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:

Clinical targeting of the TNF and TNFR superfamilies

Nature Reviews Drug Discovery volume 12, pages 147–168 (2013)Cite this article

Subjects

Key Points

  • Inhibitors of tumour necrosis factor (TNF) are among the most successful protein-based drugs for reducing inflammation associated with several autoimmune diseases. Five distinct antibody- or receptor-based drugs directed at blocking TNF are approved for treating rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, psoriasis, ankylosing spondylitis, Crohn's disease and ulcerative colitis.

  • TNF belongs to a superfamily of molecules comprising 19 structurally related proteins (ligands) that bind to one or more molecules in a family of 29 structurally similar receptors. Members of this superfamily initiate a broad range of physiological functions and provide key communication to regulate the development and activity of the immune, nervous, bone and ectodermal systems in mammals.

  • Biologics targeting many of the proteins related to TNF or their cognate receptors are now in preclinical or clinical development.

  • Therapeutic approaches include generating blocking and/or neutralizing reagents to prevent the TNFSF–TNFRSF interactions in order to reduce pathology in autoimmune and inflammatory diseases or other indications; developing agonist reagents to enhance signalling through a TNFRSF member to augment immune responses against tumours; and producing immunotoxins or death-inducing reagents that bind to TNFSF or TNFRSF members for the direct killing of tumours.

  • Studies so far have led to the successful development of three drugs in addition to the TNF inhibitors: targeting CD30 to kill certain cancers, blocking receptor activator of NF-κB ligand (RANKL) to reduce osteoporosis, and inhibiting B cell activating factor (BAFF) to suppress symptoms of systemic lupus erythematosus.

  • This article reviews the current range of biologics targeting all of the molecules in the TNF and TNF receptor superfamily that have been or are in clinical trials for autoimmune and inflammatory diseases, cancer and several other indications, focusing on the challenges in their development as well as emerging therapeutic targets.

Abstract

Inhibitors of tumour necrosis factor (TNF) are among the most successful protein-based drugs (biologics) and have proven to be clinically efficacious at reducing inflammation associated with several autoimmune diseases. As a result, attention is focusing on the therapeutic potential of additional members of the TNF superfamily of structurally related cytokines. Many of these TNF-related cytokines or their cognate receptors are now in preclinical or clinical development as possible targets for modulating inflammatory diseases and cancer as well as other indications. This Review focuses on the biologics that are currently in clinical trials for immune-related diseases and other syndromes, discusses the successes and failures to date as well as the expanding therapeutic potential of modulating the activity of this superfamily of molecules.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Pro-inflammatory and death-inducing activity of TNFSF members.
Figure 2: TNFSF targets and therapeutics in autoimmunity and inflammation.
Figure 3: TNFRSF targets and therapeutics in cancer.

Similar content being viewed by others

References

  1. Bodmer, J. L., Schneider, P. & Tschopp, J. The molecular architecture of the TNF superfamily. Trends Biochem. Sci. 27, 19–26 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Locksley, R. M., Killeen, N. & Lenardo, M. J. The TNF & TNF receptor superfamilies: integrating mammalian biology. Cell 104, 487–501 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Croft, M. Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? Nature Rev. Immunol. 3, 609–620 (2003).

    Article  CAS  Google Scholar 

  4. Ware, C. F. Network communications: lymphotoxins, LIGHT, and TNF. Annu. Rev. Immunol. 23, 787–819 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Croft, M. The role of TNF superfamily members in T-cell function and diseases. Nature Rev. Immunol. 9, 271–285 (2009). This is an in-depth focus on the basic biology of several TNFR molecules that control T cell activity.

    Article  CAS  Google Scholar 

  6. Steinberg, M. W., Cheung, T. C. & Ware, C. F. The signaling networks of the herpesvirus entry mediator (TNFRSF14) in immune regulation. Immunol. Rev. 244, 169–187 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Croft, M. et al. TNF superfamily in inflammatory disease: translating basic insights. Trends Immunol. 33, 144–152 (2012).

    Article  CAS  PubMed  Google Scholar 

  8. Mackay, F. & Schneider, P. Cracking the BAFF code. Nature Rev. Immunol. 9, 491–502 (2009).

    Article  CAS  Google Scholar 

  9. Stohl, W. & Hilbert, D. M. The discovery and development of belimumab: the anti-BLyS-lupus connection. Nature Biotech. 30, 69–77 (2012). This review provides a historic backdrop to the development of drugs targeting BAFF.

    Article  CAS  Google Scholar 

  10. Treml, J. F., Hao, Y., Stadanlick, J. E. & Cancro, M. P. The BLyS family: toward a molecular understanding of B cell homeostasis. Cell Biochem. Biophys. 53, 1–16 (2009).

    Article  CAS  PubMed  Google Scholar 

  11. Benson, M. J. et al. Cutting edge: the dependence of plasma cells and independence of memory B cells on BAFF and APRIL. J. Immunol. 180, 3655–3659 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Furie, R. et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 63, 3918–3930 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Navarra, S. V. et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 377, 721–731 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. Dall'Era, M. et al. Reduced B lymphocyte and immunoglobulin levels after atacicept treatment in patients with systemic lupus erythematosus: results of a multicenter, phase Ib, double-blind, placebo-controlled, dose-escalating trial. Arthritis Rheum. 56, 4142–4150 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Munafo, A., Priestley, A., Nestorov, I., Visich, J. & Rogge, M. Safety, pharmacokinetics and pharmacodynamics of atacicept in healthy volunteers. Eur. J. Clin. Pharmacol. 63, 647–656 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Nestorov, I., Munafo, A., Papasouliotis, O. & Visich, J. Pharmacokinetics and biological activity of atacicept in patients with rheumatoid arthritis. J. Clin. Pharmacol. 48, 406–417 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. Genovese, M. C., Kinnman, N., de La Bourdonnaye, G., Pena Rossi, C. & Tak, P. P. Atacicept in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor antagonist therapy: results of a phase II, randomized, placebo-controlled, dose-finding trial. Arthritis Rheum. 63, 1793–1803 (2011).

    Article  CAS  PubMed  Google Scholar 

  18. van Vollenhoven, R. F., Kinnman, N., Vincent, E., Wax, S. & Bathon, J. Atacicept in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase II, randomized, placebo-controlled trial. Arthritis Rheum. 63, 1782–1792 (2011).

    Article  CAS  PubMed  Google Scholar 

  19. Hartung, H. P. & Kieseier, B. C. Atacicept: targeting B cells in multiple sclerosis. Ther. Adv. Neurol. Disord. 3, 205–216 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kim, S. S., Richman, D. P., Zamvil, S. S. & Agius, M. A. Accelerated central nervous system autoimmunity in BAFF-receptor-deficient mice. J. Neurol. Sci. 306, 9–15 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Matsushita, T., Yanaba, K., Bouaziz, J. D., Fujimoto, M. & Tedder, T. F. Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression. J. Clin. Invest. 118, 3420–3430 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Yang, M. et al. Novel function of B cell-activating factor in the induction of IL-10-producing regulatory B cells. J. Immunol. 184, 3321–3325 (2010).

