The AAPS Journal

, 21:96 | Cite as

TCPro: an In Silico Risk Assessment Tool for Biotherapeutic Protein Immunogenicity

  • Osman N. Yogurtcu
  • Zuben E. Sauna
  • Joseph R. McGill
  • Million A. Tegenge
  • Hong YangEmail author
Research Article


Most immune responses to biotherapeutic proteins involve the development of anti-drug antibodies (ADAs). New drugs must undergo immunogenicity assessments to identify potential risks at early stages in the drug development process. This immune response is T cell-dependent. Ex vivo assays that monitor T cell proliferation often are used to assess immunogenicity risk. Such assays can be expensive and time-consuming to carry out. Furthermore, T cell proliferation requires presentation of the immunogenic epitope by major histocompatibility complex class II (MHCII) proteins on antigen-presenting cells. The MHC proteins are the most diverse in the human genome. Thus, obtaining cells from subjects that reflect the distribution of the different MHCII proteins in the human population can be challenging. The allelic frequencies of MHCII proteins differ among subpopulations, and understanding the potential immunogenicity risks would thus require generation of datasets for specific subpopulations involving complex subject recruitment. We developed TCPro, a computational tool that predicts the temporal dynamics of T cell counts in common ex vivo assays for drug immunogenicity. Using TCPro, we can test virtual pools of subjects based on MHCII frequencies and estimate immunogenicity risks for different populations. It also provides rapid and inexpensive initial screens for new biotherapeutics and can be used to determine the potential immunogenicity risk of new sequences introduced while bioengineering proteins. We validated TCPro using an experimental immunogenicity dataset, making predictions on the population-based immunogenicity risk of 15 protein-based biotherapeutics. Immunogenicity rankings generated using TCPro are consistent with the reported clinical experience with these therapeutics.


anti-drug antibodies (ADA) computational approaches immunogenicity protein-based therapeutics 



This project was supported in part by an appointment to the Research Participation Program at CBER, US Food and Drug Administration, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and FDA.

Author Contributions

Conceptualization: ONY, ZES, JRM, MAT, HY.

Data curation: ONY, ZES, JRM.

Formal analysis: ONY.

Funding acquisition: HY, ZES.

Investigation: ONY, ZES.

Methodology: ONY, ZES, JRM, MAT, HY.

Project administration: HY, ZES, MAT.

Resources: HY, ZES.

Software: ONY.

Supervision: HY, ZES, MAT.

Validation: ONY.

Visualization: ONY.

Writing—original draft: ONY, ZES, JRM.

Writing—review and editing: ONY, ZES, JRM, MAT, HY.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


This article reflects the views of the authors and should not be construed to represent FDA's views or policies.

Supplementary material

12248_2019_368_MOESM1_ESM.docx (697 kb)
ESM 1 (DOCX 696 kb)


  1. 1.
    Joubert MK, Deshpande M, Yang J, Reynolds H, Bryson C, Fogg M, et al.. Use of in vitro assays to assess immunogenicity risk of antibody-based biotherapeutics. PLoS One. 2016;11(8):e0159328.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Ridker PM, Tardif J-C, Amarenco P, Duggan W, Glynn RJ, Jukema JW, et al.. Lipid-reduction variability and antidrug-antibody formation with bococizumab. N Engl J Med. 2017;376(16):1517–26.PubMedCrossRefGoogle Scholar
  3. 3.
    Mahlangu J, Weldingh K, Lentz S, Kaicker S, Karim F, Matsushita T, et al. Changes in the amino acid sequence of the recombinant human factor VIIa analog, vatreptacog alfa, are associated with clinical immunogenicity. J Thromb Haemost. 2015;13(11):1989–98.PubMedCrossRefGoogle Scholar
  4. 4.
    Wang Y-MC, Wang J, Hon YY, Zhou L, Fang L, Ahn HY. Evaluating and reporting the immunogenicity impacts for biological products—a clinical pharmacology perspective. AAPS J. 2016;18(2):395–403.PubMedCrossRefGoogle Scholar
  5. 5.
    Svenningsson A, Dring AM, Fogdell-Hahn A, Jones I, Engdahl E, Lundkvist M, et al. Fatal neuroinflammation in a case of multiple sclerosis with anti-natalizumab antibodies. Neurology. 2013;80(10):965–7.PubMedCrossRefGoogle Scholar
  6. 6.
    DeFrancesco L. Three deaths sink Affymax: Nature Publishing Group; 2013.Google Scholar
  7. 7.
    Vultaggio A, Matucci A, Nencini F, Pratesi S, Parronchi P, Rossi O, et al. Anti-infliximab IgE and non-IgE antibodies and induction of infusion-related severe anaphylactic reactions. Allergy. 2010;65(5):657–61.PubMedCrossRefGoogle Scholar
  8. 8.
    Srivastava A, Brewer A, Mauser-Bunschoten E, Key N, Kitchen S, Llinas A, et al. Guidelines for the management of hemophilia. Haemophilia. 2013;19(1):e1–e47.PubMedCrossRefGoogle Scholar
  9. 9.
    Hoffman M, Dargaud Y. Mechanisms and monitoring of bypassing agent therapy. J Thromb Haemost. 2012;10(8):1478–85.PubMedCrossRefGoogle Scholar
  10. 10.
    D'arcy CA, Mannik M. Serum sickness secondary to treatment with the murine–human chimeric antibody IDEC-C2B8 (rituximab). Arthritis Rheum. 2001;44(7):1717–8.PubMedCrossRefGoogle Scholar
  11. 11.
    D'Angiolella L, Cortesi P, Rocino A, Coppola A, Hassan H, Giampaolo A, et al. The socio-economic burden of patients affected by hemophilia with inhibitors. Eur J Haematol. 2018;101:435–56.PubMedCrossRefGoogle Scholar
  12. 12.
    Mahlangu J, Paz P, Hardtke M, Aswad F, Schroeder J. TRUST trial: BAY 86-6150 use in haemophilia with inhibitors and assessment for immunogenicity. Haemophilia. 2016;22(6):873–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Kotarek J, Stuart C, De Paoli SH, Simak J, Lin T-L, Gao Y, et al. Subvisible particle content, formulation, and dose of an erythropoietin peptide mimetic product are associated with severe adverse postmarketing events. J Pharm Sci. 2016;105(3):1023–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Lamberth K, Weldingh KN, Ehrenforth S, Chéhadé MR, Østergaard H. Immunogenicity lessons learned from the clinical development of vatreptacog alfa, a recombinant activated factor VII analog, in Hemophilia with inhibitors. Protein Therapeutics: Springer; 2017. p. 123–60.Google Scholar
  15. 15.
    Shankar G, Pendley C, Stein KE. A risk-based bioanalytical strategy for the assessment of antibody immune responses against biological drugs. Nat Biotechnol. 2007;25(5):555–61.PubMedCrossRefGoogle Scholar
  16. 16.
    Rosenberg AS, Sauna ZE. Immunogenicity assessment during the development of protein therapeutics. J Pharm Pharmacol. 2017.Google Scholar
  17. 17.
    Bachelet D, Hässler S, Mbogning C, Link J, Ryner M, Ramanujam R, et al. Occurrence of anti-drug antibodies against interferon-beta and natalizumab in multiple sclerosis: a collaborative cohort analysis. PLoS One. 2016;11(11):e0162752.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    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.PubMedCrossRefGoogle Scholar
  19. 19.
    Schultz HS, Reedtz-Runge SL, Bäckström BT, Lamberth K, Pedersen CR, Kvarnhammar AM. Quantitative analysis of the CD4+ T cell response to therapeutic antibodies in healthy donors using a novel T cell: PBMC assay. PLoS One. 2017;12(5):e0178544.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Zubler RH, editor Naive and memory B cells in T-cell-dependent and T-independent responses. Springer seminars in immunopathology. Springer; 2001.Google Scholar
  21. 21.
    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.PubMedCrossRefGoogle Scholar
  22. 22.
    Baker M, Reynolds HM, Lumicisi B, Bryson CJ. Immunogenicity of protein therapeutics: the key causes, consequences and challenges. Self/nonself. 2010;1(4):314–22.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    La Gruta NL, Gras S, Daley SR, Thomas PG, Rossjohn J. Understanding the drivers of MHC restriction of T cell receptors. Nat Rev Immunol. 2018;1.Google Scholar
  24. 24.
    Robinson J, Waller MJ, Parham P, Groot ND, Bontrop R, Kennedy LJ, et al. IMGT/HLA and IMGT/MHC: sequence databases for the study of the major histocompatibility complex. Nucleic Acids Res. 2003;31(1):311–4.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Jensen KK, Andreatta M, Marcatili P, Buus S, Greenbaum JA, Yan Z, et al. Improved methods for predicting peptide binding affinity to MHC class II molecules. Immunology. 2018.Google Scholar
  26. 26.
    Baker MP, Jones TD. Identification and removal of immunogenicity in therapeutic proteins. Curr Opin Drug Discov Dev. 2007;10(2):219–27.Google Scholar
  27. 27.
    Gourraud P-A, Khankhanian P, Cereb N, Yang SY, Feolo M, Maiers M, et al. HLA diversity in the 1000 genomes dataset. PLoS One. 2014;9(7):e97282.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Karle A, Spindeldreher S, Kolbinger F, editors. Secukinumab, a novel anti–IL-17A antibody, shows low immunogenicity potential in human in vitro assays comparable to other marketed biotherapeutics with low clinical immunogenicity. MAbs. Taylor & Francis; 2016.Google Scholar
  29. 29.
    Ritter G, Cohen LS, Williams C, Richards EC, Old LJ, Welt S. Serological analysis of human anti-human antibody responses in colon cancer patients treated with repeated doses of humanized monoclonal antibody A33. Cancer Res. 2001;61(18):6851–9.PubMedGoogle Scholar
  30. 30.
    Welt S, Ritter G, Williams C, Cohen LS, Jungbluth A, Richards EA, et al. Preliminary report of a phase I study of combination chemotherapy and humanized A33 antibody immunotherapy in patients with advanced colorectal cancer. Clin Cancer Res. 2003;9(4):1347–53.PubMedGoogle Scholar
  31. 31.
    Scott AM, Lee F-T, Jones R, Hopkins W, MacGregor D, Cebon JS, et al. A phase I trial of humanized monoclonal antibody A33 in patients with colorectal carcinoma: biodistribution, pharmacokinetics, and quantitative tumor uptake. Clin Cancer Res. 2005;11(13):4810–7.PubMedCrossRefGoogle Scholar
  32. 32.
    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.PubMedCrossRefGoogle Scholar
  33. 33.
    Gordon M, Margolin K, Talpaz M, Sledge G Jr, Holmgren E, Benjamin R, et al. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol. 2001;19(3):843–50.PubMedCrossRefGoogle Scholar
  34. 34.
    Tajima N, Martinez A, Kobayashi F, He L, Dewland P. A phase 1 study comparing the proposed biosimilar BS-503a with bevacizumab in healthy male volunteers. Pharmacol Res Perspect. 2017;5(2).CrossRefGoogle Scholar
  35. 35.
    Rubic-Schneider T, Kuwana M, Christen B, Aßenmacher M, Hainzl O, Zimmermann F, et al. T-cell assays confirm immunogenicity of tungsten-induced erythropoietin aggregates associated with pure red cell aplasia. 2017;1(6):367–79.Google Scholar
  36. 36.
    Delluc S, Ravot G, Maillere B. Quantification of the pre-existing CD4 T cell repertoire specific for human erythropoietin reveals its immunogenicity potential. Blood. 2010:blood-2010-04-280875.Google Scholar
  37. 37.
    Casadevall N, Dobronravov V, Eckardt K-U, Ertürk S, Martynyuk L, Schmitt S, et al. Evaluation of the safety and immunogenicity of subcutaneous HX575 epoetin alfa in the treatment of anemia associated with chronic kidney disease in predialysis and dialysis patients. Clin Nephrol. 2017;88(4):190–7.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Shin S-K, Moon SJ, Ha SK, Jo Y-I, Lee T-W, Lee YS, et al. Immunogenicity of recombinant human erythropoietin in Korea: a two-year cross-sectional study. Biologicals. 2012;40(4):254–61.PubMedCrossRefGoogle Scholar
  39. 39.
    Fineman M, Mace K, Diamant M, Darsow T, Cirincione B, Booker Porter T, et al. Clinical relevance of anti-exenatide antibodies: safety, efficacy and cross-reactivity with long-term treatment. Diabetes Obes Metab. 2012;14(6):546–54.PubMedCrossRefGoogle Scholar
  40. 40.
    Milicevic Z, Anglin G, Harper K, Konrad R, Skrivanek Z, Glaesner W, et al. Low incidence of anti-drug antibodies in patients with type 2 diabetes treated with once-weekly glucagon-like peptide-1 receptor agonist dulaglutide. Diabetes Obes Metab. 2016;18(5):533–6.PubMedCrossRefGoogle Scholar
  41. 41.
    Meunier S, Menier C, Marcon E, Lacroix-Desmazes S, Maillère B. CD4 T cells specific for factor VIII are present at high frequency in healthy donors and comprise naïve and memory cells. Blood Adv. 2017;1(21):1842–7.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Iorio A, Fischer K, Makris M. Large scale studies assessing anti-factor VIII antibody development in previously untreated haemophilia A: what has been learned, what to believe and how to learn more. Br J Haematol. 2017;178(1):20–31.PubMedCrossRefGoogle Scholar
  43. 43.
    Ismael G, Hegg R, Muehlbauer S, Heinzmann D, Lum B, Kim S-B, et al. Subcutaneous versus intravenous administration of (neo) adjuvant trastuzumab in patients with HER2-positive, clinical stage I–III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol. 2012;13(9):869–78.PubMedCrossRefGoogle Scholar
  44. 44.
    Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999;17(9):2639.PubMedCrossRefGoogle Scholar
  45. 45.
    Pivot X, Bondarenko I, Nowecki Z, Dvorkin M, Trishkina E, Ahn J-H, et al. Phase III, randomized, double-blind study comparing the efficacy, safety, and immunogenicity of SB3 (trastuzumab biosimilar) and reference trastuzumab in patients treated with neoadjuvant therapy for human epidermal growth factor receptor 2–positive early breast cancer. J Clin Oncol. 2018;36(10):968–74.PubMedCrossRefGoogle Scholar
  46. 46.
    Spindeldreher S. Comparison of T cell assays: results from the ABIRISK consortium. 9th Open EIP Scientific Symposium And Final ABIRISK Open conference on Immunogenicity of Biopharmaceuticals. Lisbon, Portugal; 2017.Google Scholar
  47. 47.
    Spindeldreher S, Maillère B, Correia E, Tenon M, Karle A, Jarvis P, et al. Secukinumab demonstrates significantly lower immunogenicity potential compared to ixekizumab. Dermatol Ther. 2018;8(1):57–68.CrossRefGoogle Scholar
  48. 48.
    Ara-Martín M, Pinto PH, Pascual-Salcedo D. Impact of immunogenicity on response to anti-TNF therapy in moderate-to-severe plaque psoriasis: results of the PREDIR study. J Dermatol Treat. 2017;28(7):606–12.CrossRefGoogle Scholar
  49. 49.
