Therapeutic Interventions Targeting CD40L (CD154) and CD40: The Opportunities and Challenges

  • Che-Leung Law
  • Iqbal S. Grewal
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 647)


CD40 was originally identified as a receptor on B-cells that delivers contact-dependent T helper signals to B-cells through interaction with CD40 ligand (CD40L, CD154). The pivotal role played by CD40-CD40L interaction is illustrated by the defects in B-lineage cell development and the altered structures of secondary lymphoid tissues in patients and engineered mice deficient in CD40 or CD40L. CD40 signaling also provides critical functions in stimulating antigen presentation, priming of helper and cytotoxic T-cells and a variety of inflammatory reactions. As such, dysregulations in the CD40-CD40L costimulation pathway are prominently featured in human diseases ranging from inflammatory conditions to systemic autoimmunity and tissue-specific autoimmune diseases. Moreover, studies in CD40-expressing cancers have provided convincing evidence that the CD40-CD40L pathway regulates survival of neoplastic cells as well as presentation of tumor-associated antigens to the immune system. Extensive research has been devoted to explore CD40 and CD40L as drug targets. A number of anti-CD40L and anti-CD40 antibodies with diverse biological effects are in clinical development for treatment of cancer and autoimmune diseases. This chapter reviews the role of CD40-CD40L costimulation in disease pathogenesis, the characteristics of therapeutic agents targeting this pathway and status of their clinical development.


Systemic Lupus Erythematosus Chronic Lymphocytic Leukemia Experimental Autoimmune Encephalomyelitis Systemic Lupus Erythematosus Patient Cynomolgus Monkey 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Aggarwal BB. Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 2003; 3:745–56.PubMedCrossRefGoogle Scholar
  2. 2.
    Bishop GA, Hostager BS, Brown KD. Mechanisms of TNF receptor-associated factor (TRAF) regulation in B-lymphocytes. J Leukoc Biol 2002; 72:19–23.PubMedGoogle Scholar
  3. 3.
    Bradley JR, Pober JS. Tumor necrosis factor receptor-associated factors (TRAFs). Oncogene 2001; 20:6482–91.PubMedCrossRefGoogle Scholar
  4. 4.
    Biancone L, Cantaluppi V, Camussi G. CD40-CD154 interaction in experimental and human disease. Int J Mol Med 1999; 3:343–53.PubMedGoogle Scholar
  5. 5.
    van Kooten C, Banchereau J. CD40-CD40 ligand. J Leukoc Biol 2000; 67:2–17.PubMedGoogle Scholar
  6. 6.
    Freedman JE. CD40-CD40L and platelet function: beyond hemostasis. Circ Res 2003; 92:944–6.PubMedCrossRefGoogle Scholar
  7. 7.
    Banchereau J, Bazan F, Blanchard D et al. The CD40 antigen and its ligand. Annu Rev Immunol 1994; 12:881–922.PubMedCrossRefGoogle Scholar
  8. 8.
    van Kooten C, Banchereau J. Functions of CD40 on B-cells, dendritic cells and other cells. Curr Opin Immunol 1997; 9:330–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Young LS, Eliopoulos AG, Gallagher NJ et al. CD40 and epithelial cells: across the great divide. Immunol Today 1998; 19:502–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Grewal IS, Flavell RA. CD40 and CD154 in cell-mediated immunity. Annu Rev Immunol 1998; 16:111–35.PubMedCrossRefGoogle Scholar
  11. 11.
    Gauchat JF, Aubry JP, Mazzei G et al. Human CD40-ligand: molecular cloning, cellular distribution and regulation of expression by factors controlling IgE production. FEBS Lett 1993; 315:259–66.PubMedCrossRefGoogle Scholar
  12. 12.
    Henn V, Slupsky JR, Grafe M et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998; 391:591–4.PubMedCrossRefGoogle Scholar
  13. 13.
    Mach F, Schonbeck U, Sukhova GK et al. Reduction of atherosclerosis in mice by inhibition of CD40 signalling. Nature 1998; 394:200–3.PubMedCrossRefGoogle Scholar
  14. 14.
    Clark EA, Ledbetter JA. How B and T-cells talk to each other. Nature 1994; 367:425–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Aruffo A, Farrington M, Hollenbaugh D et al. The CD40 ligand, gp39, is defective in activated T-cells from patients with X-linked hyper-IgM syndrome. Cell 1993; 72:291–300.PubMedCrossRefGoogle Scholar
  16. 16.
    Hayward AR, Levy J, Facchetti F et al. Cholangiopathy and tumors of the pancreas, liver and biliary tree in boys with X-linked immunodeficiency with hyper-IgM. J Immunol 1997; 158:977–83.PubMedGoogle Scholar
  17. 17.
    Kinlen LJ, Webster AD, Bird AG et al. Prospective study of cancer in patients with hypogammaglobulinaemia. Lancet 1985; 1:263–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Laman JD, Claassen E, Noelle RJ. Immunodeficiency due to a faulty interaction between T-cells and B-cells. Curr Opin Immunol 1994; 6:636–41.PubMedCrossRefGoogle Scholar
  19. 19.
    Ramesh N, Morio T, Fuleihan R et al. CD40-CD40 ligand (CD40L) interactions and X-linked hyperIgM syndrome (HIGMX-1). Clin Immunol Immunopathol 1995; 76:S208–S13.PubMedCrossRefGoogle Scholar
  20. 20.
    Castigli E, Fuleihan R, Ramesh N et al. CD40 ligand/CD40 deficiency. Int Arch Allergy Immunol 1995; 107:37–39.PubMedCrossRefGoogle Scholar
  21. 21.
    Kawabe T, Naka T, Yoshida K et al. The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation. Immunity 1994; 1:167–78.PubMedCrossRefGoogle Scholar
  22. 22.
    Castigli E, Alt FW, Davidson L et al. CD40-deficient mice generated by recombination-activating gene-2-deficient blastocyst complementation. Proc Natl Acad Sci USA 1994; 91:12135–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Xu J, Foy TM, Laman JD et al. Mice deficient for the CD40 ligand. Immunity 1994; 1:423–31.PubMedCrossRefGoogle Scholar
  24. 24.
    Foy TM, Laman JD, Ledbetter JA et al. gp39-CD40 interactions are essential for germinal center formation and the development of B-cell memory. J Exp Med 1994; 180:157–63.PubMedCrossRefGoogle Scholar
  25. 25.
    Van den Eertwegh AJ, Noelle RJ, Roy M et al. In vivo CD40-gp39 interactions are essential for thymus-dependent humoral immunity. I. In vivo expression of CD40 ligand, cytokines and antibody production delineates sites of cognate T-B-cell interactions. J Exp Med 1993; 178:1555–65.PubMedCrossRefGoogle Scholar
  26. 26.
    Renshaw BR, Fanslow WC, III, Armitage RJ et al. Humoral immune responses in CD40 ligand-deficient mice. J Exp Med 1994; 180:1889–900.PubMedCrossRefGoogle Scholar
  27. 27.
    Borrow P, Tishon A, Lee S et al. CD40L-deficient mice show deficits in antiviral immunity and have an impaired memory CD8+ CTL response. J Exp Med 1996; 183:2129–42.PubMedCrossRefGoogle Scholar
  28. 28.
    Grewal IS, Xu J, Flavell RA. Impairment of antigen-specific T-cell priming in mice lacking CD40 ligand. Nature 1995; 378:617–20.PubMedCrossRefGoogle Scholar
  29. 29.
    Oxenius A, Campbell KA, Maliszewski CR et al. CD40-CD40 ligand interactions are critical in T-B cooperation but not for other anti-viral CD4+ T-cell functions. J Exp Med 1996; 183:2209–18.PubMedCrossRefGoogle Scholar
  30. 30.
    Whitmire JK, Slifka MK, Grewal IS et al. CD40 ligand-deficient mice generate a normal primary cytotoxic T-lymphocyte response but a defective humoral response to a viral infection. J Virol 1996; 70:8375–81.PubMedGoogle Scholar
  31. 31.
    Whitmire JK, Flavell RA, Grewal IS et al. CD40-CD40 ligand costimulation is required for generating antiviral CD4 T-cell responses but is dispensable for CD8 T-cell responses. J Immunol 1999; 163:3194–201.PubMedGoogle Scholar
  32. 32.
    Borrow P, Tough DF, Eto D et al. CD40 ligand-mediated interactions are involved in the generation of memory CD8(+) cytotoxic T-lymphocytes (CTL) but are not required for the maintenance of CTL memory following virus infection. J Virol 1998; 72:7440–9.PubMedGoogle Scholar
  33. 33.
    Soong L, Xu JC, Grewal IS et al. Disruption of CD40-CD40 ligand interactions results in an enhanced susceptibility to Leishmania amazonensis infection. Immunity 1996; 4:263–73.PubMedCrossRefGoogle Scholar
  34. 34.
    Roy M, Aruffo A, Ledbetter J et al. Studies on the interdependence of gp39 and B7 expression and function during antigen-specific immune responses. Eur J Immunol 1995; 25:596–603.PubMedCrossRefGoogle Scholar
  35. 35.
