Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The safety and side effects of monoclonal antibodies

Nature Reviews Drug Discovery volume 9, pages 325–338 (2010)Cite this article

Subjects

Key Points

  • Molecular engineering has enabled the fine-tuning of monoclonal antibody (mAb) function to enhance their effects and to minimize immunogenicity and side effects. In this article we take a closer look at the safety and side effects of currently available mAbs.

  • Acute infusion reactions can be caused by a range of mechanisms including anaphylaxis, anaphylactoid reactions, serum sickness, tumour lysis syndrome and cytokine release syndrome.

  • mAbs against tumour necrosis factor-α (TNFα) have been associated with reactivation of latent tuberculosis, as well as with other serious infections and malignancies.

  • Progressive multifocal leukoencephalopathy is a rare but serious complication of natalizumab (Tysabri; Biogen Idec, Elan), rituximab (Rituxan/MabThera; Genentech, Biogen Idec) and efalizumab (Raptiva; Genentech).

  • Treatment with abciximab (ReoPro; Centocor Ortho Biotech, Eli Lilly), an antiplatelet glycoprotein IIb/IIIa chimeric Fab antibody fragment, can cause thrombocytopaenia; although it can also be caused by various other mAbs due to immune thrombocytopaenia.

  • mAbs directed against TNFα can cause a lupus-like syndrome; alemtuzumab (Campath; Genzyme) can mediate thyroid disease through autoimmunity; and mAbs directed against cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) can initiate autoimmune colitis.

  • mAbs against human epidermal growth factor receptor commonly cause skin rashes, while trastuzumab (Herceptin; Genentech), an ERBB2-specific mAb, can cause cardiotoxicity.

  • The dramatic cytokine storm seen after infusion of TGN1412 (a CD28 superagonist) has resulted in the recommendation of a range of measures to improve the safety of first-in-human clinical testing with mAbs.

Abstract

Monoclonal antibodies (mAbs) are now established as targeted therapies for malignancies, transplant rejection, autoimmune and infectious diseases, as well as a range of new indications. However, administration of mAbs carries the risk of immune reactions such as acute anaphylaxis, serum sickness and the generation of antibodies. In addition, there are numerous adverse effects of mAbs that are related to their specific targets, including infections and cancer, autoimmune disease, and organ-specific adverse events such as cardiotoxicity. In March 2006, a life-threatening cytokine release syndrome occurred during a first-in-human study with TGN1412 (a CD28-specific superagonist mAb), resulting in a range of recommendations to improve the safety of initial human clinical studies with mAbs. Here, we review some of the adverse effects encountered with mAb therapies, and discuss advances in preclinical testing and antibody technology aimed at minimizing the risk of these events.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Development of monoclonal antibodies: structure and function.
Figure 2: Action of trastuzumab on breast cancer cells and on cardiomyocytes.
Figure 3: Monoclonal antibodies and the cytokine storm.

Similar content being viewed by others

References

  1. Köhler, G. & Milstein, C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256, 495–497 (1975). The original manuscript describing the breakthrough of hybridoma technology and the production of mAbs.

    Article  PubMed  Google Scholar 

  2. Strebhardt, K. & Ullrich, A. Paul Ehrlich's magic bullet concept: 100 years of progress. Nature Rev. Cancer 8, 473–480 (2008).

    Article  CAS  Google Scholar 

  3. Dubel, S. (ed.) Handbook of Therapeutic Antibodies. Volume I: Technologies, Volume II: Emerging Developments, Volume III: Approved Therapeutics (Wiley, Weinhem, 2007). A comprehensive three volume multiple-author text on therapeutic antibodies.

    Book  Google Scholar 

  4. Lonberg, N. Human antibodies from transgenic animals. Nature Biotech. 23, 1117–1125 (2005).

    Article  CAS  Google Scholar 

  5. Reichert, J. M., Rosensweig, C. J., Faden, L. B. & Dewitz, M. C. Monoclonal antibody successes in the clinic. Nature Biotech. 23, 1073–1078 (2005).

    Article  CAS  Google Scholar 

  6. Waldmann, T. A. Immunotherapy: past, present and future. Nature Med. 9, 269–277 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Reichert, J. M. & Dewitz, M. C. Anti-infective monoclonal antibodies: perils and promise of development. Nature Rev. Drug Discov. 5, 191–195 (2006).

    Article  CAS  Google Scholar 

  8. Leader, B., Baca, Q. J. & Golan, D. E. Protein therapeutics: a summary and pharmacological classification. Nature Rev. Drug Discov. 7, 21–39 (2008).

    Article  CAS  Google Scholar 

  9. Waldmann, H. & Hale, G. CAMPATH: from concept to clinic. Philos. Trans. R. Soc. Lond. B Biol. Sci. 360, 1707–1711 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Nissim, A. & Chernajovsky, Y. Historical development of monoclonal antibody therapeutics. Handb. Exp. Pharmacol. 181, 3–18 (2008).

    Article  CAS  Google Scholar 

  11. Presta, L. G. Molecular engineering and design of therapeutic antibodies. Curr. Opin. Immunol. 20, 460–470 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Hale, G. Therapeutic antibodies-delivering the promise? Adv. Drug Deliv. Rev 58, 633–639 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Tracey, D., Klareskog, L., Sasso, E. H., Salfeld, J. G. & Tak, P. P. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol. Ther. 117, 244–279 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Giezen, T. J. et al. Safety-related regulatory actions for biologicals approved in the United States and the European Union. JAMA 300, 1887–1896 (2008). An important review of regulatory actions regarding the safety of biologics.

    Article  CAS  PubMed  Google Scholar 

  15. Zink, A. et al. European biologicals registers: methodology, selected results and perspectives. Ann. Rheum. Dis. 68, 1240–1246 (2009).

    Article  CAS  PubMed  Google Scholar 

  16. Lutterotti, A. & Martin, R. Getting specific: monoclonal antibodies in multiple sclerosis. Lancet Neurol. 7, 538–547 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. Yeung, Y. A. et al. Engineering human IgG1 affinity to human neonatal Fc receptor: impact of affinity improvement on pharmacokinetics in primates. J. Immunol. 182, 7663–7671 (2009).

    Article  CAS  PubMed  Google Scholar 

  18. Chang, T. W. Developing antibodies for targeting immunoglobulin and membrane-bound immunoglobulin E. Allergy Asthma Proc. 27, S7–S14 (2006).

