메뉴 건너뛰기




Volumn 70, Issue 11, 2018, Pages 1710-1720

ABT-122, a Bispecific Dual Variable Domain Immunoglobulin Targeting Tumor Necrosis Factor and Interleukin-17A, in Patients With Rheumatoid Arthritis With an Inadequate Response to Methotrexate: A Randomized, Double-Blind Study

Author keywords

[No Author keywords available]

Indexed keywords

ABT-122; ADALIMUMAB; ANTIRHEUMATIC AGENT; IL17A PROTEIN, HUMAN; IMMUNOGLOBULIN; INTERLEUKIN 17; METHOTREXATE; TNF PROTEIN, HUMAN; TUMOR NECROSIS FACTOR;

EID: 85052820137     PISSN: 23265191     EISSN: 23265205     Source Type: Journal    
DOI: 10.1002/art.40580     Document Type: Article
Times cited : (56)

References (37)
  • 1
    • 84930607509 scopus 로고    scopus 로고
    • Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force
    • Smolen JS, Breedveld FC, Burmester GR, Bykerk V, Dougados M, Emery P, et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis 2016;75:3–15.
    • (2016) Ann Rheum Dis , vol.75 , pp. 3-15
    • Smolen, J.S.1    Breedveld, F.C.2    Burmester, G.R.3    Bykerk, V.4    Dougados, M.5    Emery, P.6
  • 3
    • 84893349162 scopus 로고    scopus 로고
    • Barriers to optimal disease control for rheumatoid arthritis patients with moderate and high disease activity
    • Tymms K, Zochling J, Scott J, Bird P, Burnet S, de Jager J, et al. Barriers to optimal disease control for rheumatoid arthritis patients with moderate and high disease activity. Arthritis Care Res (Hoboken) 2014;66:190–6.
    • (2014) Arthritis Care Res (Hoboken) , vol.66 , pp. 190-196
    • Tymms, K.1    Zochling, J.2    Scott, J.3    Bird, P.4    Burnet, S.5    de Jager, J.6
  • 4
    • 84953380615 scopus 로고    scopus 로고
    • A structured literature review of the burden of illness and unmet needs in patients with rheumatoid arthritis: a current perspective
    • Taylor PC, Moore A, Vasilescu R, Alvir J, Tarallo M. A structured literature review of the burden of illness and unmet needs in patients with rheumatoid arthritis: a current perspective. Rheumatol Int 2016;36:685–95.
    • (2016) Rheumatol Int , vol.36 , pp. 685-695
    • Taylor, P.C.1    Moore, A.2    Vasilescu, R.3    Alvir, J.4    Tarallo, M.5
  • 5
    • 84855172814 scopus 로고    scopus 로고
    • The pathogenesis of rheumatoid arthritis
    • McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med 2011;365:2205–19.
    • (2011) N Engl J Med , vol.365 , pp. 2205-2219
    • McInnes, I.B.1    Schett, G.2
  • 6
    • 84863857793 scopus 로고    scopus 로고
    • Optimizing outcomes in patients with rheumatoid arthritis and an inadequate response to anti-TNF treatment
    • Emery P. Optimizing outcomes in patients with rheumatoid arthritis and an inadequate response to anti-TNF treatment. Rheumatology (Oxford) 2012;51 Suppl 5:v22–30.
    • (2012) Rheumatology (Oxford) , vol.51 , pp. 22-30
    • Emery, P.1
  • 7
    • 64549161956 scopus 로고    scopus 로고
    • Treatment options in patients with rheumatoid arthritis failing initial TNF inhibitor therapy: a critical review
    • Rubbert-Roth A, Finckh A. Treatment options in patients with rheumatoid arthritis failing initial TNF inhibitor therapy: a critical review. Arthritis Res Ther 2009;11 Suppl 1:S1.