    Article  CAS  PubMed  Google Scholar 

  23. Huntington, N. D. et al. A BAFF antagonist suppresses experimental autoimmune encephalomyelitis by targeting cell-mediated and humoral immune responses. Int. Immunol. 18, 1473–1485 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Zhou, X. et al. BAFF promotes Th17 cells and aggravates experimental autoimmune encephalomyelitis. PLoS ONE 6, e23629 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lin, W. Y. et al. Anti-BR3 antibodies: a new class of B-cell immunotherapy combining cellular depletion and survival blockade. Blood 110, 3959–3967 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Seshasayee, D. et al. Loss of TACI causes fatal lymphoproliferation and autoimmunity, establishing TACI as an inhibitory BLyS receptor. Immunity 18, 279–288 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Varfolomeev, E. et al. APRIL-deficient mice have normal immune system development. Mol. Cell. Biol. 24, 997–1006 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Castigli, E. et al. TACI is mutant in common variable immunodeficiency and IgA deficiency. Nature Genet. 37, 829–834 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Xiao, Y., Motomura, S. & Podack, E. R. APRIL (TNFSF13) regulates collagen-induced arthritis, IL-17 production and Th2 response. Eur. J. Immunol. 38, 3450–3458 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Jacob, C. O. et al. Dispensability of APRIL to the development of systemic lupus erythematosus in NZM 2328 mice. Arthritis Rheum. 64, 1610–1619 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Jiang, C., Loo, W. M., Greenley, E. J., Tung, K. S. & Erickson, L. D. B cell maturation antigen deficiency exacerbates lymphoproliferation and autoimmunity in murine lupus. J. Immunol. 186, 6136–6147 (2011).

    Article  CAS  PubMed  Google Scholar 

  32. Peters, A. L., Stunz, L. L. & Bishop, G. A. CD40 and autoimmunity: the dark side of a great activator. Semin. Immunol. 21, 293–300 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Law, C. L. & Grewal, I. S. Therapeutic interventions targeting CD40L (CD154) and CD40: the opportunities and challenges. Adv. Exp. Med. Biol. 647, 8–36 (2009). References 32 and 33 provide a strong insight into the immunostimulatory activities of CD40.

    Article  CAS  PubMed  Google Scholar 

  34. Boumpas, D. T. et al. A short course of BG9588 (anti-CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis. Arthritis Rheum. 48, 719–727 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. 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 

  36. Kawai, T., Andrews, D., Colvin, R. B., Sachs, D. H. & Cosimi, A. B. Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand. Nature Med. 6, 114 (2000). This work provides an example of an unexpected outcome of therapy due to an unappreciated expression pattern of CD40L. Expression databases may avoid this problem in future trials.

    Article  CAS  PubMed  Google Scholar 

  37. Schuler, W. et al. Efficacy and safety of ABI793, a novel human anti-human CD154 monoclonal antibody, in cynomolgus monkey renal allotransplantation. Transplantation 77, 717–726 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Davis, J. C. et al. Phase I clinical trial of a monoclonal antibody against CD40-ligand (IDEC-131) in patients with systemic lupus erythematosus. J. Rheumatol. 28, 95–101 (2001).

    CAS  PubMed  Google Scholar 

  39. Kalunian, K. C. et al. Treatment of systemic lupus erythematosus by inhibition of T cell costimulation with anti-CD154: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 46, 3251–3258 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Adams, A. B. et al. Development of a chimeric anti-CD40 monoclonal antibody that synergizes with LEA29Y to prolong islet allograft survival. J. Immunol. 174, 542–550 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Thompson, P. et al. CD40-specific costimulation blockade enhances neonatal porcine islet survival in nonhuman primates. Am. J. Transplant. 11, 947–957 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Haanstra, K. G. et al. Prevention of kidney allograft rejection using anti-CD40 and anti-CD86 in primates. Transplantation 75, 637–643 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. 't Hart, B. A. et al. Treatment with chimeric anti-human CD40 antibody suppresses MRI-detectable inflammation and enlargement of pre-existing brain lesions in common marmosets affected by MOG-induced EAE. J. Neuroimmunol. 163, 31–39 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Kasran, A. et al. Safety and tolerability of antagonist anti-human CD40 Mab ch5D12 in patients with moderate to severe Crohn's disease. Aliment. Pharmacol. Ther. 22, 111–122 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Aoyagi, T. et al. A human anti-CD40 monoclonal antibody, 4D11, for kidney transplantation in cynomolgus monkeys: induction and maintenance therapy. Am. J. Transplant. 9, 1732–1741 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Oura, T. et al. Long-term hepatic allograft acceptance based on CD40 blockade by ASKP1240 in nonhuman primates. Am. J. Transplant. 12, 1740–1754 (2012).

    Article  CAS  PubMed  Google Scholar 

  47. Ware, C. F. Targeting the LIGHT-HVEM pathway. Adv. Exp. Med. Biol. 647, 146–155 (2009).

    Article  CAS  PubMed  Google Scholar 

  48. Browning, J. L. Inhibition of the lymphotoxin pathway as a therapy for autoimmune disease. Immunol. Rev. 223, 202–220 (2008). This article provides an excellent overview of translation efforts examining the lymphotoxin system as a target in autoimmune disease.

    Article  CAS  PubMed  Google Scholar 

  49. Chiang, E. Y. et al. In vivo depletion of lymphotoxin-α expressing lymphocytes inhibits xenogeneic graft-versus-host-disease. PLoS ONE 7, e33106 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Emu, B. et al. Safety, pharmacokinetics, and biologic activity of pateclizumab, a novel monoclonal antibody targeting lymphotoxin α: results of a phase I randomized, placebo-controlled trial. Arthritis Res. Ther. 14, R6 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chiang, E. Y. et al. Targeted depletion of lymphotoxin-α-expressing TH1 and TH17 cells inhibits autoimmune disease. Nature Med. 15, 766–773 (2009). This is a good example of how a cell depletion strategy targeting a TNFR molecule can be therapeutic in model systems and pave the path to the development of a clinical reagent.

    Article  CAS  PubMed  Google Scholar 

  52. Cheung, T. C. et al. Polymorphic variants of LIGHT (TNF superfamily-14) alter receptor avidity and bioavailability. J. Immunol. 185, 1949–1958 (2010).

    Article  CAS  PubMed  Google Scholar 

  53. Shaikh, R. B. et al. Constitutive expression of LIGHT on T cells leads to lymphocyte activation, inflammation, and tissue destruction. J. Immunol. 167, 6330–6337 (2001). This report first identified the pro-inflammatory potential of LIGHT in an in vivo model.

    Article  CAS  PubMed  Google Scholar 

  54. Cohavy, O., Zhou, J., Ware, C. F. & Targan, S. R. LIGHT is constitutively expressed on T & NK cells in the human gut and can be induced by CD2-mediated signaling. J. Immunol. 174, 646–653 (2005).

    Article  CAS  PubMed  Google Scholar 

  55. Doherty, T. A. et al. The tumor necrosis factor family member LIGHT is a target for asthmatic airway remodeling. Nature Med. 17, 596–603 (2011). This work highlighted a new role of LIGHT in chronic lung inflammation.

    Article  CAS  PubMed  Google Scholar 

  56. Croft, M. Control of immunity by the TNFR-related molecule OX40 (CD134). Annu. Rev. Immunol. 28, 57–78 (2010). This article details the history of research on OX40 and the key developments in understanding its importance in immunity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Salek-Ardakani, S. et al. OX40 (CD134) controls memory T helper 2 cells that drive lung inflammation. J. Exp. Med. 198, 315–324 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Seshasayee, D. et al. In vivo blockade of OX40 ligand inhibits thymic stromal lymphopoietin driven atopic inflammation. J. Clin. Invest. 117, 3868–3878 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Ezzat, M. H., Imam, S. S., Shaheen, K. Y. & Elbrhami, E. M. Serum OX40 ligand levels in asthmatic children: a potential biomarker of severity and persistence. Allergy Asthma Proc. 32, 313–318 (2011).

    Article  CAS  PubMed  Google Scholar 

  60. Lei, W. et al. SOX40L: an important inflammatory mediator in adult bronchial asthma. Ann. Acad. Med. Singap. 41, 200–204 (2012).

    PubMed  Google Scholar 

  61. Oflazoglu, E., Grewal, I. S. & Gerber, H. Targeting CD30/CD30L in oncology and autoimmune and inflammatory diseases. Adv. Exp. Med. Biol. 647, 174–185 (2009).

    Article  CAS  PubMed  Google Scholar 

  62. Withers, D. R. et al. OX40 and CD30 signals in CD4+ T-cell effector and memory function: a distinct role for lymphoid tissue inducer cells in maintaining CD4+ T-cell memory but not effector function. Immunol. Rev. 244, 134–148 (2011).

    Article  CAS  PubMed  Google Scholar 

  63. Winkles, J. A. The TWEAK–Fn14 cytokine–receptor axis: discovery, biology and therapeutic targeting. Nature Rev. Drug Discov. 7, 411–425 (2008).

    Article  CAS  Google Scholar 

  64. Burkly, L. C., Michaelson, J. S. & Zheng, T. S. TWEAK/Fn14 pathway: an immunological switch for shaping tissue responses. Immunol. Rev. 244, 99–114 (2011). References 63 and 64 discuss the basic biology of FN14 and how this is translating into clinical targeting.

    Article  CAS  PubMed  Google Scholar 

  65. Bhatnagar, S. & Kumar, A. The TWEAK-Fn14 system: breaking the silence of cytokine-induced skeletal muscle wasting. Curr. Mol. Med. 12, 3–13 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Kawashima, R. et al. Interleukin-13 damages intestinal mucosa via TWEAK and Fn14 in mice — a pathway associated with ulcerative colitis. Gastroenterology 141, 2119–2129.e8 (2011).

    Article  CAS  PubMed  Google Scholar 

  67. Dohi, T. & Burkly, L. C. The TWEAK/Fn14 pathway as an aggravating and perpetuating factor in inflammatory diseases; focus on inflammatory bowel diseases. J. Leukocyte Biol. 92, 265–279 (2012).

    Article  CAS  PubMed  Google Scholar 

  68. Michaelson, J. S., Wisniacki, N., Burkly, L. C. & Putterman, C. Role of TWEAK in lupus nephritis: a bench-to-bedside review. J. Autoimmun. 39, 130–142 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Placke, T., Kopp, H. G. & Salih, H. R. Glucocorticoid-induced TNFR-related (GITR) protein and its ligand in antitumor immunity: functional role and therapeutic modulation. Clin. Dev. Immunol. 2010, 239083 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Nocentini, G., Ronchetti, S., Petrillo, M. G. & Riccardi, C. Pharmacological modulation of GITRL/GITR system: therapeutic perspectives. Br. J. Pharmacol. 165, 2089–2099 (2012). References 69 and 70 highlight the complex biology of GITR and GITRL.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Bae, E. et al. Glucocorticoid-induced tumour necrosis factor receptor-related protein-mediated macrophage stimulation may induce cellular adhesion and cytokine expression in rheumatoid arthritis. Clin. Exp. Immunol. 148, 410–418 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Bae, E. M. et al. Reverse signaling initiated from GITRL induces NF-κB activation through ERK in the inflammatory activation of macrophages. Mol. Immunol. 45, 523–533 (2008).

    Article  CAS  PubMed  Google Scholar 

  73. Kim, W. J. et al. Comparative analysis of the expression patterns of various TNFSF/TNFRSF in atherosclerotic plaques. Immunol. Invest. 37, 359–373 (2008).

    Article  CAS  PubMed  Google Scholar 

  74. Cuzzocrea, S. et al. Role of glucocorticoid-induced TNF receptor family gene (GITR) in collagen-induced arthritis. FASEB J. 19, 1253–1265 (2005).

    Article  CAS  PubMed  Google Scholar 

  75. Wang, S. et al. Glucocorticoid-induced tumor necrosis factor receptor family-related protein exacerbates collagen-induced arthritis by enhancing the expansion of Th17 cells. Am. J. Pathol. 180, 1059–1067 (2012).

    Article  CAS  PubMed  Google Scholar 

  76. Snell, L. M., Lin, G. H., McPherson, A. J., Moraes, T. J. & Watts, T. H. T-cell intrinsic effects of GITR and 4-1BB during viral infection and cancer immunotherapy. Immunol. Rev. 244, 197–217 (2011). This paper compares and contrasts the activities of 4-1BB and GITR in controlling T cell responsiveness to infectious agents and tumours.

    Article  CAS  PubMed  Google Scholar 

  77. Michel, J., Langstein, J., Hofstadter, F. & Schwarz, H. A soluble form of CD137 (ILA/4-1BB), a member of the TNF receptor family, is released by activated lymphocytes and is detectable in sera of patients with rheumatoid arthritis. Eur. J. Immunol. 28, 290–295 (1998).

    Article  CAS  PubMed  Google Scholar 

  78. Jung, H. W., Choi, S. W., Choi, J. I. & Kwon, B. S. Serum concentrations of soluble 4-1BB and 4-1BB ligand correlated with the disease severity in rheumatoid arthritis. Exp. Mol. Med. 36, 13–22 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Liu, G. Z. et al. Increased soluble 4-1BB ligand (4-1BBL) levels in peripheral blood of patients with multiple sclerosis. Scand. J. Immunol. 64, 412–419 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Hamaguchi, Y. et al. Clinical association of serum CD137 (4-1BB) levels in patients with systemic sclerosis. J. Dermatol. Sci. 53, 159–161 (2009).

    Article  CAS  PubMed  Google Scholar 

  81. Maerten, P. et al. Functional expression of 4-1BB (CD137) in the inflammatory tissue in Crohn's disease. Clin. Immunol. 112, 239–246 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Olofsson, P. S. et al. CD137 is expressed in human atherosclerosis and promotes development of plaque inflammation in hypercholesterolemic mice. Circulation 117, 1292–1301 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. Vinay, D. S. & Kwon, B. S. TNF superfamily: costimulation and clinical applications. Cell Biol. Int. 33, 453–465 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Seo, S. K. et al. 4-1BB-mediated immunotherapy of rheumatoid arthritis. Nature Med. 10, 1088–1094 (2004). This is an important report showing the potential of agonist targeting of 4-1BB in expanding regulatory cells to cause suppression of autoimmune disease.

    Article  CAS  PubMed  Google Scholar 

  85. Vinay, D. S., Kim, C. H., Choi, B. K. & Kwon, B. S. Origins and functional basis of regulatory CD11c+CD8+ T cells. Eur. J. Immunol. 39, 1552–1563 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Hong, H. J. et al. A humanized anti-4-1BB monoclonal antibody suppresses antigen-induced humoral immune response in nonhuman primates. J. Immunother. 23, 613–621 (2000).

    Article  CAS  PubMed  Google Scholar 

  87. 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).

    Article  CAS  PubMed  Google Scholar 

  88. Shih, D. Q. et al. Insights into TL1A and IBD pathogenesis. Adv. Exp. Med. Biol. 691, 279–288 (2011).

    Article  CAS  PubMed  Google Scholar 

  89. Meylan, F., Richard, A. C. & Siegel, R. M. TL1A and DR3, a TNF family ligand-receptor pair that promotes lymphocyte costimulation, mucosal hyperplasia, and autoimmune inflammation. Immunol. Rev. 244, 188–196 (2011). References 88 and 89 provide an in-depth overview of the biology of TL1A and DR3.

    Article  CAS  PubMed  Google Scholar 

  90. Al-Lamki, R. S. et al. Expression of silencer of death domains and death-receptor-3 in normal human kidney and in rejecting renal transplants. Am. J. Pathol. 163, 401–411 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Bamias, G. et al. Circulating levels of TNF-like cytokine 1A (TL1A) and its decoy receptor 3 (DcR3) in rheumatoid arthritis. Clin. Immunol. 129, 249–255 (2008).

    Article  CAS  PubMed  Google Scholar 

  92. Bamias, G. et al. Upregulation and nuclear localization of TNF-like cytokine 1A (TL1A) and its receptors DR3 and DcR3 in psoriatic skin lesions. Exp. Dermatol. 20, 725–731 (2011).

    Article  CAS  PubMed  Google Scholar 

  93. Nolte, M. A., van Olffen, R. W., van Gisbergen, K. P. & van Lier, R. A. Timing and tuning of CD27–CD70 interactions: the impact of signal strength in setting the balance between adaptive responses and immunopathology. Immunol. Rev. 229, 216–231 (2009). This paper highlights the basic biology of CD27 in controlling T cell activity.

    Article  CAS  PubMed  Google Scholar 

  94. Leibbrandt, A. & Penninger, J. M. Novel functions of RANK(L) signaling in the immune system. Adv. Exp. Med. Biol. 658, 77–94 (2010). This review details new activities of RANK in controlling immune responsiveness.

    Article  CAS  PubMed  Google Scholar 

  95. Leibbrandt, A. & Penninger, J. M. TNF conference 2009: beyond bones — RANKL/RANK in the immune system. Adv. Exp. Med. Biol. 691, 5–22 (2011).

    Article  CAS  PubMed  Google Scholar 

  96. Schmaltz, C. et al. Differential use of Fas ligand and perforin cytotoxic pathways by donor T cells in graft-versus-host disease and graft-versus-leukemia effect. Blood 97, 2886–2895 (2001).

    Article  CAS  PubMed  Google Scholar 

  97. Miwa, K. et al. Therapeutic effect of an anti-Fas ligand mAb on lethal graft-versus-host disease. Int. Immunol. 11, 925–931 (1999).

    Article  CAS  PubMed  Google Scholar 

  98. Ruffin, N. et al. The involvement of epithelial Fas in a human model of graft versus host disease. Transplantation 91, 946–951 (2011).

    Article  CAS  PubMed  Google Scholar 

  99. Tecchio, C. et al. High serum levels of B-lymphocyte stimulator are associated with clinical-pathological features and outcome in classical Hodgkin lymphoma. Br. J. Haematol. 137, 553–559 (2007).

    Article  CAS  PubMed  Google Scholar 

  100. Rennert, P. et al. A soluble form of B cell maturation antigen, a receptor for the tumor necrosis factor family member APRIL, inhibits tumor cell growth. J. Exp. Med. 192, 1677–1684 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Chiu, A. et al. Hodgkin lymphoma cells express TACI and BCMA receptors and generate survival and proliferation signals in response to BAFF and APRIL. Blood 109, 729–739 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Guadagnoli, M. et al. Development and characterization of APRIL antagonistic monoclonal antibodies for treatment of B-cell lymphomas. Blood 117, 6856–6865 (2011).

    Article  CAS  PubMed  Google Scholar 

  103. Ansell, S. M. et al. Phase I clinical study of atacicept in patients with relapsed and refractory B-cell non-Hodgkin's lymphoma. Clin. Cancer Res. 14, 1105–1110 (2008).

    Article  CAS  PubMed  Google Scholar 

  104. Rossi, J. F. et al. Atacicept in relapsed/refractory multiple myeloma or active Waldenstrom's macroglobulinemia: a phase I study. Br. J. Cancer 101, 1051–1058 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Rossi, J. F. Phase I study of atacicept in relapsed/refractory multiple myeloma (MM) and Waldenstrom's macroglobulinemia. Clin. Lymphoma Myeloma Leuk. 11, 136–138 (2011).

    Article  CAS  PubMed  Google Scholar 

  106. Vonderheide, R. H. et al. Clinical activity and immune modulation in cancer patients treated with CP-870893, a novel CD40 agonist monoclonal antibody. J. Clin. Oncol. 25, 876–883 (2007).

    Article  CAS  PubMed  Google Scholar 

  107. Ruter, J., Antonia, S. J., Burris, H. A., Huhn, R. D. & Vonderheide, R. H. Immune modulation with weekly dosing of an agonist CD40 antibody in a phase I study of patients with advanced solid tumors. Cancer Biol. Ther. 10, 983–993 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Beatty, G. L. et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331, 1612–1616 (2011). This paper provides new insights into the potential efficacy of CD40 agonists in patients with cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Tai, Y. T. et al. Mechanisms by which SGN-40, a humanized anti-CD40 antibody, induces cytotoxicity in human multiple myeloma cells: clinical implications. Cancer Res. 64, 2846–2852 (2004).

    Article  CAS  PubMed  Google Scholar 

  110. Kelley, S. K. et al. Preclinical pharmacokinetics, pharmacodynamics, and activity of a humanized anti-CD40 antibody (SGN-40) in rodents and non-human primates. Br. J. Pharmacol. 148, 1116–1123 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Furman, R. R., Forero-Torres, A., Shustov, A. & Drachman, J. G. A phase I study of dacetuzumab (SGN-40, a humanized anti-CD40 monoclonal antibody) in patients with chronic lymphocytic leukemia. Leuk. Lymphoma 51, 228–235 (2010).

    Article  CAS  PubMed  Google Scholar 

  112. Hussein, M. et al. A phase I multidose study of dacetuzumab (SGN-40; humanized anti-CD40 monoclonal antibody) in patients with multiple myeloma. Haematologica 95, 845–848 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Tai, Y. T. et al. Human anti-CD40 antagonist antibody triggers significant antitumor activity against human multiple myeloma. Cancer Res. 65, 5898–5906 (2005).

    Article  CAS  PubMed  Google Scholar 

  114. Byrd, J. C. et al. Phase I study of the anti-CD40 humanized monoclonal antibody lucatumumab (HCD122) in relapsed chronic lymphocytic leukemia. Leuk. Lymphoma 53, 2136–2142 (2012).

    Article  CAS  PubMed  Google Scholar 

  115. Chowdhury, F., Tutt, A. L., Chan, C., Glennie, M. & Johnson, P. W. Development, validation and application of ELISAs for pharmacokinetic and HACA assessment of a chimeric anti-CD40 monoclonal antibody in human serum. J. Immunol. Methods 363, 1–8 (2010).

    Article  CAS  PubMed  Google Scholar 

  116. Vetto, J. T. et al. Presence of the T-cell activation marker OX-40 on tumor infiltrating lymphocytes and draining lymph node cells from patients with melanoma and head and neck cancers. Am. J. Surg. 174, 258–265 (1997).

    Article  CAS  PubMed  Google Scholar 

  117. Ramstad, T., Lawnicki, L., Vetto, J. & Weinberg, A. Immunohistochemical analysis of primary breast tumors and tumor-draining lymph nodes by means of the T-cell costimulatory molecule OX-40. Am. J. Surg. 179, 400–406 (2000).

    Article  CAS  PubMed  Google Scholar 

  118. Petty, J. K., He, K., Corless, C. L., Vetto, J. T. & Weinberg, A. D. Survival in human colorectal cancer correlates with expression of the T-cell costimulatory molecule OX-40 (CD134). Am. J. Surg. 183, 512–518 (2002).

    Article  CAS  PubMed  Google Scholar 

  119. Sarff, M. et al. OX40 (CD134) expression in sentinel lymph nodes correlates with prognostic features of primary melanomas. Am. J. Surg. 195, 621–625; discussion 625 (2008).

    Article  CAS  PubMed  Google Scholar 

  120. Weinberg, A. D. et al. Anti-OX40 (CD134) administration to nonhuman primates: immunostimulatory effects and toxicokinetic study. J. Immunother. 29, 575–585 (2006).

    Article  CAS  PubMed  Google Scholar 

  121. Sznol, M. et al. Phase I study of BMS-663513, a fully human anti-CD137 agonist monoclonal antibody, in patients (pts) with advanced cancer (CA). J. Clin. Oncol. Abstr. 26, 3007 (2008).

    Article  Google Scholar 

  122. Niu, L. et al. Cytokine-mediated disruption of lymphocyte trafficking, hemopoiesis, and induction of lymphopenia, anemia, and thrombocytopenia in anti-CD137-treated mice. J. Immunol. 178, 4194–4213 (2007).

    Article  CAS  PubMed  Google Scholar 

  123. Dubrot, J. et al. Treatment with anti-CD137 mAbs causes intense accumulations of liver T cells without selective antitumor immunotherapeutic effects in this organ. Cancer Immunol. Immunother. 59, 1223–1233 (2010).

    Article  CAS  PubMed  Google Scholar 

  124. Wang, J. et al. CD137-mediated pathogenesis from chronic hepatitis to hepatocellular carcinoma in hepatitis B virus-transgenic mice. J. Immunol. 185, 7654–7662 (2010).

    Article  CAS  PubMed  Google Scholar 

  125. Xia, R. et al. TNFSF9 expression in primary biliary cirrhosis and its clinical significance. Cytokine 50, 311–316 (2010).

    Article  CAS  PubMed  Google Scholar 

  126. Fisher, T. S. et al. Targeting of 4-1BB by monoclonal antibody PF-05082566 enhances T-cell function and promotes anti-tumor activity. Cancer Immunol. Immunother. 61, 1721–1733 (2012).

    Article  CAS  PubMed  Google Scholar 

  127. Schabowsky, R. H. et al. A novel form of 4-1BBL has better immunomodulatory activity than an agonistic anti-4-1BB Ab without Ab-associated severe toxicity. Vaccine 28, 512–522 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Pastor, F., Kolonias, D., McNamara Ii, J. O. & Gilboa, E. Targeting 4-1BB costimulation to disseminated tumor lesions with bi-specific oligonucleotide aptamers. Mol. Ther. 19, 1878–1886 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Imai, C. et al. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia 18, 676–684 (2004).

    Article  CAS  PubMed  Google Scholar 

  130. Morgan, R. A. et al. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol. Ther. 18, 843–851 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Porter, D. L., Levine, B. L., Kalos, M., Bagg, A. & June, C. H. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365, 725–733 (2011). This small study shows that human T cells transduced with a chimeric receptor encoding the signalling domain of 4-1BB can be tremendously efficacious in suppressing tumour growth in patients with cancer. This work has rejuvenated the field of cell-based cancer therapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Kalos, M. et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci. Transl. Med. 3, 95ra73 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Schaer, D. A., Cohen, A. D. & Wolchok, J. D. Anti-GITR antibodies — potential clinical applications for tumor immunotherapy. Curr. Opin. Invest. Drugs 11, 1378–1386 (2010).

    CAS  Google Scholar 

  134. Ponte, J. et al. Characteristics and development of TRX518, an aglycosyl humanized monoclonal antibody (Mab) agonist of huGITR. Clin. Immunol. 135, S96 (2010).

    Article  Google Scholar 

  135. Pruitt, S. K. et al. Enhancement of anti-tumor immunity through local modulation of CTLA-4 and GITR by dendritic cells. Eur. J. Immunol. 41, 3553–3563 (2011).

    Article  CAS  PubMed  Google Scholar 

  136. Law, C. L. et al. Lymphocyte activation antigen CD70 expressed by renal cell carcinoma is a potential therapeutic target for anti-CD70 antibody–drug conjugates. Cancer Res. 66, 2328–2337 (2006).

    Article  CAS  PubMed  Google Scholar 

  137. McEarchern, J. A. et al. Engineered anti-CD70 antibody with multiple effector functions exhibits in vitro and in vivo antitumor activities. Blood 109, 1185–1192 (2007).

    Article  CAS  PubMed  Google Scholar 

  138. McEarchern, J. A. et al. Preclinical characterization of SGN-70, a humanized antibody directed against CD70. Clin. Cancer Res. 14, 7763–7772 (2008).