    CAS  PubMed  Google Scholar 

  19. Hassan, M. S., bedi-Valugerdi, M., Lefranc, G., Hammarstrom, L. & Smith, C. I. Biological half-life of normal and truncated human IgG3 in SCID mice. Eur. J. Immunol. 21, 1319–1322 (1991).

    Article  CAS  PubMed  Google Scholar 

  20. Jefferis, R. Recombinant antibody therapeutics: the impact of glycosylation on mechanisms of action. Trends Pharmacol. Sci. 30, 356–362 (2009).

    Article  CAS  PubMed  Google Scholar 

  21. Holland, M. et al. Anti-neutrophil cytoplasm antibody IgG subclasses in Wegener's granulomatosis: a possible pathogenic role for the IgG4 subclass. Clin. Exp. Immunol. 138, 183–192 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. van der Neut Kolfschoten, M. et al. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science 317, 1554–1557 (2007).

    Article  CAS  Google Scholar 

  23. Tabrizi, M. A. & Roskos, L. K. Preclinical and clinical safety of monoclonal antibodies. Drug Discov. Today 12, 540–547 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Cavagnaro, J. A. (ed.) Preclinical Safety Evaluation of Biopharmaceuticals: A Science Based Approach to Facilitating Clinical Trials (Wiley, London, 2008). A recent book on preclinical safety testing of biopharmaceuticals.

    Book  Google Scholar 

  25. Longstaff, C., Whitton, C. M., Stebbings, R. & Gray, E. How do we assure the quality of biological medicines? Drug Discov. Today 14, 50–55 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. Loisel, S. et al. Relevance, advantages and limitations of animal models used in the development of monoclonal antibodies for cancer treatment. Crit. Rev. Oncol. Hematol. 62, 34–42 (2007).

    Article  PubMed  Google Scholar 

  27. Chapman, K., Pullen, N., Graham, M. & Ragan, I. Preclinical safety testing of monoclonal antibodies: the significance of species relevance. Nature Rev. Drug Discov. 6, 120–126 (2007).

    Article  CAS  Google Scholar 

  28. Presta, L. G. Engineering of therapeutic antibodies to minimize immunogenicity and optimize function. Adv. Drug Deliv. Rev. 58, 640–656 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. Chung, C. H. Managing premedications and the risk for reactions to infusional monoclonal antibody therapy. Oncologist 13, 725–732 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Klastersky, J. Adverse effects of the humanized antibodies used as cancer therapeutics. Curr. Opin. Oncol. 18, 316–320 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Kang, S. P. & Saif, M. W. Infusion-related and hypersensitivity reactions of monoclonal antibodies used to treat colorectal cancer — identification, prevention, and management. J. Support. Oncol. 5, 451–457 (2007).

    CAS  PubMed  Google Scholar 

  32. Lenz, H. J. Management and preparedness for infusion and hypersensitivity reactions. Oncologist 12, 601–609 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Coiffier, B. et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N. Engl. J. Med. 346, 235–242 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Chung, C. H. et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N. Engl. J. Med. 358, 1109–1117 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Poole, J. A., Matangkasombut, P. & Rosenwasser, L. J. Targeting the IgE molecule in allergic and asthmatic diseases: review of the IgE molecule and clinical efficacy. J. Allergy Clin. Immunol. 115, S376–S385 (2005).

    Article  PubMed  Google Scholar 

  36. Gould, H. J. & Sutton, B. J. IgE in allergy and asthma today. Nature Rev. Immunol. 8, 205–217 (2008).

    Article  CAS  Google Scholar 

  37. Cox, L. et al. American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma and Immunology Joint Task Force Report on omalizumab-associated anaphylaxis. J. Allergy Clin. Immunol. 120, 1373–1377 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Corren, J. et al. Safety and tolerability of omalizumab. Clin. Exp. Allergy 39, 788–797 (2009).

    Article  CAS  PubMed  Google Scholar 

  39. Cox, L. S. How safe are the biologicals in treating asthma and rhinitis? Allergy Asthma Clin. Immunol. 5, 4 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Limb, S. L., Starke, P. R., Lee, C. E. & Chowdhury, B. A. Delayed onset and protracted progression of anaphylaxis after omalizumab administration in patients with asthma. J. Allergy Clin. Immunol. 120, 1378–1381 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Carter, P. Improving the efficacy of antibody-based cancer therapies. Naure Rev. Cancer 1, 118–129 (2001).

    Article  CAS  Google Scholar 

  42. Loertscher, R. The utility of monoclonal antibody therapy in renal transplantation. Transplant. Proc. 34, 797–800 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Gaston, R. S. et al. OKT3 first-dose reaction: association with T cell subsets and cytokine release. Kidney Int. 39, 141–148 (1991).

    Article  CAS  PubMed  Google Scholar 

  44. Kuus-Reichel, K. et al. Will immunogenicity limit the use, efficacy, and future development of therapeutic monoclonal antibodies? Clin. Diagn. Lab. Immunol. 1, 365–372 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Mascelli, M. A. et al. Molecular, biologic, and pharmacokinetic properties of monoclonal antibodies: impact of these parameters on early clinical development. J. Clin. Pharmacol. 47, 553–565 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Carter, P. J. Potent antibody therapeutics by design. Nature Rev. Immunol. 6, 343–357 (2006).

    Article  CAS  Google Scholar 

  47. Azinovic, I. et al. Survival benefit associated with human anti-mouse antibody (HAMA) in patients with B-cell malignancies. Cancer Immunol. Immunother. 55, 1451–1458 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Clark, M. Antibody humanization: a case of the 'Emperor's new clothes'? Immunol. Today 21, 397–402 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Ransohoff, R. M. Natalizumab for multiple sclerosis. N. Engl. J. Med. 356, 2622–2629 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Cohen, B. A., Oger, J., Gagnon, A. & Giovannoni, G. The implications of immunogenicity for protein-based multiple sclerosis therapies. J. Neurol. Sci. 275, 7–17 (2008).

    Article  CAS  PubMed  Google Scholar 

  51. Schellekens, H. Factors influencing the immunogenicity of therapeutic proteins. Nephrol. Dial. Transplant. 20 (Suppl. 6), vi3–vi9 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Todd, D. J. & Helfgott, S. M. Serum sickness following treatment with rituximab. J. Rheumatol. 34, 430–433 (2007).

    PubMed  Google Scholar 

  53. Schellekens, H., Crommein, D. & Jiskoot, W. in Handbook of Therapeutic Antibodies Vol. 1 Ch. 11 (ed. Dubel, S.) (Wiley, Weinheim, 2007).

