anti-CD20 Monoclonal Antibody Research Articles

Preclinical evaluation of 64Cu/177Lu-labelled anti-CD30 monoclonal antibody for theranostics in CD30-positive lymphoma.

CD30 serves as an ideal therapeutic target for lymphoma, but its variable expression and high relapse rate pose challenges in targeted therapy. This study aims to label the anti-CD30 monoclonal antibody with 64Cu/177Lu for immuno-positron emission tomography (immuno-PET) and radioimmunotherapy (RIT). CD30 binding kinetics of anti-CD30-IgG (IMB16) were measured by Biolayer interferometry (BLI). Western blotting screened lymphoma cell lines for CD30 expression. Flow cytometry and immunofluorescence validated the specific binding of IMB16. IMB16 was conjugated to p-SCN-Bn-NOTA(NOTA) and p-SCN-Bn-DOTA(DOTA) for radiolabeling with 64Cu and 177Lu. [64Cu]Cu-NOTA-IMB16 and [177Lu]Lu-DOTA-IMB16 were used for immuno-PET and RIT in subcutaneous lymphoma NSG mouse models. IMB16 had a strong binding affinity to CD30 according to the BLI. Western blotting revealed high CD30 expression in Karpas299 cells and negative expression in Raji cells. Flow cytometry and immunofluorescence confirmed specific binding of IMB16 to CD30 on cell surface. Radiochemical purity of [64Cu]Cu-NOTA-IMB16 and [177Lu]Lu-DOTA-IMB16 exceeded 95%. In Immuno-PET imaging, CD30-positive Karpas299 tumours had a mean uptake value of 19.2 ± 0.9%ID/g (n = 3) at 24h post-injection, significantly higher than Karpas299-blocked and Raji-negative groups (P < 0.001). A high radiation dose (300µCi) of [177Lu]Lu-DOTA-IMB16 significantly inhibited tumour growth (80.2 ± 17.6% standardized tumour volume, n = 5) at 10 days post-injection, compared to controls. Ex vivo biodistribution and histological staining supported in vivo PET imaging and RIT results. Labelling IMB16 with 64Cu enabled non-invasive assessment of CD30 expression, while 177Lu labelling effectively suppressed tumour growth in CD30-positive lymphoma. CD30-targeted theranostic show promise for patient stratification and treatment enhancement, warranting further clinical evaluation.

Obinutuzumab-induced acute thrombocytopenia: a case report and literature review

BackgroundObinutuzumab, a humanized type II anti-CD20 monoclonal antibody, is widely used in the treatment of B-cell lymphomas. Thrombocytopenia typically occurs 1 to 2 weeks after administration. In rare cases, obinutuzumab can induce severe acute thrombocytopenia within days of infusion, a condition known as “obinutuzumab-induced acute thrombocytopenia (OIAT).” Rituximab, a chimeric type I anti-CD20 monoclonal antibody, is also known to cause “rituximab-induced acute thrombocytopenia (RIAT).” This report presents a case of OIAT, with subsequent treatment switched to rituximab, which did not result in thrombocytopenia recurrence.Case PresentationA 38-year-old female patient with a 2-year history of lymphadenopathy was diagnosed with follicular lymphoma (Grade I-II). She was treated with obinutuzumab combined with bendamustine. Following the first administration of obinutuzumab, her platelet count dropped to 37×10⁹/L within 2 days and further declined to 27×10⁹/L on the fourth day without bleeding symptoms. The platelet count recovered by day 8. After a second obinutuzumab infusion, the platelet count again dropped to 15×10⁹/L within 1 day. Platelet transfusion was effective, and the count eventually recovered to 95×10⁹/L by day 29. No further acute thrombocytopenia occurred after switching to rituximab.ConclusionOIAT is a rare but serious adverse effect of obinutuzumab. This case highlights the importance of early recognition and monitoring of platelet counts in patients receiving obinutuzumab. The findings in our case, along with those in the literature, suggest that switching to rituximab or extending the interval before obinutuzumab re-administration can reduce the risk of recurrent thrombocytopenia. Further research is needed to elucidate the underlying mechanisms and establish treatment guidelines for OIAT.