    Sin JI, Kim JJ, Zhang D et al. Modulation of cellular responses by plasmid CD40L: CD40L plasmid vectors enhance antigen-specific helper T-cell type 1 CD4+ T-cell-mediated protective immunity against herpes simplex virus type 2 in vivo. Hum Gene Ther 2001; 12:1091–102.PubMedCrossRefGoogle Scholar
  36. 36.
    Kiener PA, Moran-Davis P, Rankin BM et al. Stimulation of CD40 with purified soluble gp39 induces proinflammatory responses in human monocytes. J Immunol 1995; 155:4917–25.PubMedGoogle Scholar
  37. 37.
    Cella M, Scheidegger D, Palmer-Lehmann K et al. Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T-cell stimulatory capacity: T-T help via APC activation. J Exp Med 1996; 184:747–52.PubMedCrossRefGoogle Scholar
  38. 38.
    Bleharski JR, Niazi KR, Sieling PA et al. Signaling lymphocytic activation molecule is expressed on CD40 ligand-activated dendritic cells and directly augments production of inflammatory cytokines. J Immunol 2001; 167:3174–81.PubMedGoogle Scholar
  39. 39.
    Heath WR, Carbone FR. Cytotoxic T-lymphocyte activation by cross-priming. Curr Opin Immunol 1999; 11:314–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Toes RE, Schoenberger SP, van der Voort EI et al. CD40-CD40 Ligand interactions and their role in cytotoxic T-lymphocyte priming and anti-tumor immunity. Semin Immunol 1998; 10:443–8.PubMedCrossRefGoogle Scholar
  41. 41.
    French RR, Chan HT, Tutt AL et al. CD40 antibody evokes a cytotoxic T-cell response that eradicates lymphoma and bypasses T-cell help. Nat Med 1999; 5:548–53.PubMedCrossRefGoogle Scholar
  42. 42.
    Singh SR, Casper K, Summers S et al. CD40 expression and function on human dermal microvascular endothelial cells: role in cutaneous inflammation. Clin Exp Dermatol 2001; 26:434–40.PubMedCrossRefGoogle Scholar
  43. 43.
    Ciferska H, Horak P, Hermanova Z et al. The levels of sCD30 and of sCD40L in a group of patients with systemic lupus erythematodes and their diagnostic value. Clin Rheumatol 2007; 26:723–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Goules A, Tzioufas AG, Manousakis MN et al. Elevated levels of soluble CD40 ligand (sCD40L) in serum of patients with systemic autoimmune diseases. J Autoimmun 2006; 26:165–71.PubMedCrossRefGoogle Scholar
  45. 45.
    Vakkalanka RK, Woo C, Kirou KA et al. Elevated levels and functional capacity of soluble CD40 ligand in systemic lupus erythematosus sera. Arthritis Rheum 1999;42:871–81.PubMedCrossRefGoogle Scholar
  46. 46.
    Ludwiczek O, Kaser A, Tilg H. Plasma levels of soluble CD40 ligand are elevated in inflammatory bowel diseases. Int J Colorectal Dis 2003; 18:142–7.PubMedGoogle Scholar
  47. 47.
    Heeschen C, Dimmeler S, Hamm CW et al. Soluble CD40 ligand in acute coronary syndromes. N Engl J Med 2003; 348:1104–11.PubMedCrossRefGoogle Scholar
  48. 48.
    Desideri G, Cipollone F, Valeri L et al. Enhanced plasma soluble CD40 ligand levels in essential hypertensive patients with blunted nocturnal blood pressure decrease. Am J Hypertens 2007; 20:70–6; discussion 77.PubMedCrossRefGoogle Scholar
  49. 49.
    Kato K, Santana-Sahagun E, Rassenti LZ et al. The soluble CD40 ligand sCD154 in systemic lupus erythematosus. J Clin Invest 1999; 104:947–55.PubMedCrossRefGoogle Scholar
  50. 50.
    Desai-Mehta A, Lu L, Ramsey-Goldman R et al. Hyperexpression of CD40 ligand by B and T-cells in human lupus and its role in pathogenic autoantibody production. J Clin Invest 1996; 97:2063–73.PubMedCrossRefGoogle Scholar
  51. 51.
    Koshy M, Berger D, Crow MK. Increased expression of CD40 ligand on systemic lupus erythematosus lymphocytes. J Clin Invest 1996; 98:826–37.PubMedCrossRefGoogle Scholar
  52. 52.
    Liu MF, Chao SC, Wang CR et al. Expression of CD40 and CD40 ligand among cell populations within rheumatoid synovial compartment. Autoimmunity 2001; 34:107–13.PubMedGoogle Scholar
  53. 53.
    MacDonald KP, Nishioka Y, Lipsky PE et al. Functional CD40 ligand is expressed by T-cells in rheumatoid arthritis. J Clin Invest 1997; 100:2404–14.PubMedCrossRefGoogle Scholar
  54. 54.
    Harigai M, Hara M, Nakazawa S et al. Ligation of CD40 induced tumor necrosis factor-alpha in rheumatoid arthritis: a novel mechanism of activation of synoviocytes. J Rheumatol 1999; 26:1035–43.PubMedGoogle Scholar
  55. 55.
    Wagner UG, Kurtin PJ, Wahner A et al. The role of CD8+ CD40L+ T-cells in the formation of germinal centers in rheumatoid synovitis. J Immunol 1998; 161:6390–7.PubMedGoogle Scholar
  56. 56.
    Huang WX, Huang P, Hillert J. Systemic upregulation of CD40 and CD40 ligand mRNA expression in multiple sclerosis. Mult Scler 2000; 6:61–5.PubMedGoogle Scholar
  57. 57.
    Gerritse K, Laman JD, Noelle RJ et al. CD40-CD40 ligand interactions in experimental allergic encephalomyelitis and multiple sclerosis. Proc Natl Acad Sci USA 1996; 93:2499–504.PubMedCrossRefGoogle Scholar
  58. 58.
    Daoussis D, Antonopoulos I, Andonopoulos AP et al. Increased expression of CD154 (CD40L) on stimulated T-cells from patients with psoriatic arthritis. Rheumatology (Oxford) 2007; 46:227–31.CrossRefGoogle Scholar
  59. 59.
    Liu Z, Geboes K, Colpaert S et al. IL-15 is highly expressed in inflammatory bowel disease and regulates local T-cell-dependent cytokine production. J Immunol 2000; 164:3608–15.PubMedGoogle Scholar
  60. 60.
    Ohlsson M, Szodoray P, Loro LL et al. CD40, CD154, Bax and Bcl-2 expression in Sjogren’s syndrome salivary glands: a putative anti-apoptotic role during its effector phases. Scand J Immunol 2002; 56:561–71.PubMedCrossRefGoogle Scholar
  61. 61.
    Devi BS, Van Noordin S, Krausz T et al. Peripheral blood lymphocytes in SLE—hyperexpression of CD154 on T-and B-lymphocytes and increased number of double negative T-cells. J Autoimmun 1998; 11:471–5.PubMedCrossRefGoogle Scholar
  62. 62.
    Katsiari CG, Liossis SN, Dimopoulos AM et al. CD40L overexpression on T-cells and monocytes from patients with systemic lupus erythematosus is resistant to calcineurin inhibition. Lupus 2002; 11:370–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Katsiari CG, Liossis SN, Souliotis VL et al. Aberrant expression of the costimulatory molecule CD40 ligand on monocytes from patients with systemic lupus erythematosus. Clin Immunol 2002; 103:54–62.PubMedCrossRefGoogle Scholar
  64. 64.
    Battaglia E, Biancone L, Resegotti A et al. Expression of CD40 and its ligand, CD40L, in intestinal lesions of Crohn’s disease. Am J Gastroenterol 1999; 94:3279–84.PubMedCrossRefGoogle Scholar
  65. 65.
    Sawada-Hase N, Kiyohara T, Miyagawa J et al. An increased number of CD40-high monocytes in patients with Crohn’s disease. Am J Gastroenterol 2000; 95:1516–23.PubMedCrossRefGoogle Scholar
  66. 66.
    Kitagawa M, Mitsui H, Nakamura H et al. Differential regulation of rheumatoid synovial cell interleukin-12 production by tumor necrosis factor alpha and CD40 signals. Arthritis Rheum 1999; 42:1917–26.PubMedCrossRefGoogle Scholar
  67. 67.
    Mach F, Schonbeck U, Libby P. CD40 signaling in vascular cells: a key role in atherosclerosis? Atherosclerosis 1998; 137(Suppl):S89–95.CrossRefGoogle Scholar
  68. 68.
    Lutgens E, Gorelik L, Daemen MJ et al. Requirement for CD154 in the progression of atherosclerosis. Nat Med 1999; 5:1313–6.PubMedCrossRefGoogle Scholar
  69. 69.
    Monaco C, Andreakos E, Young S et al. T-cell-mediated signaling to vascular endothelium: induction of cytokines, chemokines and tissue factor. J Leukoc Biol 2002; 71:659–68.PubMedGoogle Scholar
  70. 70.
    Becher B, Blain M, Antel JP. CD40 engagement stimulates IL-12 p70 production by human microglial cells: basis for Th1 polarization in the CNS. J Neuroimmunol 2000; 102:44–50.PubMedCrossRefGoogle Scholar
  71. 71.
    Cho CS, Cho ML, Min SY et al. CD40 engagement on synovial fibroblast up-regulates production of vascular endothelial growth factor. J Immunol 2000; 164:5055–61.PubMedGoogle Scholar
  72. 72.
    Danese S, Scaldaferri F, Vetrano S et al. Critical role of the CD40-CD40 ligand pathway in governing mucosal inflammation-driven angiogenesis in inflammatory bowel disease. Gut, 2007;56:1248–56.PubMedCrossRefGoogle Scholar
  73. 73.
    Flaxenburg JA, Melter M, Lapchak PH et al. The CD40-induced signaling pathway in endothelial cells resulting in the overexpression of vascular endothelial growth factor involves Ras and phosphatidylinositol 3-kinase. J Immunol 2004; 172:7503–9.PubMedGoogle Scholar
  74. 74.
    Blazar BR, Taylor PA, Panoskaltsis-Mortari A et al. Blockade of CD40 ligand-CD40 interaction impairs CD4+ T-cell-mediated alloreactivity by inhibiting mature donor T-cell expansion and function after bone marrow transplantation. J Immunol 1997; 158:29–39.PubMedGoogle Scholar
  75. 75.
    De Jong YP, Comiskey M, Kalled SL et al. Chronic murine colitis is dependent on the CD154/CD40 pathway and can be attenuated by anti-CD154 administration. Gastroenterology 2000; 119:715–23.PubMedCrossRefGoogle Scholar
  76. 76.
    Pollard KM, Arnush M, Hultman P et al. Costimulation requirements of induced murine systemic autoimmune disease. J Immunol 2004; 173:5880–7.PubMedGoogle Scholar
  77. 77.
    Grewal IS, Foellmer HG, Grewal KD et al. Requirement for CD40 ligand in costimulation induction, T-cell activation and experimental allergic encephalomyelitis. Science 1996; 273:1864–7.PubMedCrossRefGoogle Scholar
  78. 78.
    Breslow JL. Mouse models of atherosclerosis. Science 1996; 272:685–8.PubMedCrossRefGoogle Scholar
  79. 79.
    Ma J, Xu J, Madaio MP et al. Autoimmune lpr/lpr mice deficient in CD40 ligand: spontaneous Ig class switching with dichotomy of autoantibody responses. J Immunol 1996; 157:417–26.PubMedGoogle Scholar
  80. 80.
    Kawamura T, Kanai T, Dohi T et al. Ectopic CD40 ligand expression on B-cells triggers intestinal inflammation. J Immunol 2004; 172:6388–97.PubMedGoogle Scholar
  81. 81.
    Higuchi T, Aiba Y, Nomura T et al. Cutting Edge: Ectopic expression of CD40 ligand on B-cells induces lupus-like autoimmune disease. J Immunol 2002; 168:9–12.PubMedGoogle Scholar
  82. 82.
    Mehling A, Loser K, Varga G et al. Overexpression of CD40 ligand in murine epidermis results in chronic skin inflammation and systemic autoimmunity. J Exp Med 2001; 194:615–28.PubMedCrossRefGoogle Scholar
  83. 83.
    Saito K, Sakurai J, Ohata J et al. Involvement of CD40 ligand-CD40 and CTLA4-B7 pathways in murine acute graft-versus-host disease induced by allogeneic T-cells lacking CD28. J Immunol 1998; 160:4225–31.PubMedGoogle Scholar
  84. 84.
    Durie FH, Aruffo A, Ledbetter J et al. Antibody to the ligand of CD40, gp39, blocks the occurrence of the acute and chronic forms of graft-vs-host disease. J Clin Invest 1994; 94:1333–8.PubMedCrossRefGoogle Scholar
  85. 85.
    Stuber E, Strober W, Neurath M. Blocking the CD40L-CD40 interaction in vivo specifically prevents the priming of T helper 1 cells through the inhibition of interleukin 12 secretion. J Exp Med 1996; 183:693–8.PubMedCrossRefGoogle Scholar
  86. 86.
    Banu N, Zhang Y, Meyers CM. Immune reactivity following CD40L blockade: role in autoimmune glomerulonephritis in susceptible recipients. Autoimmunity 1999; 30:21–33.PubMedCrossRefGoogle Scholar
  87. 87.
    Larsen CP, Alexander DZ, Hollenbaugh D et al. CD40-gp39 interactions play a critical role, during allograft rejection. Suppression of allograft rejection by blockade of the CD40-gp39 pathway. Transplantation 1996; 61:4–9.PubMedCrossRefGoogle Scholar
  88. 88.
    Bumgardner GL, Li J, Heininger M et al. Costimulation pathways in host immune responses to allogeneic hepatocytes. Transplantation 1998; 66:1841–5.PubMedCrossRefGoogle Scholar
  89. 89.
    Molano RD, Berney T, Li H et al. Prolonged islet graft survival in NOD mice by blockade of the CD40-CD154 pathway of T-cell costimulation. Diabetes 2001; 50:270–6.PubMedCrossRefGoogle Scholar
  90. 90.
    Tung TH, Mackinnon SE, Mohanakumar T. Long-term limb allograft survival using anti-CD40L antibody in a murine model. Transplantation 2003; 75:644–50.PubMedCrossRefGoogle Scholar
  91. 91.
    Larsen CP, Elwood ET, Alexander DZ et al. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature 1996; 381:434–8.PubMedCrossRefGoogle Scholar
  92. 92.
    Li Y, Li XC, Zheng XX et al. Blocking both signal 1 and signal 2 of T-cell activation prevents apoptosis of alloreactive T-cells and induction of peripheral allograft tolerance. Nat Med 1999; 5:1298–302.PubMedCrossRefGoogle Scholar
  93. 93.
    Elwood ET, Larsen CP, Cho HR et al. Prolonged acceptance of concordant and discordant xenografts with combined CD40 and CD28 pathway blockade. Transplantation 1998; 65:1422–8.PubMedCrossRefGoogle Scholar
  94. 94.
    Parker DC, Greiner DL, Phillips NE et al. Survival of mouse pancreatic islet allografts in recipients treated with allogeneic small lymphocytes and antibody to CD40 ligand. Proc Natl Acad Sci USA 1995; 92:9560–4.PubMedCrossRefGoogle Scholar
  95. 95.
    Markees TG, Phillips NE, Noelle RJ et al. Prolonged survival of mouse skin allografts in recipients treated with donor splenocytes and antibody to CD40 ligand. Transplantation 1997; 64:329–35.PubMedCrossRefGoogle Scholar
  96. 96.
    Durie FH, Fava RA, Foy TM et al. Prevention of collagen-induced arthritis with an antibody to gp39, the ligand for CD40. Science 1993; 261:1328–30.PubMedCrossRefGoogle Scholar
  97. 97.
    Kyburz D, Carson DA, Corr M. The role of CD40 ligand and tumor necrosis factor alpha signaling in the transgenic K/BxN mouse model of rheumatoid arthritis. Arthritis Rheum 2000; 43:2571–7.PubMedCrossRefGoogle Scholar
  98. 98.
    Tighe H, Heaphy P, Baird S et al. Human immunoglobulin (IgG) induced deletion of IgM rheumatoid factor B-cells in transgenic mice. J Exp Med 1995; 181:599–606.PubMedCrossRefGoogle Scholar
  99. 99.
    Tighe H, Warnatz K, Brinson D et al. Peripheral deletion of rheumatoid factor B-cells after abortive activation by IgG. Proc Natl Acad Sci USA 1997; 94:646–51.PubMedCrossRefGoogle Scholar
  100. 100.
    Kyburz D, Corr M, Brinson DC et al. Human rheumatoid factor production is dependent on CD40 signaling and autoantigen. J Immunol 1999; 163:3116–22.PubMedGoogle Scholar
  101. 101.
    Mohan C, Shi Y, Laman JD et al. Interaction between CD40 and its ligand gp39 in the development of murine lupus nephritis. J Immunol 1995; 154:1470–80.PubMedGoogle Scholar
  102. 102.
    Early GS, Zhao W, Burns CM. Anti-CD40 ligand antibody treatment prevents the development of lupus-like nephritis in a subset of New Zealand black x New Zealand white mice. Response correlates with the absence of an anti-antibody response. J Immunol 1996; 157:3159–64.PubMedGoogle Scholar
  103. 103.
    Wang X, Huang W, Schiffer LE et al. Effects of anti-CD154 treatment on B-cells in murine systemic lupus erythematosus. Arthritis Rheum 2003; 48:495–506.PubMedCrossRefGoogle Scholar
  104. 104.
    Kalled SL, Cutler AH, Datta SK et al. Anti-CD40 ligand antibody treatment of SNF1 mice with established nephritis: preservation of kidney function. J Immunol 1998; 160:2158–65.PubMedGoogle Scholar
  105. 105.
    Kalled SL, Cutler AH, Ferrant JL. Long-term anti-CD154 dosing in nephritic mice is required to maintain survival and inhibit mediators of renal fibrosis. Lupus 2001; 10:9–22.PubMedCrossRefGoogle Scholar
  106. 106.
    Daikh DI, Finck BK, Linsley PS et al. Long-term inhibition of murine lupus by brief simultaneous blockade of the B7/CD28 and CD40/gp39 costimulation pathways. J Immunol 1997; 159:3104–8.PubMedGoogle Scholar
  107. 107.
    Wang X, Huang W, Mihara M et al. Mechanism of action of combined short-term CTLA4Ig and anti-CD40 ligand in murine systemic lupus erythematosus. J Immunol 2002; 168:2046–53.PubMedGoogle Scholar
  108. 108.
    Laman JD, Maassen CB, Schellekens MM et al. Therapy with antibodies against CD40L (CD 154) and CD44-variant isoforms reduces experimental autoimmune encephalomyelitis induced by a proteolopid protein peptide. Mult Scler 1998; 4:147–53.PubMedGoogle Scholar
  109. 109.
    Howard LM, Miga AJ, Vanderlugt CL et al. Mechanisms of immunotherapeutic intervention by anti-CD40L (CD154) antibody in an animal model of multiple sclerosis. J Clin Invest 1999; 103:281–90.PubMedCrossRefGoogle Scholar
  110. 110.
    Schaub M, Issazadeh S, Stadlbauer TH et al. Costimulatory signal blockade in murine relapsing experimental autoimmune encephalomyelitis. J Neuroimmunol 1999; 96:158–66.PubMedCrossRefGoogle Scholar
  111. 111.
    Liu Z, Geboes K, Colpaert S et al. Prevention of experimental colitis in SCID mice reconstituted with CD45RBhighCD4+ T-cells by blocking the CD40-CD154 interactions. J Immunol 2000; 164:6005–14.PubMedGoogle Scholar
  112. 112.
    Cong Y, Brandwein SL, McCabe RP et al. CD4+ T-cells reactive to enteric bacterial antigens in spontaneously colitic C3H/HeJBir mice: increased T helper cell type 1 response and ability to transfer disease. J Exp Med 1998; 187:855–64.PubMedCrossRefGoogle Scholar
  113. 113.
    Cong Y, Weaver CT, Lazenby A et al. Colitis induced by enteric bacterial antigen-specific CD4+ T-cells requires CD40-CD40 ligand interactions for a sustained increase in mucosal IL-12. J Immunol 2000; 165:2173–82.PubMedGoogle Scholar
  114. 114.
    Schonbeck U, Sukhova GK, Shimizu K et al. Inhibition of CD40 signaling limits evolution of established atherosclerosis in mice. Proc Natl Acad Sci USA 2000; 97:7458–63.PubMedCrossRefGoogle Scholar
  115. 115.
    Lederman S, Yellin MJ, Krichevsky A et al. Identification of a novel surface protein on activated CD4+ T-cells that induces contact-dependent B-cell differentiation (help). J Exp Med 1992; 175:1091–101.PubMedCrossRefGoogle Scholar
  116. 116.
    Wagner DH Jr, Stout RD, Suttles J. Role of the CD40-CD40 ligand interaction in CD4+ T-cell contact-dependent activation of monocyte interleukin-1 synthesis. Eur J Immunol 1994; 24:3148–54.PubMedCrossRefGoogle Scholar
  117. 117.
    Yellin MJ, Sinning J, Covey LR et al. T-lymphocyte T-cell-B-cell-activating molecule/CD40-L molecules induce normal B-cells or chronic lymphocytic leukemia B-cells to express CD80 (B7/BB-1) and enhance their costimulatory activity. Immunol 1994; 153:666–74.Google Scholar
  118. 118.
    Nishioka Y, Lipsky PE. The role of CD40-CD40 ligand interaction in human T-cell-B-cell collaboration. J Immunol 1994; 153:1027–36.PubMedGoogle Scholar
  119. 119.
    Lederman S, Yellin MJ, Cleary AM et al. T-BAM/CD40-L on helper T-lymphocytes augments lymphokine-induced B-cell Ig isotype switch recombination and rescues B-cells from programmed cell death. J Immunol 1994; 152:2163–71.PubMedGoogle Scholar
  120. 120.
    Kirk AD, Harlan DM, Armstrong NN et al. CTLA4-Ig and anti-CD40 ligand prevent renal allograft rejection in primates. Proc Natl Acad Sci USA 1997; 94:8789–94.PubMedCrossRefGoogle Scholar
  121. 121.
    Gobburu JV, Tenhoor C, Rogge MC et al. Pharmacokinetics/dynamics of 5c8, a monoclonal antibody to CD154 (CD40 ligand) suppression of an immune response in monkeys. J Pharmacol Exp Ther 1998; 286:925–30.PubMedGoogle Scholar
  122. 122.
    Kirk AD, Burkly LC, Batty DS et al. Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates. Nat Med 1999; 5:686–93.PubMedCrossRefGoogle Scholar
  123. 123.
    Cho CS, Burkly LC, Fechner JH Jr, et al. Successful conversion from conventional immunosuppression to anti-CD154 monoclonal antibody costimulatory molecule blockade in rhesus renal allograft recipients. Transplantation 2001; 72:587–97.PubMedCrossRefGoogle Scholar
  124. 124.
    Xu H, Tadaki DK, Elster EA et al. Humanized anti-CD154 antibody therapy for the treatment of allograft rejection in nonhuman primates. Transplantation 2002; 74:940–3.PubMedCrossRefGoogle Scholar
  125. 125.
    Kenyon NS, Chatzipetrou M, Masetti M et al. Long-term survival and function of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CD154. Proc Natl Acad Sci USA 1999; 96:8132–7.PubMedCrossRefGoogle Scholar
  126. 126.
    Kenyon NS, Fernandez LA, Lehmann R et al. Long-term survival and function of intrahepatic islet allografts in baboons treated with humanized anti-CD154. Diabetes 1999; 48:1473–81.PubMedCrossRefGoogle Scholar
  127. 127.
    Pierson RN 3rd, Chang AC, Blum MG et al. Prolongation of primate cardiac allograft survival by treatment with ANTI-CD40 ligand (CD154) antibody. Transplantation 1999; 68:1800–5.PubMedCrossRefGoogle Scholar
  128. 128.
    Elster EA, Xu H, Tadaki DK et al. Treatment with the humanized CD154-specific monoclonal antibody, hu5C8, prevents acute rejection of primary skin allografts in nonhuman primates. Transplantation 2001; 72:1473–8.PubMedCrossRefGoogle Scholar
  129. 129.
    Jochum C, Beste M, Zellmer E et al. CD154 blockade and donor-specific transfusions in DLA-identical marrow transplantation in dogs conditioned with 1-Gy total body irradiation. Biol Blood Marrow Transplant 2007; 13:164–71.PubMedCrossRefGoogle Scholar
  130. 130.
    Huang W, Sinha J, Newman J et al. The effect of anti-CD40 ligand antibody on B-cells in human systemic lupus erythematosus. Arthritis Rheum 2002; 46:1554–62.PubMedCrossRefGoogle Scholar
  131. 131.
    Boumpas DT, Furie R, Manzi S 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 2003; 48:719–27.PubMedCrossRefGoogle Scholar
  132. 132.
    Grammer AC, Slota R, Fischer R et al. Abnormal germinal center reactions in systemic lupus erythematosus demonstrated by blockade of CD154-CD40 interactions. J Clin Invest 2003; 112:1506–20.PubMedGoogle Scholar
  133. 133.
    Brams P, Black A, Padlan EA et al. A humanized anti-human CD154 monoclonal antibody blocks CD154-CD40 mediated human B-cell activation. Int Immunopharmacol 2001; 1:277–94.PubMedCrossRefGoogle Scholar
  134. 134.
    Crowe JE Jr, Sannella EC, Pfeiffer S et al. CD154 regulates primate humoral immunity to influenza. Am J Transplant 2003; 3:680–8.PubMedCrossRefGoogle Scholar
  135. 135.
    Xu H, Montgomery SP, Preston EH et al. Studies investigating pretransplant donor-specific blood transfusion, rapamycin and the CD154-specific antibody IDEC-131 in a nonhuman primate model of skin allotransplantation. J Immunol 2003; 170:2776–82.PubMedGoogle Scholar
  136. 136.
    Azimzadeh AM, Pfeiffer S, Wu G et al. Alloimmunity in primate heart recipients with CD154 blockade: evidence for alternative costimulation mechanisms. Transplantation 2006; 81:255–64.PubMedCrossRefGoogle Scholar
  137. 137.
    Preston EH, Xu H, Dhanireddy KK et al. IDEC-131 (anti-CD154), sirolimus and donor-specific transfusion facilitate operational tolerance in non-human primates. Am J Transplant 2005; 5:1032–41.PubMedCrossRefGoogle Scholar
  138. 138.
    Kuwana M, Nomura S, Fujimura K et al. Effect of a single injection of humanized anti-CD154 monoclonal antibody on the platelet-specific autoimmune response in patients with immune thrombocytopenic purpura. Blood 2004; 103:1229–36.PubMedCrossRefGoogle Scholar
  139. 139.
    Nomura S, Uehata S, Saito S et al. Enzyme immunoassay detection of platelet-derived microparticles and RANTES in acute coronary syndrome. Thromb Haemost 2003; 89:506–12.PubMedGoogle Scholar
  140. 140.
    Davis JC Jr, Totoritis MC, Rosenberg J et al. Phase I clinical trial of a monoclonal antibody against CD40-ligand (IDEC-131) in patients with systemic lupus erythematosus. J Rheumatol 2001; 28:95–101.PubMedGoogle Scholar
  141. 141.
