Guselkumab
(Synonyms: 古塞库单抗; CNTO 1959) 目录号 : GC62685
Guselkumab 是一种重组人 IgG1 单克隆抗体，针对 IL-23p19 亚基。Guselkumab 与人和食蟹猴 IL-23 的结合值 Kd 分别为 3.3 pM 和 1.9 pM。Guselkumab 抑制 IL-23 信号通路下游细胞因子的产生，可用于银屑病关节炎的研究。
Cas No.:1350289-85-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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Guselkumab is a recombinant human IgG1 monoclonal antibody against the IL-23p19 subunit. Guselkumab binds to human and cynomolgus monkey IL-23 with Kd values of 3.3 and 1.9 pmol/L, respectively. Guselkumab inhibits production of cytokines lying downstream of the IL-23 signaling pathway and can be used for psoriatic arthritis research[1].
Guselkumab inhibits IL-23 (0.5 or 1 ng/mL)-mediated production of Th17 cytokines IL17A, IL-17F, and IL-22 in mouse splenocyteswith IC50 ranging 0.016-0.080 nM. And, it inhibits IL-23 (10 or 100 ng/mL)-mediated production of IL-10 in human NKL cells. Guselkumab has no effect on IL-12 (0.1 ng/mL)-mediated production of interferon γ (IFNγ) in NK92MI cells. [1].Guselkumab combines with IBI112 blocks IL-23-induced STAT3 phosphorylation, and Guselkumab blocks IL-23-induced STAT3 phosphorylation with an IC50 value of 102.1100±2.0053 nM[2].. Guselkumab blocks hIL-23-induced mIL-17 production in a dose-dependent manner, exhibiting an IC50 of 4.9743 ±1.2847 nM. In another experiment, Guselkumab also blocks IL-17F production in cynomolgus monkeys with an IC50 of 16.7950 nM[2].
[1]. International non-proprietary name: guselkumab Procedure No. EMEA/H/C/004271/0000par-public-assessment-report_en.pdf
[2]. Li Li, et al. IBI112, a selective anti-IL23p19 monoclonal antibody, displays high efficacy in IL-23-induced psoriasiform dermatitis. Int Immunopharmacol
| Cas No. | 1350289-85-8 | SDF | |
| 别名 | 古塞库单抗; CNTO 1959 | ||
| 分子式 | 分子量 | ||
| 溶解度 | 储存条件 | Store at -20°C | |
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Guselkumab in patients with active psoriatic arthritis who were biologic-naive or had previously received TNFα inhibitor treatment (DISCOVER-1): a double-blind, randomised, placebo-controlled phase 3 trial
Lancet 2020 Apr 4;395(10230):1115-1125.PMID:32178765DOI:10.1016/S0140-6736(20)30265-8.
Background: Many patients with psoriatic arthritis have an inadequate response to tumor necrosis factor (TNF) inhibitors. Guselkumab, a specific inhibitor of interleukin-23 (IL-23) via IL-23 p19 subunit binding, significantly improved psoriatic arthritis signs and symptoms with an acceptable safety profile in a phase 2 trial. Methods: This multicentre, double-blind, randomised, placebo-controlled, phase 3 trial was done at 86 sites in 13 countries across Asia, Australasia, Europe, and North America and enrolled adults with active psoriatic arthritis (at least three swollen and three tender joints; and C-reactive protein ≥0·3 mg/dL) despite standard therapies. Eligibility criteria included inadequate response to or intolerance of standard treatment, including at least 4 months of apremilast, at least 3 months of non-biologic disease-modifying antirheumatic drugs (DMARDs), or at least 4 weeks of non-steroidal anti-inflammatory drugs for psoriatic arthritis. About 30% of study participants could have previously received one or two TNF inhibitors. Patients were randomly assigned (1:1:1, computer-generated permuted blocks; stratified by baseline DMARD and previous TNF inhibitor use) to subcutaneous Guselkumab 100 mg every 4 weeks; Guselkumab 100 mg at weeks 0, 4, then every 8 weeks; or matching placebo. The primary endpoint was American College of Rheumatology 20% improvement (ACR20) at week 24 in all patients per assigned treatment group using non-responder imputation. Safety was assessed in all patients per treatment received. This trial is registered at ClinicalTrials.gov, NCT03162796 (active, not recruiting). Findings: From Aug 28, 2017, to Aug 17, 2018, we screened 624 patients, of whom 381 were randomly assigned and treated with Guselkumab every 4 weeks (n=128), Guselkumab every 8 weeks (n=127), or placebo (n=126). 362 patients continued study treatment up to week 24. The primary endpoint was met: ACR20 at week 24 was achieved by significantly greater proportions of patients in the Guselkumab every 4 weeks group (76 [59%] of 128 [95% CI 50-68]) and every 8 weeks group (66 [52%] of 127 [43-61]) than in the placebo group (28 [22%] of 126 [15-30]), with percentage differences versus placebo of 37% (95% CI 26-48) for the every 4 weeks group and 30% (19-41) for the every 8 weeks group (both p<0·0001). Serious adverse events up to week 24 occurred in no patients receiving Guselkumab every 4 weeks, four (3%) patients receiving Guselkumab every 8 weeks, and five (4%) patients receiving placebo. Up to week 24, one patient in the placebo group died from cardiac failure and two had serious infections; no guselkumab-treated patient died or had serious infections. Interpretation: Guselkumab demonstrated a favourable benefit-risk profile and might be an effective treatment option for patients with active psoriatic arthritis. Funding: Janssen Research and Development.
