FK506-binding protein 12 F36V-containing fusion protein (FKBP12(F36V) fusion protein)

FK506-binding protein 12 (FKBP12) F36V-containing fusion proteins are synthetic constructs designed for use in cell-based therapies to provide precise pharmacological control over cellular activities. This system utilizes a modified version of the human FKBP12 protein featuring a phenylalanine-to-valine substitution at position 36 (F36V), which creates a unique hydrophobic pocket. This pocket specifically binds to "bumped" synthetic ligands like rimiducid (AP1903) with high affinity, while avoiding interaction with endogenous wild-type FKBP12 or natural ligands like FK506 [1][2]. The most prominent application is the inducible Caspase-9 (iCasp9) safety switch, where the FKBP12(F36V) domain is fused to a truncated human Caspase-9. Upon administration of rimiducid, the drug acts as a chemical inducer of dimerization (CID), cross-linking two fusion proteins and triggering the apoptotic cascade to eliminate the engineered cells [1][3]. Beyond safety switches, these fusion proteins are also employed in inducible activation systems, such as the iMC (inducible MyD88/CD40) platform, to enhance the potency and persistence of chimeric antigen receptor (CAR) T cells in treating various cancers [4]. This technology allows clinicians to mitigate severe toxicities like graft-versus-host disease or cytokine release syndrome by selectively depleting the therapeutic cells. References: [1] Di Stasi A, et al. N Engl J Med. 2011;365(18):1673-1683. [2] Clackson T, et al. Proc Natl Acad Sci U S A. 1998;95(18):10437-10442. [3] Gargett T, Brown MP. Front Pharmacol. 2014;5:235. [4] Foster AE, et al. Mol Ther. 2017;25(5):1076-1085.

Other names

FKBP12v36FKBP(F36V)Inducible Caspase-9iCasp9Inducible MyD88/CD40iMCChemical inducer of dimerization (CID) system

Rimiducid acts as a bivalent chemical inducer of dimerization (CID) that binds to two FKBP12(F36V) domains simultaneously, bringing the attached effector proteins into close proximity to initiate downstream biological signaling or apoptosis [1][3].