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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, Robertson, Neil, Schmierer, Klaus, Giovannoni, Gavin, Gnananpavan, Sharmilee, Baker, David, Tallantyre, Emma and Kang, Angray 2020. Detecting and predicting neutralization of alemtuzumab responses in multiple sclerosis. Neurology, Neuroimmunology and Neuroinflammation

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Abstract

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
Schools: Medicine
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: 31 May 2020 16:30
URI: http://orca.cf.ac.uk/id/eprint/131039

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