Enhancement of complement-dependent cytotoxicity by linking factor-H derived short consensus repeats 19-20 to CD20 antibodies.

Antibody-mediated complement-dependent cytotoxicity (CDC) on malignant cells is regulated by several complement control proteins, including the inhibitory complement factor H (fH). fH consists of 20 short consensus repeat elements (SCRs) with specific functional domains. Previous research revealed that the fH-derived SCRs 19-20 (SCR1920) can displace full-length fH on the surface of chronic lymphocytic leukemia (CLL) cells, which sensitizes CLL cells for e.g. CD20-targeting therapeutic monoclonal antibody (mAb) induced CDC. Therefore, we constructed lentiviral vectors for the generation of cell lines that stably produce mAb-SCR-fusion variants starting from the clinically approved parental mAbs rituximab, obinutuzumab and ofatumumab, respectively. Flow-cytometry revealed that the modification of the mAbs by the SCRs does not impair the binding to CD20. Increased in vitro lysis potency compared to their parental mAbs was corroborated by showing specific and dose dependent target cell elimination by CDC when compared to their parental mAbs. Lysis of CLL cells was not affected by the depletion of NK cells, suggesting that antibody-dependent cellular cytotoxicity plays a minor role in this context. Overall, this study emphasizes the crucial role of CDC in the elimination of CLL cells by mAbs and introduces a novel approach for enhancing CDC by directly fusing fH SCR1920 with mAbs.

[Optimal patient profile for ofatumumab treatment: analysis of Russian data from the Phase 3 study]. / Optimal'nyi profil' patsienta dlya lecheniya ofatumumabom: analiz rossiiskikh dannykh iz issledovaniya 3-i fazy.

The article provides an analysis of the features of the action of ofatumumab in subgroups of patients with multiple sclerosis (MS) who participated in phase 3 ASCLEPIOS I and II studies both in the general subgroup of 1882 patients and among 352 patients from the Russian Federation who participated in these studies. The results of the influence of age, gender, body weight of patients, as well as the basic level of disability on the EDSS scale, the presence of active foci on MRI and previously received therapy with drugs that alter the course of MS (PITRS) are presented. In a total group of 1.882 patients, a more positive effect of ofatumumab compared with teriflunomide was noted on the average annual incidence of exacerbations in men, younger people and with a mild baseline disability level - with a baseline EDSS level less than or equal to 3. In a subgroup of 352 patients from Russia, the same trends were noted, but dependencies were also revealed from the number of previously taken PITRS: a more significant difference was noted in patients with the lowest number of PITRS in the anamnesis. This feature was also confirmed by analyzing the secondary endpoints of the study: the number of active foci on MRI and the confirmed progression of disability according to the EDSS scale. Analysis in clinical subgroups makes it possible to clarify the profile of patients in whom the greatest clinical effect can be expected when using this new drug for the treatment of MS.

Successful treatment of relapsed and refractory CIDP with ofatumumab: a first case report.

Background: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a heterogeneous but treatable immune-mediated neuropathy. Ofatumumab (OFA) is a fully human anti-CD20 monoclonal antibody that has shown promising efficacy in central demyelinating diseases, such as multiple sclerosis (MS). However, there is a lack of studies on the usage of OFA in peripheral demyelinating diseases, particularly CIDP. A case of relapsed and refractory CIDP with an ineffective response to conventional immunotherapy and intolerance to rituximab (RTX) but a positive response to subcutaneous injections of OFA is presented. Case presentation: The patient, a 46-year-old man diagnosed with CIDP, received high-dose intravenous methylprednisolone, intravenous immunoglobulin (IVIG), and plasma exchange(PE) during the acute phase of the disease, and long-term oral administration of prednisone, azathioprine (AZA), and mycophenolate mofetil (MMF) during the remission phase. However, the patient suffered six relapses over a five-year period, and because of these, along with an ineffective response to conventional immunotherapy, and intolerance to RTX, subcutaneous injections of OFA were selected as a prophylactic treatment against relapses. After a total of six injections of OFA, CD19+B cells were substantially depleted. The patient has been followed for more than 23 months without relapse. Conclusions: This case demonstrates the effectiveness and good tolerability of OFA in the treatment of relapsed and refractory CIDP. Further studies are needed to investigate the efficacy and safety of OFA in patients with relapsed and refractory CIDP, especially in those who have shown an ineffective response to conventional immunotherapy and are intolerant to RTX.

Case report: Ofatumumab treatment in anti-DPPX autoimmune encephalitis.

Dipeptidyl peptidase-like protein 6 (DPPX) antibody encephalitis is a rare autoimmune encephalitis. Diagnosis and treatment of DPPX remain challenging, particularly in patients with refractory disease. Herein, we report the first case of anti-DPPX encephalitis treated with ofatumumab. The patient had a chronic insidious onset and predominantly presented with severe neuropsychiatric symptoms and the typical triad of symptoms (weight loss, central nervous system hyperexcitability, and cognitive dysfunction). Positive anti-DPPX antibodies in the serum (1:1,000) and cerebrospinal fluid (CSF) (1:100) were detected at the disease peak. The patient was unresponsive to four types of standard immunotherapies (intravenous globulin, plasma exchange, steroids, and tacrolimus), resulting in a treatment switch to ofatumumab. After five doses of injection and 12 months of follow-up, the patient improved well, with only a mild cognitive deficit.

Quality of life and tolerability of B-cell directed therapy of multiple sclerosis with ofatumumab in a patient-centered real-world observational study.

INTRODUCTION: Ofatumumab (Kesimpta®) is a subcutaneous CD20-targeting antibody approved in Germany in 2021 for the treatment of relapsing multiple sclerosis (RMS). After careful instruction, patients can administer the treatment themselves. We previously reported data of 101 patients (Klimas et al. in Nervenarzt 94:923-933, 2023). The objective of this longitudinal study is to explore the tolerability and acceptability of ofatumumab from a patient perspective over a follow up period of 6 months. METHODS: In this prospective observational real-world study, we report follow up data of 81 patients. We evaluated sociodemographic data, disease duration, duration and side effects of ofatumumab use, expanded disability status scale (EDSS), Beck Depression Inventory II (BDI-II), Short-Form 36 (SF-36), Fatigue Scale of Motor and Cognitive Functions (FSMC), and modified Multiple Sclerosis Functional Composite Test (MSFC). In addition, we asked for subjective treatment outcomes, such as impact on quality of life, walking distance, concentration, mood, medication adherence, fatigue and the subjective course of MS on a numerical rating scale (1 = very negative; 5 = very positive). Furthermore, treatment discontinuations were recorded. RESULTS: The average duration of ofatumumab treatment was 10 months. In comparison to previous published data of our cohort, patients reported a significant increase in headache (10% up to 26%, p = 0.004) and limb pain (5% up to 26%, p < 0.001) as persistent side effects after the injections. More patients reported a very positive effect (p < 0.0001) on quality of life. 4 confirmed relapses occurred but no EDSS worsening, and no treatment discontinuations were documented during the observation period. DISCUSSION: As previously described, our prospective study indicates that patients have a good tolerability of ofatumumab, precisely because of the mild and few side effects at the first administration. However, the longer the observation period, the more headaches and limb pain occurred after the injections. Despite this, patients' subjective quality of life improved. There were no discontinuations during the follow-up period, with the limitation of a high loss to follow-up.

Comparison of injective related reactions following ofatumumab and ocrelizumab in patients with multiple sclerosis: data from the European spontaneous reporting system.

Introduction: In 2021 ofatumumab, a recombinant human anti-CD20 monoclonal antibody (mAb) already authorized for the treatment of chronic lymphocytic leukemia, received the marketing approval for the treatment of relapsing forms of multiple sclerosis (MS). Differently from ocrelizumab, that is administered intravenously, ofatumumab if the first anti-CD20 mAb to be administered subcutaneously without a premedication. Methods and objectives: In this study we aimed to describe and compare the main characteristics of Individual Case Safety Reports (ICSRs) describing the occurrence of Injective Related Reactions (IRRs) following the treatment with ocrelizumab and ofatumumab reported in the Eudravigilance (EV) database during years 2021-2023. Results: A total of 860 ICSRs with either ofatumumab and ocrelizumab as suspected drug were retrieved from Eudravigilance, of which 51% associated with ofatumumab and 49% with ocrelizumab. The majority of patients who experienced IRRs following ocrelizumab belonged to the age group of 18-64 years (73%), while the age-group was mostly not specified (55%) in ICSRs reporting ofatumumab as suspected. The distribution of gender was almost similar in the two groups, with the majority of ICSRs related to female patients. "Pyrexia" was the Preferred Term (PT) most reported for ofatumumab, while "Infusion related reaction" were more frequently reported with ocrelizumab. Premedication drugs were reported in 148 ICSRs. Out of 89 ICSRs for which the Time to Event (TTE) was calculated, 74 reported IRRs that occurred the same day of the drug administration. Discussion: Based on the results of this study, although a risk of ofatumumab-induced IRRs cannot be excluded, it should be considered as manageable considering that the drug seems to be mostly associated with the occurrence of fever. Thus, it is important to continue to closely monitor the use of these in clinical practice to improve the knowledge on their long-term safety.

