Ctla4-Fasl, The Hexameric Targeted Fasl Fusion Protein, As Potential Novel Treatment For Dlbcl

The bi-functional drug CTLA4-FasL (KAHR-102) is a fusion protein composed of the extracellular domains of CTLA4 and FasL. It naturally forms a stable homo-hexamer capable of targeting two different cellular receptors; the CTLA4 domains target B7 receptors (CD80 and CD86) on cells bearing these receptors, while the FasL domains target functional Fas-receptors (CD95) to induce apoptosis. Although CTLA4-FasL can induce apoptosis in all cells expressing functional Fas receptors, it is at least 100 times more potent on cells expressing both B7 and functional Fas receptors. The higher efficacy in cells expressing both receptors is adjoined by robust activation of pro-apoptotic intracellular pathways in conjunction to abrogation of anti-apoptotic ones. This unique combined activity cannot be detected in cells bearing just Fas receptors and can be blocked by preventing the binding of the protein to CD80 and CD86. Both B7 and functional Fas receptors are expressed on lymphoma cells, mainly of the B cell lineage, making them exceptionally sensitive to the CTLA4-FasL apoptotic effect.