Daclizumab (Zenapax®) inhibits early interleukin-2 receptor signal transduction events

Proc. Natl. Acad. Sci. U.S.A.

Catálfamo

Reichert-Scrivner

et al. 2006

557

542

Administration of daclizumab, a humanized mAb directed against the IL-2R␣ chain, strongly reduces brain inflammation in multiple sclerosis patients. Here we show that daclizumab treatment leads to only a mild functional blockade of CD4 ؉ T cells, the major candidate in multiple sclerosis pathogenesis. Instead, daclizumab therapy was associated with a gradual decline in circulating CD4 ؉ and CD8 ؉ T cells and significant expansion of CD56 bright natural killer (NK) cells in vivo, and this effect correlated highly with the treatment response. In vitro studies showed that NK cells inhibited T cell survival in activated peripheral blood mononuclear cell cultures by a contact-dependent mechanism. Positive correlations between expansion of CD56 bright NK cells and contraction of CD4 ؉ and CD8 ؉ T cell numbers in individual patients in vivo provides supporting evidence for NK cell-mediated negative immunoregulation of activated T cells during daclizumab therapy. Our data support the existence of an immunoregulatory pathway wherein activated CD56 bright NK cells inhibit T cell survival. This immunoregulation has potential importance for the treatment of autoimmune diseases and transplant rejection and toward modification of tumor immunity.CD25 ͉ IL-2 ͉ immunoregulatory natural killer cells M ultiple sclerosis (MS) is an inflammatory͞demyelinating disease of the CNS that is one of the leading causes of neurological disability in young adults (1). It is believed that MS is a T cell-mediated autoimmune disease, and therefore the search for new therapies focuses on agents that affect lymphocyte function. Daclizumab (Zenapax), a humanized mAb that blocks the IL-2 binding site on the IL-2R␣ chain, CD25 (i.e., Tac epitope), is among these novel agents (2). The IL-2R complex is comprised of three subunits: IL-2R␣ (CD25), IL-2R␤ (CD122), and IL-2R␥ (CD132). CD122 and CD132 have intracellular signaling motifs and together form the intermediate-affinity (K dis Ϸ 0.1-1 nM) IL-2R. CD25 binds IL-2 with low (K dis Ϸ 10 nM) affinity, but when it associates with CD122͞CD132 it stabilizes the complex to form the highaffinity (K dis Ϸ 10 pM) receptor (3). CD25 is present at low levels in resting human T cells (with the exception of T regulatory cells) but is significantly up-regulated on activated T cells, enabling them to receive a high-affinity IL-2 signal (4). Therefore, it is believed that the blockade of CD25 will result in selective functional inhibition of activated T cells (5). Although it has been demonstrated that daclizumab (or the original murine anti-Tac mAb) inhibits early IL-2R signal transduction events (6, 7) and blocks T cell activation and expansion in vitro (8), a comprehensive characterization of its in vivo effects is still lacking.We recently concluded a phase II, open-label, baseline-versustreatment crossover trial of daclizumab in 10 MS patients with incomplete therapeutic response to IFN-␤. Daclizumab showed a profound inhibitory effect on brain inflammatory activity (78% reduction) and subsequent stabilization o...

Section: Discussionmentioning

confidence: 86%

Section: Ultiple Sclerosis (Ms) Is An Inflammatory͞demyelinatingmentioning

confidence: 99%

Regulatory CD56^brightnatural killer cells mediate immunomodulatory effects of IL-2Rα-targeted therapy (daclizumab) in multiple sclerosis

Proc. Natl. Acad. Sci. U.S.A.

