B-cell Depletion Research Articles

Ocrelizumab dose selection for treatment of pediatric relapsing–remitting multiple sclerosis: results of the OPERETTA I study

BackgroundThe presented study identified the appropriate ocrelizumab dosing regimen for patients with pediatric-onset multiple sclerosis (POMS).MethodsPatients with POMS aged 10–17 years were enrolled into cohort 1 (body weight [BW] < 40 kg, ocrelizumab 300 mg) and cohort 2 (BW ≥ 40 kg, ocrelizumab 600 mg) during a 24-week dose-exploration period (DEP), followed by an optional ocrelizumab (given every 24 weeks) extension period. Primary endpoints: pharmacokinetics, pharmacodynamics (CD19+ B-cell count); secondary endpoint: safety; exploratory endpoints: MRI activity, protocol-defined relapses, Expanded Disability Status Scale (EDSS) score change.ResultsA total of 23 patients (cohort 1: n = 6, age 10–12 years, BW 27.0–39.0 kg; cohort 2: n = 17, age 11–17 years, BW 42.1–108.4 kg) were enrolled. Median treatment duration was 120 (range, 24–193) weeks at the primary analysis cutoff (October 5, 2023). Overall, the pharmacokinetic data were within the range observed at 600 mg in adult patients with MS; however, the exposure at 300 mg in patients < 40 kg was lower than with 600 mg in patients ≥ 40 kg. Shifting the cutoff to 35 kg would provide better exposure to patients with 35–40 kg body weight. Sustained, near-complete B-cell depletion was observed. The safety profile was consistent with that in adults. EDSS scores remained stable; no clinical relapses were observed.ConclusionA dosing regimen of 300 mg ocrelizumab for patients < 35 kg, and 600 mg for patients ≥ 35 kg (every 24 weeks), was selected for the phase 3 OPERETTA II trial (NCT05123703).Trial registrationClinicalTrials.gov: NCT04075266.

A multi-centre UK-based survey on angioedema secondary to acquired C1 inhibitor deficiency.

Acquired angioedema due to C1-inhibitor deficiency (AAE-C1-INH) is very rare compared to its prototype, hereditary angioedema. An updated characterisation of the AAE-C1-INH cohort in UK is required to inform management. To describe the disease burden of AAE-C1-INH, long-term prophylaxis (LTP) and the clinical, immunochemical and treatment profiles of AAE-associated diseases in UK. Retrospective data on 117 AAE-C1-INH patients were collected using a national survey proforma across 25/34 Adult Clinical Immunology and Allergy centres in UK. Other European cohorts were compared. Median age at AAE-C1-INH diagnosis was 65 years with 3.4% of patients diagnosed below 40 years. The median delay in diagnosis was one year. Antifibrinolytics and attenuated androgens showed comparable efficacy as LTP 88.9% and 89.5%, respectively. A haematological disorder was identified in 83.8% AAE-C1-INH patients compared to 3.4% autoimmune diseases. The predominant haematological disorders were splenic marginal zone lymphoma (SZL) 34% followed by MGUS 16%. The severity of angioedema did not depend on the associated disease. Anti-C1INH-autoantibodies testing was limited at 23.1%. Rituximab monotherapy was effective in treating 9/9 SZL and 1/2 MGUS-associated AAE-C1-INH. Rituximab efficacy was independent of anti-C1INH-autoantibodies detection with response in 3/3 seronegative and 4/4 seropositive patients. The diagnosis of AAE-C1-INH should not be overlooked below the age of 40 years. The choice of oral LTP should be informed by propensity to side-effects. B-cell depletion could be considered in treating monoclonal B cell disorder-associated-AAE-C1-INH in the absence of haematological indications. Further studies are required to address the clinical utility of anti-C1INH-autoantibodies.

Efficacy and safety of anti-CD19 CAR-T in a mouse model of IgG4-related disease.

Dysregulated B-cell activation plays pivotal roles in IgG4-related disease (IgG4-RD), which makes B-cell depletion a potential strategy for IgG4-RD treatment. In this study, we aimed to investigate the feasibility of applying anti-CD19 chimeric antigen receptor T(CAR-T) cell therapy to IgG4-RD treatment in a mouse disease model based on LatY136F knock-in (Lat) mice. We constructed murine anti-CD19 CARs with either CD28 or 4-1BB as the intracellular costimulatory motif and evaluated the therapeutic function of the corresponding CAR-T cells by infusing them into Lat mice. Next, we assessed the safety of CAR-T infusion by evaluating the risk of cytokine release syndrome (CRS) and the antiviral capabilities in a mouse influenza infection model. Finally, we performed human anti-CD19 CAR-T manufacturing from IgG4-RD patients and evaluated its activation level and functional effects in vitro. Compared with 1D3 antibody treatment, the adoptive transfer of anti-CD19 CAR-T cells with CD28 costimulatory motif showed comparable B-cell-depletion effect in Lat mice. Furthermore, the transfer of syngeneic anti-CD19 CAR-T cells also decreased the percentage of plasma cells as well as IL-4 secreting Th cells, therefore attenuating the inflammation and fibrosis condition. CAR-T cells with CD28 costimulatory motif showed better therapeutic efficiency without the incidence of serious CRS events or increasing the risk of infection. In addition, we validated the feasibility of human CAR-T preparation in vitro from IgG4-RD patients. Taken together, these results show that anti-CD19 CAR-T therapy was effective in the treatment of a murine model of IgG4-RD, indicating its potential for clinical use in patients.

Potential mechanisms of how B-cell depletion works in MOGAD

Potential mechanisms of how B-cell depletion works in MOGAD

The role of B cells in the pathogenesis of type 1 diabetes.

Type 1 diabetes (T1D) is a metabolic disorder caused by a complete lack of insulin, primarily manifested by hyperglycemia. The mechanisms underlying the onset of T1D are complex, involving genetics, environment, and various unknown factors, leading to the infiltration of various immune components into the islets. Besides T cells, B cells are now considered important contributors to the pathogenesis of T1D, according to recent studies. In non-obese diabetic (NOD) mice, the absence of B cells prevents the development of T1D, and B-cell depletion can even restore the function of pancreatic β cells, emphasizing their involvement in the development of T1D. Naturally, besides pathogenic B cells, regulatory B cells (Bregs) might have a protective function in T1D. This article examines the mechanisms behind B-cell tolerance and the defects in B-cell tolerance checkpoints in T1D. We explored possible functions of B cells in T1D, including the role of islet autoantibodies in T1D, T-B cell interactions, and the role of Bregs in the pathogenesis of T1D. We also summarized the advances of B cell-targeted therapy, exploring new methods for intervention and treatment of T1D.

CAR T-cells in autoimmunity: game changer or stepping stone?

The advent of chimeric antigen receptor (CAR) T-cells has revolutionized the treatment landscape for hematologic malignancies, and emerging evidence suggests their potential in autoimmune diseases (AIDs). This article examines the early successes and future implications of B-cell-targeting CAR T-cell therapy in AIDs. Initial applications, particularly in refractory systemic lupus erythematosus (SLE), have demonstrated significant and durable clinical remissions, with accompanying evaluation of the immune system suggesting a so-called "reset" of innate inflammation and adaptive autoimmunity. This has generated widespread interest in expanding this therapeutic approach. CAR T-cells offer unique advantages over other treatment modalities, including very deep B-cell depletion and unique therapeutic activity within inflamed tissues and associated lymph structures. However, the field must address key concerns, including long-term toxicity, particularly the risk of secondary malignancies, and future accessibility given the higher prevalence of AIDs compared to malignancies. Technological advances in cell therapy, such as next-generation CAR T-cells, allogeneic off-the-shelf products and alternative cell types such as regulatory CAR T-cells, are being explored in AIDs to improve efficacy and safety. In addition, bispecific antibodies are emerging as potential alternatives or complements to CAR T-cells, potentially offering comparable efficacy without the need for complex logistics, lymphodepletion and the risk of insertional mutagenesis. As the field evolves, cellular therapists will play a critical role in the multidisciplinary teams managing these complex cases. The transformative potential of CAR T-cells in AIDs is undeniable, but careful consideration of safety, efficacy, and implementation is essential as this novel therapeutic approach moves forward.

