anti-CD20 Monoclonal Antibody Rituximab Research Articles

A Glimpse into Humoral Response and Related Therapeutic Approaches of Takayasu's Arteritis.

Takayasu's arteritis (TAK) manifests as an insidiously progressive and debilitating form of granulomatous inflammation including the aorta and its major branches. The precise etiology of TAK remains elusive, with current understanding suggesting an autoimmune origin primarily driven by T cells. Notably, a growing body of evidence bears testimony to the widespread effects of B cells on disease pathogenesis and progression. Distinct alterations in peripheral B cell subsets have been described in individuals with TAK. Advancements in technology have facilitated the identification of novel autoantibodies in TAK. Moreover, emerging data suggest that dysregulated signaling cascades downstream of B cell receptor families, including interactions with innate pattern recognition receptors such as toll-like receptors, as well as co-stimulatory molecules like CD40, CD80 and CD86, may result in the selection and proliferation of autoreactive B cell clones in TAK. Additionally, ectopic lymphoid neogenesis within the aortic wall of TAK patients exhibits functional characteristics. In recent decades, therapeutic interventions targeting B cells, notably utilizing the anti-CD20 monoclonal antibody rituximab, have demonstrated efficacy in TAK. Despite the importance of the humoral immune response, a systematic understanding of how autoreactive B cells contribute to the pathogenic process is still lacking. This review provides a comprehensive overview of the biological significance of B cell-mediated autoimmunity in TAK pathogenesis, as well as insights into therapeutic strategies targeting the humoral response. Furthermore, it examines the roles of T-helper and T follicular helper cells in humoral immunity and their potential contributions to disease mechanisms. We believe that further identification of the pathogenic role of autoimmune B cells and the underlying regulation system will lead to deeper personalized management of TAK patients. We believe that further elucidation of the pathogenic role of autoimmune B cells and the underlying regulatory mechanisms holds promise for the development of personalized approaches to managing TAK patients.

The IPTA Nashville consensus conference on post-transplant lymphoproliferative disorders after solid organ transplantation in children: IV-consensus guidelines for the management of post-transplant lymphoproliferative disorders in children and adolescents.

The International Pediatric Transplant Association convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post-transplant lymphoproliferative disorders (PTLD) after pediatric solid organ transplantation. This report addresses the outcomes of deliberations by the PTLD Management Working Group. A strong recommendation was made for reduction in immunosuppression as the first step in management. Similarly, strong recommendations were made for the use of the anti-CD20 monoclonal antibody (rituximab) as was the case for chemotherapy in selected scenarios. In some scenarios, there is uncoupling of the strength of the recommendations from the available evidence in situations where such evidence is lacking but collective clinical experiences drive decision-making. Of note, there are no large, randomized phase III trials of any treatment for PTLD in the pediatric age group. Current gaps and future research priorities are highlighted.

Potential role of IGF-1R in the interaction between orbital fibroblasts and B lymphocytes: an implication for B lymphocyte depletion in the active inflammatory phase of thyroid-associated ophthalmopathy

BackgroundThyroid eye disease (TED) is an inflammatory process involving lymphocyte-mediated immune response and orbital tissue damage. The anti-insulin-like growth factor-1 receptor (IGF-1R) antibodies produced by B lymphocytes are involved in the activation of orbital fibroblasts and the inflammatory process of orbital tissue damage in TED. The purpose of this study was to explore the role of IGF-1R in the mechanistic connection between orbital fibroblasts and B lymphocytes in TED.MethodsOrbital fibroblasts sampled from orbital connective tissues and peripheral B lymphocytes isolated from peripheral blood, which were obtained from 15 patients with TED and 15 control patients, were co-cultured at a ratio of 1:20. The level of IGF-1R expression in orbital fibroblasts was evaluated by flow cytometry and confocal microscopy. Transient B lymphocyte depletion was induced with anti-CD20 monoclonal antibody rituximab, while the IGF-1R pathway was blocked by the IGF-1R binding protein. The expression levels of interleukin-6 (IL-6) and regulated upon activation, normal T cell expressed and secreted (RANTES) in the co-culture model were quantified via ELISA.ResultsIGF-1R expression was significantly elevated in TED orbital fibroblasts compared to that of controls. A 24-h co-culture of orbital fibroblasts with peripheral B lymphocytes induced elevated expression levels of IL-6 and RANTES in each group (TED patients and controls), with the highest levels occurring in TED patients (T + T group). Rituximab and IGF-1R binding protein significantly inhibited increased levels of IL-6 and RANTES in the co-culture model of TED patients.ConclusionsIGF-1R may mediate interaction between orbital fibroblasts and peripheral B lymphocytes; thus, blocking IGF-1R may reduce the local inflammatory response in TED. Rituximab-mediated B lymphocyte depletion played a role in inhibiting inflammatory responses in this in vitro co-culture model, providing a theoretical basis for the clinical application of anti-CD20 monoclonal antibodies in TED.

