Skip to main content
SpringerLink
Log in

Immunogenicity of Therapeutic Proteins

  • Chapter
  • First Online:
Protein-based Therapeutics

  • 756 Accesses

Abstract

Therapeutic proteins are potent medications that have shown substantial promise in treating a wide range of illnesses and conditions. Immunogenicity is a unique obstacle that must be overcome when dealing with protein therapy. The immune response is triggered when there is a change in the structure of the protein, which may occur because of posttranslational changes such as the administration, storage, or manufacturing process of the product. The structure of the protein may affect immunotolerance; for example, low-abundance proteins have a lower overall tolerance. Antidrug antibodies (ADAs) may influence the pharmacokinetics, pharmacodynamics, and efficacy of therapeutic proteins. When it comes to the development of ADAs, one of the primary sources of concern is the interaction that therapeutic proteins have with endogenous proteins. In this chapter, we discuss the significant elements associated with the immunogenicity of therapeutic proteins.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 179.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Leader B, Baca QJ, Golan DE (2008) Protein therapeutics: a summary and pharmacological classification. Nat Rev Drug Discov 7:21–39. https://doi.org/10.1038/nrd2399

    Article  CAS  PubMed  Google Scholar 

  2. Singh DB, Tripathi T (2020) Frontiers in protein structure, function, and dynamics. Springer Nature, Singapore

    Book  Google Scholar 

  3. Saudagar P, Tripathi T (2023) Advanced spectroscopic methods to study biomolecular structure and dynamics, 1st edn. Academic Press, Cambridge, MA

    Google Scholar 

  4. Tripathi T, Dubey VK (2022) Advances in protein molecular and structural biology methods, 1st edn. Academic Press, Cambridge, MA

    Google Scholar 

  5. Lagassé HAD, Alexaki A, Simhadri VL, Katagiri NH, Jankowski W, Sauna ZE, Kimchi-Sarfaty C (2017) Recent advances in (therapeutic protein) drug development. F1000Research 6:113. https://doi.org/10.12688/f1000research.9970.1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kimchi-Sarfaty C, Schiller T, Hamasaki-Katagiri N, Khan MA, Yanover C, Sauna ZE (2013) Building better drugs: developing and regulating engineered therapeutic proteins. Trends Pharmacol Sci 34:534–548. https://doi.org/10.1016/j.tips.2013.08.005

    Article  CAS  PubMed  Google Scholar 

  7. Oprea TI, Bologa CG, Brunak S, Campbell A, Gan GN, Gaulton A, Gomez SM, Guha R, Hersey A, Holmes J, Jadhav A, Jensen LJ, Johnson GL, Karlson A, Leach AR, Ma’ayan A, Malovannaya A, Mani S, Mathias SL, McManus MT, Meehan TF, von Mering C, Muthas D, Nguyen D-T, Overington JP, Papadatos G, Qin J, Reich C, Roth BL, Schürer SC, Simeonov A, Sklar LA, Southall N, Tomita S, Tudose I, Ursu O, Vidović D, Waller A, Westergaard D, Yang JJ, Zahoránszky-Köhalmi G (2018) Unexplored therapeutic opportunities in the human genome. Nat Rev Drug Discov 17:317–332. https://doi.org/10.1038/nrd.2018.14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Barbosa MDFS, Celis E (2007) Immunogenicity of protein therapeutics and the interplay between tolerance and antibody responses. Drug Discov Today 12:674–681. https://doi.org/10.1016/j.drudis.2007.06.005

    Article  CAS  PubMed  Google Scholar 

  9. De Groot AS, Moise L (2007) Prediction of immunogenicity for therapeutic proteins: state of the art. Curr Opin Drug Discov Devel 10:332–340

    PubMed  Google Scholar 

  10. De Groot AS, Scott DW (2007) Immunogenicity of protein therapeutics. Trends Immunol 28:482–490. https://doi.org/10.1016/j.it.2007.07.011

    Article  CAS  PubMed  Google Scholar 

  11. Schellekens H (2002) Immunogenicity of therapeutic proteins: clinical implications and future prospects. Clin Ther 24:1720–1740.; discussion 1719. https://doi.org/10.1016/s0149-2918(02)80075-3

    Article  CAS  PubMed  Google Scholar 

  12. Sherman A, Biswas M, Herzog RW (2017) Innovative approaches for immune tolerance to factor VIII in the treatment of hemophilia A. Front Immunol 8. https://doi.org/10.3389/fimmu.2017.01604

  13. Scott DW, Pratt KP (2019) Factor VIII: perspectives on immunogenicity and tolerogenic strategies. Front Immunol 10:3078. https://doi.org/10.3389/fimmu.2019.03078

    Article  CAS  PubMed  Google Scholar 

  14. Pasi KJ, Rangarajan S, Georgiev P, Mant T, Creagh MD, Lissitchkov T, Bevan D, Austin S, Hay CR, Hegemann I, Kazmi R, Chowdary P, Gercheva-Kyuchukova L, Mamonov V, Timofeeva M, Soh C-H, Garg P, Vaishnaw A, Akinc A, Sørensen B, Ragni MV (2017) Targeting of antithrombin in hemophilia A or B with RNAi therapy. N Engl J Med 377:819–828. https://doi.org/10.1056/NEJMoa1616569

    Article  CAS  PubMed  Google Scholar 

  15. Fineberg SE, Kawabata TT, Finco-Kent D, Fountaine RJ, Finch GL, Krasner AS (2007) Immunological responses to exogenous insulin. Endocr Rev 28:625–652. https://doi.org/10.1210/er.2007-0002

    Article  CAS  PubMed  Google Scholar 

  16. Pechlaner C, Knapp E, Wiedermann CJ (2001) Hypersensitivity reactions associated with recombinant tissue-type plasminogen activator and urokinase. Blood Coagul Fibrinolysis 12:491–494. https://doi.org/10.1097/00001721-200109000-00010

    Article  CAS  PubMed  Google Scholar 

  17. Moreland L, Bate G, Kirkpatrick P (2006) Abatacept. Nat Rev Drug Discov 5:185–186. https://doi.org/10.1038/nrd1989

    Article  CAS  PubMed  Google Scholar 

  18. Kirk AD, Harlan DM, Armstrong NN, Davis TA, Dong Y, Gray GS, Hong X, Thomas D, Fechner JHJ, Knechtle SJ (1997) CTLA4-Ig and anti-CD40 ligand prevent renal allograft rejection in primates. Proc Natl Acad Sci U S A 94:8789–8794. https://doi.org/10.1073/pnas.94.16.8789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Larsen CP, Pearson TC, Adams AB, Tso P, Shirasugi N, Strobert E, Anderson D, Cowan S, Price K, Naemura J, Emswiler J, Greene J, Turk LA, Bajorath J, Townsend R, Hagerty D, Linsley PS, Peach RJ (2005) Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg 5:443–453. https://doi.org/10.1111/j.1600-6143.2005.00749.x

    Article  CAS  Google Scholar 

  20. Adams AB, Ford ML, Larsen CP (2016) Costimulation blockade in autoimmunity and transplantation: the CD28 pathway. J Immunol 197:2045–2050. https://doi.org/10.4049/jimmunol.1601135

    Article  CAS  PubMed  Google Scholar 

  21. Ramsden L, Rider CC (1992) Selective and differential binding of interleukin (IL)-1 alpha, IL-1 beta, IL-2 and IL-6 to glycosaminoglycans. Eur J Immunol 22:3027–3031. https://doi.org/10.1002/eji.1830221139

    Article  CAS  PubMed  Google Scholar 

  22. Kaneko N, Kurata M, Yamamoto T, Morikawa S, Masumoto J (2019) The role of interleukin-1 in general pathology. Inflamm Regen 39:12. https://doi.org/10.1186/s41232-019-0101-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Macdougall IC (2000) Novel erythropoiesis stimulating protein. Semin Nephrol 20:375–381

    CAS  PubMed  Google Scholar 

  24. Schellekens H (2005) Factors influencing the immunogenicity of therapeutic proteins. Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc - Eur Ren Assoc 20 Suppl 6:vi3-9. https://doi.org/10.1093/ndt/gfh1092

    Article  CAS  Google Scholar 

  25. Scepanovic P, Alanio C, Hammer C, Hodel F, Bergstedt J, Patin E, Thorball CW, Chaturvedi N, Charbit B, Abel L, Quintana-Murci L, Duffy D, Albert ML, Fellay J (2018) Human genetic variants and age are the strongest predictors of humoral immune responses to common pathogens and vaccines. Genome Med 10:59. https://doi.org/10.1186/s13073-018-0568-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Fakhir FZ, Lkhider M, Badre W, Alaoui R, Meurs EF, Pineau P, Ezzikouri S, Benjelloun S (2018) Genetic variations in toll-like receptors 7 and 8 modulate natural hepatitis C outcomes and liver disease progression. Liver Int 38:432–442. https://doi.org/10.1111/liv.13533

    Article  CAS  PubMed  Google Scholar 

  27. Thomas SS, Borazan N, Barroso N, Duan L, Taroumian S, Kretzmann B, Bardales R, Elashoff D, Vangala S, Furst DE (2015) Comparative immunogenicity of TNF inhibitors: impact on clinical efficacy and tolerability in the management of autoimmune diseases. A systematic review and meta-analysis. BioDrugs 29:241–258. https://doi.org/10.1007/s40259-015-0134-5

    Article  CAS  PubMed  Google Scholar 

  28. Kelly J (2008) Pre-existing antibodies explain severe cetuximab reactions. Lancet Oncol 9:419. https://doi.org/10.1016/s1470-2045(08)70120-7

    Article  Google Scholar 

  29. Kuriakose A, Chirmule N, Nair P (2016) Immunogenicity of biotherapeutics: causes and association with posttranslational modifications. J Immunol Res 2016:1–18. https://doi.org/10.1155/2016/1298473

    Article  CAS  Google Scholar 

  30. Scheiblhofer S, Laimer J, Machado Y, Weiss R, Thalhamer J (2017) Influence of protein fold stability on immunogenicity and its implications for vaccine design. Expert Rev Vaccines 16:479–489. https://doi.org/10.1080/14760584.2017.1306441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ryff JC (1997) Clinical investigation of the immunogenicity of interferon-alpha 2a. J Interf Cytokine Res 17(Suppl 1):S29–S33. http://www.ncbi.nlm.nih.gov/pubmed/9241613

    CAS  Google Scholar 

  32. Jakimovski D, Kolb C, Ramanathan M, Zivadinov R, Weinstock-Guttman B (2018) Interferon β for multiple sclerosis. Cold Spring Harb Perspect Med 8:a032003. https://doi.org/10.1101/cshperspect.a032003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Guo S, Bozkaya D, Ward A, OʼBrien JA, Ishak K, Bennett R, Al-Sabbagh A, Meletiche DM (2009) Treating relapsing multiple sclerosis with subcutaneous versus intramuscular interferon-Beta-1a. PharmacoEconomics 27:39–53. https://doi.org/10.2165/00019053-200927010-00005

    Article  PubMed  Google Scholar 

  34. Narhi LO, Schmit J, Bechtold-Peters K, Sharma D (2012) Classification of protein aggregates. J Pharm Sci 101:493–498. https://doi.org/10.1002/jps.22790

    Article  CAS  PubMed  Google Scholar 

  35. Ross CA, Poirier MA (2004) Protein aggregation and neurodegenerative disease. Nat Med 10(Suppl):S10–S17. https://doi.org/10.1038/nm1066

    Article  CAS  PubMed  Google Scholar 

  36. Baker MP, Reynolds HM, Lumicisi B, Bryson CJ (2010) Immunogenicity of protein therapeutics: the key causes, consequences and challenges. Self Nonself 1:314–322. https://doi.org/10.4161/self.1.4.13904

    Article  PubMed  PubMed Central  Google Scholar 

  37. Ratanji KD, Derrick JP, Dearman RJ, Kimber I (2014) Immunogenicity of therapeutic proteins: influence of aggregation. J Immunotoxicol 11:99–109. https://doi.org/10.3109/1547691X.2013.821564

    Article  CAS  PubMed  Google Scholar 

  38. Alberts B, Johnson A, Lewis J (2002) Chapter 24 - the adaptive immune system. Mol Biol Cell:1363–1422

    Google Scholar 

  39. Ward JR, Francis SE, Marsden L, Suddason T, Lord GM, Dower SK, Crossman DC, Sabroe I (2009) A central role for monocytes in toll-like receptor-mediated activation of the vasculature. Immunology 128:58–68. https://doi.org/10.1111/j.1365-2567.2009.03071.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Jawa V, Terry F, Gokemeijer J, Mitra-Kaushik S, Roberts BJ, Tourdot S, De Groot AS (2020) T-cell dependent immunogenicity of protein therapeutics pre-clinical assessment and mitigation-updated consensus and review 2020. Front Immunol 11:1301. https://doi.org/10.3389/fimmu.2020.01301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Rehman K, Hamid Akash MS, Akhtar B, Tariq M, Mahmood A, Ibrahim M (2016) Delivery of therapeutic proteins: challenges and strategies. Curr Drug Targets 17:1172–1188. https://doi.org/10.2174/1389450117666151209120139

    Article  CAS  PubMed  Google Scholar 

  42. Jarvi NL, Balu-Iyer SV (2021) Immunogenicity challenges associated with subcutaneous delivery of therapeutic proteins. BioDrugs 35:125–146. https://doi.org/10.1007/s40259-020-00465-4

    Article  PubMed  PubMed Central  Google Scholar 

  43. Zaman R, Islam RA, Ibnat N, Othman I, Zaini A, Lee CY, Chowdhury EH (2019) Current strategies in extending half-lives of therapeutic proteins. J Control Release Off J Control Release Soc 301:176–189. https://doi.org/10.1016/j.jconrel.2019.02.016

