Inducible human CD40 chimeric receptor (iCD40) (iCD40)

The inducible human CD40 chimeric receptor (iCD40) is an engineered signaling protein utilized in BPX-101, an autologous dendritic cell vaccine (Bellicum Pharmaceuticals, 2014). It consists of the cytoplasmic signaling domain of the CD40 receptor fused to one or more FK506-binding protein (FKBP12) domains containing a F36V mutation (Spencer et al., 1993; Hanks et al., 2005). This chimeric construct is designed to be activated by rimiducid (AP1903), a lipid-permeable small-molecule dimerizer (Slawin et al., 2014). When rimiducid binds to the iCD40 receptors, it causes them to dimerize, mimicking the natural activation signal usually provided by CD40 ligand (Collisson et al., 2011). This activation triggers the maturation of the dendritic cells, enhancing their ability to present antigens and stimulate a robust T-cell-mediated immune response against tumor cells (Foster et al., 2017). The signaling cascade involves the activation of NF-κB and MAPK pathways, leading to the secretion of pro-inflammatory cytokines like IL-12 (Hanks et al., 2005). BPX-101 has primarily been investigated as a cellular immunotherapy for metastatic castrate-resistant prostate cancer (NCT01916655). This technology allows for the temporal and spatial control of immune activation, potentially reducing systemic toxicity compared to traditional CD40 agonists (Sadelain et al., 2017).

Other names

iCD40Inducible CD40BPX-101Chimeric CD40 receptorAP1903-inducible CD40

Rimiducid-induced dimerization of the cytoplasmic CD40 signaling domains triggers downstream NF-κB and MAPK pathways, leading to dendritic cell maturation and enhanced production of pro-inflammatory cytokines like IL-12.