Development and Role in Therapy of Canakinumab in Adult-Onset Still's Disease

Abstract

Adult-onset Still's disease (AOSD) is a rare inflammatory disease of unknown etiology typically characterized by episodes of spiking fever, evanescent rash, arthralgia, leukocytosis, and hyperferritinemia. The pivotal role of interleukin (IL)-1 and other pro-inflammatory cytokines gives rise to the development of new targeted therapies. Currently, AOSD patients can benefit from efficient and well tolerated biologic agents, such as IL-1, IL-6, and tumour necrosis factor (TNF)-α antagonists. Canakinumab, a human monoclonal anti-IL-1β antibody, is indicated for the treatment of different autoinflammatory syndromes in adults, adolescents, and children and it has recently been approved for AOSD treatment. In this article, we summarize the structural and biochemical data describing the molecular interactions between Canakinumab and its target antigen. Some special considerations of the pharmacological properties of Canakinumab are included. We also review the safety, efficacy and tolerability of this drug for the treatment of AOSD.

Keywords: Adult-onset Still’s disease; Canakinumab; Interleukin-1 beta; drug development; therapy.

FIGURE 1

Mode of action of IL-1 and its inhibitors. (A) The IL-1 inhibitors (anakinra, rilonacept, and canakinumab). Anakinra (on the left) competes with free IL-1β for the binding with IL-1RI but not with the adaptor protein, thus preventing signal transduction. Rilonacept (in the middle) and Canakinumab (on the right) bind to circulating IL-1β. (B) Binding of IL-1β to the IL-1 receptor type I (IL-1RI) heterodimer complex results in signal transduction. IL-1β binds to the membrane-bound IL-1RI to form a complex with the IL-1 receptor accessory protein (IL-1RAcP). This complex recruits the IL-1RI-associated kinase (IRAK), leading to signal transduction and gene activation.

FIGURE 2

(A) Steric complementarity between Canakinumab and IL-1β. Canakinumab (gray) binding to IL-1β (blues) largely obeys a lock-and-key type mechanism, with contributions by all CDRs and without any large structural changes of the paratope. (B,C) Hydrophobic potential of Canakinumab’s Fab heavy and light chain. The surfaces are colored according to amino acid hydrophobicity. The hydrophobic residues (larger positive values of hydrophobicity) are maroon, while the hydrophilic residues (negative values of hydrophobicity) are cyan. The binding interface is remarkably flat, extensively hydrated, and very large. The IL-1β epitope does not include any aromatic or bulky hydrophobic residues. (2 B) surface epitope; (2 C) surface paratope. (D) All kind of interactions (polar and no polar, favorable) between Canakinumab and IL-1β. The paratope residues that stand out in terms of number of intermolecular contacts to IL-1β are colored in yellow: Arginine (Arg) H101, Tryptophan (Trp) H52, Tyrosine (Tyr) H53, Tyr H32 and Tyr L50. Arg H101 of the H-CDR3 loop plays an important role by forming strong electrostatic interactions with the epitope residue Glutamic acid (Glu) 64 (orange). Lysine (Lys) 27 (green) forms salt-bridge interactions.