Light-responsive cytokine prodrugs with controlled activation for improved cancer immunotherapy.
While recombinant cytokines hold great potential for cancer immunotherapy, their clinical use has greatly declined in recent years. Their off-target toxicity/pleiotropic effects and poor circulation are major issues and challenging to control. There is a need to develop improved cytokines therapy with no or less side effects and improved circulation to eliminate the need of frequent and high dosing.
Emory inventors have engineered a new class of cytokines that enable spatiotemporal activation of therapeutic cytokines in response to external light exposure. In nature, some cytokines are expressed in a latent form (“shielded”) and remain dormant until a specific condition is triggered. The triggering event leads to activation of these cytokines by “de-shielding” and specific signaling pathways are then activated. Therapeutically promising cytokines IL-2, IL12, IL-15 are not expressed in a latent form and known to have poor circulation due to their small size and rapid clearance. The light-sensitive cage enables spatiotemporal activation of these cytokines. Signaling pathways can be activated by exposing these light sensitive cytokines to a light source (with specific wavelength – 356 nm (blue) and NIR (730 nm, more clinically relevant light wavelength – pulse oximeter, etc). “Caged structure” is also just large enough to be above the renal clearance cutoff, leading to prolonged circulation and the observation of less prevalent or severe toxic side effects. These photokines are rapidly triggered, highly color selective, and their activity can be spatially constrained with micrometer-scale resolution. In vivo experiments showed 11-fold increase in circulation half-life in C57BL/6 mice after the tail injection of scIL-12. Prolonged circulation and improved tumor accumulation may necessitate less frequent dosing.
In vivo testing for size, binding affinity and half-life performed.
Publication: Perdue, L. A. et al. (2020). Biomacromolecules.
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