Using Mass Spectrometry to Quantify Rituximab and Perform Individualized Immunoglobulin Phenotyping in ANCA-Associated Vasculitis

Mills, John R.; Cornec, Divi; Dasari, Surendra; Ladwig, Paula M.; Hummel, Amber M.; Cheu, Melissa; Murray, David; Willrich, Maria Alice V.; Snyder, Melissa R.; Hoffman, Gary S.; Kallenberg, Cees G. M.; Langford, Carol A.; Merkel, Peter A.; Monach, Paul A.; Seo, Philip; Spiera, Robert; Clair, E. William St.; Stone, John H.; Specks, Ulrich; Barnidge, David R.

doi:10.1021/acs.analchem.6b00544

Cited by 27 publications

(8 citation statements)

References 21 publications

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“…Such differences may be related to different dosing schedules (taking into account the weight (here and [20]) or not [16] for TCZ), as well as the various analytical methods used to quantify the mAbs. Here, we used a highly specific LC-MS/MS method, adapted from our previously published method [27,30], whereas other studies used various ELISA methods [16,20,36,43], for which the analytical limits have been well-described [25,28,44,45]. For example, Mazilu et al used the Promonitor â assay, for which a large bias was found relative to our LC-MS/MS method (mean underestimation of RTX concentration of 69%) or the Lisa-tracker â kit [30].…”

Section: Variability Of Rituximab and Tocilizumab Concentrationsmentioning

confidence: 99%

“…These studies all used immunoassays to quantify RTX or TCZ in the serum of RA patients, whereas the analytical limitations of these methods, in terms of lack of specificity and variability between different kits, have been well-described [24][25][26]. Thus, highly specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods have been recently developed to quantify mAbs in human samples to overcome these limitations [27][28][29][30].…”

Section: Introductionmentioning

confidence: 99%

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Variability of rituximab and tocilizumab trough concentrations in patients with rheumatoid arthritis

Truffot

Gautier-Veyret

Baillet

et al. 2021

Fundamemntal Clinical Pharma

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Patients with rheumatoid arthritis (RA) are eligible for treatment with therapeutic monoclonal antibodies (mAbs) that target tumor necrosis factor α (TNFα), as well as others, such as rituximab (RTX) and tocilizumab (TCZ). Although pharmacokinetic variability and the link between concentration‐clinical response of anti‐TNFα mAbs have been well‐described, little is known about RTX and TCZ. We aimed to evaluate the variability of RTX and TCZ serum concentrations in RA patients treated in second‐line and the relationship between RTX/TCZ concentrations and the clinical response. Serum mAb trough concentrations of RA patients treated with RTX (n = 35) or TCZ (n = 46) were determined at week 24 by liquid chromatography‐tandem mass spectrometry. The clinical response was assessed at week 24 by the change in the disease activity score in the 28 joints‐erythrocyte sedimentation rate from baseline (ΔDAS28‐Erythrocyte Sedimentation Rate) and according to the European League Against Rheumatism (EULAR) recommendations. RTX and TCZ trough concentrations were highly variable, with a coefficient of variation of 171.3% for RTX (median [10th‐90th percentiles]: <1.0 µg/mL [<1.0–5.1]) and 132.6% for TCZ (median [10th‐90th percentiles]: 5.4 µg/mL [<1.0–27.8]). Univariate analysis did not identify any determinants of such variability, except cotreatment with methotrexate, which was associated with lower RTX concentrations (P = 0.03). The response to treatment was not related to the RTX or TCZ trough concentration. RTX and TCZ trough concentrations at 24 weeks were highly variable in RA patients treated in the second line, without any link concentration‐clinical response having been demonstrated.

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Section: Variability Of Rituximab and Tocilizumab Concentrationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Variability of rituximab and tocilizumab trough concentrations in patients with rheumatoid arthritis

Truffot

Gautier-Veyret

Baillet

et al. 2021

Fundamemntal Clinical Pharma

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“…In that study, the therapeutic MAb was used as the model system to identify an endogenous monoclonal Ig in patients with multiple myeloma (60). This method was then adapted for utilization for the quantitation of the therapeutic MAb RTX in patients being treated for vasculitis (61). Quantification of MAb by measurement of its intact light chain mass utilizes Melon Gel (Thermo-Fisher Scientific, Waltham, MA) for extraction, an inexpensive, simple, and fast method to enrich a serum sample for Igs.…”

Section: Intact Light Chain Methodsmentioning

confidence: 99%

Mass Spectrometry Approaches for Identification and Quantitation of Therapeutic Monoclonal Antibodies in the Clinical Laboratory