    Google Scholar 

  54. Shankar, G., Shores, E., Wagner, C. & Mire-Sluis, A. Scientific and regulatory considerations on the immunogenicity of biologics. Trends Biotechnol. 24, 274–280 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Aarden, L., Ruuls, S. R. & Wolbink, G. Immunogenicity of anti-tumor necrosis factor antibodies-toward improved methods of anti-antibody measurement. Curr. Opin. Immunol. 20, 431–435 (2008).

    Article  CAS  PubMed  Google Scholar 

  56. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins. Doc. Ref. EMEA/CHMP/BMWP/14327/2006. EMA website [online], (2007).

  57. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). Concept paper on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use. Doc. Ref. EMEA/CHMP/BMWP/114720/2009. EMA website [online], (2009). Recent EMA guidelines on immunogenicity testing of mAbs.

  58. Coiffier, B., Altman, A., Pui, C. H., Younes, A. & Cairo, M. S. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J. Clin. Oncol. 26, 2767–2778 (2008).

    Article  CAS  PubMed  Google Scholar 

  59. Tosi, P. et al. Consensus conference on the management of tumor lysis syndrome. Haematologica 93, 1877–1185 (2008).

    Article  PubMed  Google Scholar 

  60. Otrock, Z. K., Hatoum, H. A. & Salem, Z. M. Acute tumor lysis syndrome after rituximab administration in Burkitt's lymphoma. Intern. Emerg. Med. 3, 161–163 (2008).

    Article  PubMed  Google Scholar 

  61. Feusner, J. H., Ritchey, A. K., Cohn, S. L. & Billett, A. L. Management of tumor lysis syndrome: need for evidence-based guidelines. J. Clin. Oncol. 26, 5657–5658 (2008).

    Article  PubMed  Google Scholar 

  62. Taylor, P. C. & Feldmann, M. Anti-TNF biologic agents: still the therapy of choice for rheumatoid arthritis. Nature Rev. Rheumatol. 5, 578–582 (2009).

    Article  CAS  Google Scholar 

  63. Feldmann, M. & Maini, S. R. Role of cytokines in rheumatoid arthritis: an education in pathophysiology and therapeutics. Immunol. Rev. 223, 7–19 (2008).

    Article  CAS  PubMed  Google Scholar 

  64. Moss, M. L., Sklair-Tavron, L. & Nudelman, R. Drug insight: tumor necrosis factor-converting enzyme as a pharmaceutical target for rheumatoid arthritis. Nature Clin. Pract. Rheumatol. 4, 300–309 (2008).

    Article  CAS  Google Scholar 

  65. Keane, J. TNF-blocking agents and tuberculosis: new drugs illuminate an old topic. Rheumatology 44, 714–720 (2005).

    Article  CAS  PubMed  Google Scholar 

  66. Askling, J. et al. Risk and case characteristics of tuberculosis in rheumatoid arthritis associated with tumor necrosis factor antagonists in Sweden. Arthritis Rheum. 52, 1986–1992 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. 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).

    Article  CAS  PubMed  Google Scholar 

  68. Schneeweiss, S. et al. Anti-tumor necrosis factor alpha therapy and the risk of serious bacterial infections in elderly patients with rheumatoid arthritis. Arthritis Rheum. 56, 1754–1764 (2007).

    Article  CAS  PubMed  Google Scholar 

  69. Theis, V. S. & Rhodes, J. M. Review article: minimizing tuberculosis during anti-tumour necrosis factor-alpha treatment of inflammatory bowel disease. Aliment. Pharmacol. Ther. 27, 19–30 (2008).

    Article  CAS  PubMed  Google Scholar 

  70. 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).

    Article  CAS  PubMed  Google Scholar 

  71. British Thoracic Society Standards of Care Committee. BTS recommendations for assessing risk and for managing Mycobacterium tuberculosis infection and disease in patients due to start anti-TNF-α treatment. Thorax 60, 800–805 (2005).

  72. Major, E. O. Progressive multifocal leukoencephalopathy in patients on immunomodulatory therapies. Annu. Rev. Med. 61, 35–47 (2010).

    Article  CAS  PubMed  Google Scholar 

  73. 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).

    Article  CAS  PubMed  Google Scholar 

  74. Lopez-Diego, R. S. & Weiner, H. L. Novel therapeutic strategies for multiple sclerosis — a multifaceted adversary. Nature Rev. Drug Discov. 7, 909–925 (2008).

    Article  CAS  Google Scholar 

  75. Sadiq, S. A., Puccio, L. M. & Brydon, E. W. JCV detection in multiple sclerosis patients treated with natalizumab. J. Neurol. 7 Jan 2010 (doi:10.1007/s00415-009-5444-4).

    Article  CAS  PubMed  Google Scholar 

  76. Major, E. O. Reemergence of PML in natalizumab-treated patients — new cases, same concerns. N. Engl. J. Med. 361, 1041–1043 (2009).

    Article  CAS  PubMed  Google Scholar 

  77. Kleinschmidt-DeMasters, B. K. & Tyler, K. L. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon β-1a for multiple sclerosis. N. Engl. J. Med. 353, 369–374 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Langer-Gould, A., Atlas, S. W., Green, A. J., Bollen, A. W. & Pelletier, D. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N. Engl. J. Med. 353, 375–381 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. Van Assche, G. et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N. Engl. J. Med. 353, 362–368 (2005). References 77–79 are the original descriptions of cases of PML with natalizumab.

    Article  CAS  PubMed  Google Scholar 

  80. Wenning, W. et al. Treatment of progressive multifocal leukoencephalopathy associated with natalizumab. N. Engl. J. Med. 361, 1075–1080 (2009).

    Article  CAS  PubMed  Google Scholar 

  81. Linda, H. et al. Progressive multifocal leukoencephalopathy after natalizumab monotherapy. N. Engl. J. Med. 361, 1081–1087 (2009). References 80 and 81 are recent descriptions of cases of PML with natalizumab.

    Article  CAS  PubMed  Google Scholar 

  82. Yousry, T. A. et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N. Engl. J. Med. 354, 924–933 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kappos, L. et al. Natalizumab treatment for multiple sclerosis: recommendations for patient selection and monitoring. Lancet Neurol. 6, 431–441 (2007).

