Advertisement

The AAPS Journal

, Volume 19, Issue 2, pp 377–385 | Cite as

Approaches to Mitigate the Unwanted Immunogenicity of Therapeutic Proteins during Drug Development

  • Laura I. Salazar-FontanaEmail author
  • Dharmesh D. Desai
  • Tarik A. Khan
  • Renuka C. Pillutla
  • Sandra Prior
  • Radha Ramakrishnan
  • Jennifer Schneider
  • Alexandra Joseph
Review Article Theme: Controlling Unwanted Immunogenicity to Biotherapeutics
Part of the following topical collections:
  1. Theme: Controlling Unwanted Immunogenicity to Biotherapeutics

ABSTRACT

All biotherapeutics have the potential to induce an immune response. This immunological response is complex and, in addition to antibody formation, involves T cell activation and innate immune responses that could contribute to adverse effects. Integrated immunogenicity data analysis is crucial to understanding the possible clinical consequences of anti-drug antibody (ADA) responses. Because patient- and product-related factors can influence the immunogenicity of a therapeutic protein, a risk-based approach is recommended and followed by most drug developers to provide insight over the potential harm of unwanted ADA responses. This paper examines mitigation strategies currently implemented and novel under investigation approaches used by drug developers. The review describes immunomodulatory regimens used in the clinic to mitigate deleterious ADA responses to replacement therapies for deficiency syndromes, such as hemophilia A and B, and high risk classical infantile Pompe patients (e.g., cyclophosphamide, methotrexate, rituximab); novel in silico and in vitro prediction tools used to select candidates based on their immunogenicity potential (e.g., anti-CD52 antibody primary sequence and IFN beta-1a formulation); in vitro generation of tolerogenic antigen-presenting cells (APCs) to reduce ADA responses to factor VIII and IX in murine models of hemophilia; and selection of novel delivery systems to reduce in vivo ADA responses to highly immunogenic biotherapeutics (e.g., asparaginase). We conclude that mitigation strategies should be considered early in development for biotherapeutics based on our knowledge of existing clinical data for biotherapeutics and the immune response involved in the generation of these ADAs.

KEY WORDS

anti-drug antibodies immune mitigation immune prediction therapeutic proteins tolerance 

Notes

Acknowledgements

This work was sponsored by the Therapeutic Product Immunogenicity Focus Group (TPIFG) of the BIOTEC Section, American Association of Pharmaceutical Scientists. Special thanks to Gopi Shankar and the TPIFG steering committee for their valuable feedback on the content of the manuscript and their support on the publication of this review.

