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July 2020; 7 (4) ArticleOpen Access

Detecting and predicting neutralization of alemtuzumab responses in MS

Gauri Saxena, James M. Moore, Meleri Jones, Gareth Pryce, Liaqat Ali, Georgia R. Leisegang, Vivek Vijay, Samantha Loveless, Neil P. Robertson, View ORCID ProfileKlaus Schmierer, Gavin Giovannoni, Sharmilee Gnananpavan, David Baker, Emma C. Tallantyre, View ORCID ProfileAngray S. Kang
First published June 4, 2020, DOI: https://doi.org/10.1212/NXI.0000000000000767
Gauri Saxena
From the Blizard Institute (G.S., M.J., G.P., L.A., G.R.L., V.V., K.S., G.G., S.G., D.B., A.S.K.), Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Division of Psychological Medicine and Clinical Neurosciences (J.M.M., S.L., N.P.R., E.C.T.), Cardiff University School of Medicine, United Kingdom; Department of Biological Sciences (L.A.), National University of Medical Sciences, Rawalpindi, Pakistan; Centre for Oral Immunobiology and Regenerative Medicine (G.R.L., A.S.K.), Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Clinical Board:Medicine (Neuroscience) (V.V., K.S., G.G., S.G.), The Royal London Hospital, Barts Health NHS Trust; and Welsh Neuroscience Research Tissue Bank (S.L., N.P.R.), Cardiff University, United Kingdom.
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James M. Moore
From the Blizard Institute (G.S., M.J., G.P., L.A., G.R.L., V.V., K.S., G.G., S.G., D.B., A.S.K.), Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Division of Psychological Medicine and Clinical Neurosciences (J.M.M., S.L., N.P.R., E.C.T.), Cardiff University School of Medicine, United Kingdom; Department of Biological Sciences (L.A.), National University of Medical Sciences, Rawalpindi, Pakistan; Centre for Oral Immunobiology and Regenerative Medicine (G.R.L., A.S.K.), Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Clinical Board:Medicine (Neuroscience) (V.V., K.S., G.G., S.G.), The Royal London Hospital, Barts Health NHS Trust; and Welsh Neuroscience Research Tissue Bank (S.L., N.P.R.), Cardiff University, United Kingdom.
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Meleri Jones
From the Blizard Institute (G.S., M.J., G.P., L.A., G.R.L., V.V., K.S., G.G., S.G., D.B., A.S.K.), Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Division of Psychological Medicine and Clinical Neurosciences (J.M.M., S.L., N.P.R., E.C.T.), Cardiff University School of Medicine, United Kingdom; Department of Biological Sciences (L.A.), National University of Medical Sciences, Rawalpindi, Pakistan; Centre for Oral Immunobiology and Regenerative Medicine (G.R.L., A.S.K.), Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Clinical Board:Medicine (Neuroscience) (V.V., K.S., G.G., S.G.), The Royal London Hospital, Barts Health NHS Trust; and Welsh Neuroscience Research Tissue Bank (S.L., N.P.R.), Cardiff University, United Kingdom.
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Gareth Pryce
From the Blizard Institute (G.S., M.J., G.P., L.A., G.R.L., V.V., K.S., G.G., S.G., D.B., A.S.K.), Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Division of Psychological Medicine and Clinical Neurosciences (J.M.M., S.L., N.P.R., E.C.T.), Cardiff University School of Medicine, United Kingdom; Department of Biological Sciences (L.A.), National University of Medical Sciences, Rawalpindi, Pakistan; Centre for Oral Immunobiology and Regenerative Medicine (G.R.L., A.S.K.), Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Clinical Board:Medicine (Neuroscience) (V.V., K.S., G.G., S.G.), The Royal London Hospital, Barts Health NHS Trust; and Welsh Neuroscience Research Tissue Bank (S.L., N.P.R.), Cardiff University, United Kingdom.
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Liaqat Ali
From the Blizard Institute (G.S., M.J., G.P., L.A., G.R.L., V.V., K.S., G.G., S.G., D.B., A.S.K.), Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Division of Psychological Medicine and Clinical Neurosciences (J.M.M., S.L., N.P.R., E.C.T.), Cardiff University School of Medicine, United Kingdom; Department of Biological Sciences (L.A.), National University of Medical Sciences, Rawalpindi, Pakistan; Centre for Oral Immunobiology and Regenerative Medicine (G.R.L., A.S.K.), Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Clinical Board:Medicine (Neuroscience) (V.V., K.S., G.G., S.G.), The Royal London Hospital, Barts Health NHS Trust; and Welsh Neuroscience Research Tissue Bank (S.L., N.P.R.), Cardiff University, United Kingdom.
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Georgia R. Leisegang
From the Blizard Institute (G.S., M.J., G.P., L.A., G.R.L., V.V., K.S., G.G., S.G., D.B., A.S.K.), Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Division of Psychological Medicine and Clinical Neurosciences (J.M.M., S.L., N.P.R., E.C.T.), Cardiff University School of Medicine, United Kingdom; Department of Biological Sciences (L.A.), National University of Medical Sciences, Rawalpindi, Pakistan; Centre for Oral Immunobiology and Regenerative Medicine (G.R.L., A.S.K.), Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Clinical Board:Medicine (Neuroscience) (V.V., K.S., G.G., S.G.), The Royal London Hospital, Barts Health NHS Trust; and Welsh Neuroscience Research Tissue Bank (S.L., N.P.R.), Cardiff University, United Kingdom.
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Vivek Vijay
From the Blizard Institute (G.S., M.J., G.P., L.A., G.R.L., V.V., K.S., G.G., S.G., D.B., A.S.K.), Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Division of Psychological Medicine and Clinical Neurosciences (J.M.M., S.L., N.P.R., E.C.T.), Cardiff University School of Medicine, United Kingdom; Department of Biological Sciences (L.A.), National University of Medical Sciences, Rawalpindi, Pakistan; Centre for Oral Immunobiology and Regenerative Medicine (G.R.L., A.S.K.), Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Clinical Board:Medicine (Neuroscience) (V.V., K.S., G.G., S.G.), The Royal London Hospital, Barts Health NHS Trust; and Welsh Neuroscience Research Tissue Bank (S.L., N.P.R.), Cardiff University, United Kingdom.
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Samantha Loveless
