Immunogenicity of protein therapeutics: The key causes, consequences and challenges

Self/Nonself - Immune Recognition and Signaling

Volumn 1, Issue 4, 2010, Pages 314-322

  Baker, Matthew P ^a   Reynolds, Helen M ^a   Lumicisi, Brooke ^a   Bryson, Christine J ^a  

^a Antitope Ltd   (United Kingdom)

Author keywords

Deimmunization; Immunogenicity; Neutralizing antibody; Protein therapeutic; T cells

Indexed keywords

ABCIXIMAB; ADALIMUMAB; ALEMTUZUMAB; ALPHA 1 ANTITRYPSIN; ARCITUMOMAB TC 99M; BASILIXIMAB; BETA1A INTERFERON; BEVACIZUMAB; BOTULINUM ANTISERUM; CANAKINUMAB; CAPROMAB PENDETIDE IN 111; CERTOLIZUMAB PEGOL; CETUXIMAB; COMPLEMENT COMPONENT C1S INHIBITOR; DACLIZUMAB; DENOSUMAB; DORNASE ALFA; ECULIZUMAB; EFALIZUMAB; EVITHROM; EXENDIN 4; FANOLESOMAB TC 99M; GEMTUZUMAB; GEMTUZUMAB OZOGAMICIN; GOLIMUMAB; HUMAN GROWTH HORMONE; IBRITUMOMAB TIUXETAN; IMCIROMAB PENTETATE; IMIGLUCERASE; INFLIXIMAB; INSULIN ASPART; INTERFERON BETA SERINE; NATALIZUMAB; NOFETUMOMAB MERPENTAN TC 99M; OFATUMUMAB; OKT 3; OMALIZUMAB; PALIVIZUMAB; PANITUMUMAB; PEGADEMASE; RANIBIZUMAB; RECOMBINANT ALPHA2B INTERFERON; RECOMBINANT ANTITHROMBIN III; RECOMBINANT BLOOD CLOTTING FACTOR 7A; RECOMBINANT BLOOD CLOTTING FACTOR 8; RECOMBINANT BLOOD CLOTTING FACTOR 9; RECOMBINANT ERYTHROPOIETIN; RECOMBINANT GRANULOCYTE COLONY STIMULATING FACTOR; RECOMBINANT GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; RECOMBINANT INTERLEUKIN 2; RECOTHROM; RETEPLASE; RHOPHYLAC; RITUXIMAB; TOCILIZUMAB; TOSITUMOMAB; TOSITUMOMAB I 131; TRASTUZUMAB; UNCLASSIFIED DRUG; UNINDEXED DRUG; USTEKINUMAB; WILATE; ZYNTHA;

ACUTE GRANULOCYTIC LEUKEMIA; ADAPTIVE IMMUNITY; ANKYLOSING SPONDYLITIS; ANTIGEN PRESENTATION; APPENDICITIS; ASTHMA; B CELL LEUKEMIA; BREAST CANCER; CARDIAC IMAGING; CHRONIC LYMPHATIC LEUKEMIA; COLORECTAL CANCER; CROHN DISEASE; CRYOPIRIN ASSOCIATED PERIODIC SYNDROME; DRUG INDUCED DISEASE; EXPERIMENTAL MODEL; GRAFT REJECTION; HUMAN; IMMUNOGENICITY; KIDNEY CANCER; LUNG NON SMALL CELL CANCER; NONHODGKIN LYMPHOMA; NONHUMAN; OSTEOPOROSIS; PAROXYSMAL NOCTURNAL HEMOGLOBINURIA; PROSTATE CANCER; PSORIASIS; PSORIASIS VULGARIS; RESPIRATORY SYNCYTIAL VIRUS INFECTION; RETINA MACULA DEGENERATION; REVIEW; RHEUMATOID ARTHRITIS; T LYMPHOCYTE; TRANSLUMINAL CORONARY ANGIOPLASTY;

