The Pharmacogenetics of Rituximab: Potential Implications for Anti-CD20 Therapies in Multiple Sclerosis
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The Pharmacogenetics of Rituximab: Potential Implications for Anti-CD20 Therapies in Multiple Sclerosis Michael Zhong 1,2 & Anneke van der Walt 1,2 & Maria Pia Campagna 1 & Jim Stankovich 1 & Helmut Butzkueven 1,2 & Vilija Jokubaitis 1,2 Accepted: 9 October 2020 # The American Society for Experimental NeuroTherapeutics, Inc. 2020
Abstract There are a broad range of disease-modifying therapies (DMTs) available in relapsing-remitting multiple sclerosis (RRMS), but limited biomarkers exist to personalise DMT choice. All DMTs, including monoclonal antibodies such as rituximab and ocrelizumab, are effective in preventing relapses and preserving neurological function in MS. However, each agent harbours its own risk of therapeutic failure or adverse events. Pharmacogenetics, the study of the effects of genetic variation on therapeutic response or adverse events, could improve the precision of DMT selection. Pharmacogenetic studies of rituximab in MS patients are lacking, but pharmacogenetic markers in other rituximab-treated autoimmune conditions have been identified. This review will outline the wider implications of pharmacogenetics and the mechanisms of anti-CD20 agents in MS. We explore the non-MS rituximab literature to characterise pharmacogenetic variants that could be of prognostic relevance in those receiving rituximab, ocrelizumab or other monoclonal antibodies for MS. Key words Multiple sclerosis . rituximab . ocrelizumab . monoclonal antibody . pharmacogenetics . pharmacogenomics
Introduction For patients with relapsing-remitting multiple sclerosis (RRMS), available disease-modifying therapies (DMTs) are key, but imperfect, in preventing relapses and disease progression. Delayed effective treatment and prolonged exposure to suboptimal therapy increases the risk of irreversible disability [1–3] and adverse events. The sources of inter-individual therapeutic variability, particularly genetic factors, are incompletely understood. Pharmacogenetic markers could optimise long-term disease outcomes by improving treatment selection for a given patient. Existing pharmacogenetic and pharmacogenomic studies of MS DMTs have not yet led to significant changes in prescribing practice, and are largely limited to examinations of interferon-beta and glatiramer acetate [4]. Some pharmacogenetic markers for these two * Michael Zhong [email protected] 1
Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia
2
Department of Neurology, Alfred Health, Level 6, Alfred Centre, 99 Commercial Road, Melbourne, Victoria 3004, Australia
modestly effective agents have been replicated and show promise as predictors of therapeutic success. However, a more complete understanding of the gene-drug interactions that dictate the efficacy of DMTs, particularly higher efficacy therapies including monoclonal antibodies, is required. Rituximab, an anti-CD20 monoclonal antibody with demonstrated efficacy in RRMS and other neurological, rheumatological and haematological conditions
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