Desensitization of Highly Immunized Kidney Transplant Recipients Awaiting Transplantation—Polish Single-Center Experience

IntroductionThe increasing number of highly immunized patients waiting for kidney transplantation is a significant problem in Europe as the proportion of such patients has doubled in the last decade. Transplantation in this group is enabled by desensitization methods, i.e., intravenous pharmacotherapy with human immunoglobulin (IVIG), anti-CD20 monoclonal antibody (rituximab), and plasma exchange. The objective was to evaluate the efficacy and safety of this protocol. Material and MethodsThe inclusion criteria: presence of established anti-HLA antibodies with complement-binding capacity, i.e., anti-HLAC1q+ (>MFI 15,000 for the most common antigens), no renal transplantation within 1 year after activation on the waiting list. Thirteen patients were selected for the procedure. IVIG was administered twice (2 g/kg-maximum 140 g/dose). Between IVIG doses, patients received rituximab (375 mg/m2). Anti-HLA was tested after 1 and 2 months after completion of the procedure. ResultsAll patients have completed the protocol. No significant changes after desensitization in the amount/profile of alloantibodies were observed. However, with negative vCM for HLA-A/B/DR (no DSA against the reported donor) and negative CM-CDC, according to the allocation system, patients were given priority on the recipient list. Seven out of 13 patients received a transplant within 12 months after treatment (mean 11.5 weeks). Renal graft function was good (mean creatinine level after 1 month: 1.5 mg/dL). No incidents of acute rejection were reported. The most common complications were infections (especially pneumonia). ConclusionThe desensitization protocol (IVIG + rituximab) allows highly immunized patients to undergo organ transplantation. In short-term analysis, no acute rejection was observed, graft function was satisfactory. Desensitization was associated with an increased risk of infection.

Maintenance therapy for chronic lymphocytic leukaemia.

Maintenance therapy for chronic lymphocytic leukaemia.

Rare primary pulmonary mucosa-associated lymphoid tissue lymphoma misdiagnosed with tuberculosis: A case report.

Primary pulmonary mucosa-associated lymphoid tissue lymphoma (MALToma) is a rare subtype of non-Hodgkin lymphoma with a relatively low incidence rate clinically. Atypical clinical symptoms and nonspecific chest computed tomography features of the disease make it difficult to determine and treatment is delayed. We discuss the diagnosis and treatment of a patient with primary pulmonary MALToma to raise clinicians' awareness of this condition. A 66-year-old male patient with a medical history of tuberculosis has been experiencing progressive exacerbation of respiratory symptoms and nonresponsive treatment without an unclear diagnosis for 5 years. He was transferred to our hospital because a nonspecific soft tissue mass in the right upper lobe of the lung was found on his chest computed tomography. Laboratory results with serum immunofixation electrophoresis showed polyclonal immunoglobulin (Ig) G, IgM, IgA, and λ-light chain on admission. Pathological examination and immunohistochemical staining of lung biopsy revealed a definitive diagnosis of pulmonary MALToma with stage IV. The patient received immunotherapy with anti-CD20 monoclonal antibody (rituximab), and showed significant clinical improvement at the 6-month follow-up. Diagnosis of primary pulmonary MALToma mainly relies on histopathological examination, and comprehensive laboratory examinations are also necessary. Clinicians should combine laboratory tests (such as immunofixation electrophoresis in our case) to assist in medical diagnosis in cases of atypical clinical manifestations and imaging characteristics. Immunotherapy appears to be the main treatment protocol for advanced patients.

Results from a Phase 1 Study of ACTR707 in Combination with Rituximab in Patients with Relapsed or Refractory CD20+ B Cell Lymphoma