Catálfamo

Reichert-Scrivner

et al. 2006

557

542

“…Undeniably, daclizumab, or its original murine anti-Tac mAb, which was developed in the laboratory of Thomas Waldmann in the intramural NIH/National Cancer Institute (NCI), inhibits T-cell signaling to IL-2 in vitro and in vivo [12][13][14]. Subsequent demonstration that addition of daclizumab to standard immunosuppressive regimens (i.e., cyclosporine and steroids) provided clinical benefit for the prevention of the rejection of allogeneic renal transplants [5], was fully in agreement with this putative MOA on effector T cells.…”

Section: Development Of Daclizumab As a Therapeuticmentioning

confidence: 99%

Daclizumab Therapy for Multiple Sclerosis

2013

Neurotherapeutics

Daclizumab is a humanized monoclonal antibody of IgG1 subtype that binds to the Tac epitope on the interleukin-2 (IL-2) receptor α-chain (CD25), thus, effectively blocking the formation of the high-affinity IL-2 receptor. Because the high-affinity IL-2 receptor signaling promotes expansion of activated T cells in vitro, daclizumab was designed as a therapy that selectively inhibits T-cell activation. Assuming the previous statement, daclizumab received regulatory approval as add-on therapy to standard immunosuppressive regimen for the prevention of acute allograft rejection in renal transplantation. Based on its putative mechanism of action (MOA), daclizumab represented an ideal therapy for T-cell-mediated autoimmune diseases and was subsequently tested in inflammatory uveitis and multiple sclerosis (MS). In both of these diseases, daclizumab therapy significantly inhibited target organ inflammation. Mechanistic studies in MS demonstrated that the MOA of daclizumab is surprisingly broad and that the drug exerts unexpected effects on multiple components of the innate immune system. Specifically, daclizumab dramatically expands and activates immunoregulatory CD56 bright NK cells, which gain access to the intrathecal compartment in MS and can kill autologous activated T cells. Daclizumab also blocks trans-presentation of IL-2 by mature dendritic cells to primed T cells, resulting in profound inhibition of antigen-specific T cells. Finally, daclizumab modulates the development of innate lymphoid cells. In conclusion, daclizumab therapy, which is currently in phase III testing for inflammatory MS, has a unique MOA that does not limit migration of immune cells into the intrathecal compartment, but rather provides multifactorial immunomodulatory effects with resultant inhibition of MS-related inflammation.

“…Therefore, it was postulated that the blockade of CD25 would result in selective functional inhibition of activated T cells. 68 Indeed, it has been demonstrated that daclizumab (or the original murine anti-Tac Ab) inhibits early IL-2R signal transduction events 69,70 and blocks T-cell activation and expansion in vitro. 71 Furthermore, daclizumab has proven its therapeutic efficacy in preventing rejection of different solid organ transplants (reviewed in Waldmann and O'Shea 72 ).…”

Section: Daclizumab (Zenapax; Anti-cd25 Ab)mentioning

confidence: 99%

Emerging Therapies for Multiple Sclerosis

Muraro

2007

Neurotherapeutics

Summary:This review examines the mode of action, safety profile and clinical efficacy of some of the most promising new therapeutic strategies for multiple sclerosis. Autologous hematopoietic stem cell transplantation can regenerate a new and tolerant immune system and is a potentially effective rescue therapy in a subset of patients with aggressive forms of MS refractory to approved immunomodulatory and immunosuppressive agents. High-dose cyclophosphamide without stem cell support is suggested to induce prolonged remissions through similar immunological mechanisms with less toxicity. Fingolimod (FTY720) is a novel oral immunomodulating agent that acts through preventing lymphocyte recirculation from lymphoid organs. Monoclonal antibody therapy has provided scientists and clinicians the opportunity to rationally direct the therapeutic intervention against specific molecules. Targeting molecules of the immune system such as CD52 (alemtuzumab), CD25 (daclizumab), VLA-4 (natalizumab) and CD20 (rituximab) have resulted in potent immunomodulatory effects through sometimes unpredicted mechanisms. The potential of immunoglobulins to induce remyelination in the CNS is being investigated in an attempt to develop therapies promoting tissue repair and functional recovery. The evidence supporting the potential of these emerging immunotherapies suggests that strong progress is being made in the development of effective cures for multiple sclerosis.