FK506-binding protein 12 (FKBP12) domain within the inducible caspase 9 (iCasp9) suicide construct (iCasp9)

The FK506-binding protein 12 (FKBP12) domain within the inducible caspase 9 (iCasp9) suicide construct is a critical regulatory component used in adoptive cell therapies to provide a safety "kill switch." This domain is typically a modified version of human FKBP12, containing a phenylalanine-to-valine substitution at position 36 (F36V), which creates a specialized binding pocket for synthetic dimerizing agents like Rimiducid (AP1903) (Di Stasi et al., 2011; Gargett & Brown, 2014). In the iCasp9 system, this FKBP12(F36V) domain is fused to a human caspase 9 protein that lacks its endogenous recruitment domain. When a patient experiences severe adverse effects, such as graft-versus-host disease (GvHD) or cytokine release syndrome, the administration of Rimiducid causes the FKBP12 domains to dimerize, thereby bringing the attached caspase 9 molecules together (Tey et al., 2007). This dimerization activates the caspase 9, which then triggers the executioner caspases and leads to rapid programmed cell death of the engineered cells. This technology allows for the precise elimination of therapeutic cells while sparing the rest of the patient's immune system, significantly improving the safety profile of treatments like CAR-T cell therapy and haploidentical stem cell transplants (Zhou et al., 2015).

Other names

iCasp9Inducible caspase 9FKBP12-caspase 9 fusion proteinFKBP12(F36V)-Caspase 9Suicide gene safety switchiC9

Small molecule-induced dimerization of the FKBP12(F36V) domains leads to the activation of the fused caspase 9 protease, which initiates the apoptotic signaling cascade (Di Stasi et al., 2011).