    Article  CAS  PubMed  Google Scholar 

  139. Ryan, M. C. et al. Targeting pancreatic and ovarian carcinomas using the auristatin-based anti-CD70 antibody–drug conjugate SGN-75. Br. J. Cancer 103, 676–684 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Vitale, L. et al. Development of a human monoclonal antibody for potential therapy of CD27-expressing lymphoma and leukemia. Clin. Cancer Res. 18, 3812–3821 (2012).

    Article  CAS  PubMed  Google Scholar 

  141. Van Nuffel, A. M. et al. Intravenous and intradermal TriMix-dendritic cell therapy results in a broad T-cell response and durable tumor response in a chemorefractory stage IV-M1c melanoma patient. Cancer Immunol. Immunother. 61, 1033–1043 (2011).

    Article  PubMed  Google Scholar 

  142. Falini, B. et al. Response of refractory Hodgkin's disease to monoclonal anti-CD30 immunotoxin. Lancet 339, 1195–1196 (1992).

    Article  CAS  PubMed  Google Scholar 

  143. Terenzi, A. et al. Anti-CD30 (BER=H2) immunotoxins containing the type-1 ribosome-inactivating proteins momordin and PAP-S (pokeweed antiviral protein from seeds) display powerful antitumour activity against CD30+ tumour cells in vitro and in SCID mice. Br. J. Haematol. 92, 872–879 (1996).

    Article  CAS  PubMed  Google Scholar 

  144. Wahl, A. F. et al. The anti-CD30 monoclonal antibody SGN-30 promotes growth arrest and DNA fragmentation in vitro and affects antitumor activity in models of Hodgkin's disease. Cancer Res. 62, 3736–3742 (2002).

    CAS  PubMed  Google Scholar 

  145. Forero-Torres, A. et al. A Phase II study of SGN-30 (anti-CD30 mAb) in Hodgkin lymphoma or systemic anaplastic large cell lymphoma. Br. J. Haematol. 146, 171–179 (2009).

    Article  CAS  PubMed  Google Scholar 

  146. Duvic, M. et al. A phase II study of SGN-30 in cutaneous anaplastic large cell lymphoma and related lymphoproliferative disorders. Clin. Cancer Res. 15, 6217–6224 (2009).

    Article  CAS  PubMed  Google Scholar 

  147. Bartlett, N. L. et al. A phase 1 multidose study of SGN-30 immunotherapy in patients with refractory or recurrent CD30+ hematologic malignancies. Blood 111, 1848–1854 (2008).

    Article  CAS  PubMed  Google Scholar 

  148. Francisco, J. A. et al. cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood 102, 1458–1465 (2003).

    Article  CAS  PubMed  Google Scholar 

  149. Younes, A. et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J. Clin. Oncol. 30, 2183–2189 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Fanale, M. A. et al. A phase I weekly dosing study of brentuximab vedotin in patients with relapsed/refractory CD30-positive hematologic malignancies. Clin. Cancer Res. 18, 248–255 (2012). The studies reported in references 149 and 150 (and in prior references on the clinical development of CD30-targeting antibodies) led to the clinical approval of brentuximab vedotin for the treatment of Hodgkin's lymphoma and ALCL.

    Article  CAS  PubMed  Google Scholar 

  151. Blum, K. A. et al. Serious pulmonary toxicity in patients with Hodgkin's lymphoma with SGN-30, gemcitabine, vinorelbine, and liposomal doxorubicin is associated with an FcγRIIIa-158 V/F polymorphism. Ann. Oncol. 21, 2246–2254 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Savoldo, B. et al. Epstein Barr virus-specific cytotoxic T lymphocytes expressing the anti-CD30ζ artificial chimeric T-cell receptor for immunotherapy of Hodgkin disease. Blood 110, 2620–2630 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Di Stasi, A. et al. T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. Blood 113, 6392–6402 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Huang, Y. & Sheikh, M. S. TRAIL death receptors and cancer therapeutics. Toxicol. Appl. Pharmacol. 224, 284–289 (2007).

    Article  CAS  PubMed  Google Scholar 

  155. Fox, N. L., Humphreys, R., Luster, T. A., Klein, J. & Gallant, G. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-1 and receptor-2 agonists for cancer therapy. Expert Opin. Biol. Ther. 10, 1–18 (2010). This is a comprehensive review of clinical trial results and differences in specific drugs targeting the TRAIL cytokine system in patients with cancer.

    Article  CAS  PubMed  Google Scholar 

  156. Gerspach, J., Pfizenmaier, K. & Wajant, H. Therapeutic targeting of CD95 and the TRAIL death receptors. Recent Pat. Anticancer Drug Discov. 6, 294–310 (2011).

    Article  CAS  PubMed  Google Scholar 

  157. Ashkenazi, A., Holland, P. & Eckhardt, S. G. Ligand-based targeting of apoptosis in cancer: the potential of recombinant human apoptosis ligand 2/tumor necrosis factor-related apoptosis-inducing ligand (rhApo2L/TRAIL). J. Clin. Oncol. 26, 3621–3630 (2008).

    Article  CAS  PubMed  Google Scholar 

  158. Hellwig, C. T. & Rehm, M. TRAIL signaling and synergy mechanisms used in TRAIL-based combination therapies. Mol. Cancer Ther. 11, 3–13 (2012).

    Article  CAS  PubMed  Google Scholar 

  159. Soria, J. C. et al. Randomized phase II study of dulanermin in combination with paclitaxel, carboplatin, and bevacizumab in advanced non-small-cell lung cancer. J. Clin. Oncol. 29, 4442–4451 (2011).

    Article  CAS  PubMed  Google Scholar 

  160. Shepard, B. D. & Badley, A. D. The biology of TRAIL and the role of TRAIL-based therapeutics in infectious diseases. Antiinfect. Agents Med. Chem. 8, 87–101 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Younes, A. et al. A Phase 1b/2 trial of mapatumumab in patients with relapsed/refractory non-Hodgkin's lymphoma. Br. J. Cancer 103, 1783–1787 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Trarbach, T. et al. Phase II trial of mapatumumab, a fully human agonistic monoclonal antibody that targets and activates the tumour necrosis factor apoptosis-inducing ligand receptor-1 (TRAIL-R1), in patients with refractory colorectal cancer. Br. J. Cancer 102, 506–512 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Bajaj, M. & Heath, E. I. Conatumumab: a novel monoclonal antibody against death receptor 5 for the treatment of advanced malignancies in adults. Expert Opin. Biol. Ther. 11, 1519–1524 (2011).

    Article  CAS  PubMed  Google Scholar 

  164. Demetri, G. D. et al. First-line treatment of metastatic or locally advanced unresectable soft tissue sarcomas with conatumumab in combination with doxorubicin or doxorubicin alone: a phase I/II open-label and double-blind study. Eur. J. Cancer 48, 547–563 (2012).

    Article  CAS  PubMed  Google Scholar 

  165. Kindler, H. L. et al. A randomized, placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer. Ann. Oncol. 23, 2834–2842 (2012).

