Discovery and mechanism of ustekinumab: A human monoclonal antibody targeting interleukin-12 and interleukin-23 for treatment of immune-mediated disorders

mAbs

Volumn 3, Issue 6, 2011, Pages

  Benson, Jacqueline M ^a   Peritt, David ^b   Scallon, Bernard J ^a   Heavner, George A ^a   Shealy, David J ^a   Giles Komar, Jill M ^a   Mascelli, Mary Ann ^c  

^a CENTOCOR INC   (United States)

^b Hospira Inc   (United States)

^c Biopharmaceutical Consultant   (United States)

Author keywords

Interleukin 12 23p40; Monoclonal antibody; Psoriasis; Ustekinumab

Indexed keywords

CHEMOKINE RECEPTOR CCR6; ETANERCEPT; GAMMA INTERFERON; IMMUNOGLOBULIN KAPPA CHAIN; INTERLEUKIN 12; INTERLEUKIN 13; INTERLEUKIN 17F; INTERLEUKIN 22; INTERLEUKIN 23; INTERLEUKIN 4; INTERLEUKIN 5; PLACEBO; STAT4 PROTEIN; STAT6 PROTEIN; TRANSCRIPTION FACTOR FOXP3; TRANSCRIPTION FACTOR GATA 3; USTEKINUMAB; MONOCLONAL ANTIBODY;

BINDING AFFINITY; CELL DIFFERENTIATION; CELL FUNCTION; CELL MATURATION; CROHN DISEASE; CYTOKINE PRODUCTION; DISEASE SEVERITY; DRUG EFFICACY; DRUG HALF LIFE; DRUG MECHANISM; DRUG PROTEIN BINDING; DRUG TARGETING; GENETIC VARIABILITY; HELPER CELL; HUMAN; HUMORAL IMMUNITY; IMMUNE DEFICIENCY; IMMUNIZATION; INJECTION SITE REACTION; LYMPHOCYTE; NATURAL KILLER CELL; NONHUMAN; PHASE 3 CLINICAL TRIAL (TOPIC); PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; PSORIATIC ARTHRITIS; REVIEW; SIGNAL TRANSDUCTION; TH17 CELL; ANIMAL; IMMUNOLOGY; MOUSE; PSORIASIS; TREATMENT OUTCOME;

ANIMALS; ANTIBODIES, MONOCLONAL; HUMANS; INTERLEUKIN-12; INTERLEUKIN-23; MICE; PSORIASIS; TREATMENT OUTCOME;

EID: 81255210898     PISSN: 19420862     EISSN: 19420870     Source Type: Journal    
DOI: 10.4161/mabs.3.6.17815     Document Type: Review

References (82)

