anti-CD20 Monoclonal Antibody Research Articles

Pomalidomide, Bortezomib and Dexamethasone in Multiple Myeloma Patients Double Refractory to Lenalidomide and Anti-CD38 Monoclonal Antibodies: A Multicentric Italian Retrospective Study

Pomalidomide, Bortezomib and Dexamethasone in Multiple Myeloma Patients Double Refractory to Lenalidomide and Anti-CD38 Monoclonal Antibodies: A Multicentric Italian Retrospective Study

Preliminary Results of a Retrospective Study on a Regimen Based on Orelabrutinib Combined with Anti-CD20 Monoclonal Antibody in Patients with Marginal Zone Lymphoma

Preliminary Results of a Retrospective Study on a Regimen Based on Orelabrutinib Combined with Anti-CD20 Monoclonal Antibody in Patients with Marginal Zone Lymphoma

SG301, a Novel Anti-CD38 Monoclonal Antibody, in Patients with Relapsed/Refractory Multiple Myeloma: A First-in-Human, Multicentre, Phase 1 Trial

SG301, a Novel Anti-CD38 Monoclonal Antibody, in Patients with Relapsed/Refractory Multiple Myeloma: A First-in-Human, Multicentre, Phase 1 Trial

A Novel Anti-CD20 Monoclonal Antibody for Treating Relapsed Immune Thrombocytopenia

A Novel Anti-CD20 Monoclonal Antibody for Treating Relapsed Immune Thrombocytopenia

Using Soluble CD38 to Overcome Daratumumab Interference in Pretransfusion Compatibility Testing

Background: CD38 is a protein highly expressed on myeloma (MM) cells that has been shown to be an effective target antigen for monoclonal antibody therapies, so treatment with anti-CD38 monoclonal antibodies is a first line therapy for patients with MM. Although CD38 is weaker expressed on erythocytes anti-CD38 binds to CD38 on reagent RBCs and cause panreactivity in vitro and subsequent false positive reactions in indirect antiglobulin tests (IAT), antibody detection (screening) tests, antibody identification panels, and anti-human globulin (AHG) crossmatches. These findings suggest that the soluble CD38 method could improve transfusion safety for patients receiving anti-CD38 therapy, particularly in urgent clinical settings This study aims to evaluate the effectiveness of a new soluble CD38-based method in mitigating Daratumumab interference during pretransfusion compatibility testing." Methods: We evaluated the Grifols sCD38 method in 20 patients and compared it with the DTT method Results: In our experience the sCD38 method reduced testing time from 150 to 50 minutes and demonstrated 100% efficacy, compared to 90% with DTT. The sCD38 effectively mitigated the interference caused by anti-CD38 antibodies in 10 (100% efficacy) of patient samples tested while DTT was successful in only 9/10 (90% efficacy); no interference was observed in patients presenting anti erythrocyte antibodies. Moreover, there was no negative influence on DTT sensitive blood group systems such as KEL upon sCD38 treatment. Conclusions: In our Laboratory, in the year 2023, we processed 129 patients treated with anti-CD38. Therefore the reduction from 150 to 50 minutes in the time needed to perform tests for mitigation of anti-CD38 interference appears to be relevant with a recovery of approximately 210 technical-hours per year. Another highly appreciated operational aspect was the possibility of treating the patient's plasma and perform tests using automatic instruments (Erytra Grifols) available in our laboratory. In the evaluation of this new method, we did not observe failures in the mitigation of anti-CD38 interference. Furthermore, the results obtained in the samples that presented allo or auto antibodies were not affected by the treatment with sCD38. In our experience Grifols sCD38 assay is straightforward and quick to perform ant it is superior to DTT treatment in the mitigation of anti-CD38 antibody interference in MM patients treated with Daratumumab.

Asciminib stands out as the superior tyrosine kinase inhibitor to combine with anti-CD20 monoclonal antibodies for the treatment of CD20+ Philadelphia-positive B-cell precursor acute lymphoblastic leukemia in preclinical models.

Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia (Ph+ BCP-ALL) is a high-risk subtype of acute lymphoblastic leukemia characterized by the presence of the BCR::ABL1 fusion gene. Tyrosine kinase inhibitors (TKI) combined with chemotherapy are established as the first-line treatment. Additionally, rituximab, an anti-CD20 monoclonal antibody is administered to adult BCP-ALL patients with ≥20% CD20+ blasts. In this study, we observed a marked prevalence of CD20 expression in patients diagnosed with Ph+ BCP-ALL, indicating a potential widespread clinical application of rituximab in combination with TKI. Consequently, we examined the influence of TKI on the antitumor effectiveness of anti-CD20 monoclonal antibodies by evaluating levels of CD20 on the cell surface and conducting in vitro functional assays. All tested TKI were found to uniformly downregulate CD20 on leukemic cells, diminishing the efficacy of rituximab-mediated complement- dependent cytotoxicity. Interestingly, these TKI displayed varied effects on natural killer (NK) cell-mediated antibody- dependent cytotoxicity and macrophage phagocytic function. While asciminib demonstrated no inhibition of effector cell functions, dasatinib notably suppressed the anti-CD20-monoclonal antibody-mediated NK cell cytotoxicity and macrophage phagocytosis of BCP-ALL cells. Dasatinib and ponatinib also decreased NK cell degranulation in vitro. Importantly, oral administration of dasatinib, but not asciminib, compromised NK cell activity in patients' blood, as determined by an ex vivo degranulation assay. Our results indicate that asciminib might be preferred over other TKI for combination therapy with anti-CD20 monoclonal antibodies.

Hypogammaglobulinemia and severe infections in Multiple Sclerosis patients on anti-CD20 agents: a multicentre study

BackgroundHypogammaglobulinemia (HG) is a known side effect of treatment with anti-CD20 monoclonal antibodies, and it is associated with the risk of infections. ObjectivesAim of this retrospective multicentre study was to assess the frequency of HG in Multiple Sclerosis (MS) and Neuromyelitis Optica Spectrum Disorder patients treated with Ocrelizumab or Rituximab and its association with the occurrence of severe infections (SI). Furthermore, predictors of HG and SI were sought. MethodsWe included 556 patients (190M, 366F, mean age: 47 years) with a mean follow-up of 28 months (range 12-90 months). ResultsIgG HG occurred in 20% and IgM HG in 34% of patients. At multivariable analysis, the risk of IgG HG was influenced by an older age (≥50 years) (OR 1.64, 95%CI: 1.06-2.54, p=0.027), and by the number of treatment cycles (OR: 1.20, 95%CI: 1.09-1.33, p<0.001).A total of 25 SI occurred (100 person-years rate: 1.8), with a disease phenotype other than relapsing-remitting (OR 1.50, 95%CI: 1.02-2.20; p=0.039) and IgG HG (OR 2.65, 95%CI: 1.15-6.12; p=0.022) increasing its risk. ConclusionsIgG and IgM HG occurred in a considerable proportion of patients. IgG HG increased the risk of SI, which were, nevertheless, relatively infrequent. Our results highlight the importance of monitoring immunoglobulin levels during treatment with anti-CD20 agents, to personalize treatment strategies.

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.

The Functional Transcriptomic Landscape Informs Therapeutic Strategies in Multiple Myeloma.

Several therapeutic agents have been approved for treating multiple myeloma (MM), a cancer of bone marrow resident plasma cells. Predictive biomarkers for drug response could help guide clinical strategies to optimize outcomes. Here, we present an integrated functional genomic analysis of tumor samples from MM patients that were assessed for their ex vivo drug sensitivity to 37 drugs, clinical variables, cytogenetics, mutational profiles, and transcriptomes. This analysis revealed a MM transcriptomic topology that generates "footprints" in association with ex vivo drug sensitivity that have both predictive and mechanistic applications. Validation of the transcriptomic footprints for the anti-CD38 monoclonal antibody daratumumab and the nuclear export inhibitor selinexor demonstrated that these footprints can accurately classify clinical responses. The analysis further revealed that daratumumab and selinexor have anti-correlated mechanisms of resistance, and treatment with a selinexor-based regimen immediately after a daratumumab-containing regimen was associated with improved survival in three independent clinical trials, supporting an evolutionary-based strategy involving sequential therapy. These findings suggest that this unique repository and computational framework can be leveraged to inform underlying biology and to identify therapeutic strategies to improve treatment of MM.