The antibody-coupled T cell receptor (ACTR) platform is an autologous engineered T cell therapy combining the cell-killing ability of T cells and the tumor-targeting ability of coadministered antibodies. Activation of the T cell product ACTR707 is dependent on the engagement of antibody bound to target cells via the CD16 domain of the chimeric receptor (CD16V-CD28-CD3ζ). ACTR707 in combination with the anti-CD20 monoclonal antibody rituximab was evaluated in the ATTCK-20-03 study, a multisite, single-arm, open-label phase I trial in B cell non-Hodgkin lymphoma (NHL). The primary objectives of this study were to evaluate the safety of the combination of ACTR707 and rituximab and to determine a recommended phase 2 dose (RP2D). Secondary objectives included evaluation of antitumor activity and ACTR T cell persistence. The study design included an ACTR707 cell dose escalation phase and an expansion phase at the RP2D. Escalating dose levels of ACTR707 in combination with rituximab were explored in 5 dose cohorts, with 25 subjects receiving study treatment. Subjects received lymphodepleting chemotherapy (cyclophosphamide 400 mg/m2/day and fludarabine 30 mg/m2/day) for 3 days, followed by rituximab 375 mg/m2 and, 24 to 48 hours later, a single dose of ACTR707. Additional doses of rituximab were administered every 3 weeks until disease progression, unacceptable toxicity, or investigator decision. Blood samples were collected at various time points to assess levels of rituximab, cytokines, inflammatory markers, and ACTR707 T cells. The overall response rate of ACTR707 plus rituximab was 56% (14 of 25) across all dose levels. Ten subjects (40.0%) achieved a complete response, with the longest duration of 586 days (range, 85 to 586 days), and 4 subjects (16.0%) experienced a partial response, with the longest duration of 130 days (range, 44 to 130 days). Only 1 case of cytokine release syndrome (grade 2) and no events of neurotoxicity were reported. There were no dose-limiting toxicities or events leading to death. ACTR707 plus rituximab resulted in only 1 adverse event (neutropenia), leading to study discontinuation of rituximab. The ATTCK-20-03 trial serves as proof of principle regarding the ACTR approach that potentially could be used with other antibodies targeting other markers in other malignancies. Although the ACTR707 program has been discontinued, these results may support other programs in the use of similar novel approaches of antibody-coupled T cell activation.

Identification of Covariates Modulating B-Cell Repopulation Kinetics in Subjects Receiving Rituximab Treatment.

B-cell depletion using the anti-CD20 monoclonal antibody rituximab is a cornerstone in the therapeutic concept of multiple autoimmune diseases. B-cell depletion is associated with a higher risk for severe infections, and the time span of B-cell repopulation differs greatly between individuals. Data on factors influencing B-cell repopulation kinetics are limited. This study aims to identify patient-specific and therapy-associated covariates that modulate B-cell repopulation. This single-center retrospective observational study presents data of 839 subjects receiving 2,017 courses of rituximab for autoimmune diseases. Assessed covariates are patient-specific factors (sex, age, kidney function, and underlying disease) and co-immunosuppression with common agents (azathioprine, cyclosporine A, cyclophosphamide, hydroxychloroquine, methotrexate, mycophenolate mofetil, tacrolimus, and corticosteroids). The primary end point is the time to B-cell repopulation (≥5/μl). The secondary end point is the time to B-cell reconstitution (≥50/μl). Multivariate time-to-event analysis and logistic regression models were applied to estimate the influence of covariates. Age over 60 years (hazard ratio [HR] 0.71 for repopulation, P = 0.008), impaired kidney function (HR 0.72, P = 0.001), antineutrophil cytoplasmic antibody-associated vasculitis (HR 0.61, P < 0.001), solid organ transplantation (HR 0.4, P < 0.001), and co-immunosuppression with corticosteroids (HR 0.64, P < 0.001) or azathioprine (HR 0.49, P < 0.001) were associated with impaired B-cell repopulation and reconstitution. Effects of corticosteroids (P = 0.043) and azathioprine (P = 0.025) were dose dependent. Prolonged rituximab dosing intervals may be effective to achieve B-cell depletion and reduce risk of infection in advanced age or patients with impaired kidney function. Co-medication with corticosteroids or azathioprine prolongs B-cell recovery, which may increase therapeutic effects but also the rate of adverse events.

T-cell redirecting therapies for B-cell non-Hodgkin lymphoma: recent progress and future directions.

Several key advances in the treatment of B-cell non-Hodgkin lymphoma (B-NHL) over the past two decades have strategically exploited B-cell lineage markers suitable for targeting by immunotherapies. First, the addition of the anti-CD20 monoclonal antibody (mAb) rituximab to a range of standard therapies conferred remarkable outcomes improvements in diverse settings, perhaps most prominently an overall survival advantage in newly diagnosed diffuse large B-cell lymphoma (DLBCL). Subsequently, multiple chimeric antigen receptor (CAR) T-cell therapies targeting CD19 have revolutionized the treatment of relapsed/refractory (rel/ref) DLBCL and are active in other B-NHL subtypes as well. Most recently, the longstanding aspiration to exploit patients' endogenous T-cells to combat lymphoma has been achieved via T-cell redirecting therapies such as bispecific antibodies (BsAbs) that incorporate dual targeting of a T-cell antigen such as CD3 plus a B-cell antigen such as CD19 or CD20 expressed by the tumor. These novel agents have demonstrated impressive activity as monotherapies in patients with heavily pre-treated, rel/ref B-NHL of a variety of subtypes. Now, myriad clinical trials are exploring combinations of T-cell redirectors with targeted therapies, antibody-drug conjugates, conventional chemotherapy, and even new immunotherapies. Here, we highlight key landmarks in the development of T-cell redirecting therapies for the treatment of B-NHL, emerging evidence and lessons from recent clinical trials, and exciting new directions in this arena.

