Membrane-bound interleukin-15 (mbIL-15)

The Membrane-bound interleukin-15 (mbIL-15) regulatory module is a synthetic biological construct designed to enhance the metabolic fitness, persistence, and anti-tumor activity of adoptive cell therapies, such as Chimeric Antigen Receptor (CAR) T and Natural Killer (NK) cells (Hurton et al., 2016, PNAS). By tethering the IL-15 cytokine to the cell membrane—typically through a fusion with the IL-15 receptor alpha (IL-15Rα) subunit—this module mimics the physiological trans-presentation of IL-15 to its cognate receptors (Liu et al., 2020, NEJM). This localized signaling provides a continuous autocrine stimulus to the engineered cells, promoting their survival and proliferation within the immunosuppressive tumor microenvironment without the systemic toxicities associated with soluble IL-15 administration (Ma et al., 2020, Blood). In clinical development, this module is integrated into armored CAR constructs to treat various hematologic and solid malignancies, as seen in the FT596 and TAK-007 programs (Fate Therapeutics, 2023; Takeda). The module primarily signals through the JAK/STAT pathway, specifically activating STAT5 to drive effector functions and prevent exhaustion of the therapeutic cells. Some engineered versions include regulatory elements such as inducible promoters or safety switches to control the intensity and duration of the IL-15 signal, thereby mitigating the risk of uncontrolled lymphoid expansion (Imura et al., 2020, Scientific Reports).

Other names

mbIL15Membrane-bound IL-15/IL-15Rα fusion proteinTethered IL-15IL-15/IL-15Rα sushi domain fusionEngineered IL-15 regulatory moduleArmored IL-15

Provides continuous autocrine and paracrine stimulation of the IL-2/IL-15 receptor beta (CD122) and common gamma chain (CD132) complex, mimicking physiological trans-presentation to promote the persistence and metabolic fitness of engineered immune cells.