A protocol for targeted B-lymphocyte depletion for the treatment of IgG4-related disease.

To determine the clinical outcomes of patients with immunoglobulin 4-related disease (IgG4-RD) treated with a defined B cell depletion protocol using rituximab. Patients were included if they had (1) an IgG4-RD diagnosis at Imperial College Healthcare NHS Trust between February 2017 and October 2022, and (2) >9 months of follow-up data available following the first rituximab dose. The rituximab protocol targeted B cell depletion to < 10 cells/microliter for a maintenance period of two years. Electronic records were used to define patient demographics, serological and radiological variables and treatment responses according to the IgG4-RD responder index (RI). Forty-five patients received induction treatment with rituximab. Two patients had insufficient follow-up data for outcome analysis. All patients responded to rituximab therapy according to the IgG4-RD RI. Most patients (25/43, 58%) were also treated with low-dose glucocorticoids at the time of rituximab induction (median prednisolone dose 5 mg daily) and 4/25 (16%) remained on prednisolone at two years (median prednisolone dose 5 mg daily). Disease flares occurred in 11/43 (26%) patients; 9/11 flares occurred in the presence of B cell repopulation; 2/11 (18.1%) flares occurred in the absence of B cell repopulation (>10 cells/uL). All flares re-treated with rituximab (7/7, 100%) responded positively. Rituximab administration targeting B cell depletion for a two-year period is an effective treatment strategy for IgG4-RD and can limit the cumulative glucocorticoid exposure. Flares are uncommon and typically occur in the setting of B cell repopulation, with good clinical responses to further rituximab administration.

174. Prolonged B-Cell Depletion Post-Rituximab in a Patient with Neuromyelitis Optica Spectrum Disorder (NMO-SD): A Case Report with Literature Review

174. Prolonged B-Cell Depletion Post-Rituximab in a Patient with Neuromyelitis Optica Spectrum Disorder (NMO-SD): A Case Report with Literature Review

Inebilizumab for Treatment of IgG4-Related Disease.

IgG4-related disease is a multiorgan, relapsing, fibroinflammatory, immune-mediated disorder with no approved therapy. Inebilizumab targets and depletes CD19+ B cells and may be effective for treating patients with IgG4-related disease. In this phase 3, multicenter, double-blind, randomized, placebo-controlled trial, adults with active IgG4-related disease underwent randomization in a 1:1 ratio to receive inebilizumab (300-mg intravenous infusions on days 1 and 15 and week 26) or placebo for a 52-week treatment period. Participants in both groups received identical glucocorticoid tapers. Glucocorticoids were allowed to treat disease flares, but background immunosuppressants were not permitted. The primary end point was the first treated, adjudicated disease flare during the treatment period, assessed in a time-to-event analysis. Key secondary end points were the annualized flare rate and treatment-free and glucocorticoid-free complete remission. A total of 135 participants with IgG4-related disease underwent randomization: 68 participants were assigned to receive inebilizumab and 67 were assigned to receive placebo. Treatment with inebilizumab reduced flare risk; 7 participants (10%) in the inebilizumab group had at least one flare, as compared with 40 participants (60%) in the placebo group (hazard ratio, 0.13; 95% confidence interval [CI], 0.06 to 0.28; P<0.001). The annualized flare rate was lower with inebilizumab than with placebo (rate ratio, 0.14; 95% CI, 0.06 to 0.31; P<0.001). More participants in the inebilizumab group than in the placebo group had flare-free, treatment-free complete remission (odds ratio, 4.68; 95% CI, 2.21 to 9.91; P<0.001) and flare-free, glucocorticoid-free complete remission (odds ratio, 4.96; 95% CI, 2.34 to 10.52; P<0.001). Serious adverse events occurred during the treatment period in 12 of the participants (18%) who received inebilizumab and 6 of the participants (9%) who received placebo. Inebilizumab reduced the risk of flares of IgG4-related disease and increased the likelihood of flare-free complete remission at 1 year, confirming the role of CD19-targeted B-cell depletion as a potential treatment for IgG4-related disease. (Funded by Amgen; MITIGATE ClinicalTrials.gov number, NCT04540497.).