Ocrelizumab and ofatumumab comparison: an Italian real-world propensity score matched study.

BACKGROUND: The management of Multiple Sclerosis (MS) has undergone transformative evolution with the introduction of high-efficacy disease-modifying therapies (DMTs), specifically anti-CD20 monoclonal antibodies, such as ocrelizumab (OCR) and ofatumumab (OFA). MATERIALS AND METHODS: This is an independent retrospective cohort study in Relapsing MS (RMS) patients followed at eight Italian MS centers who initiated treatment with OCR or OFA in the participating centers and with at least 12 months on therapy. A generalized linear regression model inverse probability of treatment weight (IPTW) PS-adjusted was performed to evaluate the relationship between annualized relapse rate (ARR) and treatment groups. No evidence of disease activity-NEDA-3 at 12-month score was also collected. Safety profile of the investigated DMTs was recorded. RESULTS: A total cohort of 396 RMS patients fulfilled the required criteria and were enrolled in the study. Out of them, 216 had a prescription of OCR and 180 of OFA. The mean follow-up was 13.2 ± 1.9 months. The estimated means for ARR did not show differences between the two groups, 0.059 for patients on OCR and 0.038 for patients on OFA (p = 0.185). The generalized regression model IPTW PS-adjusted did not reveal differences between patients on OCR and OFA (ExpBOFA 0.974, 95%CI 934-1.015, p = 0.207). NEDA-3 at 12 months was experienced by 199(92.1%) patients on OCR and 170(94.4%) patients on OFA (p = 0.368). Generally, both therapies exhibit good tolerability. CONCLUSIONS: The treatment with OCR and OFA resulted in comparable control of disease activity with good safety profile. Our results need further validation in larger multicentre studies with long-term follow-up.

Case report: Identification of Hepatitis B Virus in the cerebrospinal fluid of neuromyelitis optica spectrum disorders and successful treatment with ofatumumab and inebilizumab.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare demyelinating disease of the central nervous system primarily affecting the optic nerves, spinal cord, and brainstem. Viral infection may trigger NMOSD. Here, we report the case of a 34-year-old female presenting with a range of symptoms including nausea, vomiting, dysphagia, choking, and fatigue with unsteady gait, diplopia, hearing loss, left-sided facial paralysis, breathing difficulties, and hoarseness of voice. Her HBV DNA concentration, as determined by quantitative PCR analysis, exceeded 5×107 IU/ml in serum and 4.48×102 IU/ml in CSF. Next-generation sequencing of CSF revealed 1,528 HBV sequences in DNA analysis and 6 sequences in RNA analysis. Serum aquaporin-4 antibody (AQP4-Ab) titer was 1:10, and the CSF titer was 1:3.2. Brain magnetic resonance imaging showed high signal intensities in the brain stem, medulla oblongata, and left middle cerebellar peduncle with mild restricted-diffusion. The patient received antiviral and hepatoprotective medications before the high-dose methylprednisolone pulse therapy. However, the patient did not respond well to the first-line treatment. Subsequently, the patient received ofatumumab and inebilizumab. Throughout the follow-up period, there was a gradual improvement in her neurological symptoms, with no reactivation of hepatitis B or deterioration of liver function observed. Thereby, to the best of our knowledge, we report the first case of successful treatment with ofatumumab and inebilizumab in a patient with NMOSD concurrent with HBV infection.

Successful switch to ofatumumab after liver injury associated with ocrelizumab treatment in multiple sclerosis: a case report.

