Measurement of serum levels of natalizumab, an immunoglobulin G4 therapeutic monoclonal antibody

Rispens, Theo; Leeuwen, Astrid van; Vennegoor, Anke; Killestein, Joep; Aalberse, Rob C.; Wolbink, Gertjan; Aarden, Lucien A.

doi:10.1016/j.ab.2011.01.001

Cited by 66 publications

(51 citation statements)

References 20 publications

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“…Rispens et al [15] , for example, investigated natalizumab serum concentrations from patient blood collected after 4-weekly infusion intervals and reported individuals with exceptionally high natalizumab levels. Extremely high serum levels are probably associated with differences in the pharmacokinetic turnover of natalizumab between individual patients.…”

Section: Discussionmentioning

confidence: 99%

Flow cytometry and drug-monitoring of natalizumab saturation of immune cells in multiple sclerosis1)

Harrer

Oppermann

Pilz

et al. 2013

Laboratoriumsmedizin

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Background: Natalizumab (Tysabri) is a blocking antibody specific to the α -4 integrin subunit and can be detected on the surface of immune cells by flow cytometry. We investigated if the determination of natalizumab saturation of immune cells has the potential to act as a biomarker for treatment effectiveness in multiple sclerosis (MS). Methods: Natalizumab saturation of immune cells from 11 patients was measured before the start of treatment and after 4, 8, and 12 weeks of natalizumab therapy on T cells (CD3 + ) and T cell subsets [naive (CD45RA + /memory (CD45R0 + ) CD4 + and CD8 + ] by flow cytometry. Results: At weeks 4, 8, and 12 the average (n = 9) natalizumab saturation of T cells approximated 80%. One patient with natalizumab neutralizing antibodies (NABs) and another patient with irregular infusion intervals were identified by abnormalities in the natalizumab saturation of cells. Different α -4 expression levels of T cell subpopulations were irrelevant to measuring cellular natalizumab saturation. Conclusions: We showed that monitoring natalizumab saturation of T cells by flow cytometry is a useful and routine-qualified method to identify patients with a reduced treatment effect due to NABs or irregular infusion intervals. Further studies to determine a cut-off value for suboptimal natalizumab saturation of immune cells will also show the potential of this parameter concerning more individualized treatment schedules. Considering the risk of opportunistic infections it is very important to increase the safety of this highly effective MS therapy.

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Section: Discussionmentioning

confidence: 99%

Flow cytometry and drug-monitoring of natalizumab saturation of immune cells in multiple sclerosis1)

Harrer

Oppermann

Pilz

et al. 2013

Laboratoriumsmedizin

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“…Salvage from lysosomal degradation by Fc receptors of neonatal (FcRn) and escape from immune-mediated elimination mechanisms due to its IgG4 framework cause the extremely low systemic clearance and prolonged terminal half-life of natalizumab [6], [36]. Rispens et al [37] recently developed a sophisticated ELISA for quantifying serum natalizumab and identified single patients with exceptional high natalizumab levels four weeks post infusion. The substantial differences in individual pharmacokinetics and the reduced cellular natalizumab surface load during therapy add one more indication for monitoring natalizumab binding to immune cells by flow cytometry.…”

Section: Discussionmentioning

confidence: 99%

Lymphocyte Subsets Show Different Response Patterns to In Vivo Bound Natalizumab—A Flow Cytometric Study on Patients with Multiple Sclerosis

et al. 2012

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Natalizumab is an effective monoclonal antibody therapy for the treatment of relapsing- remitting multiple sclerosis (RRMS) and interferes with immune cell migration into the central nervous system by blocking the α4 subunit of very-late activation antigen-4 (VLA-4). Although well tolerated and very effective, some patients still suffer from relapses in spite of natalizumab therapy or from unwanted side effects like progressive multifocal leukoencephalopathy (PML). In search of a routine-qualified biomarker on the effectiveness of natalizumab therapy we applied flow cytometry and analyzed natalizumab binding to α4 and α4 integrin surface levels on T-cells, B-cells, natural killer (NK) cells, and NKT cells from 26 RRMS patients under up to 72 weeks of therapy. Four-weekly infusions of natalizumab resulted in a significant and sustained increase of lymphocyte-bound natalizumab (p<0.001) which was paralleled by a significant decrease in detectability of the α4 integrin subunit on all lymphocyte subsets (p<0.001). We observed pronounced natalizumab accumulations on T and B cells at single measurements in all patients who reported clinical disease activity (n = 4). The natalizumab binding capacity of in vitro saturated lymphocytes collected during therapy was strongly diminished compared to treatment-naive cells indicating a therapy-induced reduction of α4. Summing up, this pilot study shows that flow cytometry is a useful method to monitor natalizumab binding to lymphocytes from RRMS patients under therapy. Investigating natalizumab binding provides an opportunity to evaluate the molecular level of effectiveness of natalizumab therapy in individual patients. In combination with natalizumab saturation experiments, it possibly even provides a means of studying the feasability of patient-tailored infusion intervals. A routine-qualified biomarker on the basis of individual natalizumab saturation on lymphocyte subsets might be an effective tool to improve treatment safety.

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“…The assay was set up analogously to a previously developed adalimumab assay, using the target (interleukin‐12) to capture ustekinumab, and rabbit antiustekinumab for detection . The antigen‐binding test was carried out essentially as described for infliximab …”

Section: Patient Characteristics (N = 41)mentioning

confidence: 99%

The correlation of clinical efficacy, serum trough levels and antidrug antibodies in ustekinumab-treated patients with psoriasis in a clinical-practice setting

et al. 2015

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Measurement of serum levels of natalizumab, an immunoglobulin G4 therapeutic monoclonal antibody

Cited by 66 publications

References 20 publications

Flow cytometry and drug-monitoring of natalizumab saturation of immune cells in multiple sclerosis1)

Flow cytometry and drug-monitoring of natalizumab saturation of immune cells in multiple sclerosis1)

Lymphocyte Subsets Show Different Response Patterns to In Vivo Bound Natalizumab—A Flow Cytometric Study on Patients with Multiple Sclerosis

The correlation of clinical efficacy, serum trough levels and antidrug antibodies in ustekinumab-treated patients with psoriasis in a clinical-practice setting

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