Monitoring CD49d Receptor Occupancy: A Method to Optimize and Personalize Natalizumab Therapy in Multiple Sclerosis Patients

Puñet-Ortiz, Joan; Hervás-García, J.V.; Teniente-Serra, Aina; Cano-Orgaz, Antonio; Mansilla, María José; Quirant‐Sánchez, Bibiana; Navarro‐Barriuso, Juan; Fernández-Sanmartín, Marco Antonio; Presas-Rodríguez, Silvia; Ramo-Tello, Cristina; Martínez-Cáceres, Eva

doi:10.1002/cyto.b.21527

Cited by 20 publications

(30 citation statements)

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“…Using quantitative flow cytometry as a tool for immune-monitoring, a method for immunomonitoring CD49d receptor occupancy in MS patients under natalizumab therapy has been reported. Using this method, it is possible to determine the percentage of CD49d molecules bound to natalizumab and identify those patients with low receptor occupancy (suboptimal doses), which in a long-term sustained therapy context would show a decrease in treatment efficacy (99).…”

Section: Changes In Lymphocyte Subpopulations As Biomarkers Of Therapmentioning

confidence: 99%

Immunomonitoring Lymphocyte Subpopulations in Multiple Sclerosis Patients

Teniente‐Serra¹,

Ramo‐Tello

Martı́nez-Cáceres

2017

Multiple Sclerosis: Perspectives in Treatment and Pathogenesis

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Abstract:Advances in the understanding of pathogenic mechanisms of diseases have led to the defining of new biomarkers for diagnosis, prognosis, and therapy response. In this context, flow cytometry has been positioned as one of the most useful technologies for monitoring immune-mediated diseases, such as multiple sclerosis (MS), allowing a detailed analysis of lymphocyte subpopulations in peripheral blood. The autoimmune inflammatory response in MS results in changes in lymphocyte subpopulations that might be useful as surrogate markers for the evaluation of disease activity, progression, and monitoring of therapy response. This chapter discusses the role of T-lymphocyte and B-lymphocyte subpopulations in MS pathogenesis, the effect of MS treatments on these subsets, and their potential usefulness as biomarkers of treatment response.

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Section: Changes In Lymphocyte Subpopulations As Biomarkers Of Therapmentioning

confidence: 99%

Immunomonitoring Lymphocyte Subpopulations in Multiple Sclerosis Patients

Teniente‐Serra¹,

Ramo‐Tello

Martı́nez-Cáceres

2017

Multiple Sclerosis: Perspectives in Treatment and Pathogenesis

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“…Receptor occupancy data can contribute to determining the minimal anticipated biological effect level (MABEL) which is often better suited than NOAEL to predict safe starting doses in first-in-human clinical trials. Unfortunately, blocking of CD49d can also lead to progressive multifocal leukoencephalopathy, a potentially lethal side effect of natalizumab treatment (8). During later-phase trials, receptor occupancy data can monitor therapeutic response and guide optimal dosing for individual patients.…”

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confidence: 99%

“…During later-phase trials, receptor occupancy data can monitor therapeutic response and guide optimal dosing for individual patients. Bringeland et al (1) and others (8) have investigated the use of RO assays for dosing of natalizumab, an effective therapy for multiple sclerosis patients. Multiple sclerosis is a chronic inflammatory autoimmune disease of the central nervous system, and natalizumab is a blocking antibody against CD49d, a cell adhesion molecule used by lymphocytes to enter the inflamed brain.…”

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confidence: 99%

“…Multiple sclerosis is a chronic inflammatory autoimmune disease of the central nervous system, and natalizumab is a blocking antibody against CD49d, a cell adhesion molecule used by lymphocytes to enter the inflamed brain. Unfortunately, blocking of CD49d can also lead to progressive multifocal leukoencephalopathy, a potentially lethal side effect of natalizumab treatment (8). In a personalized therapy setting, monitoring CD49d receptor occupancy on peripheral blood leucocytes during natalizumab treatment can optimize the dosing to increase the therapeutic effect and at the same time reduce severe side effects.…”

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confidence: 99%

“…This strategy enabled them to follow the total receptor level over time and reveal changes in receptor levels induced by the treatment. This was important as natalizumab treatment is known to downregulate the surface expression of CD49d on lymphocytes (8). The main challenge with this strategy is that the signal strength differs between the mass channels in a mass cytometer.…”

