Fas-chimera death receptor (TNFR1-Fas) (Fas-chimera)

The Fas-chimera death receptor is a synthetic fusion protein engineered for targeted anti-angiogenic therapy, most notably as the functional component of the gene therapy ofranergene obadenovec (VB-111) [1, 4]. It consists of the extracellular domain of the Tumor Necrosis Factor Receptor 1 (TNFR1) fused to the transmembrane and intracellular signaling domains of the Fas (CD95) death receptor [3, 4]. This chimeric receptor is typically expressed under the control of a tissue-specific promoter, such as PPE-1-3x, which restricts its expression to the angiogenic endothelial cells found within the tumor microenvironment [1, 2]. When circulating TNF-alpha binds to the TNFR1 portion of the chimera, it activates the intracellular Fas death domain, triggering the extrinsic apoptotic pathway and leading to the selective destruction of tumor-associated blood vessels [1, 4]. This vascular disruption strategy aims to starve the tumor of oxygen and nutrients while minimizing systemic toxicity by utilizing the tumor's own inflammatory environment (high TNF-alpha) against its blood supply [2, 4]. The Fas-chimera has been investigated in clinical trials for various solid tumors, including recurrent glioblastoma and platinum-resistant ovarian cancer [2, 5].

Other names

TNFR1-Fas chimeraTNFR1-CD95 fusion proteinVB-111 transgene productChimeric death receptor (CDR)Ofranergene obadenovec transgene

The Fas-chimera acts as a vascular disruption agent by hijacking the pro-inflammatory TNF-alpha signal; the extracellular TNFR1 domain binds circulating TNF-alpha, which then triggers the intracellular Fas domain to induce apoptosis specifically in angiogenic endothelial cells [1, 4].