Guselkumab in biologic-naive patients with active psoriatic arthritis (DISCOVER-2): a double-blind, randomised, placebo-controlled phase 3 trial
Lancet 2020 Apr 4;395(10230):1126-1136.PMID:32178766DOI:10.1016/S0140-6736(20)30263-4.
Background: The interleukin-23 (IL-23)/T-helper 17 cell pathway is implicated in psoriatic arthritis pathogenesis. Guselkumab, an IL-23 inhibitor that specifically binds the IL-23 p19 subunit, significantly and safely improved psoriatic arthritis in a phase 2 study. DISCOVER-2 was a phase 3 trial to assess Guselkumab in biologic-naive patients with psoriatic arthritis. Methods: This phase 3, double-blind, placebo-controlled study was done at 118 sites in 13 countries across Asia, Europe, and North America. We enrolled biologic-naive patients with active psoriatic arthritis (at least five swollen joints, at least five tender joints, and C-reactive protein ≥0·6 mg/dL) despite standard therapies. Patients were randomly assigned (1:1:1, computer-generated permuted blocks; stratified by baseline disease-modifying antirheumatic drug use and C-reactive protein concentration) to subcutaneous injections of Guselkumab 100 mg every 4 weeks; Guselkumab 100 mg at weeks 0, 4, then every 8 weeks; or placebo. The primary endpoint was American College of Rheumatology 20% improvement (ACR20) response at week 24 in all patients per assigned treatment group. Safety was assessed in all patients per treatment received. This trial is registered at ClinicalTrials.gov, NCT03158285 (active, not recruiting). Findings: From July 13, 2017, to Aug 3, 2018, 1153 patients were screened, of whom 741 were randomly assigned to receive Guselkumab every 4 weeks (n=246), every 8 weeks (n=248), or placebo (n=247). One patient in the every 4 weeks group and one in the placebo group did not start treatment, and the remaining 739 patients started treatment; 716 patients continued treatment up to week 24. Significantly greater proportions of patients in the Guselkumab every 4 weeks group (156 [64%] of 245 [95% CI 57-70]) and every 8 weeks group (159 [64%] of 248 [58-70]) than in the placebo group (81 [33%] of 246 [27-39]) achieved an ACR20 response at week 24 (percentage differences vs placebo 31% [95% CI 22-39] for the every 4 weeks group and 31% [23-40] for the every 8 weeks group; both p<0·0001). Up to week 24, serious adverse events occurred in eight (3%) of 245 patients receiving Guselkumab every 4 weeks (three serious infections), three (1%) of 248 receiving Guselkumab every 8 weeks (one serious infection), and seven (3%) of 246 receiving placebo (one serious infection). No deaths occurred. Interpretation: Guselkumab, a human monoclonal antibody that specifically inhibits IL-23 by binding the cytokine's p19 subunit, was efficacious and demonstrated an acceptable benefit-risk profile in patients with active psoriatic arthritis who were naive to treatment with biologics. These data support the use of selective inhibition of IL-23 to treat psoriatic arthritis. Funding: Janssen Research and Development.
Efficacy and safety of Guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: Results from the phase III, double-blinded, placebo- and active comparator-controlled VOYAGE 1 trial
J Am Acad Dermatol 2017 Mar;76(3):405-417.PMID:28057360DOI:10.1016/j.jaad.2016.11.041.
Background: Guselkumab, an interleukin-23 blocker, was superior to adalimumab in treating moderate to severe psoriasis in a phase II trial. Objectives: We sought to compare efficacy and safety of Guselkumab with adalimumab and placebo in patients with psoriasis treated for 1 year. Methods: Patients were randomized to Guselkumab 100 mg (weeks 0 and 4, then every 8 weeks; n = 329); placebo→Guselkumab (weeks 0, 4, and 12 then Guselkumab at weeks 16 and 20, then every 8 weeks; n = 174); or adalimumab (80 mg week 0, 40 mg week 1, then 40 mg every 2 weeks through week 47; n = 334). Physician-reported outcomes (Investigator Global Assessment, Psoriasis Area and Severity Index [PASI]), patient-reported outcomes (Dermatology Life Quality Index, Psoriasis Symptoms and Signs Diary), and safety were evaluated through week 48. Results: Guselkumab was superior (P < .001) to placebo at week 16 (85.1% vs 6.9% [Investigator Global Assessment score of 0/1 (cleared/minimal)] and 73.3% vs 2.9% [90% or greater improvement in PASI score from baseline (PASI 90)]). Guselkumab was also superior (P < .001) to adalimumab for Investigator Global Assessment 0/1 and PASI 90 at week 16 (85.1% vs 65.9% and 73.3% vs 49.7%), week 24 (84.2% vs 61.7% and 80.2% vs 53.0%), and week 48 (80.5% vs 55.4% and 76.3% vs 47.9%). Furthermore, Guselkumab significantly improved patient-reported outcomes through week 48. Adverse event rates were comparable between treatments. Limitations: Analyses were limited to 48 weeks. Conclusions: Guselkumab demonstrated superior efficacy compared with adalimumab and was well tolerated in patients with psoriasis through 1 year.
