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Detecting and predicting neutralization of alemtuzumab responses in MS.

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.

Authors+Show Affiliations

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.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.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.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.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.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.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.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.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.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.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.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.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.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.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. a.s.kang@qmul.ac.uk.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32499328

Citation

Saxena, Gauri, et al. "Detecting and Predicting Neutralization of Alemtuzumab Responses in MS." Neurology(R) Neuroimmunology & Neuroinflammation, vol. 7, no. 4, 2020.
Saxena G, Moore JM, Jones M, et al. Detecting and predicting neutralization of alemtuzumab responses in MS. Neurol Neuroimmunol Neuroinflamm. 2020;7(4).
Saxena, G., Moore, J. M., Jones, M., Pryce, G., Ali, L., Leisegang, G. R., Vijay, V., Loveless, S., Robertson, N. P., Schmierer, K., Giovannoni, G., Gnananpavan, S., Baker, D., Tallantyre, E. C., & Kang, A. S. (2020). Detecting and predicting neutralization of alemtuzumab responses in MS. Neurology(R) Neuroimmunology & Neuroinflammation, 7(4). https://doi.org/10.1212/NXI.0000000000000767
Saxena G, et al. Detecting and Predicting Neutralization of Alemtuzumab Responses in MS. Neurol Neuroimmunol Neuroinflamm. 2020;7(4) PubMed PMID: 32499328.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Detecting and predicting neutralization of alemtuzumab responses in MS. AU - Saxena,Gauri, AU - Moore,James M, AU - Jones,Meleri, AU - Pryce,Gareth, AU - Ali,Liaqat, AU - Leisegang,Georgia R, AU - Vijay,Vivek, AU - Loveless,Samantha, AU - Robertson,Neil P, AU - Schmierer,Klaus, AU - Giovannoni,Gavin, AU - Gnananpavan,Sharmilee, AU - Baker,David, AU - Tallantyre,Emma C, AU - Kang,Angray S, Y1 - 2020/06/04/ PY - 2020/01/10/received PY - 2020/04/13/accepted PY - 2020/6/6/entrez PY - 2020/6/6/pubmed PY - 2020/6/6/medline JF - Neurology(R) neuroimmunology & neuroinflammation JO - Neurol Neuroimmunol Neuroinflamm VL - 7 IS - 4 N2 - 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. SN - 2332-7812 UR - https://www.unboundmedicine.com/medline/citation/32499328/Detecting_and_predicting_neutralization_of_alemtuzumab_responses_in_MS L2 - http://nn.neurology.org/cgi/pmidlookup?view=long&pmid=32499328 DB - PRIME DP - Unbound Medicine ER -
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