    • (2009) Arthritis Res Ther , vol.11 , pp. S1
    • Rubbert-Roth, A.1    Finckh, A.2
  • 8
    • 84939264864 scopus 로고    scopus 로고
    • Anti-tumour necrosis factor treatment increases circulating T helper type 17 cells similarly in different types of inflammatory arthritis
    • Hull DN, Williams RO, Pathan E, Alzabin S, Abraham S, Taylor PC. Anti-tumour necrosis factor treatment increases circulating T helper type 17 cells similarly in different types of inflammatory arthritis. Clin Exp Immunol 2015;181:401–6.
    • (2015) Clin Exp Immunol , vol.181 , pp. 401-406
    • Hull, D.N.1    Williams, R.O.2    Pathan, E.3    Alzabin, S.4    Abraham, S.5    Taylor, P.C.6
  • 9
    • 84906827120 scopus 로고    scopus 로고
    • Rheumatoid arthritis pathophysiology: update on emerging cytokine and cytokine-associated cell targets
    • Furst DE, Emery P. Rheumatoid arthritis pathophysiology: update on emerging cytokine and cytokine-associated cell targets. Rheumatology (Oxford) 2014;53:1560–9.
    • (2014) Rheumatology (Oxford) , vol.53 , pp. 1560-1569
    • Furst, D.E.1    Emery, P.2
  • 10
    • 79960883879 scopus 로고    scopus 로고
    • Increasing levels of circulating Th17 cells and interleukin-17 in rheumatoid arthritis patients with an inadequate response to anti-TNF-α therapy
    • Chen DY, Chen YM, Chen HH, Hsieh CW, Lin CC, Lan JL. Increasing levels of circulating Th17 cells and interleukin-17 in rheumatoid arthritis patients with an inadequate response to anti-TNF-α therapy. Arthritis Res Ther 2011;13:R126.
    • (2011) Arthritis Res Ther , vol.13 , pp. R126
    • Chen, D.Y.1    Chen, Y.M.2    Chen, H.H.3    Hsieh, C.W.4    Lin, C.C.5    Lan, J.L.6
  • 11
    • 33751521013 scopus 로고    scopus 로고
    • Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction
    • Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med 2006;203:2673–82.
    • (2006) J Exp Med , vol.203 , pp. 2673-2682
    • Sato, K.1    Suematsu, A.2    Okamoto, K.3    Yamaguchi, A.4    Morishita, Y.5    Kadono, Y.6
  • 12
    • 40449113569 scopus 로고    scopus 로고
    • IL-17RA and IL-17RC receptors are essential for IL-17A-induced ELR+ CXC chemokine expression in synoviocytes and are overexpressed in rheumatoid blood
    • Zrioual S, Toh ML, Tournadre A, Zhou Y, Cazalis MA, Pachot A, et al. IL-17RA and IL-17RC receptors are essential for IL-17A-induced ELR+ CXC chemokine expression in synoviocytes and are overexpressed in rheumatoid blood. J Immunol 2008;180:655–63.
    • (2008) J Immunol , vol.180 , pp. 655-663
    • Zrioual, S.1    Toh, M.L.2    Tournadre, A.3    Zhou, Y.4    Cazalis, M.A.5    Pachot, A.6
  • 13
    • 80052611560 scopus 로고    scopus 로고
    • Serum and synovial fluid levels of interleukin-17 in correlation with disease activity in patients with RA
    • Metawi SA, Abbas D, Kamal MM, Ibrahim MK. Serum and synovial fluid levels of interleukin-17 in correlation with disease activity in patients with RA. Clin Rheumatol 2011;30:1201–7.
    • (2011) Clin Rheumatol , vol.30 , pp. 1201-1207
    • Metawi, S.A.1    Abbas, D.2    Kamal, M.M.3    Ibrahim, M.K.4
  • 14
    • 85054668839 scopus 로고    scopus 로고
    • Dual neutralization of TNF and IL-17 provides greater efficacy in collagen induced arthritis through regulation of a gene transcription program that includes CXCL1 and CXCL5 [abstract]
    • Cuff C, Hsieh C, Mathieu S, Murtaza A, Hugunin M, Bryant S, et al. Dual neutralization of TNF and IL-17 provides greater efficacy in collagen induced arthritis through regulation of a gene transcription program that includes CXCL1 and CXCL5 [abstract]. Arthritis Rheumatol 2013;65 Suppl:948.