    Kalunian KC, Davis JC Jr, Merrill JT 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 2002; 46:3251–8.PubMedCrossRefGoogle Scholar
  142. 142.
    Schuler W, Bigaud M, Brinkmann V et al. Efficacy and safety of ABI793, a novel human anti-human CD154 monoclonal antibody, in cynomolgus monkey renal allotransplantation. Transplantation 2004; 77:717–26.PubMedCrossRefGoogle Scholar
  143. 143.
    Kanmaz T, Fechner JJ Jr, Torrealba J et al. Monotherapy with the novel human anti-CD154 monoclonal antibody ABI793 in rhesus monkey renal transplantation model. Transplantation 2004; 77:914–20.PubMedCrossRefGoogle Scholar
  144. 144.
    Knosalla C, Ryan DJ, Moran K et al. Initial experience with the human anti-human CD154 monoclonal antibody, ABI793, in pig-to-baboon xenotransplantation. Xenotransplantation 2004; 11:353–60.PubMedCrossRefGoogle Scholar
  145. 145.
    Kawai T, Andrews D, Colvin RB et al. Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand. Nat Med 2000; 6:114.CrossRefGoogle Scholar
  146. 146.
    Buhler L, Alwayn IP, Appel JZ 3rd et al. Anti-CD154 monoclonal antibody and thromboembolism. Transplantation 2001; 71:491.PubMedCrossRefGoogle Scholar
  147. 147.
    Roth GA, Zuckermann A, Klepetko W et al. Thrombophilia associated with anti-CD154 monoclonal antibody treatment and its prophylaxis in nonhuman primates. Transplantation 2004; 78:1238–9; author reply 39.PubMedCrossRefGoogle Scholar
  148. 148.
    Knosalla C, Gollackner B, Cooper DK. Anti-CD154 monoclonal antibody and thromboembolism revisted. Transplantation 2002; 74:416–7PubMedCrossRefGoogle Scholar
  149. 149.
    Koyama I, Kawai T, Andrews D et al. Thrombophilia associated with anti-CD154 monoclonal antibody treatment and its prophylaxis in nonhuman primates. Transplantation 2004; 77:460–2.PubMedCrossRefGoogle Scholar
  150. 150.
    Sanchez-Fueyo A, Domenig C, Strom TB et al. The complement dependent cytotoxicity (CDC) immune effector mechanism contributes to anti-CD154 induced immunosuppression. Transplantation 2002; 74:898–900.PubMedCrossRefGoogle Scholar
  151. 151.
    Monk NJ, Hargreaves RE, Marsh JE et al. Fc-dependent depletion of activated T-cells occurs through CD40L-specific antibody rather than costimulation blockade. Nat Med 2003; 9:1275–80.PubMedCrossRefGoogle Scholar
  152. 152.
    Ferrant JL, Benjamin CD, Cutler AH et al. The contribution of Fc effector mechanisms in the efficacy of anti-CD154 immunotherapy depends on the nature of the immune challenge. Int Immunol 2004; 16:1583–94.PubMedCrossRefGoogle Scholar
  153. 153.
    Waldmann H. The new immunosuppression: just kill the T-cell. Nat Med 2003; 9:1259–60.PubMedCrossRefGoogle Scholar
  154. 154.
    Nagelkerken L, Haspels I, van Rijs W et al. FcR interactions do not play a major role in inhibition of experimental autoimmune encephalomyelitis by anti-CD154 monoclonal antibodies. J Immunol 2004; 173:993–9.PubMedGoogle Scholar
  155. 155.
    Schuler W, Bigaud M, Di Padova F et al. ABI793, a novel, fully human anti-CD154 monoclonal antibody: efficacy in cynomolgus monkey kidney allo-transplantation. Am J Transpl 2003; 3:290.Google Scholar
  156. 156.
    Armour KL, van de Winkel JG, Williamson LM et al. Differential binding to human FcgammaRIIa and FcgammaRIIb receptors by human IgG wildtype and mutant antibodies. Mol Immunol 2003; 40:585–93.PubMedCrossRefGoogle Scholar
  157. 157.
    Schuler W, Bigaud M, Gram H et al. Efficacy of human anti-human CD154 monoclonal antibodies in allotransplantation is dependent on Fc-mediated effector functions. 12th International Congress of Immunology 2004: Abstract # 3117.Google Scholar
  158. 158.
    Shields RL, Namenuk AK, Hong K et al. High resolution mapping of the binding site on human IgG 1 for Fc gamma RI, Fc gamma RII, Fc gamma RIII and FcRn and design of IgG1 variants with improved binding to the Fc gamma R. J Biol Chem 2001; 276:6591–604.PubMedCrossRefGoogle Scholar
  159. 159.
    Presta LG. Engineering of therapeutic antibodies to minimize immunogenicity and optimize function. Adv Drug Deliv Rev 2006; 58:640–56.PubMedCrossRefGoogle Scholar
  160. 160.
    Blick SK, Curran MP. Certolizumab pegol: in Crohn’s disease. BioDrugs 2007; 21:195–201; discussion 02–3.PubMedCrossRefGoogle Scholar
  161. 161.
    Molineux G. The design and development of pegfilgrastim (PEG-rmetHuG-CSF, Neulasta). Curr Pharm Des 2004; 10:1235–44.PubMedCrossRefGoogle Scholar
  162. 162.
    Wang YS, Youngster S, Grace M et al. Structural and biological characterization of pegylated recombinant interferon alpha-2b and its therapeutic implications. Adv Drug Deliv Rev 2002; 54:547–70.PubMedCrossRefGoogle Scholar
  163. 163.
    Allen SD, Rawale SV, Whitacre CC et al. Therapeutic peptidomimetic strategies for autoimmune diseases: costimulation blockade. J Pept Res 2005; 65:591–604.PubMedCrossRefGoogle Scholar
  164. 164.
    Fournel S, Wieckowski S, Sun W et al. C3-symmetric peptide scaffolds are functional mimetics of trimeric CD40L. Nat Chem Biol 2005; 1:377–82.PubMedCrossRefGoogle Scholar
  165. 165.
    Kitagawa M, Goto D, Mamura M et al. Identification of three novel peptides that inhibit CD40-CD154 interaction. Mod Rheumatol 2005; 15:423–6.PubMedCrossRefGoogle Scholar
  166. 166.
    Hargreaves RE, Monk NJ, Jurcevic S. Selective depletion of activated T-cells: the CD40L-specific antibody experience. Trends Mol Med 2004; 10:130–5.PubMedCrossRefGoogle Scholar
  167. 167.
    McEarchern JA, Oflazoglu E, Francisco L et al. Engineered anti-CD70 antibody with multiple effector functions exhibits in vitro and in vivo antitumor activities. Blood 2007; 109:1185–92.PubMedCrossRefGoogle Scholar
  168. 168.
    Wu AM, Senter PD. Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol 2005; 23:1137–46.PubMedCrossRefGoogle Scholar
  169. 169.
    Pagano L, Fianchi L, Caira M et al. The role of gemtuzumab ozogamicin in the treatment of acute myeloid leukemia patients. Oncogene 2007; 26:3679–90.PubMedCrossRefGoogle Scholar
  170. 170.
    Wong BY, Gregory, SA, Dang NH. Denileukin diftitox as novel targeted therapy for lymphoid malignancies. Cancer Invest 2007; 25:495–501.PubMedCrossRefGoogle Scholar
  171. 171.
    Francisco JA, Cerveny CG, Meyer DL et al. cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood 2003; 102:1458–65.PubMedCrossRefGoogle Scholar
  172. 172.
    Law CL, Gordon KA, Toki BE et al. Lymphocyte activation antigen CD70 expressed by renal cell carcinoma is a potential therapeutic target for anti-CD70 antibody-drug conjugates. Cancer Res 2006; 66:2328–37.PubMedCrossRefGoogle Scholar
  173. 173.
    Ziebold JL, Hixon J, Boyd A et al. Differential effects of CD40 stimulation on normal and neoplastic cell growth. Arch Immunol Ther Exp (Warsz) 2000; 48:225–33.Google Scholar
  174. 174.
    Costello RT, Gastaut JA, Olive D. What is the real role of CD40 in cancer immunotherapy? Immunol Today 1999; 20:488–93.PubMedCrossRefGoogle Scholar
  175. 175.
    Clark EA, Ledbetter JA. Activation of human B-cells mediated through two distinct cell surface differentiation antigens, Bp35 and Bp50. Proc Natl Acad Sci USA 1986; 83:4494–8.PubMedCrossRefGoogle Scholar
  176. 176.
    Inui S, Kaisho T, Kikutani H et al. Identification of the intracytoplasmic region essential for signal transduction through a B-cell activation molecule, CD40. Eur J Immunol 1990; 20:1747–53.PubMedCrossRefGoogle Scholar
  177. 177.
    Heath AW, Chang R, Harada N et al. Antibodies to murine CD40 stimulate normal B-lymphocytes but inhibit proliferation of B-lymphoma cells. Cell Immunol 1993; 152:468–80.PubMedCrossRefGoogle Scholar
  178. 178.
    Funakoshi S, Longo DL, Murphy WJ. Differential in vitro and in vivo antitumor effects mediated by anti-CD40 and anti-CD20 monoclonal antibodies, against human B-cell lymphomas. J Immunother Emphasis Tumor Immunol 1996; 19:93.PubMedGoogle Scholar
  179. 179.