Age and memory B cells at baseline are associated with risk of relapse and memory B-cell reappearance following anti-CD20 treatment in pediatric frequently-relapsing/steroid-dependent nephrotic syndrome

B-cell depleting anti-CD20 monoclonal antibodies, mainly rituximab, have proven efficacy in children with frequently-relapsing/steroid-dependent nephrotic syndrome (FR/SDNS). However, drug-free remission is variable and specific baseline markers predictive of relapse after anti-CD20 treatment are still being defined. To clarify this, we performed a bicentric observational study in a large cohort of 102 children and young adults with FR/SDNS treated with anti-CD20 monoclonal antibodies (rituximab and ofatumumab). Sixty-two patients (60.8%) relapsed during a 24-month period (median [interquartile range] relapse-free survival, 14.4 months [7.9-24.0]). A higher risk of relapse was significantly associated with a younger age (under 9.8 years, hazard ratio, 0.44; 95% confidence interval, 0.26-0.74) and with significantly higher circulating levels of memory B cells (1.14; 1.09-1.32) at time of anti-CD20 infusion, independent of time elapsed from onset, previous anti-CD20 treatment, type of administered anti-CD20 monoclonal antibodies, previous or maintenance oral immunosuppression. Patients younger than 9.8 years at anti-CD20 infusion had a subsequent higher recovery of total, transitional, mature-naïve and memory B-cell subsets independent of previous anti-CD20 treatment and maintenance immunosuppression. Significantly, younger age and higher circulating levels of memory B cells at time of anti-CD20 infusion were also independently associated with the recovery of memory B cells by linear mixed-effects modelling. Thus, both younger age and higher circulating levels of memory B cells at time of infusion are independently associated with a higher risk of relapse and an earlier recovery of memory B cells following anti-CD20 treatment in children with FR/SDNS.

217-LB: Heterogeneity of Single Cells Obtained from Peripheral Blood Mononuclear Cells Collected from Youth with Recent-Onset Type 1 Diabetes

Whole blood bulk RNA sequencing has been used to guide T1D clinical trial design and assess response to disease modifying interventions, whereas it is with limited information about cell specific gene expression changes. Here, we aimed to apply computational strategies to deconvolute cell type composition using cell specific gene expression references. Single-cell RNA sequencing (scRNA-seq) was conducted to profile 108,795 peripheral blood mononuclear cells obtained from 5 youth within 48 hrs of Stage 3 T1D onset (avg age 11.4; 3M;2F) and 5 age- and sex-matched controls and identified 31 distinct cell clusters. In T1D, the proportion of CD4+ T central memory (TCM) cells was increased (P = 0.018), while plasmacytoid dendritic cells (pDC), platelets, and hematopoietic stem and progenitor cells (HSPC) proportions were reduced (P = 0.021, 0.012 and 0.017 respectively) compared to controls. The most robust transcriptomic changes were observed in CD14+ and CD16+ monocyte populations and CD1C+ conventional type-2 dendritic (cDC2) cells. Using this scRNA-seq reference dataset, we ran computational algorithms CIBERSORTx and our in-house reference-free method ICTD to deconvolute cell proportions using public clinical trial data testing the anti-CD20 monoclonal antibody rituximab (n=37) vs. placebo (n=17). Strong correlation was observed between the methods for cell proportion estimates (P &amp;lt; 2.2*10-16). It showed that B cell subsets were reduced by rituximab. At baseline, non-responders had a higher proportion of CD8+ T cells (P = 0.04), and responders had higher proportions of neutrophils (P =0.04). These data suggest that deconvolution approaches can be utilized for secondary analysis of existing clinical trial bulk RNA-seq data, to link cell specific immune signatures associated with drug responder status. Disclosure W. Wu: None. C. Parks-schenck: None. T. Guo: None. C. Zhang: None. R. G. Mirmira: None. C. Evans-molina: Advisory Panel; Provention Bio, Inc., DiogenX, Avotres Inc., Neurodon, MaiCell Therapeutics, Other Relationship; Isla Technology, Bristol-Myers Squibb Company, Nimbus Therapeutics, Research Support; Lilly, Astellas Pharma Inc. Funding dkNET; Indiana University Center for Diabetes and Metabolic Diseases; National Institutes of Health (U01DK127786)

MAHOGANY: A phase 3 trial of zanubrutinib plus anti-CD20 antibodies vs lenalidomide plus rituximab in patients with relapsed or refractory follicular or marginal zone lymphoma.

