gp130-specific single domain antibodies - Single domain antibodies for use in autoimmunity or cancer

Excessive gp130 activation via IL-6-type cytokines like IL-6, IL-11, or OSM mediates a variety of diseases including autoimmune-diseases (rheumatoid arthritis or inflammatory bowel disease), fibrotic diseases, and different forms of cancer. IL-6 type cytokine signaling is mediated through the common receptor gp130, which makes it an attractive therapeutic target. Antibodies or single domain antibodies (sdAbs) directed against gp130 or IL-6 cytokines can selectively block excessive signaling, thereby limiting chronic inflammation, autoimmune diseases, and tumor progression. sdAbs additionally offer advantages such as high stability, tissue penetration, and straightforward production.

Four high affinity sdAbs directed against the D2 doain of gp130 were identified. The identified sdAbs bind gp130 with high affinity (1.1 to 5.6 nM) and inhibit different IL-6 type cytokines signaling pathways including IL-6, IL-11, OSM and LIF with high efficiency (IC50 values in single to three digit nanomolar range). Interestingly, different signaling pathways where inhibited with different efficiences. In contrast to the clinically-approved IL-6R antibody Tocilizumab, the sdAbs very efficiently inhibited proinflammatory IL-6 trans-signaling, but not protective IL-6 classic-signaling. IL-11 and OSM signaling were also inhibited efficiently, while there was weaker inhibition of LIF signaling and barely any effect on CNTF signaling and no effect on IL-27 signaling. Hence, the sdAbs seems to preferentially inhibit specific IL-6 signaling pathways.