Intrathecal effects of daclizumab treatment of multiple sclerosis

Abstract

Objectives:We previously reported that daclizumab, a humanized monoclonal antibody against CD25, reduced contrast-enhancing lesions (CEL) in patients with multiple sclerosis (MS) who were suboptimal responders to interferon-␤ and that this response correlated with expansion of CD56 bright NK cells. These data have been reproduced in a placebo-controlled multicenter trial (CHOICE study). The current study investigates whether daclizumab monotherapy reduces CEL in untreated patients with relapsing-remitting MS (RRMS) and the effects of daclizumab on the intrathecal immune system. Methods:Sixteen patients with RRMS with high inflammatory activity were enrolled in an open-label, baseline-vs-treatment, phase II trial of daclizumab monotherapy for 54 weeks and followed by serial clinical and MRI examinations and immunologic biomarkers measured in the whole blood and CSF. Results:The trial achieved predefined outcomes. There was an 87.7% reduction in brain CEL (primary) and improvements in Multiple Sclerosis Functional Composite (secondary), Scripps Neurologic Rating Scale, and Expanded Disability Status Scale (tertiary) outcomes. There was significant expansion of CD56 bright NK cells in peripheral blood and CSF, with resultant decrease in T cells/NK cells and B cells/NK cells ratios and IL-12p40 in the CSF. Surprisingly, CD25 Tac epitope was equally blocked on the immune cells in the CSF and in peripheral blood. Conclusions: Daclizumab monotherapy inhibits formation of MS plaques in patients with RRMSand immunoregulatory NK cells may suppress activation of pathogenic immune responses directly in the CNS compartment. Classification of evidence:The study provides Class III evidence that daclizumab reduces the number of contrast-enhancing lesions in treatment-naive patients with RRMS over a 54-week period. Neurology ® 2011;77:1877-1886 GLOSSARY Ab ϭ antibodies; BFV ϭ brain fractional volume; CEL ϭ contrast-enhancing lesion; EDSS ϭ Expanded Disability Status Scale; FLAIR ϭ fluid-attenuation inversion recovery; FSE ϭ fast spin echo; IFN-␤ ϭ interferon-␤; IL ϭ interleukin; mAb ϭ monoclonal antibody; MOA ϭ mechanism of action; MFI ϭ mean fluorescence intensity; MS ϭ multiple sclerosis; MSFC ϭ Multiple Sclerosis Functional Composite; MTR ϭ magnetization transfer ratio; NRS ϭ Neurological Rating Scale; RRMS ϭ relapsing-remitting multiple sclerosis; T2LV ϭ T2 lesion volume; TNF␣ ϭ tumor necrosis factor ␣.We previously reported that patients with persistent MS disease activity on interferon-␤ (IFN-␤) therapy were successfully treated by the addition of daclizumab, a humanized monoclonal antibody (mAb) against the ␣-chain of the interleukin (IL)-2 receptor (CD25). 1-3 The efficacy of therapeutic response correlated with the expansion of immunoregulatory CD56 bright NK cells,4 suggesting that this measurement may become a useful biomarker in therapeutic development of daclizumab.2 All of these observations have now been reproduced in an independent, multicenter, placebo-controlled clinical trial of daclizumab in MS (CHOI...

CNS vasculitis in a patient with MS on daclizumab monotherapy

“…[1][2][3][4][5][6] Clinical efficacy of daclizumab treatment in MS has been linked to the expansion of CD56 bright NK cells, 3,6,7 which can regulate adaptive immunity by killing activated autologous T cells. 7 We describe a 42-year-old Caucasian woman (ZAP10) with a 5-year history of relapsing-remitting MS (RRMS) who completed a phase II clinical trial of daclizumab monotherapy in MS. 2 METHODS Magnetic resonance images were obtained at the height of the patient's symptoms using described methodology. 2 CSF was collected during pretreatment baseline, month 1.5, and month 6.5 on daclizumab therapy on NIH protocol, and during clinical deterioration on daclizumab therapy outside of NIH clinical trial.…”

“…7 We describe a 42-year-old Caucasian woman (ZAP10) with a 5-year history of relapsing-remitting MS (RRMS) who completed a phase II clinical trial of daclizumab monotherapy in MS. 2 METHODS Magnetic resonance images were obtained at the height of the patient's symptoms using described methodology. 2 CSF was collected during pretreatment baseline, month 1.5, and month 6.5 on daclizumab therapy on NIH protocol, and during clinical deterioration on daclizumab therapy outside of NIH clinical trial. CSF was spun within 30 minutes of collection and cell-free supernatants were cryopreserved until analysis.…”

“…Thus, we conclude that it is much more likely that the induction of vasculitis was linked to daclizumab treatment. Careful immunologic analysis of ZAP10 in relationship to other patients with MS who participated in NIH clinical trials of daclizumab in MS [1][2][3] demonstrated that ZAP10 had comparable daclizumab-induced decrease in proportion, absolute numbers, and proliferation (i.e., Ki67-staining) of FoxP31 regulatory CD4 T cells ( figure 3A). However, in contrast to other trial participants, ZAP10 did not expand immunoregulatory CD56…”

Pharmacodynamic effects of daclizumab in the intrathecal compartment

“…The interesting question is how low measured intrathecal concentration of daclizumab (i.e., 15.1 ng/mL) can inhibit consumption of IL‐2 by intrathecal T cells. The answer resides in the previously published observations that in RRMS patients, virtually all CSF T cells had completely blocked CD25 after initiation of dosing by former (i.e., Zenapax)19 or current (i.e., Zinbryta)8 daclizumab formulations. This agrees with another published observation that in contrast to progressive MS, where majority of patients have inflammation compartmentalized to CNS tissue with little turnover between blood and intrathecal compartment, majority of RRMS patients have communicating inflammation, where immune cells are constantly accessing intrathecal compartment from the blood, as already activated T or B cells 20.…”

“…(3) Relatively small sample size . Based on previous CSF studies,19, 21 we estimated that 15 patients analyzed before and after therapy provide sufficient power to reproducibly identify 20–30% effect sizes. High statistical significance, reproducibility of results between STT, LTT, and LTT+1y time points and between Cohorts A and B support our conclusion that the study is powered to detect biologically meaningful effect sizes.…”