Anti-Human IL-36R (Spesolimab) (I-2180-50mg)

Generalized pustular psoriasis (GPP) is a rare, potentially life-threatening disease characterized by the extensive eruption of skin pustules where approximately half of these flares require hospitalization1. IL-36 signaling is particularly important in GPP pathogenesis2. IL-36 cytokines play a key role in epithelial innate immunity along with the heterodimeric receptor IL-36R. IL- 36R ligands are over-expressed in lesional GPP skin and a feed-forward loop of unopposed IL- 36 signaling can occur. IL-36R signaling has also been implicated in psoriatic and rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, and inflammatory bowel disease3. IL- 36R is therefore a target of immunotherapy1,3. BI-655130 (Spesolimab) is a humanized monoclonal antibody that binds specifically to IL-36R, blocking IL-36 signaling and thus preventing cognate ligands IL-36 α, β and γ from activating IL-36R1. This ultimately prevents the activation of pro-inflammatory and pro-fibrotic pathways. BI-655130 (Spesolimab) was generated by immunizing mice with recombinant human IL-36R4. Hybridomas were produced by fusion to PAI myeloma cells. Functionally potent monoclonal antibodies were identified by screening for blockade of NFκB activation induced by IL-36 ligands in an ovarian epithelial cell line expressing endogenous functional IL-36R. The murine antibody with the best properties (MAB92) was humanized as BI-655130 (Spesolimab) by sub- cloning the mouse variable region with human constant domains and optimizing. Epitope mapping shows significant protection of residues 9 to 14, 96 to 110, 113 to 119, 149 to 154 and 177 to 186 on IL-36R, which coincides with domain 2. Substantial differences exist between human and cynomolgus monkey in the lead-binding epitope and Spesolimab does not cross-react with the cynomolgus IL-36R. Spesolimab also does not cross-react with rhesus, marmoset, mouse, rat, minipig, or hamster IL-36R.