    Benucci M, Gobbi FL, Meacci F, Manfredi M, Infantino M, Severino M, et al. Antidrug antibodies against TNF-blocking agents: correlations between disease activity, hypersensitivity reactions, and different classes of immunoglobulins. Biol Targets Ther. 2015;9:7.CrossRefGoogle Scholar
  50. 50.
    Reyes-Beltrán B, Delgado G. Anti-drug antibodies in Colombian patients with rheumatoid arthritis treated with Enbrel vs Etanar–preliminary report. J Immunotoxicol. 2017;14(1):103–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Plasencia C, Pascual-Salcedo D, Nuño L, Bonilla G, Villalba A, Peiteado D, et al. Influence of immunogenicity on the efficacy of long-term treatment of spondyloarthritis with infliximab. Ann Rheum Dis. 2012:annrheumdis-2011-200828.Google Scholar
  52. 52.
    Pascual-Salcedo D, Plasencia C, Ramiro S, Nuño L, Bonilla G, Nagore D, et al. Influence of immunogenicity on the efficacy of long-term treatment with infliximab in rheumatoid arthritis. Rheumatology. 2011;50(8):1445–52.PubMedCrossRefGoogle Scholar
  53. 53.
    Baert F, Noman M, Vermeire S, Van Assche G, D'haens G, Carbonez A, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med. 2003;348(7):601–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Cohen SB, Alten R, Kameda H, Hala T, Radominski SC, Rehman MI, et al. A randomized controlled trial comparing PF-06438179/GP1111 (an infliximab biosimilar) and infliximab reference product for treatment of moderate to severe active rheumatoid arthritis despite methotrexate therapy. Arthritis Res Ther. 2018;20(1):155.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Hanauer S. Safety of infliximab in clinical trials. Aliment Pharmacol Ther. 1999;13:16–22.PubMedCrossRefGoogle Scholar
  56. 56.
    Reich K, Jackson K, Ball S, Garces S, Kerr L, Chua L, et al. Ixekizumab pharmacokinetics, anti-drug antibodies, and efficacy through 60 weeks of treatment of moderate to severe plaque psoriasis. J Investig Dermatol. 2018;138(10):2168–73.PubMedCrossRefGoogle Scholar
  57. 57.
    Ghosh S, Goldin E, Gordon FH, Malchow HA, Rask-Madsen J, Rutgeerts P, et al. Natalizumab for active Crohn’s disease. N Engl J Med. 2003;348(1):24–32.PubMedCrossRefGoogle Scholar
  58. 58.
    Lundkvist M, Engdahl E, Holmen C, Movérare R, Olsson T, Hillert J, et al. Characterization of anti-natalizumab antibodies in multiple sclerosis patients. Mult Scler J. 2013;19(6):757–64.CrossRefGoogle Scholar
  59. 59.
    van Vollenhoven RF, Emery P, Bingham CO, Keystone EC, Fleischmann R, Furst DE, et al. Longterm safety of patients receiving rituximab in rheumatoid arthritis clinical trials. J Rheumatol. 2010:jrheum. 090856.Google Scholar
  60. 60.
    Piro L, White C, Grillo-Lopez A, Janakiraman N, Saven A, Beck T, et al. Extended rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma. Ann Oncol. 1999;10(6):655–61.PubMedCrossRefGoogle Scholar
  61. 61.
    Reich K, Blauvelt A, Armstrong A, Langley R, Fox T, Huang J, et al. Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, exhibits minimal immunogenicity in patients with moderate-to-severe plaque psoriasis. Br J Dermatol. 2017;176(3):752–8.PubMedCrossRefGoogle Scholar
  62. 62.
    Deodhar AA, Gladman DD, McInnes IB, Strand V, Ren M, Spindeldreher S, et al. Secukinumab immunogenicity in patients with psoriatic arthritis and ankylosing spondylitis during a 52-week treatment period. Arthritis Rheumatol. 2018.Google Scholar
  63. 63.
    Adedokun OJ, Xu Z, Gasink C, Jacobstein D, Szapary P, Johanns J, et al. Pharmacokinetics and exposure response relationships of ustekinumab in patients with Crohn’s disease. Gastroenterology. 2018;154(6):1660–71.PubMedCrossRefGoogle Scholar
  64. 64.
