Peptidyl-prolyl cis-trans isomerase FKBP1A (FKBP12-F36V) (FKBP12-F36V)

The mutant FKBP12 dimerization domain (specifically the F36V variant) is a synthetic protein component integrated into the inducible MyD88/CD40 (iMC) module, which is a cornerstone of GoCAR-T cell therapy (Source: Bellicum Pharmaceuticals). This domain is an engineered version of the human Peptidyl-prolyl cis-trans isomerase FKBP1A (FKBP12), where a phenylalanine-to-valine substitution at position 36 creates a unique binding pocket (Source: Clackson et al., 1998). This "hole" is designed to specifically accommodate the "bump" of the synthetic small-molecule drug rimiducid (AP1903), while avoiding interaction with endogenous wild-type FKBP12 (Source: PubMed: 25605371). In the iMC module, the FKBP12-F36V domain is fused to the signaling domains of MyD88 and CD40. Upon administration of rimiducid, the drug acts as a chemical inducer of dimerization (CID), cross-linking two iMC modules and triggering downstream NF-kappaB signaling (Source: Foster et al., 2017). This process provides potent co-stimulatory signals that enhance the proliferation, survival, and anti-tumor efficacy of engineered T cells within the immunosuppressive tumor microenvironment (Source: PubMed: 30249038). This technology allows for precise external control over the timing and intensity of the immune response, offering a potential solution to the challenges of treating solid tumors with adoptive cell therapies (Source: ClinicalTrials.gov: NCT03851146).

Other names

FKBP12-F36V dimerization domainFKBP12v36iMC dimerization domainInducible MyD88/CD40 switch domainAP1903-binding domain

Rimiducid acts as a chemical inducer of dimerization (CID) that binds to two FKBP12-F36V domains, causing the dimerization and activation of the fused MyD88/CD40 signaling modules (Source: Foster et al., 2017; PubMed: 25605371).