    Article  PubMed  Google Scholar 

  84. Clifford, D. B. Natalizumab and PML: a risky business? Gut 57, 1347–1349 (2008).

    Article  PubMed  Google Scholar 

  85. Landry, M. L., Eid, T., Bannykh, S. & Major, E. False negative PCR despite high levels of JC virus DNA in spinal fluid: implications for diagnostic testing. J. Clin. Virol. 43, 247–249 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Chen, Y. et al. Asymptomatic reactivation of JC virus in patients treated with natalizumab. N. Engl. J. Med. 361, 1067–1074 (2009).Documentation that reactivation of JCV occurs commonly with natalizumab therapy in multiple sclerosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Delbue, S., Tremolada, S. & Ferrante, P. Application of molecular tools for the diagnosis of central nervous system infections. Neurol. Sci. 29 (Suppl. 2), 283–285 (2008).

    Article  Google Scholar 

  88. Molloy, E. S. & Calabrese, L. H. Therapy: targeted but not trouble-free: efalizumab and PML. Nature Rev. Rheumatol. 5, 418–419 (2009).

    Article  CAS  Google Scholar 

  89. Bonig, H., Wundes, A., Chang, K. H., Lucas, S. & Papayannopoulou, T. Increased numbers of circulating hematopoietic stem/progenitor cells are chronically maintained in patients treated with the CD49d blocking antibody natalizumab. Blood 111, 3439–3441 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Zohren, F. et al. The monoclonal anti-VLA-4 antibody natalizumab mobilizes CD34+ hematopoietic progenitor cells in humans. Blood 111, 3893–3895 (2008).

    Article  CAS  PubMed  Google Scholar 

  91. Aksoy, S. et al. Rituximab-related viral infections in lymphoma patients. Leuk. Lymphoma 48, 1307–1312 (2007).

    Article  CAS  PubMed  Google Scholar 

  92. Carson, K. R. et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood 113, 4834–4840 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Aster, R. H. & Bougie, D. W. Drug-induced immune thrombocytopenia. N. Engl. J. Med. 357, 580–587 (2007).

    Article  PubMed  Google Scholar 

  94. Topol, E. J., Byzova, T. V. & Plow, E. F. Platelet GPIIb-IIIa blockers. Lancet 353, 227–231 (1999).

    Article  CAS  PubMed  Google Scholar 

  95. Tcheng, J. E. et al. Abciximab readministration: results of the ReoPro Readministration Registry. Circulation 104, 870–875 (2001).

    Article  CAS  PubMed  Google Scholar 

  96. Topol, E. J. et al. Multi-year follow-up of abciximab therapy in three randomized, placebo-controlled trials of percutaneous coronary revascularization. Am. J. Med. 113, 1–6 (2002).

    Article  CAS  PubMed  Google Scholar 

  97. Tamhane, U. U. & Gurm, H. S. The chimeric monoclonal antibody abciximab: a systematic review of its safety in contemporary practice. Expert Opin. Drug Saf. 7, 809–819 (2008).

    Article  CAS  PubMed  Google Scholar 

  98. Curtis, B. R., Divgi, A., Garritty, M. & Aster, R. H. Delayed thrombocytopenia after treatment with abciximab: a distinct clinical entity associated with the immune response to the drug. J. Thromb. Haemost. 2, 985–992 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. Curtis, B. R., Swyers, J., Divgi, A., McFarland, J. G. & Aster, R. H. Thrombocytopenia after second exposure to abciximab is caused by antibodies that recognize abciximab-coated platelets. Blood 99, 2054–2059 (2002).

    Article  CAS  PubMed  Google Scholar 

  100. McCorry, R. B. & Johnston, P. Fatal delayed thrombocytopenia following abciximab therapy. J. Invasive Cardiol. 18, E173–E174 (2006).

    PubMed  Google Scholar 

  101. Mukherjee, D. & Roffi, M. Glycoprotein IIb/IIIa receptor inhibitors in 2008: do they still have a role? J. Interv. Cardiol. 21, 118–121 (2008).

    Article  PubMed  Google Scholar 

  102. Cox, A. L. et al. Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis. Eur. J. Immunol. 35, 3332–3342 (2005).

    Article  CAS  PubMed  Google Scholar 

  103. Lorenzi, A. R. et al. Morbidity and mortality in rheumatoid arthritis patients with prolonged therapy-induced lymphopenia: twelve-year outcomes. Arthritis Rheum. 58, 370–375 (2008).

    Article  PubMed  Google Scholar 

  104. Chakrabarti, S. et al. T-cell depletion with Campath-1H “in the bag” for matched related allogeneic peripheral blood stem cell transplantation is associated with reduced graft-versus-host disease, rapid immune constitution and improved survival. Br. J. Haematol. 121, 109–118 (2003).

    Article  PubMed  Google Scholar 

  105. Hale, G. et al. CD52 antibodies for prevention of graft-versus-host disease and graft rejection following transplantation of allogeneic peripheral blood stem cells. Bone Marrow Transplant. 26, 69–76 (2000).

    Article  CAS  PubMed  Google Scholar 

  106. Lin, T. S. Novel agents in chronic lymphocytic leukemia: efficacy and tolerability of new therapies. Clin. Lymphoma Myeloma. 8 (Suppl. 4), 137–143 (2008).

    Article  CAS  Google Scholar 

  107. Watson, C. J. et al. Alemtuzumab (CAMPATH 1H) induction therapy in cadaveric kidney transplantation — efficacy and safety at five years. Am. J. Transplant. 5, 1347–1353 (2005).

    Article  CAS  PubMed  Google Scholar 

  108. Coles, A. J. et al. Alemtuzumab vs. interferon β-1a in early multiple sclerosis. N. Engl. J. Med. 359, 1786–1801 (2008).

    Article  PubMed  Google Scholar 

  109. Hauser, S. L. Multiple lessons for multiple sclerosis. N. Engl. J. Med. 359, 1838–1841 (2008).

    Article  CAS  PubMed  Google Scholar 

  110. Haider, I. & Cahill, M. Fatal thrombocytopaenia temporally related to the administration of alemtuzumab (MabCampath) for refractory CLL despite early discontinuation of therapy. Hematology 9, 409–411 (2004).

    Article  CAS  PubMed  Google Scholar 

  111. Gibbs, S. D., Westerman, D. A., McCormack, C., Seymour, J. F. & Miles, P. H. Severe and prolonged myeloid haematopoietic toxicity with myelodysplastic features following alemtuzumab therapy in patients with peripheral T-cell lymphoproliferative disorders. Br. J. Haematol. 130, 87–91 (2005).

    Article  CAS  PubMed  Google Scholar 

  112. Patel, V. L., Schwartz, J. & Bussel, J. B. The effect of anti-CD40 ligand in immune thrombocytopenic purpura. Br. J. Haematol. 141, 545–548 (2008).