EID: 79851475357     PISSN: 19382030     EISSN: 19382049     Source Type: Journal    
DOI: 10.4161/self.1.4.13904     Document Type: Review

References (92)

1. Bertolotto A, Malucchi S, Sala A, Orefice G, Carrieri PB, Capobianco M, et al. Differential effects of three interfeorn betas on neutralising antibodies in patients with multiple sclerosis: a follow up study in an independent laboratory. J Neurol Neurosurg Psychiatry 2002; 73:148-53.
2. Bertolotto A, Sala A, Malucchi S, Marnetto F, Caldano M, Di Sapio A, et al. Biological activity of interferon betas in patients with multiple sclerosis is affected by treatment regimen and neutralising antibodies. J Neurol Neurosurg Psychiatry 2004; 75:1294-9.
3. Cook SD, Quinless JR, Jotkowitz A, Beaton P. Serum IFN neutralizing antibodies and neopterin levels in a cross-section of MS patients. Neurology 2001; 57:1080-4.
4. Ryff JC. Clinical investigation of the immunogenicity of interferon-alpha2a. J Interferon Cytokine Res 1997; 17:29-33.
5. Von Wussow P, Hehlmann R, Hochhaus T, Jakschies D, Nolte KU, Prümmer O, et al. Roferon (rIFNalpha2a) is more immunogenic than intron A (rIFNalpha2b) in patients with chronic myelogenous leukemia. J Interferon Res 1994; 14:217-9.
6. Wadhwa M, Meager A, Dilger P, Bird C, Dolman C, Das RG, et al. Neutralizing antibodies to granulocyte-macrophage colony-stimulating factor, interleukin-1alpha and interferon-alpha but not other cytokines in human immunoglobulin preparations. Immunology 2000; 99:113-23.
7. 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; 348:601-8.
8. Radstake TR, Svenson M, Eijsbouts AM, van den Hoogen FH, Enevold C, van Riel PL, et al. Formation of antibodies against infliximab and adalimumab strongly correlates with functional drug levels and clinical responses in rheumatoid arthritis. Ann Rheum Dis 2009; 68:1739-45.
9. Ritter G, Cohen LS, Williams C Jr, 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; 61:6851-9.
10. Cassinotti A, Ardizzone S, Porro GB. Adalimumab for the treatment of Crohn's disease. Biologics 2008; 2:763-77.
11. Casadevall N, Nataf J, Viron B, Kolta A, Kiladjian JJ, Martin-Dupont P, et al. Pure red-cell aplasia and anti-erythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med 2002; 346:469-75.
12. Vos Q, Lees A, Wu ZQ, Snapper CM, Mond JJ. B-cell activation by T-cell-independent type 2 antigens as an integral part of the humoral immune response to pathogenic microorganisms. Immunol Rev 2000; 176:154-70.
13. Geijtenbeek TB, van Vliet SJ, Engering A, 't Hart BA, van Kooyk Y. Self- and nonself-recognition by C-type lectins on dendritic cells. Annu Rev Immunol 2004; 22:33-54.
14. Diebold SS. Activation of dendritic cells by toll-like receptors and C-type lectins. Handb Exp Pharmacol 2009; 188:3-30.
15. Bonifaz LC, Bonnyay DP, Charalambous A, Darguste DI, Fujii S, Soares H, et al. In vivo targeting of antigens to maturing dendritic cells via the DEC-205 receptor improves T cell vaccination. J Exp Med 2004; 199:815-24.
16. Tacken PJ, de Vries IJ, Gijzen K, Joosten B, Wu D, Rother RP, et al. Effective induction of naive and recall T-cell responses by targeting antigen to human dendritic cells via a humanized anti-DC-SIGN antibody. Blood 2005; 106:1278-85.
17. Merlo A, Calcaterra C, Mènard S, Balsari A. Cross-talk between toll-like receptors 5 and 9 on activation of human immune responses. J Leukoc Biol 2007; 82:509-18.
18. Dudziak D, Kamphorst AO, Heidkamp GF, Buchholz VR, Trumpfheller C, Yamazaki S, et al. Differential antigen processing by dendritic cell subsets in vivo. Science 2007; 315:107-11.
19. Adams EW, Ratner DM, Seeberger PH, Hacohen N. Carbohydratemediated targeting of antigen to dendritic cells leads to enhanced presentation of antigen to T cells. Chembiochem 2008; 9:294-303.
20. Hou B, Reizis B, DeFranco AL. Toll-like receptors activate innate and adaptive immunity by using dendritic cell-intrinsic and -extrinsic mechanisms. Immunity 2008; 29:272-82.
21. Honda K, Ohba Y, Yanai H, Negishi H, Mizutani T, Takaoka A, et al. Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature 2005; 434:1035-40.
22. Martin F, Oliver A, Kearney J. Marginal zone and B1 B cells unite in the early response against T-independent blood-borne particulate antigens. Immunity 2001; 14:617-29.
23. Fehr T, Bachmann MF, Bucher E, Kalinke U, Di Padova FE, Lang AB, et al. Role of repetitive antigen patterns for induction of antibodies against antibodies. J Exp Med 1997; 185:1785-92.
24. Fehr T, Naim HY, Bachmann MF, Ochsenbein AF, Spielhofer P, Bucher E, et al. T-cell independent IgM and enduring protective IgG antibodies induced by chimeric measles viruses. Nat Med 1998; 4:945-8.
25. Bachmann MF, Zinkernagel RM. Neutralizing antiviral B cell responses. Annu Rev Immunol 1997; 15:235-70.
26. Braun A, Kwee L, Labow MA, Alsenz J. Protein aggregates seem to play a key role among the parameters influencing the antigenicity of interferon alpha (IFNalpha) in normal and transgenic mice. Pharm Res 1997; 14:1472-8.
27. Hermeling S, Schellekens H, Maas C, Gebbink MF, Crommelin DJ, Jiskoot W. Antibody response to aggregated human interferon alpha2b in wild-type and transgenic immune tolerant mice depends on type and level of aggregation. J Pharm Sci 2006; 95:1084-96.
28. Cerottini JC, McConahey PJ, Dixon FJ. The immunosuppressive effect of passively administered antibody IgG fragments. J Immunol 1969; 102:1008-15.
29. Klaus GGB. Generation of memory cells. III. Antibody class requirements for the generation of B-memory cells by antigen-antibody complexes. Immunology 1979; 37:345-51.
30. Karlsson MCI, Getahun A, Heyman B. FccRIIB in IgG-mediated suppression of antibody responses: different impact in vivo and in vitro. J Immunol 2001; 67:5558-64.
31. Heyman B, Wiersma E, Nose M. Complement activation is not required for IgG-mediated suppression of the antibody response. Eur J Immunol 1988; 18:1739-43.
32. Daëron M. Fc receptor biology. Annu Rev Immunol 1997; 15:203-34.
33. Amigorena S, Bonnerot C, Drake JR, Choquet D, Hunziker W, Guillet JG, et al. Cytoplasmic domain heterogeneity and functions of IgG Fc receptors in B lymphocytes. Science 1992; 256:1808-12.
34. Muta T, Kurosaki T, Misulovin Z, Sanchez M, Nussenzweig MC, Ravetch JV. A 13-amino-acid motif in the cytoplasmic domain of FccRIIB modulates B-cell receptor signalling. Nature 1994; 368:70-3.
35. Getahun A, Heyman B. Studies on the mechanism by which antigen-specific IgG suppresses primary antibody responses: evidence for epitope masking and decreased localization of antigen in the spleen. Scand J Immunol 2009; 70:277-87.
36. Heyman B, Pilstrom L, Shulman MJ. Complement activation is required for IgM-mediated enhancement of the antibody response. J Exp Med 1988; 167:1999-2004.
