FKBP12-inducible Caspase 9 fusion protein (iCasp9) (iCasp9)

The FKBP12-inducible Caspase 9 (iCasp9) fusion protein is a synthetic safety switch incorporated into rivogenlecleucel (BPX-501) T cells to provide a pharmacological method for controlling adverse immune reactions (Di Stasi et al., 2011, N Engl J Med; Zhou et al., 2015, Blood). It consists of a modified human FK506-binding protein (FKBP12) with an F36V mutation linked to a truncated human pro-caspase 9 that lacks its endogenous caspase activation and recruitment domain (Straathof et al., 2005, Blood; Gargett & Brown, 2014, Front Pharmacol). This system is designed to mitigate graft-versus-host disease (GvHD) in patients receiving hematopoietic stem cell transplants by allowing for the selective elimination of donor T cells (Zhou et al., 2015, Blood). When the small molecule dimerizer drug, rimiducid (AP1903), is administered, it binds to the FKBP12 domains, causing the iCasp9 proteins to dimerize and activate (Iuliucci et al., 2001, J Clin Pharmacol; Spencer et al., 1993, Science). This activation triggers the apoptotic cascade, leading to the rapid and selective elimination of the engineered T cells within hours (Di Stasi et al., 2011, N Engl J Med). This technology allows for the benefits of donor T-cell infusion, such as immune reconstitution and graft-versus-leukemia effects, while providing a 'kill switch' to manage life-threatening toxicity (Gargett & Brown, 2014, Front Pharmacol).

Other names

Inducible Caspase 9iCasp9FKBP12-Caspase 9Caspase 9 suicide switchBPX-501 safety switchFKBP12(F36V)-Caspase 9

Small molecule-induced dimerization of the FKBP12(F36V) domain leads to the activation of the linked Caspase 9 protease, which initiates the intrinsic apoptotic pathway and results in rapid cell death (Di Stasi et al., 2011, N Engl J Med; Straathof et al., 2005, Blood).