Sirukumab Overview

Introduction of Sirukumab

Sirukumab (developmental code name CNTO-136) is a human monoclonal antibody (mAb) designed for the treatment of rheumatoid arthritis (RA). It acts against the proinflammatory cytokine interleukin (IL) -6 (IL-6). Sirukumab was evaluated in five Phase 3 studies of patients with RA. In September 2016, Janssen submitted a biologics license application (BLA) seeking approval of sirukumab for the treatment of moderately to severely active RA, but they announced in September 2017 that they received a complete response letter from the Food and Drug Administration (FDA) indicating additional clinical data were needed to further evaluate the safety of sirukumab in that patient population. Janssen subsequently decided not to pursue global approvals of sirukumab for the treatment of moderately to severely active RA. Sirukumab was being evaluated in a Phase 3 study (NCT02531633) of another inflammatory disease, giant cell arteritis. This study, sponsored by GlaxoSmithKline (GSK), was terminated in November 2017 due to GSK’s decision to return rights to sirukumab to Janssen and discontinue sirukumab development in giant cell arteritis. Also, in November 2017, a Phase 3 study (NCT02899026) sponsored by GSK of sirukumab in patients with polymyalgia rheumatica, an inflammatory disorder that causes muscle pain and stiffness, was withdrawn prior to enrollment.

Mechanism of Action of Sirukumab

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease of the intra-articular synovial tissue. Studies to uncover the cause of RA have ended up scrutinizing the importance of proinflammatory cytokine such as tumor necrosis factor a (TNF-a) and IL-6 in the pathogenesis of RA. IL-6 is a pro-inflammatory cytokine with pleiotropic biological activities. The signaling pathway of IL-6 includes two molecules, a specific receptor for IL-6 and a cell-surface glycoprotein called gp130 as a signal transducer. IL-6 transmits its signal through binding to membrane-bound IL-6R (mIL-6R) or soluble IL-6R (sIL-6R) that are respectively called classic signaling and trans-signaling. Binding of IL-6 to mIL-6R or sIL-6R recruits two molecules of ubiquitously expressed gp130 and induces their homodimerization. The formation of functional receptor complex of IL-6, IL-6R, and gp130 subsequently triggers downstream signaling pathway via Janus kinase (JAK) leading to the regulation of transcription factors including STAT3 in target cells. The sIL-6R generated by limited proteolysis of mIL-6R or alternative splicing plays an important role especially in the cells which do not express mIL-6R. In the serum of RA patients, elevated levels of IL-6 and sIL-6R are detected with positive correlation to RA disease severity and radiological joint damage. Moreover, overproduction of IL-6 has been found in the synovial cell and macrophage of the joint of RA patients. IL-6 contributes to induction and maintenance of autoimmune process through B cell modulation and Th17 cell differentiation. IL-6 also plays a role in angiogenesis by inducing intracellular adhesion molecules. These functions of IL-6 in the pathogenesis of RA make IL-6 as a remarkable target for the RA therapy. Sirukumab binds IL-6 with high affinity and specificity, thereby inhibiting IL-6-mediated effects.

Fig.1 Mechanism of action of sirukumab

Clinical Projects of Sirukumab*

What We Provide

Therapeutic Antibody

Sirukumab

We provide high-quality Sirukumab for use in WB, FC, IP, ELISA, Neut, FuncS, IF and most other immunological methods. For lab research use only, not for diagnostic, therapeutic or any in vivo human use.

* The table was excerpted from the following website
https://clinicaltrials.gov/ct2/results?cond=&term=Sirukumab

For research use only. Not intended for any clinical use.