    Article  CAS  PubMed  Google Scholar 

  166. Camidge, D. R. et al. A phase I safety and pharmacokinetic study of the death receptor 5 agonistic antibody PRO95780 in patients with advanced malignancies. Clin. Cancer Res. 16, 1256–1263 (2010).

    Article  CAS  PubMed  Google Scholar 

  167. Wilson, N. S. et al. An Fcγ receptor-dependent mechanism drives antibody-mediated target-receptor signaling in cancer cells. Cancer Cell 19, 101–113 (2011). This report shows that, in mice, the antitumour activity of a TRAILR2-specific monoclonal antibody currently in clinical trials (drozitumab) is augmented through its interaction with leukocytes expressing both activating and inhibitory FcγRs.

    Article  CAS  PubMed  Google Scholar 

  168. Buchsbaum, D. J. et al. Antitumor efficacy of TRA-8 anti-DR5 monoclonal antibody alone or in combination with chemotherapy and/or radiation therapy in a human breast cancer model. Clin. Cancer Res. 9, 3731–3741 (2003).

    CAS  PubMed  Google Scholar 

  169. Saleh, M. N. et al. A phase I study of CD-1008 (humanized monoclonal antibody targeting death receptor 5 or DR5), administered weekly to patients with advanced solid tuors or lymphomas. J. Clin. Oncol. Abstr. 26, 3537 (2008).

    Article  Google Scholar 

  170. Sharma, S. et al. Phase I trial of LBY135, a monoclonal antibody agonist to DR5, alone and in combination with capecitabine in advanced solid tumors. J. Clin. Oncol. Abstr. 26, 3538 (2008).

    Article  Google Scholar 

  171. Culp, P. A. et al. Antibodies to TWEAK receptor inhibit human tumor growth through dual mechanisms. Clin. Cancer Res. 16, 497–508 (2010).

    Article  CAS  PubMed  Google Scholar 

  172. Michaelson, J. S. et al. Development of an Fn14 agonistic antibody as an anti-tumor agent. MAbs 3, 362–375 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Michaelson, J. S. et al. The anti-Fn14 antibody BIIB036 inhibits tumor growth in xenografts and patient derived primary tumor models and enhances efficacy of chemotherapeutic agents in multiple xenograft models. Cancer Biol. Ther. 13, 812–821 (2012).

    Article  CAS  PubMed  Google Scholar 

  174. Chao, D. T. et al. Expression of TweakR in breast cancer and preclinical activity of enavatuzumab, a humanized anti-TweakR mAb. J. Cancer Res. Clin. Oncol. 17 Oct 2012 (doi:10.1007/s00432-012-1332-x).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Yu, P. & Fu, Y. X. Targeting tumors with LIGHT to generate metastasis-clearing immunity. Cytokine Growth Factor Rev. 19, 285–294 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Zhu, M. & Fu, Y. X. The role of core TNF/LIGHT family members in lymph node homeostasis and remodeling. Immunol. Rev. 244, 75–84 (2011). Together with reference 6, references 175 and 176 provide an overview of the latest developments in research on HVEM, LIGHT and their binding partners that relate to inflammatory disease and cancer.

    Article  CAS  PubMed  Google Scholar 

  177. Tamada, K. et al. Modulation of T-cell-mediated immunity in tumor and graft-versus-host disease models through the LIGHT co-stimulatory pathway. Nature Med. 6, 283–289 (2000).

    Article  CAS  PubMed  Google Scholar 

  178. Lukashev, M. et al. Targeting the lymphotoxin-β receptor with agonist antibodies as a potential cancer therapy. Cancer Res. 66, 9617–9624 (2006).

    Article  CAS  PubMed  Google Scholar 

  179. Haybaeck, J. et al. A lymphotoxin-driven pathway to hepatocellular carcinoma. Cancer Cell 16, 295–308 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Ammirante, M., Luo, J. L., Grivennikov, S., Nedospasov, S. & Karin, M. B-cell-derived lymphotoxin promotes castration-resistant prostate cancer. Nature 464, 302–305 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Bouillet, P. & O'Reilly, L. A. CD95, BIM and T cell homeostasis. Nature Rev. Immunol. 9, 514–519 (2009).

    Article  CAS  Google Scholar 

  182. Strasser, A., Jost, P. J. & Nagata, S. The many roles of FAS receptor signaling in the immune system. Immunity 30, 180–192 (2009). References 181 and 182 describe the activities of FAS in controlling immune responses.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Lin, W. W. & Hsieh, S. L. Decoy receptor 3: a pleiotropic immunomodulator and biomarker for inflammatory diseases, autoimmune diseases and cancer. Biochem. Pharmacol. 81, 838–847 (2011).

    Article  CAS  PubMed  Google Scholar 

  184. Schungel, S. et al. The strength of the Fas ligand signal determines whether hepatocytes act as type 1 or type 2 cells in murine livers. Hepatology 50, 1558–1566 (2009).

    Article  CAS  PubMed  Google Scholar 

  185. Verbrugge, I. et al. Combining radiotherapy with APO010 in cancer treatment. Clin. Cancer Res. 15, 2031–2038 (2009).

    Article  CAS  PubMed  Google Scholar 

  186. Eisele, G. et al. APO010, a synthetic hexameric CD95 ligand, induces human glioma cell death in vitro and in vivo. Neuro-oncology 13, 155–164 (2011).

    Article  CAS  PubMed  Google Scholar 

  187. Lacey, D. L. et al. Bench to bedside: elucidation of the OPG–RANK–RANKL pathway and the development of denosumab. Nature Rev. Drug Discov. 11, 401–419 (2012). This is a comprehensive review of the research and clinical history resulting in the development of denosumab for the treatment of bone-related disorders.

    Article  CAS  Google Scholar 

  188. Johnson-Pais, T. L. et al. Identification of a novel tandem duplication in exon 1 of the TNFRSF11A gene in two unrelated patients with familial expansile osteolysis. J. Bone Miner. Res. 18, 376–380 (2003).

    Article  CAS  PubMed  Google Scholar 

  189. Whyte, M. P. & Hughes, A. E. Expansile skeletal hyperphosphatasia is caused by a 15-base pair tandem duplication in TNFRSF11A encoding RANK and is allelic to familial expansile osteolysis. J. Bone Miner. Res. 17, 26–29 (2002).

    Article  CAS  PubMed  Google Scholar 

  190. Nakatsuka, K., Nishizawa, Y. & Ralston, S. H. Phenotypic characterization of early onset Paget's disease of bone caused by a 27-bp duplication in the TNFRSF11A gene. J. Bone Miner. Res. 18, 1381–1385 (2003).

    Article  CAS  PubMed  Google Scholar 

  191. Whyte, M. P. et al. Osteoprotegerin deficiency and juvenile Paget's disease. N. Engl. J. Med. 347, 175–184 (2002).

    Article  CAS  PubMed  Google Scholar 

  192. Cummings, S. R. et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N. Engl. J. Med. 361, 756–765 (2009).

    Article  CAS  PubMed  Google Scholar 

  193. Papapoulos, S. et al. Five years of denosumab exposure in women with postmenopausal osteoporosis: results from the first two years of the FREEDOM extension. J. Bone Miner. Res. 27, 694–701 (2012).

