Inducible Caspase-9 fusion protein (FKBP12F36V-truncated Caspase-9) (iC9)

The FKBP12F36V–ΔCaspase-9 fusion protein is a synthetic suicide switch engineered into T cells, such as rivogenlecleucel (BPX-501), to provide a safety mechanism against Graft-versus-Host Disease (GvHD) (Di Stasi et al., 2011). It consists of a modified human FK506-binding protein (FKBP12) with a Phenylalanine-to-Valine mutation at position 36, fused to a truncated human pro-caspase-9 that lacks its endogenous caspase activation and recruitment domain (CARD) (Gargett & Brown, 2014). The F36V mutation creates a hydrophobic pocket that specifically binds the small-molecule dimerizing drug rimiducid (AP1903) with high affinity, while avoiding interaction with endogenous FKBP12 ligands (Bell et al., 2014). Upon administration of rimiducid, the drug acts as a chemical inducer of dimerization, cross-linking the FKBP12F36V domains and bringing the fused Caspase-9 molecules into close proximity (Zhou et al., 2015). This dimerization triggers the autocatalytic activation of Caspase-9, which then initiates the executioner caspase cascade (Caspase-3, -6, and -7), leading to rapid apoptosis of the engineered T cells (Di Stasi et al., 2011). This system allows for the selective elimination of donor T cells if they cause severe GvHD after hematopoietic stem cell transplantation, thereby improving the safety profile of haploidentical transplants (Bellotti et al., 2022).

Other names

iCasp9iCaspase-9BPX-501 suicide gene productFKBP12F36V-Caspase-9 fusionInducible pro-apoptotic proteinChemical inducer of dimerization (CID) suicide switch

Rimiducid acts as a chemical inducer of dimerization (CID) that binds with high affinity to the mutated FKBP12F36V domain, forcing the fusion proteins to dimerize and trigger the autocatalytic activation of the Caspase-9 domain, which subsequently initiates the executioner caspase cascade leading to rapid cell death.