Tocilizumab
(Synonyms: 托珠单抗; Anti-Human IL6R, Humanized Antibody) 目录号 : GC37809
Tocilizumab (Anti-Human IL6R, Humanized Antibody) 是一种抗人白细胞介素 6 受体 (IL-6R) 中和抗体，可防止 IL-6 与 IL-6R 结合，从而抑制经典和反式信号传导。
Cas No.:375823-41-9
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| Cell experiment [1]: | |
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Cell lines |
U266B1 cells |
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Preparation Method |
Cell Proliferation Assays U266B1 cells were suspended with SOMAmer (1, 10, or 100 μg/ml) or tocilizumab (1, 10, or 100 μg/ml) in RPMI 1640 medium containing 10% FBS at 104 cells per well and cultured for 30 min at 37 °C in a 5% CO2 incubator. |
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Reaction Conditions |
1, 10, or 100 μg/ml，30 min at 37 °C |
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Applications |
SL1026 achieved complete inhibition of IL-6 at 1 μg/ml (83 nm), whereas tocilizumab achieved 60% inhibition at a roughly equivalent molar concentration (67 nm) . |
| Animal experiment [2]: | |
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Animal models |
Patients with rheumatoid arthritis |
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Preparation Method |
Patients (n=1262) were randomised 1:1 to receive Tocilizumab-SC 162 mg weekly (qw)+placebo-IV every four weeks (q4w) or Tocilizumab-IV 8 mg/kg q4w+placebo-SC qw in combination with DMARD(s). Maintenance of clinical responses and safety through week 97 were assessed. |
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Dosage form |
8 mg/kg; SC,IV |
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Applications |
Tocilizumab-SC had a comparable safety profile to Tocilizumab-IV through week 97, except that injection site reactions (ISRs) were more common with Tocilizumab-SC. Safety profiles in patients who switched were similar to those in patients who received continuous Tocilizumab-SC or Tocilizumab-IV treatment. |
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References: [1]. [1]Gupta S, et al. Chemically modified DNA aptamers bind interleukin-6 with high affinity and inhibit signaling by blocking its interaction with interleukin-6 receptor. J Biol Chem. 2014 Mar 21;289(12):8706-19. [2]. Burmester GR, et al. Efficacy and safety of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional DMARDs in patients with RA at week 97 (SUMMACTA). Ann Rheum Dis. 2016 Jan;75(1):68-74. |
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Tocilizumab, as a humanised monoclonal antibody, can target both membrane-bound and soluble forms of the IL-6 receptor.[1] Tocilizumab has been approved for treatment in patients with rheumatologic disorders and chimeric antigen receptor T cell-induced cytokine release syndrome.[3]
In vitro efficacy test it shown that treatment with tocilizumab (1 or 10 μm) or SOMAmer (0.83 or 8.3 μm), SOMAmer suppressed the proliferation of U87MG and HepG2 cells to a greater extent than tocilizumab at similar molar concentrations.[7]
In vivo efficacy test it indicated that treatment with 8 mg/kg tocilizumab using two consecutive intravenous infusions 12 h apart in 100 patients with COVID-19 and ARDS requiring ventilatory support in Brescia (Italy) has 20% mortality according to an optional third infusion based on clinical response.[1] In vivo, tocilizumab 8 mg/kg?×?1 in mechanically ventilated patients, the results shown that receipt of tocilizumab was independently associated with improved survival.[2] In vivo study for the treatment of rheumatoid arthritis, treatment with 4?mg/kg tocilizumab, the results exhibited that the average IL-6 level reached the peak at the second week after administration, and then decreased gradually.[4] In a 61-year-old man with COVID-19, treatment with 324 mg Tocilizumab via subcutaneous with hydroxychloroquine can successfully manage the infection.[6] In addition, the recommended dose of Tocilizumab is 4–8 mg/kg administered as a single 60- minute intravenous infusion every 4 weeks for treatment in moderate to severe active arthritis in adults, Giant cell arthritis, Polyarticular juvenile idiopathic arthritis and cytokine release syndrome in patients 2 years of age older with active disease.[5]
References:
[1] Lan SH, et al. Tocilizumab for severe COVID-19: a systematic review and meta-analysis. Int J Antimicrob Agents. 2020 Sep;56(3):106103.
