Rondeau, Jean-Michel, Ramage, Paul, Zurini, Mauro and Gram, Hermann (2015) The molecular mode of action and species specificity of canakinumab, a human monoclonal antibody neutralizing IL-1β. mAbs, 7 (6). pp. 1151-1160. ISSN 1942-08621942-0870

Abstract

Interleukin-1β (IL-1β) plays a key role in autoinflammatory diseases, such as systemic juvenile idiopathic arthritis (sJIA) or hereditary periodic fevers. Canakinumab, a human monoclonal anti-IL-1β antibody was recently approved for human use under the trade 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. The X-ray study further reveals the mechanism of action at the molecular level. 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. Biochemical assays with recombinant IL-1RI and IL-1RII confirmed the proposed mode of action.

Item Type:	Article
Keywords:	canakinumab, therapeutic antibody, Interleukin-1β, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, gouty arthritis, species specificity, crystal structure, mode of action
Date Deposited:	26 Apr 2016 23:45
Last Modified:	26 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/25938