37. Applequist SE, Dahlstrom J, Jiang N, Molina H, Heyman B. Antibody production in mice deficient for complement receptors 1 and 2 can be induced by IgG/Ag and IgE/Ag, but not IgM/Ag complexes. J Immunol 2000; 165:2398-403.
38. Diaz de Stahl T, Dahlstrom J, Carroll MC, Heyman B. A role for complement in feedback-enhancement of antibody responses by IgG3. J Exp Med 2003; 197:1183-90.
39. Greenspan NS, Cooper LJN. Intermolecular cooperativity: a clue to why mice have IgG3? Immunol Today 1992; 13:164-8.
40. Dempsey PW, Allison ME, Akkaraju S, Goodnow CC, Fearon DT. C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science 1996; 271:348-50.
41. Getahun A, Dahlstrom J, Wernersson S, Heyman B. IgG2a-mediated enhancement of Ab- and T-cell responses and its relation to inhibitory and activating FccRs. J Immunol 2004; 172:5269-76.
42. Hermeling S, Crommelin DJ, Schellekens H, Jiskoot W. Structure-immunogenicity relationships of therapeutic proteins. Pharm Res 2004; 21:897-903.
43. + T cell response to Factor VIII in haemophilia A, acquired haemophilia and healthy subjects. Thromb Haemost 1999; 82:509-15.
44. + T cells to coagulation Factor VIII: Response in congenital and acquired haemophilia patients and in healthy subjects. Thromb Haemost 2000; 84:643-52.
45. Bachmann MF, Kundig TM, Kalberer CP, Hengartner H, Zinkernagel RM. How many specific B cells are needed to protect against a virus? J Immunol 1994; 152:4235-41.
46. Sallusto F, Schaerli P, Loetscher P, Schaniel C, Lenig D, Mackay CR, et al. Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation. Eur J Immunol 1998; 28:2760-9.
47. Sparwasser T, Koch ES, Vabulas RM, Heeg K, Lipford GB, Ellwart JW, et al. Bacterial DNA and immunostimulatory CpG oligonucleotides trigger maturation and activation of murine dendritic cells. Eur J Immunol 1998; 28:2045-54.
48. De Smedt T, Pajak B, Muraille E, Lespagnard L, Heinen E, DeBaetselier P, et al. Regulation of dendritic cell numbers and maturation by lipopolysaccharide in vivo. J Exp Med 1996; 184:1413-24.
49. Coulie P, Van Snick J. Enhancement of IgG anti-carrier responses by IgG2-anti-hapten antibodies in mice. Eur J Immunol 1985; 15:793-9.
50. van der Laken CJ, Voskuyl AE, Roos JC, Stigter van WM, de Groot ER, Wolbink G, et al. Imaging and serum analysis of immune complex formation of radiolabeled infliximab and anti-infliximab in responders and non-responders to therapy for rheumatoid arthritis. Ann Rheum Dis 2007; 66:253-6.
51. Bajtay Z, Csomor E, Sándor N, Erdei A. Expression and role of Fc- and complement-receptors on human dendritic cells. Immunol Lett 2006; 104:46-52.
52. Bartelds GM, Wijbrandts CA, Nurmohamed MT, Stapel S, Lems WF, Aarden L, et al. Anti-infliximab and anti-adalimumab antibodies in relation to response to adalimumab in infliximab switchers and anti-tumour necrosis factor naive patients: a cohort study. Ann Rheum Dis 2010; 69:817-21.
53. Ehrenforth S, Kreuz W, Scharrer I, Linde R, Funk M, Güngör T, et al. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 1992; 339:594-8.
54. Reding MT, Lei S, Lei H, Green D, Gill J, Conti-Fine BM. Distribution of Th1- and Th2-induced anti-factor VIII IgG subclasses in congenital and acquired hemophilia patients. Thromb Haemost 2002; 88:568-75.
55. Reding MT. Immunological aspects of inhibitor development. Haemophilia 2006; 12:30-5.
56. DiMichele DM, Hoots WK, Pipe SW, Rivard GE, Santagostino E. International workshop on immune tolerance induction: consensus recommendations. Haemophilia 2007; 13:1-22.
57. Wagner CL, Schantz A, Barnathan E, Olson A, Mascelli MA, Ford J, et al. Consequences of immunogenicity to the therapeutic monoclonal antibodies ReoPro and Remicade. Dev Biol (Basel) 2003; 112:37-53.
58. Meritet JF, Maury C, Tovey MG. Induction of tolerance to recombinant therapeutic proteins. J Interferon Cytokine Res 2001; 21:1031-8.
59. Nagler-Anderson C, Terhoust C, Bhan AK, Podolsky DK. Mucosal antigen presentation and the control of tolerance and immunity. Trends Immunol 2001; 22:120-2.
60. Stickler M, Valdes AM, Gebel W, Razo OJ, Faravashi N, Chin R, et al. The HLA-DR2 haplotype is associated with an increased proliferative response to the immunodominant CD4(+) T-cell epitope in human interferon-beta. Genes Immun 2004; 5:1-7.
61. + T cell epitope from the C1 domian of factor VIII. J Thromb Haemost 2005; 3:991-1000.
62. Tangri S, Mothe BF, Eisenbraun J, Sidney J, Southwood S, Briggs K, et al. Rationally engineered therapeutic proteins with reduced immunogenicity. J Immunol 2005; 174:3187-96.
63. Barbosa MD, Vielmetter J, Chu S, Smith DD, Jacinto J. Clinical link between MHC class II haplotype and interferon-beta (IFNbeta) immunogenicity. Clin Immunol 2006; 118:42-50.
64. Harding FA, Stickler MM, Razo J, Dubridge RB. The immunogenicity of humanized and fully human antibodies: Residual immunogenicity resides in the CDR regions. MAbs 2010; 1:2.
65. + T cell epitope in human IFNbeta does not result in an in vivo response directed at the subdominant epitope. J Immunol 2004; 172:6658-65.
66. 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; 43:1256-61.
67. Jaber A, Driebergen R, Giovannoni G, Schellekens H, Simsarian J, Antonelli M. The Rebif new formulation story: it's not trials and error. Drugs R D 2007; 8:335-48.
68. Giovannoni G, Barbarash O, Casset-Semanaz F, King J, Metz L, Pardo G, et al. On behalf of the Rebif® New Formulation Study Group. Safety and immunogenicity of a new formulation of interferon {beta}-1a (Rebif(R) New Formulation) in a Phase IIIb study in patients with relapsing multiple sclerosis: 96-week results. Mult Scler 2009; 15:219-28.
69. Janeway CA. "Approaching the asymptote? Evolution and revolution in immunology," Cold Spring Harb Symp Quant Biol 1989; 54:1-13.
70. Rosloniec EF, Brand DD, Myers LK, Whittington KB, Gumanovskaya M, Zaller DM, et al. An HLA-DR1 transgene confers susceptibility to collagen-induced arthritis elicited with human type II collagen. J Exp Med 1997; 185:1113-22.
71. Black KE, Murray JA, David CS. HLA-DQ determines the response to exogenous wheat proteins: a model of gluten sensitivity in transgenic knockout mice. J Immunol 2002; 169:5595-600.
72. Madoiwa S, Yamauchi T, Hakamata Y, Kobayashi E, Arai M, Sugo T, et al. Induction of immune tolerance by neonatal intravenous injection of human factor VIII in murine hemophilia A. J Thromb Haemost 2004; 2:754-62.
73. Madoiwa S, Yamauchi T, Kobayashi E, Hakamata Y, Dokai M, Makino N, et al. Induction of factor VIII-specific unresponsiveness by intrathymic factor VIII injection in murine hemophilia A. J Thromb Haemost 2009; 2:754-62. Erratum in: J Thromb Haemost 2004; 2:1504.
