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Toward Personalized Dosing of B-Cell–Depleting Therapy
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- The humanized anti-CD20 monoclonal antibody ocrelizumab is frequently used to treat MS. The current maintenance treatment schedule includes administration of one dose every 6 months indefinitely. The recent literature suggests that less frequent dosing may be feasible and does not result in a return of inflammatory disease activity. One gap in the literature remains: identification of a clinically useful biomarker to help guide the dosing schedule and personalize treatments to maximize benefits over risks of immune depletion. This study carefully characterized B-cell subsets in treatment-naive patients with MS before and after ocrelizumab administration. None of the patients received prior disease-modifying therapy; ocrelizumab therapy was their initial disease-modifying therapy. The team further characterized the B cells after ocrelizumab treatment was stopped for clinical reasons at a mean duration of 14 months from the last infusion. Interestingly, the investigators identified at least five clusters of B cells and generated heat maps before and after treatment. Cluster 5, in particular, represented activated class-switched memory B cells and was significantly different from healthy controls. Of interest, this cluster of cells depleted to healthy control levels after two treatment cycles of ocrelizumab (first loading doses and one maintenance dose) and did not return to abnormal levels even after holding ocrelizumab for up to 19 months in some patients, with no return of clinical disease activity. This finding is of great clinical interest as identifying these cells can be done easily using flow cytometry in clinical laboratories, and this cluster of cells can be studied in larger cohorts as a biomarker to guide therapy administration. Further, the team identified groups of B cells that are resistant to depletion with ocrelizumab and are being investigated further and may provide insights into retaining the ability to provide immune responses against pathogens in B-cell–depleted patients.
- This study identified clinically useful immune biomarkers that can be measured using flow cytometry in any clinical laboratory to track subpopulations of B cells that may guide personalized therapy in the future. Prospective studies are needed to incorporate blood biomarkers to guide the dosing frequency of B-cell–depleting therapies.
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersIn multiple sclerosis (MS) the B cell depleting drug ocrelizumab has shown high efficacy in reducing inflammatory activity. Its mechanism of action is unclear due to B cell subset complexity and unknown roles in pathogenesis. Here, we comprehensively phenotyped and quantitated peripheral blood B cell subsets before and after ocrelizumab infusion to gain insight into the fate of B cell subsets with pathogenic potential. Peripheral blood B cells were collected from treatment naïve patients at baseline and months one, three, and six following the first course of ocrelizumab treatment; at 6 months following the second treatment cycle; ∼14 months following their last infusion; and from healthy controls. Flow cytometry combined with cluster analysis was used to track depletion and repletion of naïve, memory, and antibody secreting cells. By month one, naïve B cells were depleted, but a small subset of memory B cells were retained with no depletion of antibody secreting cells. Uniform manifold approximation and projection for dimension reduction analysis of flow cytometry data revealed two non-class switched naïve clusters and two class switched memory clusters. One class switched cluster was activated in MS patients but largely absent in healthy controls. Both memory B cell subsets underwent depletion after a single six-month course of ocrelizumab treatment after which their proportions were reset to heathy control levels. These observations suggest that activated class-switched memory B cells could serve as a biomarker of recent or ongoing MS disease activity to guide redosing.
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Elevated frequencies of activated memory B cells in multiple sclerosis are reset to healthy control levels after B cell depletion with Ocrelizumab
J. Neuroimmunol. 2024 Dec 02;399(xx)578502, CJ Gurski, Z Hajiyeva, AJ Veltri, K Fenton, S O'Dell, AZ Obeidat, BN DittelFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.