FK506-binding protein 12 (F36V) dimerization domain (FKBP(F36V))

The FKBP-derived dimerization domain in iMC (inducible MyD88/CD40) is a synthetic protein component designed for use in chimeric antigen receptor (CAR) T-cell therapies to provide a controllable switch for immune activation. This domain is an engineered variant of the human FK506-binding protein 12 (FKBP12), typically featuring a phenylalanine-to-valine substitution at position 36 (F36V). This mutation creates a unique binding pocket that specifically accommodates the small-molecule dimerizer rimiducid (AP1903), while preventing interaction with endogenous FKBP12 or natural immunosuppressants like tacrolimus (Foster et al., 2017). In the iMC construct, the FKBP(F36V) domain is fused to the intracellular signaling domains of MyD88 and CD40. When rimiducid is administered, it cross-links two FKBP(F36V) domains, bringing the MyD88 and CD40 components into proximity to initiate downstream signaling cascades, such as the NF-kappaB pathway (Collinson-Pautz et al., 2019). This inducible co-stimulation enhances the potency, persistence, and proliferation of CAR-T cells, particularly in the immunosuppressive environment of solid tumors. By decoupling T-cell activation from antigen recognition, this technology allows clinicians to modulate the intensity of the immune response through rimiducid dosing (Bellicum Pharmaceuticals).

Other names

FKBP12(F36V)iMC dimerization domainInducible MyD88/CD40 dimerization domainF36V-FKBP12FKBP-derived dimerization domain

Rimiducid (AP1903) acts as a chemical inducer of dimerization (CID) by binding to two FKBP(F36V) domains simultaneously, which are fused to MyD88 and CD40 signaling components. This dimerization triggers the activation of NF-kappaB and other downstream pathways, providing essential co-stimulatory signals to CAR-T cells (Foster et al., 2017; Collinson-Pautz et al., 2019).