    Article  CAS  Google Scholar 

  44. Kromminga A, Schellekens H (2005) Antibodies against erythropoietin and other protein-based therapeutics: an overview. Ann N Y Acad Sci 1050:257–265. https://doi.org/10.1196/annals.1313.027

    Article  CAS  PubMed  Google Scholar 

  45. Nagata S, Pastan I (2009) Removal of B cell epitopes as a practical approach for reducing the immunogenicity of foreign protein-based therapeutics. Adv Drug Deliv Rev 61:977–985. https://doi.org/10.1016/j.addr.2009.07.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Jevsevar S, Kunstelj M, Porekar VG (2010) PEGylation of therapeutic proteins. Biotechnol J 5:113–128. https://doi.org/10.1002/biot.200900218

    Article  CAS  PubMed  Google Scholar 

  47. Dozier JK, Distefano MD (2015) Site-specific PEGylation of therapeutic proteins. Int J Mol Sci 16:25831–25864. https://doi.org/10.3390/ijms161025831

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hutt M, Färber-Schwarz A, Unverdorben F, Richter F, Kontermann RE (2012) Plasma half-life extension of small recombinant antibodies by fusion to immunoglobulin-binding domains. J Biol Chem 287:4462–4469. https://doi.org/10.1074/jbc.M111.311522

    Article  CAS  PubMed  Google Scholar 

  49. Trüssel S, Dumelin C, Frey K, Villa A, Buller F, Neri D (2009) New strategy for the extension of the serum half-life of antibody fragments. Bioconjug Chem 20:2286–2292. https://doi.org/10.1021/bc9002772

    Article  CAS  PubMed  Google Scholar 

  50. Veronese FM, Mero A (2008) The impact of PEGylation on biological therapies. BioDrugs 22:315–329. https://doi.org/10.2165/00063030-200822050-00004

    Article  CAS  PubMed  Google Scholar 

  51. Gaberc-Porekar V, Zore I, Podobnik B, Menart V (2008) Obstacles and pitfalls in the PEGylation of therapeutic proteins. Curr Opin Drug Discov Devel 11:242–250

    CAS  PubMed  Google Scholar 

  52. Roopenian DC, Low BE, Christianson GJ, Proetzel G, Sproule TJ, Wiles MV (2015) Albumin-deficient mouse models for studying metabolism of human albumin and pharmacokinetics of albumin-based drugs. MAbs 7:344–351. https://doi.org/10.1080/19420862.2015.1008345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Fathallah AM, Bankert RB, Balu-Iyer SV (2013) Immunogenicity of subcutaneously administered therapeutic proteins--a mechanistic perspective. AAPS J 15:897–900. https://doi.org/10.1208/s12248-013-9510-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Tiede A, Friedrich U, Stenmo C, Allen G, Giangrande P, Goudemand J, Hay C, Holmström M, Klamroth R, Lethagen S, McKenzie S, Miesbach W, Negrier C, Yuste VJ, Berntorp E (2011) Safety and pharmacokinetics of subcutaneously administered recombinant activated factor VII (rFVIIa). J Thromb Haemost 9:1191–1199. https://doi.org/10.1111/j.1538-7836.2011.04293.x

    Article  CAS  PubMed  Google Scholar 

  55. Bartelds GM, Krieckaert CLM, Nurmohamed MT, van Schouwenburg PA, Lems WF, Twisk JWR, Dijkmans BAC, Aarden L, Wolbink GJ (2011) Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA 305:1460–1468. https://doi.org/10.1001/jama.2011.406

    Article  CAS  PubMed  Google Scholar 

  56. Peng A, Kosloski MP, Nakamura G, Ding H, Balu-Iyer SV (2012) PEGylation of a factor VIII-phosphatidylinositol complex: pharmacokinetics and immunogenicity in hemophilia A mice. AAPS J 14:35–42. https://doi.org/10.1208/s12248-011-9309-2

    Article  CAS  PubMed  Google Scholar 

  57. Torosantucci R, Sharov VS, van Beers M, Brinks V, Schöneich C, Jiskoot W (2013) Identification of oxidation sites and covalent cross-links in metal catalyzed oxidized interferon Beta-1a: potential implications for protein aggregation and immunogenicity. Mol Pharm 10:2311–2322. https://doi.org/10.1021/mp300665u

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Jenkins N (2007) Modifications of therapeutic proteins: challenges and prospects. Cytotechnology 53:121–125. https://doi.org/10.1007/s10616-007-9075-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Cudna RE, Dickson AJ (2003) Endoplasmic reticulum signaling as a determinant of recombinant protein expression. Biotechnol Bioeng 81:56–65. https://doi.org/10.1002/bit.10445

    Article  CAS  PubMed  Google Scholar 

  60. Soto C, Pritzkow S (2018) Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases. Nat Neurosci 21:1332–1340. https://doi.org/10.1038/s41593-018-0235-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Demeule B, Lawrence MJ, Drake AF, Gurny R, Arvinte T (2007) Characterization of protein aggregation: the case of a therapeutic immunoglobulin. Biochim Biophys Acta 1774:146–153. https://doi.org/10.1016/j.bbapap.2006.10.010

    Article  CAS  PubMed  Google Scholar 

  62. Wang W, Singh S, Zeng DL, King K, Nema S (2007) Antibody structure, instability, and formulation. J Pharm Sci 96:1–26. https://doi.org/10.1002/jps.20727

    Article  CAS  PubMed  Google Scholar 

  63. Loladze VV, Makhatadze GI (2011) Energetics of charge-charge interactions between residues adjacent in sequence. Proteins 79:3494–3499. https://doi.org/10.1002/prot.23132

    Article  CAS  PubMed  Google Scholar 

  64. Walsh G, Jefferis R (2006) Post-translational modifications in the context of therapeutic proteins. Nat Biotechnol 24:1241–1252. https://doi.org/10.1038/nbt1252

    Article  CAS  PubMed  Google Scholar 

  65. Shishido SN, Varahan S, Yuan K, Li X, Fleming SD (2012) Humoral innate immune response and disease. Clin Immunol 144:142–158. https://doi.org/10.1016/j.clim.2012.06.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Dingman R, Balu-Iyer SV (2019) Immunogenicity of protein pharmaceuticals. J Pharm Sci 108:1637–1654. https://doi.org/10.1016/j.xphs.2018.12.014

    Article  CAS  PubMed  Google Scholar 

  67. Ghaderi D, Taylor RE, Padler-Karavani V, Diaz S, Varki A (2010) Implications of the presence of N-glycolylneuraminic acid in recombinant therapeutic glycoproteins. Nat Biotechnol 28:863–867. https://doi.org/10.1038/nbt.1651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Matucci A, Nencini F, Maggi E, Vultaggio A (2019) Hypersensitivity reactions to biologics used in rheumatology. Expert Rev Clin Immunol 15:1263–1271. https://doi.org/10.1080/1744666X.2020.1684264

    Article  CAS  PubMed  Google Scholar 

  69. Tang L, Persky AM, Hochhaus G, Meibohm B (2004) Pharmacokinetic aspects of biotechnology products. J Pharm Sci 93:2184–2204. https://doi.org/10.1002/jps.20125

    Article  CAS  PubMed  Google Scholar 

  70. Shankar G, Devanarayan V, Amaravadi L, Barrett YC, Bowsher R, Finco-Kent D, Fiscella M, Gorovits B, Kirschner S, Moxness M, Parish T, Quarmby V, Smith H, Smith W, Zuckerman LA, Koren E (2008) Recommendations for the validation of immunoassays used for detection of host antibodies against biotechnology products. J Pharm Biomed Anal 48:1267–1281. https://doi.org/10.1016/j.jpba.2008.09.020

    Article  CAS  PubMed  Google Scholar 

  71. Barbosa MDFS, Vielmetter J, Chu S, Smith DD, Jacinto J (2006) Clinical link between MHC class II haplotype and interferon-beta (IFN-beta) immunogenicity. Clin Immunol 118:42–50. https://doi.org/10.1016/j.clim.2005.08.017

    Article  CAS  PubMed  Google Scholar 

  72. Carpenter J, Cherney B, Lubinecki A, Ma S, Marszal E, Mire-Sluis A, Nikolai T, Novak J, Ragheb J, Simak J (2010) Meeting report on protein particles and immunogenicity of therapeutic proteins: filling in the gaps in risk evaluation and mitigation. Biol J Int Assoc Biol Stand 38:602–611. https://doi.org/10.1016/j.biologicals.2010.07.002

    Article  Google Scholar 

  73. Hansel TT, Kropshofer H, Singer T, Mitchell JA, George AJT (2010) The safety and side effects of monoclonal antibodies. Nat Rev Drug Discov 9:325–338. https://doi.org/10.1038/nrd3003

    Article  CAS  PubMed  Google Scholar 

  74. Raoufi E, Hemmati M, Eftekhari S, Khaksaran K, Mahmodi Z, Farajollahi MM, Mohsenzadegan M (2020) Epitope prediction by novel immunoinformatics approach: a state-of-the-art review. Int J Pept Res Ther 26:1155–1163. https://doi.org/10.1007/s10989-019-09918-z

    Article  CAS  PubMed  Google Scholar 

  75. Tomar N, De RK (2014) Immunoinformatics: a brief review. Methods Mol Biol 1184:23–55. https://doi.org/10.1007/978-1-4939-1115-8_3

