Dataset Information

Anti-CD20-Mediated B Cell Depletion Is Associated With Bone Preservation in Lymphoma Patients and Bone Mass Increase in Mice.

ABSTRACT: Immunotherapy with anti-CD20-specific antibodies (rituximab), has become the standard of care for B cell lymphoproliferative disorders and many autoimmune diseases. In rheumatological patients the effect of rituximab on bone mass yielded conflicting results, while in lymphoma patients it has not yet been described. Here, we used cross-sectional X-ray imaging (CT/PET-CT) to serially assess bone density in patients with follicular lymphoma receiving rituximab maintenance therapy. Remarkably, this treatment prevented the decline in bone mass observed in the control group of patients who did not receive active maintenance therapy. In accordance with these data, anti-CD20-mediated B cell depletion in normal C57BL/6J female mice led to a significant increase in bone mass, as reflected by a 7.7% increase in bone mineral density (whole femur), and a ~5% increase in cortical as well as trabecular tissue mineral density. Administration of anti-CD20 antibodies resulted in a significant decrease in osteoclastogenic signals, including RANKL, which correlated with a reduction in osteoclastogenic potential of bone marrow cells derived from B-cell-depleted animals. Taken together, our data suggest that in addition to its anti-tumor activity, anti-CD20 treatment has a favorable effect on bone mass. Our murine studies indicate that B cell depletion has a direct effect on bone remodeling.

SUBMITTER: Kolomansky A

PROVIDER: S-EPMC7604358 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Anti-CD20-Mediated B Cell Depletion Is Associated With Bone Preservation in Lymphoma Patients and Bone Mass Increase in Mice.

Kolomansky Albert A Kaye Irit I Ben-Califa Nathalie N Gorodov Anton A Awida Zamzam Z Sadovnic Ofer O Ibrahim Maria M Liron Tamar T Hiram-Bab Sahar S Oster Howard S HS Sarid Nadav N Perry Chava C Gabet Yankel Y Mittelman Moshe M Neumann Drorit D

Frontiers in immunology 20201019

Immunotherapy with anti-CD20-specific antibodies (rituximab), has become the standard of care for B cell lymphoproliferative disorders and many autoimmune diseases. In rheumatological patients the effect of rituximab on bone mass yielded conflicting results, while in lymphoma patients it has not yet been described. Here, we used cross-sectional X-ray imaging (CT/PET-CT) to serially assess bone density in patients with follicular lymphoma receiving rituximab maintenance therapy. Remarkably, this ...[more]

PMID: 33193330

Similar Datasets

Project description:BackgroundClinical trials evaluating anti-CD20-mediated B-cell depletion in multiple sclerosis (MS) and neuromyelitis optica (NMO) generated encouraging results. Our recent studies in the MS model experimental autoimmune encephalomyelitis (EAE) attributed clinical benefit to extinction of activated B-cells, but cautioned that depletion of naïve B-cells may be undesirable. We elucidated the regulatory role of un-activated B-cells in EAE and investigated whether anti-CD20 may collaterally diminish regulatory B-cell properties in treatment of neuroimmunological disorders.MethodsMyelin oligodendrocyte glycoprotein (MOG) peptide-immunized C57Bl/6 mice were depleted of B-cells. Functional consequences for regulatory T-cells (Treg) and cytokine production of CD11b+ antigen presenting cells (APC) were assessed. Peripheral blood mononuclear cells from 22 patients receiving anti-CD20 and 23 untreated neuroimmunological patients were evaluated for frequencies of B-cells, T-cells and monocytes; monocytic reactivity was determined by TNF-production and expression of signalling lymphocytic activation molecule (SLAM).ResultsWe observed that EAE-exacerbation upon depletion of un-activated B-cells closely correlated with an enhanced production of pro-inflammatory TNF by CD11b+ APC. Paralleling this pre-clinical finding, anti-CD20 treatment of human neuroimmunological disorders increased the relative frequency of monocytes and accentuated pro-inflammatory monocyte function; when reactivated ex vivo, a higher frequency of monocytes from B-cell depleted patients produced TNF and expressed the activation marker SLAM.ConclusionsThese data suggest that in neuroimmunological disorders, pro-inflammatory APC activity is controlled by a subset of B-cells which is eliminated concomitantly upon anti-CD20 treatment. While this observation does not conflict with the general concept of B-cell depletion in human autoimmunity, it implies that its safety and effectiveness may further advance by selectively targeting pathogenic B-cell function.

Project description:OBJECTIVE:This study was designed to determine the safety, pharmacokinetics and biologic effects of a human-mouse chimeric anti-CD20 monoclonal antibody (SCT400) in Chinese patients with CD20-positive B-cell non-Hodgkin's lymphoma (CD20(+) B-cell NHL). SCT400 has an identical amino acid sequence as rituximab, with the exception of one amino acid in the CH1 domain of the heavy chain, which is common in Asians. METHODS:Fifteen patients with CD20(+) B-cell NHL received dose-escalating SCT400 infusions (250 mg/m(2): n=3; 375 mg/m(2): n=9; 500 mg/m(2): n=3) once weekly for 4 consecutive weeks with a 24-week follow-up period. The data of all patients were collected for pharmacokinetics and pharmacodynamics analyses. RESULTS:No dose-limiting toxicities were observed. Most drug-related adverse events were grade 1 or 2. Two patients had grade 3 or 4 neutropenia. Under premedication, the drug-related infusion reaction was mild. A rapid, profound and durable depletion of circulating B cells was observed in all dose groups without significant effects on T cell count, natural killer (NK) cell count or immunoglobulin levels. No patient developed anti-SCT400 antibodies during the course of the study. SCT400 serum half-life (T1/2), maximum concentration (Cmax) and area under the curve (AUC) generally increased between the first and fourth infusions (P<0.05). At the 375 mg/m(2) dose, the T1/2 was 122.5±46.7 h vs. 197.0±75.0 h, respectively, and the Cmax was 200.6±20.2 g/mL vs. 339.1±71.0 g/mL, respectively. From 250 mg/m(2) to 500 mg/m(2), the Cmax and AUC increased significantly in a dose-dependent manner (P<0.05). Patients with a high tumor burden had markedly lower serum SCT400 concentrations compared with those without or with a low tumor burden. Of the 9 assessable patients, 1 achieved complete response and 2 achieved partial responses. CONCLUSIONS:SCT400 is well-tolerated and has encouraging preliminary efficacy in Chinese patients with CD20(+) B-cell NHL.

Dataset Information

Anti-CD20-Mediated B Cell Depletion Is Associated With Bone Preservation in Lymphoma Patients and Bone Mass Increase in Mice.

Publications

Anti-CD20-Mediated B Cell Depletion Is Associated With Bone Preservation in Lymphoma Patients and Bone Mass Increase in Mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets