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

Cell Rep. 2022 Oct 25;41(4):111555. doi: 10.1016/j.celrep.2022.111555.

Abstract

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.

Keywords: CP: Cancer; CP: Immunology; X-ray crystal structure; antibody; antibody affinity maturation; complex structure; humanized antibody; interleukin-17 receptor B, IL-17RB; pancreatic cancer; targeting therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / metabolism
  • Antibodies, Neutralizing / metabolism
  • Carcinogenesis
  • Fibronectins / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Interleukin-17* / metabolism
  • Ligands
  • Mice
  • Receptors, Interleukin-17* / metabolism

Substances

  • Receptors, Interleukin-17
  • Interleukin-17
  • Fibronectins
  • Ligands
  • Antibodies, Neutralizing
  • Antibodies, Monoclonal