    Funakoshi S, Longo DL, Murphy WJ. Differential in vitro and in vivo antitumor effects mediated by anti-CD40 and anti-CD20 monoclonal antibodies against human B-cell lymphomas. J Immunother Emphasis Tumor Immunol 1996; 19: 93PubMedGoogle Scholar
  180. 180.
    Francisco JA, Donaldson KL, Chace D et al. Agonistic properties and in vivo antitumor activity of the anti-CD40 antibody SGN-14. Cancer Res 2000; 60:3225–31.PubMedGoogle Scholar
  181. 181.
    Szocinski JL, Khaled AR, Hixon J et al. Activation-induced cell death of aggressive histology lymphomas by CD40 stimulation: induction of bax. Blood 2002; 100:217–23.PubMedCrossRefGoogle Scholar
  182. 182.
    Garrone P, Neidhardt EM, Garcia E et al. Fas ligation induces apoptosis of CD40-activated human B-lymphocytes. J Exp Med 1995; 182:1265–73.PubMedCrossRefGoogle Scholar
  183. 183.
    Rothstein TL, Wang JK, Panka DJ et al. Protection against Fas-dependent Th1-mediated apoptosis by antigen receptor engagement in B-cells. Nature 1995; 374:163–5.PubMedCrossRefGoogle Scholar
  184. 184.
    Schattner EJ, Elkon KB, Yoo DH et al. CD40 ligation induces Apo-1/Fas expression on human B-lymphocytes and facilitates apoptosis through the Apo-1/Fas pathway. J Exp Med 1995; 182:1557–65.PubMedCrossRefGoogle Scholar
  185. 185.
    Schattner EJ, Mascarenhas J, Bishop J et al. CD4+ T-cell induction of Fas-mediated apoptosis in Burkitt’s lymphoma B-cells. Blood 1996; 88:1375–82.PubMedGoogle Scholar
  186. 186.
    Wang D, Freeman GJ, Levine H et al. Role of the CD40 and CD95 (APO-1/Fas) antigens in the apoptosis of human B-cell malignancies. Br J Haematol 1997; 97:409–17.PubMedCrossRefGoogle Scholar
  187. 187.
    Iuczynski W, Kowalczuk O, Ilendo E et al. CD40L and IL-4 stimulation of acute lymphoblastic leukemia cells results in upregulation of mRNA level of FLICE—an important component of apoptosis. Folia Histochem Cytobiol 2007; 45:15–20.Google Scholar
  188. 188.
    Segui B, Andrieu-Abadie N, Adam-Klages S et al. CD40 signals apoptosis through FAN-regulated activation of the sphingomyelin-ceramide pathway. J Biol Chem 1999; 274:37251–8.PubMedCrossRefGoogle Scholar
  189. 189.
    Hollmann CA, Owens T, Nalbantoglu J et al. Constitutive activation of extracellular signal-regulated kinase predisposes diffuse large B-cell lymphoma cell lines to CD40-mediated cell death. Cancer Res 2006; 66:3550–7.PubMedCrossRefGoogle Scholar
  190. 190.
    Hollmann AC, Gong Q, Owens T. CD40-mediated apoptosis in murine B-lymphoma lines containing mutated p53. Exp Cell Res 2002; 280:201–11.PubMedCrossRefGoogle Scholar
  191. 191.
    Dicker F, Kater AP, Prada CE et al. CD154 induces p73 to overcome the resistance to apoptosis of chronic lymphocytic leukemia cells lacking functional p53. Blood 2006; 108:3450–7.PubMedCrossRefGoogle Scholar
  192. 192.
    Lotz M, Ranheim E, Kipps TJ. Transforming growth factor beta as endogenous growth inhibitor of chronic lymphocytic leukemia B-cells. J Exp Med 1994; 179:999–1004.PubMedCrossRefGoogle Scholar
  193. 193.
    Planken EV, Dijkstra NH, Willemze R et al. Proliferation of B-cell malignancies in all stages of differentiation upon stimulation in the ‘CD40 system’. Leukemia 1996; 10:488–93.PubMedGoogle Scholar
  194. 194.
    Younes A, Snell V, Consoli U et al. Elevated levels of biologically active soluble CD40 ligand in the serum of patients with chronic lymphocytic leukaemia. Br J Haematol 1998; 100:135–41.PubMedCrossRefGoogle Scholar
  195. 195.
    Kitada S, Zapata JM, Andreeff M et al. Bryostatin and CD40-ligand enhance apoptosis resistance and induce expression of cell survival genes in B-cell chronic lymphocytic leukaemia. Br J Haematol 1999; 106:995–1004.PubMedCrossRefGoogle Scholar
  196. 196.
    Schattner EJ. CD40 ligand in CLL pathogenesis and therapy. Leuk Lymphoma 2000; 37:461–72.PubMedGoogle Scholar
  197. 197.
    Romano MF, Lamberti A, Tassone P et al. Triggering of CD40 antigen inhibits fludarabine-induced apoptosis in B chronic lymphocytic leukemia cells. Blood 1998; 92:990–5.PubMedGoogle Scholar
  198. 198.
    Ranheim EA, Kipps TJ. Activated T-cells induce expression of B7/BB1 on normal or leukemic B-cells through a CD40-dependent signal. J Exp Med 1993; 177:925–35.PubMedCrossRefGoogle Scholar
  199. 199.
    Van den Hove LE, Van Gool SW, Vandenberghe P et al. CD40 triggering of chronic lymphocytic leukemia B-cells results in efficient alloantigen presentation and cytotoxic T-lymphocyte induction by up-regulation of CD80 and CD86 costimulatory molecules. Leukemia 1997; 11:572–80.PubMedCrossRefGoogle Scholar
  200. 200.
    Wierda WG, Kipps TJ. Gene therapy and active immune therapy of hematologic malignancies. Best Pract Res Clin Haematol 2007; 20:557–68.PubMedCrossRefGoogle Scholar
  201. 201.
    Takahashi S, Yotnda P, Rousseau RF et al. Transgenic expression of CD40L and interleukin-2 induces an autologous antitumor immune response in patients with non-Hodgkin’s lymphoma. Cancer Gene Ther 2001; 8:378–87.PubMedCrossRefGoogle Scholar
  202. 202.
    Willimott S, Baou M, Naresh K et al. CD154 induces a switch in pro-survival Bcl-2 family members in chronic lymphocytic leukaemia. Br J Haematol 2007; 138:721–32.PubMedCrossRefGoogle Scholar
  203. 203.
    de Totero D, Tazzari PL, Capaia M et al. CD40 triggering enhances fludarabine-induced apoptosis of chronic lymphocytic leukemia B-cells through autocrine release of tumor necrosis factor-alpha and interferon-gama and tumor necrosis factor receptor-I-II upregulation. Haematologica 2003; 88:148–58.PubMedGoogle Scholar
  204. 204.
    Dicker F, Kater AP, Fukuda T et al. Fas-ligand (CD178) and TRAIL synergistically, induce apoptosis of CD40-activated chronic lymphocytic leukemia B-cells. Blood 2005; 105:3193–8.PubMedCrossRefGoogle Scholar
  205. 205.
    Kater AP, Dicker F, Mangiola M et al. Inhibitors of XIAP sensitize CD40-activated chronic lymphocytic leukemia cells to CD95-mediated apoptosis. Blood 2005; 106:1742–8.PubMedCrossRefGoogle Scholar
  206. 206.
    de Totero D, Meazza R, Zupo S et al. Interleukin-21 receptor (IL-21R) is up-regulated by CD40 triggering and mediates proapoptotic signals in chronic lymphocytic leukemia B-cells. Blood 2006; 107:3708–15.PubMedCrossRefGoogle Scholar
  207. 207.
    Tong AW, Zhang BQ, Mues G et al. Anti-CD40 antibody binding modulates human multiple myeloma clonogenicity in vitro. Blood 1994; 84:3026–33.PubMedGoogle Scholar
  208. 208.
    Westendorf JJ, Ahmann GJ, Armitage RJ et al. CD40 expression in malignant plasma cells. Role in stimulation of autocrine IL-6 secretion by a human myeloma cell line. J Immunol 1994; 152:117–28.PubMedGoogle Scholar
  209. 209.
    Zhou ZH, Wang JF, Wang YD et al. An agonist anti-human CD40 monoclonal antibody that induces dendritic cell formation and maturation and inhibits proliferation of a myeloma cell line. Hybridoma 1999; 18:471–8.PubMedGoogle Scholar
  210. 210.
    Pellat-Deceunynck C, Amiot M, Robillard N et al. CD11a-CD18 and CD102 interactions mediate human myeloma cell growth arrest induced by CD40 stimulation. Cancer Res 1996; 56:1909–16.PubMedGoogle Scholar
  211. 211.
    Bergamo A Bataille R, Pellat-Deceunynck C CD40 and CD95 induce programmed cell death in the human myeloma cell line XG2. Br J Haematol 1997; 97:652–55.PubMedCrossRefGoogle Scholar
  212. 212.
    Tai YT, Catley LP, Mitsiades CS et al. Mechanisms by which SGN-40, a humanized anti-CD40 antibody, induces cytotoxicity in human multiple myeloma cells: clinical implications. Cancer Res 2004; 64:2846–52.PubMedCrossRefGoogle Scholar
  213. 213.