Preventing Severe COVID-19 with Tixagevimab-Cilgavimab in Hematological Patients Treated with Anti-CD20 Monoclonal Antibodies: An International Multicenter Study.

Despite the declining public health emergency status, COVID-19 still poses significant risks, especially for immunocompromised individuals. We aimed to evaluate the effectiveness of tixagevimab-cilgavimab (T-C) prophylaxis in preventing severe COVID-19 in patients with hematologic malignancies (HM) treated with anti-CD20 therapy during the early Omicron variant phase of the pandemic. The European Society of Clinical Microbiology and Infectious Diseases Study Group for Respiratory Viruses (ESGREV) conducted a multicenter retrospective cohort study involving 15 centers from 5 countries. The study included 749 patients with HM treated with anti-CD20 between February 15 and June 30, 2022, comparing 215 who received T-C prophylaxis to 534 who did not. The study revealed a significant reduction in the risk of COVID-19 among patients who received T-C prophylaxis compared to those who did not (11.2% vs 23.4%, p < 0.001), with hazard ratio (HR) of 0.40 (95% CI 0.26-0.63), adjusted for age, sex, vaccination status, baseline HM malignancy and type of anti-CD-20. We also demonstrated a reduction for severe-critical diseases within all study populations, 1.4% vs 5.2%, p = 0.017, HR 0.26 (95% CI 0.08-0.84). T-C prophylaxis effectively prevented COVID-19 and severe-critical COVID-19 in patients with HM treated with anti-CD20 monoclonal antibodies during the early Omicron variant phase of the pandemic. Even though T-C is ineffective against current variants, these findings highlight the importance of additional protective measures and the continued development of monoclonal antibodies to protect immunocompromised individuals to mitigate the impact of COVID-19 and other respiratory viral diseases.

Daratumumab or Active Monitoring for High-Risk Smoldering Multiple Myeloma.

Daratumumab, an anti-CD38 monoclonal antibody, has been approved for the treatment of multiple myeloma. Data are needed regarding the use of daratumumab for high-risk smoldering multiple myeloma, a precursor disease of active multiple myeloma for which no treatments have been approved. In this phase 3 trial, we randomly assigned patients with high-risk smoldering multiple myeloma to receive either subcutaneous daratumumab monotherapy or active monitoring. Treatment was continued for 39 cycles, for 36 months, or until confirmation of disease progression, whichever occurred first. The primary end point was progression-free survival; progression to active multiple myeloma was assessed by an independent review committee in accordance with International Myeloma Working Group diagnostic criteria. Among the 390 enrolled patients, 194 were assigned to the daratumumab group and 196 to the active-monitoring group. With a median follow-up of 65.2 months, the risk of disease progression or death was 51% lower with daratumumab than with active monitoring (hazard ratio, 0.49; 95% confidence interval [CI], 0.36 to 0.67; P<0.001). Progression-free survival at 5 years was 63.1% with daratumumab and 40.8% with active monitoring. A total of 15 patients (7.7%) in the daratumumab group and 26 patients (13.3%) in the active-monitoring group died (hazard ratio, 0.52; 95% CI, 0.27 to 0.98). Overall survival at 5 years was 93.0% with daratumumab and 86.9% with active monitoring. The most common grade 3 or 4 adverse event was hypertension, which occurred in 5.7% and 4.6% of the patients in the daratumumab group and the active-monitoring group, respectively. Adverse events led to treatment discontinuation in 5.7% of the patients in the daratumumab group, and no new safety concerns were identified. Among patients with high-risk smoldering multiple myeloma, subcutaneous daratumumab monotherapy was associated with a significantly lower risk of progression to active multiple myeloma or death and with higher overall survival than active monitoring. No unexpected safety concerns were identified. (Funded by Janssen Research and Development; AQUILA ClinicalTrials.gov number, NCT03301220.).

Anti-CD19 antibody cotreatment enhances serial killing activity of anti-CD19 CAR-T/-NK cells and reduces trogocytosis.

