Photo by Rhoda Baer
Researchers say they have created interleukin-2 (IL-2) variants that function as IL-2-receptor signaling “clamps” and allow for “fine tuning” of the signaling amplitude.
One variant, known as H9-RETR, was able to inhibit the actions of endogenous IL-2 and IL-15, prolong survival in a mouse model of graft-vs-host disease (GVHD), and inhibit the proliferation of cells derived from a patient with smoldering adult T-cell
leukemia (ATL).
The researchers reported these results in Immunity.
Warren J. Leonard, MD, of the National Heart, Lung, and Blood Institute in Bethesda, Maryland, and his colleagues developed IL-2 variants in which activity can be tuned to either boost or block immune responses, depending on the desired therapeutic application.
The researchers said these variants had high affinity for IL-2Rβ and inhibited binding of endogenous IL-2, but their interaction with γc was weakened, thereby weakening IL-2Rβ-γc heterodimerization.
The team found that IL-2 signaling strength was inversely correlated with the degree of mutation at the γc interface. And differential effects on cell proliferation were dependent upon the cells’ state of activation.
One of the IL-2 variants, H9-RETR, inhibited IL-2- and IL-15-mediated proliferation and cytotoxicity. H9-RETR inhibited cytokine signaling and natural killer cell activity as well or better than blocking antibodies to IL-2Rα and IL-2Rβ.
In experiments with cells isolated from a patient with smoldering ATL, H9-RETR blocked IL-2 signaling and inhibited the spontaneous proliferation of ATL cells. In this regard, H9-RETR was at least as effective as the anti-IL-2Rα antibody daclizumab and much more effective than the anti-IL-2Rβ antibody Mikβ1.
In a mouse model of GVHD, animals that received a stabilized, Fc-fusion version of H9-RETR (H9-RETR-Fc4) had significantly longer survival than control mice (which received only Fc4 protein).
All of the control mice had died by 40 days post-injection, but it took 60 days for all of the H9-RETR-Fc4-treated mice to die (P=0.0001).
The researchers believe their receptor-clamping approach could potentially be used to engineer other immune-system cytokines with therapeutic potential.