TPS7590 Background: Inhibition of Bruton tyrosine kinase (BTK) has emerged as a strategy for treatment of patients (pts) with B-cell malignancies including indolent non-Hodgkin lymphomas. Zanubrutinib is a second-generation, potent, and specific BTK inhibitor and has shown to be more effective and better tolerated than first-generation BTK inhibitors in several diseases including chronic lymphocytic leukemia/small lymphocytic lymphoma and Waldenström macroglobulinemia. Zanubrutinib is approved in &gt;15 countries, including the United States and European Union, for pts with relapsed or refractory (R/R) marginal zone lymphoma (MZL) who received ≥1 anti-CD20–based regimen, based on the single-arm MAGNOLIA trial (Opat et al. Clin Cancer Res 2021). In R/R follicular lymphoma (FL), ROSEWOOD, a phase 2 randomized study of zanubrutinib plus obinutuzumab (ZO) vs obinutuzumab, met its primary endpoint of increased overall response rate (ORR) at primary analysis (Zinzani et al. J Clin Oncol 2022). In this trial, ZO in pts with R/R FL demonstrated deep and durable responses with a favorable safety profile. Methods: MAHOGANY (BGB-3111-308, NCT05100862) is a phase 3 randomized, open-label trial that compares efficacy and safety of a combination of zanubrutinib plus anti-CD20 monoclonal antibody vs lenalidomide plus rituximab in 2 independent cohorts, for pts with either R/R FL or MZL. Key eligibility criteria include histologically confirmed FL (grades 1-3A) or MZL, previously treated with ≥1 anti-CD20–based regimen, relapsed after or refractory to the most recent systemic therapy, in need of treatment, no prior BTK inhibitor exposure, and no prior resistance to a lenalidomide-based regimen. In the FL cohort, pts will be randomized 1:1 to ZO (N = 300) and lenalidomide plus rituximab (N = 300). Randomization is stratified by age (≥60 years vs &lt; 60 years), number of prior lines of therapy (1-2 vs &gt; 2) and rituximab-refractory status (yes vs no). The primary endpoint is progression-free survival (PFS) assessed by an independent review committee (IRC), according to Lugano 2014 criteria. Key secondary endpoints are ORR by IRC assessment and overall survival. In the MZL cohort, pts will be randomized 1:1 to zanubrutinib plus rituximab (N = 75) and lenalidomide plus rituximab (N = 75). Randomization is stratified by age (≥60 years vs &lt; 60 years) and number of prior lines of therapy (1-2 vs &gt; 2). The primary endpoint is PFS assessed by IRC according to Lugano 2014 criteria. The key secondary endpoint is ORR by IRC assessment. Zanubrutinib is given at 160 mg twice daily or 320 mg once daily according to investigator, until progression or unacceptable toxicity. Obinutuzumab or rituximab are given for up to 8 infusions. Lenalidomide is given according to approved label for up to 12 cycles. Recruitment is ongoing. Clinical trial information: NCT05100862 .