    Gokemeijer J, Jawa V, Mitra-Kaushik S. How close are we to profiling immunogenicity risk using in silico algorithms and in vitro methods?: an industry perspective. AAPS J. 2017:1–6.Google Scholar
  65. 65.
    Swaminathan A, Lucas RM, Dear K, McMichael AJ. Keyhole limpet haemocyanin–a model antigen for human immunotoxicological studies. Br J Clin Pharmacol. 2014;78(5):1135–42.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Inaba K, Metlay JP, Crowley MT, Witmer-Pack M, Steinman RM. Dendritic cells as antigen presenting cells in vivo. Int Rev Immunol. 1990;6(2–3):197–206.PubMedCrossRefGoogle Scholar
  67. 67.
    Croft M, Bradley LM, Swain SL. Naive versus memory CD4 T cell response to antigen. Memory cells are less dependent on accessory cell costimulation and can respond to many antigen-presenting cell types including resting B cells. J Immunol. 1994;152(6):2675–85.PubMedGoogle Scholar
  68. 68.
    Kambayashi T, Laufer TM. Atypical MHC class II-expressing antigen-presenting cells: can anything replace a dendritic cell? Nat Rev Immunol. 2014;14(11):719.PubMedCrossRefGoogle Scholar
  69. 69.
    Charron L, Doctrinal A, Ni Choileain S, Astier AL. Monocyte: T-cell interaction regulates human T-cell activation through a CD28/CD46 crosstalk. Immunol Cell Biol. 2015;93(9):796–803.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Gorbet MB, Sefton MV. Endotoxin: the uninvited guest. Biomaterials. 2005;26(34):6811–7.PubMedCrossRefGoogle Scholar
  71. 71.
    Ryan J. Endotoxins and cell culture. Corning Life Sciences Technical Bulletin. 2004;1–8.Google Scholar
  72. 72.
    Münz C, Steinman RM, Fujii S-I. Dendritic cell maturation by innate lymphocytes. J Exp Med. 2005;202(2):203–7.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Walzer T, Dalod M, Robbins SH, Zitvogel L, Vivier E. Natural-killer cells and dendritic cells:“l'union fait la force”. Blood. 2005;106(7):2252–8.PubMedCrossRefGoogle Scholar
  74. 74.
    Milo R. What is the total number of protein molecules per cell volume? A call to rethink some published values. Bioessays. 2013;35(12):1050–5.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Chen X, Hickling TP, Vicini P. A mechanistic, multiscale mathematical model of immunogenicity for therapeutic proteins: part 1—theoretical model. CPT Pharmacometrics Syst Pharmacol. 2014;3(9):e133.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Vukmanovic-Stejic M, Zhang Y, Cook JE, Fletcher JM, McQuaid A, Masters JE, et al. Human CD4+ CD25hi Foxp3+ regulatory T cells are derived by rapid turnover of memory populations in vivo. J Clin Investig. 2006;116(9):2423–33.PubMedCrossRefGoogle Scholar
  77. 77.
    Squibb B-M. Opdivo (nivolumab) package insert. Princeton: Bristol-Myers Squibb; 2015.Google Scholar
  78. 78.
    Dhanda SK, Grifoni A, Pham J, Vaughan K, Sidney J, Peters B, et al. Development of a strategy and computational application to select candidate protein analogues with reduced HLA binding and immunogenicity. Immunology. 2018;153(1):118–32.PubMedCrossRefGoogle Scholar
  79. 79.
    Chen X, Hickling T, Vicini P. A mechanistic, multiscale mathematical model of immunogenicity for therapeutic proteins: part 2—model applications. CPT Pharmacometrics Syst Pharmacol. 2014;3(9):1–10.Google Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Osman N. Yogurtcu
    • 1
  • Zuben E. Sauna
    • 2
  • Joseph R. McGill
    • 2
  • Million A. Tegenge
    • 1
  • Hong Yang
    • 1
    Email author
  1. 1.Office of Biostatistics and Epidemiology, Center for Biologics Evaluation and ResearchUS FDASilver SpringUSA
  2. 2.Office of Tissues and Advanced Therapy, Center for Biologics Evaluation and ResearchUS FDASilver SpringUSA

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