The symptoms of inherited autoinflammatory syndromes, which include
recurrent fever, joint pain, and rash, are a result of the aberrant signaling
of the proinflammatory cytokine IL-1β. As the central component of the cryopyrin
inflammasome, excess cryopyrin leads to stimulation of the inflammasome resulting in the activation of the other major component of the
inflammasone, caspase 1, which is responsible for the processing of proIL-1β to its functional form. Rilonacept’s mechanism of intervention
in the pathogenesis of CAPS is the blockade of the excessive IL-1β
signaling. As an engineered fusion protein, rilonacept combines the
extracellular binding domains of the human IL-1 receptor component
(IL-1R1) and IL-1 receptor accessory protein (IL-1RAcP) in a single
chain, with two of these chains joined to the Fc portion of human
immunoglobulin G (IgG) creating a dimeric molecule. Rilonacept serves
as an effective soluble IL-1β sink or trap since the coupled receptor
components bind IL-1βwith higher affinity than either individual
receptor. The equilibrium dissociation constants for IL-1b and IL-1a are
0.5 and 1.4 pM, respectively. Compared to other IL-1 antagonists,
rilonacept may provide improved efficacy with its offering of dual
receptor occupancy; agents containing a single soluble receptor have
been hypothesized to potentially induce immune responses since IL-1
exerts its signaling through a multi-component receptor system. Likewise, drugs that target only one of the components, such as the IL-1R1
antagonist anakinra, have been less effective in treating CAPS, possibly due to receptor occupancy issues.