[2]Somers EC, et al. Tocilizumab for Treatment of Mechanically Ventilated Patients With COVID-19. Clin Infect Dis. 2021 Jul 15;73(2):e445-e454.
[3]Wei Q, et al. Tocilizumab treatment for COVID-19 patients: a systematic review and meta-analysis. Infect Dis Poverty. 2021 May 18;10(1):71.
[4]Smolen J.S, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial.?Lancet.?2008;371(9617):987–997.
[5]Sebba A, et al. Tocilizumab: the first interleukin -6 receptor inhibitor.?Am J Health Syst Pharm.?2008;65(15):1413–1418. ?
[6]Fontana F, et al. Covid-19 pneumonia in a kidney transplant recipient successfully treated with Tocilizumab and Hydroxychloroquine.?Am. J. Transplant. American J. Transplant.?2020;20(7).
[7]Gupta S, et al. Chemically modified DNA aptamers bind interleukin-6 with high affinity and inhibit signaling by blocking its interaction with interleukin-6 receptor. J Biol Chem. 2014 Mar 21;289(12):8706-19.
Tocilizumab 作为一种人源化单克隆抗体，可以靶向 IL-6 受体的膜结合和可溶形式。[1] Tocilizumab 已被批准用于治疗风湿病和嵌合体疾病患者抗原受体T细胞诱导的细胞因子释放综合征。[3]
体外功效测试表明，在相似的摩尔浓度下，用托珠单抗（1 或 10 μm）或 SOMAmer（0.83 或 8.3 μm）处理时，SOMAmer 比托珠单抗更能抑制 U87MG 和 HepG2 细胞的增殖。<sup >[7]
体内疗效测试表明，在布雷西亚（意大利）需要通气支持的 100 名 COVID-19 和 ARDS 患者中，使用间隔 12 小时连续两次静脉输注 8 mg/kg tocilizumab 的死亡率为 20%，根据可选的根据临床反应进行第三次输注。[1] 在机械通气患者体内，tocilizumab 8 mg/kg‰×‰1，结果显示接受 tocilizumab 与改善生存独立相关。[ 2] 治疗类风湿性关节炎的体内研究，4〉mg/kg tocilizumab治疗，结果显示平均IL-6水平在给药后第二周达到峰值，然后逐渐下降。< sup>[4] 在一名患有 COVID-19 的 61 岁男性中，通过皮下注射 324 mg 托珠单抗和羟氯喹可以成功控制感染。[6] 此外，托珠单抗的推荐剂量为 4-8 mg/kg，单次给药每 4 周静脉输注 60 分钟，用于治疗成人中度至重度活动性关节炎、巨细胞性关节炎、多关节幼年特发性关节炎和 2 岁以上活动性疾病患者的细胞因子释放综合征。[5]
| Cas No. | 375823-41-9 | SDF | |
| 别名 | 托珠单抗; Anti-Human IL6R, Humanized Antibody | ||
| Canonical SMILES | [Tocilizumab] | ||
| 分子式 | 分子量 | ||
| 溶解度 | Soluble in water | 储存条件 | Store at -80°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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Tocilizumab: A Review in Rheumatoid Arthritis
Drugs 2017 Nov;77(17):1865-1879.PMID:29094311DOI:10.1007/s40265-017-0829-7.
Intravenous (IV) and subcutaneous (SC) Tocilizumab (RoActemra®), an IL-6 receptor antagonist, are approved (± methotrexate) in numerous countries throughout the world, for the treatment of adults with moderate to severe active rheumatoid arthritis (RA). Extensive clinical experience has firmly established the short- and long-term efficacy and safety of Tocilizumab [monotherapy or in combination with conventional synthetic DMARDs (csDMARDs)] in adults with early-stage and longer-duration established RA. In the clinical trial and real-world settings, Tocilizumab monotherapy or combination therapy provided rapid and sustained improvements in clinical and radiographic outcomes and health-related quality of life. The safety profile of Tocilizumab is consistent over time and, in general, is consistent with that of other immunomodulatory agents. This narrative review, written from an EU perspective, summarizes the clinical use of IV and SC Tocilizumab in RA. Given its low risk of immunogenicity, the flexibility of IV and SC administration and the convenience of the once-weekly, self-administered, SC regimen, Tocilizumab provides an effective treatment for severe, active and progressive RA in adults not previously treated with methotrexate and an effective biologic first- or subsequent-line treatment for moderate to severe active RA in adults who have either responded inadequately to or were intolerant of previous therapy with ≥ 1 csDMARD or TNF inhibitor.
Trial of Tocilizumab in Giant-Cell Arteritis
N Engl J Med 2017 Jul 27;377(4):317-328.PMID:28745999DOI:10.1056/NEJMoa1613849.
Background: Giant-cell arteritis commonly relapses when glucocorticoids are tapered, and the prolonged use of glucocorticoids is associated with side effects. The effect of the interleukin-6 receptor alpha inhibitor Tocilizumab on the rates of relapse during glucocorticoid tapering was studied in patients with giant-cell arteritis. Methods: In this 1-year trial, we randomly assigned 251 patients, in a 2:1:1:1 ratio, to receive subcutaneous Tocilizumab (at a dose of 162 mg) weekly or every other week, combined with a 26-week prednisone taper, or placebo combined with a prednisone taper over a period of either 26 weeks or 52 weeks. The primary outcome was the rate of sustained glucocorticoid-free remission at week 52 in each Tocilizumab group as compared with the rate in the placebo group that underwent the 26-week prednisone taper. The key secondary outcome was the rate of remission in each Tocilizumab group as compared with the placebo group that underwent the 52-week prednisone taper. Dosing of prednisone and safety were also assessed. Results: Sustained remission at week 52 occurred in 56% of the patients treated with Tocilizumab weekly and in 53% of those treated with Tocilizumab every other week, as compared with 14% of those in the placebo group that underwent the 26-week prednisone taper and 18% of those in the placebo group that underwent the 52-week prednisone taper (P<0.001 for the comparisons of either active treatment with placebo). The cumulative median prednisone dose over the 52-week period was 1862 mg in each Tocilizumab group, as compared with 3296 mg in the placebo group that underwent the 26-week taper (P<0.001 for both comparisons) and 3818 mg in the placebo group that underwent the 52-week taper (P<0.001 for both comparisons). Serious adverse events occurred in 15% of the patients in the group that received Tocilizumab weekly, 14% of those in the group that received Tocilizumab every other week, 22% of those in the placebo group that underwent the 26-week taper, and 25% of those in the placebo group that underwent the 52-week taper. Anterior ischemic optic neuropathy developed in one patient in the group that received Tocilizumab every other week. Conclusions: Tocilizumab, received weekly or every other week, combined with a 26-week prednisone taper was superior to either 26-week or 52-week prednisone tapering plus placebo with regard to sustained glucocorticoid-free remission in patients with giant-cell arteritis. Longer follow-up is necessary to determine the durability of remission and safety of Tocilizumab. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT01791153 .).
Tocilizumab (Actemra)
Hum Vaccin Immunother 2017 Sep 2;13(9):1972-1988.PMID:28841363DOI:10.1080/21645515.2017.1316909.
Tocilizumab (TCZ), is a recombinant humanized anti-interleukin-6 receptor (IL-6R) monoclonal antibody which has a main use in the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis (sJIA) and polyarticular juvenile idiopathic arthritis (pJIA). This article provides an overview of TCZ including looking into the past at the discovery of interleukin-6 (IL-6) as a pro-inflammatory cytokine. It also looks at how Tocilizumab was developed, manufactured and tested to ensure both safety and efficacy in a human population. The article then explores the advantages and disadvantages of using TCZ when compared to other biologics approved in RA, sJIA and pJIA and finally looks ahead to the future and the emerging role of IL-6 and its blockade by TCZ as a treatment for giant cell arteritis (GCA), polymyalgia rheumatica (PMR) and large vessel vasculitis (LVV).
Tocilizumab: the first interleukin-6-receptor inhibitor
Am J Health Syst Pharm 2008 Aug 1;65(15):1413-8.PMID:18653811DOI:10.2146/ajhp070449.
Purpose: The pharmacology, pharmacokinetics, clinical efficacy, safety, and role of Tocilizumab in rheumatoid arthritis (RA) are reviewed. Summary: Tocilizumab is a novel monoclonal antibody that competitively inhibits the binding of interleukin-6 (IL-6) to its receptor (IL-6R). Inhibiting the entire receptor complex prevents IL-6 signal transduction to inflammatory mediators that summon B and T cells. Tocilizumab has a nonlinear pharmacokinetic profile. The hypothesis that targeting and inhibiting IL-6R with Tocilizumab can result in significant improvement of the signs and symptoms of RA appears to have been substantiated in one Phase III and two Phase II clinical trials, which have demonstrated a marked reduction in disease activity and the acute-phase response. The results of these studies indicate that Tocilizumab treatment, both as a combination with methotrexate and as monotherapy, has a safety profile consistent with that of other biological and immunosuppressive therapies. In general, Tocilizumab as monotherapy and in combination with methotrexate appears to be well tolerated. Adverse events were not dose dependent and were of similar frequency in all groups. Tocilizumab appears to provide an additional option for those patients who do not respond sufficiently to methotrexate. Since IL-6R inhibition has a distinct mechanism of action, some patients who do not respond to antitumor necrosis factor agents or who have a partial response may respond to Tocilizumab. Conclusion: Tocilizumab, a novel IL-6R inhibitor, may be beneficial for the treatment of RA in patients who do not respond to methotrexate or disease-modifying antirheumatic drugs. A large clinical trial is needed to confirm Tocilizumab's clinical efficacy and safety.
Tocilizumab treatment for COVID-19 patients: a systematic review and meta-analysis
Infect Dis Poverty 2021 May 18;10(1):71.PMID:34001244DOI:10.1186/s40249-021-00857-w.
Background: Coronavirus disease 2019 (COVID-19) has killed over 2.5 million people worldwide, but effective care and therapy have yet to be discovered. We conducted this analysis to better understand Tocilizumab treatment for COVID-19 patients. Main text: We searched major databases for manuscripts reporting the effects of Tocilizumab on COVID-19 patients. A total of 25 publications were analyzed with Revman 5.3 and R for the meta-analysis. Significant better clinical outcomes were found in the Tocilizumab treatment group when compared to the standard care group [odds ratio (OR) = 0.70, 95% confidential interval (C): 0.54-0.90, P = 0.007]. Tocilizumab treatment showed a stronger correlation with good prognosis among COVID-19 patients that needed mechanical ventilation (OR = 0.59, 95% CI, 0.37-0.93, P = 0.02). Among stratified analyses, reduction of overall mortality correlates with Tocilizumab treatment in patients less than 65 years old (OR = 0.68, 95% CI: 0.60-0.77, P < 0.00001), and with intensive care unit patients (OR = 0.62, 95% CI: 0.55-0.70, P < 0.00001). Pooled estimates of hazard ratio showed that Tocilizumab treatment predicts better overall survival in COVID-19 patients (HR = 0.45, 95% CI: 0.24-0.84, P = 0.01), especially in severe cases (HR = 0.58, 95% CI 0.49-0.68, P < 0.00001). Conclusions: Our study shows that Tocilizumab treatment is associated with a lower risk of mortality and mechanical ventilation requirement among COVID-19 patients. Tocilizumab may have substantial effectiveness in reducing mortality among COVID-19 patients, especially among critical cases. This systematic review provides an up-to-date evidence of potential therapeutic role of Tocilizumab in COVID-19 management.