    Article  CAS  PubMed  Google Scholar 

  194. McClung, M. R. et al. Effect of denosumab on bone mineral density and biochemical markers of bone turnover: 8-year results of a phase 2 clinical trial. Osteoporos. Int. 10 Jul 2012 (doi:10.1007/s00198-012-2052-4).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Sharp, J. T. et al. Denosumab prevents metacarpal shaft cortical bone loss in patients with erosive rheumatoid arthritis. Arthritis Care Res. 62, 537–544 (2010).

    Article  Google Scholar 

  196. Deodhar, A. et al. Denosumab-mediated increase in hand bone mineral density associated with decreased progression of bone erosion in rheumatoid arthritis patients. Arthritis Care Res. 62, 569–574 (2010).

    Article  CAS  Google Scholar 

  197. Bekker, P. J. et al. The effect of a single dose of osteoprotegerin in postmenopausal women. J. Bone Miner. Res. 16, 348–360 (2001).

    Article  CAS  PubMed  Google Scholar 

  198. Dougall, W. C. Molecular pathways: osteoclast-dependent and osteoclast-independent roles of the RANKL/RANK/OPG pathway in tumorigenesis and metastasis. Clin. Cancer Res. 18, 326–335 (2012).

    Article  CAS  PubMed  Google Scholar 

  199. Body, J. J. et al. A phase I study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases. Cancer 97, 887–892 (2003).

    Article  PubMed  Google Scholar 

  200. Hill, R. Blocking the effects of NGF as a route to safe and effective pain relief — fact or fancy? Pain 152, 2200–2201 (2011).

    Article  PubMed  Google Scholar 

  201. Holmes, D. Anti-NGF painkillers back on track? Nature Rev. Drug Discov. 11, 337–338 (2012). References 200 and 201 discuss the potential of targeting NGF for pain.

    Article  CAS  Google Scholar 

  202. Lane, N. E. et al. Tanezumab for the treatment of pain from osteoarthritis of the knee. N. Engl. J. Med. 363, 1521–1531 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Katz, N. et al. Efficacy and safety of tanezumab in the treatment of chronic low back pain. Pain 152, 2248–2258 (2011).

    Article  CAS  PubMed  Google Scholar 

  204. Nagashima, H., Suzuki, M., Araki, S., Yamabe, T. & Muto, C. Preliminary assessment of the safety and efficacy of tanezumab in Japanese patients with moderate to severe osteoarthritis of the knee: a randomized, double-blind, dose-escalation, placebo-controlled study. Osteoarthritis Cartilage 19, 1405–1412 (2011).

    Article  CAS  PubMed  Google Scholar 

  205. Schnitzer, T. J. et al. Long-term open-label study of tanezumab for moderate to severe osteoarthritic knee pain. Osteoarthritis Cartilage 19, 639–646 (2011).

    Article  CAS  PubMed  Google Scholar 

  206. Brown, M. T. et al. Tanezumab reduces osteoarthritic knee pain: results of a randomized, double-blind, placebo-controlled phase III trial. J. Pain 13, 790–798 (2012).

    Article  CAS  PubMed  Google Scholar 

  207. 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 

  208. Lichtenstein, G. R., Yan, S., Bala, M., Blank, M. & Sands, B. E. Infliximab maintenance treatment reduces hospitalizations, surgeries, and procedures in fistulizing Crohn's disease. Gastroenterology 128, 862–869 (2005).

    Article  CAS  PubMed  Google Scholar 

  209. Sandborn, W. J. et al. Etanercept for active Crohn's disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology 121, 1088–1094 (2001).

    Article  CAS  PubMed  Google Scholar 

  210. Ware, C. F. & Sedy, J. R. TNF superfamily networks: bidirectional and interference pathways of the herpesvirus entry mediator (TNFSF14). Curr. Opin. Immunol. 23, 627–631 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Gregory, A. P. et al. TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis. Nature 488, 508–511 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. van Oosten, B. W. et al. Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2. Neurology 47, 1531–1534 (1996).

    Article  CAS  PubMed  Google Scholar 

  213. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. Neurology 53, 457–465 (1999).

  214. Salek-Ardakani, S. & Croft, M. Tumor necrosis factor receptor/tumor necrosis factor family members in antiviral CD8 T-cell immunity. J. Interferon Cytokine Res. 30, 205–218 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Furst, D. E. The risk of infections with biologic therapies for rheumatoid arthritis. Semin. Arthritis Rheum. 39, 327–346 (2010).

    Article  CAS  PubMed  Google Scholar 

  216. Kim, S. Y. & Solomon, D. H. Tumor necrosis factor blockade and the risk of viral infection. Nature Rev. Rheumatol. 6, 165–174 (2010).

    Article  CAS  Google Scholar 

  217. Wang, X. Y., Zuo, D., Sarkar, D. & Fisher, P. B. Blockade of cytotoxic T-lymphocyte antigen-4 as a new therapeutic approach for advanced melanoma. Expert Opin. Pharmacother. 12, 2695–2706 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Weinblatt, M. et al. Selective costimulation modulation using abatacept in patients with active rheumatoid arthritis while receiving etanercept: a randomised clinical trial. Ann. Rheum. Dis. 66, 228–234 (2007).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

M.C. is supported by the following grants from the US National Institutes of Health (NIH): CA91837, AI49453, AI089624, AI100905 and AI070535. C.F.W. is supported by NIH grants AI33068, AI48073 and CA164679; and C.A.B. is supported by an NIH grant (AI101403) and an American Heart Association (AHA) grant (7510081). This is publication #1426 from the La Jolla Institute for Allergy and Immunology.

Author information

Author notes

  1. cware@sanfordburnham.org

Authors and Affiliations

  1. Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, 92037, California, USA

    Michael Croft & Chris A. Benedict

  2. Michael Croft & Chris A. Benedict

  3. Laboratory of Molecular Immunology, Infectious and Inflammatory Diseases Center, Sanford Burnham Medical Research Institute, La Jolla, 92037, California, USA

    Carl F. Ware

Authors
  1. Michael Croft
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chris A. Benedict
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carl F. Ware
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

M.C. and C.F.W. have licensed patents on several TNFSF and TNFRSF molecules. C.A.B. declares no competing financial interests.

Supplementary information

Related links

Related links

FURTHER INFORMATION

Michael Croft's homepage

Chris A. Benedict's homepage

Carl F. Ware's homepage

ClinicalTrials.gov website

Advances in Prostate Cancer Immunotherapy at Providence Health & Services

Glossary

ACR-50 score

American College of Rheumatology score indicating a 50% improvement in symptoms.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Croft, M., Benedict, C. & Ware, C. Clinical targeting of the TNF and TNFR superfamilies. Nat Rev Drug Discov 12, 147–168 (2013). https://doi.org/10.1038/nrd3930

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd3930

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer