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Efficient long-term depletion of CD20+ B cells by rituximab does not affect gut-resident plasma cells.

ABSTRACT: The vast majority of antibody-producing B cells are located within the gastrointestinal tract and are key players in maintaining homeostasis. The failure of rituximab, a potent B cell-depleting agent, to ameliorate ulcerative colitis in a single clinical trial has dampened enthusiasm to study B cells in patients with inflammatory bowel disease (IBD). However, several lines of evidence suggest that intestinal B cells may be affected in IBD. Additionally, the pathophysiological mechanisms underlying rituximab's lack of efficacy in IBD remain unclear. Here, on the basis of detailed immunophenotyping of a patient who underwent a colonoscopy 6 months after the end of rituximab-based therapy, we observed that rituximab did not deplete colon-resident plasma cells (PCs) while ablating all CD20+ B cells in tissues and in the circulation. On the basis of these observations, we propose that one factor underlying the lack of efficacy of rituximab relates to the fact that it does not affect the entire B cell compartment in tissues, sparing the intestinal-resident PCs while effectively depleting CD20+ B cell populations. Thus, we contend that, despite the results of the Rituximab study, there is a need for more intensive B cell-oriented research in inflammatory disorders, including IBD.

SUBMITTER: Uzzan M

PROVIDER: S-EPMC6368409 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Efficient long-term depletion of CD20<sup>+</sup> B cells by rituximab does not affect gut-resident plasma cells.

Uzzan Mathieu M Ko Huaibin M HM Rosenstein Adam K AK Pourmand Kamron K Colombel Jean-Frederic JF Mehandru Saurabh S

Annals of the New York Academy of Sciences 20171231 1

The vast majority of antibody-producing B cells are located within the gastrointestinal tract and are key players in maintaining homeostasis. The failure of rituximab, a potent B cell-depleting agent, to ameliorate ulcerative colitis in a single clinical trial has dampened enthusiasm to study B cells in patients with inflammatory bowel disease (IBD). However, several lines of evidence suggest that intestinal B cells may be affected in IBD. Additionally, the pathophysiological mechanisms underlyi ...[more]

PMID: 29291255

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Project description:The CD20-specific monoclonal antibody rituximab (MabThera(®), Rituxan(®)) is widely used as the backbone of treatment for patients with hematologic disorders. Intravenous administration of rituximab is associated with infusion times of 4-6 hours, and can be associated with infusion-related reactions. Subcutaneous administration of rituximab may reduce this and facilitate administration without infusion-related reactions. We sought to determine the feasibility of achieving equivalent efficacy (measured by endogenous B-cell depletion) and long-term durability of CD20 target coverage for subcutaneously administered rituximab compared with intravenous dosing. In these preclinical studies, male cynomolgus monkeys were treated with either intravenous rituximab or novel subcutaneous formulation of rituximab containing human recombinant DNA-derived hyaluronidase enzyme. Peripheral blood samples were analyzed for serum rituximab concentrations, peripheral B-cell depletion, and CD20 target coverage, including subset analysis according to CD21+ status. Distal lymph node B-cell depletion and CD20 target coverage were also measured. Initial peak serum concentrations of rituximab were significantly higher following intravenous administration than subcutaneous. However, the mean serum rituximab trough concentrations were comparable at 2 and 7 days post-first dose and 9 and 14 days post-second dose. Efficacy of B-cell depletion in both peripheral blood and distal lymph nodes was comparable for both methods. In lymph nodes, 9 days after the second dose with subcutaneous and intravenous rituximab, B-cell levels were decreased by 57% and 42% respectively. Similarly, levels of peripheral blood B cells were depleted by >94% for both subcutaneous and intravenous dosing at all time points. Long-term recovery of free unbound surface CD20 levels was similar, and the duration of B-cell depletion was equally sustained over 2 months for both methods. These results demonstrate that, despite initial peak serum drug level differences, subcutaneous rituximab has similar durability, pharmacodynamics, and efficacy compared with intravenous rituximab.

Project description:Chronic fatigue syndrome (CFS) is a disease of unknown aetiology. Major CFS symptom relief during cancer chemotherapy in a patient with synchronous CFS and lymphoma spurred a pilot study of B-lymphocyte depletion using the anti-CD20 antibody Rituximab, which demonstrated significant clinical response in three CFS patients.In this double-blind, placebo-controlled phase II study (NCT00848692), 30 CFS patients were randomised to either Rituximab 500 mg/m(2) or saline, given twice two weeks apart, with follow-up for 12 months. Xenotropic murine leukemia virus-related virus (XMRV) was not detected in any of the patients. The responses generally affected all CFS symptoms. Major or moderate overall response, defined as lasting improvements in self-reported Fatigue score during follow-up, was seen in 10 out of 15 patients (67%) in the Rituximab group and in two out of 15 patients (13%) in the Placebo group (p?=?0.003). Mean response duration within the follow-up period for the 10 responders to Rituximab was 25 weeks (range 8-44). Four Rituximab patients had clinical response durations past the study period. General linear models for repeated measures of Fatigue scores during follow-up showed a significant interaction between time and intervention group (p?=?0.018 for self-reported, and p?=?0.024 for physician-assessed), with differences between the Rituximab and Placebo groups between 6-10 months after intervention. The primary end-point, defined as effect on self-reported Fatigue score 3 months after intervention, was negative. There were no serious adverse events. Two patients in the Rituximab group with pre-existing psoriasis experienced moderate psoriasis worsening.The delayed responses starting from 2-7 months after Rituximab treatment, in spite of rapid B-cell depletion, suggests that CFS is an autoimmune disease and may be consistent with the gradual elimination of autoantibodies preceding clinical responses. The present findings will impact future research efforts in CFS.ClinicalTrials.gov NCT00848692.

Project description:Rituximab, a murine-human chimera, is the first monoclonal antibody (mAb) developed as a therapeutic agent to target CD20 protein. Its Fab domain and its interaction with CD20 have been extensively studied and high-resolution atomic models obtained by X-ray diffraction or cryo-electron microscopy are available. However, the structure of the full-length antibody is still missing as the inherent protein flexibility hampers the formation of well-diffracting crystals and the reconstruction of 3D microscope images. The global structure of rituximab from its dilute solution is here elucidated by small-angle X-ray scattering (SAXS). The limited data resolution achievable by this technique has been compensated by intensive computational modelling that led to develop a new and effective procedure to characterize the average mAb conformation as well as that of the single domains. SAXS data indicated that rituximab adopts an asymmetric average conformation in solution, with a radius of gyration and a maximum linear dimension of 52 Å and 197 Å, respectively. The asymmetry is mainly due to an uneven arrangement of the two Fab units with respect to the central stem (the Fc domain) and reflects in a different conformation of the individual units. As a result, the Fab elbow angle, which is a crucial determinant for antigen recognition and binding, was found to be larger (169°) in the more distant Fab unit than that in the less distant one (143°). The whole flexibility of the antibody has been found to strongly depend on the relative inter-domain orientations, with one of the Fab arms playing a major role. The average structure and the amount of flexibility has been studied in the presence of different buffers and additives, and monitored at increasing temperature, up to the complete unfolding of the antibody. Overall, the structural characterization of rituximab can help in designing next-generation anti-CD20 antibodies and finding more efficient routes for rituximab production at industrial level.

Dataset Information

Efficient long-term depletion of CD20+ B cells by rituximab does not affect gut-resident plasma cells.

Publications

Efficient long-term depletion of CD20<sup>+</sup> B cells by rituximab does not affect gut-resident plasma cells.

Similar Datasets

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