    Article  CAS  PubMed  Google Scholar 

  76. Antonets DV, Maksiutov AZ (2010) TEpredict: software for T-cell epitope prediction. Mol Biol (Mosk) 44:130–139

    Article  CAS  PubMed  Google Scholar 

  77. Zhou Y, Penny HL, Kroenke MA, Bautista B, Hainline K, Chea LS, Parnes J, Mytych DT (2022) Immunogenicity assessment of bispecific antibody-based immunotherapy in oncology. J Immunother Cancer 10:e004225. https://doi.org/10.1136/jitc-2021-004225

    Article  PubMed  PubMed Central  Google Scholar 

  78. Brinks V, Weinbuch D, Baker M, Dean Y, Stas P, Kostense S, Rup B, Jiskoot W (2013) Preclinical models used for immunogenicity prediction of therapeutic proteins. Pharm Res 30:1719–1728. https://doi.org/10.1007/s11095-013-1062-z

    Article  CAS  PubMed  Google Scholar 

  79. Strand V, Balsa A, Al-Saleh J, Barile-Fabris L, Horiuchi T, Takeuchi T, Lula S, Hawes C, Kola B, Marshall L (2017) Immunogenicity of biologics in chronic inflammatory diseases: a systematic review. BioDrugs 31:299–316. https://doi.org/10.1007/s40259-017-0231-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Mufarrege EF, Giorgetti S, Etcheverrigaray M, Terry F, Martin W, De Groot AS (2017) De-immunized and functional therapeutic (DeFT) versions of a long lasting recombinant alpha interferon for antiviral therapy. Clin Immunol 176:31–41. https://doi.org/10.1016/j.clim.2017.01.003

    Article  CAS  PubMed  Google Scholar 

  81. De Groot AS, Terry F, Cousens L, Martin W (2013) Beyond humanization and de-immunization: tolerization as a method for reducing the immunogenicity of biologics. Expert Rev Clin Pharmacol 6:651–662. https://doi.org/10.1586/17512433.2013.835698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. De Groot AS, Desai AK, Lelias S, Miah SMS, Terry FE, Khan S, Li C, Yi JS, Ardito M, Martin WD, Kishnani PS (2021) Immune tolerance-adjusted personalized immunogenicity prediction for Pompe disease. Front Immunol 12:636731. https://doi.org/10.3389/fimmu.2021.636731

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Sydow JF, Lipsmeier F, Larraillet V, Hilger M, Mautz B, Mølhøj M, Kuentzer J, Klostermann S, Schoch J, Voelger HR, Regula JT, Cramer P, Papadimitriou A, Kettenberger H (2014) Structure-based prediction of asparagine and aspartate degradation sites in antibody variable regions. PLoS One 9:e100736. https://doi.org/10.1371/journal.pone.0100736

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Irudayanathan FJ, Zarzar J, Lin J, Izadi S (2021) Divining deamidation and isomerization in therapeutic proteins: effect of neighboring residue. Bio Rxiv. 2021.07.26.453885. https://doi.org/10.1101/2021.07.26.453885

  85. Wang W, Wang EQ, Balthasar JP (2008) Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 84:548–558. https://doi.org/10.1038/clpt.2008.170

    Article  CAS  PubMed  Google Scholar 

  86. Craik DJ, Fairlie DP, Liras S, Price D (2013) The future of peptide-based drugs. Chem Biol Drug Des 81:136–147. https://doi.org/10.1111/cbdd.12055

    Article  CAS  PubMed  Google Scholar 

  87. Verma S, Goand UK, Husain A, Katekar RA, Garg R, Gayen JR (2021) Challenges of peptide and protein drug delivery by oral route: current strategies to improve the bioavailability. Drug Dev Res 82:927–944. https://doi.org/10.1002/ddr.21832

    Article  CAS  PubMed  Google Scholar 

  88. Krause ME, Sahin E (2019) Chemical and physical instabilities in manufacturing and storage of therapeutic proteins. Curr Opin Biotechnol 60:159–167. https://doi.org/10.1016/j.copbio.2019.01.014

    Article  CAS  PubMed  Google Scholar 

  89. Hsiao K, Alves J, Patel R, Adams M, Nashine V, Goueli S (2017) A high-throughput bioluminescent assay to monitor the deamidation of asparagine and isomerization of aspartate residues in therapeutic proteins and antibodies. J Pharm Sci 106:1528–1537. https://doi.org/10.1016/j.xphs.2017.02.022

    Article  CAS  PubMed  Google Scholar 

  90. Naik J, Kulkarni D, Kadu P, Pandya A, Kale P (2022) Use of in silico tools for screening buffers to overcome physical instability of abatacept. Transpl Immunol 71:101551. https://doi.org/10.1016/j.trim.2022.101551