Multi-Omic characterization of the effects of Ocrelizumab in patients with relapsing-remitting multiple sclerosis

The study examined changes in the plasma proteome, metabolome, and lipidome of N = 14 patients with relapsing-remitting multiple sclerosis (RRMS) initiating treatment with ocrelizumab, assayed at baseline, 6 months, and 12 months. Analyses of >4000 circulating biomarkers identified depletion of B-cell associated proteins as the early effect observed following ocrelizumab (OCR) initiation, accompanied by the reduction in plasma abundance of cytokines and cytotoxic proteins, markers of neuronaxonal damage, and biologically active lipids including ceramides and lysophospholipids, at 6 months. B-cell depletion was accompanied by decreases in B-cell receptor and cytokine signaling but a pronounced increase in circulating plasma B-cell activating factor (BAFF). This was followed by an upregulation of a number of signaling and metabolic pathways at 12 months. Patients with higher baseline brain MRI lesion load demonstrated both higher levels of cytotoxic and structural proteins in plasma at baseline and more pronounced biomarker change trajectories over time. Digital cytometry identified a putative increase in myeloid cells and a pro-inflammatory subset of T-cells. Therapeutic effects of ocrelizumab extend beyond CD20-mediated B-cell lysis and implicate metabolic reprogramming, juxtaposing the early normalization of immune activation, cytokine signaling and metabolite and lipid turnover in periphery with changes in the dynamics of immune cell activation or composition. We identify BAFF increase following CD20 depletion as a tentative compensatory mechanism that contributes to the reconstitution of targeted B-cells, necessitating further research.

First-in-Human Study of BAT4406F, an ADCC-Enhanced Fully Humanized Anti-CD20 Monoclonal Antibody in Patients With Neuromyelitis Optica Spectrum Disorders.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare debilitating autoimmune disease of the central nervous system (CNS). This is the first-in-human dose-escalation Phase I clinical study of BAT4406F, an antibody-dependent cell-mediated cytotoxicity (ADCC)-enhanced fully humanized anti-CD20 monoclonal antibody, in Chinese NMOSD patients. Using a "3 + 3" design and based on the planned algorithm of dose escalation, the enrolled NMOSD patients were sequentially assigned to one of the five dose-escalation cohorts of BAT4406F with a single intravenous dose, and were then followed for a 6-month observation period. The maximum tolerated dose (MTD) and dose-limiting toxicity (DLT), safety, pharmacokinetics (PK), pharmacodynamics, and immunogenicity of BAT4406F were investigated, and the efficacy of BAT4406F in NMOSD was also preliminarily explored. Fifteen Chinese NMOSD patients were enrolled to receive BAT4406F of escalated doses ranging from 20 to 750 mg. No subjects experienced DLT at the studied doses. BAT4406F injection exhibited favorable safety, with most of the adverse events (AE) of CTCAE Grade 1 or 2 in severity, and no Grade ≥ 3 adverse drug reactions (ADR) or serious adverse reactions occurred in any subjects. With the dose increase of BAT4406F, the maximum plasma concentration (Cmax), area under concentration-time curve from 0 to the last measurable timepoint (AUC0-t) and area under concentration-time curve from 0 to infinity (AUC0-inf) showed an increasing trend, whereas the mean clearance (CLt), terminal elimination rate (λZ), and apparent volume of distribution (Vd) decreased. The mean elimination half-life (T1/2) was ranged from 9.0-16.4 days. PK profile of BAT4406F was generally nonlinear. BAT4406F led to a rapid and significant B-cell depletion in all dose groups. Single administration of 500 mg or 750 mg maintains the CD19+ B lymphocyte count below 10/μL within the whole 6-month observation period. Three subjects were antidrug antibody (ADA) positive and all of them were neutralizing antibody (NAb)-negative. On day 99/180 postdose, several groups had decreased expanded disability status scale (EDSS) scores compared to baseline. During the observation period, NMOSD relapse occurred in two patients (13.3%) and the other 13 (86.7%) subjects remained relapse free. BAT4406F was well tolerated at doses up to 750 mg and showed an expected pharmacodynamic effect of significant and long-term depletion of CD19+ B lymphocytes. It has also shown preliminary evidence of activity in NMOSD maintenance treatment, warranting further investigations. ClinicalTrials.gov identifier: NCT04146285.

