Single injection of modified self-amplifying RNA encoding a CD19 bispecific T cell engager mediates long-term malignant B cell clearance
Li, K.; McGee, J. E.; Wong, W.; Grinstaff, M.
Show abstract
Bispecific T cell engagers (BiTEs) are a novel cancer immunotherapy modality that achieves significant clinical success. However, conventional single-chain variable fragment (scFv)-based BiTE therapy requires continuous intravenous infusion due to BiTEs short half-life, limiting patient access and increasing healthcare cost. Self-amplifying RNA (saRNA), an emerging RNA technology, enables durable protein production in situ. Here, we report a 5-methylcytidine (m5C)-modified saRNA encoded BiTE system (saRNA-BiTE) targeting CD19. saRNA-BiTE induces prolonged, antigen-specific target cell lysis in vitro. In an acute lymphoblastic leukemia rechallenge model, a single intravenous injection of saRNA-BiTE formulated in lipid nanoparticles eradicates malignant cells and prevents disease recurrence for 3 months. saRNA-BiTE maintains more stable systemic level than protein BiTE or mRNA-BiTE without generating an initial burst BiTE exposure and affords functional BiTE expression for 6 weeks post administration. This work establishes saRNA-BiTE as a robust platform for extended in situ BiTE expression with enhanced long-term efficacy and facile production.
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