The molecular mode of action and species specificity of canakinumab, a human monoclonal antibody neutralizing IL-1β.
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.
a Novartis Institutes for BioMedical Research ; Basel , Switzerland.
Jean-Michel
JM
Rondeau
a Novartis Institutes for BioMedical Research ; Basel , Switzerland.
Paul
P
Ramage
a Novartis Institutes for BioMedical Research ; Basel , Switzerland.
Mauro
M
Zurini
a Novartis Institutes for BioMedical Research ; Basel , Switzerland.
Hermann
H
Gram
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing / Q000276:immunology* / Q000378:metabolism; D000918:Antibody Specificity / Q000276:immunology*; D001667:Binding, Competitive / Q000276:immunology; D002144:Callithrix; D003429:Cross Reactions / Q000276:immunology; D018360:Crystallography, X-Ray; D000939:Epitopes / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D018698:Glutamic Acid / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D008251:Macaca; D051379:Mice; D008958:Models, Molecular; D011485:Protein Binding / Q000276:immunology; D017434:Protein Structure, Tertiary; D011817:Rabbits; D051381:Rats; D017472:Receptors, Interleukin-1 / Q000276:immunology / Q000378:metabolism; D013045:Species Specificity
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D000939:Epitopes; D053583:Interleukin-1beta; D017472:Receptors, Interleukin-1; C541220:canakinumab; D018698:Glutamic Acid
Interleukin-1β; canakinumab; cryopyrin-associated periodic syndrome; crystal structure; gouty arthritis; mode of action; species specificity; systemic juvenile idiopathic arthritis; therapeutic antibody