Sunday, 28 July 2013

Macrophages nick target for daclizumab from T cells

Zhang Y, McClellan M, Efros L, Shi D, Bielekova B, Tang M, Vexler V, Sheridan J. Daclizumab reduces CD25 levels on T cells through monocyte-mediated trogocytosis.  Mult Scler. 2013 Jul  [Epub ahead of print]


Daclizumab is a humanized monoclonal antibody that prevents interleukin-2 (IL-2) binding to CD25, blocking IL-2 signaling by cells that require high-affinity IL-2 receptors to mediate IL-2 signaling. The phase 2a CHOICE study evaluating daclizumab as a treatment for multiple sclerosis (MS) included longitudinal analysis of activated T cell counts. Whereas an exposure-dependent relationship was observed between daclizumab and reductions in HLA-DR+-activated T cells, a similar relationship was not observed for reductions in CD25 levels. The objective of this report is to determine the mechanism by which daclizumab reduces CD25 levels on peripheral blood mononuclear cells (PBMCs) using cytometric techniques. Daclizumab reduced T cell CD25 levels through a mechanism that required the daclizumab-Fc domain interaction with Fc receptors (FcR) on monocytes, but not on natural killer (NK) cells, and was unrelated to internalization or cell killing. Activated CD4+ T cells and FoxP3+ Treg cells showed evidence of trogocytosis of the CD25 antigen in the presence of monocytes. A daclizumab variant that retained affinity for CD25 but lacked FcR binding did not induce trogocytosis and was significantly less potent as an inhibitor of IL-2-induced proliferation of PBMCs. In conclusion, Daclizumab-induced monocyte-mediated trogocytosis of CD25 from T cells appears to be an additional mechanism contributing to daclizumab inhibition of IL-2 signalling.


Daclizumab blocks a T cell growth factor and affects natural killer cell function. How does it work, well in this study binding of the antibody to the target stimulates blood macrophage to bind to the antibody and pull the target for daculizumab off the T cell. This is a process known as Trogocytosis.  If T cells loose this marker they can not respond to the cell growth factor. 

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