References

  1. 1.
    Malucchi S, Bertolotto A. Clinical aspects of immunogenicity to biopharmaceuticals. In: Weert M, Moller EH, editors. Immunogenicity of biopharmaceuticals. Biotechnology: pharmaceutical aspects. XII. 1st ed. New York: Springer; 2008. p. 27–56.CrossRefGoogle Scholar
  2. 2.
    Bartelds GM, Krieckaert CL, Nurmohamed MT, van Schouwenburg PA, Lems WF, Twisk JW, et al. Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA. 2011;305(14):1460–8.CrossRefPubMedGoogle Scholar
  3. 3.
    Goodnow CC. Transgenic mice and analysis of B-cell tolerance. Annu Rev Immunol. 1992;10:489–518.CrossRefPubMedGoogle Scholar
  4. 4.
    Hogquist KA, Baldwin TA, Jameson SC. Central tolerance: learning self-control in the thymus. Nat Rev Immunol. 2005;5(10):772–82.CrossRefPubMedGoogle Scholar
  5. 5.
    Khan TA, Reddy ST. Immunological principles regulating immunomodulation with biomaterials. Acta Biomater. 2014;10(4):1720–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Koren E, Smith HW, Shores E, Shankar G, Finco-Kent D, Rup B, et al. Recommendations on risk-based strategies for detection and characterization of antibodies against biotechnology products. J Immunol Methods. 2008;333(1–2):1–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Hwang WY, Foote J. Immunogenicity of engineered antibodies. Methods. 2005;36(1):3–10.CrossRefPubMedGoogle Scholar
  8. 8.
    Singh SK. Impact of product-related factors on immunogenicity of biotherapeutics. J Pharm Sci. 2011;100(2):354–87.CrossRefPubMedGoogle Scholar
  9. 9.
    Stephens S, Emtage S, Vetterlein O, Chaplin L, Bebbington C, Nesbitt A, et al. Comprehensive pharmacokinetics of a humanized antibody and analysis of residual anti-idiotypic responses. Immunology. 1995;85(4):668–74.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Elliott P, Billingham S, Bi J, Zhang H. Quality by design for biopharmaceuticals: a historical review and guide for implementation. Pharm Bioprocess. 2013;1(1):105–22.CrossRefGoogle Scholar
  11. 11.
    Zurdo J, Arnell A, Obrezanova O, Smith N, Gomez de la Cuesta R, Gallagher TR, et al. Early implementation of QbD in biopharmaceutical development: a practical example. Biomed Res Int. 2015;2015:605427.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Gorovits B, Clements-Egan A, Birchler M, Liang M, Myler H, Peng K, et al. Pre-existing antibody: biotherapeutic modality-based review. AAPS J. 2016:1–10.Google Scholar
  13. 13.
    Rathore AS, Winkle H. Quality by design for biopharmaceuticals. Nat Biotechnol. 2009;27(1):26–34.CrossRefPubMedGoogle Scholar
  14. 14.
    Guideline IHT. ICH Q9 quality risk management. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. 2005.Google Scholar
  15. 15.
    Buttel IC, Chamberlain P, Chowers Y, Ehmann F, Greinacher A, Jefferis R, et al. Taking immunogenicity assessment of therapeutic proteins to the next level. Biologicals. 2011;39(2):100–9.CrossRefPubMedGoogle Scholar
  16. 16.
    van Beers MM, Bardor M. Minimizing immunogenicity of biopharmaceuticals by controlling critical quality attributes of proteins. Biotechnol J. 2012;7(12):1473–84.CrossRefPubMedGoogle Scholar
  17. 17.
    Bessa J, Boeckle S, Beck H, Buckel T, Schlicht S, Ebeling M, et al. The immunogenicity of antibody aggregates in a novel transgenic mouse model. Pharm Res. 2015;32(7):2344–59.CrossRefPubMedGoogle Scholar
  18. 18.
    Folzer E, Diepold K, Bomans K, Finkler C, Schmidt R, Bulau P, et al. Selective oxidation of methionine and tryptophan residues in a therapeutic IgG1 molecule. J Pharm Sci. 2015;104(9):2824–31.CrossRefPubMedGoogle Scholar
  19. 19.
    Joubert MK, Hokom M, Eakin C, Zhou L, Deshpande M, Baker MP, et al. Highly aggregated antibody therapeutics can enhance the in vitro innate and late-stage T-cell immune responses. J Biol Chem. 2012;287(30):25266–79.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Kumar S, Mitchell MA, Rup B, Singh SK. Relationship between potential aggregation-prone regions and HLA-DR-binding T-cell immune epitopes: implications for rational design of novel and follow-on therapeutic antibodies. J Pharm Sci. 2012;101(8):2686–701.CrossRefPubMedGoogle Scholar