1. Winau F, Westphal O, Winau R. Paul Ehrlich - in search of a magic bullet. Microbes Infect 2004; 6: 786-9.
2. Raju TN. The Nobel chronicles. 1972: Gerald M Edelman (b 1929) and Rodney R Porter (1917-85). Lancet 1999; 354:1040.
3. Orthoclone OKT® 3 prescribing information. www.janssenbiotech.com/ assets/OKT3-PI.pdf
4. Hansel TT, Kropshofer H, Singer T, Mitchell JA, George AJT. The safety and side effects of monoclonal antibodies. Nat Rev Drug Discov 2010; 9:325-38.
5. Reichert JM. Antibodies to watch in 2010. mAbs 2010; 2:84-100.
6. Rituximab prescribing information. www.gene.com/gene/products/ information/pdf/rituxan-prescribing.pdf
7. Abatacept prescribing information. packageinserts.bms.com/pi/pi-orencia. pdf
8. Kristensen M, Chu CQ, Eedy DJ, Feldmann M, Brennan FM, Breathnach SM. Localization of tumour necrosis factor-alpha (TNFalpha) and its receptors in normal and psoriatic skin: epidermal cells express the 55-kD but not the 75-kD TNF receptor. Clin Exp Immunol 1993; 94:354-62. (Pubitemid 23337840)
9. Koczan D, Drynda S, Hecker M, Drunda A, Guthke R, Kekow J, et al. Molecular discrimination of responders and nonresponders to anti-TNFalpha therapy in rheumatoid arthritis by etanercept. Arthritis Res Ther 2008; 10:R50.
10. Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: A comprehensive review. Pharmacol Ther 2008; 117:244-79.
11. Kobayashi M, Fitz L, Ryan M, Hewick RM, Clark SC, Chan S, et al. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med 1989; 170:827-45. (Pubitemid 19226667)
12. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 1986; 136:2348-57. (Pubitemid 16136806)
13. Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 2003; 3:133-46.
14. Fiorentino DF, Bond MW, Mosmann TR. Two types of mouse T helper cell IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med 1989; 170:2081-95.
15. Wilson NJ, Boniface K, Chan JR, McKenzie BS, Blumenschein WM, Mattson JD, et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol 2007; 8:950-7.
16. Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem 2003; 278:1910-4.
17. Duvallet E, Semerano L, Assier E, Falgarone G, Bossier MC. Interleukin-23: A key cytokine in inflammatory diseases. Ann Med 2011; 1-9.
18. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 2005; 201:233-40.
19. Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F. Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol 2007; 8:942-9.
20. Eijnden SV, Goriely S, De Wit D, Willems F, Goldman M. IL-23 upregulates IL-10 and induces IL-17 synthesis by polyclonally activated naïve T cells in human. Eur J Immunol 2005; 35:469-75.
21. + NK-like T cell function differentially from IL-12. Internat Immunol 2008; 21:145-53.
22. Rachitskaya AV, Hansen AM, Horai R, Li Z, Villasmil R, Luger D, et al. Cutting edge: NKT cells constitutively express IL-23 receptor and RORãô and rapidly produce IL-17 upon receptor ligation in an IL-6-independent fashion. J Immunol 2008; 180:5167-71.
23. Ness-Schwickerath KJ, Jin C, Morita CT. Cytokine requirements for the differentiation and expansion of IL-17A-and IL-22-producing human V γ2Vδ2 T cells. J Immunol 2010; 184:7268-80.
24. O'Brien RL, Roark CL, Born WK. IL-17-producing γδ T cells. Eur J Immunol 2009; 39:634-75.
25. Geremia A, Aranchibia-Cárcamo CV, Fleming MPP, Rust N, Singh B, Mortensen NJ, et al. IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease. J Exp Med 2011; 208:1127-33.
26. Vinuesa CG, Tangye SG, Moser B, Mackay CR. Follicular B helper T cells in antibody responses and autoimmunity. Nat Rev Immunol 2005; 5:853-65.
27. Trifari S, Kaplan CD, Tran EH, Crellin NK, Spits H. Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and T(H)2 cells. Nat Immunol 2009; 10:864-72.
28. Staudt V, Bothur E, Klein M, Lingnau K, Reuter S, Grebe N, et al. Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity 2010; 33:192-202.
29. + T cell lineage differentiation. Immunity 2009; 30: 646-55.
30. - T cells or are self-induced to become Th17 cells in the absence of exogenous TGFβ. J Immunol 2007; 178:6725-9.
31. Fishwild DM, O'Donnell SL, Bengoechea T, Hudson DV, Harding F, Bernhard SL, et al. High-avidity human IgG(kappa) monoclonal antibodies from a novel strain of minilocus transgenic mice. Nat Biotechnol 1996; 14:845-51. (Pubitemid 26239182)
