Siltuximab

Siltuximab (INN, trade name Sylvant; also known as CNTO 328, anti-IL-6 chimeric monoclonal antibody or cCLB8) is a chimeric (made from human and mouse proteins) monoclonal antibody. It binds to interleukin-6.[1][2] Siltuximab has been investigated for the treatment of neoplastic diseases:[3] metastatic renal cell cancer,[4] prostate cancer,[5] and Castleman's disease,[6][7] among other types of cancer.[8]

Siltuximab
Monoclonal antibody
TypeWhole antibody
SourceChimeric (mouse/human)
TargetIL-6
Clinical data
Trade namesSylvant
Other namesCNTO 328
License data
Pregnancy
category
  • US: C (Risk not ruled out)
    ATC code
    Legal status
    Legal status
    Identifiers
    CAS Number
    ChemSpider
    • none
    UNII
    KEGG
    Chemical and physical data
    FormulaC6450H9932N1688O2016S50
    Molar mass144983.21 g·mol−1
     NY (what is this?)  (verify)

    On April 23, 2014, siltuximab was FDA approved under the brand name of Sylvant[9] for the treatment of patients with idiopathic multicentric Castleman’s disease (iMCD) who do not have human immunodeficiency virus (HIV) or human herpesvirus-8 (HHV-8).[10][11]

    Medical uses

    Used for the treatment of idiopathic multicentric Castleman disease (iMCD).[12]

    Clinical trials

    Siltuximab has demonstrated significant efficacy and safety in patients with idiopathic multicentric Castleman disease.[13][14] Treatment results with Siltuximab in B-cell non-Hodgkin's lymphoma are inferior to those obtained in multicentric Castleman disease.[15] Siltuximab has also been evaluated in the treatment ovarian cancer, however the efficacy for this cancer is debatable.[16] In addition, siltuximab has been evaluated for multiple myeloma, but there was an insignificant increase in response rates.[17]

    Side effects

    Siltuximab may lower resistance to infections and should not be administered to patients with severe infections. Siltuximab should be discontinued in patients with severe infusion related reactions, anaphylaxis, severe allergic reactions or cytokine release syndromes. Live vaccines should not be administered to patients receiving siltuximab since IL-6 inhibition may interfere with normal immune response to new antigens.[12]

    Common The following has been shown to occur in treatment of Multicentric Castleman's disease with siltuximab during a clinical trial (>10% compared to placebo):[12]

    Long term exposure

    Drug interactions

    Siltuximab may increase CYP450 activity leading to increased metabolism of drugs that are CYP450 substrates. Co-administration of siltuximab and CYP450 substrates with narrow therapeutic index such as warfarin, ciclosporin or theophylline should be closely monitored.[12]

    Mechanism of action

    Siltuximab is a chimeric monoclonal antibody that binds to interleukin-6 (IL-6), preventing binding to soluble and membrane bound interleukin-6 receptors. Siltuximab interferes with IL-6 mediated growth of B-lymphocytes and plasma cells, secretion of vascular endothelial growth factor (VEGF) and autoimmune phenomena.[12]

    References
    1. International Nonproprietary Names for Pharmaceutical Substances (INN, prepublication copy), World Health Organization.
    2. "Siltuximab mechanism of action". HemOnc.org - A Free Hematology/Oncology Reference.
    3. Korneev KV, Atretkhany KN, Drutskaya MS, Grivennikov SI, Kuprash DV, Nedospasov SA (January 2017). "TLR-signaling and proinflammatory cytokines as drivers of tumorigenesis". Cytokine. 89: 127–135. doi:10.1016/j.cyto.2016.01.021. PMID 26854213.
    4. Rossi JF, Négrier S, James ND, Kocak I, Hawkins R, Davis H, et al. (October 2010). "A phase I/II study of siltuximab (CNTO 328), an anti-interleukin-6 monoclonal antibody, in metastatic renal cell cancer". British Journal of Cancer. 103 (8): 1154–62. doi:10.1038/sj.bjc.6605872. PMC 2967052. PMID 20808314.
    5. Karkera J, Steiner H, Li W, Skradski V, Moser PL, Riethdorf S, et al. (September 2011). "The anti-interleukin-6 antibody siltuximab down-regulates genes implicated in tumorigenesis in prostate cancer patients from a phase I study". The Prostate. 71 (13): 1455–65. doi:10.1002/pros.21362. PMID 21321981.
    6. van Rhee F, Fayad L, Voorhees P, Furman R, Lonial S, Borghaei H, et al. (August 2010). "Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman's disease". Journal of Clinical Oncology. 28 (23): 3701–8. doi:10.1200/JCO.2009.27.2377. PMID 20625121.
    7. Williams SC (October 2013). "First IL-6-blocking drug nears approval for rare blood disorder". Nature Medicine. 19 (10): 1193. doi:10.1038/nm1013-1193. PMID 24100967.
    8. "Siltuximab". ClinicalTrials.gov.
    9. "Sylvant official website".
    10. "Siltuximab approval". 23 April 2014. Archived from the original on 3 June 2014.
    11. "Castleman disease: Siltuximab cancer regimen & references". HemOnc.org - A Free Hematology/Oncology Reference.
    12. "Sylvant Prescribing Information" (PDF). janssenmd. Retrieved 3 November 2014.
    13. Fajgenbaum DC, Kurzrock R (2016). "Siltuximab: a targeted therapy for idiopathic multicentric Castleman disease". Immunotherapy. 8 (1): 17–26. doi:10.2217/imt.15.95. PMID 26634298.
    14. Sarosiek S, Shah R, Munshi NC (December 2016). "Review of siltuximab in the treatment of multicentric Castleman's disease". Therapeutic Advances in Hematology. 7 (6): 360–366. doi:10.1177/2040620716653745. PMC 5089324. PMID 27904739.
    15. Ferrario A, Merli M, Basilico C, Maffioli M, Passamonti F (March 2017). "Siltuximab and hematologic malignancies. A focus in non Hodgkin lymphoma". Expert Opinion on Investigational Drugs. 26 (3): 367–373. doi:10.1080/13543784.2017.1288213. PMID 28140696.
    16. Kampan NC, Xiang SD, McNally OM, Stephens AN, Quinn MA, Plebanski M (2018). "Immunotherapeutic Interleukin-6 or Interleukin-6 Receptor Blockade in Cancer: Challenges and Opportunities". Current Medicinal Chemistry. 25 (36): 4785–4806. doi:10.2174/0929867324666170712160621. PMID 28707587.
    17. Naymagon L, Abdul-Hay M (June 2016). "Novel agents in the treatment of multiple myeloma: a review about the future". Journal of Hematology & Oncology. 9 (1): 52. doi:10.1186/s13045-016-0282-1. PMC 4929712. PMID 27363832.
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