FK506-binding protein 12 (F36V) domain of inducible Caspase 9 (iCasp9) (iCasp9)

The engineered FKBP domain of iCasp9 is a synthetic safety switch designed for use in adoptive cell therapies, such as CAR-T cells and hematopoietic stem cell transplants [1]. It consists of a modified human FK506-binding protein 12 (FKBP12) containing a phenylalanine-to-valine mutation at position 36 (F36V), which is fused to a truncated human Caspase 9 [2]. This specific mutation creates a subpocket that allows the domain to bind with high affinity to a synthetic, bio-inert small molecule dimerizer, such as Rimiducid (AP1903), while avoiding interaction with endogenous FKBP12 or natural ligands like FK506 [3]. When the dimerizer is administered, it cross-links two FKBP domains, bringing the associated Caspase 9 monomers into close proximity. This dimerization mimics the physiological activation of Caspase 9, triggering a rapid apoptotic cascade that eliminates the engineered cells [1, 2]. This suicide gene system is primarily employed to manage severe adverse events like graft-versus-host disease or cytokine release syndrome by providing a controlled method to terminate the therapy [4]. [1] Di Stasi, A., et al. (2011) NEJM. [2] Straathof, K. C., et al. (2005) Blood. [3] Clackson, T., et al. (1998) PNAS. [4] Gargett, T., & Brown, M. P. (2014) Front Pharmacol.

Other names

Inducible Caspase 9FKBP12-F36VCaspase 9 suicide geneiC9Chemical inducer of dimerization (CID) system

Small molecule-induced dimerization of the FKBP12-F36V domain leads to the activation of the fused Caspase 9 enzyme, triggering the intrinsic apoptotic pathway.