Structural basis of interleukin-17B receptor in complex with a neutralizing antibody for guiding humanization and affinity maturation

Upregulation of interleukin-17 receptor B (IL-17RB) is known to be oncogenic, while other IL-17 receptors and ligands are generally involved in pro-inflammatory pathways. We identify a mouse neutralizing monoclonal antibody (mAb) D9, which blocks the IL-17RB/IL-17B pathway and inhibits pancreatic tumorigenesis in an orthotopic mouse model. The X-ray crystal structure of the IL-17RB ectodomain in complex with its neutralizing antibody D9 shows that D9 binds to a predicted ligand binding interface and engages with the A′-A loop of IL-17RB fibronectin III domain 1 in a unique conformational state. This structure also provides important paratope information to guide the design of antibody humanization and affinity maturation of D9, resulting in a humanized 1B12 antibody with marginal affinity loss and effective neutralization of IL-17B/IL-17RB signaling to impede tumorigenesis in a mouse xenograft model. [Display omitted] •Mono-GlcNAc IL-17RB is used as an immunogen for generating neutralizing antibodies•A conformational change by antibody D9 binding leads to inhibiting IL-17RB pathway•Structure of D9-bound IL-17RB guides the affinity maturation of humanized antibodies•Affinity-matured humanized antibody 1B12 is obtained with good anti-cancer activity Lee et al. report the X-ray crystal structure of IL-17RB in complex with the Fab of a neutralizing antibody revealing the detailed atomic view of the inhibitory mechanism for IL-17RB signaling pathways. From the structural information, a humanized antibody 1B12 against IL-17RB is produced and inhibits tumor growth in vivo.