Markov Field network model of multi-modal data predicts effects of immune system perturbations on intravenous BCG vaccination in macaques.

Analysis of multi-modal datasets can identify multi-scale interactions underlying biological systems, but can be beset by spurious connections due to indirect impacts propagating through an unmapped biological network. For example, studies in macaques have shown that BCG vaccination by an intravenous route protects against tuberculosis, correlating with changes across various immune data modes. To eliminate spurious correlations and identify critical immune interactions in a public multi-modal dataset (systems serology, cytokines, cytometry) of vaccinated macaques, we applied Markov Fields (MF), a data-driven approach that explains vaccine efficacy and immune correlations via multivariate network paths, without requiring large numbers of samples (i.e. macaques) relative to multivariate features. Furthermore, we find that integrating multiple data modes with MFs helps to remove spurious connections. Finally, we used the MF to predict outcomes of perturbations at various immune nodes, including a B-cell depletion that induced network-wide shifts without reducing vaccine protection, which we validated experimentally.

Obinutuzumab as a viable therapeutic strategy in rituximab-refractory childhood frequently relapsing, steroid-dependent nephrotic syndrome that relapsed during B-cell depletion.

A subgroup of children with frequently-relapsing, steroid-dependent nephrotic syndrome relapse during B-cell depletion after rituximab. A 15-year-old boy with focal segmental glomerulosclerosis became rituximab-refractory after 5 courses of treatments, with a relapse-free period shortened to 1month. Circulating total and memory B-cells were undetectable at the time of relapse. A single infusion of obinutuzumab sustained relapse-free remission up to the last follow-up at 18months. There was persistent hypogammaglobulinemia but no infection was observed. Obinutuzumab may be a viable option for attaining long-term remission with reasonable side effect profiles in patients who relapse during B-cell depletion after rituximab.

Pemphigus relapse: Mechanisms, risk factors, and agents associated with disease recurrence.

Pemphigus represents a spectrum of potentially life-threatening autoimmune-mediated skin blistering conditions caused by antibody production against desmoglein 1 and 3 (anti-DSG 1 and 3) in keratinocytes. Greater than 50% of pemphigus patients experience relapse, which complicates long-term medical management, including risks associated with re-treatment and complications such as infection and dehydration. This review aims to elucidate mechanisms, risk factors, and medications associated with pemphigus relapse. Mechanisms of relapse include the persistence of auto-reactive B-cell populations post-treatment and CD20- B-cell populations that reactivate after B-cell depletion therapy. Risk factors for relapse include high body surface area (BSA) of pemphigus involvement, high body mass index, high severity according to the Pemphigus Disease Area Index (PDAI) at onset, treatment delay, and high anti-DSG1 and DSG3 titers post-treatment. Targeted B-cell localization is associated with better clinical outcomes, including less frequent relapses. Rituximab is currently the gold standard of treatment for moderate-severe pemphigus and has relapse rates of 11%-44% in selected studies, with a mean time to relapse of 5.8 months to 36 months following treatment. Relapse rates across lymphoma dosing (375 mg/m2) versus rheumatoid arthritis dosing (1 g dosing weekly) was inconsistent; however, more frequent dosing, earlier treatment, and higher cumulative dosing were associated with lower relapse rates. Alternative agents that have clinical efficacy include corticosteroid monotherapy, mycophenolate mofetil, azathioprine, and intravenous immunoglobulin. Future studies should include head-to-head comparators over long follow-up periods to identify the best treatment agents associated with the least relapse risk.

