TAK-101 Nanoparticles Induce Gluten-Specific Tolerance in Celiac Disease: A Randomized, Double-Blind, Placebo-Controlled Study

      Background & aims

      In celiac disease (CeD), gluten induces immune activation, leading to enteropathy. TAK-101, gluten protein (gliadin) encapsulated in negatively charged poly(dl-lactide-co-glycolic acid) nanoparticles, is designed to induce gluten-specific tolerance.


      TAK-101 was evaluated in phase 1 dose escalation safety and phase 2a double-blind, randomized, placebo-controlled studies. Primary endpoints included pharmacokinetics, safety, and tolerability of TAK-101 (phase 1) and change from baseline in circulating gliadin-specific interferon-γ–producing cells at day 6 of gluten challenge, in patients with CeD (phase 2a). Secondary endpoints in the phase 2a study included changes from baseline in enteropathy (villus height to crypt depth ratio [Vh:Cd]), and frequency of intestinal intraepithelial lymphocytes and peripheral gut-homing T cells.


      In phase 2a, 33 randomized patients completed the 14-day gluten challenge. TAK-101 induced an 88% reduction in change from baseline in interferon-γ spot-forming units vs placebo (2.01 vs 17.58, P = .006). Vh:Cd deteriorated in the placebo group (−0.63, P = .002), but not in the TAK-101 group (−0.18, P = .110), although the intergroup change from baseline was not significant (P = .08). Intraepithelial lymphocyte numbers remained equal. TAK-101 reduced changes in circulating α4β7+CD4+ (0.26 vs 1.05, P = .032), αEβ7+CD8+ (0.69 vs 3.64, P = .003), and γδ (0.15 vs 1.59, P = .010) effector memory T cells. TAK-101 (up to 8 mg/kg) induced no clinically meaningful changes in vital signs or routine clinical laboratory evaluations. No serious adverse events occurred.


      TAK-101 was well tolerated and prevented gluten-induced immune activation in CeD. The findings from the present clinical trial suggest that antigen-specific tolerance was induced and represent a novel approach translatable to other immune-mediated diseases.

      Graphical abstract


      Abbreviations used in this paper:

