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Interleukin-6 (IL-6) plays a central role in idiopathic Multicentric Castleman Disease (iMCD) pathology, biochemical alteration and symptomology. It is hypothesised that IL-6 drives plasma cell proliferation and systemic manifestations.1,2

SYLVANT® is a monoclonal antibody that binds to soluble human IL-6 with high affinity, preventing it from binding IL-6 receptors (both soluble and membrane bound).2 Consequently the IL-6 signaling pathway is disrupted, inhibiting the cytokine’s pleiotropic pro-inflammatory effects.

Mode of action

IL-6 signalling in a patient with iMCD. An uninhibited overproduction of IL-6 is the most common pathological driver of iMCD and its symptoms.1,2 IL-6 signalling occurs when the protein interacts with soluble IL-6R. In association with the signal transducer gp130, this complex results in dimerisation and activation of the JAK/STAT signalling cascade.1

Mode of action

Mechanism of action in an iMCD patient treated with SYLVANT®. SYLVANT® prevents the binding of the protein IL-6 to both soluble and membrane-bound IL-6R, thus inhibiting the formation of the hexameric signaling complex with gp130 on the cell surface.1 This binding of SYLVANT® to IL-6 therefore blocks the downstream signaling cascade.3 It’s hypothesised that this prevents the proliferation of plasma cells.1

Abbreviations: gp130, glycoprotein 130; HHV-8, human herpesvirus-8; HIV, human immunodeficiency virus; IL-6, interleukin-6; IL-6R, IL-6 receptor; iMCD, idiopathic Multicentric Castleman Disease; mAb, monoclonal antibody.

References
1. SYLVANT® Summary of Product Characteristics (2019)
2. Sarosiek S, Shah R, Munshi NC. Review of siltuximab in the treatment of multicentric Castleman’s disease. Ther Adv Hematol. 2016;7(6):360-6.
3. van Rhee F, Voohees P, Dispenzieri A, et al. Blood. 2018; 132 (20): 2115-2125.
4. van Rhee F, et al. Hematol Oncol Clin N Am. 2018; 32: 89–106.