From the Blizard Institute (G.S., M.J., G.P., L.A., G.R.L., V.V., K.S., G.G., S.G., D.B., A.S.K.), Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Division of Psychological Medicine and Clinical Neurosciences (J.M.M., S.L., N.P.R., E.C.T.), Cardiff University School of Medicine, United Kingdom; Department of Biological Sciences (L.A.), National University of Medical Sciences, Rawalpindi, Pakistan; Centre for Oral Immunobiology and Regenerative Medicine (G.R.L., A.S.K.), Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Clinical Board:Medicine (Neuroscience) (V.V., K.S., G.G., S.G.), The Royal London Hospital, Barts Health NHS Trust; and Welsh Neuroscience Research Tissue Bank (S.L., N.P.R.), Cardiff University, United Kingdom.
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Neil P. Robertson
From the Blizard Institute (G.S., M.J., G.P., L.A., G.R.L., V.V., K.S., G.G., S.G., D.B., A.S.K.), Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Division of Psychological Medicine and Clinical Neurosciences (J.M.M., S.L., N.P.R., E.C.T.), Cardiff University School of Medicine, United Kingdom; Department of Biological Sciences (L.A.), National University of Medical Sciences, Rawalpindi, Pakistan; Centre for Oral Immunobiology and Regenerative Medicine (G.R.L., A.S.K.), Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Clinical Board:Medicine (Neuroscience) (V.V., K.S., G.G., S.G.), The Royal London Hospital, Barts Health NHS Trust; and Welsh Neuroscience Research Tissue Bank (S.L., N.P.R.), Cardiff University, United Kingdom.
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Klaus Schmierer
From the Blizard Institute (G.S., M.J., G.P., L.A., G.R.L., V.V., K.S., G.G., S.G., D.B., A.S.K.), Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Division of Psychological Medicine and Clinical Neurosciences (J.M.M., S.L., N.P.R., E.C.T.), Cardiff University School of Medicine, United Kingdom; Department of Biological Sciences (L.A.), National University of Medical Sciences, Rawalpindi, Pakistan; Centre for Oral Immunobiology and Regenerative Medicine (G.R.L., A.S.K.), Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Clinical Board:Medicine (Neuroscience) (V.V., K.S., G.G., S.G.), The Royal London Hospital, Barts Health NHS Trust; and Welsh Neuroscience Research Tissue Bank (S.L., N.P.R.), Cardiff University, United Kingdom.
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Gavin Giovannoni
From the Blizard Institute (G.S., M.J., G.P., L.A., G.R.L., V.V., K.S., G.G., S.G., D.B., A.S.K.), Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Division of Psychological Medicine and Clinical Neurosciences (J.M.M., S.L., N.P.R., E.C.T.), Cardiff University School of Medicine, United Kingdom; Department of Biological Sciences (L.A.), National University of Medical Sciences, Rawalpindi, Pakistan; Centre for Oral Immunobiology and Regenerative Medicine (G.R.L., A.S.K.), Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Clinical Board:Medicine (Neuroscience) (V.V., K.S., G.G., S.G.), The Royal London Hospital, Barts Health NHS Trust; and Welsh Neuroscience Research Tissue Bank (S.L., N.P.R.), Cardiff University, United Kingdom.
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Sharmilee Gnananpavan
From the Blizard Institute (G.S., M.J., G.P., L.A., G.R.L., V.V., K.S., G.G., S.G., D.B., A.S.K.), Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Division of Psychological Medicine and Clinical Neurosciences (J.M.M., S.L., N.P.R., E.C.T.), Cardiff University School of Medicine, United Kingdom; Department of Biological Sciences (L.A.), National University of Medical Sciences, Rawalpindi, Pakistan; Centre for Oral Immunobiology and Regenerative Medicine (G.R.L., A.S.K.), Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Clinical Board:Medicine (Neuroscience) (V.V., K.S., G.G., S.G.), The Royal London Hospital, Barts Health NHS Trust; and Welsh Neuroscience Research Tissue Bank (S.L., N.P.R.), Cardiff University, United Kingdom.
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David Baker
From the Blizard Institute (G.S., M.J., G.P., L.A., G.R.L., V.V., K.S., G.G., S.G., D.B., A.S.K.), Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Division of Psychological Medicine and Clinical Neurosciences (J.M.M., S.L., N.P.R., E.C.T.), Cardiff University School of Medicine, United Kingdom; Department of Biological Sciences (L.A.), National University of Medical Sciences, Rawalpindi, Pakistan; Centre for Oral Immunobiology and Regenerative Medicine (G.R.L., A.S.K.), Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Clinical Board:Medicine (Neuroscience) (V.V., K.S., G.G., S.G.), The Royal London Hospital, Barts Health NHS Trust; and Welsh Neuroscience Research Tissue Bank (S.L., N.P.R.), Cardiff University, United Kingdom.
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Emma C. Tallantyre
From the Blizard Institute (G.S., M.J., G.P., L.A., G.R.L., V.V., K.S., G.G., S.G., D.B., A.S.K.), Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Division of Psychological Medicine and Clinical Neurosciences (J.M.M., S.L., N.P.R., E.C.T.), Cardiff University School of Medicine, United Kingdom; Department of Biological Sciences (L.A.), National University of Medical Sciences, Rawalpindi, Pakistan; Centre for Oral Immunobiology and Regenerative Medicine (G.R.L., A.S.K.), Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Clinical Board:Medicine (Neuroscience) (V.V., K.S., G.G., S.G.), The Royal London Hospital, Barts Health NHS Trust; and Welsh Neuroscience Research Tissue Bank (S.L., N.P.R.), Cardiff University, United Kingdom.
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Angray S. Kang
From the Blizard Institute (G.S., M.J., G.P., L.A., G.R.L., V.V., K.S., G.G., S.G., D.B., A.S.K.), Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Division of Psychological Medicine and Clinical Neurosciences (J.M.M., S.L., N.P.R., E.C.T.), Cardiff University School of Medicine, United Kingdom; Department of Biological Sciences (L.A.), National University of Medical Sciences, Rawalpindi, Pakistan; Centre for Oral Immunobiology and Regenerative Medicine (G.R.L., A.S.K.), Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Clinical Board:Medicine (Neuroscience) (V.V., K.S., G.G., S.G.), The Royal London Hospital, Barts Health NHS Trust; and Welsh Neuroscience Research Tissue Bank (S.L., N.P.R.), Cardiff University, United Kingdom.
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Citation
Detecting and predicting neutralization of alemtuzumab responses in MS
Gauri Saxena, James M. Moore, Meleri Jones, Gareth Pryce, Liaqat Ali, Georgia R. Leisegang, Vivek Vijay, Samantha Loveless, Neil P. Robertson, Klaus Schmierer, Gavin Giovannoni, Sharmilee Gnananpavan, David Baker, Emma C. Tallantyre, Angray S. Kang
Neurol Neuroimmunol Neuroinflamm Jul 2020, 7 (4) e767; DOI: 10.1212/NXI.0000000000000767