Zanubrutinib, obinutuzumab, and venetoclax for first-line treatment of mantle cell lymphoma with a TP53 mutation

AbstractTP53-mutant mantle cell lymphoma (MCL) is associated with poor survival outcomes with standard chemoimmunotherapy. Dual Bruton tyrosine kinase and BCL2-inhibition with or without anti-CD20 monoclonal antibody therapy has shown promising activity in TP53-mutant MCL. We conducted a multicenter, phase 2 study of zanubrutinib, obinutuzumab, and venetoclax (BOVen) in untreated patients with MCL with a TP53 mutation. Patients initially received 160 mg zanubrutinib twice daily and obinutuzumab. Obinutuzumab at a dose of 1000 mg was given on cycle 1 day 1, 8, and 15, and on day 1 of cycles 2 to 8. After 2 cycles, venetoclax was added with weekly dose ramp-up to 400 mg daily. After 24 cycles, if patients were in complete remission with undetectable minimal residual disease (MRD) using an immunosequencing assay, treatment was discontinued. The primary end point was met if ≥11 patients were progression free at 2 years. The study included 25 patients with untreated MCL with a TP53 mutation. The best overall response rate was 96% (24/25) and the complete response rate was 88% (22/25). Frequency of undetectable MRD (uMRD) at a sensitivity level of 1 × 10–5 and uMRD at a sensitivity level of 1 × 10–6 at cycle 13 was 95% (18/19) and 84% (16/19), respectively. With a median follow-up period of 28.2 months, the primary end point was met with a 2-year progression-free survival of 72%, and the 2-year disease-specific and overall survival were 91% and 76%, respectively. Common side effects were generally low grade and included diarrhea (64%), neutropenia (32%), and infusion-related reactions (24%). BOVen was well tolerated and met its primary efficacy end point in TP53-mutant MCL. These data support its use and further evaluation of the BOVen regimen in this high-risk population. This trial was registered at www.ClinicalTrials.gov as #NCT03824483.

A real-world pharmacovigilance study of tafasitamab: data mining of the US food and drug administration adverse event reporting system

ABSTRACT Background Tafasitamab is the first anti-CD19 monoclonal antibody approved for relapsed/refractory diffuse large B-cell lymphoma patients ineligible for autologous stem cell transplantation. The study was designed to evaluate tafasitamab-associated adverse events (AEs) by data mining the United States Food and Drug Administration Adverse Event Reporting System (FAERS). Research design and methods A disproportionality analysis was performed to assess the safety profile of tafasitamab based on the reports from the FAERS database between 2020Q3 and 2023Q3. Proportional reporting ratio (PRR) and empirical Bayesian geometric mean (EBGM) were used to identify the signals of AEs in patients receiving tafasitamab. Results A total of 529 reports with tafasitamab as the primary suspect drug were collected, including 1,262 AEs. Of these, 28 repeated AEs were identified using two algorithms. After excluding events unrelated to drug therapy, the top five repeated AEs by intensity ranking were cytopenia, immunosuppression, neutropenic sepsis, blood lactate dehydrogenase increased, and hematotoxicity. Unexpected significant AEs included polyneuropathy, splenomegaly, hemophagocytic lymphohistiocytosis, hypercalcemia, and ascites. Conclusions This study provides additional evidence for risk identification of tafasitamab in the real world, which could help clinicians and pharmacists increase vigilance and improve the safety of tafasitamab in clinical practice.

Inotuzumab Ozogamicin and Low-Intensity Chemotherapy in Older Patients With Newly Diagnosed CD22+ Philadelphia Chromosome-Negative B-Cell Precursor Acute Lymphoblastic Leukemia.

The use of inotuzumab ozogamicin (InO), a conjugated anti-CD22 monoclonal antibody, is becoming a promising frontline treatment for older patients with ALL. EWALL-INO is an open-label prospective multicenter phase II trial (ClinicalTrials.gov identifier: NCT03249870). Patients age 55 years and older with newly diagnosed CD22+ Philadelphia chromosome-negative (Ph-) B-cell precursor (BCP) ALL were eligible. After a prephase, a first induction consisting of vincristine, dexamethasone, and three injections of InO (0.8 mg/m2 day 1, 0.5 mg/m2 day 8/day 15) was followed by a second induction combining cyclophosphamide, dexamethasone, and two injections of InO (0.5 mg/m2 day 1/day 8). Responders received up to six cycles of chemotherapy consolidation and 18-month chemotherapy maintenance. Allotransplant was allowed after three consolidations. The primary end point was 1-year overall survival (OS). Between December 2017 and March 2022, 131 patients (median age 68 years) were included. Three patients died during induction 1 (n = 130), two from multiple organ failure and one from hemorrhage, and none during induction 2 (n = 120). After induction 2, 90% of the patients achieved complete remission (CR) or CR with incomplete platelet recovery (CRp) and 80% had measurable residual disease (MRD2) <10-4. Among responders (n = 119), 47 relapsed and 14 died in CR/CRp. One-year OS, relapse-free survival (RFS), and cumulative incidence of relapse (CIR) rates were 73.2%, 66%, and 25%, respectively. High-risk cytogenetics and lower CD22 expression (<70%) were associated with worse OS, while both high-risk cytogenetics and MRD2 ≥10-4 were associated with lower RFS and higher CIR. The 10 allotransplanted patients had very favorable outcomes (90% 2-year OS/RFS and no relapse). Only one nonfatal sinusoidal obstructive syndrome was documented during the study. Our results support InO's use in first-line regimens for older patients with CD22+ Ph- BCP-ALL.

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.

Clinical Efficacy of Isatuximab Plus Carfilzomib and Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients.

Isatuximab, a novel anti-CD38 monoclonal antibody, is approved in combination with carfilzomib and dexamethasone (Isa-Kd) in relapsed/refractory multiple myeloma (RRMM) patients. Because of its recent introduction, real-world efficacy and safety are poorly reported. In this Italian multicenter real-life observational retrospective study, efficacy and safety of the Isa-Kd regimen were evaluated in a cohort of 103 RRMM patients. Overall response rate (ORR) was 85%, with stringent (sCR) or complete response (CR) in 18% of cases and very good partial response (VGPR) in 39%. Median PFS and OS were not reached within the study period, while 1-year PFS and OS were 72% and 77%, respectively. Hematological toxicities were observed in 42% of subjects, and cardiac toxicities occurred in 24% of cases. Moreover, we conducted a subanalysis on patients (N = 69) treated with Isa-Kd after one prior line of therapy, showing an ORR of 88%, with sCR + CR in 20% of subjects, VGPR in 46%, and PR in 22% of patients. In this group, median PFS and OS were not reached, while 1-year PFS and OS were 92% and 95%, respectively. In conclusions, our study confirmed Isa-Kd as an effective treatment option for RRMM with a manageable safety profile even in real-life settings.

Obinutuzumab treatment for membranous nephropathy: effectiveness and safety concerns during the COVID-19 pandemic.

Obinutuzumab is a humanized and glycoengineered anti-CD20 monoclonal antibody that has been shown to induce more profound B-cell depletion than rituximab. The effectiveness and safety of obinutuzumab in the treatment of membranous nephropathy remain unclear. This was a retrospective study conducted in Huashan Hospital, Fudan University between 1 December 2021 and 30 November 2023. Patients with membranous nephropathy were included to assess the effectiveness and safety of obinutuzumab and prevalence of severe pneumonia during the outbreak of COVID-19 in China. Eighteen patients were included in the study assessing the effectiveness of obinutuzumab. After a 12-month follow-up, 14 patients (78%) achieved remission, with six (33%) achieving complete remission and eight (44%) achieving partial remission. Among the 18 obinutuzumab-treated patients contracting COVID-19 for the first time, six (33%) developed severe pneumonia, and one died. By contrast, two of the 37 patients receiving glucocorticoids combined with cyclophosphamide, and none of the 44 patients on calcineurin inhibitors or the 46 patients on rituximab developed severe pneumonia. However, compared to patients receiving rituximab or glucocorticoids plus cyclophosphamide, the obinutuzumab-treated patients had a longer duration of membranous nephropathy and immunosuppressive therapy. Therefore, cardinal matching was employed to balance these baseline characteristics. Owing to small sample size for each regimen, patients receiving all the three non-obinutuzumab immunosuppressive regimens were grouped as a control cohort. After matching for age, gender, remission status, duration of membranous nephropathy, duration of immunosuppressive therapy, and ongoing immunosuppression, the obinutuzumab-treated patients still had a significantly higher incidence of severe pneumonia compared to those on other regimens (P=.019). Obinutuzumab was an effective treatment option for patients with membranous nephropathy. On the other hand, it was associated with a higher incidence of severe pneumonia following COVID-19 infection compared to other immunosuppressive regimens.

Level of CD11a among Newly Diagnosed ITP Patients and after 6 Months Follow Up

Abstract Background and Objectives Immune thrombocytopenia (ITP) is a relatively frequent acquired bleeding disorders. Etiology is not yet well understood. Lymphocytic function associated antigen-1(LFA-1) might play an important role in signal coordination and lymphocyte activation. The aim of this study was to assess CD11a expression on lymphocytes in newly diagnosed ITP patients and to correlate it with bleeding severity in ITP and to evaluate the effect of immunomodulation medications on CD11a expression in children with ITP. Patients and Methods This is a prospective case-control study enrolling children with ITP attending pediatric Hematology clinic, Ain Shams University Hospitals through November 2021-November 2022 and near equal number of age and sex matched control subjects were randomly selected. All necessary laboratory tests for diagnosis of ITP were performed and the expression of CD11a on lymphocytes was analyzed by flow cytometry at the start of the study and after 6 months of follow up and assessment of bleeding manifestations according to ITP- specific bleeding assessment tool (ITP-BAT). Results Thirty-five patients aged (2-15) years with median age 6.5 years. 21 males and 14 females were enrolled as newly diagnosed primary ITP. The mean platelet count in these patients was 13(103/ul) initially and 239(103/ul) at follow up with response rate of 94.1%. The treatment received in ITP patients was corticosteroid (97.1%),IVIG (11.6%),thrombopoietin receptor agonist (17.4%) and anti CD20 monoclonal antibody (5.8%). The mean fluorescence intensity (MFI) of CD11a was 95.7% initially and 94.7 % at follow up and it was 94.3% in the control group. The mean fluorescence intensity (MFI) of CD11a on lymphocytes showed significant difference in ITP patients initially compared to healthy controls (p value= 0.001) and (MFI) of CD11a on lymphocytes show significant difference between patients before and after treatment (p value=0.001). Conclusion CD11a had a possible role in the pathogenesis of ITP. Immune-modulatory therapy for ITP affects the level of CD11a expression on lymphocytes. CD11a expressions on lymphocytes were not correlated with the platelet counts nor the bleeding score in ITP.

Efficacy and Safety of Inebilizumab, an Anti-CD19 Monoclonal Antibody, for the Treatment of Neuromyelitis Optica Spectrum Disorder: Based on the N-MOmentum Trial

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathic disease of the central nervous system characterized by severe optic neuritis and transverse myelitis. The antibody against aquaporin 4 (AQP4), a water channel mainly expressed in astrocytes, is specific to NMOSD and may be detected in >70% of all cases. Inebilizumab is a humanized IgG1 monoclonal antibody against CD19. Anti-AQP4 antibodies are produced by CD19-positive plasmablasts, and inebilizumab administration significantly reduces the number of CD19-positive B cells and has therapeutic effects on NMOSD. The efficacy and safety of inebilizumab have been verified in the N-MOmentum trial, an international double-blind, placebo-controlled phase II/III study, in which Japanese patients also participated. Inebilizumab was approved for the treatment of NMOSD with AQP4-IgG in Japan in March 2021. In this review, we summarize the efficacy and safety of inebilizumab in the treatment of NMOSD and, focus on findings from the primary and additional analyses of the N-MOmentum trial. These results suggest that inebilizumab is effective and safe in preventing the recurrence of NMOSD in populations with different backgrounds and that long-term treatment with inebilizumab is beneficial.

A Phase 1b, Single-Arm, Open-Label Study of Budoprutug, an Anti-CD19 Monoclonal Antibody with Enhanced Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC), in Primary Membranous Nephropathy

A Phase 1b, Single-Arm, Open-Label Study of Budoprutug, an Anti-CD19 Monoclonal Antibody with Enhanced Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC), in Primary Membranous Nephropathy

Follow Up of Total B Cells (CD 19) Count after B Cell Depleting Therapy in Relapse Remitting Multiple Sclerosis Disorder in Egyptian Patients

Abstract Background Multiple Sclerosis (MS) is a chronic neurological disorder affecting central nervous system. It is classified as the most common neurological cause of disability in young adults. However the aetiology is not well understood, but most propably multifactorial involvement is the most convenient theory till now. It is characterized by inflammation, demyelinaion, axonal loss and degeneration. Ocrelizumab (ocrevus®) (OCR) was approved as treatment for relapsing and progressive patients in 2017. It is a humanized IgG1 monoclonal antibody anti CD20, a cell surface antigen found on pre-B cells, mature B cells and memory B cells. Aim of the Work To follow up total B cell count along the course of B cell depletion therapy in MS patients, correlating it with disease activity, in an attempt to investigate whether routine measurement of B cell counts may serve for dosage and time-to-infusion decision making in those patients. Subjects and Methods It was a prospective cohort study carried on 30 Egyptian patients diagnosed with Relapse remitting multiple sclerosis according to McDonald criteria 2017. They were recruited from Multiple sclerosis unit at Ain Shams University Hospitals, both genders were included and age older than 18 years old. Results This study showed that most of patients were females by 73.3%, but males were 26.7%. The mean age at onset of illness was 29.93 ± 5.55 years and the mean duration of illness was 6.9 ± 4.96. 70% of patients had ≤3 relapses in previous 2 years, while 86.7% had improvement in the annual relapse rate. Regarding history of DMT most patients (66.7%) had two, but only 13.3% were naïve. The mean count of CD19 B cells was cells/µl 65.98 ± 79.04 and significantly depleted to, 3.59 ± 2.94, 25.6 ± 43.98 and 11.11 ± 19.53 cells/µl after 1, 6 and 12 months respectively. this was associated with significant decline in the median (IQR) ARR from 20 (66.67%) to 0 (0%) after 12 months of ocrelizumab therapy and the median (IQR) EDSS from 4.5 (3.5 – 5.5) pretreatment to 3.5 (2.5 - 4.5) and 2.5(2.5-4.5) after 6 and 12 months respectively. Most patients showed either stationary cerebral and cord lesions (as regards number and size of the lesions) and also as regard gadolinium enhanced cerebral lesions, there was a statistically significant decrease in number of patients after 1 year as p-value was &amp;lt;0.05. In our study, the changes in the Multiple Sclerosis Functional Composite score (a composite measure of walking speed, upper-limb movements, and cognition) show statistically significant improvement in all parameters of assessment across three time points. As long as, the depletion of CD19 B cell counts was associated with marked clinical and radiological improvement. We found statistically significant correlation between CD19 B cell counts and EDSS. Furthermore, there was no statistically significant correlation with changes in the multiple sclerosis functional composite score (a composite measure of walking speed, upper-limb movements, and cognition) and MRI Disease activity. Conclusion Ocrelizumab was highly efficacious in reducing relapses, preventing disability progression and reducing activity either clinically as EDSS and functional composite score or radiologically in Egyptian MS patients. A fixed-dose schedule of 6-monthly infusion achieved a good relapse free rate. Repeated treatment with ocrelizumab in patients with MS leads to sustained CD19 B cells depletion.

B cells drive neuropathic pain-related behaviors in mice through IgG-Fc gamma receptor signaling.

Neuroimmune interactions are essential for the development of neuropathic pain, yet the contributions of distinct immune cell populations have not been fully unraveled. Here, we demonstrate the critical role of B cells in promoting mechanical hypersensitivity (allodynia) after peripheral nerve injury in male and female mice. Depletion of B cells with a single injection of anti-CD20 monoclonal antibody at the time of injury prevented the development of allodynia. B cell-deficient (muMT) mice were similarly spared from allodynia. Nerve injury was associated with increased immunoglobulin G (IgG) accumulation in ipsilateral lumbar dorsal root ganglia (DRGs) and dorsal spinal cords. IgG was colocalized with sensory neurons and macrophages in DRGs and microglia in spinal cords. IgG also accumulated in DRG samples from human donors with chronic pain, colocalizing with a marker for macrophages and satellite glia. RNA sequencing revealed a B cell population in naive mouse and human DRGs. A B cell transcriptional signature was enriched in DRGs from human donors with neuropathic pain. Passive transfer of IgG from injured mice induced allodynia in injured muMT recipient mice. The pronociceptive effects of IgG are likely mediated through immune complexes interacting with Fc gamma receptors (FcγRs) expressed by sensory neurons, microglia, and macrophages, given that both mechanical allodynia and hyperexcitability of dissociated DRG neurons were abolished in nerve-injured FcγR-deficient mice. Consistently, the pronociceptive effects of IgG passive transfer were lost in FcγR-deficient mice. These data reveal that a B cell-IgG-FcγR axis is required for the development of neuropathic pain in mice.