Siltuximab
(Synonyms: CNTO-328) 目录号 : GC68336Siltuximab 是一种 anti-IL-6 (interleukin-6) 单克隆抗体，具有抗肿瘤活性。Siltuximab 可用于多中心性巨大淋巴结增生症 (MCD) 和 COVID-19 的研究。
Cas No.:541502-14-1
Sample solution is provided at 25 µL, 10mM.
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Siltuximab is an anti-IL-6 (interleukin-6) monoclonal antibody, and shows antitumor activity. Siltuximab can be used in Multicentric Castleman's Disease (MCD) and COVID-19 research[1][2][3].
Siltuximab (intraperitoneal injection; 10 mg/kg; 3 times per week) inhibits the growth of lung cancer cells in xenograft mouse model[1].
Siltuximab (intraperitoneal injection; 20 mg/kg; twice per week; 6 w) inhibits the growth of MCF-7 tumor in xenograft model[4].
| Animal Model: | Female CD-1 nu/nu mice injected with H1650 (adenocarcinoma), H322 (adenocarcinoma), or H157 (squamous) cells[1] |
| Dosage: | 10 mg/kg |
| Administration: | Intraperitoneal injection; 10 mg/kg; 3 times per week |
| Result: | Repressed PY-STAT3 levels stimulated by IL-6 in H322 cells. Repressed PY-STAT3 levels in H1650 cells. Inhibited the growth of tumors with H322 and CAF cells. Inhibited the growth of tumors with H1650 and CAF cells. |
| Animal Model: | Female NOD-SCID mice with MCF-7 tumor[4] |
| Dosage: | 20 mg/kg |
| Administration: | Intraperitoneal injection; 20 mg/kg; twice per week; 6 weeks |
| Result: | Blocked MCF-7 engraftment, induced regressions in 90% of tumors. |
[1]. Karkera J, et al. The anti-interleukin-6 antibody siltuximab down-regulates genes implicated in tumorigenesis in prostate cancer patients from a phase I study. Prostate. 2011 Sep 15;71(13):1455-65.
[2]. Khan FA, et al. Systematic review and meta-analysis of anakinra, sarilumab, siltuximab and tocilizumab for COVID-19. Thorax. 2021 Sep;76(9):907-919. doi: 10.1136/thoraxjnl-2020-215266. Epub 2021 Feb 12.
[3]. Song L, et al. Antitumor efficacy of the anti-interleukin-6 (IL-6) antibody siltuximab in mouse xenograft models of lung cancer. J Thorac Oncol. 2014 Jul;9(7):974-982.
[4]. Casneuf T, et al. Interleukin-6 is a potential therapeutic target in interleukin-6 dependent, estrogen receptor-α-positive breast cancer. Breast Cancer (Dove Med Press). 2016 Feb 3;8:13-27.
| Cas No. | 541502-14-1 | SDF | Download SDF |
| 别名 | CNTO-328 | ||
| 分子式 | 分子量 | ||
| 溶解度 | 储存条件 | Store at -20°C | |
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Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial
Lancet Oncol 2014 Aug;15(9):966-74.PMID:25042199DOI:10.1016/S1470-2045(14)70319-5.
Background: Multicentric Castleman's disease is a rare lymphoproliferative disorder driven by dysregulated production of interleukin 6. No randomised trials have been done to establish the best treatment for the disease. We assessed the safety and efficacy of siltuximab-a chimeric monoclonal antibody against interleukin 6-in HIV-negative patients with multicentric Castleman's disease. Methods: We did this randomised, double-blind, placebo-controlled study at 38 hospitals in 19 countries worldwide. We enrolled HIV-negative and human herpesvirus-8-seronegative patients with symptomatic multicentric Castleman's disease. Treatment allocation was randomised with a computer-generated list, with block size six, and stratification by baseline corticosteroid use. Patients and investigators were masked to treatment allocation. Patients were randomly assigned (2:1) to Siltuximab (11 mg/kg intravenous infusion every 3 weeks) or placebo; all patients also received best supportive care. Patients continued treatment until treatment failure. The primary endpoint was durable tumour and symptomatic response for at least 18 weeks for the intention-to-treat population. Enrolment has been completed. The study is registered with ClinicalTrials.gov, number NCT01024036. Findings: We screened 140 patients, 79 of whom were randomly assigned to Siltuximab (n=53) or placebo (n=26). Durable tumour and symptomatic responses occurred in 18 (34%) of 53 patients in the Siltuximab group and none of 26 in the placebo group (difference 34·0%, 95% CI 11·1-54·8, p=0·0012). The incidence of grade 3 or more adverse events (25 [47%] vs 14 [54%]) and serious adverse events (12 [23%] vs five [19%]) was similar in each group despite longer median treatment duration with Siltuximab than with placebo (375 days [range 1-1031] vs 152 days [23-666]). The most common grade 3 or higher were fatigue (five vs one), night sweats (four vs one), and anaemia (one vs three). Three (6%) of 53 patients had serious adverse events judged reasonably related to Siltuximab (lower respiratory tract infection, anaphylactic reaction, sepsis). Interpretation: Siltuximab plus best supportive care was superior to best supportive care alone for patients with symptomatic multicentric Castleman's disease and well tolerated with prolonged exposure. Siltuximab is an important new treatment option for this disease. Funding: Janssen Research & Development.
Siltuximab: A Review in Idiopathic (Human Herpesvirus-8-Negative) Multicentric Castleman Disease
BioDrugs 2015 Dec;29(6):399-406.PMID:26394632DOI:10.1007/s40259-015-0142-5.
Siltuximab (Sylvant™), an interleukin (IL)-6 chimeric immunoglobulin Gк monoclonal antibody, is a currently the only agent approved to treat human idiopathic (herpesvirus-8 negative) multicentric Castleman disease (iMCD), which is a rare lymphoproliferative disorder. iMCD is caused by dysregulated production of IL-6 in the lymph nodes, and is associated with high morbidity, and potentially fatal consequences. Siltuximab binds to human IL-6 with high affinity and specificity, thereby preventing it from binding to IL-6 receptors, and neutralizing IL-6 bioactivity. In clinical trials in patients with iMCD, Siltuximab reduced levels of C-reactive protein (a biomarker for IL-6), and provided clinical responses. Relative to placebo, the addition of Siltuximab to best supportive care improved tumor- and symptom-related outcomes, with patients also reporting improvements in MCD symptoms, functional status, and well-being. Siltuximab has an acceptable tolerability profile, with the majority of treatment-emergent adverse events being manageable and/or of mild severity. In the absence of a cure, Siltuximab represents a significant achievement in the management of this difficult-to-treat orphan disease.
Siltuximab: first global approval
Drugs 2014 Jul;74(10):1147-52.PMID:24958337DOI:10.1007/s40265-014-0249-x.
The anti-interleukin-6 (IL-6) chimeric monoclonal antibody Siltuximab is the first drug to be approved for the treatment of multicentric Castleman's disease (MCD) in the US and European union (EU), having gained approval under the FDA priority review program in the US and from an accelerated assessment and recommendation by the Committee for Medicinal Products for Human Use (CHMP) in the EU. Development of the drug is continuing in smoldering multiple myeloma. This article summarizes the milestones in the development of Siltuximab leading to this first approval for MCD.
Clinical development of Siltuximab
Curr Oncol Rep 2015 Jul;17(7):29.PMID:25986720DOI:10.1007/s11912-015-0453-1.
Siltuximab is a chimeric monoclonal antibody targeting interleukin-6 (IL-6), which in the fall of 2014 became the first FDA-approved treatment of the rare disease idiopathic multicentric Castleman's disease (MCD). MCD is a non-clonal lymphoproliferative disorder in which common symptoms include fever, night sweats, weight loss, and fatigue. Symptoms are driven by an overall hypercytokinemia, predominantly IL-6. While under clinical development, Siltuximab was studied in several other disease states including multiple myeloma, non-Hodgkin lymphomas, and several solid tumors in which it did not demonstrate significant benefit. The efficacy of Siltuximab in MCD is mainly confined to systemic symptomatic response and quality of life benefits with minimal complete responses and approximately 30 % partial responses, by radiographic criteria. Siltuximab treatment therefore is important in the overall treatment of this rare disease state. This review focuses on the clinical development and pharmaceutical approval of Siltuximab.
Siltuximab and hematologic malignancies. A focus in non Hodgkin lymphoma
Expert Opin Investig Drugs 2017 Mar;26(3):367-373.PMID:28140696DOI:10.1080/13543784.2017.1288213.
The role of interleukin-6 (IL-6) in tumorigenesis and in particular in haematological malignancies is crucial. On the basis of the favourable results obtained in the subset of multicentric Castleman disease (MCD), Siltuximab, a chimeric, human-murine, immunoglobulin (Ig) Gk monoclonal antibody directed against human IL-6 has been evaluated in haematological malignancies such as multiple myeloma, myelodisplastic syndromes and non Hodgkin lymphomas. Areas covered: This review discusses available data related to the role of IL-6 as a therapeutic target, the characteristics of Siltuximab in term pharmacokinetics and pharmacodynamics properties and a detailed analysis of the studies involving haematological malignancies with a peculiar focus on non Hodgkin lymphoma. Expert opinion: The results obtained with Siltuximab in haematological malignancies and in particular with non Hodgkin lymphoma are inferior to those obtained in MCD. The complex interaction between malignant clones, inflammatory background and host response could justify this difference. New interesting areas of study are the role of Siltuximab in early phase of multiple myeloma (smoldering multiple myeloma) and if there may be a possible future application in the treatment of Waldenström macroglobulinemia.