In the August 1st Issue of Multiple Sclerosis, Sheridan et al. reported their findings about a novel biomarker of daclizumab – a humanized anti-CD25 therapeutic mAb – activity in multiple sclerosis (MS) patients. My interest in this article is many fold. First, the work presented in this report is an excellent example of in-depth biomarker qualification, combining clinical observations and laboratory experiments. Second, this article concludes a remarkable journey in translational research during which the authors showed a remarkable readiness to embrace unexpected observations. Finally, although I had nothing to do with the actual work presented in the current article, I was involved with this project at its very beginning, making me a somewhat privileged observer of this journey.
Let me set the stage. In 2004, Bibiana Bielekova and colleagues published exciting observations from a small exploratory phase 2 study of daclizumab in IFN-gamma-refractory MS patients. The remarkable aspect of this study was that the treatment with daclizumab did not appear to have profound effect on T cells in the patients but instead, the treatment appeared to stimulate the expansion of a subset of regulatory Natural Killer cells (CD56bright NK cells; see reference). At the time, daclizumab was assumed to be primarily an inhibitor of T cell activation thanks to its ability to block the high-affinity IL2 receptor CD25. This T-cell centric mechanism of action was the based for daclizumab’s approval for the prevention of transplant rejection (marketed as Zenapax). At the same time, the biology of IL-2 was undergoing a major update: The observation that IL-2 deficiency in mice resulted in a massive autoimmune syndrome forced the immunology community to consider the immuno-regulatory property of IL-2. Finally, my colleagues and I at Protein Design Labs (now Abbot Biotherapeutics) had observed that daclizumab does not simply block the binding of IL-2 to the high-affinity IL-2R (CD25) it also induces a rapid and profound down-regulation of this receptor without affecting the low-affinity sub-units of the IL-2R (CD122 & CD132). The beauty of the paper by Sheridan et al. is that they embraced these seemingly conflicting observations to show that by blocking CD25, daclizumab redirects the signaling pathway of IL-2 towards the low affinity IL-2R which in turn provides the necessary stimuli to expand regulatory CD56bright NK cells. This expansion of the CD56bright NK cells is a reliable predictor of lower disease activity (as assessed by newly formed Gg-enhancing and T2-MRI lesions) in treated patients, providing an early indicator of disease modification. Furthermore, it seems that the baseline number of CD56bright NK cells, that express the low-affinity IL2R (CD122), is a predictor of positive response to treatment with daclizumab.
Beyond the value of this paper as a model of effective translational research and biomarker development, this work by Sheridan et al. also identifies a potential new mode of intervention in multiple sclerosis which had been neglected until now.
Thierry
Sornasse for Integrated Biomarker Strategy
