Dataset Information

Belimumab alters transitional B-cell subset proportions in patients with stable systemic lupus erythematosus.

ABSTRACT:

Objective

We evaluated the effects of the B-cell activating factor (BAFF)-targeting antibody Belimumab on human nonmemory B-cell pools. Human B-cell pools were identified using surface markers adapted from mouse studies that specifically assessed reductions in immature B cells due to BAFF depletion. Patients with systemic lupus erythematosus (SLE) have high levels of both BAFF and immature B cells. Mechanistic mouse studies provide a framework for understanding human responses to therapies that target B cells.

Methods

Peripheral blood mononuclear cells were isolated from healthy donors and SLE patients on Belimumab or standard-of-care therapy (SCT). Cells were stained for flow cytometry to identify B-cell subsets based on CD21/CD24. Differences in subset proportions were determined by one-way ANOVA and Tukey's post hoc test.

Results

Patients treated with Belimumab show alterations in the nonmemory B-cell pool characterized by a decrease in the Transitional 2 (T2) subset (p?=?0.002), and an increase in the proportion of Transitional 1 (T1) cells (p?=?0.005) as compared with healthy donors and SCT patients. The naïve B-cell compartment showed no significant differences between the groups (p?=?0.293).

Conclusion

Using a translational approach, we show that Belimumab-mediated BAFF depletion reduces the T2 subset in patients, similar to observations in mouse models with BAFF depletion.

SUBMITTER: Benitez A

PROVIDER: S-EPMC7769209 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Publications

Belimumab alters transitional B-cell subset proportions in patients with stable systemic lupus erythematosus.

Benitez A A Torralba K K Ngo M M Salto L M LM Choi K S KS De Vera M E ME Payne K J KJ

Lupus 20190818 11

<h4>Objective</h4>We evaluated the effects of the B-cell activating factor (BAFF)-targeting antibody Belimumab on human nonmemory B-cell pools. Human B-cell pools were identified using surface markers adapted from mouse studies that specifically assessed reductions in immature B cells due to BAFF depletion. Patients with systemic lupus erythematosus (SLE) have high levels of both BAFF and immature B cells. Mechanistic mouse studies provide a framework for understanding human responses to therapi ...[more]

PMID: 31423896

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Project description:Background and objectiveIntravenous (IV) belimumab is the first treatment approved for children ≥5 years of age with active autoantibody-positive systemic lupus erythematosus (SLE) in the USA, Europe, and Japan. Pharmacokinetic data for belimumab were collected from several clinical trials in Chinese and non-Chinese adults and non-Chinese pediatric patients with SLE. This study aimed to predict the belimumab dose-exposure relationship to Chinese pediatric patients with SLE, as part of the belimumab registration process for this population in China, using a population PK modeling approach.MethodsAn initial linear two-compartment population pharmacokinetic model was built using data from adults only, and considering and adjusting for the covariates age, body weight, body mass index, fat-free mass, race, baseline albumin and immunoglobulin G levels. The model was used to study possible ethnic differences between Chinese and non-Chinese adults and to predict pediatric pharmacokinetic data in a study of non-Chinese pediatric patients (PLUTO study; NCT01649765). The predicted data were compared with the observed data from PLUTO. The model was then updated with pediatric data from PLUTO to predict steady-state belimumab exposure in Chinese pediatric patients with SLE receiving belimumab 10 mg/kg IV every 4 weeks.ResultsThe dataset comprised 9650 sampled concentration values from 1783 patients. The pharmacokinetics of belimumab were adequately described by the final model using all adult and pediatric data with the estimated typical clearance of 238 ml/day in adult and pediatric patients and steady-state volume of distribution of 4915 ml in adults. Between-patient variability was modest (coefficients of variation: 26.1% for clearance; 8.9% and 28.5%, respectively, for volumes of distribution of the central and peripheral compartments). Six covariates were identified that influenced pharmacokinetics: age, fat-free mass, an indicator of North East Asian race, baseline albumin, immunoglobulin G, and an early study indicator (two early phase I and phase II belimumab studies: LBSL01 and LBSL02). The analysis showed no apparent difference in steady-state exposure between Chinese and non-Chinese populations and between pediatric and adult populations receiving belimumab 10 mg/kg IV.ConclusionsIn Chinese pediatric patients with SLE, belimumab 10 mg/kg IV every 4 weeks is expected to have exposure similar to that in Chinese adults and non-Chinese pediatric patients with SLE, supporting the use of this regimen in Chinese pediatric patients with SLE.Clinical trial registration numbersNCT01649765, NCT00657007, NCT00071487, NCT01345253, NCT01516450, NCT00410384, NCT00424476, NCT02880852, NCT01583530.

Project description:Patients with systemic lupus erythematosus (SLE) with B-lymphocyte stimulator (BLyS) levels???2?ng/mL are at increased risk of flare. A regression analysis was undertaken to identify routine clinical measures that correlate with BLyS???2?ng/mL. Efficacy and safety of belimumab 10?mg/kg were examined in patients with BLyS???2?ng/mL and <?2?ng/mL.Data from BLISS-52 and -76 (N?=?1684) were pooled post hoc. A univariate logistic regression was employed to identify factors predictive of baseline BLyS???2?ng/mL. Factors significant at the 0.05 level then entered a stepwise logistic regression as covariates. Efficacy endpoints included SLE responder index (SRI), ??4-point reduction in Safety of Estrogens in Lupus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) and risk of severe flare over 52 weeks. Adverse events (AEs) were analyzed for each treatment arm and BLyS subgroup.Baseline predictors of BLyS???2?ng/mL included positive anti-Smith (??15 U/mL), low complement (C) 3 (<?900?mg/L), anti-double-stranded DNA (anti-dsDNA) 80-200 and ??200?IU/mL, immunosuppressant usage, proteinuria, elevated C-reactive protein (CRP), and low total lymphocyte count for all patients. Belimumab 10?mg/kg led to significantly greater SRI responses over 52 weeks versus placebo in both BLyS subgroups, though treatment differences were numerically greater at Week 52 in the BLyS???2?ng/mL group (24.1%, p?<?0.0001) compared with BLyS?<?2?ng/mL (8.2%, p?=?0.0158). Results were similar for???4-point reduction in SELENA-SLEDAI. Risk of severe flare over 52 weeks was significantly reduced with belimumab 10?mg/kg versus placebo in the BLyS???2?ng/mL group (p?=?0.0002). AEs were similar across treatment arms and BLyS subgroups.Positive anti-Smith, low C3, anti-dsDNA???80?IU/mL, immunosuppressant usage, proteinuria, elevated CRP, and low total lymphocyte count were predictors of BLyS???2?ng/mL. Monitoring these factors could identify patients with BLyS???2?ng/mL who are at risk of flare.

Dataset Information

Belimumab alters transitional B-cell subset proportions in patients with stable systemic lupus erythematosus.

Objective

Methods

Results

Conclusion

Publications

Belimumab alters transitional B-cell subset proportions in patients with stable systemic lupus erythematosus.

Similar Datasets

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