FK506-binding protein 12–caspase-9 fusion protein (iCasp9)

The FK506-binding protein 12–caspase-9 fusion protein, commonly referred to as inducible caspase-9 (iCasp9), is a synthetic safety switch engineered into T-cells, such as those in the therapeutic product rivogenlecleucel (Di Stasi et al., 2011, NEJM). This fusion protein consists of a modified human FK506-binding protein 12 (FKBP12) with an F36V mutation, which is linked to the catalytic domain of human caspase-9 (Zhou et al., 2015, Stem Cells International). The system remains dormant and monomeric within the cell until the administration of rimiducid (AP1903), a small-molecule dimerizing agent (Gargett & Brown, 2014, Frontiers in Pharmacology). Upon binding rimiducid, the fusion proteins undergo dimerization, which activates the caspase-9 proteolytic cascade and induces rapid apoptosis of the engineered cells (Bell et al., 2011, NEJM). This technology is primarily used to control graft-versus-host disease (GvHD) in the context of hematopoietic stem cell transplantation, providing a mechanism to eliminate donor T-cells if they attack the recipient's healthy tissues (Di Stasi et al., 2011, NEJM). By enabling the precise removal of therapeutic cells, the iCasp9 system significantly improves the safety profile of adoptive immunotherapy and allows for more aggressive treatment strategies (Zhou et al., 2015, Stem Cells International).

Other names

Inducible caspase-9iC9FKBP12-F36V/caspase-9BPX-501 safety switchInducible apoptosis safety switch

Small-molecule induced dimerization of the fusion protein leads to the activation of the caspase-9 proteolytic domain, initiating the intrinsic apoptotic pathway (Di Stasi et al., 2011, NEJM).