  21. 21.
    Chung CH, Mirakhur B, Chan E, Le QT, Berlin J, Morse M, et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med. 2008;358(11):1109–17.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Sinclair AM, Elliott S. Glycoengineering: the effect of glycosylation on the properties of therapeutic proteins. J Pharm Sci. 2005;94(8):1626–35.CrossRefPubMedGoogle Scholar
  23. 23.
    Rosenberg AS. Effects of protein aggregates: an immunologic perspective. AAPS J. 2006;8(3):E501–7.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Rombach-Riegraf V, Karle AC, Wolf B, Sorde L, Koepke S, Gottlieb S, et al. Aggregation of human recombinant monoclonal antibodies influences the capacity of dendritic cells to stimulate adaptive T-cell responses in vitro. PLoS One. 2014;9(1):e86322.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Telikepalli S, Shinogle HE, Thapa PS, Kim JH, Deshpande M, Jawa V, et al. Physical characterization and in vitro biological impact of highly aggregated antibodies separated into size-enriched populations by fluorescence-activated cell sorting. J Pharm Sci. 2015;104(5):1575–91.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Moussa EM, Panchal JP, Moorthy BS, Blum JS, Joubert MK, Narhi LO, et al. Immunogenicity of therapeutic protein aggregates. J Pharm Sci. 2016;105(2):417–30.CrossRefPubMedGoogle Scholar
  27. 27.
    Flower DR. Towards in silico prediction of immunogenic epitopes. Trends Immunol. 2003;24(12):667–74.CrossRefPubMedGoogle Scholar
  28. 28.
    Jawa V, Cousens LP, Awwad M, Wakshull E, Kropshofer H, De Groot AS. T-cell dependent immunogenicity of protein therapeutics: preclinical assessment and mitigation. Clin Immunol. 2013;149(3):534–55.CrossRefPubMedGoogle Scholar
  29. 29.
    Bryson CJ, Jones TD, Baker MP. Prediction of immunogenicity of therapeutic proteins: validity of computational tools. BioDrugs. 2010;24(1):1–8.CrossRefPubMedGoogle Scholar
  30. 30.
    Onda M. Reducing the immunogenicity of protein therapeutics. Curr Drug Targets. 2009;10(2):131–9.CrossRefPubMedGoogle Scholar
  31. 31.
    Wang X, Das TK, Singh SK, Kumar S. Potential aggregation prone regions in biotherapeutics: a survey of commercial monoclonal antibodies. MAbs. 2009;1(3):254–67.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Kumar S, Singh SK, Wang X, Rup B, Gill D. Coupling of aggregation and immunogenicity in biotherapeutics: T- and B-cell immune epitopes may contain aggregation-prone regions. Pharm Res. 2011;28(5):949–61.CrossRefPubMedGoogle Scholar
  33. 33.
    Lazarski CA, Chaves FA, Sant AJ. The impact of DM on MHC class II-restricted antigen presentation can be altered by manipulation of MHC-peptide kinetic stability. J Exp Med. 2006;203(5):1319–28.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Szabo TG, Palotai R, Antal P, Tokatly I, Tothfalusi L, Lund O, et al. Critical role of glycosylation in determining the length and structure of T cell epitopes. Immunome Res. 2009;5:4.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    van Haren SD, Herczenik E, ten Brinke A, Mertens K, Voorberg J, Meijer AB. HLA-DR-presented peptide repertoires derived from human monocyte-derived dendritic cells pulsed with blood coagulation factor VIII. Mol Cell Proteomics. 2011;10(6):M110 002246.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Giese C, Lubitz A, Demmler CD, Reuschel J, Bergner K, Marx U. Immunological substance testing on human lymphatic micro-organoids in vitro. J Biotechnol. 2010;148(1):38–45.CrossRefPubMedGoogle Scholar
  37. 37.