74. Southwood S, Sidney J, Kondo A, del Guercio MF, Appella E, Hoffman S, et al. Several common HLA-DR types share largely overlapping peptide binding repertoires. J Immunol 1998; 160:3363-73.
75. Traggiai E, Chicha L, Mazzucchelli L, Bronz L, Piffaretti JC, Lanzavecchia A, et al. Development of a human adaptive immune system in cord blood cell-transplanted mice. Science 2004; 304:104-7.
76. Ishikawa F, Yasukawa M, Lyons B, Yoshida S, Miyamoto T, Yoshimoto G, et al. Development of functional human blood and immune systems in NOD/SCID/IL2 receptor {gamma} chain(null) mice. Blood 2005; 106:1565-73.
77. Watanabe Y, Takahashi T, Okajima A, Shiokawa M, Ishii N, Katano I, et al. The analysis of the functions of human B and T cells in humanized NOD/shi-scid/gammac(null) (NOG) mice (hu-HSC NOG mice). Int Immunol 2009; 21:843-58.
78. Bontrop RE, Otting N, de Groot NG, Doxiadis GG. Major histocompatibility complex class II polymorphisms in primates. Immunol Rev 1999; 167:339-50.
79. Baker MP, Jones TD. Identification and removal of immunogenicity in therapeutic proteins. Curr Opin Drug Discov Devel 200; 10:219-27.
80. Perry LC, Jones TD, Baker MP. New approaches to prediction of immune responses to therapeutic proteins during preclinical development. Drugs RD 2008; 9:385-96.
81. Harding FA, Stickler MM, Razo J, Dubridge RB. The immunogenicity of humanized and fully human antibodies: Residual immunogenicity resides in the CDR regions. MAbs 2010; 2.
82. Marshall SA, Lazar GA, Chirino AJ, Desjarlais JR. Rational design and engineering of therapeutic proteins. Drug Discov Today 2003; 8:212-21.
83. Reding MT, Okita DK, Diethelm-Okita BM, Anderson TA, Conti-Fine BM. Epitope repertoire of human CD4(+) T cells on the A3 domain of coagulation factor VIII. J Thromb Haemost 2004; 2:1385-94.
84. + T-cell epitope repertoire on the C2 domain of coagulation factor VIII. J Thromb Haemost 2003; 1:1777-84.
85. Jones TD, Hanlon M, Smith BJ, Heise CT, Nayee PD, Sanders DA, et al. The development of a modified human IFNalpha2b linked to the Fc portion of human IgG1 as a novel potential therapeutic for the treatment of hepatitis C virus infection. J Interferon Cytokine Res 2004; 24:560-72.
86. Stickler M, Rochanayon N, Razo OJ, Mucha J, Gebel W, Faravashi N, et al. An in vitro human cell-based assay to rank the relative immunogenicity of proteins. Toxicol Sci 2004; 77:280-9.
87. Stickler M, Chin R, Faravashi N, Gebel W, Razo OJ, Rochanayon N, et al. Human population-based identification of CD4(+) T-cell peptide epitope determinants. J Immunol Methods 2003; 281:95-108.
88. Jones TD, Crompton LJ, Carr FJ, Baker MP. Deimmunization of monoclonal antibodies. Methods Mol Biol 2009; 525:405-23.
89. Morris MJ, Divgi CR, Pandit-Taskar N, Batraki M, Warren N, Nacca A, et al. Pilot trial of unlabeled and indium-111-labeled anti-prostate-specific membrane antigen antibody J591 for castrate metastatic prostate cancer. Clin Cancer Res 2005; 11:7454-61.
90. 177Lu-labeled J591 monoclonal antibodies: effect of multiple treatments on myelotoxicity. Clin Cancer Res 2005; 11:7195-200.
91. 90Y radioimmunotherapy. J Nucl Med 2008; 49:1066-74.
92. Galsky MD, Eisenberger M, Moore-Cooper S, Kelly WK, Slovin SF, DeLaCruz A, et al. Phase I trial of the prostate-specific membrane antigen-directed immunoconjugate MLN2704 in patients with progressive metastatic castration-resistant prostate cancer. J Clin Oncol 2008; 26:2147-54.