A Very Long-Acting IL-15: Implications for the Immunotherapy of Cancer
Posted by Adam Awdish on
Innovative Grade US Origin Mouse C57BL6 Plasma from Innovative Research was used in the following study:
A Very Long-Acting IL-15: Implications for the Immunotherapy of Cancer
John A. Hangasky, Wei Chen, Sigrid Dubois, Anusara Daenthanasanmak, Jürgen Müller, Ralph Reid, Thomas A. Waldmann, and Daniel V. Santi
Journal for Immunotherapy of Cancer
January 31, 2022
Interleukin-15 (IL-15) is a protein essential for maintenance and survival of natural killer (NK) and CD8+ T cells, making it an interleukin of interest as an immune-oncology agent. IL-2 and IL-15 both bind to NK and CD8+ T cells, however, regulatory T cells are primarily stimulated by IL-2. Considering this, despite IL-15 showing promise as an anticancer agent on its own, there is currently more interest in using it in combination with other immune-oncology agents.
Proliferation and maintenance of NK and memory T cells requires exposure to IL-15 at a concentration above a specific threshold for a prolonged period, however, IL-15 has a short t1/2 of roughly 2.5 hours in humans. Further, the high dose required to achieve adequate sustained exposure from a single treatment comes with high Cmax and other associated toxicities. Due to this, there have been extensive efforts in developing potent, long-acting IL-15 receptor agonists capable of maintaining the desired therapeutic concentration for a prolonged period.
The most common methods currently used usually involve attempting to increase the molecular size of the agent to reduce the renal elimination rate by targeting the neonatal Fc receptor (FcRn). Another common approach has been to use a continuous intravenous infusion (CIV) to maintain a steady concentration of IL-15 over a prolonged period, though this is a less practical method of treatment. Strangely, however, these methods have only been able to extend the t1/2 of IL-15 agonists by mere hours, in contrast to a week or longer when used to extend the half-life of other interleukin proteins.
In this study, researchers developed a general approach to extending the half-life of therapeutic agents in which the drug’s pharmacokinetics (PK) when in circulation mimic that of a continuous infusion. In their approach, the drug is covalently tethered to a long-lasting carrier via a linker which slowly cleaves by β-elimination, thus releasing the free drug. The linkers are extremely stable when stored at a low pH and temperature and are not affected by enzymes. The researchers also used slower cleaving β-eliminative linkers, allowing for degradation of the polymers to occur in vivo following the release of the drug.
Results following subcutaneous administration of the experimental IL-15 to mice showed that the cytokine maintained a half-life of roughly 168 hours for five days post-injection. This was followed by an abrupt drop in half-life to about 30 hours in accordance with the development of a cytokine sink. For two weeks following a single injection NK and ɣδ T cell levels increased at a remarkable rate, and CD44hiCD8+ T cell concentrations expanded for four weeks following the injection. These results suggest that the experimental injection, MS~IL-15, provides a long-acting concentration of IL-15 with low Cmax and can trigger prolonged expansion of target immune cells with high anticancer activity.
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