Immunogenicity of Therapeutic Fusion Proteins: Contributory Factors and Clinical Experience

Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges

Volumn , Issue , 2013, Pages 75-90

  Jawa, Vibha ^a   Cousens, Leslie ^b   De Groot, Anne S ^b,c  

^a AMGEN INC   (United States)

^b EpiVax Inc   (United States)

^c UNIVERSITY OF RHODE ISLAND   (United States)

Author keywords

FP clinical immunogenicity; Immunogenicity; Risk assessment; Silico risk estimates; Therapeutic proteins

Indexed keywords

EID: 84878807734     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1002/9781118354599.ch5     Document Type: Chapter

References (89)

1. De Groot AS, Scott DW. (2007) Immunogenicity of protein therapeutics. Trends Immunol. 28, 482-490.
2. Kuus-Reichel K, Grauer LS, Karavodin LM, Knott C, Krusemeier M, Kay NE. (1994) Will immunogenicity limit the use, efficacy, and future development of therapeutic monoclonal antibodies? Clin. Diagn. Lab. Immunol. 1, 365-372.
3. Goodnow CC, Vinuesa CG, Randall KL, Mackay F, Brink R. (2010) Control systems and decision making for antibody production. Nat. Immunol. 11, 681-688.
4. Zubler RH. (2001) Naive and memory B cells in T-celldependent and T-independent responses. Springer Semin. Immunopathol. 23, 405-419.
5. Onda M. (2009) Reducing the immunogenicity of protein therapeutics. Curr. Drug Targets 10, 131-139.
6. Casadevall N, Nataf J, Viron B, Kolta A, Kiladjian JJ, Martin- Dupont P, et al. (2002) Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N. Engl. J. Med. 346, 469-475.
7. Li J, Yang C, Xia Y, Bertino A, Glaspy J, Roberts M, et al. (2001) Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood 98, 3241-3248.
8. Baert F, Noman M, Vermeire S, Van Assche G, G DH, Carbonez A, et al. (2003) Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N. Engl. J. Med. 348, 601-608.
9. De Groot AS, Martin W. (2009) Reducing risk, improving outcomes: bioengineering less immunogenic protein therapeutics. Clin. Immunol. 131, 189-201.
10. Valmori D, Levy F, Godefroy E, Scotto L, Souleimanian NE, Karbach J, et al. (2007) Epitope clustering in regions undergoing efficient proteasomal processing defines immunodominant CTL regions of a tumour antigen. Clin. Immunol. 122, 163-172.
11. Zhang GL, Khan AM, Srinivasan KN, Heiny A, Lee K, Kwoh CK, et al. (2008) Hotspot hunter: a computational system for large-scale screening and selection of candidate immunological hotspots in pathogen proteomes. BMC Bioinform. 9(Suppl. 1), S19.
12. Fooksman DR, Gronvall GK, Tang Q, Edidin M. (2006) Clustering class I MHC modulates sensitivity of T cell recognition. J. Immunol. 176, 6673-6680.
13. Rammensee HG. (1996) Antigen presentation-recent developments. Int. Arch. Allergy. Immunol. 110, 299-307.
14. Podojil JR, Miller SD. (2009) Molecular mechanisms of T-cell receptor and costimulatory molecule ligation/blockade in autoimmune disease therapy. Immunol. Rev. 229, 337-355.
15. Brusko TM, Putnam AL, Bluestone JA. (2008) Human regulatory T cells: role in autoimmune disease and therapeutic opportunities. Immunol. Rev. 223, 371-390.
16. Reveille JD. (2006) The genetic basis of autoantibody production. Autoimmun. Rev. 5, 389-398.
17. Pulendran B, Tang H, Manicassamy S. (2010) Programming dendritic cells to induce T(H)2 and tolerogenic responses. Nat. Immunol. 11, 647-655.
18. Bluestone JA, Abbas AK. (2003) Natural versus adaptive regulatory T cells. Nat. Rev. Immunol. 3, 253-257.