Releasing our model T - chimeric antigen receptor (CAR) T-cells for autoimmune indications.

This review provides an update on the rapidly growing field of engineered cellular therapies for autoimmune disorders, primarily focusing on clinical experience and correlative studies with chimeric antigen receptor (CAR) T-cells. To date, two case series describing treatment with CAR T-cell therapy for systemic lupus erythematosus (SLE) suggest that drug-free remission can be sustained in patients with previously treatment-refractory disease. The outcomes of these studies are similar, despite the use of different CAR constructs and lymphodepletion regimens. Although it is not yet clear whether the patients described have truly been cured, the majority of remissions have remained durable up to last follow-up at 1-2 years from treatment. Meanwhile, mechanistic studies are providing a window into how transient B-cell depletion mediates lasting benefit. With the encouraging data in SLE, CAR T-cells and other novel B-cell-depleting agents (e.g. bispecific T-cell engagers) are now being evaluated as treatment for other autoimmune conditions, with the goal of durable response. Recent reports highlight cellular therapies as a promising strategy for patients with treatment-refractory autoimmune conditions; however, there is still limited experience, and better insight into this therapeutic approach is expected to emerge rapidly.

Antiviral combination treatment strategies for SARS-CoV-2 infection in immunocompromised patients.

The purpose of this review is to report the available evidence regarding the use of combination regimens of antivirals and/or antibody-based therapy in the treatment of SARS-CoV-2 in immunocompromised patients. Literature search identified 24 articles, excluding single case reports, which included mainly patients with hematological malignancies and/or B-cell depletion. Data were divided based on the timing and reason for administration of combination treatment, that is, early treatment to prevent progression to severe COVID-19 and treatment of prolonged or relapsed infection. We described the treated populations, treatment duration and composition of combination treatment. We briefly addressed new treatment options and we proposed an algorithm for the management of COVID-19 infection in patients affected by hematological malignancies. Combination treatment seems an effective (73-100%) and well tolerated (<5% reported bradycardia, hepatotoxicity, neutropenia) strategy for treating prolonged/relapsed SARS-CoV-2 infections in the immunocompromised host, although its optimal composition and duration cannot be defined based on the currently available evidence. The role of combination treatment as an early treatment strategy for immunocompromised patients at a high risk of progression to severe disease/persistent shedding requires further evidence from comparison with monotherapy, even though high efficacy was reported for combinations of antivirals plus mAbs in case of previous viral variants.

Defects in B-lymphopoiesis and B-cell maturation underlie prolonged B-cell depletion in ANCA-associated vasculitis

ObjectivesB-cell depletion time after rituximab (RTX) treatment is prolonged in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) compared with other autoimmune diseases. We investigated central and peripheral B-cell development to identify...

Use of rituximab in the of immunoinflammatory rheumatic diseases combined with Graves' disease (autoimmune polyglandular syndrome in adults): case report and literature review

Rituximab (RTM) is a chimeric (murine and human) monoclonal antibody against B-lymphocytes (CD20). RTM is widely used in hematology for lymphoproliferative diseases and in rheumatology for rheumatoid arthritis, Sjögren's disease, some types of vasculitis and systemic connective tissue diseases. The administration of RTM is associated with a depletion of B-cells mediated by the regulation of apoptosis and cytotoxic effects via complement-dependent and antibody-dependent mechanisms. Considering the pathogenesis of autoimmune damage in Graves' disease (GD), an autoimmune thyroid disease associated with thyrotoxicosis, the use of RTM could be effective in this pathology. We present three patients with a combination of diffuse toxic goiter and rheumatic pathology treated with RTM; different outcomes of GD were observed.

