Inducible caspase 9 fusion protein (FKBP12-F36V-Caspase 9) (iCasp9)

The FKBP12-F36V-iCasp9 fusion protein is a synthetic suicide gene system engineered into T-cells, such as rivogenlecleucel (BPX-501), to provide a safety mechanism after hematopoietic stem cell transplantation (Di Stasi et al., 2011, NEJM). It consists of a modified human FK506-binding protein (FKBP12) containing a phenylalanine-to-valine substitution at residue 36 (F36V), which is fused to a truncated human pro-caspase 9 (Zhou et al., 2015, Stem Cells). This specific mutation creates a hydrophobic pocket that allows the protein to bind with high affinity to a synthetic dimerizing agent, rimiducid (AP1903), while avoiding interaction with endogenous FKBP12 or natural ligands (Clackson et al., 1998, PNAS). In the event of graft-versus-host disease (GvHD), the administration of rimiducid induces the dimerization of the iCasp9 fusion proteins, which activates the caspase cascade and leads to the rapid, selective apoptosis of the engineered T-cells (Gargett & Brown, 2014, Frontiers in Pharmacology). This technology allows for the infusion of donor T-cells to promote immune reconstitution and graft-versus-leukemia effects while maintaining a pharmacological off-switch to control severe adverse immune reactions (Foster et al., 2021, Blood).

Other names

iCasp9Inducible caspase 9FKBP12-F36V-CASP9BPX-501 suicide geneCaspase 9 safety switch

Rimiducid acts as a chemical inducer of dimerization (CID) that binds to the mutated FKBP12 (F36V) domains of the fusion protein (Clackson et al., 1998, PNAS). This binding brings two caspase 9 molecules into close proximity, leading to their dimerization and activation, which triggers the intrinsic apoptotic pathway and rapid elimination of the modified T-cells (Di Stasi et al., 2011, NEJM).