19. Lo D, Reilly C, Marconi LA, Ogata L,Wei Q, Prud'homme G, et al. (1995) Regulation of CD4 T cell reactivity to self and non-self. Int. Rev. Immunol. 13, 147-160.
20. Nurnberger T, Brunner F, Kemmerling B, Piater L. (2004) Innate immunity in plants and animals: striking similarities and obvious differences. Immunol. Rev. 198, 249-266.
21. Rosenberg SA, Sherry RM, Morton KE, Yang JC, Topalian SL, Royal RE, et al. (2006) Altered CD8(+) T-cell responses when immunizing with multiepitope peptide vaccines. J. Immunother. 29, 224-231.
22. Xu D, Liu H, Komai-Koma M. (2004) Direct and indirect role of Toll-like receptors in T cell mediated immunity. Cell Mol. Immunol. 1, 239-246.
23. Flanagan ML, Arias RS, Hu P, Khawli LA, Epstein AL. (2007) Soluble Fc fusion proteins for biomedical research. Methods Mol. Biol. 378, 33-52.
24. Dumont JA, Low SC, Peters RT, Bitonti AJ. (2006) Monomeric Fc fusions: impact on pharmacokinetic and biological activity of protein therapeutics. BioDrugs 20, 151-160.
25. Sallusto F, Cella M, Danieli C, Lanzavecchia A. (1995) Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products. J. Exp. Med. 182, 389-400.
26. Gillies S. (2006) Reducing the immunogenicity of fusion proteins. USPTO, U.P. Office, ed. (US).
27. Wolbink GJ, Aarden LA, Dijkmans BA. (2009) Dealing with immunogenicity of biologicals: assessment and clinical relevance. Curr. Opin. Rheumatol. 21, 211-215.
28. Swanson SJ, Ferbas J, Mayeux P, Casadevall N. (2004) Evaluation of methods to detect and characterize antibodies against recombinant human erythropoietin. Nephron Clin. Pract. 96, c88-c95.
29. Lazarski CA, Chaves FA, Jenks SA, Wu S, Richards KA, Weaver JM, et al. (2005) The kinetic stability of MHC class II: peptide complexes is a key parameter that dictates immunodominance. Immunity 23, 29-40.
30. Van Regenmortel MH. (2009) What is a B-cell epitope? Methods Mol. Biol. 524, 3-20.
31. Roggen EL. (2006) Recent developments with B-cell epitope identification for predictive studies. J. Immunotoxicol. 3, 137-149.
32. Southwood S, Sidney J, Kondo A, del Guercio MF, Appella E, Hoffman S, et al. (1998) Several common HLA-DR types share largely overlapping peptide binding repertoires. J. Immunol. 160, 3363-3373.
33. Kim Y, Sette A, Peters B. (2010) Applications for T-cell epitope queries and tools in the immune epitope database and analysis resource. J. Immunol. Methods. 2011; 374:62-69.
34. Sette A, Buus S, Appella E, Smith JA, Chesnut R, Miles C, et al. (1989) Prediction of major histocompatibility complex binding regions of protein antigens by sequence pattern analysis. Proc. Natl. Acad. Sci. USA 86, 3296-3300.
35. Zhang GL, Petrovsky N, Kwoh CK, August JT, Brusic V. (2006) PRED(TAP): a system for prediction of peptide binding to the human transporter associated with antigen processing. Immunome Res. 2, 3.
36. De Groot AS, Rayner J, Martin W. (2003) Modelling the immunogenicity of therapeutic proteins using T cell epitope mapping. Dev. Biol. (Basel) 112, 71-80.
37. Ahlers JD, Belyakov IM, Thomas EK, Berzofsky JA. (2001) High-affinity T helper epitope induces complementary helper and APC polarization, increased CTL, and protection against viral infection. J. Clin. Invest. 108, 1677-1685.
38. De Groot AS, Rivera DS, McMurry JA, Buus S, Martin W. (2008) Identification of immunogenic HLA-B7 "Achilles' heel" epitopes within highly conserved regions of HIV. Vaccine 26, 3059-3071.
