Engineered caspase-9–FKBP12 fusion protein (iCasp9) (iCasp9)

The engineered caspase-9–FKBP12 fusion protein, commonly known as inducible caspase-9 (iCasp9), is a synthetic safety switch designed for adoptive cell therapies such as rivogenlecleucel (BPX-501) (Di Stasi et al., 2011, NEJM). It consists of a truncated human pro-caspase-9 protein fused to a human FK506-binding protein (FKBP12) variant containing an F36V mutation (Straathof et al., 2005, Blood). This specific mutation allows the FKBP12 domain to bind with high affinity to a synthetic small-molecule dimerizer, rimiducid (AP1903), while avoiding interaction with endogenous FK506 (Gargett & Brown, 2014, Frontiers in Pharmacology). In the absence of the dimerizer, the iCasp9 fusion protein remains in an inactive monomeric state within the cytoplasm of the engineered T cells. Upon administration of rimiducid, the drug induces the dimerization of the iCasp9 proteins, which triggers the intrinsic apoptotic pathway and leads to the rapid, selective elimination of the transduced cells (Zhou et al., 2015, Blood). This mechanism is primarily utilized to mitigate the risk of severe graft-versus-host disease (GvHD) in patients undergoing hematopoietic stem cell transplantation by providing a way to 'turn off' the donor T cells if they become harmful (Budde et al., 2013, PLOS ONE).

Other names

Inducible caspase-9iCasp9Caspase-9–FKBP12 fusion proteinBPX-501 suicide gene product

Small-molecule-induced dimerization of the FKBP12 domain leads to the activation of the caspase-9 domain, triggering the intrinsic apoptotic pathway in the host cell (Gargett & Brown, 2014).