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Expanding the Clinical Cytometry Toolbox—Receptor Occupancy by Mass Cytometry

Huse

2019

Cytometry Pt A

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DETERMINATION of the optimal therapeutic dose is a key challenge in drug development. Receptor occupancy assays (RO assays) measure the binding of biotherapeutics to their cellular targets and are one of the tools used to determine starting doses in clinical and preclinical studies. Flow cytometry-based RO assays have been developed for heterogeneous cell populations in suspension and are well suited for evaluating therapeutics targeting peripheral blood cells. Mass cytometry would further expand the possibilities to measure receptor occupancy of complex cell types as metallabeled antibodies and minimal overlap between channels allow for more than 40 markers to be detected simultaneously without loss of sensitivity. Bringeland et al. (1) have developed a mass cytometry-based RO assay, recently described in a technical note. With a backbone of 15 lineage markers, they identified eight cell types of interest and obtained receptor occupancy data for each cell population.Receptor occupancy assays can prevent life-threatening side effects in clinical trials, exemplified by the disastrous TGN1412 first-in-human clinical trial in 2006 (2). TGN1412 is an anti-CD28 superagonistic monoclonal antibody that stimulates T cells, intended for treatment of B-cell chronic lymphocytic leukemia and rheumatoid arthritis. In preclinical trials, cynomolgus monkeys were used to determine toxicity, and starting doses in the first human clinical trial was calculated based on the no-adverse-effect level (NOAEL) in these animals (3). However, despite using doses 500 times lower than the dose found safe in animal models, the human volunteers involved in the trial suffered severe cytokine release syndrome and multiple organ failure after receiving the drug (2). Follow-up studies revealed that biological differences between humans and monkeys, in this case different expression levels of CD28 on their respective T cells, resulted in 90% receptor occupancy and severe cytokine release syndrome with a dose that was expected to lead to only 10% receptor occupancy (4). A simple RO assay could have revealed these differences, and as a consequence of this trial, the procedures for first-in-human clinical trials were changed (5).Today, RO assays play an increasing role in drug development (3,4) and have been used in testing of therapeutic antibodies like anti-PD-1 (6) and anti-PD-L1 (7). Receptor occupancy data can contribute to determining the minimal anticipated biological effect level (MABEL) which is often better suited than NOAEL to predict safe starting doses in first-in-human clinical trials. In addition to revealing safety hazards, RO assays can limit the extent of preclinical testing, which could reduce costs for the pharmaceutical industry and benefit patients by introducing potentially life-saving drugs earlier. During later-phase trials, receptor occupancy data can monitor therapeutic response and guide optimal dosing for individual patients. Bringeland et al. (1) and others (8) have investigated the use of RO assays for dosing of natalizu...

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Improving risk‐stratification of natalizumab‐associated PML

Tugemann¹,

Berger

2021

Ann Clin Transl Neurol

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Based on publicly available data, we reevaluated current algorithms for stratifying the risk of progressive multifocal leukoencephalopathy (PML) in natalizumab‐treated patients with multiple sclerosis, and found that there are a number of issues. First and foremost, our analysis highlights the necessity of separate PML incidence assessments for the U.S. versus Europe, and indicates that the risk in John Cunningham virus (JCV) antibody‐negative patients may be higher than previously communicated. Additionally, we advocate introducing a low‐risk JCV index threshold of 0.45 for individuals with prior exposure to an immunosuppressant, and setting the low‐risk threshold at 0.6 instead of 0.9 for those without such pretherapies. On the other hand, the risk of PML on natalizumab, in general, appears to not only plateau but to actually decrease after about 5 years of continuous dosing.

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Monitoring CD49d Receptor Occupancy: A Method to Optimize and Personalize Natalizumab Therapy in Multiple Sclerosis Patients

Abstract: Following up CD49d RO levels with a well-regulated monitoring work scheme is crucial to further identify over-/under-treated patients and to define a safe, personalized natalizumab regimen. © 2017 International Clinical Cytometry Society.

Cited by 20 publications

References 20 publications

Immunomonitoring Lymphocyte Subpopulations in Multiple Sclerosis Patients

Immunomonitoring Lymphocyte Subpopulations in Multiple Sclerosis Patients

Expanding the Clinical Cytometry Toolbox—Receptor Occupancy by Mass Cytometry

Improving risk‐stratification of natalizumab‐associated PML

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