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Inhibition of Bruton tyrosine kinase (BTK) has emerged as a strategy for treatment of patients (pts) with B-cell malignancies including indolent non-Hodgkin lymphomas. Zanubrutinib is a second-generation, potent, and specific BTK inhibitor and has shown to be more effective and better tolerated than first-generation BTK inhibitors in several diseases including chronic lymphocytic leukemia/small lymphocytic lymphoma and Waldenström macroglobulinemia. Zanubrutinib is approved in >15 countries, including the United States and European Union, for pts with relapsed/refractory (R/R) marginal zone lymphoma (MZL) who received ≥1 anti-CD20–based regimen, based on the single-arm MAGNOLIA trial (Opat et al. Clin Cancer Res 2021). In R/R follicular lymphoma (FL), ROSEWOOD, a phase 2 randomized study of zanubrutinib plus obinutuzumab versus obinutuzumab, met its primary endpoint of increased overall response rate (ORR) at primary analysis (Zinzani et al. J Clin Oncol 2022). In this trial, zanubrutinib plus obinutuzumab in pts with R/R FL demonstrated deep and durable responses with a favorable safety profile. Methods: MAHOGANY (BGB-3111-308, NCT05100862) is a phase 3 randomized, open-label trial that compares efficacy and safety of a combination of zanubrutinib plus anti-CD20 monoclonal antibody versus lenalidomide plus rituximab in 2 independent cohorts, for pts with either R/R FL or MZL. Key eligibility criteria include histologically confirmed FL (grades 1–3A) or MZL, previously treated with ≥1 anti-CD20-based regimen, relapsed after or refractory to the most recent systemic therapy, in need of treatment, no prior BTK inhibitor exposure, and no prior resistance to a lenalidomide-based regimen. In the FL cohort, pts will be randomized 1:1 to zanubrutinib plus obinutuzumab (N = 300) and lenalidomide plus rituximab (N = 300). Randomization is stratified by age (≥60 vs. <60 years), number of prior lines of therapy (1–2 vs. >2), and rituximab-refractory status (yes vs. no). The primary endpoint is progression-free survival (PFS) assessed by an independent review committee (IRC) according to Lugano 2014 criteria. Key secondary endpoints are ORR by IRC assessment and overall survival. In the MZL cohort, pts will be randomized 1:1 to zanubrutinib plus rituximab (N = 75) and lenalidomide plus rituximab (N = 75). Randomization is stratified by age (≥60 vs. <60 years) and number of prior lines of therapy (1–2 vs. >2). The primary endpoint is PFS assessed by IRC according to Lugano 2014 criteria. The key secondary endpoint is ORR by IRC assessment. Zanubrutinib is given at 160 mg twice daily or 320 mg once daily according to investigator, until progression or unacceptable toxicity. Obinutuzumab or rituximab are given for up to 8 infusions. Lenalidomide is given according to approved label for up to 12 cycles. Recruitment is ongoing. Encore Abstract—previously submitted to ASCO 2023 and EHA 2023 The research was funded by: BeiGene Keywords: aggressive B-cell non-Hodgkin lymphoma, combination therapies Conflicts of interests pertinent to the abstract L. Sehn Consultant or advisory role AbbVie, Seattle Genetics, Janssen, Amgen, Roche/Genentech, Gilead Sciences, Kite, a Gilead Company, Merck, Teva, TG Therapeutics, AstraZeneca, Incyte, Sandoz-Novartis, Genmab, Celgene/BMS, BeiGene Honoraria: Amgen, AbbVie, Gilead Sciences, Janssen-ORtho, Kite, a Gilead Company, Merck, Roche/Genentech, Seattle Genetics, Teva, AstraZeneca, Incyte, Sandoz-Novartis, Genmab, Celgene/BMS, BeiGene Research funding: Roche/Genentech, Teva C. Sarkozy Consultant or advisory role Janssen, GSK, Incyte, BMS Honoraria: AbbVie Research funding: Roche Educational grants: Roche, Incyte Other remuneration: Incyte A. Salar Consultant or advisory role BeiGene, Roche Research funding: Roche, AbbVie Other remuneration: Kite, a Gilead Company, Janssen J. Trotman Consultant or advisory role BeiGene WM Advisory Board 2022 (uncompensated) Research funding: BeiGene, Janssen, Pharmacyclics, Roche, Celgene/BMS, Selectar P. L. Zinzani Consultant or advisory role Celltrion, Gilead Sciences, Janssen-Cilag, BMS, Servier, Sandoz, MSD, Roche, EUSA Pharma, Kyowa Kirin, Takeda, Secura Bio, TG Therapeutics, Novartis, ADC Therapeutics, Incyte, BeiGene, Novartis J. Zhang Employment or leadership position: BeiGene Stock ownership: BeiGene P. Fustier Employment or leadership position: BeiGene Stock ownership: BeiGene R. Delarue Employment or leadership position: Celgene/BMS, BeiGene Stock ownership: Celgene/BMS, BeiGene L. Nastoupil Consultant or advisory role Sirpant, Iterus Bios Honoraria: Gilead Sciences, Novartis, Janssen Oncology, TG Therapeutics, BMS, ADC Therapeutics, Morphosys, Epizyme, Genmab, Takeda, Genentech/Roche, Caribou Biosciences Research funding: Janssen Biotech, Genentech/Roche, Epizyme, Novartis, IgM Biosciences, Gilead Sciences, Allogene Therapeutics, Takeda, BMS/Celgene Educational grants: Genentech/Roche

Low incidence and morbidity of Epstein-Barr virus reactivation following donor lymphocyte infusions.

Low incidence and morbidity of Epstein-Barr virus reactivation following donor lymphocyte infusions.