    Tai YT, Li XF, Catley L et al. Immunomodulatory drug lenalidomide (CC-5013, IMiD3) augments anti-CD40 SGN-40-induced cytotoxicity in human multiple myeloma: clinical implications. Cancer Res 2005; 65: 11712–20.PubMedCrossRefGoogle Scholar
  214. 214.
    Hess S, Engelmann H. A novel function of CD40: induction of cell death in transformed cells. J Exp Med 1996; 183:159–67.PubMedCrossRefGoogle Scholar
  215. 215.
    Hirano A, Longo DL, Taub DD et al. Inhibition of human breast carcinoma growth by a soluble recombinant human CD40 ligand. Blood 1999; 93:2999–3007.PubMedGoogle Scholar
  216. 216.
    Alexandroff AB, Jackson AM, Paterson T et al. Role for CD40-CD40 ligand interactions in the immune response to solid tumours. Mol Immunol 2000; 37:515–26.PubMedCrossRefGoogle Scholar
  217. 217.
    Tong AW, Stone MJ. Prospects for CD40-directed experimental therapy of human cancer. Cancer Gene Ther 2003; 10:1–13.PubMedCrossRefGoogle Scholar
  218. 218.
    Ghamande S, Hylander BL, Oflazoglu E et al. Recombinant CD40 ligand therapy has significant antitumor effects on CD40-positive ovarian tumor xenografts grown in SCID mice and demonstrates an augmented effect with cisplatin. Cancer Res 2001; 61:7556–62.PubMedGoogle Scholar
  219. 219.
    Gallagher NJ, Eliopoulos AG, Agathangelo A et al. CD40 activation in epithelial ovarian carcinoma cells modulates growth, apoptosis and cytokine secretion. Mol Pathol 2002; 55:110–20.PubMedCrossRefGoogle Scholar
  220. 220.
    Elipoulos AG, Davies C, Knox PG et al. CD40 induces apoptosis in carcinoma cells through activation of cytotoxic ligands of the tumor necrosis factor superfamily. Mol Cell Biol 2000; 20: 5503–15.CrossRefGoogle Scholar
  221. 221.
    Elipoulos AG, Dawson CW, Mosialos G et al. CD40-induced growth inhibition in epithelial cells is mimicked by Epstein-Barr Virus-encoded LMP1: involvement of TRAF3 as a common mediator. Oncogene 1996; 13:2243–54.Google Scholar
  222. 222.
    Eliopoulos AG, Stack M, Dawson CW et al. Epstein-Barr virus-encoded LMP1 and CD40 mediate IL-6 production in epithelial cells via an NF-kappaB pathway involving TNF receptor-associated factors. Oncogene 1997; 14:2899–916.PubMedCrossRefGoogle Scholar
  223. 223.
    Mackey MF, Gunn JR, Ting PP et al. Protective immunity induced by tumor vaccines requires interaction between CD40 and its ligand, CD154. Cancer Res 1997; 57:2569–74.PubMedGoogle Scholar
  224. 224.
    van Mierlo GJ, den Boer AT, Medema JP et al. CD40 stimulation leads to effective therapy of CD40(−) tumors through induction of strong systemic cytotoxic T-lymphocyte immunity. Proc Natl Acad Sci USA 2002; 99:5561–6.PubMedCrossRefGoogle Scholar
  225. 225.
    Antonia SJ, Extermann M, Flavell RA. Immunologic nonresponsiveness to tumors. Crit Rev Oncog 1998; 9:35–41.PubMedGoogle Scholar
  226. 226.
    Yamada M, Shiroko T, Kawaguchi Y et al. CD40-CD40 ligand (CD154) engagement is required but not sufficient for modulating MHC class I, ICAM-1 and Fas expression and proliferation of human non-small cell lung tumors. Int J Cancer 2001; 92:589–99.PubMedCrossRefGoogle Scholar
  227. 227.
    Gruss HJ, Hirschstein D, Wright B et al. Expression and function of CD40 on Hodgkin and Reed-Sternberg cells and the possible relevance for Hodgkin’s disease. Blood 1994 84:2305–14.PubMedGoogle Scholar
  228. 228.
    Gruss HJ, Ulrich D, Braddy S et al. Recombinant CD30 ligand and CD40 ligand share common biological activities on Hodgkin and Reed-Sternberg cells. Eur J Immunol 1995; 25:2083–9.PubMedCrossRefGoogle Scholar
  229. 229.
    Barr TA, Heath AW. Functional activity of CD40 antibodies correlates to the position of binding relative to CD154. Immunology 2001; 102:39–43.PubMedCrossRefGoogle Scholar
  230. 230.
    Malmborg Hager AC, Ellmark P, Borrebaeck CA et al. Affinity and epitope profiling of mouse anti-CD40 monoclonal antibodies. Scand J Immunol 2003; 57:517–24.CrossRefGoogle Scholar
  231. 231.
    Bjorck P, Braesch-Andersen S, Paulie S. Antibodies to distinct epitopes on the CD40 molecule co-operate in stimulation and can be used for the detection of soluble CD40. Immunology 1994; 83:430–37.PubMedGoogle Scholar
  232. 232.
    Pound JD, Challa A, Holder MJ et al. Minimal cross-linking and epitope requirements for CD40-dependent suppression of apoptosis contrast with those for promotion of the cell cycle and homotypic adhesions in human B-cells. Int Immunol 1999; 11:11–20.PubMedCrossRefGoogle Scholar
  233. 233.
    Schwabe RF, Hess S, Johnson JP et al. Modulation of soluble CD40 ligand bioactivity with anti-CD40 antibodies. Hybridoma 1997; 16:217–26.PubMedCrossRefGoogle Scholar
  234. 234.
    Kwekkeboom J, De Boer M, Tager JM et al. CD40 plays an essential role in the activation of human B-cells by murine EL4B5 cells. Immunology 1993; 79:439–44.PubMedGoogle Scholar
  235. 235.
    Bjorck P, Paulie S. CD40 antibodies defining distinct epitopes display qualitative differences in their induction of B-cell differentiation. Immunology 1996; 87:291–5.PubMedCrossRefGoogle Scholar
  236. 236.
    Challa A, Pound JD, Armitage RJ et al. Epitope-dependent synergism and antagonism between CD40 antibodies and soluble CD40 ligand for the regulation of CD23 expression and IgE synthesis in human B-cells. Allergy 1999; 54:576–83.PubMedCrossRefGoogle Scholar
  237. 237.
    Hasbold J, Johnson-Leger C, Atkins CJ et al. Properties of mouse CD40: cellular distribution of CD40 and B-cell activation by monoclonal anti-mouse CD40 antibodies. Eur J Immunol 1994; 24:1835–42.PubMedCrossRefGoogle Scholar
  238. 238.
    Heath AW, Wu WW, Howard MC. Monoclonal antibodies to murine CD40 define two distinct functional epitopes. Eur J Immunol 1994; 24:1828–34.PubMedCrossRefGoogle Scholar
  239. 239.
    Morris, AE, Remmele RL Jr, Klinke R et al. Incorporation of an isoleucine zipper motif enhances the biological activity of soluble CD40L (CD154). J Biol Chem 1999; 274:418–23.PubMedCrossRefGoogle Scholar
  240. 240.
    Vonderheide RH, Dutcher JP, Anderson JE et al. Phase I study of recombinant human CD40 ligand in cancer patients. J Clin Oncol 2001; 19:3280–7.PubMedGoogle Scholar
  241. 241.
    Schultze JL, Anderson KC, Gilleece MH et al. A pilot study of combined immunotherapy with autologous adoptive tumour-specific T-cell transfer, vaccination with CD40-activated malignant B-cells and interleukin 2. Br J Haematol 2001; 113:455–60.PubMedCrossRefGoogle Scholar
  242. 242.
    Wierda WG, Cantwell MJ, Woods SJ et al. CD40-ligand (CD154) gene therapy for chronic lymphocytic leukemia. Blood 2000; 96:2917–24.PubMedGoogle Scholar
  243. 243.
    Younes A. CD40 ligand therapy of lymphoma patients. J Clin Oncol 2001; 19:4351–3.PubMedGoogle Scholar
  244. 244.
    Koho H, Paulie S, Ben Aissa H et al. Monoclonal antibodies to antigens associated with transitional cell carcinoma of the human urinary bladder. I. Determination of the selectivity of six antibodies by cell ELISA and immunofluorescence. Cancer Immunol Immunother 1984; 17:165–72.PubMedCrossRefGoogle Scholar
  245. 245.
    Paulie S, Koho H, Ben Aissa H et al. Monoclonal antibodies to antigens associated with transitional cell carcinoma of the human urinary bladder. II. Identification of the cellular target structures by immunoprecipitation and SDS-PAGE analysis. Cancer Immunol Immunother 1984; 17:173–9.PubMedCrossRefGoogle Scholar
  246. 246.
    Paulie S, Ehlin-Henriksson B, Mellstedt H et al. A p50 surface antigen restricted to human urinary bladder carcinomas and B-lymphocytes. Cancer Immunol Immunother 1985; 20:23–8.PubMedCrossRefGoogle Scholar
  247. 247.
