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Master Thesis

Anti-CD20 monoclonal antibodies immuno-monitoring in primary membranous nephropathy to guide personalized treatment

Abstract : Background: Rituximab (RTX), a murine 1 human chimeric monoclonal antibody (mAb) directed against the CD20, induced clinical remission in 60 to 80% of patients with primary membranous nephropathy (MN). However, mAb as RTX can induce immunogenicity, in a substantial number of patients, resulting in a Joss of efficacy oftreatment. ln this study, we aim to monitor RTX therapy in a cohort of patients treated for primary MN and to assess wh ether new humanized and fully-human antiCD20 mAbs could be a therapeutic alternative.
Materials and methods: we measured rituximab levels and anti-RTX antibodies at month 3 and month 6 by ELISA in 22 MN patients treated by lg DO and 015 by RTX. We studied anti-CD20 mAbs B cells cytotoxicity in presence or absence ofanti-RTX antibodies. Tested anti-CD20 mAbs were: RTX, ocrelizumab (OCRE) and obinutuzumab (OBI) (humanized anti-CD20 mAbs) and ofatumumab (OFA) (fully human anti-CD20 mAb).
Results: residual serum RTX leve! at month 3 was significantly correlated with anti-PLA2RI antibodies titer at month 6 (r= -0.609, p = 0.0044). lt was also correlated with proteinuria at month 6 (r=-0.750 p = 0.000 l) whereas there was no correlation with baseline proteinuria (r= -0.085 p = O. 7136). High serum RTX levels at mon th 3 and low anti-PLA2R l an ti bodies at mon th 6 were associated with clinical remission at mon th 6 (p=O.OO Il and p= 0.0095 respectively). There was no statistical difference between serum RTX concentrations at month 3 between patients with or without anti-RTX antibodies. ln our 22 patients cohort, 5 (23%) developed anti-RTX antibodies. Patients with anti-RTX antibodies have been more retreated before month 12 for relapse or incomplete response (p = 0.039) than patients without anti-RTX antibodies. Anti-RTX antibodies were neutralizing in 80% of cases. For two patients, they also blocked both OBI, OCRE and OF A B cells cytotoxicity whereas no cross-reactivity was observed for three patients.
Discussion and conclusion: measurement of residual serum RTX concentration at 3 months could be a useful adjunct to monitoring of MN patients, while early measurements at day 15 were shown not tonbe predictive. Undetectable serum RTX at month 3 could impact treatment as encouraging a third RTX infusion in patients with persistent anti-PLA2R 1 activity. Neutralizing anti-RTX antibodies are not rare and their presence at month 6 is associated with subsequent MN relapse. They can also neutralize other anti-CD20 mAbs. Further studies are needed to develop personalized therapeutic strategies in primary MN based on drug monitoring and immunogenicity testing.
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Master Thesis
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Submitted on : Wednesday, October 23, 2019 - 11:47:24 AM
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Sonia Boyer. Anti-CD20 monoclonal antibodies immuno-monitoring in primary membranous nephropathy to guide personalized treatment. Human health and pathology. 2017. ⟨dumas-02328650⟩

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