Challenges and approaches for the development of safer immunomodulatory biologics

Nature Reviews Drug Discovery

Volumn 12, Issue 4, 2013, Pages 306-324

  Sathish, Jean G ^a   Sethu, Swaminathan ^a   Bielsky, Marie Christine ^b   De Haan, Lolke ^c   French, Neil S ^a   Govindappa, Karthik ^a   Green, James ^d   Griffiths, Christopher E M ^e   Holgate, Stephen ^f   Jones, David ^b   Kimber, Ian ^e   Moggs, Jonathan ^g   Naisbitt, Dean J ^a   Pirmohamed, Munir ^a   Reichmann, Gabriele ^h   Sims, Jennifer ⁱ   Subramanyam, Meena ^j   Todd, Marque D ^k   Van Der Laan, Jan Willem ^l   Weaver, Richard J ^m   Park, B Kevin ^a   more..

^a UNIVERSITY OF LIVERPOOL   (United Kingdom)

^b MEDICINES AND HEALTHCARE PRODUCTS REGULATORY AGENCY   (United Kingdom)

^c MEDIMMUNE   (United States)

^d Boehringer Ingelheim   (United States)

^e UNIVERSITY OF MANCHESTER   (United Kingdom)

^f SOUTHAMPTON GENERAL HOSPITAL   (United Kingdom)

^g WSH 2881129   (Switzerland)

^h PAUL EHRLICH INSTITUT   (Germany)

ⁱ Integrated Biologix GmbH   (Switzerland)

^j BIOGEN   (United States)

^k PFIZER INC   (United States)

^l MEDICINES EVALUATION BOARD   (Netherlands)

^m INSTITUT DE RECHERCHES INTERNATIONALES SERVIER   (France)

more..

Author keywords

[No Author keywords available]

Indexed keywords

ABATACEPT; ADALIMUMAB; ALEMTUZUMAB; ALPHA INTERFERON; BASILIXIMAB; BELATACEPT; BELIMUMAB; BETA1A INTERFERON; BRENTUXIMAB VEDOTIN; CATUMAXOMAB; DENILEUKIN DIFTITOX; GAMMA INTERFERON; IBRITUMOMAB TIUXETAN; IMMUNOMODULATING AGENT; INTERFERON BETA SERINE; NATALIZUMAB; OFATUMUMAB; OKT 3; OMALIZUMAB; PEGINTERFERON ALPHA2A; PEGINTERFERON ALPHA2B; RECOMBINANT GRANULOCYTE COLONY STIMULATING FACTOR; RECOMBINANT GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; RECOMBINANT INTERLEUKIN 2; RITUXIMAB; TGN 1412; TOCILIZUMAB; TOSITUMOMAB; TUMOR NECROSIS FACTOR INHIBITOR; UNINDEXED DRUG;

ACUTE GRANULOCYTIC LEUKEMIA; ADVERSE DRUG REACTION; ALBERS SCHOENBERG DISEASE; ANAPHYLAXIS; ANKYLOSING SPONDYLITIS; ARTICLE; ASTHMA; B CELL LEUKEMIA; CHRONIC GRANULOMATOUS DISEASE; CHRONIC LYMPHATIC LEUKEMIA; CHRONIC MYELOID LEUKEMIA; CROHN DISEASE; CYTOKINE RELEASE SYNDROME; DRUG HYPERSENSITIVITY; DRUG MECHANISM; DRUG SAFETY; GRAFT REJECTION; HAIRY CELL LEUKEMIA; HEPATITIS C; HODGKIN DISEASE; HUMAN; IMMUNE RESPONSE; IMMUNOGENICITY; IMMUNOMODULATION; IMMUNOSTIMULATION; IMMUNOTOXICITY; INFECTION; INFUSION RELATED REACTION; JUVENILE RHEUMATOID ARTHRITIS; KAPOSI SARCOMA; KIDNEY METASTASIS; LARGE CELL LYMPHOMA; LYMPHOPROLIFERATIVE DISEASE; MALIGNANT ASCITES; METASTATIC MELANOMA; MICROSCOPIC POLYANGIITIS; MULTIPLE SCLEROSIS; NEOPLASM; NEUTROPENIA; NONHODGKIN LYMPHOMA; NONHUMAN; PARASITOSIS; PATIENT SATISFACTION; PHASE 1 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; PSORIATIC ARTHRITIS; RANDOMIZED CONTROLLED TRIAL (TOPIC); RHEUMATOID ARTHRITIS; RISK ASSESSMENT; T CELL LYMPHOMA; WEGENER GRANULOMATOSIS;

ANIMALS; AUTOIMMUNE DISEASES; DRUG DESIGN; HUMANS; IMMUNOLOGIC FACTORS; NEOPLASMS; RISK ASSESSMENT; RISK MANAGEMENT;

EID: 84875720612     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd3974     Document Type: Article

References (182)