    • (2013) Arthritis Rheumatol , vol.65 , pp. 948
    • Cuff, C.1    Hsieh, C.2    Mathieu, S.3    Murtaza, A.4    Hugunin, M.5    Bryant, S.6
  • 15
    • 85035126791 scopus 로고    scopus 로고
    • Dual neutralization of TNF and IL-17 with a DVD-Ig protein is efficacious in collagen induced arthritis [abstract]
    • Cuff C, Bryant S, Hugunin M, Kamath R, Voss J, Olson L, et al. Dual neutralization of TNF and IL-17 with a DVD-Ig protein is efficacious in collagen induced arthritis [abstract]. Ann Rheum Dis 2014;73 Suppl S2:S363.
    • (2014) Ann Rheum Dis , vol.73 , pp. S363
    • Cuff, C.1    Bryant, S.2    Hugunin, M.3    Kamath, R.4    Voss, J.5    Olson, L.6
  • 16
    • 2342551979 scopus 로고    scopus 로고
    • Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate
    • Genovese MC, Cohen S, Moreland L, Lium D, Robbins S, Newmark R, et al. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum 2004;50:1412–9.
    • (2004) Arthritis Rheum , vol.50 , pp. 1412-1419
    • Genovese, M.C.1    Cohen, S.2    Moreland, L.3    Lium, D.4    Robbins, S.5    Newmark, R.6
  • 17
    • 33846853779 scopus 로고    scopus 로고
    • Selective costimulation modulation using abatacept in patients with active rheumatoid arthritis while receiving etanercept: a randomised clinical trial
    • Weinblatt M, Schiff M, Goldman A, Kremer J, Luggen M, Li T, et al. Selective costimulation modulation using abatacept in patients with active rheumatoid arthritis while receiving etanercept: a randomised clinical trial. Ann Rheum Dis 2007;66:228–34.
    • (2007) Ann Rheum Dis , vol.66 , pp. 228-234
    • Weinblatt, M.1    Schiff, M.2    Goldman, A.3    Kremer, J.4    Luggen, M.5    Li, T.6
  • 18
    • 33749365296 scopus 로고    scopus 로고
    • Safety of the selective costimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease-modifying antirheumatic drugs: a one-year randomized, placebo-controlled study
    • Weinblatt M, Combe B, Covucci A, Aranda R, Becker JC, Keystone E. Safety of the selective costimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease-modifying antirheumatic drugs: a one-year randomized, placebo-controlled study. Arthritis Rheum 2006;54:2807–16.
    • (2006) Arthritis Rheum , vol.54 , pp. 2807-2816
    • Weinblatt, M.1    Combe, B.2    Covucci, A.3    Aranda, R.4    Becker, J.C.5    Keystone, E.6
  • 19
    • 84975777122 scopus 로고    scopus 로고
    • FRI0303 Discovery and characterization of ABT-122, an anti-TNF/IL-17 DVD-IG™ molecule as a potential therapeutic candidate for rheumatoid arthritis [abstract]
    • Hsieh CM, Cuff C, Tarcsa E, Hugunin M. FRI0303 Discovery and characterization of ABT-122, an anti-TNF/IL-17 DVD-IG™ molecule as a potential therapeutic candidate for rheumatoid arthritis [abstract]. Ann Rheum Dis 2014;73 Suppl 2:495.