39. De Groot AS, Martin W. (2003) From immunome to vaccine: epitope mapping and vaccine design tools. Novartis Found. Symp. 254, 57-72; discussion 72-76, 98-101, 250-252.
40. De Groot AS, Bosma A, Chinai N, Frost J, Jesdale BM, Gonzalez MA, et al. (2001) From genome to vaccine: in silico predictions, ex vivo verification. Vaccine 19, 4385-4395.
41. De Groot AS, Ardito M, McClaine EM, Moise L, Martin WD. (2009) Immunoinformatic comparison of T-cell epitopes contained in novel swine-origin influenza A (H1N1) virus with epitopes in 2008-2009 conventional influenza vaccine. Vaccine 27, 5740-5747.
42. Inaba H, Martin W, De Groot AS, Qin S, De Groot LJ. (2006) Thyrotropin receptor epitopes and their relation to histocompatibility leukocyte antigen-DR molecules in Graves' disease. J. Clin. Endocrinol. Metab. 91, 2286-2294.
43. De Groot AS, Moise L. (2007) Prediction of immunogenicity for therapeutic proteins: state of the art. Curr. Opin. Drug Discov. Devel. 10, 332-340.
44. Sturniolo T, Bono E, Ding J, Raddrizzani L, Tuereci O, Sahin U, et al. (1999) Generation of tissue-specific and promiscuous HLA ligand databases using DNA microarrays and virtual HLA class II matrices. Nat. Biotechnol. 17, 555-561.
45. Koita OA, Dabitao D, Mahamadou I, Tall M, Dao S, Tounkara A, et al. (2006) Confirmation of immunogenic consensus sequence HIV-1 T-cell epitopes in Bamako, Mali and Providence, Rhode Island. Hum. Vaccin. 2, 119-128.
46. Bond KB, Sriwanthana B, Hodge TW, De Groot AS, Mastro TD, Young NL, et al. (2001) An HLA-directed molecular and bioinformatics approach identifies new HLA-A11 HIV-1 subtype E cytotoxic T lymphocyte epitopes in HIV-1-infected Thais. AIDS Res. Hum. Retroviruses 17, 703-717.
47. Dong Y, Demaria S, Sun X, Santori FR, Jesdale BM, De Groot AS, et al. (2004) HLA-A2-restricted CD8+-cytotoxic-T-cell responses to novel epitopes in Mycobacterium tuberculosis superoxide dismutase, alanine dehydrogenase, and glutamine synthetase. Infect. Immun. 72, 2412-2415.
48. McMurry J, Sbai H, Gennaro ML, Carter EJ, Martin W, De Groot AS. (2005) Analyzing Mycobacterium tuberculosis proteomes for candidate vaccine epitopes. Tuberculosis (Edinb.) 85, 95-105.
49. Cohen T, Moise L, Ardito M, MartinW, De Groot AS. (2010) A method for individualizing the prediction of immunogenicity of protein vaccines and biologic therapeutics: individualized T cell epitope measure (iTEM). J. Biomed. Biotechnol. 2010; 2010: 961752. Published online 2010 July 18. doi: 10.1155/2010/961752.
50. Moise L, Buller RM, Schriewer J, Lee J, Frey SE, Weiner DB, et al. (2010) VennVax, a DNA-prime, peptide-boost multi- T-cell epitope poxvirus vaccine, induces protective immunity against vaccinia infection by T cell response alone. Vaccine. 2011; 29:501-511.
51. Tatarewicz SM, Wei X, Gupta S, Masterman D, Swanson SJ, Moxness MS. (2007) Development of a maturing T-cellmediated immune response in patients with idiopathic Parkinson's disease receiving r-metHuGDNF via continuous intraputaminal infusion. J. Clin. Immunol. 27, 620-627.
52. Koren E, De Groot AS, Jawa V, Beck KD, Boone T, Rivera D, et al. (2007) Clinical validation of the "in silico" prediction of immunogenicity of a human recombinant therapeutic protein. Clin. Immunol. 124, 26-32.
53. Baker MP, Jones TD. (2007) Identification and removal of immunogenicity in therapeutic proteins. Curr. Opin. Drug Discov. Devel. 10, 219-227.
54. Wullner D, Zhou L, Bramhall E, Kuck A, Goletz TJ, Swanson S, et al. (2010) Considerations for optimization and validation of an in vitro PBMC derived T cell assay for immunogenicity prediction of biotherapeutics. Clin. Immunol. 137, 5-14.