32. Lonberg N. Human antibodies from transgenic animals. Nat Biotechnol 2005; 23:1117-25.
33. Luo J, Wu SJ, Lacy ER, Orlovsky Y, Baker A, Teplyakov A, et al. Structural basis for dual recognition of IL-12 and IL-23 by ustekinumab. J Mol Biol 2010; 402:797-812.
34. Presky DH, Yang H, Minetti LJ, Chua AO, Nabavi N, Wu CY, et al. A functional interleukin 12 receptor complex is composed of two beta-type cytokine receptor subunits. Proc Natl Acad Sci USA 1996; 93: 14002-7.
35. Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 2000; 13: 715-25.
36. Parham C, Chirica M, Timans J, Vaisberg E, Travis M, Cheung J, et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. J Immunol 2002; 168:5699-708. (Pubitemid 34556153)
37. Benson JM, Sachs CW, Treacy G, Zhou H, Pendley CE, Brodmerkel C, et al. Therapeutic targeting of the IL-12/23 pathways: generation and characterization of ustekinumab. Nature Biotech 2011; 29:615-24.
38. Yoon C, Johnston SC, Tang J, Stahl M, Tobin JF, Somers WS. Charged residues dominate a unique interlocking topography in the heterodimeric cytokine interleukin-12. EMBO J 2000; 19:3530-41. (Pubitemid 30462112)
39. Lupardus PJ, Garcia KC. The structure of interleukin- 23 reveals the molecular basis of p40 subunit sharing with interleukin-12. J Mol Biol 2008; 382:931-41.
40. Hong K, Chu A, Lúdivíksson BR, Berg EL, Ehrardt RO. IL-12, independently of IFNγ plays a crucial role in the pathogenesis of a murine psoriasis-like skin disorder. J Immunol 1999; 162:7480-91. (Pubitemid 29277728)
41. Davidson NJ, Hudak SA, Lesley RE, Menon S, Leach MW, Rennick DM. IL-12, but not IFNγ, plays a major role in sustaining the chronic phase of cholitis in IL-10 deficient mice. J Immunol 1998; 161:3143-9. (Pubitemid 28425743)
42. Neurath MF, Fuss I, Kelsall BL, Stüber E, Strober W. Antibodies to interleukin 12 abrogate established experimental colitis in mice. J Exp Med 1995; 182:1281-90.
43. Malfait AM, Butler DM, Presky DH, Maini RN, Brennan FM, Feldmann M. Blockade of IL-12 during the induction of collagen-induced arthritis (CIA) markedly attenuates the severity of the arthritis. Clin Exp Immunol 1998; 111:377-83.
44. Leonard JP, Waldburger KE, Goldman SJ. Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12. J Exp Med 1995; 181:381-6.
45. Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 2003; 198:1951-7.
46. Gran B, Zhang GX, Yu S, Li J, Chen XH, Ventura ES, et al. IL-12p35-deficient mice are susceptible to experimental autoimmune encephalomyelitis: evidence for redundancy in the IL-12 system in the induction of central nervous system autoimmune demyelination. J Immunol 2002; 169:7104-10. (Pubitemid 36899299)
47. Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, et al. Interleukin-23 rather than interleukin- 12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003; 421:744-8.
48. Yawalker N, Karlen S, Hunger R, Brand CU, Braathen LR. Expression of IL-12 is increased in psoratic skin. J Invest Dermatol 1998; 111:1053-7.
49. Monteleone G, Biancone L, Marasco R, Morrone G, Marasco O, Luzza F, et al. Interleukin 12 is expressed and actively released by Crohn's disease intestinal lamina propria mononuclear cells. Gastroenterology 1997; 112:1169-78.
50. Berrebi D, Besnard M, Fromont-Hankard G, Paris R, Mougenot JF, De Lagausie P, et al. Interleukin-12 expression is focally enhanced in the gastric mucosa of pediatric patients with Crohn's disease. Am J Pathol 1998; 152:667-72. (Pubitemid 28110712)
51. Windhagen A, Newcombe J, Dangond F, Strand C, Woodroofe MN, Cuzner ML, et al. Expression of costimulatory molecules B7-1 (CD80), B7-2 (CD86), and interleukin 12 cytokine in multiple sclerosis lesions. J Exp Med 1995; 182:1985-96.
52. Nicoletti F, Patti F, Cocuzza C, Zaccone P, Nicoletti A, Di Marco R, et al. Elevated serum levels of interleukin- 12 in chronic progressive multiple sclerosis. J Neuroimmunol 1996; 70:87-90.
53. Fassbender K, Ragoschke A, Rossol S, Schwartz A, Mielke O, Paulig A, et al. Increased release of interleukin- 12p40 in MS: association with intracerebral inflammation. Neurology 1998; 51:753-8. (Pubitemid 28449255)
54. Torti DC, Feldman SR. Interleukin-12, interleukin-23, and psoriasis: current prospects. J Am Acad Dermatol 2007; 57:1059-68.
