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Mult Scler. 2019 Mar;25(3):392-398. doi: 10.1177/1352458517753721. Epub 2018 Jan 16.

Prediction of natalizumab anti-drug antibodies persistency.

Author information

1
Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
2
Euro Diagnostica, Malmö, Sweden.
3
Clinical Neuroscience, CMM, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
4
Departments of Biomedicine and Neurology, University Hospital Basel, Basel, Switzerland.
5
DMSC, Department of Neurology, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark.
6
UCB Celltech, Slough, UK.
7
GlaxoSmithKline, Upper Merion Township, PA, USA.
8
INSERM UMR-S 996, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.
9
Centre de Physiopathologie Toulouse-Purpan, INSERM UMR-1043, CNRS UMR 5282, Université Toulouse III, Toulouse, France.

Abstract

BACKGROUND::

Anti-drug antibodies (ADA) against natalizumab develop early during treatment. ADA persistency is defined by two consecutive positive results as performed by the current qualitative ELISA assay (positive/negative). Very little is known about the magnitude of the natalizumab ADA response and persistency.

DESIGN/METHODS::

We developed a highly sensitive natalizumab ADA titration assay on the Meso Scale Discovery (MSD) platform and a pharmacokinetic (PK) assay. We included 43 patients with a positive ELISA-ADA result within 6 months of treatment initiation (baseline) of whom a follow-up serum sample was available 12-30 months after treatment start. MSD-ADA titres and drug levels were measured.

RESULTS::

Median MSD-ADA titre at baseline was 4881 and 303 at follow-up. A titre of >400 at baseline had a 94% sensitivity and 89% specificity to predict ADA persistency. Reversion to ADA negativity occurred in 10 patients with mean drug levels of 10.8 μg/mL. The median trough drug level in ADA-positive samples was 0 µg/mL. PK levels and ADA titres correlated strongly negatively ( r = -0.67).

CONCLUSION::

High baseline natalizumab ADA titres accurately predict persistency. Despite continuous treatment, the majority of patients with persistent ADA had no detectable drug levels indicating loss of efficacy in line with phase 3 study results.

KEYWORDS:

Natalizumab; anti-drug antibodies; outcome measurement; treatment response

PMID:
29336205
DOI:
10.1177/1352458517753721

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