Disease-Specific Treatment For Primary Membranous Nephropathy: The Role of Monoclonal Antibodies

Primary Membranous Nephropathy is an autoimmune disease caused by the deposition of Immunoglobulin G and complement components on the subepithelial layer of the glomerular capillary wall. It affects 5-10 patients per million population and is the second cause of nephrotic syndrome in adults after diabetic kidney disease. For decades steroids and non-specific immunosuppressive medications have been advocated as a therapeutic option for patients with membranous nephropathy at increased risk of kidney failure because of persistent nephrotic syndrome. These medications, however, have major and potentially fatal adverse effects that offset their potential benefits and should be abandoned. The discovery of nephritogenic autoantibodies against podocyte M-type phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing protein 7A (THSD7A) antigens provided a clear pathophysiological rationale for interventions specifically targeting B cell lineages to prevent antibody production and subepithelial deposition. The first-in-class anti-CD20 monoclonal antibody rituximab is safe and achieves remission in approximately two-thirds of patients with nephrotic membranous nephropathy. In PLA2R-related disease, remission is invariably preceded by depletion of anti PLA2R autoantibodies and relapse by their re-emergence into the circulation. Because of its superior risk/benefit profile as compared to non-specific immunosuppressive therapy, rituximab is now first-line therapy for patients with membranous nephropathy at risk of kidney failure. Novel monoclonal antibodies targeting CD20 cells (such as ofatumumab and obinutuzumab) and their differentiation (belimumab) or targeting long-living antibody producing CD38 memory cells (daratumumab, felzartamab) along with proteasome inhibitors such as bortezomib are being evaluated for the treatment of nephrotic patients with membranous nephropathy who are resistant or intolerant to rituximab. Complement inhibitor therapy might serve to stop the glomerular inflammatory process until the benefits of these medications become effective. Thus, major advances in the understanding of the mechanisms of membranous nephropathy have led to novel treatment perspectives. The integrated evaluation of serum autoantibody titer and proteinuria, together with serum albumin levels in patients with overt nephrotic syndrome, could guide diagnosis of membranous nephropathy and individually tailored treatment protocols. The introduction of monoclonal antibodies targeting disease-specific mechanisms will pave the way for a novel therapeutic paradigm based on the principle of precision medicine and personalized therapy.

Implications of rituximab pharmacokinetic and pharmacodynamic alterations in various immune-mediated glomerulopathies and potential anti-CD20 therapy alternatives.

The specific B-cell depleting anti-CD20 monoclonal antibody rituximab (RTX) is effective in terms of the treatment of various immune-mediated glomerulopathies. The administration of RTX has been shown to be reliable and highly effective particularly in patients with ANCA-associated vasculitis, which is manifested predominantly with non-nephrotic proteinuria. Stable long-term B-cell depletion is usually readily attained in such patients using standard dosing regimens. However, in patients with nephrotic syndrome and non-selective proteinuria, the RTX pharmacokinetics is altered profoundly and RTX does not maintain high enough levels for a sufficiently long period, which may render RTX treatment ineffective. Since complement-derived cytotoxicity is one of the important modes of action of RTX, hypocomplementemia, frequently associated with systemic lupus erythematodes, may act to hamper the efficacy of RTX in the treatment of patients with lupus nephritis. This review provides a description of RTX pharmacokinetics and pharmacodynamics in several selected glomerulopathies, as well as the impact of proteinuria, anti-drug antibodies and other clinical variables on the clearance and volume of distribution of RTX. The impact of plasmapheresis and peritoneal dialysis on the clearance of RTX is also discussed in the paper. A review is provided of the potential association between pharmacokinetic and pharmacodynamic alterations in various kidney-affecting glomerular diseases, the sustainability of B-cell depletion and the clinical efficacy of RTX, with proposals for potential dosing implications. The role of therapeutic drug monitoring in treatment tailoring is also discussed, and various previously tested RTX dosing schedules are compared in terms of their clinical and laboratory treatment responses. Since alternative anti-CD20 molecules may prove effective in RTX unresponsive patients, their pharmacokinetics, pharmacodynamics and current role in the treatment of glomerulopathies are also mentioned.

Role of Rituximab in the Treatment of Pemphigus Vulgaris: Patient Selection and Acceptability

Anti-CD20 monoclonal antibody rituximab is an approved adjuvant treatment, in combination with oral corticosteroids, for patients with pemphigus vulgaris, a severe and potentially life-threatening autoimmune blistering skin disorder. Updated approaches to the management of pemphigus vulgaris support rituximab as a first-line adjuvant treatment to induce remission early in the course of disease; however, its feasibility in the clinical setting is often reduced by a series of limitations, including high cost of this biological drug, physician and patient concern for the risk of adverse reactions, and uncertainty regarding the optimum dosing and schedule of administration. The standard approved rituximab dosages, which are derived from lymphoma protocols, have been recognized to exceed the effective dose required for inducing B cell depletion, since the B cell burden in pemphigus vulgaris is much lower than in lymphoproliferative disorders. To overcome these limitations, recent research has investigated alternative regimens of rituximab, using lower doses of the drug. Moreover, differences in patient and disease characteristics that are highlighted in the literature strongly suggest that therapy should be tailored individually on a case-by-case basis: personalized treatment schedules may be necessary to optimize response to treatment and tolerability in different subjects, with the possibility of repeated infusions for severe forms and in case of relapse. Finally, low-dose regimens of rituximab were suggested to be favorable during the COVID-19 pandemic by providing a lesser degree of immune cell depletion while retaining a sufficient response. In conclusion, the current literature suggests that lower-dose regimens of rituximab are not only tolerable and cost-effective but may also be associated with a positive response in pemphigus vulgaris, comparable to that achieved with higher doses especially in early disease. Further evidence from rigorous clinical trials will be required to optimize lower-dose regimens of RTX and establish their position within the treatment scenario of pemphigus vulgaris.

Patient-derived Siglec-6-targeting antibodies engineered for T-cell recruitment have potential therapeutic utility in chronic lymphocytic leukemia

BackgroundDespite numerous therapeutic options, safe and curative therapy is unavailable for most patients with chronic lymphocytic leukemia (CLL). A drawback of current therapies such as the anti-CD20 monoclonal antibody (mAb)...

Treatment with the anti-CD20 monoclonal antibody rituximab mitigates gonadal disruptions in the collagen-induced arthritis in male DBA/1 J mouse model

Rheumatoid arthritis (RA), which is driven by persistent activation of the immune system, primarily affects the joints. Several reports have estimated the risk of gonadal disruptions in arthritic patients, with potential attributable risk factors such as treatments with the disease-modifying antirheumatic drugs and the influence of the disease itself. The FDA approved rituximab, a therapy for non-Hodgkin's lymphoma, for management of RA in February 2006. However, the influence of repeated treatment with rituximab on gonadal function in RA has not been reported yet. Thus, the aim of the presents study is to evaluate whether repeated treatment with the clinically relevant dose of rituximab may change the gonadal disruptions in collagen-induced arthritis in male DBA/1 J mouse, a model of RA. Testicular disruptions, as determined by the sperm DNA strand breaks, spermatocyte chromosomal analysis and spermiogram examination have been conducted by the use of standard techniques. Additionally, we aimed to test whether the anti-rheumatic effect of rituximab also decreases the cellular oxidant-antioxidant imbalance in arthritic male DBA/1 J mice. Repeated treatment of naïve control DBA/1 J mice with rituximab did not exhibit any significant deleterious effects. Moreover, repeated administration of rituximab to the arthritic DBA/1 J mice suppressed disease severity and decreased testicular disruptions. Rituximab treatment also diminished gonadal oxidative stress, through decreasing reactive oxygen species generation and restoring the reduced glutathione level in arthritic DBA/1 J mice. In conclusion, rituximab is a safe therapeutic agent and can mitigate gonadal disruptions induced by arthritis, which insinuates the importance for arthritic patients especially at reproductive age.

Immunosuppressed non-responders to two doses of mRNA SARS-CoV-2 vaccines achieve an immune response comparable to those of immunocompetent individuals after a third dose.

The SARS-CoV-2 vaccines trigger the production of neutralizing antibodies to the SARS-CoV-2 spike (S) protein and induce a T cell-mediated immune response. However, the antibody titers that confer protection against the SARS-CoV-2 virus are currently not well-established. While immunocompetent individuals achieve a high level of immune response after SARS-CoV-2 vaccination, it now appears that a high proportion of immunosuppressed or immunocompromised, patients exhibit low or no response to two doses of the vaccines. Most non-responders are on treatment with either glucocorticoids, mycophenolate-mofetil (MMF), the anti-CD20 monoclonal antibody rituximab, calcineurin inhibitors like cyclosporine and tacrolimus, rapamycin (mTOR) signaling cascade inhibitors (i.e., sirolimus and everolimus), azathioprine, or methotrexate given for a variety of diseases including autoimmune disorders, hematological malignancies, and solid cancers, while recipients of solid organ transplants also fall within this category. Recently, several published reports have suggested that a third dose of these vaccines induces an elevated antibody response against the SARS-CoV-2 S protein.