The molecular mode of action and species specificity of canakinumab, a human monoclonal antibody neutralizing IL-1β

We identified marmoset as the only non-human primate species that carries Glu 64 in its IL-1b and demonstrates full cross-reactivity of canakinumab, thereby enabling toxicological studies in this species

Jean-Michel Rondeau; Paul Ramage; Mauro Zurini; Hermann Gram

2015

Scholarcy highlights

  • Human IL-1b is a highly regulated, highly active pro-inflammatory cytokine that plays a key role in autoinflammatory and autoimmune diseases. IL-1b signaling requires the sequential assembly of a heterotrimeric complex comprising IL-1b and 2 transmembrane receptors, the type I IL-1 receptor and the IL-1 receptor accessory protein
  • Overall structure of the canakinumab Fab The crystalstructure of the free canakinumab Fab was determined to 2.0 A resolution from a monoclinic crystal with 4 Fab molecules in the asymmetric unit
  • The crystal structures of the canakinumab Fab in the free and IL-1b-bound states reported here were determined from crystal forms that were distinct from those recently reported
  • Human dermal fibroblasts were stimulated with recombinant human IL-1b or cell derived marmoset IL-1b in the presence of canakinumab or recombinant human IL-1 receptor antagonist
  • The structural overlay presented here proves that the canakinumab VH-VL domain binds its antigen essentially as a rigid body, which is typical of affinity-matured antibodies
  • Regarding the mechanism of action, our results indicate that canakinumab inhibits the first step in the assembly of the IL-1 receptor ternary complex, the association of IL-1b with IL-1RI
  • 360 images of 0.5 oscillation each were recorded at a crystal-to-detector distance of 200 mm, and processed with HKL2000.29 The structure was determined by molecular replacement with the program Phaser, using PDB entry 2I1B for human IL-1b4 and the structure of the free canakinumab Fab. Initial refinement was performed with the programs CNX27 and O28 as before

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