5BVP

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

5BVP の概要

• エントリーDOI: 10.2210/pdb5bvp/pdb
• 分子名称: canakinumab Fab heavy-chain, Interleukin-1 beta, Canakinumab Fab light-chain, ... (5 entities in total)
• 機能のキーワード: immunoglobulin, fab, cytokine, beta trefoil, immune system
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 65027.70

構造登録者

Rondeau, J.M. (登録日: 2015-06-05, 公開日: 2015-09-02, 最終更新日: 2024-11-06)

主引用文献

Rondeau, J.M.,Ramage, P.,Zurini, M.,Gram, H.
The molecular mode of action and species specificity of canakinumab, a human monoclonal antibody neutralizing IL-1 beta.
Mabs, 7:1151-1160, 2015

PubMed Abstract: Interleukin-1β (IL-1β) plays a key role in autoinflammatory diseases, such as systemic juvenile idiopathic arthritis (sJIA) or cryopyrin-associated periodic syndrome (CAPS). Canakinumab, a human monoclonal anti-IL-1β antibody, was recently approved for human use under the brand name Ilaris®. Canakinumab does not cross-react with IL-1β from mouse, rat, rabbit, or macaques. The crystal structure of the canakinumab Fab bound to human IL-1β was determined in an attempt to rationalize the species specificity. The X-ray analysis reveals a complex surface epitope with an intricate network of well-ordered water molecules at the antibody-antigen interface. The canakinumab paratope is largely pre-organized, as demonstrated by the structure determination of the free Fab. Glu 64 of human IL-1β is a pivotal epitope residue explaining the exquisite species specificity of canakinumab. We identified marmoset as the only non-human primate species that carries Glu 64 in its IL-1β and demonstrates full cross-reactivity of canakinumab, thereby enabling toxicological studies in this species. As demonstrated by the X-ray structure of the complex with IL-1β, canakinumab binds IL-1β on the opposite side with respect to the IL-1RAcP binding site, and in an approximately orthogonal orientation with respect to IL-1RI. However, the antibody and IL-1RI binding sites slightly overlap and the VH region of canakinumab would sterically interfere with the D1 domain of IL-1RI, as shown by a structural overlay with the IL-1β:IL-1RI complex. Therefore, direct competition with IL-1RI for IL-1β binding is the molecular mechanism of neutralization by canakinumab, which is also confirmed by competition assays with recombinant IL-1RI and IL-1RII.

PubMed: 26284424
DOI: 10.1080/19420862.2015.1081323

実験手法

X-RAY DIFFRACTION (2.2 Å)