Chemistry:Siltuximab

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Short description: Pharmaceutical drug
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
 ☒N☑Y (what is this?)  (verify)

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.[2][3] Siltuximab has been investigated for the treatment of neoplastic diseases:[4] metastatic renal cell cancer,[5] prostate cancer,[6] other types of cancer,[7] and for Castleman's disease.[8][9]

On April 23, 2014, siltuximab was FDA approved under the brand name of Sylvant[10] 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).[11][12]

Medical uses

Used for the treatment of idiopathic multicentric Castleman disease (iMCD).[13]

Clinical trials

Siltuximab has demonstrated significant efficacy and safety in patients with idiopathic multicentric Castleman disease.[14][15] Treatment results with Siltuximab in B-cell non-Hodgkin's lymphoma are inferior to those obtained in multicentric Castleman disease.[16] Siltuximab has also been evaluated in the treatment ovarian cancer, however the efficacy for this cancer is debatable.[17] In addition, siltuximab has been evaluated for multiple myeloma, but there was an insignificant increase in response rates.[18]

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.[13]

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):[13]

  • Peripheral edema
  • Abdominal Pain
  • Pruritus
  • Increased weight
  • Rash
  • Hyperuricemia
  • Upper respiratory tract infections

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.[13]

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.[13]

References

  1. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2015". 21 June 2022. https://www.tga.gov.au/prescription-medicines-registration-new-chemical-entities-australia-2015. 
  2. ↑ International Nonproprietary Names for Pharmaceutical Substances (INN, prepublication copy), World Health Organization.
  3. ↑ "Siltuximab mechanism of action". HemOnc.org - A Free Hematology/Oncology Reference. http://hemonc.org/wiki/Siltuximab_(Sylvant). 
  4. ↑ "TLR-signaling and proinflammatory cytokines as drivers of tumorigenesis". Cytokine 89: 127–135. January 2017. doi:10.1016/j.cyto.2016.01.021. PMID 26854213. 
  5. ↑ "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. October 2010. doi:10.1038/sj.bjc.6605872. PMID 20808314. 
  6. ↑ "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. September 2011. doi:10.1002/pros.21362. PMID 21321981. 
  7. ↑ "Siltuximab". ClinicalTrials.gov. http://www.clinicaltrials.gov/ct2/results?term=siltuximab. 
  8. ↑ "Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman's disease". Journal of Clinical Oncology 28 (23): 3701–8. August 2010. doi:10.1200/JCO.2009.27.2377. PMID 20625121. 
  9. ↑ "First IL-6-blocking drug nears approval for rare blood disorder". Nature Medicine 19 (10): 1193. October 2013. doi:10.1038/nm1013-1193. PMID 24100967. 
  10. ↑ "Sylvant official website". http://www.sylvant.com/. 
  11. ↑ "Siltuximab approval". 23 April 2014. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm394675.htm. 
  12. ↑ "Castleman disease: Siltuximab cancer regimen & references". HemOnc.org - A Free Hematology/Oncology Reference. http://hemonc.org/wiki/Castleman%E2%80%99s_disease#Siltuximab_.28Sylvant.29. 
  13. ↑ 13.0 13.1 13.2 13.3 13.4 "Sylvant Prescribing Information". http://www.janssenmd.com/pdf/sylvant/SYLVANT-PI.pdf. 
  14. ↑ "Siltuximab: a targeted therapy for idiopathic multicentric Castleman disease". Immunotherapy 8 (1): 17–26. 2016. doi:10.2217/imt.15.95. PMID 26634298. 
  15. ↑ "Review of siltuximab in the treatment of multicentric Castleman's disease". Therapeutic Advances in Hematology 7 (6): 360–366. December 2016. doi:10.1177/2040620716653745. PMID 27904739. 
  16. ↑ "Siltuximab and hematologic malignancies. A focus in non Hodgkin lymphoma". Expert Opinion on Investigational Drugs 26 (3): 367–373. March 2017. doi:10.1080/13543784.2017.1288213. PMID 28140696. 
  17. ↑ "Immunotherapeutic Interleukin-6 or Interleukin-6 Receptor Blockade in Cancer: Challenges and Opportunities". Current Medicinal Chemistry 25 (36): 4785–4806. 2018. doi:10.2174/0929867324666170712160621. PMID 28707587. 
  18. ↑ "Novel agents in the treatment of multiple myeloma: a review about the future". Journal of Hematology & Oncology 9 (1): 52. June 2016. doi:10.1186/s13045-016-0282-1. PMID 27363832. 



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