Introduction of Lebrikizumab

Lebrikizumab (INN) is a humanized monoclonal antibody and an experimental immunosuppressive drug for the treatment of asthma that cannot be adequately controlled with inhalable glucocorticoids. The drug was created under the name TNX-650, and a phase I clinical trial for refractory Hodgkin’s lymphoma had been performed in 2007. It has successfully completed a Phase II clinical trial for the treatment of asthma.

Mechanism of Action of Lebrikizumab

Asthma is a complex, chronic and heterogeneous inflammatory disease characterised by airway hyper-responsiveness in association with airway inflammation. The cytokine interleukin 13 (IL-13), produced by Th2 cells, a type of white blood cells, is a major effector molecule for T-helper type 2 (Th2) inflammation and is pathogenic in allergic diseases such as asthma. IL-13 is a member of the four-helix bundle short-chain cytokine family, along with the closely related cytokine IL-4, has been shown to drive key disease mechanisms in asthma including airway hyper-responsiveness, mucus hypersecretion, eosinophilia and fibrosis development.

IL-13 mediates its biological effects by binding to two receptors: (1) the heterodimeric combination of IL-13Rα1 and IL-4Rα or (2) IL-13Rα2. Of these, the heterodimeric receptor of IL-13Rα1 and IL-4Rα is also bound by IL-4. IL-13 initially binds to IL-13Rα1 with a modest affinity on one side and then recruiting IL-4Rα on the opposite side with a weak affinity to form a signal transducer and activator of transcription 6 signaling complex in which IL-13 is in the middle of the two receptors, leading to the formation of IL-13/IL-13Rα1/IL-4Rα complexes. In contrast, IL-13 binds to IL-13Rα2 with a very high affinity using the combination of two well separated binding sites, more or less at opposite ends of IL-13 helix D, to interact with all three domains of the IL-13Rα2 extracellular region. IL-13Rα2 lacks a significant cytoplasmic tail and is generally considered to be a decoy involved in removing IL-13 by internalisation. The IL-13Rα1 binding site on IL-13 strongly overlaps with the IL- 13Rα2 binding site, with differences in detail accounting for the large difference in affinity. Differently, the IL-4Rα binding site on IL-13 is distinct from those of IL-13Rα1 and IL-13Rα2, on the opposite side of IL-13 and composed of elements from helices A and C.

Antibodies raised against IL-13 can block its inflammatory effects by interfering with binding to either of the two receptor polypeptides. Lebrikizumab is a monoclonal anti-IL-13 antibody that has shown clinical benefit for the treatment of moderate-to-severe uncontrolled asthma and improved lung function. Lebrikizumab inhibits IL-13 signaling by binding to IL-13 with very high affinity and blocking IL-13 binding to IL-4Rα. Thereby preventing the formation of an active cytokine/receptor complex consisting of IL-13, IL- 13Rα1, and IL-4Rα, resulting the intrinsic affinity between IL-13 and IL-4Rα alone is too low for direct testing in a similar ELISA assay.

Clinical Projects of Lebrikizumab *

Approved Drugs of Lebrikizumab**

Resources
* The table was excerpted from the following website
https://clinicaltrials.gov/ct2/results?term=Lebrikizumab&Search=Apply&recrs=b&recrs=a&recrs=f&recrs=d&age_v=&gndr=&type=&rslt=

** Information presented in the table were collected from the following websites:
http://www.ema.europa.eu/docs/en_GB/document_library/PIP_decision/WC500199542.pdf

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