Inducible Caspase 9 fusion protein (iCasp9)

The FKBP12-iCaspase 9 fusion protein is a synthetic safety switch engineered into T cells, such as rivogenlecleucel (BPX-501), to provide a controlled mechanism for cell elimination (Di Stasi et al., 2011, NEJM). It comprises a modified human FK506-binding protein (FKBP12) with an F36V mutation fused to a truncated human Caspase 9 (Zhou et al., 2015, Stem Cells). The system remains dormant until the administration of rimiducid (AP1903), a small-molecule dimerizing agent that specifically binds the mutated FKBP12 domains (Bell et al., 2011, NEJM). This binding induces dimerization of the Caspase 9 molecules, triggering the intrinsic apoptotic pathway and leading to the rapid death of the engineered cells. This technology is primarily used in hematopoietic stem cell transplantation to mitigate graft-versus-host disease (GvHD) by allowing for the selective depletion of donor T cells if they become pathogenic (Gargett & Brown, 2014, Frontiers in Pharmacology). The fusion protein is often co-expressed with a truncated CD19 marker to allow for the selection and monitoring of the modified cells (Tey et al., 2007, Biology of Blood and Marrow Transplantation).

Other names

FKBP12-iCaspase 9iCasp9 safety switchFKBP12(F36V)-Caspase 9BPX-501 safety switchInducible suicide gene

Small-molecule induced dimerization of the FKBP12-Caspase 9 fusion protein leads to the activation of the apoptotic cascade.