Daclizumab: Mechanisms of Action, Therapeutic Efficacy, Adverse Events and Its Uncovering the Potential Role of Innate Immune System Recruitment as a Treatment Strategy for Relapsing Multiple Sclerosis

Abstract

Daclizumab (DAC) is a humanized, monoclonal antibody that blocks CD25, a critical element of the high-affinity interleukin-2 receptor (IL-2R). DAC HYP blockade of CD25 inhibits effector T cell activation, regulatory T cell expansion and survival, and activation-induced T-cell apoptosis. Because CD25 blockade reduces IL-2 consumption by effector T cells, it increases IL-2 bioavailability allowing for greater interaction with the intermediate-affinity IL-2R, and therefore drives the expansion of CD56bright natural killer (NK) cells. Furthermore, there appears to be a direct correlation between CD56bright NK cell expansion and DAC HYP efficacy in reducing relapses and MRI evidence of disease activity in patients with RMS in phase II and phase III double-blind, placebo- and active comparator-controlled trials. Therapeutic efficacy was maintained during open-label extension studies. However, treatment was associated with an increased risk of rare adverse events, including cutaneous inflammation, autoimmune hepatitis, central nervous system Drug Reaction with Eosinophilia Systemic Symptoms (DRESS) syndrome, and autoimmune Glial Fibrillary Acidic Protein (GFAP) alpha immunoglobulin-associated encephalitis. As a result, DAC HYP was removed from clinical use in 2018. The lingering importance of DAC is that its use led to a deeper understanding of the underappreciated role of innate immunity in the potential treatment of autoimmune disease.

Affinity improvement of the fully human anti‑TSLP recombinant antibody

“…at present, there is no anti-TSlP antibody approved by the uS Food and drug administration (32). as a therapeutic antibody, affinity is the most important characteristic (33). In the present study, an anti-TSlP-scFv-Fc recombinant antibody was successfully constructed and its affinity was increased using dS 4.5 software.…”

IL-2 and Mycobacterial Lipoarabinomannan as Targets of Immune Responses in Multiple Sclerosis Patients

“…Low doses of IL-2 have been successfully employed as add-on MS therapy [10], while the detection of increased IL-2 levels in MS patients has led to the development of therapeutic approaches targeting IL-2 receptor [11]. However, further observations have demonstrated that side effects such as severe inflammatory brain disorders [12,13] and resistance to antagonistic antibody therapies that target receptors at the cell surface may arise in a relatively short time [14]. Moreover, high expression of IL-2 has been reported in animals after Mycobacterium tuberculosis and MAP infection [15,16].…”

Characterization of the impact of daclizumab beta on circulating natural killer cells by mass cytometry

“…Daclizumab is a humanized monoclonal antibody that irreversibly blocks CD25, preventing signaling through the high affinity IL-2R while increasing IL-2 bioavailability to bind to the low affinity receptor (reviewed in (Cohan et al 2019;Bielekova 2019)). Due to the complex roles of IL-2 in vivo, daclizumab induces several immunological changes, including inhibition of T cell activation, reduction in the frequency and survival of regulatory T cells, and expansion of CD56 bright NK cells (Cohan et al 2019;Bielekova 2019). It was originally developed as an intravenous treatment for several disease indications, including the prevention of transplant rejection and the treatment of severe uveitis and T cell leukemia (Cohan et al 2019;Bielekova 2019).…”

“…Due to the complex roles of IL-2 in vivo, daclizumab induces several immunological changes, including inhibition of T cell activation, reduction in the frequency and survival of regulatory T cells, and expansion of CD56 bright NK cells (Cohan et al 2019;Bielekova 2019). It was originally developed as an intravenous treatment for several disease indications, including the prevention of transplant rejection and the treatment of severe uveitis and T cell leukemia (Cohan et al 2019;Bielekova 2019). Later a subcutaneous form (daclizumab beta) was developed and approved for the treatment of relapsing forms of multiple sclerosis (RMS) due to its beneficial effects including reduction in lesion size and slowed disease progression (Bielekova et al 2006(Bielekova et al , 2009Elkins et al 2015;Wynn et al 2010;Elkins et al 2012); (Gold et al 2013).…”

“…While no longer used therapeutically, a better understanding of the effects of daclizumab beta may provide insight into the pleiotropic effects of IL-2 in the setting of RMS. Surprisingly, the beneficial effects of daclizumab beta treatment were linked not to changes in T cell function, but instead were strongly correlated with expansion of CD56 bright NK cells (Bielekova et al 2006;Elkins et al 2015;Cohan et al 2019;Bielekova 2019). Although CD56 bright NK cells generally have poor cytotoxic activity, the daclizumab beta-expanded CD56 bright NK cells could kill activated, autologous CD4 + T cells, potentially driving the therapeutic effect by eliminating autoreactive T cells ( Bielekova et al 2006;Jiang et al 2011).…”