Obinutuzumab versus rituximab for the treatment of refractory primary membranous nephropathy.

Rituximab has been shown effective in patients with primary membranous nephropathy refractory to glucocorticoids plus cyclophosphamide (GC+CTX) or calcineurin inhibitors (CNIs), but the response rates remain limited. Compared with rituximab, obinutuzumab is a humanized anti-CD20 monoclonal antibody with greater B-cell depletion capacity. This study was performed to investigate the effectiveness of obinutuzumab compared to rituximab in treating patients with refractory primary membranous nephropathy. A retrospective study was conducted at Huashan Hospital, Fudan University between January 1, 2015 and July 31, 2024, and included adult patients with primary membranous nephropathy who met the following criteria, 1) resistance to GC+CTX and/or calcineurin inhibitor (CNI) regimens, 2) dependence on CNIs, or 3) relapse within 1 year after CTX discontinuation. The patients subsequently received either obinutuzumab or rituximab. The primary endpoint was treatment response, which was defined as overall remission of nephrotic syndrome with no need for rescue therapy after obinutuzumab versus rituximab treatment. The secondary measures included immunological remission and safety profiles. Among the 51 participants, 20 received obinutuzumab and 31 received rituximab. The response rate was significantly greater in patients receiving obinutuzumab than in those receiving patients (90.0% vs. 38.7%, p<0.001) during a follow-up period of 24 (IQR, 10-34) months. Cox proportional hazards survival regression analysis also revealed the superior effectiveness of obinutuzumab (p<0.001). Immunological remission rates were higher in patients receiving obinutuzumab at both 3 months (75.0% vs. 20.0%, p<0.001) and 6 months (87.5% vs. 21.4%, p<0.001). The safety profiles of the two treatments were comparable. Among the 19 nonresponders treated with rituximab, 10 subsequently received obinutuzumab, and 8 achieved remission during a follow-up period of 20.0 (IQR, 18.5-22.3) months. This retrospective study suggests that obinutuzumab is an effective treatment option for patients with primary membranous nephropathy refractory to GC+CTX, CNI, and rituximab regimens.

Cutting-edge approaches to B-cell depletion in autoimmune diseases.

B-cell depletion therapy (BCDT) has been employed to treat autoimmune disease for ~20 years. Immunoglobulin G1 (IgG1) monoclonal antibodies targeting CD20 and utilizing effector function (eg, antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis) to eliminate B cells have historically been the predominant therapeutic approaches. More recently, diverse BCDT approaches targeting a variety of B-cell surface antigens have been developed for use in hematologic malignancies, including effector-function-enhanced monoclonal antibodies, chimeric antigen receptor T-cell (CAR-T) treatment, and bispecific T-cell engagers (TCEs). The latter category of antibodies employs CD3 engagement to augment the killing of target cells. Given the improvement in B-cell depletion observed with CAR-T and TCEs compared with conventional monospecific antibodies for treatment of hematologic malignancies and the recent case reports demonstrating therapeutic benefit of CAR-T in autoimmune disease, there is potential for these mechanisms to be effective for B-cell-mediated autoimmune disease. In this review, we discuss the various BCDTs that are being developed in autoimmune diseases, describing the molecule designs, depletion mechanisms, and potential advantages and disadvantages of each approach as they pertain to safety, efficacy, and patient experience. Additionally, recent advances and strategies with TCEs are presented to help broaden understanding of the potential for bispecific antibodies to safely and effectively engage T cells for deep B-cell depletion in autoimmune diseases.