    Holgate RG, Weldon R, Jones TD, Baker MP. Characterisation of a novel anti-CD52 antibody with improved efficacy and reduced immunogenicity. PLoS One. 2015;10(9):e0138123.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Jaber A, Baker M. Assessment of the immunogenicity of different interferon beta-1a formulations using ex vivo T-cell assays. J Pharm Biomed Anal. 2007;43(4):1256–61.CrossRefPubMedGoogle Scholar
  39. 39.
    Delluc S, Ravot G, Maillere B. Quantitative analysis of the CD4 T-cell repertoire specific to therapeutic antibodies in healthy donors. FASEB J. 2011;25(6):2040–8.CrossRefPubMedGoogle Scholar
  40. 40.
    Wullner D, Zhou L, Bramhall E, Kuck A, Goletz TJ, Swanson S, et al. Considerations for optimization and validation of an in vitro PBMC derived T cell assay for immunogenicity prediction of biotherapeutics. Clin Immunol. 2010;137(1):5–14.CrossRefPubMedGoogle Scholar
  41. 41.
    Giovannoni G, Barbarash O, Casset-Semanaz F, Jaber A, King J, Metz L, et al. Immunogenicity and tolerability of an investigational formulation of interferon-beta1a: 24- and 48-week interim analyses of a 2-year, single-arm, historically controlled, phase IIIb study in adults with multiple sclerosis. Clin Ther. 2007;29(6):1128–45.CrossRefPubMedGoogle Scholar
  42. 42.
    Collin M, McGovern N, Haniffa M. Human dendritic cell subsets. Immunology. 2013;140(1):22–30.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Lutz MB, Schuler G. Immature, semi-mature and fully mature dendritic cells: which signals induce tolerance or immunity? Trends Immunol. 2002;23(9):445–9.CrossRefPubMedGoogle Scholar
  44. 44.
    Penna G, Amuchastegui S, Laverny G, Adorini L. Vitamin D receptor agonists in the treatment of autoimmune diseases: selective targeting of myeloid but not plasmacytoid dendritic cells.Google Scholar
  45. 45.
    Carreno LJ, Riedel CA, Kalergis AM. Induction of tolerogenic dendritic cells by NF-kappaB blockade and Fcgamma receptor modulation. Methods Mol Biol. 2011;677:339–53.CrossRefPubMedGoogle Scholar
  46. 46.
    Sule G, Suzuki M, Guse K, Cela R, Rodgers JR, Lee B. Cytokine-conditioned dendritic cells induce humoral tolerance to protein therapy in mice. Hum Gene Ther. 2012;23(7):769–80.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Fathallah AM, Ramakrishnan R, Balu-Iyer SV. O-phospho-l-serine mediates hyporesponsiveness toward FVIII in hemophilia A-murine model by inducing tolerogenic properties in dendritic cells. J Pharm Sci. 2014;103(11):3457–63.CrossRefPubMedGoogle Scholar
  48. 48.
    Charbonnier LM, van Duivenvoorde LM, Apparailly F, Cantos C, Han WG, Noel D, et al. Immature dendritic cells suppress collagen-induced arthritis by in vivo expansion of CD49b+ regulatory T cells. J Immunol. 2006;177(6):3806–13.CrossRefPubMedGoogle Scholar
  49. 49.
    Raker VK, Domogalla MP, Steinbrink K. Tolerogenic dendritic cells for regulatory T cell induction in man. Front Immunol. 2015;6:569.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol. 2009;9(5):313–23.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Coombes JL, Powrie F. Dendritic cells in intestinal immune regulation. Nat Rev Immunol. 2008;8(6):435–46.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Varshney P, Jones SM, Scurlock AM, Perry TT, Kemper A, Steele P, et al. A randomized controlled study of peanut oral immunotherapy: clinical desensitization and modulation of the allergic response. J Allergy Clin Immunol. 2011;127(3):654–60.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Verma D, Moghimi B, LoDuca PA, Singh HD, Hoffman BE, Herzog RW, et al. Oral delivery of bioencapsulated coagulation factor IX prevents inhibitor formation and fatal anaphylaxis in hemophilia B mice. Proc Natl Acad Sci U S A. 2010;107(15):7101–6.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Sherman A, Su J, Lin S, Wang X, Herzog RW, Daniell H. Suppression of inhibitor formation against FVIII in a murine model of hemophilia A by oral delivery of antigens bioencapsulated in plant cells. Blood. 2014;124(10):1659–68.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Su J, Sherman A, Doerfler PA, Byrne BJ, Herzog RW, Daniell H. Oral delivery of Acid Alpha Glucosidase epitopes expressed in plant chloroplasts suppresses antibody formation in treatment of Pompe mice. Plant Biotechnol J. 2015;13(8):1023–32.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Oliveira RP, Santiago AF, Ficker SM, Gomes-Santos AC, Faria AM. Antigen administration by continuous feeding enhances oral tolerance and leads to long-lasting effects. J Immunol Methods. 2015;421:36–43.CrossRefPubMedGoogle Scholar