    Article  CAS  PubMed  Google Scholar 

  113. Koyama, I. et al. Thrombophilia associated with anti-CD154 monoclonal antibody treatment and its prophylaxis in nonhuman primates. Transplantation 77, 460–462 (2004).

    Article  CAS  PubMed  Google Scholar 

  114. Kawai, T., Andrews, D., Colvin, R. B., Sachs, D. H. & Cosimi, A. B. Letters to the Editor: Thromboembolic complications after treatment with monoclonal antibody against CD49 ligand. Nature Med. 6, 114 (2000).

    Article  CAS  PubMed  Google Scholar 

  115. Kirk, A. D. & Harlan, D. M. Letters to the Editor: Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand. Nature Med. 6, 114 (2000).

    Article  CAS  Google Scholar 

  116. Mirabet, M., Barrabes, J. A., Quiroga, A. & Garcia-Dorado, D. Platelet pro-aggregatory effects of CD40L monoclonal antibody. Mol. Immunol. 45, 937–944 (2008).

    Article  CAS  PubMed  Google Scholar 

  117. Langer, F. et al. The role of CD40 in CD40L- and antibody-mediated platelet activation. Thromb. Haemost. 93, 1137–1146 (2005).

    Article  CAS  PubMed  Google Scholar 

  118. Scappaticci, F. A. et al. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J. Natl Cancer Inst. 99, 1232–1239 (2007).

    Article  PubMed  Google Scholar 

  119. Nalluri, S. R., Chu, D., Keresztes, R., Zhu, X. & Wu, S. Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA 300, 2277–2285 (2008).

    Article  CAS  PubMed  Google Scholar 

  120. Mongey, A. B. & Hess, E. V. Drug insight: autoimmune effects of medications — what's new? Nature Clin. Pract. Rheumatol. 4, 136–144 (2008).

    Article  CAS  Google Scholar 

  121. Ramos-Casals, M. et al. Autoimmune diseases induced by TNF-targeted therapies: analysis of 233 cases. Medicine 86, 242–251 (2007).

    Article  PubMed  Google Scholar 

  122. Haraoui, B. & Keystone, E. Musculoskeletal manifestations and autoimmune diseases related to new biologic agents. Curr. Opin. Rheumatol. 18, 96–100 (2006).

    Article  PubMed  Google Scholar 

  123. Coles, A. J. et al. Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet 354, 1691–1695 (1999).

    Article  CAS  PubMed  Google Scholar 

  124. Fong, L. & Small, E. J. Anti-cytotoxic T-lymphocyte antigen-4 antibody: the first in an emerging class of immunomodulatory antibodies for cancer treatment. J. Clin. Oncol. 26, 5275–5283 (2008).

    Article  CAS  PubMed  Google Scholar 

  125. Maker, A. V., Attia, P. & Rosenberg, S. A. Analysis of the cellular mechanism of antitumor responses and autoimmunity in patients treated with CTLA-4 blockade. J. Immunol. 175, 7746–7754 (2005).

    Article  CAS  PubMed  Google Scholar 

  126. Peggs, K. S., Quezada, S. A., Korman, A. J. & Allison, J. P. Principles and use of anti-CTLA4 antibody in human cancer immunotherapy. Curr. Opin. Immunol. 18, 206–213 (2006).

    Article  CAS  PubMed  Google Scholar 

  127. Weber, J. Review: anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse events. Oncologist 12, 864–872 (2007).

    Article  CAS  PubMed  Google Scholar 

  128. Kaufman, H. L. & Wolchok, J. D. Is tumor immunity the same thing as autoimmunity? Implications for cancer immunotherapy. J. Clin. Oncol. 24, 2230–2232 (2006).

    Article  CAS  PubMed  Google Scholar 

  129. Askling, J. & Bongartz, T. Malignancy and biologic therapy in rheumatoid arthritis. Curr. Opin. Rheumatol. 20, 334–339 (2008).

    Article  CAS  PubMed  Google Scholar 

  130. Scott, D. L. & Kingsley, G. H. Tumor necrosis factor inhibitors for rheumatoid arthritis. N. Engl. J. Med. 355, 704–712 (2006).

    Article  CAS  PubMed  Google Scholar 

  131. Dixon, W. & Silman, A. Is there an association between anti-TNF monoclonal antibody therapy in rheumatoid arthritis and risk of malignancy and serious infection? Commentary on the meta-analysis by Bongartz. et al. Arthritis Res. Ther. 8, 111 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Askling, J. et al. Risks of solid cancers in patients with rheumatoid arthritis and after treatment with tumour necrosis factor antagonists. Ann. Rheum. Dis. 64, 1421–1426 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Setoguchi, S. et al. Tumor necrosis factor alpha antagonist use and cancer in patients with rheumatoid arthritis. Arthritis Rheum. 54, 2757–2764 (2006).

    Article  CAS  PubMed  Google Scholar 

  134. Biancone, L., Calabrese, E., Petruzziello, C. & Pallone, F. Treatment with biologic therapies and the risk of cancer in patients with IBD. Nature Clin. Pract. Gastroenterol. Hepatol. 4, 78–91 (2007).

    Article  CAS  Google Scholar 

  135. Rennard, S. I. et al. The safety and efficacy of infliximab in moderate-to-severe chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 175, 926–934 (2007).

    Article  CAS  PubMed  Google Scholar 

  136. Rosh, J. R., Gross, T., Mamula, P., Griffiths, A. & Hyams, J. Hepatosplenic T-cell lymphoma in adolescents and young adults with Crohn's disease: a cautionary tale? Inflamm. Bowel Dis. 13, 1024–1030 (2007).

    Article  PubMed  Google Scholar 

  137. Krueger, G. G. et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N. Engl. J. Med. 356, 580–592 (2007).

    Article  CAS  PubMed  Google Scholar 

  138. Sandborn, W. J. Current directions in IBD therapy: what goals are feasible with biological modifiers? Gastroenterology 135, 1442–1447 (2008).

    Article  PubMed  Google Scholar 

  139. Segal, B. M. et al. Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing–remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol. 7, 796–804 (2008).

    Article  CAS  PubMed  Google Scholar 

  140. Weiss, J. M., Subleski, J. J., Wigginton, J. M. & Wiltrout, R. H. Immunotherapy of cancer by IL-12-based cytokine combinations. Expert. Opin. Biol. Ther. 7, 1705–1721 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Langowski, J. L. et al. IL-23 promotes tumour incidence and growth. Nature 442, 461–465 (2006).