Guselkumab for the Treatment of Crohn's Disease: Induction Results From the Phase 2 GALAXI-1 Study
Gastroenterology 2022 May;162(6):1650-1664.e8.PMID:35134323DOI:10.1053/j.gastro.2022.01.047.
Background & aims: Guselkumab, a selective p19 interleukin-23 antagonist, is approved for the treatment of plaque psoriasis and psoriatic arthritis. This study evaluated the efficacy and safety of Guselkumab in patients with moderately to severely active Crohn's disease with inadequate response or intolerance to conventional or biologic therapy. Methods: GALAXI-1, a phase 2, double-blind, placebo-controlled study, randomized patients 1:1:1:1:1 to intravenous Guselkumab 200 mg, 600 mg, or 1200 mg at weeks 0, 4, and 8; intravenous ustekinumab approximately 6 mg/kg at week 0 and 90 mg subcutaneously at week 8; or placebo. Change from baseline in Crohn's Disease Activity Index score (primary end point), clinical remission, clinical response, Patient Reported Outcomes-2 remission, clinical-biomarker response, endoscopic response (major secondary end points), and safety in guselkumab-treated patients vs placebo were evaluated through week 12. Ustekinumab was a reference arm. Results: Of 309 patients evaluated, approximately 50% had disease refractory to prior biologic therapy. At week 12, significantly greater reductions in Crohn's Disease Activity Index from baseline (least squares means: 200 mg: -160.4, 600 mg: -138.9, and 1200 mg: -144.9 vs placebo: -36.2; all, P < .05) and significantly greater proportions of patients achieved clinical remission in each Guselkumab group vs placebo (Crohn's Disease Activity Index <150; 57.4%, 55.6%, and 45.9% vs 16.4%; all, P < .05). Greater proportions of patients receiving Guselkumab achieved clinical response, Patient Reported Outcomes-2 remission, clinical-biomarker response, and endoscopic response at week 12 vs placebo. Efficacy of ustekinumab vs placebo was also demonstrated. Safety event rates were generally similar across treatment groups. Conclusions: At week 12, all 3 dose regimens of Guselkumab induced greater clinical and endoscopic improvements vs placebo, with a favorable safety profile. Clinicaltrials: gov, Number: NCT03466411.
Efficacy and safety of Guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: Results from the phase III, double-blind, placebo- and active comparator-controlled VOYAGE 2 trial
J Am Acad Dermatol 2017 Mar;76(3):418-431.PMID:28057361DOI:10.1016/j.jaad.2016.11.042.
Background: Phase II data suggested that Guselkumab, an anti-interleukin-23 monoclonal antibody, was efficacious in psoriasis. Objective: We sought to assess efficacy and safety of Guselkumab in moderate to severe psoriasis versus placebo and adalimumab, including interrupted treatment and switching adalimumab nonresponders to Guselkumab. Methods: Patients were randomized to Guselkumab 100 mg (weeks 0 and 4, then every 8 weeks; n = 496); placebo→Guselkumab (weeks 0, 4, and 12 then Guselkumab at weeks 16 and 20; n = 248); or adalimumab (80 mg week 0, then 40 mg week 1, and every 2 weeks through week 23; n = 248). At week 28, Guselkumab 90% or greater improvement in Psoriasis Area and Severity Index (PASI) score from baseline (PASI 90) responders were rerandomized to Guselkumab or placebo with Guselkumab after loss of response. Placebo→Guselkumab responders and adalimumab responders received placebo, then Guselkumab after loss of response. Nonresponders received Guselkumab. Results: At week 16, more patients receiving Guselkumab achieved an Investigator Global Assessment (IGA) score 0/1 (cleared/minimal) (84.1% vs 8.5%) and PASI 90 (70.0% vs 2.4%) versus placebo (coprimary end points). Guselkumab was superior to adalimumab at week 16 (IGA score 0/1, 75% or greater improvement in PASI score from baseline, and PASI 90) and week 24 (IGA score 0/1 and 0, PASI 90, 100% improvement in PASI score from baseline) (P < .001). From weeks 28 to 48, better persistence of response was observed in Guselkumab maintenance versus withdrawal groups (P < .001). Of adalimumab nonresponders who switched to Guselkumab, 66.1% achieved PASI 90 at week 48. Guselkumab improved patient-reported outcomes. Adverse events were comparable among groups. Limitations: One-year follow-up limits retreatment data. Conclusions: Guselkumab is a highly effective, well-tolerated, maintenance therapy, including in adalimumab nonresponders.