  57. 57.
    Friedman A, Weiner HL. Induction of anergy or active suppression following oral tolerance is determined by antigen dosage. Proc Natl Acad Sci U S A. 1994;91(14):6688–92.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Weiner HL, da Cunha AP, Quintana F, Wu H. Oral tolerance. Immunol Rev. 2011;241(1):241–59.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Gray M, Gray D. Regulatory B cells mediate tolerance to apoptotic self in health: implications for disease. Int Immunol. 2015;27(10):505–11.CrossRefPubMedGoogle Scholar
  60. 60.
    Gaitonde P, Ramakrishnan R, Chin J, Kelleher Jr RJ, Bankert RB, Balu-Iyer SV. Exposure to factor VIII protein in the presence of phosphatidylserine induces hypo-responsiveness toward factor VIII challenge in hemophilia A mice. J Biol Chem. 2013;288(24):17051–6.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Lorentz KM, Kontos S, Diaceri G, Henry H, Hubbell JA. Engineered binding to erythrocytes induces immunological tolerance to E. coli asparaginase. Sci Adv. 2015;1(6):e1500112.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Lee RA, Gabardi S. Current trends in immunosuppressive therapies for renal transplant recipients. Am J Health Syst Pharm. 2012;69(22):1961–75.CrossRefPubMedGoogle Scholar
  63. 63.
    Meffre E, Wardemann H. B-cell tolerance checkpoints in health and autoimmunity. Curr Opin Immunol. 2008;20(6):632–8.CrossRefPubMedGoogle Scholar
  64. 64.
    Galibert L, Burdin N, Barthelemy C, Meffre G, Durand I, Garcia E, et al. Negative selection of human germinal center B cells by prolonged BCR cross-linking. J Exp Med. 1996;183(5):2075–85.CrossRefPubMedGoogle Scholar
  65. 65.
    Witmer C, Young G. Factor VIII inhibitors in hemophilia A: rationale and latest evidence. Ther Adv Hematol. 2013;4(1):59–72.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Fulcher CA, de Graaf Mahoney S, Zimmerman TS. FVIII inhibitor IgG subclass and FVIII polypeptide specificity determined by immunoblotting. Blood. 1987;69(5):1475–80.PubMedGoogle Scholar
  67. 67.
    Kempton CL, White 2nd GC. How we treat a hemophilia A patient with a factor VIII inhibitor. Blood. 2009;113(1):11–7.CrossRefPubMedGoogle Scholar
  68. 68.
    Banugaria SG, Patel TT, Mackey J, Das S, Amalfitano A, Rosenberg AS, et al. Persistence of high sustained antibodies to enzyme replacement therapy despite extensive immunomodulatory therapy in an infant with Pompe disease: need for agents to target antibody-secreting plasma cells. Mol Genet Metab. 2012;105(4):677–80.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Gagnon RF, MacLennan IC. The effect of chronic daily cyclophosphamide administration on established antibody responses. Clin Exp Immunol. 1981;46(1):178–84.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Garman RD, Munroe K, Richards SM. Methotrexate reduces antibody responses to recombinant human alpha-galactosidase A therapy in a mouse model of Fabry disease. Clin Exp Immunol. 2004;137(3):496–502.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Garces S, Demengeot J, Benito-Garcia E. The immunogenicity of anti-TNF therapy in immune-mediated inflammatory diseases: a systematic review of the literature with a meta-analysis. Ann Rheum Dis. 2013;72(12):1947–55.CrossRefPubMedGoogle Scholar
  72. 72.
    Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology. 2000;47(2–3):85–118.CrossRefPubMedGoogle Scholar
  73. 73.
    Klarmann D, Martinez Saguer I, Funk MB, Knoefler R, von Hentig N, Heller C, et al. Immune tolerance induction with mycophenolate-mofetil in two children with haemophilia B and inhibitor. Haemophilia. 2008;14(1):44–9.CrossRefPubMedGoogle Scholar
  74. 74.
    Lederer SR, Friedrich N, Banas B, Welser G, Albert ED, Sitter T. Effects of mycophenolate mofetil on donor-specific antibody formation in renal transplantation. Clin Transpl. 2005;19(2):168–74.CrossRefGoogle Scholar
  75. 75.
    Joseph A, Munroe K, Housman M, Garman R, Richards S. Immune tolerance induction to enzyme-replacement therapy by co-administration of short-term, low-dose methotrexate in a murine Pompe disease model. Clin Exp Immunol. 2008;152(1):138–46.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Ohashi T, Iizuka S, Shimada Y, Higuchi T, Eto Y, Ida H, et al. Administration of anti-CD3 antibodies modulates the immune response to an infusion of alpha-glucosidase in mice. Mol Ther. 2012;20(10):1924–31.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Waters B, Qadura M, Burnett E, Chegeni R, Labelle A, Thompson P, et al. Anti-CD3 prevents factor VIII inhibitor development in hemophilia A mice by a regulatory CD4+CD25+-dependent mechanism and by shifting cytokine production to favor a Th1 response. Blood. 2009;113(1):193–203.CrossRefPubMedGoogle Scholar
  78. 78.
    Collins PW. Therapeutic challenges in acquired factor VIII deficiency. Hematology Am Soc Hematol Educ Program. 2012;2012:369–74.PubMedGoogle Scholar
  79. 79.
    Banugaria SG, Prater SN, McGann JK, Feldman JD, Tannenbaum JA, Bailey C, et al. Bortezomib in the rapid reduction of high sustained antibody titers in disorders treated with therapeutic protein: lessons learned from Pompe disease. Genet Med. 2013;15(2):123–31.CrossRefPubMedGoogle Scholar
  80. 80.
    Elder ME, Nayak S, Collins SW, Lawson LA, Kelley JS, Herzog RW, et al. B-cell depletion and immunomodulation before initiation of enzyme replacement therapy blocks the immune response to acid alpha-glucosidase in infantile-onset Pompe disease. J Pediatr. 2013;163(3):847–54 e1.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Kakkis E, Lester T, Yang R, Tanaka C, Anand V, Lemontt J, et al. Successful induction of immune tolerance to enzyme replacement therapy in canine mucopolysaccharidosis I. Proc Natl Acad Sci U S A. 2004;101(3):829–34.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Doerfler PA, Nayak S, Herzog RW, Morel L, Byrne BJ. BAFF blockade prevents anti-drug antibody formation in a mouse model of Pompe disease. Clin Immunol. 2015;158(2):140–7.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Chatham WW, Wallace DJ, Stohl W, Latinis KM, Manzi S, McCune WJ, et al. Effect of belimumab on vaccine antigen antibodies to influenza, pneumococcal, and tetanus vaccines in patients with systemic lupus erythematosus in the BLISS-76 trial. J Rheumatol. 2012;39(8):1632–40.CrossRefPubMedGoogle Scholar
  84. 84.
    Joly MS, Martin RP, Mitra-Kaushik S, Phillips L, D’Angona A, Richards SM, et al. Transient low-dose methotrexate generates B regulatory cells that mediate antigen-specific tolerance to alglucosidase alfa. J Immunol. 2014;193(8):3947–58.CrossRefPubMedGoogle Scholar
  85. 85.
    Joseph A, Neff K, Richard J, Gao L, Bangari D, Joly M, et al. Transient low-dose methotrexate induces tolerance to murine anti-thymocyte globulin and together they promote long-term allograft survival. J Immunol. 2012;189(2):732–43.CrossRefPubMedGoogle Scholar
  86. 86.
    Iwata Y, Matsushita T, Horikawa M, Dilillo DJ, Yanaba K, Venturi GM, et al. Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. Blood. 2011;117(2):530–41.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Becker C, Bopp T, Jonuleit H. Boosting regulatory T cell function by CD4 stimulation enters the clinic. Front Immunol. 2012;3:164.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Mayer CT, Tian L, Hesse C, Kuhl AA, Swallow M, Kruse F, et al. Anti-CD4 treatment inhibits autoimmunity in scurfy mice through the attenuation of co-stimulatory signals. J Autoimmun. 2014;50:23–32.CrossRefPubMedGoogle Scholar