Drug-induced liver injury (DILI) is a potential adverse event of disease-modifying therapies (DMTs) for the treatment of multiple sclerosis (MS), as well as of methylprednisolone pulsed therapy used in case of MS relapse. DILI may be induced by different mechanisms, including idiosyncratic reaction, autoimmune hepatitis or viral reactivation. In patients receiving the humanized anti-CD20 monoclonal antibody (mAb) ocrelizumab, DILI has been rarely reported and was mostly associated with hepatitis B virus (HBV) reactivation. Here we present the case of a woman with highly active relapsing-remitting MS who had experienced two episodes of DILI while receiving different DMTs, and was successfully switched to ofatumumab, a fully human anti-CD20 mAb, after a further event associated with ocrelizumab treatment and unrelated to HBV reactivation. Despite sharing the mechanism of action, differences in structure, pharmacokinetic/pharmacodynamic profile, and use of ancillary drugs (only needed for ocrelizumab) may have accounted for the successful switch. To our knowledge, this is the first report of a successful switch from ocrelizumab to ofatumumab due to DILI. Ofatumumab may therefore represent a valid therapeutic option for patients experiencing DMTs- and ocrelizumab-induced liver injury, providing that HBV reactivation has been ruled out.

Vaccine-derived yellow fever in an immunocompromised patient on anti-CD20-antibody therapy and its treatment with sofosbuvir.

Yellow fever (YF) is a potentially lethal viral hemorrhagic fever that can be prevented with the 17D live attenuated YF vaccine. However, this vaccination can cause severe adverse reactions including vaccine-associated YF. Here, we describe the case of a 32-year-old female who was permanently immunosuppressed with an anti-CD20 antibody due to multiple sclerosis. Following YF vaccination, the patient developed a variety of symptoms such as febrile temperatures, muscle and joint pain, headaches, and dysuria. A vaccine-associated YF with viremia was diagnosed. To avoid a potentially severe course of the disease, sofosbuvir was used as antiviral treatment followed by the resolution of symptoms and serological response. As travelers with chronic diseases and immunosuppression will increasingly engage in long distance travel, this case demonstrates the importance of assessing patient history prior to the administration of live vaccines and points towards a possible therapeutic approach in those suffering from vaccine-associated YF.

Long-term follow up of the combination of ofatumumab, high-dose methylprednisolone, and lenalidomide for untreated chronic lymphocytic leukemia with biomarker analysis.

BACKGROUND: Advancements in frontline therapy and chemotherapy-sparing treatments in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have altered the treatment algorithms of this disease. We present a frontline alternative for treatment- naïve (TN) CLL/SLL patients. METHODS: This was a single-center, phase 2 study of high-dose methylprednisolone (HDMP) and ofatumumab with lenalidomide and ofatumumab consolidative therapy for all comers with TN CLL/SLL. Treatment was continued until disease progression or intolerable side effects. Patients were assessed for response per iwCLL 2008 criteria after completing cycles 3 and 12. RESULTS: Forty-five patients were enrolled (median age, 62.6 years). High-risk features included del17p (18%), Del11q (22%), and unmutated IGHV gene (76%). Median treatment duration was 32·2 (2·7-75·9) months. Thirty-six patients discontinued treatment due to disease progression (22%), adverse events (40%), allogeneic hematopoietic cell transplantation (allo-HCT) (7%), consent withdrawal (4%), and secondary malignancies (7%). The best overall and complete response rates were 96& and 29% respectively. At median follow-up of 61·7 (5·6-84·9) months, 9 patients remained on treatment. Median progression-free survival was 54·4 (2·9-77·6) months. Three patients underwent allo-HCT after a median of 3 (3-4) treatment cycles. Treatment was well tolerated, with a grade 3/4 infusion reaction in one patient. The most common grade 3/4 hematological adverse event was neutropenia (69%). Four patients had grade 3/4 infections. No grade 3/4 tumor flares, tumor lysis syndrome, or thrombosis were observed. CONCLUSION: The combination of ofatumumab, HDMP, and lenalidomide was effective and relatively well tolerated in treatment-naive CLL/SLL. Its role in the frontline setting remains unclear given the current available and effective treatment options. FUNDING: The funders had no role in the study.

Neutralizing antibody titers over 12 months after SARS-CoV-2 mRNA vaccine booster in patients with relapsing multiple sclerosis continuously treated with ofatumumab.