    Article  CAS  PubMed  Google Scholar 

  142. Knox, S. J. et al. Yttrium-90-labeled anti-CD20 monoclonal antibody therapy of recurrent B-cell lymphoma. Clin. Cancer Res. 2, 457–470 (1996).

    CAS  PubMed  Google Scholar 

  143. Witzig, T. E. et al. Long-term responses in patients with recurring or refractory B-cell non-Hodgkin lymphoma treated with yttrium 90 ibritumomab tiuxetan. Cancer 109, 1804–1810 (2007).

    Article  CAS  PubMed  Google Scholar 

  144. Jean, G. W. & Shah, S. R. Epidermal growth factor receptor monoclonal antibodies for the treatment of metastatic colorectal cancer. Pharmacotherapy 28, 742–754 (2008).

    Article  CAS  PubMed  Google Scholar 

  145. Perez-Soler, R. & Saltz, L. Cutaneous adverse effects with HER1/EGFR-targeted agents: is there a silver lining? J. Clin. Oncol. 23, 5235–5246 (2005).

    Article  PubMed  Google Scholar 

  146. Bianchini, D., Jayanth, A., Chua, Y. J. & Cunningham, D. Epidermal growth factor receptor inhibitor-related skin toxicity: mechanisms, treatment, and its potential role as a predictive marker. Clin. Colorectal Cancer 7, 33–43 (2008).

    Article  CAS  PubMed  Google Scholar 

  147. Saif, M. W., Longo, W. L. & Israel, G. Correlation between rash and a positive drug response associated with bevacizumab in a patient with advanced colorectal cancer. Clin. Colorectal Cancer 7, 144–148 (2008).

    Article  CAS  PubMed  Google Scholar 

  148. Bauer, K. A., Hammerman, S., Rapoport, B. & Lacouture, M. E. Completeness in the reporting of dermatologic adverse drug reactions associated with monoclonal antibody epidermal growth factor receptor inhibitors in phase II and III colorectal cancer clinical trials. Clin. Colorectal Cancer 7, 309–314 (2008).

    Article  PubMed  Google Scholar 

  149. Bernier, J. et al. Consensus guidelines for the management of radiation dermatitis and coexisting acne-like rash in patients receiving radiotherapy plus EGFR inhibitors for the treatment of squamous cell carcinoma of the head and neck. Ann. Oncol. 19, 142–149 (2008).

    Article  CAS  PubMed  Google Scholar 

  150. Scope, A. et al. Randomized double-blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab-associated acne-like eruption. J. Clin. Oncol. 25, 5390–5396 (2007).

    Article  CAS  PubMed  Google Scholar 

  151. Hudis, C. A. Trastuzumab — mechanism of action and use in clinical practice. N. Engl. J. Med. 357, 39–51 (2007).

    Article  CAS  PubMed  Google Scholar 

  152. Force, T., Krause, D. S. & Van Etten, R. A. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nature Rev. Cancer 7, 332–344 (2007).

    Article  CAS  Google Scholar 

  153. Guglin, M., Cutro, R. & Mishkin, J. D. Trastuzumab-induced cardiomyopathy. J. Card. Fail. 14, 437–444 (2008).

    Article  CAS  PubMed  Google Scholar 

  154. Klein, P. M. & Dybdal, N. Trastuzumab and cardiac dysfunction: update on preclinical studies. Semin. Oncol. 30, 49–53 (2003).

    Article  CAS  PubMed  Google Scholar 

  155. Perez, E. A. Cardiac toxicity of ErbB2-targeted therapies: what do we know? Clin. Breast Cancer 8 (Suppl. 3), 114–120 (2008).

    Article  Google Scholar 

  156. Chien, K. R. Herceptin and the heart — a molecular modifier of cardiac failure. N. Engl. J. Med. 354, 789–790 (2006).

    Article  CAS  PubMed  Google Scholar 

  157. Joensuu, H. et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N. Engl. J. Med. 354, 809–820 (2006).

    Article  CAS  PubMed  Google Scholar 

  158. Force, T. & Kerkela, R. Cardiotoxicity of the new cancer therapeutics — mechanisms of, and approaches to, the problem. Drug Discov. Today 13, 778–784 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Chen, M. H., Kerkela, R. & Force, T. Mechanisms of cardiac dysfunction associated with tyrosine kinase inhibitor cancer therapeutics. Circulation 117, 84–95 (2008).

    Article  Google Scholar 

  160. Crone, S. A. et al. ErbB2 is essential in the prevention of dilated cardiomyopathy. Nature Med. 8, 459–465 (2002).

    Article  CAS  PubMed  Google Scholar 

  161. Kuramochi, Y., Guo, X. & Sawyer, D. B. Neuregulin activates erbB2-dependent src/FAK signaling and cytoskeletal remodeling in isolated adult rat cardiac myocytes. J. Mol. Cell Cardiol. 41, 228–235 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Grazette, L. P. et al. Inhibition of ErbB2 causes mitochondrial dysfunction in cardiomyocytes: implications for herceptin-induced cardiomyopathy. J. Am. Coll. Cardiol. 44, 2231–2238 (2004).

    Article  CAS  PubMed  Google Scholar 

  163. Lemmens, K., Doggen, K. & Keulenaer, G. W. Neuregulin-1 and its potential role in the control of cardiac function. Heart Fail. Monit. 5, 119–124 (2008).

    CAS  PubMed  Google Scholar 

  164. Clark, I. A. The advent of the cytokine storm. Immunol. Cell Biol. 85, 271–273 (2007).

    Article  CAS  PubMed  Google Scholar 

  165. Wing, M. Monoclonal antibody first dose cytokine release syndromes — mechanisms and prediction. J. Immunotoxicol. 5, 11–15 (2008).

    Article  CAS  PubMed  Google Scholar 

  166. Plevy, S. et al. A Phase I study of visilzumab, a humanised anti-CD3 monoclonal antibody, in severe steroid-refractory ulcerative colitis. Gastroenterology 133, 1414–1422 (2007).

    Article  CAS  PubMed  Google Scholar 

  167. Wing, M. G., Waldmann, H., Isaacs, J., Compston, D. A. & Hale, G. Ex-vivo whole blood cultures for predicting cytokine-release syndrome: dependence on target antigen and antibody isotype. Ther. Immunol. 2, 183–190 (1995).

