating systemic side effects via liposome-anchored combinatorial immunotherapy. Biomaterials. Aug. 2011;32(22):5134-47. [cited by applicant]
Liu et al., DNA-based micelles: synthesis, micellar properties and size-dependent cell permeability. Chemistry. Mar. 22, 2010;16(12):3791-7. [cited by applicant]
Liu et al., Guiding principles in the design of molecular bioconjugates for vaccine applications. Bioconjug Chem. May 20, 2015;26(5):791-801. [cited by applicant]
Liu et al., Membrane anchored immunostimulatory oligonucleotides for in vivo cell modification and localized immunotherapy. Angew Chem Int Ed Engl. Jul. 25, 2011;50(31):7052-5. [cited by applicant]
Manolova et al., Nanoparticles target distinct dendritic cell populations according to their size. Eur J Immunol. May 2008;38(5):1404-13. [cited by applicant]
McLennan et al., Subcutaneous drug delivery and the role of the lymphatics. Drug Discov Today Technol. 2005 Spring;2(1):89-96. [cited by applicant]
Mishra et al., Improved leishmanicidal effect of phosphorotioate antisense oligonucleotides by LDL-mediated delivery. Biochim Biophys Acta. Nov. 7, 1995;1264(2):229-37. [cited by applicant]
Moon et al., Engineering nano- and microparticles to tune immunity. Adv Mater. Jul. 24, 2012;24(28):3724-46. [cited by applicant]
Moyle et al., Modern subunit vaccines: development, components, and research opportunities. ChemMedChem. Mar. 2013;8(3):360-76. [cited by applicant]
Oyewumi et al., Nano-microparticles as immune adjuvants: correlating particle sizes and the resultant immune responses. Expert Rev Vaccines. Sep. 2010;9(9):1095-107. [cited by applicant]
Pal et al., The role of the lymphatic system in vaccine trafficking and immune response. Adv Drug Deliv Rev. Sep. 10, 2011;63(10-11):909-22. [cited by applicant]
Pape et al., The humoral immune response is initiated in lymph nodes by B cells that acquire soluble antigen directly in the follicles. Immunity. Apr. 2007;26(4):491-502. [cited by applicant]
Paramasivan et al., Circular dichroism of quadruplex DNAs: applications to structure, cation effects and ligand binding. Methods. Dec. 2007;43(4):324-31. [cited by applicant]
Perrie et al., Vaccine adjuvant systems: enhancing the efficacy of sub-unit protein antigens. Int J Pharm. Dec. 8, 2008;364(2):272-80. [cited by applicant]
Pilishvili et al., Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine. J Infect Dis. Jan. 1, 2010;201(1):32-41. [cited by applicant]
Rao et al., Biodegradable PLGA based nanoparticles for sustained regional lymphatic drug delivery. J Pharm Sci. Apr. 2010;99(4):2018-31. [cited by applicant]
Reddy et al., Exploiting lymphatic transport and complement activation in nanoparticle vaccines. Nat Biotechnol. Oct. 2007;25(10):1159-64. [cited by applicant]
Robbins et al., Polysaccharide-protein conjugates: a new generation of vaccines. J Infect Dis. May 1990;161 (5):821-32. [cited by applicant]
Schnorrer et al., The dominant role of CD8+ dendritic cells in cross-presentation is not dictated by antigen capture. Proc Natl Acad Sci U S A. Jul. 11, 2006;103(28):10729-34. [cited by applicant]
Senti et al., Intralymphatic immunotherapy. Curr Opin Allergy Clin Immunol. Dec. 2009;9(6):537-43. [cited by applicant]
Shariat et al., P5 HER2/neu-derived peptide conjugated to liposomes containing MPL adjuvant as an effective prophylactic vaccine formulation for breast cancer. Cancer Lett. Dec. 1, 2014;355(1):54-60. [cited by applicant]
Singh et al., Nanoparticles and microparticles as vaccine-delivery systems. Expert Rev Vaccines. Oct. 2007;6 (5):797-808. [cited by applicant]
Slovin et al., Carbohydrate vaccines as immunotherapy for cancer. Immunol Cell Biol. Aug. 2005;83(4):418-28. [cited by applicant]
Smith et al., Cutting edge: conventional CD8 alpha+ dendritic cells are preferentially involved in CTL priming after footpad infection with herpes simplex virus-1. J Immunol. May 1, 2003;170(9):4437-40. [cited by applicant]
St. John et al., Synthetic mast-cell granules as adjuvants to promote and polarize immunity in lymph nodes. Nat Mater. Jan. 22, 2012;11(3):250-7. [cited by applicant]
Storhoff et al., One-Pot Colorimetric Differentiation of Polynucleotides with Single Base Imperfections Using Gold Nanoparticle Probes. J Am. Chem. Soc. 1998;120(9):1959-64. [cited by applicant]
Tacken et al., Dendritic-cell immunotherapy: from ex vivo loading to in vivo targeting. Nat Rev Immunol. Oct. 2007;7 (10):790-802. [cited by applicant]
Takakura et al., Development of a novel polymeric prodrug of mitomycin C, mitomycin C-dextran conjugate with anionic charge. II. Disposition and pharmacokinetics following intravenous and intramuscular administration. I… [cited by applicant]
Tenbusch et al., Immunogenicity of DNA vaccines encoding simian immunodeficiency virus antigen targeted to dendritic cells in rhesus macaques. PLoS One. 2012;7(6):e39038. [cited by applicant]
Tsopelas et al., Why certain dyes are useful for localizing the sentinel lymph node. J Nucl Med. Oct. 2002;43 (10):1377-82. [cited by applicant]
Vollmer et al., Immunotherapeutic applications of CpG oligodeoxynucleotide TLR9 agonists. Adv Drug Deliv Rev. Mar. 28, 2009;61(3):195-204. [cited by applicant]
Von Beust et al., Improving the therapeutic index of CpG oligodeoxynucleotides by intralymphatic administration. Eur J Immunol. Jun. 2005;35(6):1869-76. [cited by applicant]
Wilson et al., Lipid-based delivery of CpG oligonucleotides enhances immunotherapeutic efficacy. Adv Drug Deliv Rev. Mar. 28, 2009;61(3):233-42. [cited by applicant]
Wong et al., Lymphatic drainage of skin to a sentinel lymph node in a feline model. Ann Surg. Nov. 1991;214 (5):637-41. [cited by applicant]
Wu et al., Fluorescence imaging of the lymph node uptake of proteins in mice after subcutaneous injection: molecular weight dependence. Pharm Res. Jul. 2012;29(7):1843-53. [cited by applicant]
Zepp. Principles of vaccine design—Lessons from nature. Vaccine. Aug. 31, 2010;28 Suppl 3:C14-24. [cited by applicant]