Anti-CD19 chimeric antigen receptor (CAR)-engineered T and NK cell therapies have revolutionized the treatment of B cell malignancies, but challenges including CD19 antigen loss greatly hinder their full therapeutic potential. Here we demonstrated that co-treatment with anti-CD19 monoclonal antibody enhances antitumor activity of anti-CD19 CAR-T and -NK cells. Even though the treated antibody interferes with CD19 antigen binding of CAR, it significantly induces rapid detachment of anti-CD19 CAR effector cells from target cells, facilitating improved serial killing. This reduced interaction between CAR effector cells and target cells also leads to the alleviation of CAR-mediated trogocytosis. Interestingly, co-treatment with anti-CD19 antibody reveals time-dependent effects on the antitumor activity of anti-CD19 CAR-T cells, characterized by a reduction in early T cell activation followed by sustained high activity during prolonged exposure to target cells. This temporal modulation ultimately results in enhanced antitumor potency in vivo. These findings underscore the improved therapeutic efficacy achieved by combining anti-CD19 antibody with anti-CD19 CAR-T or -NK cells against B cell malignancies.

Comparative efficacy and tolerability of ublituximab vs. other monoclonal antibodies in the treatment of relapsing multiple sclerosis: a systematic review and network meta-analysis of randomized trials

BackgroundRelapsing multiple sclerosis (RMS) is a chronic, inflammatory disease of the central nervous system. Ublituximab, an anti-CD20 monoclonal antibody (mAb), is indicated for the treatment of RMS. We performed a systematic literature review (SLR) to identify randomized trials reporting the clinical efficacy and tolerability of ublituximab or comparator disease-modifying therapies (DMTs) for treatment of RMS, and assessed their comparative effects using network meta-analysis (NMA).MethodsThe SLR involved a comprehensive search across various medical databases to identify relevant studies. Included studies were randomized controlled trials (RCTs) of an adult RMS population, focusing on treatment with at least one of ublituximab, alemtuzumab, natalizumab, ocrelizumab, or ofatumumab. For outcomes included in the NMA (annualized relapse rate (ARR), confirmed disability progression (CDP), and treatment discontinuation rate), rate ratios (RR) or hazard ratios (HR), along with their 95% confidence intervals (CIs), were calculated. We performed NMA using a contrast-based random-effects model within a frequentist framework for all outcomes. Ranking probabilities among comparators, and intervention rankings for the NMA, were estimated using surface under the cumulative ranking curve (SUCRA).ResultsWe included 15 RCTs in the review. For the ARR outcome, there was no statistically significant difference between ublituximab and the other included mAbs [ofatumumab (RR 1.02 (95% CI 0.64–1.62)), natalizumab (RR 0.99 (0.59–1.65)), alemtuzumab (RR 0.86 (0.51–1.46)), and ocrelizumab (RR 0.75 (0.44–1.28))]. For CDP at 6 months, our results showed no statistically significant difference between ublituximab and the comparator mAbs [ofatumumab (HR 0.97 (0.49–1.92)), natalizumab (HR 1.13 (0.53–2.40)), alemtuzumab (HR 1.25 (0.56–2.81)), and ocrelizumab (HR 1.29 (0.57–2.90))]. For CDP at 3 and 6 months, there was no statistically significant difference between ublituximab and placebo. The all-cause treatment discontinuation rate analysis showed no significant difference between ublituximab and other mAbs, except for alemtuzumab.ConclusionsResults of this SLR-informed NMA showed that there is no statistically significant difference between ublituximab and the other mAbs in terms of clinical efficacy. Additionally, the findings show that there is no statistically significant difference in discontinuation rates with the exception of the comparison with alemtuzumab, which may be attributed to its unique dosing schedule.

Elotuzumab in combination with pomalidomide, bortezomib, and dexamethasone in relapsed and refractory multiple myeloma.

Elotuzumab is an approved monoclonal antibody targeting SLAMF7 on plasma and NK cells that enhances the activity of lenalidomide, pomalidomide, and bortezomib in multiple myeloma (MM). The OPTIMISMM study showed improved outcomes with the combination of pomalidomide, bortezomib, and dexamethasone (PVd) in relapsed/refractory MM. We therefore studied adding elotuzumab to PVd (elo-PVd) in relapsed/refractory MM in a multicenter phase 2 trial. The primary objective was to determine the overall response rate (ORR). Patients with relapsed/refractory disease and ≥1 prior line of treatment (including lenalidomide and a proteasome inhibitor) were eligible. For each 28 day cycle, elotuzumab was weekly for the first 2 cycles and then every other week; pomalidomide was on days 1-21; bortezomib was on days 1, 8, 15; and dexamethasone was weekly. The trial completed accrual in September 2018 with 48 patients receiving treatment. The median age was 64 (range 40-80) and the median number of prior lines was 3 (range 1-9); 25% had high risk FISH. Prior therapies included: pomalidomide (33%), daratumumab (25%), and isatuximab (4%). Best ORR was 56.3% and median PFS was 10 months. In patients with 1 prior line of therapy, ORR was 73.7% and median PFS was 23.4 months. Common grade ≥3 adverse events were neutropenia (33%); infections, any (33%); lung infection (27%); hypophosphatemia (19%); and thrombocytopenia (15%). Elo-PVd is one of the first trials of a quadruplet regimen in relapsed/refractory MM incorporating a monoclonal antibody to show efficacy across diverse prior treatments, including triple class exposed with prior anti-CD38 monoclonal antibody.

Real-world treatment patterns and clinical outcomes in patients with multiple myeloma previously treated with lenalidomide and an anti-CD38 monoclonal antibody

Real-world treatment patterns and clinical outcomes in patients with multiple myeloma previously treated with lenalidomide and an anti-CD38 monoclonal antibody

Early Rituximab versus Escalating Therapy in Neuromyelitis Optica: A Cost and Quality of Life Analysis

Introduction: Rituximab, an anti-CD20 monoclonal antibody, has shown effectiveness in reducing disease relapses and disability accrual through relapses in patients with neuromyelitis optica spectrum disorders (NMOSD). However, its higher cost compared to oral immunosuppressants raises questions about its cost-effectiveness, particularly in low and middle-income countries. This study aimed to compare the cost-effectiveness of early rituximab treatment versus escalation treatment in NMOSD patients. Methods: We conducted a retrospective study of NMOSD patients treated with rituximab in the first five years of disease at a hospital in São Paulo, Brazil, from 2015 to 2019. The Early Group consisted of NMOSD patients who received rituximab as a first-line treatment. The Escalating Therapy Group included patients who were prescribed rituximab after experiencing disease activity while on oral immunosuppressants, primarily azathioprine. An economic model based on Expanded Disability Status Score (EDSS) transitions was used to assess cost-effectiveness. Cost and utility data were derived from previous studies, and sensitivity analyses for different willingness to pay (WTP) thresholds and percentage of patients upscaling from oral immunossupressants to rituximab were performed. Results: Thirty NMOSD patients were included. In the Early Group, the proportion of patients reaching the highest EDSS states (6.5 or more) decreased over five years compared to baseline. In contrast, the Escalating Therapy Group experienced an increase in this proportion over the same period. Cost-effectiveness was achieved for willingness to pay (WTP) of €20-80,000 in our main analysis, sustained in our sensitivity analysis. Conclusion: Early treatment with rituximab has the potential to lower healthcare costs and enhance quality of life for NMOSD patients, supporting its early prescription for preventive treatment.

Convalescent plasma in patients receiving Rituximab or Ocrelizumab for Multiple Sclerosis or Neuromyelitis Optica Spectrum Disorder with COVID-19: A Multicenter Retrospective Study

BackgroundDespite vaccination, patients receiving anti-CD20 monoclonal antibodies (mAbs) for multiple sclerosis (MS) or neuromyelitis optica spectrum disorders (NMOSD) have an increased risk of developing severe or protracted COVID-19. The aim of this study was to describe the effect of COVID-19 convalescent plasma (CCP) in patients with MS or NMOSD exposed to anti-CD20 and infected by SARS-CoV-2. MethodsThis French national, retrospective cohort study was conducted between November 2020 and June 2023. Patients with MS or NMOSD, under anti-CD20 mAbs, with symptomatic COVID-19 and treated by CCP were screened. Protracted COVID-19 was defined by a duration of symptoms > 21 days. The primary endpoint was the overall survival 30 days after CCP administration. ResultsNinety-two patients from 34 hospitals were included, 84 (91%) with MS and 8 (9%) with NMOSD. Overall, 30-day survival was 97% (IC95%: 91-99). SARS-CoV-2 viremia was positive in 47/75 (61%) patients before CCP versus 9/59 (15%) seven days post-CCP. In the 52 patients (57%) with protracted COVID-19, the duration of symptoms before CCP was 51 [28-69] days, including fever in 75% of cases, which disappeared in 100% of patients seven days post-CCP. ConclusionsCCP could be a therapeutic option in patients exposed to anti-CD20 mAbs for inflammatory demyelinating disease, particularly in those with protracted COVID-19.

A Phase 1/2 study of teclistamab, a humanized BCMA × CD3 bispecific Ab in Japanese patients with relapsed/refractory MM.

We characterized the safety and efficacy of the bispecific antibody teclistamab in Japanese patients with relapsed/refractory multiple myeloma (RRMM). Patients were pretreated with a proteasome inhibitor (PI), immunomodulatory drug (IMiD), and anti-CD38 monoclonal antibody (mAb). The primary endpoint was frequency and type of treatment-emergent adverse events (TEAEs) in phase 1, and overall response rate (ORR; ≥ partial response [PR]) in phase 2. In phase 1, 14 patients received once-weekly (QW) subcutaneous teclistamab (0.72mg/kg [n = 5]; 1.5mg/kg [n = 5]; 3mg/kg [n = 4]). No dose-limiting toxicities were observed. As of April 2024, 26 phase-2 patients received the recommended phase-2 dose (QW) (RP2D: 1.5mg/kg) of teclistamab. Biweekly (Q2W) dosing was allowed after maintaining response for ≥ 6months. At a median follow-up of 14.32months, ORR was 76.9% (≥ very good PR: 76.9%; ≥ complete response: 65.4%). Median duration of response, progression-free survival, and overall survival were not reached. Common TEAEs included CRS (grade ≤ 2), neutropenia, and infections. No patient had immune effector cell-associated neurotoxicity syndrome (ICANS) and dose reductions. Teclistamab demonstrated deep and durable responses in Japanese patients with RRMM, consistent with the global pivotal MajesTEC-1 study, supporting the potential for a new standard of care for Japanese RRMM patients.

The evolving frontline management of CLL: are triplets better than doublets? How will we find out?

Frontline therapy for chronic lymphocytic leukemia (CLL) has substantially advanced in the previous decade. While monotherapy with a Bruton's tyrosine kinase (BTK) inhibitor is an excellent option for many patients, combination therapies are of high clinical interest as they can induce deep responses and durable remissions, and in many cases allow discontinuation of therapy. There are several doublet therapies that are currently in clinical use. These include combinations of BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) or BCL2 inhibitors (venetoclax) with anti-CD20 monoclonal antibodies, and combinations of BTK and BCL2 inhibitors. While BTK inhibitors with anti-CD20 monoclonal antibodies still typically require indefinite therapy, combinations involving the BCL2 inhibitor venetoclax have allowed for successful therapy discontinuation. Triplets, which combine all 3 of these paradigms, are of interest especially for patients with higher-risk disease. While triplets have been mainly studied in single-arm trials with excellent outcomes, comparative data to doublets are limited. In this article, we outline the doublet and triplet regimens that have been evaluated in CLL as well as the data from trials comparing doublets and triplets.

Catastrophic antiphospholipid syndrome: a CAPS-tivating hematologic disease.

Catastrophic antiphospholipid syndrome (CAPS) is a rare but life-threatening form of antiphospholipid syndrome (APS) defined by the rapid onset of large and small vessel thrombosis occurring simultaneously across multiple sites, resulting in multiorgan dysfunction. The presence of underlying immune dysfunction causing activation of coagulation and, in many cases, abnormal complement regulation predisposes these patients to thrombotic events. CAPS is often preceded by triggering factors such as infection, surgery, trauma, anticoagulation discontinuation, and malignancy. Given the high mortality rate, which may exceed 50%, prompt recognition and initiation of management is required. The detection of antiphospholipid antibodies and the histopathologic identification of microvascular ischemia via tissue biopsy are required to diagnose CAPS. However, these patients are often too unwell to obtain results and wait for them. As such, investigations should not delay CAPS therapy, especially if there is strong clinical suspicion. Management of CAPS requires "triple therapy" with glucocorticoids, intravenous heparin, therapeutic plasma exchange, and/or intravenous immunoglobulin. Treatment for refractory disease is based on poor-quality evidence but includes anti-CD20 (rituximab) or anticomplement (eculizumab) monoclonal antibodies and other immunosuppressant agents, either alone or in combination. The rarity of this syndrome and the subsequent lack of randomized clinical trials have led to a paucity of high-quality evidence to guide management. Continued international collaboration to expand ongoing CAPS registries will allow a better understanding of the response to newer targeted therapy.

Transplant in myeloma: who, when, and why?

High-dose melphalan supported by autologous transplantation has been the standard of care for eligible patients with newly diagnosed multiple myeloma for nearly 30 years. Several randomized clinical trials have reaffirmed the strong position of transplant in the era of triplets combining proteasome inhibitors, immunomodulatory drugs, and dexamethasone. Although quadruplets are becoming the standard in transplantation programs, no data are currently available on the need for a transplant with new regimens incorporating anti-CD38 monoclonal antibodies. Outcomes remain heterogeneous, with different response depths and durations depending on the cytogenetics at diagnosis. The improvement of disease prognostication using sensitive and specific tools allows for adapting the strategy to initial and dynamic risks. This review examines which patients need a transplant, when transplantation is preferable, and why.

CD38 modulates cytokine secretion by NK cells through the Sirt1/NF-κB pathway, suppressing immune surveillance in colorectal cancer.

Tregs and M2-type macrophages are essential for immune surveillance. CD38 + NK cells are involved in immunoregulation by modulating cytokine secretion. This study investigated how CD38 + NKs affect Tregs and macrophages in colorectal cancer (CRC). Higher proportions of CD38 + NKs and Tregs were detected in bloods and tumor tissues of CRC patients than that in the samples from healthy controls (HCs). Compared with CD38 + NKs from HCs, the NK cells from CRC promoted the differentiation of Tregs from CD4 + T cells, and secreted increased levels of IL-10, TGF-β and TNF-α and decreased levels of IFN-γ. CD38 + NKs from CRC expressed higher levels of CD38, NF-κB and acetyl-NF-κB and lower levels of Sirt1. When CRC CD38 + NK cells were treated with anti-CD38 monoclonal antibody, the above trends were reversed. CRC CD38 + NKs with treatment of NF-κB inhibitor also showed opposite effects on cytokine secretion and CD4 + T-cell differentiation. After treatment with a Sirt1 activator, NF-κB signaling was inhibited in these CD38 + NKs, whereas treatment with a Sirt1 inhibitor activated NF-κB signaling. The supernatants of CRC CD38 + NK culture promoted M0 macrophage polarization to M2-type. We suggest that CD38 modulates cytokine secretion by NK cells through Sirt1/NF-κB signaling pathway, thereby suppressing immune surveillance in tumorigenesis.

Efficacy of Anti-CD38 Monoclonal Antibodies for Relapsed or Refractory Multiple Myeloma in Stem Cell Transplant-Ineligible Patients Aged over 65 Years: A Propensity Score-Matched Study.

The development of newer agents, including anti-CD38 monoclonal antibodies (mAbs), has significantly improved overall survival (OS) in patients with relapsed or refractory multiple myeloma (RRMM). However, the treatment of older patients with RRMM who are transplant-ineligible remains challenging. We retrospectively evaluated OS in 78 transplant-ineligible patients with RRMM who were aged ≥ 65 years and treated at our institution between February 2012 and November 2023. Unadjusted OS was significantly longer in the anti-CD38 mAb-exposed group (i.e., those previously treated with daratumumab and receiving isatuximab plus pomalidomide and low-dose dexamethasone because of disease progression during treatment with daratumumab [n = 6], daratumumab plus pomalidomide and low-dose dexamethasone [n = 9], or isatuximab plus pomalidomide and low-dose dexamethasone without daratumumab-exposure [n = 14]) than in the anti-CD38 mAb-naïve group (no exposure to daratumumab or isatuximab [n = 49]) (p < 0.001). To address potential confounder factors associated with use or nonuse of anti-CD38 mAbs, we performed propensity score matching (PSM) using age, sex, performance status, and Geriatric 8 and Instrumental Activities of Daily Living scores. PSM identified 14 subjects from the anti-CD38 mAb-exposed group with baseline characteristics similar to those of 14 subjects from the anti-CD38 mAb-naïve group. After PSM, the adjusted OS was significantly longer in the anti-CD38 mAb-exposed group than in the anti-CD38 mAb-naïve group (p < 0.001). These findings provide insights into the optimal use of anti-CD38 mAbs in patients with RRMM who are transplant-ineligible and aged ≥65 years and on candidates who are appropriate for novel approaches, such as chimeric antigen receptor T-cell or bispecific T-cell engager therapy.

Enhanced Prenatal and Postnatal Development Study in Marmoset Monkeys Following Administration of Felzartamab.

Felzartamab is a recombinant fully human immunoglobulin G1 anti-CD38 monoclonal antibody under clinical investigation for immune-mediated diseases. In support of felzartamab clinical development, toxicology studies were conducted in marmoset monkeys, which was the most relevant species based on CD38 binding affinity, pharmacologic activity, and target expression. The felzartamab toxicology program included an enhanced prenatal and postnatal development (ePPND) study to identify potential reproductive and postnatal development risks. In this ePPND study, pregnant marmoset monkeys were randomized to receive vehicle (0mg/kg) or felzartamab at two dose levels (15mg/kg and 75mg/kg) twice per week until parturition, and maternal animals and infants were evaluated for 6 months thereafter. Felzartamab exposure was confirmed in maternal animals and infants in both dosing groups. Overall, felzartamab was well tolerated by pregnant animals at the evaluated doses, with no effect on body weight or body weight gain during pregnancy. No felzartamab-related effects on pregnancy loss or stillbirth rate were observed, and litter counts and numbers of liveborn infants were similar between the vehicle and felzartamab groups. Among infants, there were no felzartamab-related malformations or variations in external anatomy or skeletal morphology and no felzartamab-related observations in histopathology, hematologic and immune cell development, or humoral immune response to vaccination. In conclusion, among pregnant marmoset monkeys dosed with felzartamab, the lack of reproductive toxicity and felzartamab-related effects on offspring supports the clinical evaluation of felzartamab in women of childbearing potential and further demonstrates the suitability of the marmoset monkey for ePPND studies.

Elranatamab (Elrexfio)

Reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class. The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada’s federal, provincial, and territorial governments, with the exception of Quebec. This review assesses elranatamab (Elrexfio), 40 mg/mL, solution for subcutaneous injection supplied as 76 mg/1.9 mL (40 mg/mL) in a single-dose vial and 44 mg/1.1 mL (40 mg/mL) in a single-dose vial. Indication: For the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 3 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody, and who have demonstrated disease progression on the last therapy.

The essential roles of memory B cells in the pathogenesis of systemic lupus erythematosus.

Emerging evidence indicates that memory B cells are dysfunctional in systemic lupus erythematosus (SLE). They are hyporesponsive to signalling through the B cell receptor (BCR) but retain responsiveness to Toll-like receptor (TLR) and type I interferon signalling, as well as to T cell-mediated activation via CD40-CD154. Chronic exposure to immune complexes of ribonucleoprotein (RNP)-specific autoantibodies and TLR-engaging or BCR-engaging cargo is likely to contribute to this partially anergic phenotype. TLR7 or TLR8 signalling and the resulting production of type I interferon, as well as the sustained activation by bystander T cells, fuel a positive feedforward loop in memory B cells that can evade negative selection and permit preferential expansion of anti-RNP autoantibodies. Clinical trials of autologous stem cell transplantation or of B cell-targeted monoclonal antibodies and chimeric antigen receptor (CAR) T cells have correlated replenishment of the memory B cell population with relapse of SLE. Moreover, the BCR hyporesponsiveness of memory B cells might explain the failure of non-depleting B cell-targeting approaches in SLE, including BTK inhibitors and anti-CD22 monoclonal antibodies. Thus, targeting of dysfunctional memory B cells might prove effective in SLE, while also avoiding the adverse events of broad-spectrum targeting of B celland plasma cell subsets that are not directly involved in disease pathogenesis.

Efficacy and Safety of Daratumumab in Light Chain Amyloidosis: A Single-Center Retrospective Study

Purpose Light chain amyloidosis (AL) is a disease marked by the misfolding of immunoglobulin light chains, leading to amyloid deposits in various tissues and organs. The prognosis is particularly poor for patients with significant organ involvement. Daratumumab, an anti-CD38 monoclonal antibody, has shown promising results with an overall response rate (ORR) exceeding 80% in various studies. This retrospective study aims to evaluate the efficacy and safety of Daratumumab in treating AL amyloidosis, providing additional clinical insights. Methods The study included newly diagnosed or relapsed/refractory AL patients treated at Tongji Hospital, Huazhong University of Science and Technology, between May 2021 and May 2024. Patients received at least three courses of Daratumumab, administered in various regimens: Daratumumab with lenalidomide and dexamethasone (DRD group), bortezomib and dexamethasone (DVD group), pomalidomide and dexamethasone (DPD group), selinexol and dexamethasone (SDD group), isazomib and dexamethasone (DID group), dexamethasone alone (DD group), and carfizomib and dexamethasone (DKD group). Efficacy was measured through hematological remission and organ response. Results The study cohort consisted of 41 patients, with 31 initially diagnosed and 10 relapsed/refractory. The median age was 59 years (range: 38-75). Of these patients, 56.1% were classified as Mayo stage III-IV, with 76% having cardiac involvement, 52% with renal involvement, and 13 with dual cardiac and renal involvement. Median NT-proBNP was 2375 ng/L, median 24-hour urine protein was 0.683 g, median estimated glomerular filtration rate (eGFR) was 71.1 mL/min/1.73 m², and median difference free light chain (dFLC) was 132.05 mg/L. The DRD group showed 72.2% achieving very good partial response (VGPR) or better at 12 months, while 60% in the DVD group reached similar outcomes. Overall, the ORR at one month was 53.6% (22/41), including 4 complete remissions (CR), 14 VGPR, and 4 partial remissions (PR). At six months, the ORR increased to 72.9% (27/37), with 10 CRs, 13 VGPRs, and 4 PRs, reaching 90.9% (10/11) at 12 months, comprising 8 CR, 1 VGPR, and 1 PR. Cardiac response rates improved from 48.3% at three months to 78% at six months and 85% at 12 months. Among those with renal involvement, 52.3% demonstrated an organ response at 12 months. These findings indicate that Daratumumab not only significantly improves hematological outcomes but also promotes recovery of organ function. Conclusion This retrospective study confirms that Daratumumab is an effective and safe treatment option for AL amyloidosis, delivering rapid and sustained hematologic and organ responses. Most adverse events were mild and manageable, affirming the treatment's safety profile. However, the retrospective design and small sample size may limit the study's applicability. Larger, randomized controlled trials are necessary to validate these findings and further optimize the use of Daratumumab in clinical practice for AL amyloidosis.