  89. 89.
    Abraham RT, Wiederrecht GJ. Immunopharmacology of rapamycin. Annu Rev Immunol. 1996;14:483–510.CrossRefPubMedGoogle Scholar
  90. 90.
    Benjamin D, Colombi M, Moroni C, Hall MN. Rapamycin passes the torch: a new generation of mTOR inhibitors. Nat Rev Drug Discov. 2011;10(11):868–80.CrossRefPubMedGoogle Scholar
  91. 91.
    Weichhart T, Saemann MD. The multiple facets of mTOR in immunity. Trends Immunol. 2009;30(5):218–26.CrossRefPubMedGoogle Scholar
  92. 92.
    Thomson AW, Turnquist HR, Raimondi G. Immunoregulatory functions of mTOR inhibition. Nat Rev Immunol. 2009;9(5):324–37.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Delgoffe GM, Kole TP, Zheng Y, Zarek PE, Matthews KL, Xiao B, et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity. 2009;30(6):832–44.CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Delgoffe GM, Pollizzi KN, Waickman AT, Heikamp E, Meyers DJ, Horton MR, et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol. 2011;12(4):295–303.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Kang J, Huddleston SJ, Fraser JM, Khoruts A. De novo induction of antigen-specific CD4+CD25+Foxp3+ regulatory T cells in vivo following systemic antigen administration accompanied by blockade of mTOR. J Leukoc Biol. 2008;83(5):1230–9.CrossRefPubMedGoogle Scholar
  96. 96.
    Wekerle T. T-regulatory cells—what relationship with immunosuppressive agents? Transplant Proc. 2008;40(10 Suppl):S13–6.CrossRefPubMedGoogle Scholar
  97. 97.
    Zhang S, Readinger JA, DuBois W, Janka-Junttila M, Robinson R, Pruitt M, et al. Constitutive reductions in mTOR alter cell size, immune cell development, and antibody production. Blood. 2011;117(4):1228–38.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Li X, Li JJ, Yang JY, Wang DS, Zhao W, Song WJ, et al. Tolerance induction by exosomes from immature dendritic cells and rapamycin in a mouse cardiac allograft model. PLoS One. 2012;7(8):e44045.CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Nayak S, Cao O, Hoffman BE, Cooper M, Zhou S, Atkinson MA, et al. Prophylactic immune tolerance induced by changing the ratio of antigen-specific effector to regulatory T cells. J Thromb Haemost. 2009;7(9):1523–32.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Moghimi B, Sack BK, Nayak S, Markusic DM, Mah CS, Herzog RW. Induction of tolerance to factor VIII by transient co-administration with rapamycin. J Thromb Haemost. 2011;9(8):1524–33.CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Maldonado RA, LaMothe RA, Ferrari JD, Zhang AH, Rossi RJ, Kolte PN, et al. Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance. Proc Natl Acad Sci U S A. 2015;112(2):E156–65.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2017

Authors and Affiliations

  • Laura I. Salazar-Fontana
    • 1
    Email author
  • Dharmesh D. Desai
    • 2
  • Tarik A. Khan
    • 3
  • Renuka C. Pillutla
    • 2
  • Sandra Prior
    • 4
  • Radha Ramakrishnan
    • 5
    • 6
  • Jennifer Schneider
    • 6
  • Alexandra Joseph
    • 1
  1. 1.Translational Medicine and Early DevelopmentSanofi Genzyme R&DFraminghamUSA
  2. 2.Bioanalytical Sciences-BiologicsBristol-Myers SquibbPrincetonUSA
  3. 3.Pharmaceutical Development & Supplies, PTD Biologics EuropeF. Hoffmann-La Roche Ltd.BaselSwitzerland
  4. 4.Division of BiotherapeuticsNational Institute for Biological Standards and Control (NIBSC)HertfordshireUK
  5. 5.Department of Metabolism and PharmacokineticsBristol-Myers SquibbPenningtonUSA
  6. 6.Department of Pharmaceutical SciencesUniversity at Buffalo, the State University of New YorkBuffaloUSA

Personalised recommendations