55. Steere AC, Klitz W, Drouin EE, Falk BA, Kwok WW, Nepom GT, et al. (2006) Antibiotic-refractory Lyme arthritis is associated with HLA-DR molecules that bind a Borrelia burgdorferi peptide. J. Exp. Med. 203, 961-971.
56. McMurry JA, Kimball S, Lee JH, Rivera D, Martin W, Weiner DB, et al. (2007) Epitope-driven TB vaccine development: a streamlined approach using immuno-informatics, ELISpot assays, and HLA transgenic mice. Curr. Mol. Med. 7, 351-368.
57. Jaber A, Baker M. (2007) Assessment of the immunogenicity of different interferon beta-1a formulations using ex vivo T-cell assays. J. Pharm. Biomed. Anal. 43, 1256-1261.
58. Vossen MT,Westerhout EM, Soderberg-Naucler C,Wiertz EJ. (2002) Viral immune evasion: a masterpiece of evolution. Immunogenetics 54, 527-542.
59. De Groot AS, Knopp PM, Martin W. (2005) De-immunization of therapeutic proteins by T-cell epitope modification. Dev. Biol. (Basel) 122, 171-194.
60. Podojil JR, Turley DM, Miller SD. (2008) Therapeutic blockade of T-cell antigen receptor signal transduction and costimulation in autoimmune disease. Adv. Exp. Med. Biol. 640, 234-251.
61. Tsuji NM, Kosaka A. (2008) Oral tolerance: intestinal homeostasis and antigen-specific regulatory T cells. Trends Immunol. 29, 532-540.
62. Chatenoud L, Bluestone JA. (2007) CD3-specific antibodies: a portal to the treatment of autoimmunity. Nat. Rev. Immunol. 7, 622-632.
63. Alegre ML, Fallarino F. (2006) Mechanisms of CTLA-4-Ig in tolerance induction. Curr. Pharm. Des. 12, 149-160.
64. Pechhold K, Koczwara K. (2008) Immunomodulation of autoimmune diabetes by dendritic cells. Curr. Diab. Rep. 8, 107-113.
65. Skupsky J, Su Y, Lei TC, Scott DW. (2007) Tolerance induction by gene transfer to lymphocytes. Curr. Gene Ther. 7, 369-380.
66. Borel Y, Borel H. (1988) Oligonucleotide linked to human gammaglobulin specifically diminishes anti-DNA antibody formation in cultured lymphoid cells from patients with systemic lupus erythematosus. J. Clin. Invest. 82, 1901-1907.
67. Zambidis ET, Scott DW. (1996) Epitope-specific tolerance induction with an engineered immunoglobulin. Proc. Natl. Acad. Sci. USA 93, 5019-5024.
68. Zambidis ET, Kurup A, Scott DW. (1997) Genetically transferred central and peripheral immune tolerance via retroviralmediated expression of immunogenic epitopes in hematopoietic progenitors or peripheral B lymphocytes. Mol. Med. 3, 212-224.
69. Soukhareva N, Jiang Y, Scott DW. (2006) Treatment of diabetes in NOD mice by gene transfer of Ig-fusion proteins into B cells: role of T regulatory cells. Cell Immunol. 240, 41-46.
70. De Groot AS, Moise L, McMurry JA, Wambre E, Van Overtvelt L, Moingeon P, et al. (2008) Activation of natural regulatory T cells by IgG Fc-derived peptide "Tregitopes". Blood 112, 3303-3311.
71. Maddur MS, Othy S, Hegde P, Vani J, Lacroix-Desmazes S, Bayry J, et al. (2010) Immunomodulation by intravenous immunoglobulin: role of regulatory T cells. J. Clin. Immunol. 30(Suppl. 1), S4-S8.
72. Ephrem A, Chamat S, Miquel C, Fisson S, Mouthon L, Caligiuri G, et al. (2008) Expansion of CD4+CD25+ regulatory T cells by intravenous immunoglobulin: a critical factor in controlling experimental autoimmune encephalomyelitis. Blood 111, 715-722.
73. Kaveri S, Prasad N, Vassilev T, Hurez V, Pashov A, Lacroix- Desmazes S, et al. (1997) Modulation of autoimmune responses by intravenous immunoglobulin (IVIg). Mult. Scler. 3, 121-128.