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Abstract

Objective To test the hypothesis that antidrug antibodies (ADAs) 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 ADAs. Alemtuzumab immunoglobulin G Alexa Fluor 488 conjugate was used in a competitive binding cell-based assay to detect neutralizing ADAs. The assays were used to retrospectively screen, blinded, banked serum samples from people with MS (n = 32) who had received 3 or more cycles of alemtuzumab. Lymphocyte depletion was measured between baseline and about 1 month postinfusion.

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. ADA responses were detected in 29/32 (90.6%) individuals. Neutralizing antibodies occurred before the development of limited depletion in 6/7 individuals (18.8% of the whole sample). Preinfusion, ADA levels predicted limited, postinfusion lymphocyte depletion.

Conclusions Although ADAs 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 antidrug response may be of practical value in patients requiring additional cycles of alemtuzumab. ADA detection may help to inform on retreatment or switching to another treatment.

Glossary

ADA=
antidrug antibody;
DMT=
disease-modifying treatment;
EDSS=
Expanded Disability Status Scale;
PwMS=
people with MS;
WNRTB=
Welsh Neuroscience Research Tissue Bank

Footnotes

  • Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.

  • ↵* Joint first/senior authors.

  • The Article Processing Charge was funded by the authors.

  • Received January 10, 2020.
  • Accepted in final form April 13, 2020.
  • Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

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.

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