      AE (adverse event), Ag (antigen), APC (antigen-presenting cell), CeD (celiac disease), CyTOF (time-of-flight mass cytometry), ELISpot (enzyme-linked immunospot), GFD (gluten-free diet), HLA (human leukocyte antigen), IEL (intraepithelial lymphocyte), IFN (interferon), IL (interleukin), MARCO (macrophage receptor with collagenous structure), PBMC (peripheral blood mononuclear cell), PK (pharmacokinetics), PLGA (poly(dl-lactide-co-glycolide)), SFU (spot-forming unit), Th (T helper cell), Treg (regulatory T cell), Vh:Cd (villus height to crypt depth ratio)
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        • Green P.H.
        • Lebwohl B.
        • Greywoode R.
        Celiac disease.
        J Allergy Clin Immunol. 2015; 135: 1099-1106
        • Singh P.
        • Arora A.
        • Strand T.A.
        • et al.
        Global prevalence of celiac disease: systematic review and meta-analysis.
        Clin Gastroenterol Hepatol. 2018; 16: 823-836.e2
        • Malamut G.
        • El Machhour R.
        • Montcuquet N.
        • et al.
        IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis.
        J Clin Invest. 2010; 120: 2131-2143
        • Mazzarella G.
        • Stefanile R.
        • Camarca A.
        • et al.
        Gliadin activates HLA class I-restricted CD8+ T cells in celiac disease intestinal mucosa and induces the enterocyte apoptosis.
        Gastroenterology. 2008; 134: 1017-1027
        • Han A.
        • Newell E.W.
        • Glanville J.
        • et al.
        Dietary gluten triggers concomitant activation of CD4+ and CD8+ αβ T cells and γδ T cells in celiac disease.
        Proc Natl Acad Sci U S A. 2013; 110: 13073-13078
        • Fasano A.
        • Catassi C.
        Clinical practice. Celiac disease.
        N Engl J Med. 2012; 367: 2419-2426
        • Green P.H.
        • Cellier C.
        Celiac disease.
        N Engl J Med. 2007; 357: 1731-1743
        • Schuppan D.
        • Junker Y.
        • Barisani D.
        Celiac disease: from pathogenesis to novel therapies.
        Gastroenterology. 2009; 137: 1912-1933
        • Ludvigsson J.F.
        • Aro P.
        • Walker M.M.
        • et al.
        Celiac disease, eosinophilic esophagitis and gastroesophageal reflux disease, an adult population-based study.
        Scand J Gastroenterol. 2013; 48: 808-814
        • Laurin P.
        • Wolving M.
        • Falth-Magnusson K.
        Even small amounts of gluten cause relapse in children with celiac disease.
        J Pediatr Gastroenterol Nutr. 2002; 34: 26-30
        • Leffler D.A.
        • Acaster S.
        • Gallop K.
        • et al.
        A novel patient-derived conceptual model of the impact of celiac disease in adults: implications for patient-reported outcome and health-related quality-of-life instrument development.
        Value Health. 2017; 20: 637-643
        • Rubio-Tapia A.
        • Hill I.D.
        • Kelly C.P.
        • et al.
        ACG clinical guidelines: diagnosis and management of celiac disease.
        Am J Gastroenterol. 2013; 108 (quiz 677): 656-676
        • Getts D.R.
        • Shea L.D.
        • Miller S.D.
        • et al.
        Harnessing nanoparticles for immune modulation.
        Trends Immunol. 2015; 36: 419-427
        • Getts D.R.
        • Terry R.L.
        • Getts M.T.
        • et al.
        Therapeutic inflammatory monocyte modulation using immune-modifying microparticles.
        Sci Transl Med. 2014; 6: 219ra7
        • Getts D.R.
        • Martin A.J.
        • McCarthy D.P.
        • et al.
        Microparticles bearing encephalitogenic peptides induce T-cell tolerance and ameliorate experimental autoimmune encephalomyelitis.
        Nat Biotechnol. 2012; 30: 1217-1224
        • McCarthy D.P.
        • Hunter Z.N.
        • Chackerian B.
        • et al.
        Targeted immunomodulation using protein coated nanoparticles.
        WIRES Nanomed Nanobiotechnol. 2014; 8: 2148-2160
        • Prasad S.
        • Neef T.
        • Xu D.
        • et al.
        Tolerogenic Ag-PLG nanoparticles induce Tregs to suppress activated diabetogenic CD4 and CD8 T cells.
        J Autoimmun. 2018; 89: 112-124
        • Freitag T.L.
        • Podojil J.R.
        • Pearson R.M.
        • et al.
        Gliadin nanoparticles induce immune tolerance to gliadin in mouse models of celiac disease.
        Gastroenterology. 2020; 158: 1667-1681.e12
        • Freitag T.L.
        • Rietdijk S.
        • Junker Y.
        • et al.
        Gliadin-primed CD4+CD45RBlowCD25− T cells drive gluten-dependent small intestinal damage after adoptive transfer into lymphopenic mice.
        Gut. 2009; 58: 1597-1605
        • Hunter Z.
        • McCarthy D.P.
        • Yap W.T.
        • et al.
        A biodegradable nanoparticle platform for the induction of antigen-specific immune tolerance for treatment of autoimmune disease.
        ACS Nano. 2014; 8: 2148-2160
        • McCarthy D.P.
        • Yap J.W.
        • Harp C.T.
        • et al.
        An antigen-encapsulating nanoparticle platform for TH1/17 immune tolerance therapy.
        Nanomedicine. 2017; 13: 191-200
        • Jamison B.L.
        • Neef T.
        • Goodspeed A.
        • et al.
        Nanoparticles containing an insulin-ChgA hybrid peptide protect from transfer of autoimmune diabetes by shifting the balance between effector T cells and regulatory T cells.
        J Immunol. 2019; 203: 48-57
      1. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.
        JAMA. 2013; 310: 2191-2194
        • Tye-Din J.A.