74. Lopez M, Clarkson MR, Albin M, Sayegh MH, Najafian N. (2006) A novel mechanism of action for anti-thymocyte globulin: induction of CD4+CD25+Foxp3+ regulatory T cells. J. Am. Soc. Nephrol. 17, 2844-2853.
75. De Groot AS. (2008) IgG Tregitopes and AITD-ASATI: antigen specific tolerance induction in autoimmune thyroid disease. Tregs and Th17 Cells in Autoimmunity, Washington, DC.
76. De Groot AS, Moise L, Li X, Su Y, YangW, Desrosiers J, et al. (2009) Effect of Tregitopes on T1D Immune response in vitro and on diabetes in NOD mice. 2nd European Congress of Immunology, Berlin, Germany.
77. D'Addio F, Boenisch O, Wattanabe T, De Groot AS, Sayegh MH, Najafian N. (2009) Immuno-modulatory functions of a novel IgG Fc-derived peptides, Tregitopes, in alloimmunity. American Transplant Conference, Boston, MA.
78. Su Y, Moise L, Li X, Rossi R, Skupsky J, Martin WD, et al. (2009) T cell epitopes (Tregitopes) contained in IgG constant domains activate natural Tregs. 1st International Conference on Tolerance, Elsevier, Boston, MA.
79. Mingozzi F, Finn JD, Zhou S, Hui DJ, Pien GC, Basner- Tschakarjan E, et al. (2009) Suppression of CTL responses against AAV-capsid epitopes by peptide-induced regulatory T cells. American Society for Hematology, Oral Session: Gene Therapy and Transfer, New Orleans, LA.
80. Buhlmann JE, Najafian N, Hui DJ, D'Addio F, Mingozzi F, Moise L, et al. (2010) Preclinical design of less immunogenic biologics: tregitopes and tolerance. Annual Meeting of the American Association of Immunologists, Baltimore, MD.
81. De Groot AS, Najafian N, Hui DJ, D'Addio F, Mingozzi F, Moise L, et al. (2010) Preclinical design of less immunogenic biologics: tregitopes and tolerance. AAPS 2010 National Biotechnology Conference, San Francisco, CA.
82. Sharabi A, Lapter S, Mozes E. (2010) Bcl-xL is required for the development of functional regulatory CD4 cells in lupus- afflicted mice following treatment with a tolerogenic peptide. J. Autoimmun. 34, 87-95.
83. Sharabi A, Zinger H, Zborowsky M, Sthoeger ZM, Mozes E. (2006) A peptide based on the complementarity-determining region 1 of an autoantibody ameliorates lupus by up-regulating CD4+CD25+ cells and TGF-beta. Proc. Natl. Acad. Sci. USA 103, 8810-8815.
84. Hahn BH, Singh RP, La Cava A, Ebling FM. (2005) Tolerogenic treatment of lupus mice with consensus peptide induces Foxp3-expressing, apoptosis-resistant, TGFbetasecreting CD8+ T cell suppressors. J. Immunol. 175, 7728-7737.
85. Hanvesakul R, Maillere B, Briggs D, Baker R, Larche M, Ball S. (2007) Indirect recognition of T-cell epitopes derived from the alpha 3 and transmembrane domain of HLA-A2. Am. J. Transplant. 7, 1148-1157.
86. van Schouwenburg PA, Bartelds GM, Hart MH, Aarden L, Wolbink GJ, Wouters D. (2010) A novel method for the detection of antibodies to adalimumab in the presence of drug reveals "hidden" immunogenicity in rheumatoid arthritis patients. J. Immunol. Methods. 362, 82-88.
87. Swanson SJ. (2006) Immunogenicity issues in drug development. J. Immunotoxicol. 3, 165-172.
88. Moxness M, Tatarewicz S, Weeraratne D, Murakami N, Wullner D, Mytych D, et al. (2005) Immunogenicity testing by electrochemiluminescent detection for antibodies directed against therapeutic human monoclonal antibodies. Clin. Chem. 51, 1983-1985.
89. Koren E. (2002) From characterization of antibodies to prediction of immunogenicity. Dev. Biol. (Basel) 109, 87-95.