Lebrikizumab (lebri) is a novel, monoclonal antibody that selectively targets interleukin (IL)-13 and prevents formation of the IL-13 receptor alpha 1 (Rα1)/IL-4 receptor alpha (Rα) heterodimer receptor signaling complex. A previous crystal structure report showed that lebri does not interfere with binding of IL-13 to the IL-13 Receptor alpha 2 (Ra2) decoy receptor. In contrast, other IL-13 antibodies tralokinumab and cendakimab had been reported to inhibit IL-13 binding to both IL-13Ra1 and IL-13Ra2. We wanted to investigate whether lebri binding to IL-13 interfered with IL-13 binding to IL-13Ra2 and the subsequent internalization. Through competitive binding experiments using surface plasmon resonance, we confirmed that lebri can bind to the tralokinumab/IL-13 and cendakimab/IL-13 complexes. These data showed that lebri binds to IL-13 at a different epitope. First, we induced IL-13Rα2 expression on HaCaT cells, a spontaneously transformed keratinocyte cell line from adult human skin, using co-treatment of IL-13 and TNF-alpha. Then, we fluorescently stained these cells and confirmed the increased expression of IL-13Rα2. Using live-cell confocal imaging, we observed that IL-13 can bind IL-13Ra2 and is internalized into the cells. These experiments were conducted in the presence of an IL-13Rα1 inhibitory antibody to ensure the observed binding is only through IL-13Rα2. Importantly, we also observed binding and internalization of the IL-13/lebri complex, while IL-13/tralokinumab and IL-13/cendakimab complexes do not bind to the IL-13Rα2 receptor and are not internalized into the cells. The internalized IL-13/lebri complex colocalized with a lysosome marker, indicating that it is likely to be degraded in lysosomes. In summary, lebri allows IL-13 to bind and internalize through the IL-13Rα2. This mode of action differentiates it from tralokinumab and cendakimab, since lebri allows natural clearance of IL-13 levels through IL-13Rα2.

ESDR109 - Lebrikizumab Allows Interleukin-13 Membrane Binding and Subsequent Internalization through the Decoy Receptor Interleukin-13 Receptor Alpha 2

The scientific meeting of the European Society for Dermatological Research (ESDR) is held yearly, usually in September. With an international attendance of more than 1000 skin scientists from around the globe, the four-day event includes short oral presentations from peer-reviewed abstracts, keynote lectures from international experts, sponsored symposia, satellite programs, educational events as well as an important focus on posters, networking and building collaborations amongst scientists. For more information about this year’s meeting visit our website.