The Irony of Humanization: Alemtuzumab, the First, But One of the Most Immunogenic, Humanized Monoclonal Antibodies
Alemtuzumab was designed to reduce the immunogenicity of the parent CD52-specific rat immunoglobulin. Although originally marketed for use in cancer (Mabcampath®), alemtuzumab is currently licensed and formulated for the treatment of relapsing multiple sclerosis (Lemtrada®). Perhaps due to its histo...
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Frontiers Media S.A.
2020-02-01
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Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.00124/full |
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doaj-628cfa68c52f4ac0a00b5bff39da13e7 |
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Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
David Baker Liaqat Ali Liaqat Ali Gauri Saxena Gareth Pryce Meleri Jones Klaus Schmierer Klaus Schmierer Gavin Giovannoni Gavin Giovannoni Sharmilee Gnanapavan Sharmilee Gnanapavan Kathleen C. Munger Lawrence Samkoff Andrew Goodman Angray S. Kang Angray S. Kang |
spellingShingle |
David Baker Liaqat Ali Liaqat Ali Gauri Saxena Gareth Pryce Meleri Jones Klaus Schmierer Klaus Schmierer Gavin Giovannoni Gavin Giovannoni Sharmilee Gnanapavan Sharmilee Gnanapavan Kathleen C. Munger Lawrence Samkoff Andrew Goodman Angray S. Kang Angray S. Kang The Irony of Humanization: Alemtuzumab, the First, But One of the Most Immunogenic, Humanized Monoclonal Antibodies Frontiers in Immunology anti-drug antibodies CD52 humanized immunoglobulin immunogenicity multiple sclerosis |
author_facet |
David Baker Liaqat Ali Liaqat Ali Gauri Saxena Gareth Pryce Meleri Jones Klaus Schmierer Klaus Schmierer Gavin Giovannoni Gavin Giovannoni Sharmilee Gnanapavan Sharmilee Gnanapavan Kathleen C. Munger Lawrence Samkoff Andrew Goodman Angray S. Kang Angray S. Kang |
author_sort |
David Baker |
title |
The Irony of Humanization: Alemtuzumab, the First, But One of the Most Immunogenic, Humanized Monoclonal Antibodies |
title_short |
The Irony of Humanization: Alemtuzumab, the First, But One of the Most Immunogenic, Humanized Monoclonal Antibodies |
title_full |
The Irony of Humanization: Alemtuzumab, the First, But One of the Most Immunogenic, Humanized Monoclonal Antibodies |
title_fullStr |
The Irony of Humanization: Alemtuzumab, the First, But One of the Most Immunogenic, Humanized Monoclonal Antibodies |
title_full_unstemmed |
The Irony of Humanization: Alemtuzumab, the First, But One of the Most Immunogenic, Humanized Monoclonal Antibodies |
title_sort |
irony of humanization: alemtuzumab, the first, but one of the most immunogenic, humanized monoclonal antibodies |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2020-02-01 |
description |
Alemtuzumab was designed to reduce the immunogenicity of the parent CD52-specific rat immunoglobulin. Although originally marketed for use in cancer (Mabcampath®), alemtuzumab is currently licensed and formulated for the treatment of relapsing multiple sclerosis (Lemtrada®). Perhaps due to its history as the first humanized antibody, the potential of immunogenicity of the molecule has been considered inconsequential, and anti-drug antibodies (ADA) responses were similarly reported as being clinically insignificant. Nonetheless, despite humanization and depletion of peripheral T and B cells, alemtuzumab probably generates the highest frequency of binding and neutralizing ADA of all humanized antibodies currently in clinical use, and they occur rapidly in a large majority of people with MS (pwMS) on alemtuzumab treatment. These ADA appear to be an inherent issue of the biology of the molecule—and more importantly, the target—such that avoidance of immunogenicity-related effects has been facilitated by the dosing schedule used in clinical practice. At the population level this enables the drug to work in most pwMS, but in some individuals, as we show here, antibody neutralization appears to be sufficiently severe to reduce efficacy and allow disease breakthrough. It is therefore imperative that efficacy of lymphocyte depletion and the anti-drug response is monitored in people requiring additional cycles of treatment, notably following disease breakthrough. This may help inform whether to re-treat or to switch to another disease-modifying treatment. |
topic |
anti-drug antibodies CD52 humanized immunoglobulin immunogenicity multiple sclerosis |
url |
https://www.frontiersin.org/article/10.3389/fimmu.2020.00124/full |
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doaj-628cfa68c52f4ac0a00b5bff39da13e72020-11-25T01:01:15ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-02-011110.3389/fimmu.2020.00124507483The Irony of Humanization: Alemtuzumab, the First, But One of the Most Immunogenic, Humanized Monoclonal AntibodiesDavid Baker0Liaqat Ali1Liaqat Ali2Gauri Saxena3Gareth Pryce4Meleri Jones5Klaus Schmierer6Klaus Schmierer7Gavin Giovannoni8Gavin Giovannoni9Sharmilee Gnanapavan10Sharmilee Gnanapavan11Kathleen C. Munger12Lawrence Samkoff13Andrew Goodman14Angray S. Kang15Angray S. Kang16Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United KingdomBlizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United KingdomDepartment of Biological Sciences, National University of Medical Sciences (NUMS), Rawalpindi, PakistanBlizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United KingdomBlizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United KingdomBlizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United KingdomBlizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United KingdomClinical Board: Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, United KingdomBlizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United KingdomClinical Board: Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, United KingdomBlizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United KingdomClinical Board: Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, United KingdomDepartment of Neurology, University of Rochester Medical Center, School of Medicine and Dentistry, Rochester, NY, United StatesDepartment of Neurology, University of Rochester Medical Center, School of Medicine and Dentistry, Rochester, NY, United StatesDepartment of Neurology, University of Rochester Medical Center, School of Medicine and Dentistry, Rochester, NY, United StatesBlizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United KingdomCentre for Oral Immunobiology and Regenerative Medicine, Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United KingdomAlemtuzumab was designed to reduce the immunogenicity of the parent CD52-specific rat immunoglobulin. Although originally marketed for use in cancer (Mabcampath®), alemtuzumab is currently licensed and formulated for the treatment of relapsing multiple sclerosis (Lemtrada®). Perhaps due to its history as the first humanized antibody, the potential of immunogenicity of the molecule has been considered inconsequential, and anti-drug antibodies (ADA) responses were similarly reported as being clinically insignificant. Nonetheless, despite humanization and depletion of peripheral T and B cells, alemtuzumab probably generates the highest frequency of binding and neutralizing ADA of all humanized antibodies currently in clinical use, and they occur rapidly in a large majority of people with MS (pwMS) on alemtuzumab treatment. These ADA appear to be an inherent issue of the biology of the molecule—and more importantly, the target—such that avoidance of immunogenicity-related effects has been facilitated by the dosing schedule used in clinical practice. At the population level this enables the drug to work in most pwMS, but in some individuals, as we show here, antibody neutralization appears to be sufficiently severe to reduce efficacy and allow disease breakthrough. It is therefore imperative that efficacy of lymphocyte depletion and the anti-drug response is monitored in people requiring additional cycles of treatment, notably following disease breakthrough. This may help inform whether to re-treat or to switch to another disease-modifying treatment.https://www.frontiersin.org/article/10.3389/fimmu.2020.00124/fullanti-drug antibodiesCD52humanizedimmunoglobulinimmunogenicitymultiple sclerosis |