Booster vaccinations against SARS-CoV-2 are recommended 6-12 months after the last dose or infection in elderly and high-risk groups. The present analysis aims to evaluate whether an interval shorter than 12 months is required in multiple sclerosis patients receiving ofatumumab. Neutralizing antibody status over 1 year in patients receiving booster vaccination in the non-interventional, multicenter KYRIOS study under continued ofatumumab treatment was analyzed. Fifteen patients were included. At the time of the first booster vaccination, ten patients were seropositive for neutralizing antibodies, four patients were seronegative, and for one patient, no baseline levels were available. All patients who were seropositive at baseline showed >2-fold increase in neutralizing antibody titers after the first booster and two patients (20%) showed a >10-fold increase. Among seronegative patients, three (75%) had a >10-fold increase in neutralizing antibody titers. Seropositivity was maintained in almost all patients until month 12. One initially seronegative patient had less than 2-fold increase in neutralizing antibody titers after the booster vaccination and can be considered a non-responder. Most patients with continued ofatumumab treatment are able to maintain permanent seropositivity and therefore presumably constant protection against severe courses of COVID-19 if repeated booster vaccinations are applied.

Normalized circulating Tfh and Th17 associates with improvement in myasthenia gravis treated with ofatumumab.

Objective: To assess the effect of B cell depletion therapy (BCDT) on circulating T follicular helper (cTfh) and circulating T helper 17 (cTh17) cells and its relation to clinical improvement in patients with myasthenia gravis (MG). Methods: 28 anti-AchR positive MG patients treated with ofatumumab and 28 healthy controls (HCs) were included. Frequencies of cTfh and cTh17 cells were monitored by flow cytometry at baseline and 4, and 12 weeks after the initial dose ofatumumab. Serum cytokines associated with cTfh and cTh17, including IL-6, IL-21, and IL-17, were also analyzed. Results: The frequency of cTfh and cTh17 significantly increased in MG patients compared with HCs. Additionally, elevated levels of both T-cell subsets correlated with MG severity. During the follow-up, cTfh and cTh17 return to normal after BCDT. Furthermore, the decrease in cTfh and cTh17 was associated with MG scores improvement over time. Notably, cTfh- and cTh17-related cytokines, including IL-6, IL-21, and IL-17, exhibited a marked decrease following ofatumumab therapy. Conclusions: Abnormal expansion of cTfh and cTh17 cells may be key features in the immunopathology of MG. Their levels returned to normal after BCDT, which was closely correlated with clinical amelioration. This result suggests that these two T-cell subsets may be targets for BCDT treatment of MG.

The Oncogenic Lipid Sphingosine-1-Phosphate Impedes the Phagocytosis of Tumor Cells by M1 Macrophages in Diffuse Large B Cell Lymphoma.

BACKGROUND: A total of 30-40% of diffuse large B cell lymphoma (DLBCL) patients will either not respond to the standard therapy or their disease will recur. The first-line treatment for DLBCL is rituximab and combination chemotherapy. This treatment involves the chemotherapy-induced recruitment of tumor-associated macrophages that recognize and kill rituximab-opsonized DLBCL cells. However, we lack insights into the factors responsible for the recruitment and functionality of macrophages in DLBCL tumors. METHODS: We have studied the effects of the immunomodulatory lipid sphingosine-1-phosphate (S1P) on macrophage activity in DLBCL, both in vitro and in animal models. RESULTS: We show that tumor-derived S1P mediates the chemoattraction of both monocytes and macrophages in vitro and in animal models, an effect that is dependent upon the S1P receptor S1PR1. However, S1P inhibited M1 macrophage-mediated phagocytosis of DLBCL tumor cells opsonized with the CD20 monoclonal antibodies rituximab and ofatumumab, an effect that could be reversed by an S1PR1 inhibitor. CONCLUSIONS: Our data show that S1P signaling can modulate macrophage recruitment and tumor cell killing by anti-CD20 monoclonal antibodies in DLBCL. The administration of S1PR1 inhibitors could enhance the phagocytosis of tumor cells and improve outcomes for patients.

Ofatumumab subcutaneous injection successfully treated patients with pemphigus vulgaris relapse post rituximab.

The therapeutic strategy for the treatment of pemphigus vulgaris (PV) still needs optimization because of the multiple deficiencies of glucocorticoid and rituximab. Ofatumumab, another CD20 monoclonal antibody administrated subcutaneously, provides a possible alternative option. In this study, three patients experienced PV relapse after clinical remission induced by rituximab. With written informed consent, they received an ofatumumab (20 mg) subcutaneous injection twice (2 weeks apart) in combination with a prednisone dose adjusted according to their weight and disease severity. Over the 24-week observation, two of three patients achieved lesion clear-up under prednisone (0.2 mg/kg per day), and the other patient's pemphigus disease area index dropped from 39 to 3 with prednisone (15 mg/day). The anti-desmoglein antibody levels and CD19+B cell counts declined compared to those at baseline. No severe adverse events were observed within the 24-week follow-up. In summary, we propose a protocol of ofatumumab for patients with refractory PV and report positive treatment outcomes of three patients who received this regimen.

Key characteristics of anti-CD20 monoclonal antibodies and clinical implications for multiple sclerosis treatment.

The recent success of anti-CD20 monoclonal antibody therapies in the treatment of multiple sclerosis (MS) has highlighted the role of B cells in the pathogenesis of MS. In people with MS, the inflammatory characteristics of B-cell activity are elevated, leading to increased pro-inflammatory cytokine release, diminished anti-inflammatory cytokine production and an accumulation of pathogenic B cells in the cerebrospinal fluid. Rituximab, ocrelizumab, ofatumumab, ublituximab and BCD-132 are anti-CD20 therapies that are either undergoing clinical development, or have been approved, for the treatment of MS. Despite CD20 being a common target for these therapies, differences have been reported in their mechanistic, pharmacological and clinical characteristics, which may have substantial clinical implications. This narrative review explores key characteristics of these therapies. By using clinical trial data and real-world evidence, we discuss their mechanisms of action, routes of administration, efficacy (in relation to B-cell kinetics), safety, tolerability and convenience of use. Clinicians, alongside patients and their families, should consider the aspects discussed in this review as part of shared decision-making discussions to improve outcomes and health-related quality of life for people living with MS.

Ofatumumab in Rituximab-Resistant and Rituximab-Intolerant Patients With Primary Membranous Nephropathy: A Case Series.

RATIONALE & OBJECTIVE: Rituximab is the first-choice therapy for patients with primary membranous nephropathy (MN) and nephrotic syndrome. However, approximately 30% of patients are treatment-resistant or become treatment-intolerant with hypersensitivity reactions upon repeated drug exposures. We aimed to assess whether ofatumumab, a fully human second-generation anti-CD20 antibody, could be a valuable alternative to rituximab in this population. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 7 rituximab-intolerant and 10 rituximab-resistant patients with MN who consented to receive ofatumumab (50-300mg, single intravenous infusion) and were followed at the nephrology unit of Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII (Bergamo, Italy) between September 2015 and January 2019. FINDINGS: Over a median (IQR) follow-up of 5.0 (3.0-9.8) months, all 7 rituximab-intolerant and 3 of the 10 rituximab-resistant patients exhibited complete (proteinuria<0.3g/d) or partial (proteinuria<3.5g/d with≥50% reduction vs baseline) remission of nephrotic syndrome. Circulating B cells were similarly depleted in all patients by 1 week, and serum anti-phospholipase A2 receptor antibody concentrations decreased to<2.7 relative units/mL in 3 of 4 rituximab-intolerant and 4 of 8 rituximab-resistant patients with phospholipase A2 receptor-related disease. Ofatumumab significantly reduced 24-hour urinary protein and immunoglobulin G excretion and increased serum albumin and immunoglobulin G levels. These effects were greater in rituximab-intolerant than in rituximab-resistant patients. Measured glomerular filtration rate significantly increased by an average of 13.4% at 24 months compared with baseline (P=0.036) among all patients in the series. There were 14 nonserious infusion-related adverse events in 9 patients that recovered with temporary infusion interruption. LIMITATIONS: Retrospective design, limited number of patients. CONCLUSIONS: Ofatumumab may represent an effective and safe treatment for rituximab-intolerant cases of MN. Larger prospective studies will be needed to validate these preliminary findings and explore the effectiveness of other second-generation anti-CD20 antibodies in this clinical setting. PLAIN-LANGUAGE SUMMARY: Primary membranous nephropathy (MN) is one of the most frequent causes of nephrotic syndrome (NS) in adults. In this case series, we explored the efficacy of ofatumumab, a fully human second-generation anti-CD20 antibody, in 17 patients with MN and NS who were intolerant or unresponsive to rituximab. All 7 rituximab-intolerant patients exhibited complete or partial clinical remission, compared with only 3 of the 10 rituximab-resistant patients. Autoantibody levels decreased in all patients with phospholipase A2 receptor-related disease. Ofatumumab achieved a significant reduction in urinary protein and immunoglobulin G excretion while increasing serum albumin and immunoglobulin G levels. Ofatumumab may be a promising option for patients with MN who are rituximab-intolerant. Further investigations are warranted to validate these preliminary findings.

Unleashing the power of anti-CD20 immunotherapy: Mitigating multiple sclerosis risk in Epstein-Barr virus latent infections.

Multiple sclerosis (MS) is a chronic inflammatory, demyelinating, and neurodegenerative connective tissue disease affecting the central nervous system (CNS). Recently, there has been a dramatic improvement in several vital concepts of immune pathophysiology underlying MS. Notably, one of the prerequisites to MS development is Epstein-Barr virus (EBV) infection. Greater attention has been drawn towards promising, innovative immunotherapies in the management and treatment of MS. Whilst there are numerous immunotherapies currently proposed for MS, the B cell depleting therapy that predominantly uses the anti-CD20 monoclonal antibodies (mAbs) such as rituximab, ocrelizumab, and ofatumumab have demonstrated promising clinical benefits by targeting the memory B cells, which are the primary reservoir of EBV latency. Although mAbs have proved beneficial in the treatment of MS, they pose the risk of potential adverse effects. The current systematic review was undertaken to explore the therapeutic role of anti-CD20 therapy and its downsides in the treatment of MS and EBV infection. Clinical trials and prospective and retrospective studies reporting anti-CD20 therapy were carefully reviewed. The initial sections discuss the clinical features of MS, the probable link between EBV and MS, and the role of B cells in MS pathogenesis. Here, we show the potential role of anti-CD20 therapy more of a boon than a bane as the therapy yields more promising results for MS treatment. Nevertheless, the adverse effects could be minimized following a planned therapeutic regimen for treating MS patients.

Therapeutic effect of ofatumumab in patients with myasthenia gravis: immunoregulation of follicular T helper cells and T helper type 17 cells.

Introduction: This study aimed to study the therapeutic effects of ofatumumab in patients with myasthenia gravis (MG) in addition to the immunomodulatory effects on peripheral follicular T helper (Tfh) cells and T helper type 17 (Th17) cells. Methods: Thirty-one patients with anti-acetylcholine receptor (AChR) antibody-positive MG were included in this study. At weeks 0, 1, 2, and 4, an initial dose of 20 mg of ofatumumab was injected subcutaneously, with a 2-month follow-up after completing this first cycle. At baseline, 1 month, and 3 months, we assessed the Quantitative MG (QMG), 15-item MG-Quality of Life (MG-QOL15), and MG-Activities of Daily Living (MG-ADL) scales and measured the frequencies of Tfh, Th17, and B cells and the levels of anti-AChR antibody, IL-6, IL-21, and IL-17 in the peripheral blood. Results: At 1 month and 3 months, the QMG, MG-QOL15, and MG-ADL scores were all significantly reduced. At 3 months, doses of prednisone were reduced by an average of 37%. Decreased frequencies of Tfh and Th17 cells, depletion of B cells, and reduced levels of IL-6, IL-21, and IL-17 were all observed at 1 month or 3 months. Discussion: Therefore, the therapeutic effect of ofatumumab could be detected after one cycle of treatment, which was maintained for 2 months. The immunomodulatory effect of ofatumumab during the observation period may involve depletion of B cells, reduction of Tfh and Th17 cells frequencies, and reduced levels of IL-6, IL-21, and IL-17. The findings provide novel data for the potential application of ofatumumab in MG.

Ofatumumab Desensitization Protocol: A Case of Refractory Immune Thrombocytopenic Purpura.

Chronic immune thrombocytopenic purpura (ITP) is an acquired hematologic condition that involves immune-mediated platelet destruction with resultant bleeding of variable severity. Refractory ITP occurs when patients fail to tolerate and/or respond to multiple treatment modalities. In this case, we examine the clinical course of a 39-year-old female with refractory ITP and discuss how we navigated a multitude of challenges by adapting an established desensitization protocol to meet our patient's needs. To our knowledge, we describe the first successful desensitization to ofatumumab for use in ITP in the current literature.