    CAS  PubMed  Google Scholar 

  168. Wing, M. G. et al. Mechanism of first-dose cytokine-release syndrome by CAMPATH 1-H: involvement of CD16 (FcgammaRIII) and CD11a/CD18 (LFA-1) on NK cells. J. Clin. Invest. 98, 2819–2826 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Winkler, U. et al. Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8). Blood 94, 2217–2224 (1999).

    Article  CAS  PubMed  Google Scholar 

  170. 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). A detailed description of the laboratory events and clinical course after administration of TGN1412 to healthy volunteers: the cytokine storm.

    Article  CAS  Google Scholar 

  171. Kenter, M. J. & Cohen, A. F. Establishing risk of human experimentation with drugs: lessons from TGN1412. Lancet 368, 1387–1391 (2006).

    Article  CAS  PubMed  Google Scholar 

  172. Expert Group on Phase One Clinical Trials (Chairman: Professor Gordon W.Duff) Expert Scientific Group on Phase One Clinical Trials: Final Report (The Stationery Office, Norwich, UK, 2006). Report of a UK Expert Group commenting on safety of Phase I studies in the light of the TGN1412 cytokine storm.

  173. Association of the British Pharmaceutical Industry (ABPI), BioIndustry Association (BIA).Early Stage Clinical Trial Taskforce — Joint ABPI/BIA Report. ABPI website [online], (2006).

  174. 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).

    Article  CAS  PubMed  Google Scholar 

  175. Beyersdorf, N., Hanke, T., Kerkau, T. & Hunig, T. Superagonistic anti-CD28 antibodies: potent activators of regulatory T cells for the therapy of autoimmune diseases. Ann. Rheum. Dis. 64 (Suppl. 4), iv91–iv95 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Beyersdorf, N. et al. Selective targeting of regulatory T cells with CD28 superagonists allows effective therapy of experimental autoimmune encephalomyelitis. J. Exp. Med. 202, 445–455 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Hunig, T. & Dennehy, K. CD28 superagonists: mode of action and therapeutic potential. Immunol. Lett. 100, 21–28 (2005).

    Article  PubMed  CAS  Google Scholar 

  178. Muller, N. et al. A CD28 superagonistic antibody elicits 2 functionally distinct waves of T cell activation in rats. J. Clin. Invest. 118, 1405–1416 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  179. Hunig, T. Manipulation of regulatory T-cell number and function with CD28-specific monoclonal antibodies. Adv. Immunol. 95, 111–148 (2007).

    Article  PubMed  CAS  Google Scholar 

  180. Schraven, B. & Kalinke, U. CD28 superagonists: what makes the difference in humans? Immunity 28, 591–595 (2008).

    Article  CAS  PubMed  Google Scholar 

  181. Liu, E. H., Siegel, R. M., Harlan, D. M. & O'Shea, J. J. T cell-directed therapies: lessons learned and future prospects. Nature Immunol. 8, 25–30 (2007).

    Article  CAS  Google Scholar 

  182. Sharpe, A. H. & Abbas, A. K. T-cell costimulation-biology, therapeutic potential, and challenges. N. Engl. J. Med. 355, 973–975 (2006).

    Article  CAS  PubMed  Google Scholar 

  183. Dayan, C. M. & Wraith, D. C. Preparing for first-in-man studies: the challenges for translational immunology post-TGN1412. Clin. Exp. Immunol. 151, 231–234 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. St Clair, E. W. The calm after the cytokine storm: lessons from the TGN1412 trial. J. Clin. Invest. 118, 1344–1347 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Hanke, T. Lessons from TGN1412. Lancet 368, 1569–1570 (2006).

    Article  PubMed  Google Scholar 

  186. Ohresser, M., Olive, D., Vanhove, B. & Watier, H. Risk in drug trials. Lancet 368, 2205–2206 (2006).

    Article  PubMed  Google Scholar 

  187. Waibler, Z. et al. Signaling signatures and functional properties of anti-human CD28 superagonistic antibodies. PLoS ONE 3, e1708 (2008). In vitro studies on human blood cell signalling with superagonist human CD28-specific mAbs.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  188. Mehrishi, J. N., Szabo, M. & Bakacs, T. Some aspects of the recombinantly expressed humanised superagonist anti-CD28 mAb, TGN1412 trial catastrophe lessons to safeguard mAbs and vaccine trials. Vaccine 25, 3517–3523 (2007).

    Article  CAS  PubMed  Google Scholar 

  189. Yokosuka, T. & Saito, T. Dynamic regulation of T-cell costimulation through TCR-CD28 microclusters. Immunol. Rev. 229, 27–40 (2009).

    Article  CAS  PubMed  Google Scholar 

  190. Buysmann, S. et al. Activation and increased expression of adhesion molecules on peripheral blood lymphocytes is a mechanism for the immediate lymphocytopenia after administration of OKT3. Blood 87, 404–411 (1996).

    Article  CAS  PubMed  Google Scholar 

  191. Mourad, G. J. et al. Humanized IgG1 and IgG4 anti-CD4 monoclonal antibodies: effects on lymphocytes in the blood, lymph nodes, and renal allografts in cynomolgus monkeys. Transplantation 65, 632–641 (1998).

    Article  CAS  PubMed  Google Scholar 

  192. Hernandez-Caselles, T. et al. A study of CD33 (SIGLEC-3) antigen expression and function on activated human T and NK cells: two isoforms of CD33 are generated by alternative splicing. J. Leukoc. Biol. 79, 46–58 (2006).

    Article  CAS  PubMed  Google Scholar 

  193. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Isaacs, J. D. et al. A therapeutic human IgG4 monoclonal antibody that depletes target cells in humans. Clin. Exp. Immunol. 106, 427–433 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Avril, T., Attrill, H., Zhang, J., Raper, A. & Crocker, P. R. Negative regulation of leucocyte functions by CD33-related siglecs. Biochem. Soc. Trans. 34, 1024–1027 (2006).

    Article  CAS  PubMed  Google Scholar 

  196. Crocker, P. R., Paulson, J. C. & Varki, A. Siglecs and their roles in the immune system. Nature Rev. Immunol. 7, 255–266 (2007).

    Article  CAS  Google Scholar 

  197. Crocker, P. R. & Redelinghuys, P. Siglecs as positive and negative regulators of the immune system. Biochem. Soc. Trans. 36, 1467–1471 (2008).

    Article  CAS  PubMed  Google Scholar 

  198. Gogishvili, T. et al. Rapid regulatory T-cell response prevents cytokine storm in CD28 superagonist treated mice. PLoS ONE 4, e4643 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  199. Perruche, S. et al. Lethal effect of CD3-specific antibody in mice deficient in TGF-β1 by uncontrolled flu-like syndrome. J. Immunol. 183, 953–961 (2009).

