RT Journal Article SR Electronic T1 Detecting and predicting neutralization of alemtuzumab responses in MS JF Neurology - Neuroimmunology Neuroinflammation JO Neurol Neuroimmunol Neuroinflamm FD Lippincott Williams & Wilkins SP e767 DO 10.1212/NXI.0000000000000767 VO 7 IS 4 A1 Gauri Saxena A1 James M. Moore A1 Meleri Jones A1 Gareth Pryce A1 Liaqat Ali A1 Georgia R. Leisegang A1 Vivek Vijay A1 Samantha Loveless A1 Neil P. Robertson A1 Klaus Schmierer A1 Gavin Giovannoni A1 Sharmilee Gnananpavan A1 David Baker A1 Emma C. Tallantyre A1 Angray S. Kang YR 2020 UL http://nn.neurology.org/content/7/4/e767.abstract AB 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.ADA=antidrug antibody; DMT=disease-modifying treatment; EDSS=Expanded Disability Status Scale; PwMS=people with MS; WNRTB=Welsh Neuroscience Research Tissue Bank