1. Swinney, D. C. & Anthony, J. How were new medicines discovered? Nature Rev. Drug Discov. 10, 507-519 (2011).
2. Leader, B., Baca, Q. J. & Golan, D. E. Protein therapeutics: a summary and pharmacological classification. Nature Rev. Drug Discov. 7, 21-39 (2008).
3. Hansel, T. T., Kropshofer, H., Singer, T., Mitchell, J. A. & George, A. J. The safety and side effects of monoclonal antibodies. Nature Rev. Drug Discov. 9, 325-338 (2010).
4. Sorensen, P. S. et al. Risk stratification for progressive multifocal leukoencephalopathy in patients treated with natalizumab. Mult. Scler. 18, 143-152 (2012).
5. Bloomgren, G. et al. Risk of natalizumab-associated progressive multifocal leukoencephal-opathy. N. Engl. J. Med. 366, 1870-1880 (2012).
6. Bongartz, T. et al. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 295, 2275-2285 (2006).
7. Bongartz, T. et al. Etanercept therapy in rheumatoid arthritis and the risk of malignancies: a systematic review and individual patient data meta-analysis of randomised controlled trials. Ann. Rheum. Dis. 68, 1177-1183 (2009).
8. US Food and Drug Administration. Tumor necrosis factor (TNF) blockers, azathioprine and/or mercaptopurine: update on reports of hepatosplenic T-cell lymphoma in adolescents and young adults. FDA website [online], http://www.fda.gov/Safety/MedWatch/SafetyInformation/ SafetyAlertsforHumanMedical Products/ucm251443.htm (2011).
9. Dommasch, E. D. et al. The risk of infection and malignancy with tumor necrosis factor antagonists in adults with psoriatic disease: a systematic review and meta-analysis of randomized controlled trials. J. Am. Acad. Dermatol. 64, 1035-1050 (2011).
10. Beukelman, T. et al. Rates of malignancy associated with juvenile idiopathic arthritis and its treatment. Arthritis Rheum. 64, 1263-1271 (2012).
11. Le Blay, P., Mouterde, G., Barnetche, T., Morel, J. & Combe, B. Short-term risk of total malignancy and nonmelanoma skin cancers with certolizumab and golimumab in patients with rheumatoid arthritis: metaanalysis of randomized controlled trials. J. Rheumatol. 39, 712-715 (2012).
12. Grivennikov, S. I., Greten, F. R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883-899 (2010).
13. Dias, C. & Isenberg, D. A. Susceptibility of patients with rheumatic diseases to B-cell non-Hodgkin lymphoma. Nature Rev. Rheumatol. 7, 360-368 (2011).
14. Grinyo, J. et al. An integrated safety profile analysis of belatacept in kidney transplant recipients. Transplantation 90, 1521-1527 (2010).
15. Arora, S., Tangirala, B., Osadchuk, L. & Sureshkumar, K. K. Belatacept: a new biological agent for maintenance immunosuppression in kidney transplantation. Expert Opin. Biol. Ther. 12, 965-979 (2012).
16. Walker, M. R., Makropoulos, D. A., Achuthanandam, R., Van Arsdell, S. & Bugelski, P. J. Development of a human whole blood assay for prediction of cytokine release similar to anti-CD28 superagonists using multiplex cytokine and hierarchical cluster analysis. Int. Immunopharmacol. 11, 1697-1705 (2011).
17. Ponce, R. Adverse consequences of immunostimulation. J. Immunotoxicol. 5, 33-41 (2008).
18. Suntharalingam, G. et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N. Engl. J. Med. 355, 1018-1028 (2006).
19. Abramowicz, D., Crusiaux, A. & Goldman, M. Anaphylactic shock after retreatment with OKT3 monoclonal antibody. N. Engl. J. Med. 327, 736 (1992).
20. Baudouin, V. et al. Anaphylactic shock caused by immunoglobulin E sensitization after retreatment with the chimeric anti-interleukin-2 receptor monoclonal antibody basiliximab. Transplantation 76, 459-463 (2003).
21. Chirmule, N., Jawa, V. & Meibohm, B. Immunogenicity to therapeutic proteins: impact on PK/PD and efficacy. AAPS J. 14, 296-302 (2012).
22. Ponce, R. et al. Immunogenicity of biologically-derived therapeutics: assessment and interpretation of nonclinical safety studies. Regul. Toxicol. Pharmacol. 54, 164-182 (2009).
23. Bendtzen, K. et al. Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor α inhibitor infliximab. Arthritis Rheum. 54, 3782-3789 (2006).
24. Bartelds, G. M. et al. Surprising negative association between IgG1 allotype disparity and anti-adalimumab formation: a cohort study. Arthritis Res. Ther. 12, R221 (2010).
25. Bartelds, G. M. et al. Anti-adalimumab antibodies in rheumatoid arthritis patients are associated with interleukin-10 gene polymorphisms. Arthritis Rheum. 60, 2541-2542 (2009).
26. European Medicines Agency. Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins. EMA website [online], http://www.ema.europa.eu/docs/en-GB/document-library/Scientific-guideline/2009/ 09/WC500003946.pdf (2008).