        • Stewart J.A.
        • Dromey J.A.
        • et al.
        Comprehensive, quantitative mapping of T cell epitopes in gluten in celiac disease.
        Sci Transl Med. 2010; 2: 41ra51
        • Beissbarth T.
        • Tye-Din J.A.
        • Smyth G.K.
        • et al.
        A systematic approach for comprehensive T-cell epitope discovery using peptide libraries.
        Bioinformatics. 2005; 21: i29-i37
        • Goel G.
        • King T.
        • Daveson A.J.
        • et al.
        Epitope-specific immunotherapy targeting CD4-positive T cells in coeliac disease: two randomised, double-blind, placebo-controlled phase 1 studies.
        Lancet Gastroenterol Hepatol. 2017; 2: 479-493
        • Anderson R.P.
        • Degano P.
        • Godkin A.J.
        • et al.
        In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant A-gliadin T-cell epitope.
        Nat Med. 2000; 6: 337-342
        • Anderson R.P.
        • van Heel D.A.
        • Tye-Din J.A.
        • et al.
        T cells in peripheral blood after gluten challenge in coeliac disease.
        Gut. 2005; 54: 1217-1223
        • Taavela J.
        • Koskinen O.
        • Huhtala H.
        • et al.
        Validation of morphometric analyses of small-intestinal biopsy readouts in celiac disease.
        PLoS One. 2013; 8e76163
        • Leffler D.
        • Vanga R.
        • Mukherjee R.
        Mild enteropathy celiac disease: a wolf in sheep's clothing?.
        Clin Gastroenterol Hepatol. 2013; 11: 259-261
        • Liu W.
        • Putnam A.L.
        • Xu-Yu Z.
        • et al.
        CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells.
        J Exp Med. 2006; 203: 1701-1711
        • Miller S.D.
        • Turley D.M.
        • Podojil J.R.
        Antigen-specific tolerance strategies for the prevention and treatment of autoimmune disease.
        Nat Rev Immunol. 2007; 7: 665-677
        • Munz C.
        • Lunemann J.D.
        • Getts M.T.
        • et al.
        Antiviral immune responses: triggers of or triggered by autoimmunity?.
        Nat Rev Immunol. 2009; 9: 246-258
        • Lebwohl B.
        • Sanders D.S.
        • Green P.H.R.
        Coeliac disease.
        Lancet. 2018; 391: 70-81
        • Nilsen E.M.
        • Jahnsen F.L.
        • Lundin K.E.
        • et al.
        Gluten induces an intestinal cytokine response strongly dominated by interferon gamma in patients with celiac disease.
        Gastroenterology. 1998; 115: 551-563
        • Lahdenpera A.I.
        • Holtta V.
        • Ruohtula T.
        • et al.
        Up-regulation of small intestinal interleukin-17 immunity in untreated coeliac disease but not in potential coeliac disease or in type 1 diabetes.
        Clin Exp Immunol. 2012; 167: 226-234
        • Monteleone I.
        • Sarra M.
        • Del Vecchio Blanco G.
        • et al.
        Characterization of IL-17A-producing cells in celiac disease mucosa.
        J Immunol. 2010; 184: 2211-2218
        • Turley D.M.
        • Miller S.D.
        Prospects for antigen-specific tolerance based therapies for the treatment of multiple sclerosis.
        Results and problems in cell differentiation. 2010; 51: 217-235
        • Serra P.
        • Santamaria P.
        Antigen-specific therapeutic approaches for autoimmunity.
        Nature Biotechnol. 2019; 37: 238-251
        • Smarr C.B.
        • Yap W.T.
        • Neef T.P.
        • et al.
        Biodegradable antigen-associated PLG nanoparticles tolerize Th2-mediated allergic airway inflammation pre- and postsensitization.
        Proc Natl Acad Sci U S A. 2016; 113: 5059-5064
        • Jabri B.
        • Sollid L.M.
        T cells in celiac disease.
        J Immunol. 2017; 198: 3005-3014
        • Leonard M.M.
        • Silvester J.A.
        • Leffler D.
        • et al.
        Evaluating responses to gluten challenge: a randomized, double-blind, 2-dose gluten challenge trial.
        Gastroenterology. 2021; 160: 720-733.e8
        • Adelman D.C.
        • Murray J.
        • Wu T.T.
        • et al.
        Measuring change in small intestinal histology in patients with celiac disease.
        Am J Gastroenterol. 2018; 113: 339-347
        • Truitt K.E.
        • Daveson A.J.M.
        • Ee H.C.
        • et al.
        Randomised clinical trial: a placebo-controlled study of subcutaneous or intradermal NEXVAX2, an investigational immunomodulatory peptide therapy for coeliac disease.
        Aliment Pharmacol Ther. 2019; 50: 547-555
        • Lutterotti A.
        • Yousef S.
        • Sputtek A.
        • et al.
        Antigen-specific tolerance by autologous myelin peptide-coupled cells: a phase 1 trial in multiple sclerosis.
        Sci Transl Med. 2013; 5: 188ra75
        • Kuo R.
        • Saito E.
        • Miller S.D.
        • et al.
        Peptide-conjugated nanoparticles reduce positive co-stimulatory expression and T cell activity to induce tolerance.
        Mol Ther. 2017; 25: 1676-1685
        • Getts D.R.
        • Turley D.M.
        • Smith C.E.
        • et al.
        Tolerance induced by apoptotic antigen-coupled leukocytes is induced by PD-L1+ and IL-10-producing splenic macrophages and maintained by T regulatory cells.
        J Immunol. 2011; 187: 2405-2417

      Supplementary References

        • Bandura D.R.
        • Baranov V.I.
        • Ornatsky O.I.
        • et al.
        Mass cytometry: technique for real time single cell multitarget immunoassay based on inductively coupled plasma time-of-flight mass spectrometry.
        Anal Chem. 2009; 81: 6813-6822