55. Cargill M, Schrodi SJ, Chang M, Garcia VE, Brandon R, Callis KP, et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet 2007; 80:273-90.
56. Capon F, Di Meglio P, Szaub J, Prescott NJ, Dunster C, Baumber L, et al. Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis. Hum Genet 2007; 122:201-6.
57. Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006; 314:1461-3.
58. Di Meglio P, Di Cesare A, Laggner U, Chu CC, Napolitano L, Villanova F, et al. The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans. PLoS ONE 2011; 6:17160.
59. Lebwohl M. Psoriasis. Lancet 2003; 361:1197-204.
60. Christophers E. Psoriasis-epidemiology and clinical spectrum. Clin Exp Dermatol 2001; 26:314-20.
61. Eghlileb AM, Davies EEG, Finlay AY. Psoriasis has a major secondary impact on the lives of family members and partners. Br J Dermatol 2007; 156:1245-50.
62. Basra MKA, Finlay AY. The family impact of skin diseases: the Greater Patient concept. Br J Dermatol 2007; 156:929-37.
63. Picardi A, Mazzotti E, Pasquini P. Prevalence and correlates of suicidal ideation among patients with skin disease. J Am Acad Dermatol 2006; 54:420-6.
64. Schon MP, Boehncke WH. Psoriasis. N Engl J Med 2005; 352:1899-912.
65. Arican O, Aral M, Sasmaz S, Ciragil P. Serum levels of TNFα, IFNγ, IL-6, IL-8, IL 12, IL-17 and IL-18 in patients with active psoriasis and correlation with disease severity. Mediators Inflamm 2005; 5:273-9.
66. Lowes MA, Kikuchi T, Fuentes-Duculan J, Cardinale I, Zaba LC, Haider AS, et al. Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. J Invest Dermatol 2008; 128:1207-11.
67. Jacob SE, Nassiri M, Kerdel FA, Vincek V. Simultaneous measurement of multiple Th1 and Th2 serum cytokines in psoriasis and correlation with disease severity. Mediators Inflamm 2003; 12:309-13.
68. Guttman-Yassky E, Krueger GG. Psoriasis: evolution of pathogenic concepts and new therapies through phases of translational research. Br J Dermatol 2007; 157:1103-15.
69. Leonardi CL, Kimball AB, Papp KA, Yeilding N, Guzzo C, Wang Y, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 2008; 371:1665-74.
70. Papp KA, Langley RG, Lebwohl M, Krueger GG, Szapary P, Yeilding N, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 2008; 371:1675-84.
71. Griffiths CE, Strober BE, van de Kerkhof P, Ho V, Fidelus-Gort R, Yeilding N, et al. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med 2010; 362:118-28.
72. Ustekinumab prescribing information. www.Stelarainfo.com/pdf/ PrescribingInformation.pdf.
73. Yeilding N, Szapary P, Brodmerkel C, Benson J, Plotnick M, Goyal K, et al. Development of IL-12/23 antagonist ustekinumab: past, present and future perspectives. Ann NY Acad Sci 2011; 1222:30-9.
74. Gottlieb A, Menter A, Mendelsohn A, Shen YK, Li S, Guzzo C, et al. Ustekinumab, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis: randomised, double-blind, placebo-controlled, crossover trial. Lancet 2009; 373:633-40.
75. http://clinicaltrials.gov/ct2/show/NCT01077362?term= ustekinumab+psoriatic+arthritis&rank =3.
76. Sandborn WJ, Gasink C, Gao LL, Blank M, Johanns J, et al. A multicenter, randomized, double-blind, placebo-controlled phase 2b study of ustekinumab, a human monoclonal antibody to IL-12/23p40, in patients with moderately to severely active Crohn's disease: results through week 22 from the Certifi Trial. Gastroenterology 2011; 140:109.
77. http://clinicaltrials.gov/ct2/results?term=ustekinumab+Crohn%27s+disease
78. Segal BM, Constantinescu CS, Raychaudhuri A, Fidelus-Gort R, Kasper LH. On behalf of the ustekinumab MS investigators. Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol 2008; 7:796-804.
79. Shigehara K, Shijubo N, Ohmichi M, Takahashi R, Kon S, Okamura H, et al. IL-12 and IL-18 are increased and stimulate IFNgamma production in sarcoid lungs. J Immunol 2001; 166:642-9. (Pubitemid 32038488)
80. Judson MA, Marchell RM, Mascelli MA, Piantone A, Barnathan ES, Petty KJ, et al. Molecular profiling and gene expression analysis in cutaneous sarcoidosis: the role of IL-12, IL-23, and the Th17 pathways. Accepted to J Amer Acad Derm May 2011.
81. http://clinicaltrials.gov/ct2/show/NCT00955279?term= ustekinumab+sarcoid&rank = 1.
82. Nestle FO, Kaplan DH, Barker J. Psoriasis. N Eng J Med 2009; 361:496-509.