Inducible Caspase 9 (iCasp9) (iCasp9)

The Inducible Caspase 9 (iCasp9) fusion protein is a synthetic safety mechanism designed for use in adoptive cellular therapies, such as CAR-T cells and hematopoietic stem cell transplants (Di Stasi et al., 2011, NEJM). It comprises a modified human FK506-binding protein (FKBP12) with a Phenylalanine-to-Valine mutation at position 36 (F36V), fused to a truncated human Caspase 9 protein (Gargett & Brown, 2014, Frontiers in Pharmacology). The F36V mutation creates a unique binding pocket that specifically accommodates a small-molecule dimerizing drug, such as Rimiducid (AP1903), which does not interact with endogenous wild-type FKBP12 (Clackson et al., 1998, PNAS). When the dimerizer is administered, it cross-links the FKBP12-F36V domains, bringing the Caspase 9 monomers into close proximity to form active dimers. This activation initiates the apoptotic cascade, resulting in the rapid and selective destruction of the engineered T cells (Zhou et al., 2015, Stem Cells Translational Medicine). This suicide switch allows clinicians to eliminate therapeutic cells in the event of severe, uncontrollable toxicities like Graft-versus-Host Disease (GvHD) or Cytokine Release Syndrome (CRS).

Other names

FKBP12-F36V-Caspase 9 fusion proteiniC9Inducible suicide geneFKBP12(V36)-Caspase 9

Small molecule-induced dimerization of the FKBP12-F36V domains leads to the proteolytic activation of the linked Caspase 9 effector domains, triggering the intrinsic apoptotic pathway (Di Stasi et al., 2011, NEJM; Gargett & Brown, 2014, Frontiers in Pharmacology).