    • (2014) Ann Rheum Dis , vol.73 , pp. 495
    • Hsieh, C.M.1    Cuff, C.2    Tarcsa, E.3    Hugunin, M.4
  • 20
    • 85035085727 scopus 로고    scopus 로고
    • FRI0164 Safety, tolerability, and functional activity of ABT-122, a dual TNF- and IL-17A–targeted DVD-IG™, following single-dose administration in healthy subjects [abstract]
    • Mansikka H, Ruzek M, Hugunin M, Ivanov A, Brito A, Clabbers A, et al. FRI0164 Safety, tolerability, and functional activity of ABT-122, a dual TNF- and IL-17A–targeted DVD-IG™, following single-dose administration in healthy subjects [abstract]. Ann Rheum Dis 2015;74 Suppl 2:482–3.
    • (2015) Ann Rheum Dis , vol.74 , pp. 482-483
    • Mansikka, H.1    Ruzek, M.2    Hugunin, M.3    Ivanov, A.4    Brito, A.5    Clabbers, A.6
  • 21
    • 85034023343 scopus 로고    scopus 로고
    • Safety, tolerability, and pharmacodynamics of ABT-122, a tumor necrosis factor– and interleukin-17–targeted dual variable domain immunoglobulin, in patients with rheumatoid arthritis
    • Fleischmann RM, Wagner F, Kivitz AJ, Mansikka HT, Khan N, Othman AA, et al. Safety, tolerability, and pharmacodynamics of ABT-122, a tumor necrosis factor– and interleukin-17–targeted dual variable domain immunoglobulin, in patients with rheumatoid arthritis. Arthritis Rheumatol 2017;69:2283–91.
    • (2017) Arthritis Rheumatol , vol.69 , pp. 2283-2291
    • Fleischmann, R.M.1    Wagner, F.2    Kivitz, A.J.3    Mansikka, H.T.4    Khan, N.5    Othman, A.A.6
  • 22
    • 85025813469 scopus 로고    scopus 로고
    • Pharmacokinetics of ABT-122, a TNF-α- and IL-17A-targeted dual-variable domain immunoglobulin, in healthy subjects and patients with rheumatoid arthritis: results from three phase I trials
    • Khatri A, Goss S, Jiang P, Mansikka H, Othman AA. Pharmacokinetics of ABT-122, a TNF-α- and IL-17A-targeted dual-variable domain immunoglobulin, in healthy subjects and patients with rheumatoid arthritis: results from three phase I trials. Clin Pharmacokinet 2018;57:613–23.
    • (2018) Clin Pharmacokinet , vol.57 , pp. 613-623
    • Khatri, A.1    Goss, S.2    Jiang, P.3    Mansikka, H.4    Othman, A.A.5
  • 23
    • 77956055481 scopus 로고    scopus 로고
    • 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative
    • Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO III, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010;62:2569–81.
    • (2010) Arthritis Rheum , vol.62 , pp. 2569-2581
    • Aletaha, D.1    Neogi, T.2    Silman, A.J.3    Funovits, J.4    Felson, D.T.5    Bingham, C.O.6
  • 24
    • 34250216054 scopus 로고    scopus 로고
    • Standardizing assessment and reporting of adverse effects in rheumatology clinical trials II: the Rheumatology Common Toxicity Criteria v. 2.0
    • Woodworth T, Furst DE, Alten R, Bingham CO III, Yocum D, Sloan V, et al. Standardizing assessment and reporting of adverse effects in rheumatology clinical trials II: the Rheumatology Common Toxicity Criteria v. 2.0. J Rheumatol 2007;34:1401–14.
    • (2007) J Rheumatol , vol.34 , pp. 1401-1414
    • Woodworth, T.1    Furst, D.E.2    Alten, R.3    Bingham, C.O.4    Yocum, D.5    Sloan, V.6
  • 25
    • 0029044362 scopus 로고
    • American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis
    • Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995;38:727–35.
