FK506-binding protein 12 (F36V)-truncated Caspase-9 fusion protein (iCasp9) (iCasp9)

The FKBP12-F36V–ΔCaspase-9 fusion protein, commonly known as the inducible Caspase-9 (iCasp9) safety switch, is a synthetic protein designed to provide a pharmacological control mechanism for engineered T cell therapies (Straathof et al., 2005). It consists of a modified human FK506-binding protein (FKBP12) containing an F36V mutation, which is fused to a truncated version of the human pro-caspase-9 enzyme (Di Stasi et al., 2011). The F36V mutation creates a specific binding pocket for a synthetic small-molecule dimerizer, such as Rimiducid (AP1903), while reducing affinity for endogenous ligands (Clackson et al., 1998). Upon administration of the dimerizer, the fusion proteins undergo rapid dimerization, which activates the caspase-9 proteolytic cascade and induces apoptosis in the engineered cells within hours (Gargett & Brown, 2014). This system is primarily utilized in chimeric antigen receptor (CAR) T cell therapy and hematopoietic stem cell transplantation to mitigate severe adverse events like graft-versus-host disease (GvHD) or cytokine release syndrome (CRS) (Zhou et al., 2015). By allowing for the selective elimination of therapeutic cells, iCasp9 enhances the safety profile of advanced cellular immunotherapies (Foster et al., 2021).

Other names

Inducible Caspase-9iC9FKBP12-F36V-Dcasp9Caspase-9 safety switchInducible apoptosis switch

Small-molecule induced dimerization of the FKBP12-F36V domain by Rimiducid leads to the proximity-induced activation of the fused truncated Caspase-9, which triggers the intrinsic apoptotic pathway and rapid cell death (Di Stasi et al., 2011).