Ladwig

Barnidge

Willrich

2017

Clin Vaccine Immunol

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Therapeutic monoclonal antibodies (MAbs) are an important class of drugs used to treat diseases ranging from autoimmune disorders to B cell lymphomas to other rare conditions thought to be untreatable in the past. Many advances have been made in the characterization of immunoglobulins as a result of pharmaceutical companies investing in technologies that allow them to better understand MAbs during the development phase. Mass spectrometry is one of the new advancements utilized extensively by pharma to analyze MAbs and is now beginning to be applied in the clinical laboratory setting. The rise in the use of therapeutic MAbs has opened up new challenges for the development of assays for monitoring this class of drugs. MAbs are larger and more complex than typical small-molecule therapeutic drugs routinely analyzed by mass spectrometry. In addition, they must be quantified in samples that contain endogenous immunoglobulins with nearly identical structures. In contrast to an enzyme-linked immunosorbent assay (ELISA) for quantifying MAbs, mass spectrometry-based assays do not rely on MAb-specific reagents such as recombinant antigens and/or anti-idiotypic antibodies, and time for development is usually shorter. Furthermore, using molecular mass as a measurement tool provides increased specificity since it is a first-order principle unique to each MAb. This enables rapid quantification of MAbs and multiplexing. This review describes how mass spectrometry can become an important tool for clinical chemists and especially immunologists, who are starting to develop assays for MAbs in the clinical laboratory and are considering mass spectrometry as a versatile platform for the task.

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“…Infliximab, adalimumab, eculizumab, vedolizumab, and rituximab were all readily identified by their LC molecular masses when spiked into patient serum at physiologically relevant concentrations. This approach has potential to be useful for accurately quantitating M-proteins in the presence of comigrating t-mAbs (37,40). Therefore, accurate molecular mass measurement of patient sera for the detection of both endogenous M-proteins and t-mAbs is a promising application of mass spectrometry.…”

Section: Mass Spectrometry-based Approachesmentioning

confidence: 99%

Identification of Friend or Foe: The Laboratory Challenge of Differentiating M-Proteins from Monoclonal Antibody Therapies

Mills

Murray

2017

The Journal of Applied Laboratory Medicine

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Background: Since the first monoclonal antibody (mAb) therapy hit the market in 1996, the number of disorders treated with this class of therapeutics has seen tremendous growth, with over 50 antibodybased therapeutics currently approved for use in the US and Europe. This class of therapeutics recently made profound progress in the treatment of refractory multiple myeloma (MM). Treating MM with the mAbs will challenge the laboratory's ability to differentiate exogenous mAbs being used to treat patients from endogenous mAbs associated with disease. Content: An overview of the therapeutic mAbs (t-mAbs) developed for the treatment of MM is provided. The anticipated impact of these therapies on patient care, laboratory testing, and clinical research is discussed. Efforts underway to develop strategies and technologies to help laboratories address the growing challenge of mAb interferences are reviewed. Summary: Laboratories can implement risk mitigation strategies at the preanalytical and postanalytical phase of testing to reduce the likelihood of reporting false-positive M-protein results in patients receiving t-mAbs. However, at the analytical phase of testing, current laboratory methods are ill-suited to differentiate between residual disease and residual drugs. Mass spectrometrybased methods might be best positioned to aid laboratories with the rapidly evolving landscape of MM treatment. IMPACT STATEMENT Patients being screened for monoclonal gammopathies, and those diagnosed with MM and currently undergoing treatment with t-mAbs will benefit from raised awareness of the potential for false-positive M-protein results due to t-mAbs. Here, an informational resource is provided to foster a better understanding of when t-mAbs are likely to be encountered and how the associated risk can be mitigated. This article reviews the emerging role of mass spectrometry as a method of measuring M-proteins and why this is less likely to be negatively affected by t-mAbs compared to current testing methods.

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Using Mass Spectrometry to Quantify Rituximab and Perform Individualized Immunoglobulin Phenotyping in ANCA-Associated Vasculitis

Cited by 27 publications

References 21 publications

Variability of rituximab and tocilizumab trough concentrations in patients with rheumatoid arthritis

Variability of rituximab and tocilizumab trough concentrations in patients with rheumatoid arthritis

Mass Spectrometry Approaches for Identification and Quantitation of Therapeutic Monoclonal Antibodies in the Clinical Laboratory

Identification of Friend or Foe: The Laboratory Challenge of Differentiating M-Proteins from Monoclonal Antibody Therapies

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