Abstract
Natalizumab is a monoclonal antibody that binds CD49d. Although it is one of the most effective treatments for Relapsing-Remitting Multiple Sclerosis (RRMS), a dosing regimen has not been optimized for safety and efficacy in individual patients. We aimed to identify biomarkers to monitor Natalizumab treatment and to establish a personalized dose utilizing an ongoing longitudinal study in 29 RRMS patients under Natalizumab with standard interval dose (SD) of 300 mg/4 wks or extended interval dose (EID) of 300 mg/6 wks. Blood samples were analyzed by flow cytometry to determine CD49d saturation and expression in several T and B lymphocytes subpopulations. Each patient was analyzed at two different timepoints separated by 3 Natalizumab administrations. Natalizumab and sVCAM-1 levels in serum were also analyzed using ELISA. To determine the reproducibility of various markers, two different timepoints were compared and no significant differences were observed for CD49d expression nor for saturation; SD patients had higher saturation levels (~80%) than EID patients (~60%). A positive correlation exists between CD49d saturation and Natalizumab serum levels. CD49d expression and saturation are stable parameters that could be used as biomarkers in the immunomonitoring of Natalizumab treatment. Moreover, Natalizumab and sVCAM-1 serum levels could be used to optimize an individual’s dosing schedule.
Highlights
The results showed a positive correlation between CD49d saturation and NTZ in serum for all the lymphocyte subpopulations in both timepoints (Figure 8), while no consistent correlation was observed between CD49d saturation and sVCAM in serum
We present data that validates the stability of CD49d saturation and expression as cellular biomarkers in both whole blood and PBMCs as well as the serum protein soluble VCAM-1 (sVCAM-1)
The central nervous system (CNS) is an immune-privileged site that generally has sufficient levels of immunosurveillance to protect it against opportunistic infections and neoplastic proliferation
Summary
Natalizumab (NTZ) is a humanized IgG4κ monoclonal antibody that selectively binds by allosteric antagonism to α4-integrin (CD49d), preventing leukocyte migration into the central nervous system (CNS) in multiple sclerosis (MS) patients [1]. α4-integrins form heterodimers with β-subunits [β1 (CD29) and β7] to form functional molecules [2].α4β1 (VLA-4) and α4β7 are located on leukocytes surface and interact with VCAM-1 and MAdCAM-1, respectively, for the firm adhesion of leukocytes to endothelial cells, a necessary step for leukocyte extravasation into the inflamed tissue.The interaction of VLA-4 with VCAM-1 facilitates adhesion of leukocytes to the endothelium enabling the transmigration of circulating leukocytes across the bloodbrain barrier (BBB) [3,4], and can increase the activation and proliferation of lymphocytes [5,6]. Pro-inflammatory factors released in autoimmune conditions such as MS can increase the expression of VCAM-1 on the endothelial cell surface allowing leukocyte binding to the BBB which, in turn, promotes the release as soluble VCAM-1 (sVCAM-1) [9]. This suggests that serum levels of sVCAM-1 could be a marker of immune cells binding to the endothelial barrier as well as endothelial barrier activity. It is one of the most effective treatments [10] its use is associated with a very severe side effect, the risk of developing Progressive Multifocal
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