Tralokinumab Overview

Introduction of Tralokinumab

Tralokinumab (CAT-354) is a human monoclonal antibody which targets the cytokine interleukin 13（IL-13）, and is designed for the treatment of asthma and other inflammatory diseases. Tralokinumab was discovered by Cambridge Antibody Technology scientists using Ribosome Display, and has taken through pre-clinical and early clinical development. After 2007 it has been developed by MedImmune, a member of the AstraZeneca group, where it is currently in Ph3 testing for asthma and Ph2b testing for atopic dermatitis. This makes it one of the few fully internally discovered and developed drug candidates in AstraZeneca's late stage development pipeline. In a study in mice, tralokinumab prevented the development of the asthmatic phenotype, including eosinophil recruitment and airway hyperresponsiveness. In clinical trials, tralokinumab demonstrated favorable safety and pharmacokinetic profiles, both in healthy volunteers and in patients with asthma.

Mechanism of Action of Tralokinumab

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. Tralokinumab is a fully human, IL-13-neutralising IgG4 monoclonal antibody with a very high affinity for IL-13. Alanine scanning mutation analysis demonstrated that tralokinumab bound to IL-13 in helix D (PCT/GB2004/003059). Tralokinumab functionally neutralises IL-13 in a range of cell-based assays (IL-13Rα1: IL-4Rα interactions) and has shown efficacy in moderate– severe asthma.

Figure 1 Mechanism of Action of Tralokinumab

Clinical Projects of Tralokinumab *

Approved Drugs of Tralokinumab **

INN (trade name)	Therapeutic area	Dose	Strength	Route	Company	Marketing start	Market
Tralokinumab	Atopic dermatitis	Solution for injection	-	Subcutaneous use	LEO Pharma A/S	March 16, 2018

What We Provide

Therapeutic Antibody

Tralokinumab

We provide high-quality Tralokinumab 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.

Resources
* The table was excerpted from the following website
https://clinicaltrials.gov/ct2/results?term=Tralokinumab&flds=aby&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/WC500250707.pdf

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