27. US Food and Drug Administration. Guidance for industry: assay development for immunogenicity testing of therapeutic proteins. FDA website [online], http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM192750.pdf (2009).
28. Dall'Acqua, W. F., Kiener, P. A. & Wu, H. Properties of human IgG1s engineered for enhanced binding to the neonatal Fc receptor (FcRn). J. Biol. Chem. 281, 23514-23524 (2006).
29. Oganesyan, V., Gao, C., Shirinian, L., Wu, H. & Dall'Acqua, W. F. Structural characterization of a human Fc fragment engineered for lack of effector functions. Acta Crystallogr. D Biol. Crystallogr. 64, 700-704 (2008).
30. Mossner, E. et al. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood 115, 4393-4402 (2010).
31. Salles, G. et al. Phase 1 study results of the type II glycoengineered humanized anti-CD20 monoclonal antibody obinutuzumab (GA101) in B-cell lymphoma patients. Blood 119, 5126-5132 (2012).
32. Davies, J. et al. Expression of GnTIII in a recombinant anti-CD20 CHO production cell line: expression of antibodies with altered glycoforms leads to an increase in ADCC through higher affinity for FCγRIII. Biotechnol. Bioeng. 74, 288-294 (2001).
33. Jefferis, R. Glycosylation as a strategy to improve antibody-based therapeutics. Nature Rev. Drug Discov. 8, 226-234 (2009).
34. Boyd, P. N., Lines, A. C. & Patel, A. K. The effect of the removal of sialic acid, galactose and total carbohydrate on the functional activity of Campath-1H. Mol. Immunol. 32, 1311-1318 (1995).
35. Slavin, R. G. et al. Asthma symptom re-emergence after omalizumab withdrawal correlates well with increasing IgE and decreasing pharmacokinetic concentrations. J. Allergy Clin. Immunol. 123, 107-113.e3 (2009).
36. Corren, J. et al. Lebrikizumab treatment in adults with asthma. N. Engl. J. Med. 365, 1088-1098 (2011).
37. Sethu, S. et al. Immunogenicity to biologics: mechanisms, prediction and reduction. Arch. Immunol. Ther. Exp. 60, 331-344 (2012).
38. Tabrizi, M. A. et al. Translational strategies for development of monoclonal antibodies from discovery to the clinic. Drug Discov. Today 14, 298-305 (2009).
39. Chapman, K. et al. Preclinical development of monoclonal antibodies: considerations for the use of non-human primates. MAbs 1, 505-516 (2009).
40. Haley, P. et al. STP position paper: best practice guideline for the routine pathology evaluation of the immune system. Toxicol. Pathol. 33, 404-407 (2005).
41. Kuper, C. F., Harleman, J. H., Richter-Reichelm, H. B. & Vos, J. G. Histopathologic approaches to detect changes indicative of immunotoxicity. Toxicol. Pathol. 28, 454-466 (2000).
42. Brennan, F. R. et al. Safety and immunotoxicity assessment of immunomodulatory monoclonal antibodies. MAbs 2, 233-255 (2010).
43. Plitnick, L. M. & Herzyk, D. J. The T-dependent antibody response to keyhole limpet hemocyanin in rodents. Methods Mol. Biol. 598, 159-171 (2010).
44. Hutto, D. L. Opportunistic infections in non-human primates exposed to immunomodulatory biotherapeutics: considerations and case examples. J. Immunotoxicol. 7, 120-127 (2010).
45. Burleson, F. G. & Burleson, G. R. Host resistance assays including bacterial challenge models. Methods Mol. Biol. 598, 97-108 (2010).
46. Wagar, E. J. et al. Regulation of human cell engraftment and development of EBV-related lymphoproliferative disorders in Hu-PBL-scid mice. J. Immunol. 165, 518-527 (2000).
47. Kawabata, T. et al. Summary of roundtable discussion meeting: non-human primates to assess risk for EBV-related lymphomas in humans. J. Immunotoxicol. 9, 121-127 (2012).
48. Kirton, C. M., Gliddon, D. R., Bannish, G., Bembridge, G. P. & Coney, L. A. In vitro cytokine release assays: reducing the risk of adverse events in man. Bioanalysis 3, 2657-2663 (2011).
49. The Health and Environmental Sciences Institute (HESI). HESI Technical Committee. Immunotoxicology: 2011-2012 Activities and Accomplishments. HESI Global [online], http://www.hesiglobal.org/files/public/Factsheets/2011/ITC-FS- 2011.pdf (2012).
50. Dhir, V. et al. A predictive biomimetic model of cytokine release induced by TGN1412 and other therapeutic monoclonal antibodies. J. Immunotoxicol. 9, 34-42 (2012).
51. Vidal, J. M. et al. In vitro cytokine release assays for predicting cytokine release syndrome: the current state-of-the-science. Report of a European Medicines Agency Workshop. Cytokine 51, 213-215 (2010).
52. Muller, P. Y., Milton, M., Lloyd, P., Sims, J. & Brennan, F. R. The minimum anticipated biological effect level (MABEL) for selection of first human dose in clinical trials with monoclonal antibodies. Curr. Opin. Biotechnol. 20, 722-729 (2009).
53. Muller, P. Y. & Brennan, F. R. Safety assessment and dose selection for first-in-human clinical trials with immunomodulatory monoclonal antibodies. Clin. Pharmacol. Ther. 85, 247-258 (2009).
54. Milton, M. N. & Horvath, C. J. The EMEA guideline on first-in-human clinical trials and its impact on pharmaceutical development. Toxicol. Pathol. 37, 363-371 (2009).
55. Inaba, H., Martin, W., De Groot, A. S., Qin, S. & De Groot, L. J. Thyrotropin receptor epitopes and their relation to histocompatibility leukocyte antigen-DR molecules in Graves' disease. J. Clin. Endocrinol. Metab. 91, 2286-2294 (2006).
56. Khan, A. M. et al. A systematic bioinformatics approach for selection of epitope-based vaccine targets. Cell. Immunol. 244, 141-147 (2006).
57. De Groot, A. S. & Berzofsky, J. A. From genome to vaccine - new immunoinformatics tools for vaccine design. Methods 34, 425-428 (2004).
58. De Groot, A. S. & Moise, L. Prediction of immunogenicity for therapeutic proteins: state of the art. Curr. Opin. Drug Discov. Devel. 10, 332-340 (2007).
59. Koren, E. et al. Clinical validation of the "in silico" prediction of immunogenicity of a human recombinant therapeutic protein. Clin. Immunol. 124, 26-32 (2007).
60. De Groot, A. S. & Martin, W. Reducing risk, improving outcomes: bioengineering less immunogenic protein therapeutics. Clin. Immunol. 131, 189-201 (2009).
61. El-Manzalawy, Y., Dobbs, D. & Honavar, V. Predicting linear B-cell epitopes using string kernels. J. Mol. Recognit. 21, 243-255 (2008).
62. Larsen, J. E., Lund, O. & Nielsen, M. Improved method for predicting linear B-cell epitopes. Immunome Res. 2, 2 (2006).
63. Sollner, J. et al. Analysis and prediction of protective continuous B-cell epitopes on pathogen proteins. Immunome Res. 4, 1 (2008).
64. Kumar, S., Mitchell, M. A., Rup, B. & Singh, S. K. Relationship between potential aggregation-prone regions and HLA-DR-binding T-cell immune epitopes: implications for rational design of novel and follow-on therapeutic antibodies. J. Pharm. Sci. 101, 2686-2701 (2012).
65. Agrawal, N. J. et al. Aggregation in protein-based biotherapeutics: computational studies and tools to identify aggregation-prone regions. J. Pharm. Sci. 100, 5081-5095 (2011).
66. Barbosa, M. D., Vielmetter, J., Chu, S., Smith, D. D. & Jacinto, J. Clinical link between MHC class II haplotype and interferon-β (IFN-β) immunogenicity. Clin. Immunol. 118, 42-50 (2006).
67. Kropshofer, H. & Singer, T. Overview of cell-based tools for pre-clinical assessment of immunogenicity of biotherapeutics. J. Immunotoxicol. 3, 131-136 (2006).
68. Jaber, A. & Baker, M. Assessment of the immunogenicity of different interferon ß-1a formulations using ex vivo T-cell assays. J. Pharm. Biomed. Anal. 43, 1256-1261 (2007).
69. Baker, M. P. & Jones, T. D. Identification and removal of immunogenicity in therapeutic proteins. Curr. Opin. Drug Discov. Devel. 10, 219-227 (2007).
70. Baker, M. P., Reynolds, H. M., Lumicisi, B. & Bryson, C. J. Immunogenicity of protein therapeutics: the key causes, consequences and challenges. Self Nonself 1, 314-322 (2010).
71. Depil, S. et al. Peptide-binding assays and HLA II transgenic Aß degrees mice are consistent and complementary tools for identifying HLA II-restricted peptides. Vaccine 24, 2225-2229 (2006).
72. Pan, S., Trejo, T., Hansen, J., Smart, M. & David, C. S. HLA-DR4 (DRB1&z.ast;0401) transgenic mice expressing an altered CD4-binding site: specificity and magnitude of DR4-restricted T cell response. J. Immunol. 161, 2925-2929 (1998).
73. Palleroni, A. V. et al. Interferon immunogenicity: preclinical evaluation of interferon-a 2a. J. Interferon Cytokine Res. 17 (Suppl. 1), 23-27 (1997).
74. Hermeling, S. et al. Antibody response to aggregated human interferon a2b in wild-type and transgenic immune tolerant mice depends on type and level of aggregation. J. Pharm. Sci. 95, 1084-1096 (2006).
75. Ishikawa, F. et al. Development of functional human blood and immune systems in NOD/SCID/IL2 receptor y chain(null) mice. Blood 106, 1565-1573 (2005).
76. Pearson, T., Greiner, D. L. & Shultz, L. D. Creation of "humanized" mice to study human immunity. Curr Protoc. Immunol. 1 May 2008 (doi:10.1002/0471142735.im1521s81).
77. King, M. et al. A new Hu-PBL model for the study of human islet alloreactivity based on NOD-scid mice bearing a targeted mutation in the IL-2 receptor y chain gene. Clin. Immunol. 126, 303-314 (2008).
78. Brinks, V., Jiskoot, W. & Schellekens, H. Immunogenicity of therapeutic proteins: the use of animal models. Pharm. Res. 28, 2379-2385 (2011).
79. Kircik, L. H. & Del Rosso, J. Q. Anti-TNF agents for the treatment of psoriasis. J. Drugs Dermatol. 8, 546-559 (2009).
80. El Mourabet, M., El-Hachem, S., Harrison, J. R. & Binion, D. G. Anti-TNF antibody therapy for inflammatory bowel disease during pregnancy: a clinical review. Curr. Drug Targets 11, 234-241 (2010).
81. Papp, K. A. et al. Long-term safety of ustekinumab in patients with moderate-to-severe psoriasis: final results from five years of follow-up. Br. J. Dermatol. 10 Jan 2013 (doi:10.1111/bjd.12214).
82. Ray, K. IBD: ustekinumab shows promise in the treatment of refractory Crohn's disease. Nature Rev Gastroenterol. Hepatol. 9, 690 (2012).
83. Parikh, A. et al. Vedolizumab for the treatment of active ulcerative colitis: a randomized controlled phase 2 dose-ranging study. Inflamm. Bowel Dis. 18, 1470-1479 (2012).
84. Haanstra, K. G. et al. Antagonizing the a4ß 1 integrin, but not a4ß7, inhibits leukocytic infiltration of the central nervous system in rhesus monkey experimental autoimmune encephalomyelitis. J. Immunol. 190, 1961-1973 (2013).
85. Li, S. et al. Pharmacokinetics and tolerability of human mouse chimeric anti-CD22 monoclonal antibody in Chinese patients with CD22-positive non-Hodgkin lymphoma. MAbs 4, 256-266 (2012).
86. Zhang, X. & Markovic-Plese, S. Interferon ß inhibits the Th17 cell-mediated autoimmune response in patients with relapsing-remitting multiple sclerosis. Clin. Neurol. Neurosurg. 112, 641-645 (2010).
87. Wang, C. et al. Small Modular ImmunoPharmaceutical (SMIPTM) molecules directed at the TCR complex (CD3) block T cell activation and cause minimal cytokine release in vitro. J. Immunol. 184, Abstract 96.25 (2010).
88. Beckett, T. et al. Small Modular ImmunoPharmaceutical (SMIPTM) molecules directed at the TCR complex block acute graft versus host disease and cause minimal cytokine release in vivo. J. Immunol. 184, Abstract 145.30 (2010).
89. Burge, D. J. et al. Pharmacokinetic and pharmacodynamic properties of TRU-015, a CD20-directed small modular immunopharmaceutical protein therapeutic, in patients with rheumatoid arthritis: a Phase I, open-label, dose-escalation clinical study. Clin. Ther. 30, 1806-1816 (2008).
90. Lee, S. & Ballow, M. Monoclonal antibodies and fusion proteins and their complications: targeting B cells in autoimmune diseases. J. Allergy Clin. Immunol. 125, 814-820 (2010).
91. Tawara, T. et al. Complement activation plays a key role in antibody-induced infusion toxicity in monkeys and rats. J. Immunol. 180, 2294-2298 (2008).
92. Nagorsen, D., Kufer, P., Baeuerle, P. A. & Bargou, R. Blinatumomab: a historical perspective. Pharmacol. Ther. 136, 334-342 (2012).
93. Gupta, P., Goldenberg, D. M., Rossi, E. A. & Chang, C. H. Multiple signaling pathways induced by hexavalent, monospecific, anti-CD20 and hexavalent, bispecific, anti-CD20/CD22 humanized antibodies correlate with enhanced toxicity to B-cell lymphomas and leukemias. Blood 116, 3258-3267 (2010).
94. Qu, Z. et al. Bispecific anti-CD20/22 antibodies inhibit B-cell lymphoma proliferation by a unique mechanism of action. Blood 111, 2211-2219 (2008).
95. Furst, D. E. Development of TNF inhibitor therapies for the treatment of rheumatoid arthritis. Clin. Exp. Rheumatol. 28, S5-S12 (2010).
96. Greenberg, J. D. et al. Association of methotrexate and tumour necrosis factor antagonists with risk of infectious outcomes including opportunistic infections in the CORRONA registry. Ann. Rheum. Dis. 69, 380-386 (2010).
97. Colombel, J. F. et al. The safety profile of infliximab in patients with Crohn's disease: the Mayo clinic experience in 500 patients. Gastroenterology 126, 19-31 (2004).
98. Zabana, Y. et al. Infliximab safety profile and longterm applicability in inflammatory bowel disease: 9-year experience in clinical practice. Aliment. Pharmacol. Ther. 31, 553-560 (2010).
99. Lane, M. A. et al. TNF-α antagonist use and risk of hospitalization for infection in a national cohort of veterans with rheumatoid arthritis. Medicine (Baltimore) 90, 139-145 (2011).
100. Favalli, E. G. et al. Serious infections during anti-TNFα treatment in rheumatoid arthritis patients. Autoimmun. Rev. 8, 266-273 (2009).
101. Singh, J. A. et al. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev 16 Feb 2011 (doi:10.1002/14651858.CD008794.pub2). This is a systematic review that enumerates the incidences of adverse reactions, particularly infections and malignancies, associated with immunomodulatory biologics.
102. Schoels, M., Aletaha, D., Smolen, J. S. & Wong, J. B. Comparative effectiveness and safety of biological treatment options after tumour necrosis factor α inhibitor failure in rheumatoid arthritis: systematic review and indirect pairwise meta-analysis. Ann. Rheum. Dis. 30 Jan 2012 (doi:10.1136/annrheumdis-2011-200490).
103. Curtis, J. R. & Singh, J. A. Use of biologics in rheumatoid arthritis: current and emerging paradigms of care. Clin. Ther. 33, 679-707 (2011).
104. Grasland, A., Sterpu, R., Boussoukaya, S. & Mahe, I. Autoimmune hepatitis induced by adalimumab with successful switch to abatacept. Eur. J. Clin. Pharmacol. 68, 895-898 (2012).
105. Germanidis, G., Hytiroglou, P., Zakalka, M. & Settas, L. Reactivation of occult hepatitis B virus infection, following treatment of refractory rheumatoid arthritis with abatacept. J. Hepatol. 56, 1420-1421 (2012).
106. Larsen, C. P. et al. Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am. J. Transplant. 5, 443-453 (2005).
107. Epping, G., van der Valk, P. D. & Hendrix, R. Legionella pneumophila pneumonia in a pregnant woman treated with anti-TNF-α antibodies for Crohn's disease: a case report. J. Crohns Colitis 4, 687-689 (2010).
108. US Food and Drug Administration. FDA drug safety communication: Drug labels for the tumor necrosis factor-α (TNFα) blockers now include warnings about infection with Legionella and Listeria bacteria. FDA website [online], http://www.fda.gov/Drugs/DrugSafety/ucm270849.htm (2011).
109. Kendler, D. L. et al. Effects of denosumab on bone mineral density and bone turnover in postmenopausal women transitioning from alendronate therapy. J. Bone Miner. Res. 25, 72-81 (2010).
110. Cohen, S. B. et al. Denosumab treatment effects on structural damage, bone mineral density, and bone turnover in rheumatoid arthritis: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial. Arthritis Rheum. 58, 1299-1309 (2008).
111. Askling, J. et al. Time-dependent increase in risk of hospitalisation with infection among Swedish RA patients treated with TNF antagonists. Ann. Rheum. Dis. 66, 1339-1344 (2007).
112. Watts, N. B. et al. Infections in postmenopausal women with osteoporosis treated with denosumab or placebo: coincidence or causal association? Osteoporos. Int. 23, 327-337 (2012).
113. Isvy, A. et al. Safety of rituximab in rheumatoid arthritis: a long-term prospective single-center study of gammaglobulin concentrations and infections. Joint Bone Spine 79, 365-369 (2012).
114. Popa, C., Leandro, M. J., Cambridge, G. & Edwards, J. C. Repeated B lymphocyte depletion with rituximab in rheumatoid arthritis over 7 yrs. Rheumatology 46, 626-630 (2007).
115. Emery, P. et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, doseranging trial. Arthritis Rheum. 54, 1390-1400 (2006).
116. Cohen, S. B. et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum. 54, 2793-2806 (2006).
117. Fleischmann, R. M. et al. Anakinra, a recombinant human interleukin-1 receptor antagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis: a large, international, multicenter, placebo-controlled trial. Arthritis Rheum. 48, 927-934 (2003).
118. Fleischmann, R. M. et al. Safety of extended treatment with anakinra in patients with rheumatoid arthritis. Ann. Rheum. Dis. 65, 1006-1012 (2006).
119. Danilenko, D. M. & Wang, H. The yin and yang of immunomodulatory biologics: assessing the delicate balance between benefit and risk. Toxicol. Pathol. 40, 272-287 (2012).
120. Boren, E. J., Cheema, G. S., Naguwa, S. M., Ansari, A. A. & Gershwin, M. E. The emergence of progressive multifocal leukoencephalopathy (PML) in rheumatic diseases. J. Autoimmun. 30, 90-98 (2008).
121. Carson, K. R. et al. Monoclonal antibody-associated progressive multifocal leucoencephalopathy in patients treated with rituximab, natalizumab, and efalizumab: a review from the Research on Adverse Drug Events and Reports (RADAR) Project. Lancet Oncol. 10, 816-824 (2009).
122. Barkholt, L., Linde, A. & Falk, K. I. OKT3 and ganciclovir treatments are possibly related to the presence of Epstein-Barr virus in serum after liver transplantation. Transpl. Int. 18, 835-843 (2005).
123. Keay, S. et al. Posttransplantation lymphoproliferative disorder associated with OKT3 and decreased antiviral prophylaxis in pancreas transplant recipients. Clin. Infect. Dis. 26, 596-600 (1998).
124. Krueger, G. G., Gottlieb, A. B., Sterry, W., Korman, N. & Van De Kerkhof, P. A multicenter, open-label study of repeat courses of intramuscular alefacept in combination with other psoriasis therapies in patients with chronic plaque psoriasis. J. Dermatolog. Treat. 19, 146-155 (2008).
125. Nguyen, D. H., Hurtado-Ziola, N., Gagneux, P. & Varki, A. Loss of Siglec expression on T lymphocytes during human evolution. Proc. Natl Acad. Sci. USA 103, 7765-7770 (2006).
126. Bugelski, P. J. & Martin, P. L. Concordance of preclinical and clinical pharmacology and toxicology of therapeutic monoclonal antibodies and fusion proteins: cell surface targets. Br. J. Pharmacol. 166, 823-846 (2012).
127. Martin, P. L. & Bugelski, P. J. Concordance of preclinical and clinical pharmacology and toxicology of monoclonal antibodies and fusion proteins: soluble targets. Br. J. Pharmacol. 166, 806-822 (2012).
128. + effector memory T-cells. Br. J. Pharmacol. 161, 512-526 (2010).
129. -/-mice. Blood 108, 238-245 (2006).
130. Luhder, F. et al. Topological requirements and signaling properties of T cell-activating, anti-CD28 antibody superagonists. J. Exp. Med. 197, 955-966 (2003).
131. Tacke, M., Hanke, G., Hanke, T. & Hunig, T. CD28-mediated induction of proliferation in resting T cells in vitro and in vivo without engagement of the T cell receptor: evidence for functionally distinct forms of CD28. Eur. J. Immunol. 27, 239-247 (1997).
132. Lin, C. H. & Hunig, T. Efficient expansion of regulatory T cells in vitro and in vivo with a CD28 superagonist. Eur. J. Immunol. 33, 626-638 (2003).
133. Stebbings, R. et al. "Cytokine storm" in the phase I trial of monoclonal antibody TGN1412: better understanding the causes to improve preclinical testing of immunotherapeutics. J. Immunol. 179, 3325-3331 (2007).
134. Birmingham, D. J. & Hebert, L. A. CR1 and CR1-like: the primate immune adherence receptors. Immunol. Rev. 180, 100-111 (2001).
135. Katschke, K. J. Jr et al. Structural and functional analysis of a C3b-specific antibody that selectively inhibits the alternative pathway of complement. J. Biol. Chem. 284, 10473-10479 (2009).
136. Warncke, M. et al. Different adaptations of IgG effector function in human and nonhuman primates and implications for therapeutic antibody treatment. J. Immunol. 188, 4405-4411 (2012).
137. O'Day, S. J. et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann. Oncol. 21, 1712-1717 (2010).
138. Kumar, S., Singh, S. K., Wang, X., Rup, B. & Gill, D. Coupling of aggregation and immunogenicity in biotherapeutics: T-and B-cell immune epitopes may contain aggregation-prone regions. Pharm. Res. 28, 949-961 (2011).
139. van Beers, M. M., Jiskoot, W. & Schellekens, H. On the role of aggregates in the immunogenicity of recombinant human interferon β in patients with multiple sclerosis. J. Interferon Cytokine Res. 30, 767-775 (2010).
140. van Beers, M. M. et al. Hybrid transgenic immune tolerant mouse model for assessing the breaking of B cell tolerance by human interferon β. J. Immunol. Methods 352, 32-37 (2010).
141. Braun, A., Kwee, L., Labow, M. A. & Alsenz, J. Protein aggregates seem to play a key role among the parameters influencing the antigenicity of interferon α (IFN-α) in normal and transgenic mice. Pharm. Res. 14, 1472-1478 (1997).
142. Joubert, M. K. et al. Highly aggregated antibody therapeutics can enhance the in vitro innate and latestage T-cell immune responses. J. Biol. Chem. 287, 25266-25279 (2012).
143. De Groot, A. S., Knopp, P. M. & Martin, W. De-immunization of therapeutic proteins by T-cell epitope modification. Dev. Biol. 122, 171-194 (2005).
144. Tangri, S. et al. Rationally engineered therapeutic proteins with reduced immunogenicity. J. Immunol. 174, 3187-3196 (2005).
145. De Groot, A. S. et al. Activation of natural regulatory T cells by IgG Fc-derived peptide "Tregitopes". Blood 112, 3303-3311 (2008).
146. Basu, A. et al. Structure-function engineering of interferon-β-1b for improving stability, solubility, potency, immunogenicity, and pharmacokinetic properties by site-selective mono-PEGylation. Bioconjug. Chem. 17, 618-630 (2006).
147. Jevsevar, S., Kunstelj, M. & Porekar, V. G. PEGylation of therapeutic proteins. Biotechnol. J. 5, 113-128 (2010).
148. Armstrong, J. K. et al. Antibody against poly(ethylene glycol) adversely affects PEG-asparaginase therapy in acute lymphoblastic leukemia patients. Cancer 110, 103-111 (2007).
149. Ganson, N. J., Kelly, S. J., Scarlett, E., Sundy, J. S. & Hershfield, M. S. Control of hyperuricemia in subjects with refractory gout, and induction of antibody against poly(ethylene glycol) (PEG), in a phase I trial of subcutaneous PEGylated urate oxidase. Arthritis Res. Ther. 8, R12 (2006).
150. Ghaderi, D., Taylor, R. E., Padler-Karavani, V., Diaz, S. & Varki, A. Implications of the presence of N-glycolylneuraminic acid in recombinant therapeutic glycoproteins. Nature Biotech. 28, 863-867 (2010).
151. von Delwig, A. et al. The impact of glycosylation on HLA-DR1-restricted T cell recognition of type II collagen in a mouse model. Arthritis Rheum. 54, 482-491 (2006).
152. Singh, S. K. Impact of product-related factors on immunogenicity of biotherapeutics. J. Pharm. Sci. 100, 354-387 (2011).
153. Meritet, J. F., Maury, C. & Tovey, M. G. Induction of tolerance to recombinant therapeutic proteins. J. Interferon Cytokine Res. 21, 1031-1038 (2001).
154. Meritet, J. F., Maury, C. & Tovey, M. G. Effect of oromucosal administration of IFN-α on allergic sensitization and the hypersensitive inflammatory response in animals sensitized to ragweed pollen. J. Interferon Cytokine Res. 21, 583-593 (2001).
155. Nagler-Anderson, C., Terhoust, C., Bhan, A. K. & Podolsky, D. K. Mucosal antigen presentation and the control of tolerance and immunity. Trends Immunol. 22, 120-122 (2001).
156. Baert, F. et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N. Engl. J. Med. 348, 601-608 (2003).
157. Somerfield, J. et al. A novel strategy to reduce the immunogenicity of biological therapies. J. Immunol. 185, 763-768 (2010).
158. [No authors listed.] Deal watch: Boosting TRegs to target autoimmune disease. Nature Rev. Drug Discov. 10, 566 (2011).
159. Maldonado, R. A. & von Andrian, U. H. How tolerogenic dendritic cells induce regulatory T cells. Adv. Immunol. 108, 111-165 (2010).
160. Bluestone, J. A., Thomson, A. W., Shevach, E. M. & Weiner, H. L. What does the future hold for cell-based tolerogenic therapy? Nature Rev. Immunol. 7, 650-654 (2007).
161. Yan, G. et al. Genome sequencing and comparison of two nonhuman primate animal models, the cynomolgus and Chinese rhesus macaques. Nature Biotech. 29, 1019-1023 (2011).
162. Stevison, L. S. & Kohn, M. H. Determining genetic background in captive stocks of cynomolgus macaques (Macaca fascicularis). J. Med. Primatol. 37, 311-317 (2008).
163. Saito, Y., Naruse, T. K., Akari, H., Matano, T. & Kimura, A. Diversity of MHC class I haplotypes in cynomolgus macaques. Immunogenetics 64, 131-141 (2012).
164. Chamanza, R., Marxfeld, H. A., Blanco, A. I., Naylor, S. W. & Bradley, A. E. Incidences and range of spontaneous findings in control cynomolgus monkeys (Macaca fascicularis) used in toxicity studies. Toxicol. Pathol. 38, 642-657 (2010).
165. Bussiere, J. L. et al. Alternative strategies for toxicity testing of species-specific biopharmaceuticals. Int. J. Toxicol. 28, 230-253 (2009).
166. Clarke, J. et al. Evaluation of a surrogate antibody for preclinical safety testing of an anti-CD11a monoclonal antibody. Regul. Toxicol. Pharmacol. 40, 219-226 (2004).
167. Hu, C. Y. et al. Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice. J. Clin. Invest. 117, 3857-3867 (2007).
168. Huang, H., Benoist, C. & Mathis, D. Rituximab specifically depletes short-lived autoreactive plasma cells in a mouse model of inflammatory arthritis. Proc. Natl Acad. Sci. USA 107, 4658-4663 (2010).
169. Abraham, D. & McGrath, K. G. Hypersensitivity to aldesleukin (interleukin-2 and proleukin) presenting as facial angioedema and erythema. Allergy Asthma Proc. 24, 291-294 (2003).
170. Strayer, D. R. & Carter, W. A. Recombinant and natural human interferons: analysis of the incidence and clinical impact of neutralizing antibodies. J. Interferon Cytokine Res. 32, 95-102 (2012).
171. Investigators, C. T. et al. Alemtuzumab versus interferon β-1a in early multiple sclerosis. N. Engl. J. Med. 359, 1786-1801 (2008).
172. Gopal, A. K. et al. Safety and efficacy of brentuximab vedotin for Hodgkin lymphoma recurring after allogeneic stem cell transplant. Blood 120, 560-568 (2012).
173. Ruf, P. et al. Pharmacokinetics, immunogenicity and bioactivity of the therapeutic antibody catumaxomab intraperitoneally administered to cancer patients. B r. J. Clin. Pharmacol. 69, 617-625 (2010).
174. Jankowitz, R., Joyce, J. & Jacobs, S. A. Anaphylaxis after administration of ibritumomab tiuxetan for follicular non-hodgkin lymphoma. Clin. Nucl. Med. 33, 94-96 (2008).
175. Jaffers, G. J. et al. Monoclonal antibody therapy. Anti-idiotypic and non-anti-idiotypic antibodies to OKT3 arising despite intense immunosuppression. Transplantation 41, 572-578 (1986).
176. Coiffier, B. et al. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study. Blood 111, 1094-1100 (2008).
177. 131I-tositumomab therapy for relapsed or refractory indolent non-Hodgkin's lymphoma. Br. J. Cancer 94, 1770-1776 (2006).
178. Bartelds, G. M. et al. Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA 305, 1460-1468 (2011).
179. Kumar, D., Bouldin, T. W. & Berger, R. G. A case of progressive multifocal leukoencephalopathy in a patient treated with infliximab. Arthritis Rheum. 62, 3191-3195 (2010).
180. Sorensen, P. S. et al. Occurrence of antibodies against natalizumab in relapsing multiple sclerosis patients treated with natalizumab. Mult. Scler. 17, 1074-1078 (2011).
181. Cruz, A. A. et al. Safety of anti-immunoglobulin E therapy with omalizumab in allergic patients at risk of geohelminth infection. Clin. Exp. Allergy 37, 197-207 (2007).
182. Stubenrauch, K. et al. Subset analysis of patients experiencing clinical events of a potentially immunogenic nature in the pivotal clinical trials of tocilizumab for rheumatoid arthritis: evaluation of an antidrug antibody ELISA using clinical adverse event-driven immunogenicity testing. Clin. Ther. 32, 1597-1609 (2010).