    Article  CAS  PubMed  Google Scholar 

  91. Azevedo Reis Teixeira A, Erasmus MF, D’Angelo S, Naranjo L, Ferrara F, Leal-Lopes C, Durrant O, Galmiche C, Morelli A, Scott-Tucker A, Bradbury ARM (2021) Drug-like antibodies with high affinity, diversity and developability directly from next-generation antibody libraries. MAbs 13:1980942. https://doi.org/10.1080/19420862.2021.1980942

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Pandey LM (2022) Physicochemical factors of bioprocessing impact the stability of therapeutic proteins. Biotechnol Adv 55:107909. https://doi.org/10.1016/j.biotechadv.2022.107909

    Article  CAS  PubMed  Google Scholar 

  93. Butreddy A, Janga KY, Ajjarapu S, Sarabu S, Dudhipala N (2021) Instability of therapeutic proteins - an overview of stresses, stabilization mechanisms and analytical techniques involved in lyophilized proteins. Int J Biol Macromol 167:309–325. https://doi.org/10.1016/j.ijbiomac.2020.11.188

    Article  CAS  PubMed  Google Scholar 

  94. Kintzing JR, Filsinger Interrante MV, Cochran JR (2016) Emerging strategies for developing next-generation protein therapeutics for cancer treatment. Trends Pharmacol Sci 37:993–1008. https://doi.org/10.1016/j.tips.2016.10.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Scott AM, Wolchok JD, Old LJ (2012) Antibody therapy of cancer. Nat Rev Cancer 12:278–287. https://doi.org/10.1038/nrc3236

    Article  CAS  PubMed  Google Scholar 

  96. Han TH, Zhao B (2014) Absorption, distribution, metabolism, and excretion considerations for the development of antibody-drug conjugates. Drug Metab Dispos 42:1914–1920. https://doi.org/10.1124/dmd.114.058586

    Article  CAS  PubMed  Google Scholar 

  97. Tibbitts J, Canter D, Graff R, Smith A, Khawli LA (2016) Key factors influencing ADME properties of therapeutic proteins: a need for ADME characterization in drug discovery and development. MAbs 8:229–245. https://doi.org/10.1080/19420862.2015.1115937

    Article  CAS  PubMed  Google Scholar 

  98. Kariolis MS, Wells RC, Getz JA, Kwan W, Mahon CS, Tong R, Kim DJ, Srivastava A, Bedard C, Henne KR, Giese T, Assimon VA, Chen X, Zhang Y, Solanoy H, Jenkins K, Sanchez PE, Kane L, Miyamoto T, Chew KS, Pizzo ME, Liang N, Calvert MEK, DeVos SL, Baskaran S, Hall S, Sweeney ZK, Thorne RG, Watts RJ, Dennis MS, Silverman AP, Zuchero YJY (2020) Brain delivery of therapeutic proteins using an Fc fragment blood-brain barrier transport vehicle in mice and monkeys. Sci Transl Med 12. https://doi.org/10.1126/scitranslmed.aay1359

  99. Hager T, Spahr C, Xu J, Salimi-Moosavi H, Hall M (2013) Differential enzyme-linked immunosorbent assay and ligand-binding mass spectrometry for analysis of biotransformation of protein therapeutics: application to various FGF21 modalities. Anal Chem 85:2731–2738. https://doi.org/10.1021/ac303203y

    Article  CAS  PubMed  Google Scholar 

  100. Li F, Weng Y, Zhang G, Han X, Li D, Neubert H (2019) Characterization and quantification of an Fc-FGF21 fusion protein in rat serum using immunoaffinity LC-MS. AAPS J 21:84. https://doi.org/10.1208/s12248-019-0356-4

    Article  CAS  PubMed  Google Scholar 

  101. Burnett MJB, Burnett AC (2020) Therapeutic recombinant protein production in plants: challenges and opportunities. Plants People Planet 2:121–132. https://doi.org/10.1002/ppp3.10073

    Article  Google Scholar 

  102. Demain AL, Vaishnav P (2009) Production of recombinant proteins by microbes and higher organisms. Biotechnol Adv 27:297–306. https://doi.org/10.1016/j.biotechadv.2009.01.008

    Article  CAS  PubMed  Google Scholar 

  103. Margolin E, Chapman R, Williamson A-L, Rybicki EP, Meyers AE (2018) Production of complex viral glycoproteins in plants as vaccine immunogens. Plant Biotechnol J 16:1531–1545. https://doi.org/10.1111/pbi.12963

    Article  PubMed  PubMed Central  Google Scholar 

  104. Sahdev S, Khattar SK, Saini KS (2008) Production of active eukaryotic proteins through bacterial expression systems: a review of the existing biotechnology strategies. Mol Cell Biochem 307:249–264. https://doi.org/10.1007/s11010-007-9603-6

    Article  CAS  PubMed  Google Scholar 

  105. Montero-Morales L, Steinkellner H (2018) Advanced plant-based glycan engineering. Front Bioeng Biotechnol 6:81. https://doi.org/10.3389/fbioe.2018.00081

    Article  PubMed  PubMed Central  Google Scholar 

  106. Lico C, Santi L, Twyman RM, Pezzotti M, Avesani L (2012) The use of plants for the production of therapeutic human peptides. Plant Cell Rep 31:439–451. https://doi.org/10.1007/s00299-011-1215-7

    Article  CAS  PubMed  Google Scholar 

  107. Fischer R, Emans N (2000) Molecular farming of pharmaceutical proteins. Transgenic Res 9:279–299. https://doi.org/10.1023/A:1008975123362

    Article  CAS  PubMed  Google Scholar 

  108. Biron KK (2006) Antiviral drugs for cytomegalovirus diseases. Antivir Res 71:154–163. https://doi.org/10.1016/j.antiviral.2006.05.002

    Article  CAS  PubMed  Google Scholar 

  109. Barnes LM, Bentley CM, Dickson AJ (2003) Stability of protein production from recombinant mammalian cells. Biotechnol Bioeng 81:631–639. https://doi.org/10.1002/bit.10517

    Article  CAS  PubMed  Google Scholar 

  110. Lim Y, Wong NSC, Lee YY, Ku SCY, Wong DCF, Yap MGS (2010) Engineering mammalian cells in bioprocessing – current achievements and future perspectives. Biotechnol Appl Biochem 55:175–189. https://doi.org/10.1042/BA20090363

    Article  CAS  PubMed  Google Scholar 

  111. Kamerzell TJ, Esfandiary R, Joshi SB, Middaugh CR, Volkin DB (2011) Protein–excipient interactions: mechanisms and biophysical characterization applied to protein formulation development. Adv Drug Deliv Rev 63:1118–1159. https://doi.org/10.1016/j.addr.2011.07.006

    Article  CAS  PubMed  Google Scholar 

  112. Kiran P, Khan A, Neekhra S, Pallod S, Srivastava R (2021) Nanohybrids as protein-polymer conjugate multimodal therapeutics. Front Med Technol 3. https://doi.org/10.3389/fmedt.2021.676025

  113. Stevens CA, Kaur K, Klok H-A (2021) Self-assembly of protein-polymer conjugates for drug delivery. Adv Drug Deliv Rev 174:447–460. https://doi.org/10.1016/j.addr.2021.05.002

    Article  CAS  PubMed  Google Scholar 

  114. Baker SL, Munasinghe A, Kaupbayeva B, Rebecca Kang N, Certiat M, Murata H, Matyjaszewski K, Lin P, Colina CM, Russell AJ (2019) Transforming protein-polymer conjugate purification by tuning protein solubility. Nat Commun 10:4718. https://doi.org/10.1038/s41467-019-12612-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Moncalvo F, Martinez Espinoza MI, Cellesi F (2020) Nanosized delivery systems for therapeutic proteins: clinically validated technologies and advanced development strategies. Front Bioeng Biotechnol 8. https://doi.org/10.3389/fbioe.2020.00089

Download references

Author information

Authors and Affiliations

  1. Amity Institute of Pharmacy, Lucknow, Amity University Uttar Pradesh, Noida, India

    Mohammad Yasir & Rahul Kumar Maurya

  2. Department of Pharmacology, S.K. Patel College of Pharmaceutical Education and Research, Ganpat University, Mehsana, India

    Alok Shiomurti Tripathi

  3. Department of Pharmaceutical Sciences, School of Health Sciences, University of Petroleum Studies, Dehradun, India

    Prashant Shukla

Authors
  1. Mohammad Yasir
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alok Shiomurti Tripathi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Prashant Shukla
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rahul Kumar Maurya
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rahul Kumar Maurya .

Editor information

Editors and Affiliations

  1. Department of Biotechnology, Siddharth University, Kapilvastu, Siddharth Nagar, Uttar Pradesh, India

    Dev Bukhsh Singh

  2. Department of Biochemistry, North Eastern Hill University, Shillong, Meghalaya, India

    Timir Tripathi

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Yasir, M., Tripathi, A.S., Shukla, P., Maurya, R.K. (2023). Immunogenicity of Therapeutic Proteins. In: Singh, D.B., Tripathi, T. (eds) Protein-based Therapeutics. Springer, Singapore. https://doi.org/10.1007/978-981-19-8249-1_9

Download citation

Publish with us

Policies and ethics

Search

Navigation