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Detecting and predicting neutralization of alemtuzumab responses in multiple sclerosis

Saxena, Gauri, Moore, James, Jones, Meleri, Pryce, Gareth, Ali, Liaqat, Leisegang, Georgia, Vijay, Vivek, Loveless, Samantha ORCID:, Robertson, Neil ORCID:, Schmierer, Klaus, Giovannoni, Gavin, Gnananpavan, Sharmilee, Baker, David, Tallantyre, Emma ORCID: and Kang, Angray 2020. Detecting and predicting neutralization of alemtuzumab responses in multiple sclerosis. Neurology, Neuroimmunology and Neuroinflammation 7 (4) , e767. 10.1212/NXI.0000000000000767

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Objective: To test the hypothesis that anti-drug antibodies against alemtuzumab could become relevant after repeated treatments for some individuals, possibly explaining occasional treatment resistance. Methods: Recombinant alemtuzumab single-chain variable fragment antibody with a dual tandem nanoluciferase reporter linker was made and used to detect binding anti-drug antibodies. Alemtuzumab IgG Alexa-Fluor 488 conjugate was used in a competitive-binding cell based assay to detect neutralizing anti-drug antibodies. The assays were used to retrospectively screen, blinded, banked-serum samples from people with multiple sclerosis (n=32) who had received three or more cycles of alemtuzumab. Lymphocyte depletion was measured between baseline and about 1 month post-infusion. Results: The number of individuals showing limited depletion of lymphocytes increased with the number of treatment cycles. Lack of depletion was also a poor prognostic feature for future disease activity. Anti-drug antibody responses were detected in 29/32 (90.6%) individuals. Neutralizing antibodies occurred prior to the development of limited depletion in 6/7 individuals (18.8% of the whole sample). Pre-infusion, anti-drug antibody levels predicted limited, post-infusion lymphocyte depletion. Conclusions: Although anti-drug antibodies to alemtuzumab have been portrayed as being of no clinical significance, alemtuzumab-specific antibodies appear to be clinically relevant for some individuals, although causation remains to be established. Monitoring of, lymphocyte depletion and the anti-drug response may be of practical value in patients requiring additional cycles of alemtuzumab. Anti-drug antibody detection may help to inform on re-treatment or switching to another treatment.

Item Type: Article
Date Type: Publication
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information: This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
Publisher: Lippincott, Williams & Wilkins: Creative Commons Attribution Non-Commercial No Derivatives License / Wolters Kluwer Health/LWW
ISSN: 2332-7812
Date of First Compliant Deposit: 16 April 2020
Date of Acceptance: 13 April 2020
Last Modified: 25 May 2024 10:22

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