    Shorts L, Weiss JM, Lee JK et al. Stimulation through CD40 on mouse and human renal cell carcinomas triggers cytokine production, leukocyte recruitment and antitumor responses that can be independent of host CD40 expression. J Immunol 2006; 176:6543–52.PubMedGoogle Scholar
  248. 248.
    Hayashi T, Treon SP, Hideshima T et al. Recombinant humanized anti-CD40 monoclonal antibody triggers autologous antibody-dependent cell-mediated cytotoxicity against multiple myeloma cells. Br J Haematol 2003; 121:592–6.PubMedCrossRefGoogle Scholar
  249. 249.
    Law CL, Gordon KA, Collier J et al. Preclinical antilymphema activity of a humanized anti-CD40 monoclonal antibody, SGN-40. Cancer Res 2005; 65:8331–8.PubMedCrossRefGoogle Scholar
  250. 250.
    Law C-L, McEarchern JA, Cerveny CG et al. The humanized anti-CD40 monoclonal antibody SGN-40 targets hodgkin’s disease cells through multiple mechanisms. Blood 2005; 106: Abstract # 1476.Google Scholar
  251. 251.
    Lewis TS, Sutherland MSK, Jonas M et al. The humanized anti-CD40 antibody, SGN-40, promotes apoptosis signaling and is effective in combination with standard therapies in lymphoma xenograft models. Blood 2006; 108: Abstract # 2499.Google Scholar
  252. 252.
    Hussein MA, Berenson JR, Niesvizky R et al. Results of a phase I trial of SGN-40 (Anti-huCD40 mAb) in patients with relapsed multiple myeloma. Blood 2006; 108: Abstract # 3576.Google Scholar
  253. 253.
    Kelley SK, Gelzleichter T, Xie D et al. Preclinical pharmacokinetics, pharmacodynamics and activity of a humanized anti-CD40 antibody (SGN-40) in rodents and non-human primates. Br J Pharmacol 2006; 148:1116–23.PubMedCrossRefGoogle Scholar
  254. 254.
    Advani R, Forero-Torres A, Furman RR et al. SGN-40 (Anti-huCD40 mAb) monotherapy induces durable objective responses in patients with relapsed aggressive non-Hodgkins lymphoma: evidence of antitumor activity from a phase I study. Blood 2006; 108: Abstract # 695.Google Scholar
  255. 255.
    Long L, Patawaran M, Tong X et al. Efficacy of an antagonistic anti-CD40 monoclonal antibody, HCD122 (CHIR-12.12), in preclinical models of human non-Hodgkins lymphoma and Hodgkins disease. Blood 2006; 108: Abstract # 230.Google Scholar
  256. 256.
    Tai YT, Li X, Tong X et al. Human anti-CD40 antagonist antibody triggers significant antitumor activity against human multiple myeloma. Cancer Res 2005; 65:5898–906.PubMedCrossRefGoogle Scholar
  257. 257.
    Hsu SJ, Esposito LA, Aukerman SL et al. HCD 122, an antagonist human anti-CD40 monoclonal antibody, inhibits tumor growth in xenograft models of human diffuse large B-cell lymphoma, a subset of non-Hodgkins lymphoma. Blood 2006; 108: Abstract # 2519.Google Scholar
  258. 258.
    Tong X, Georgakis GV, Long L et al. In vitro activity of a novel fully human anti-CD40 antibody CHIR-12. 12 in chronic lymphocytic leukemia: blockade of CD40 activation and induction of ADCC. Blood 2004; 104: Abstract # 2504.Google Scholar
  259. 259.
    Weng W-K, Tong X, Luqman M et al. A fully human anti-CD40 antagonistic antibody, CHIR-12.12, inhibit the proliferation of human B-cell non-Hodgkin’s lymphoma. Blood 2004; 104: Abstract # 3279.Google Scholar
  260. 260.
    Jeffry UB, Huh K, Tong X et al. Safety evaluation of an fully human antagonist anti-CD40 antibody, CHIR-12. 12, in a dose range-finding study in cynomologus monkeys. Blood 2004; 104: Abstract # 3282.Google Scholar
  261. 261.
    Jeffry UB, Luqman M, Huh K et al. Immunological profile and safety evaluation in a 23-week single dose study in cynomolgus monkey with CHIR-12. 12, a fully human antagonist anti-CD40 antibody. Blood 2004; 104: Abstract # 4638.Google Scholar
  262. 262.
    Byrd JC, Flinn IW, Khan KD et al. Pharmacokinetics and Pharmacodynamics from a first-in-human phase 1 dose escalation study with antagonist anti-CD40 antibody, HCD122 (Formerly CHIR-12. 12), in patients with relapsed and refractory chronic lymphocytic leukemia. Blood 2006; 108: Abstract # 2837.Google Scholar
  263. 263.
    Bensinger W, Jagannath S, Becker PS et al. A phase 1 dose escalation study of a fully human, antagonist anti-CD40 antibody, HCD122 (Formerly CHIR-12. 12) in patients with relapsed and refractory multiple myeloma. Blood 2006; 108: Abstract # 3575.Google Scholar
  264. 264.
    de Boer M, Conroy L, Min HY et al. Generation of monoclonal antibodies to human lymphocyte cell surface antigens using insect cells expressing recombinant proteins. J Immunol Methods 1992; 152: 15–23.PubMedCrossRefGoogle Scholar
  265. 265.
    Kwekkeboom J, de Rijk D, Kasran A et al. Helper effector function of human T-cells stimulated by anti-CD3 mAb can be enhanced by costimulatory signals and is partially dependent on CD40-CD40 ligand interaction. Eur J Immunol 1994; 24:508–17.PubMedCrossRefGoogle Scholar
  266. 266.
    Laman JD, t Hart BA, Brok H et al. Protection of marmoset monkeys against EAE by treatment with a murine antibody blocking CD40 (mu5D12). Eur J Immunol 2002; 32:2218–28.PubMedCrossRefGoogle Scholar
  267. 267.
    Boon L, Laman JD, Ortiz-Buijsse A et al. Preclinical assessment of anti-CD40 Mab 5D12 in cynomolgus monkeys. Toxicology 2002; 174:53–65.PubMedCrossRefGoogle Scholar
  268. 268.
    Boon L, Brok HP, Bauer J et al. Prevention of experimental auto immune encephalomyelitis in the common marmoset (Callithrix jacchus) using a chimeric antagonist monoclonal antibody against human CD40 is associated with altered B-cell responses. J Immunol 2001; 167:2942–9.PubMedGoogle Scholar
  269. 269.
    t Hart BA, Blezer EL, Brok HP 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 2005; 163:31–9.PubMedCrossRefGoogle Scholar
  270. 270.
    de Vos AF, Melief MJ, van Riel D et al. Antagonist anti-human CD40 antibody inhibits germinal center formation in cynomolgus monkeys. Eur J Immunol 2004; 34:3446–55.PubMedCrossRefGoogle Scholar
  271. 271.
    Kasran A, Boon L, Wortel CH et al. Safety and tolerability of antagonist anti-human CD40 Mab ch5D12 in patients with moderate to severe Crohn’s disease. Aliment Pharmacol Ther 2005; 22:111–22.PubMedCrossRefGoogle Scholar
  272. 272.
    Hunter TB, Alsarraj M, Gladue RP et al. An agonist antibody specific for CD40 induces dendritic cell maturation and promotes autologous anti-tumour T-cell responses in an in vitro mixed autologous tumour cell/lymph node cell model. Scand J Immunol 2007; 65:479–86.PubMedCrossRefGoogle Scholar
  273. 273.
    Kimura K, Moriwaki H, Nagaki M et al. Pathogenic role of B-cells in anti-CD40-induced necroinflammatory liver disease. Am J Pathol 2006; 168:786–95.PubMedCrossRefGoogle Scholar
  274. 274.
    Kimura K, Nagaki M, Takai S et al. Pivotal role of nuclear factor kappaB signaling in anti-CD40-induced liver injury in mice. Hepatology 2004; 40:1180–9.PubMedCrossRefGoogle Scholar
  275. 275.
    Adams AB, Shirasugi N, Jones TR et al. Development of a chimeric anti-CD40 monoclonal antibody that synergizes with LEA29Y to prolong islet allograft survival. J Immunol 2005; 174:542–50.PubMedGoogle Scholar
  276. 276.
    Pearson TC, Trambley J, Odom K et al. Anti-CD40 therapy extends renal allograft survival in rhesus macaques. Transplantation 2002; 74:933–40.PubMedCrossRefGoogle Scholar
  277. 277.
    Geldart TR, Harvey M, Carr N et al. Cancer immunotherapy with a chimeric anti-CD40 monoclonal antibody: Evidence of preclinical efficacy. J Clin Oncol 2004; 22: Abstract # 2577.Google Scholar
  278. 278.
    Vonderheide RH, Flaherty KT, Khalil M et al. Clinical activity and immune modulation in cancer patients treated with CP-870, 893, a novel CD40 agonist monoclonal antibody. J Clin Oncol 2007; 25:876–83.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2009

Authors and Affiliations

  • Che-Leung Law
    • 1
  • Iqbal S. Grewal
    • 1
  1. 1.Department of Preclinical TherapeuticsSeattle Genetics Inc.BothellUSA

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