    Article  CAS  PubMed  Google Scholar 

  200. 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).

    Article  CAS  PubMed  Google Scholar 

  201. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). Guideline on strategies to identify and mitigate risks for first in human clinical trials with investigational medicinal products. Doc. Ref. EMEA/CHMP/SWP/28367/07. EMA website [online], (2007).

  202. European Medicines Agency. ICH topic M 3 (R2): non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals. Note for guidance on non-clinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals (CPMP/ICH/286/95). EMA website [online], (2008).

  203. European Medicines Agency. ICH topic S 6: preclinical safety evaluation of biotechnology-derived pharmaceuticals. Note for guidance on preclinical safety evaluation of biotechnology-derived pharmaceuticals (CPMP/ICH/302/95). EMA website [online], (1998).

  204. Lappin, G. & Garner, R. C. The utility of microdosing over the past 5 years. Expert Opin. Drug Metab. Toxicol. 4, 1499–1506 (2008).

    Article  CAS  PubMed  Google Scholar 

  205. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). Position paper on non-clinical safety studies to support clinical trials with a single microdose. CPMP/SWP/2599/02. EMA website [online], (2004).

  206. Liedert, B., Bassus, S., Schneider, C. K., Kalinke, U. & Lower, J. Safety of phase I clinical trials with monoclonal antibodies in Germany — the regulatory requirements viewed in the aftermath of the TGN1412 disaster. Int. J. Clin. Pharmacol. Ther. 45, 1–9 (2007).

    Article  CAS  PubMed  Google Scholar 

  207. Wafelman, A. R. Commentary: symposium report — Development of safe protein therapeutics: pre-clinical, clinical and regulatory issues. Eur. J. Pharm. Sci. 34, 223–225 (2008).

    Article  CAS  PubMed  Google Scholar 

  208. 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).

    Article  CAS  PubMed  Google Scholar 

  209. Findlay, L. et al. Improved in vitro methods to predict the in vivo toxicity in man of therapeutic monoclonal antibodies including TGN1412. J. Immunol. Methods 352, 1–12 (2010).References 208 and 209 describe in vitro studies with mAbs and human blood and cell cultures to study the propensity to cause a cytokine storm.

    Article  CAS  PubMed  Google Scholar 

  210. Willmann, J. K., van, B. N., Dinkelborg, L. M. & Gambhir, S. S. Molecular imaging in drug development. Nature Rev. Drug Discov. 7, 591–607 (2008).

    Article  CAS  Google Scholar 

  211. Bullen, A. Microscopic imaging techniques for drug discovery. Nature Rev. Drug Discov. 7, 54–67 (2008).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to acknowledge the expert assistance of A. Tan with preparation of the figures and generation of the bibliography.

Author information

Authors and Affiliations

  1. Imperial Clinical Respiratory Research Unit (ICRRU), Mint Wing First Floor, St Mary's Hospital, London, W2 1NY, Paddington, UK

    Trevor T. Hansel

  2. National Heart and Lung Institute, Imperial College, Dovehouse Street, London, SW3 6LY, UK

    Trevor T. Hansel & Jane A. Mitchell

  3. F. Hoffmann-La Roche, Grenzacherstrasse 124, CH-4070 Basel, Switzerland

    Harald Kropshofer & Thomas Singer

  4. Department of Medicine, Immunobiology Section, Imperial College London, Hammersmith Hospital, London, W12 ONN, UK

    Andrew J. T. George

Authors
  1. Trevor T. Hansel
    View author publications

    Search author on:PubMed Google Scholar

  2. Harald Kropshofer
    View author publications

    Search author on:PubMed Google Scholar

  3. Thomas Singer
    View author publications

    Search author on:PubMed Google Scholar

  4. Jane A. Mitchell
    View author publications

    Search author on:PubMed Google Scholar

  5. Andrew J. T. George
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Trevor T. Hansel.

Ethics declarations

Competing interests

Trevor T. Hansel has received funding for clinical research studies from various pharmaceutical companies (GlaxoSmithKline, Pfizer, Novartis, Institute of Medicinal Molecular Design, Oxagen, Merck) in the past 5 years, and has been given fees for lecturing and attending expert groups (Thomson Reuters, Wyeth, Abbott, AstraZeneca, F. Hoffmann-La Roche, Palau Pharma).

Jane A. Mitchell holds, or has held in the past 5 years, research funds from Hoffmann-La Roche and GlaxoSmithKline. Mitchell has acted as a consultant to a number of pharmaceutical companies including Novartis and NiCOX. Mitchell has acted as an expert witness and received honoraria for guest lectures including those funded by pharmaceutical companies. She is on the scientific advisory board for Antibe Therapeutics.

Harald Kropshofer and Thomas Singer are employees of F. Hoffmann-La Roche, Basel, Switzerland, and holders of equity in this company.

Andrew J. T. George has acted as a consultant to biotechnology companies that are developing antibody therapies, and has shares in one such company.

Related links

Related links

DATABASES

Drugs@FDA 

Abciximab

alemtuzumab

bevacizumab

cetuximab

infliximab

ibritumomab

natalizumab

omalizumab

panitumumab

rituximab

tositumomab

trastuzumab

FURTHER INFORMATION

TOUCH Prescribing Program

Glossary

Serum sickness

A delayed reaction (generally over 4–10 days) to serum proteins or monoclonal antibodies, consisting of a hypersensitivity reaction with immune-complex generation and vascular damage in the skin, joints and kidneys.

Tumour lysis syndrome

(TLS). A group of metabolic complications that can occur after treatment of cancer, usually lymphomas and leukaemias. It is generally caused by therapy that initiates the acute breakdown of cancer cells. The resultant biochemical abnormalities can cause kidney damage and acute renal failure.

Cytokine release syndrome

(CRS). Also known as cytokine storm. An uncontrolled hypercytokinaemia that results in multiple organ damage and can be associated with monoclonal antibody therapy, infections and cytokine therapy.

Anaphylaxis

A generally immediate and rapid loss of blood pressure (hypotension) due to a type 1 immunoglobulin E-mediated hypersensitivity reaction.

Thrombocytopaenia

A decrease in the number of circulatory platelets in the blood.

Capillary leak syndrome

A leakage of fluid from capillaries into interstitial fluid that results in hypotension, oedema and multiple organ failure due to limited perfusion.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/nrd3003

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing