Siltuximab

Siltuximab
Monoclonal antibody
Type Whole antibody
Source Chimeric (mouse/human)
Target IL-6
Clinical data
Trade names Sylvant
Pregnancy
category
  • US: C (Risk not ruled out)
Legal status
Identifiers
CAS Number 541502-14-1 N
ATC code L04AC11
ChemSpider none
UNII T4H8FMA7IM YesY
Synonyms CNTO 328
Chemical data
Formula C6450H9932N1688O2016S50
Molar mass 145.0 kg/mol
 NYesY (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.[1][2] Siltuximab has been investigated for the treatment of metastatic renal cell cancer,[3] prostate cancer,[4] and Castleman's disease,[5][6] among other types of cancer.[7]

It has undergone a phase I clinical trial in patients With B-cell non-Hodgkin's lymphoma, multiple myeloma, or Castleman's disease.[8] There were encouraging results in a small trial for advanced ovarian cancer.[9]

Encouraging results have been reported from a phase II trial for relapsed or refractory multiple myeloma.[10]

On April 23, 2014, siltuximab was FDA approved under the brand name of Sylvant[11] for the treatment of patients with multicentric Castleman’s disease (MCD) who do not have human immunodeficiency virus (HIV) or human herpesvirus-8 (HHV-8).[12][13]

Medical uses

Used for the treatment of multicentric Castleman’s disease (MCD).[14]

A randomized double-blind placebo controlled trial demonstrated that siltuximab treatment improved symptomatic multicenric Castleman’s disease (MCD) compared to placebo. Primary endpoints in the study included durable tumor and symptomatic response defined as complete or partial response with improvement or stabilization of disease related symptoms for at least 18 weeks.

A total of 79 patients were enrolled in the study (53 assigned to siltuximab, 26 assigned to placebo. This study included HIV-negative and Human herpevisrus 8 (Kaposi's sarcoma-associated herpesvirus) seronegative patients aged 20-78 years old with symptomatic multicentric Castleman’s disease (fatigue, malaise, night sweats, peripheral sensory neuropathy, anorexia, pruritus, dyspnea, oedma, hyperhidrosis) [15]

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. [14]

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) [14]

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. [14]

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.[14]

References

  1. ↑ International Nonproprietary Names for Pharmaceutical Substances (INN, prepublication copy), World Health Organization.
  2. ↑ Siltuximab mechanism of action
  3. ↑ Rossi, J. -F.; Négrier, S.; James, N. D.; Kocak, I.; Hawkins, R.; Davis, H.; Prabhakar, U.; Qin, X.; Mulders, P.; Berns, B. (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): 1154–1162. doi:10.1038/sj.bjc.6605872. PMC 2967052. PMID 20808314.
  4. ↑ Karkera, J.; Steiner, H.; Li, W.; Skradski, V.; Moser, P. L.; Riethdorf, S.; Reddy, M.; Puchalski, T.; Safer, K.; Prabhakar, U.; Pantel, K.; Qi, M.; Culig, Z. (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): 1455–1465. doi:10.1002/pros.21362. PMID 21321981.
  5. ↑ Van Rhee, F.; Fayad, L.; Voorhees, P.; Furman, R.; Lonial, S.; Borghaei, H.; Sokol, L.; Crawford, J.; Cornfeld, M.; Qi, M.; Qin, X.; Herring, J.; Casper, C.; Kurzrock, R. (2010). "Siltuximab, a Novel Anti-Interleukin-6 Monoclonal Antibody, for Castleman's Disease". Journal of Clinical Oncology 28 (23): 3701–3708. doi:10.1200/JCO.2009.27.2377. PMID 20625121.
  6. ↑ First IL-6–blocking drug nears approval for rare blood disorder Nature Medicine, October 7, 2013
  7. ↑ ClinicalTrials.gov: Siltuximab
  8. ↑ "A Safety and Efficacy Study of CNTO 328 in Patients With B-Cell Non-Hodgkin's Lymphoma, Multiple Myeloma, or Castleman's Disease".
  9. ↑ "CNTO 328 Shows Promise For Ovarian Cancer In Small Clinical Trial, Say U.K. Scientists.". 2009.
  10. ↑ "A phase II multicenter study of CNTO 328, an anti-IL-6 monoclonal antibody, in patients (pts) with relapsed or refractory multiple myeloma (MM)". 2009.
  11. ↑ Sylvant official website
  12. ↑ FDA.gov press release for siltuximab approval, accessed April 24, 2014
  13. ↑ Siltuximab cancer regimen & references
  14. 1 2 3 4 5 "Sylvant Prescribing Information" (PDF). janssenmd. Retrieved 3 November 2014.
  15. ↑ Van Rhee, F; Wong, R; Nikhil, M; Rossi, J; Ke, X; Fossa, A; Simpson, D; Capra, M; Liu, T; Hsieh, RK; Goh, YT; Zhu, J; Cho, SG; Ren, H; Cavet, J; Rajesh, B; Rothman, M; Puchalski, TA; Reddy, M; van de Velde, H; Vermeulen, J; Casper, C (July 18, 2014). "Siltuximab for multi centric Castleman's disease: a randomised, double-blind, placebo-controlled trial". Lancet Oncology 15: 966-974. doi:10.1016/S1470-2045(14)70319-5. PMID 25042199.
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