Inducible caspase 9-FK506 binding protein 12 fusion protein (iC9-FKBP12) (iC9-FKBP12)

The iC9-FKBP12 fusion protein is a synthetic safety switch incorporated into rivogenlecleucel (BPX-501) T cells to manage potential toxicities such as graft-versus-host disease (GvHD) (Di Stasi et al., 2011). It consists of a truncated human caspase 9 enzyme fused to a modified human FK506-binding protein (FKBP12) with a specific mutation (F36V) that allows it to bind with high affinity to a small-molecule dimerizing agent, rimiducid (AP1903) (Bellicum Pharmaceuticals, n.d.). Under normal conditions, the iC9 protein remains in an inactive monomeric state within the engineered T cells. Upon administration of rimiducid, the drug cross-links two FKBP12 domains, bringing two caspase 9 molecules together to form an active dimer (Zhou et al., 2015). This activation triggers the intrinsic apoptotic pathway, leading to the rapid and selective elimination of the engineered T cells within hours (Di Stasi et al., 2011). This technology provides a critical control mechanism for clinicians to mitigate severe adverse events associated with adoptive immunotherapy (Gargett & Brown, 2014). The system is designed to be non-immunogenic by using human-derived components and to be highly specific through the use of a synthetic ligand (rimiducid) that does not interact with endogenous proteins. Rivogenlecleucel specifically utilizes this system in donor T cells to allow for safe hematopoietic stem cell transplantation from haploidentical donors.

Other names

iCasp9iC9CaspaCIDeInducible caspase 9BPX-501 safety switchInducible Caspase 9-FKBP12

Rimiducid acts as a chemical inducer of dimerization (CID) that binds to the FKBP12 domain of the fusion protein, leading to the dimerization and subsequent activation of the caspase 9 protease domain, which triggers the apoptotic cascade in the engineered T cells (Di Stasi et al., 2011).