    • (1995) Arthritis Rheum , vol.38 , pp. 727-735
    • Felson, D.T.1    Anderson, J.J.2    Boers, M.3    Bombardier, C.4    Furst, D.5    Goldsmith, C.6
  • 26
    • 0028815803 scopus 로고
    • Modified disease activity scores that include twenty-eight–joint counts: development and validation in a prospective longitudinal study of patients with rheumatoid arthritis
    • Prevoo ML, van ‘t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty-eight–joint counts: development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995;38:44–8.
    • (1995) Arthritis Rheum , vol.38 , pp. 44-48
    • Prevoo, M.L.1    van ‘t Hof, M.A.2    Kuper, H.H.3    van Leeuwen, M.A.4    van de Putte, L.B.5    van Riel, P.L.6
  • 27
    • 23944478301 scopus 로고    scopus 로고
    • Acute phase reactants add little to composite disease activity indices for rheumatoid arthritis: validation of a clinical activity score
    • Aletaha D, Nell VP, Stamm T, Uffmann M, Pflugbeil S, Machold K, et al. Acute phase reactants add little to composite disease activity indices for rheumatoid arthritis: validation of a clinical activity score. Arthritis Res Ther 2005;7:R796–806.
    • (2005) Arthritis Res Ther , vol.7 , pp. 796-806
    • Aletaha, D.1    Nell, V.P.2    Stamm, T.3    Uffmann, M.4    Pflugbeil, S.5    Machold, K.6
  • 29
    • 85041035977 scopus 로고    scopus 로고
    • Population pharmacokinetics of the TNF-α and IL-17A dual-variable domain antibody ABT-122 in healthy volunteers and subjects with psoriatic or rheumatoid arthritis: analysis of phase 1 and 2 clinical trials
    • Khatri A, Othman AA. Population pharmacokinetics of the TNF-α and IL-17A dual-variable domain antibody ABT-122 in healthy volunteers and subjects with psoriatic or rheumatoid arthritis: analysis of phase 1 and 2 clinical trials. J Clin Pharmacol 2018;58:803–13.
    • (2018) J Clin Pharmacol , vol.58 , pp. 803-813
    • Khatri, A.1    Othman, A.A.2
  • 30
    • 79953718761 scopus 로고    scopus 로고
    • Evaluation of the safety of rituximab in combination with a tumor necrosis factor inhibitor and methotrexate in patients with active rheumatoid arthritis: results from a randomized controlled trial
    • Greenwald MW, Shergy WJ, Kaine JL, Sweetser MT, Gilder K, Linnik MD. Evaluation of the safety of rituximab in combination with a tumor necrosis factor inhibitor and methotrexate in patients with active rheumatoid arthritis: results from a randomized controlled trial. Arthritis Rheum 2011;63:622–32.
    • (2011) Arthritis Rheum , vol.63 , pp. 622-632
    • Greenwald, M.W.1    Shergy, W.J.2    Kaine, J.L.3    Sweetser, M.T.4    Gilder, K.5    Linnik, M.D.6
  • 31
    • 85054674482 scopus 로고    scopus 로고
    • Dual inhibition of tumour necrosis factor and interleukin-17A with ABT-122: open-label long-term extension studies in rheumatoid arthritis or psoriatic arthritis
    • E-pub ahead of print.
    • Genovese MC, Weinblatt ME, Mease PJ, Aelion JA, Peloso PM, Chen K, et al. Dual inhibition of tumour necrosis factor and interleukin-17A with ABT-122: open-label long-term extension studies in rheumatoid arthritis or psoriatic arthritis. Rheumatology (Oxford) 2018. E-pub ahead of print.
    • (2018) Rheumatology (Oxford)
    • Genovese, M.C.1    Weinblatt, M.E.2    Mease, P.J.3    Aelion, J.A.4    Peloso, P.M.5    Chen, K.6
  • 33
    • 85040081912 scopus 로고    scopus 로고
    • Genomic and epigenetic bioinformatics demonstrate dual TNF-α and IL17a target engagement by ABT-122, and suggest mainly TNF-α–mediated relative target contribution to drug response in MTX-IR rheumatoid arthritis patients [abstract]
    • Georgantas RW, Ruzek M, Davis JW, Hong F, Asque E, Idler K, et al. Genomic and epigenetic bioinformatics demonstrate dual TNF-α and IL17a target engagement by ABT-122, and suggest mainly TNF-α–mediated relative target contribution to drug response in MTX-IR rheumatoid arthritis patients [abstract]. Arthritis Rheumatol 2016;68 Suppl 10. URL: http://acrabstracts.org/abstract/genomic-and-epigenetic-bioinformatics-demonstrate-dual-tnf-%CE%B1-and-il17a-target-engagement-by-abt-122-and-suggest-mainly-tnf-%CE%B1-mediated-relative-target-contribution-to-drug-response-i/.
    • (2016) Arthritis Rheumatol , vol.68
    • Georgantas, R.W.1    Ruzek, M.2    Davis, J.W.3    Hong, F.4    Asque, E.5    Idler, K.6
  • 34
    • 84903478179 scopus 로고    scopus 로고
    • A phase II randomized study of subcutaneous ixekizumab, an anti-interleukin-17 monoclonal antibody, in rheumatoid arthritis patients who were naive to biologic agents or had an inadequate response to tumor necrosis factor inhibitors
    • Genovese MC, Greenwald M, Cho CS, Berman A, Jin L, Cameron GS, et al. A phase II randomized study of subcutaneous ixekizumab, an anti-interleukin-17 monoclonal antibody, in rheumatoid arthritis patients who were naive to biologic agents or had an inadequate response to tumor necrosis factor inhibitors. Arthritis Rheumatol 2014;66:1693–704.
    • (2014) Arthritis Rheumatol , vol.66 , pp. 1693-1704
    • Genovese, M.C.1    Greenwald, M.2    Cho, C.S.3    Berman, A.4    Jin, L.5    Cameron, G.S.6
  • 35
    • 84877603562 scopus 로고    scopus 로고
    • Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study
    • Genovese MC, Durez P, Richards HB, Supronik J, Dokoupilova E, Mazurov V, et al. Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study. Ann Rheum Dis 2013;72:863–9.
    • (2013) Ann Rheum Dis , vol.72 , pp. 863-869
    • Genovese, M.C.1    Durez, P.2    Richards, H.B.3    Supronik, J.4    Dokoupilova, E.5    Mazurov, V.6
  • 36
    • 84940478173 scopus 로고    scopus 로고
    • A study to evaluate the safety, tolerability, and efficacy of brodalumab in subjects with rheumatoid arthritis and an inadequate response to methotrexate
    • Pavelka K, Chon Y, Newmark R, Lin SL, Baumgartner S, Erondu N. A study to evaluate the safety, tolerability, and efficacy of brodalumab in subjects with rheumatoid arthritis and an inadequate response to methotrexate. J Rheumatol 2015;42:912–9.
    • (2015) J Rheumatol , vol.42 , pp. 912-919
    • Pavelka, K.1    Chon, Y.2    Newmark, R.3    Lin, S.L.4    Baumgartner, S.5    Erondu, N.6
  • 37
    • 85054612048 scopus 로고    scopus 로고
    • Phase II study of ABT-122, a tumor necrosis factor– and interleukin-17A–targeted dual variable domain immunoglobulin, in patients with psoriatic arthritis with an inadequate methotrexate response
    • Mease PJ, Genovese MC, Weinblatt M, Peloso PM, Chen K, Othman AA, et al. Phase II study of ABT-122, a tumor necrosis factor– and interleukin-17A–targeted dual variable domain immunoglobulin, in patients with psoriatic arthritis with an inadequate methotrexate response. Arthritis Rheumatol 2018;70:1778–89.
    • (2018) Arthritis Rheumatol , vol.70 , pp. 1778-1789
    • Mease, P.J.1    Genovese, M.C.2    Weinblatt, M.3    Peloso, P.M.4    Chen, K.5    Othman, A.A.6


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.