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Abstract Purpose To provide a comprehensive review of rituximab use for the treatment of non-infectious uveitis and scleritis. Methods Review of literature through December 2020. Results Individual data was available for 229 patients with refractory non-infectious uveitis (n = 108) or scleritis (n = 121) who received treatment with rituximab (RTX). Rituximab was generally utilized as third-line or later treatment (uveitis: 67/90, 74.4%; scleritis: 90/96, 93.8%) at a mean of 33.5 months following the diagnosis of uveitis (range = 0 to 168.0 months; median = 24.0 months) and 39.4 months after diagnosis of scleritis (range = 1.0 to 168.0 months; median = 21.0 months). Patients with non-infectious uveitis and scleritis either received prior treatment with corticosteroids only (uveitis: 18/90, 20%; scleritis: 4/94, 4.3%), or with one (uveitis: 19/90, 21.1%; scleritis: 30/94, 31.9%), two (uveitis: 11/90, 12.2%; scleritis 27/94, 28.7%), or three or more (uveitis: 37/90, 41.1%; scleritis: 31/94, 33.0%) corticosteroid-sparing immunosuppressive agents with or without corticosteroids before initiation of RTX treatment. The rheumatologic protocol (two infusions of 1 gram of RTX separated by 14 days) was utilized most frequently (uveitis: 45/87, 51.7%; scleritis: 87/114, 76.3%), followed by the Foster protocol (eight weekly infusions of 375 mg/m2 RTX; uveitis: 18/87, 20.7%; scleritis: 10/114, 8.8%), and the oncologic protocol (four weekly infusions of 375 mg/m2 RTX; uveitis: 5/87, 5.7%; scleritis: 6/114, 5.3%). Various other off-label regimens were used infrequently (uveitis: 19/87, 21.8%; scleritis 11/114, 9.6%). Rituximab treatments resulted in a positive therapeutic response for the majority of patients with non-infectious uveitis (81/97, 83.5%). Commonly treated uveitic diagnoses included non-paraneoplastic autoimmune retinopathy (30/107, 28.0%), juvenile idiopathic arthritis (21/107, 19.6%), Vogt-Koyanagi-Harada disease (12/107, 11.2%), and Behçet disease (11/107, 10.3%). Cases of non-infectious scleritis were most commonly attributed to granulomatosis with polyangiitis (75/121, 62.0%) and rheumatoid arthritis (15/121, 12.4%), and showed an even greater rate of positive therapeutic response (112/120, 93.3%) following RTX treatment. No side effects were reported in 76.3% (74/97) of uveitis and 85.5% (71/83) scleritis cases. Of those cases associated with RTX-induced adverse events, the most common were infusion reactions of various severity (11/35, 31.4%). Conclusions Overall, RTX appeared to be both effective and well-tolerated as second or third-line therapy for patients with non-infectious uveitis and scleritis.

Abstract Purpose To provide a comprehensive review of rituximab use for the treatment of non-infectious/non-malignant orbital inflammation. Methods Review of literature through January 2021. Results Individual data was available for 167 patients with refractory non-infectious/non-malignant orbital inflammation who received treatment with rituximab (RTX). Rituximab was generally utilized as third-line or later treatment (108/149, 72.5%) at a mean of 44.6 months following the diagnosis of orbital inflammation (range = 0 to 360 months; median = 13.7 months). Patients with non-infectious/non-malignant orbital inflammation either received prior treatment with corticosteroids only (27/122, 22.1%), or with one (31/122, 25.4%), two (25/122, 20.5%), or three or more (25/122, 20.5%) corticosteroid-sparing immunosuppressive agents with or without corticosteroids before initiation of RTX treatment. The rheumatologic protocol (two infusions of 1 gram of RTX separated by 14 days) was utilized most frequently (80/144, 55.6%), followed by the oncologic protocol (four weekly infusions of 375 mg/m2 RTX; 51/144, 35.4%). Various other off-label regimens were used infrequently (13/144, 9.0%). Rituximab treatments resulted in a positive therapeutic response for the majority of patients with orbital inflammation (146/166, 88.0%). Commonly treated diagnoses included granulomatosis with polyangiitis (99/167, 59.3%), IgG-4 related disease (36/167, 21.6%), and orbital inflammation of indeterminate cause (25/167, 15.0%). No side effects were reported in 83.3% (55/66) of cases. The most common RTX-induced adverse event was an infusion-related temporary exacerbation of orbital disease (4/66, 6.1%), which occurred prior to the routine use of systemic corticosteroids as pre-conditioning. Conclusions Overall, RTX appears to be both efficacious and well-tolerated as second- or third-line therapy for patients with non-infectious/non-malignant orbital inflammation.

To report long-term outcomes of systemic rituximab therapy for idiopathic orbital inflammation (IOI) as both primary and salvage therapy and to review the English literature. A retrospective review of four consecutive biopsy-proven IOI cases managed with systemic rituximab including demographics, management, and outcomes, and review of English literature, were performed. Primary outcome measures included resolution of symptoms, recurrence, and length of follow up. Of four cases, systemic rituximab was the first-line therapy in two cases and salvage therapy in two cases. The mean age of the patients was 62 years (range, 50–68 years). The orbit was involved in three cases and extraocular muscle in one case. Systemic rituximab (1 g weekly for 4 weeks) was given for one session in three patients and for 12 sessions in 1 patient. All four patients responded with the resolution of all symptoms without recurrence after at least 5 years of follow up. Review of the literature showed systemic rituximab had provided clinical improvement at shorter follow up in 14 of 15 cases when used as a salvage therapy. Systemic rituximab therapy seems to be an effective therapy for IOI as salvage or first-line therapy with long-term clinical durability. [ABSTRACT FROM AUTHOR]

The risk of developing severe COVID-19 illness despite completing vaccination for patients who have previously received immunosuppressive therapy is unclear. We present three patients who received rituximab for treatment of autoimmune disorders who subsequently developed severe COVID-19 pneumonia post-vaccination requiring intensive care unit admission and found to have undetectable B cells. While there have been concerns about the effectiveness of COVID-19 vaccines in this patient cohort, this is the first case series to report development of severe COVID-19 illness after completing vaccination in those who previously received rituximab. Guidelines for the optimal timing of COVID-19 vaccination in relation to immunosuppressive therapy have been recently published, albeit after many patients in this subpopulation have already been vaccinated. This case series brings attention to the limited humoral response to vaccines in patients treated with rituximab, highlights existing guidelines and their limitations, and raises future considerations about the potential benefits to testing vaccine responsiveness. [ABSTRACT FROM AUTHOR]

Purpose: To provide a comprehensive review of rituximab use for the treatment of non-infectious/non-malignant orbital inflammation. Methods: Review of literature through January 2021. Results: Individual data was available for 167 patients with refractory non-infectious/non-malignant orbital inflammation who received treatment with rituximab (RTX). Rituximab was generally utilized as third-line or later treatment (108/149, 72.5%) at a mean of 44.6 months following the diagnosis of orbital inflammation (range = 0 to 360 months; median = 13.7 months). Patients with non-infectious/non-malignant orbital inflammation either received prior treatment with corticosteroids only (27/122, 22.1%), or with one (31/122, 25.4%), two (25/122, 20.5%), or three or more (25/122, 20.5%) corticosteroid-sparing immunosuppressive agents with or without corticosteroids before initiation of RTX treatment. The rheumatologic protocol (two infusions of 1 gram of RTX separated by 14 days) was utilized most frequently (80/144, 55.6%), followed by the oncologic protocol (four weekly infusions of 375 mg/m2 RTX; 51/144, 35.4%). Various other off-label regimens were used infrequently (13/144, 9.0%). Rituximab treatments resulted in a positive therapeutic response for the majority of patients with orbital inflammation (146/166, 88.0%). Commonly treated diagnoses included granulomatosis with polyangiitis (99/167, 59.3%), IgG-4 related disease (36/167, 21.6%), and orbital inflammation of indeterminate cause (25/167, 15.0%). No side effects were reported in 83.3% (55/66) of cases. The most common RTX-induced adverse event was an infusion-related temporary exacerbation of orbital disease (4/66, 6.1%), which occurred prior to the routine use of systemic corticosteroids as pre-conditioning. Conclusions: Overall, RTX appears to be both efficacious and well-tolerated as second- or third-line therapy for patients with non-infectious/non-malignant orbital inflammation. [ABSTRACT FROM AUTHOR]

Purpose: To provide a comprehensive review of rituximab use for the treatment of non-infectious uveitis and scleritis. Methods: Review of literature through December 2020. Results: Individual data was available for 229 patients with refractory non-infectious uveitis (n = 108) or scleritis (n = 121) who received treatment with rituximab (RTX). Rituximab was generally utilized as third-line or later treatment (uveitis: 67/90, 74.4%; scleritis: 90/96, 93.8%) at a mean of 33.5 months following the diagnosis of uveitis (range = 0 to 168.0 months; median = 24.0 months) and 39.4 months after diagnosis of scleritis (range = 1.0 to 168.0 months; median = 21.0 months). Patients with non-infectious uveitis and scleritis either received prior treatment with corticosteroids only (uveitis: 18/90, 20%; scleritis: 4/94, 4.3%), or with one (uveitis: 19/90, 21.1%; scleritis: 30/94, 31.9%), two (uveitis: 11/90, 12.2%; scleritis 27/94, 28.7%), or three or more (uveitis: 37/90, 41.1%; scleritis: 31/94, 33.0%) corticosteroid-sparing immunosuppressive agents with or without corticosteroids before initiation of RTX treatment. The rheumatologic protocol (two infusions of 1 gram of RTX separated by 14 days) was utilized most frequently (uveitis: 45/87, 51.7%; scleritis: 87/114, 76.3%), followed by the Foster protocol (eight weekly infusions of 375 mg/m2 RTX; uveitis: 18/87, 20.7%; scleritis: 10/114, 8.8%), and the oncologic protocol (four weekly infusions of 375 mg/m2 RTX; uveitis: 5/87, 5.7%; scleritis: 6/114, 5.3%). Various other off-label regimens were used infrequently (uveitis: 19/87, 21.8%; scleritis 11/114, 9.6%). Rituximab treatments resulted in a positive therapeutic response for the majority of patients with non-infectious uveitis (81/97, 83.5%). Commonly treated uveitic diagnoses included non-paraneoplastic autoimmune retinopathy (30/107, 28.0%), juvenile idiopathic arthritis (21/107, 19.6%), Vogt-Koyanagi-Harada disease (12/107, 11.2%), and Behçet disease (11/107, 10.3%). Cases of non-infectious scleritis were most commonly attributed to granulomatosis with polyangiitis (75/121, 62.0%) and rheumatoid arthritis (15/121, 12.4%), and showed an even greater rate of positive therapeutic response (112/120, 93.3%) following RTX treatment. No side effects were reported in 76.3% (74/97) of uveitis and 85.5% (71/83) scleritis cases. Of those cases associated with RTX-induced adverse events, the most common were infusion reactions of various severity (11/35, 31.4%). Conclusions: Overall, RTX appeared to be both effective and well-tolerated as second or third-line therapy for patients with non-infectious uveitis and scleritis. [ABSTRACT FROM AUTHOR]

• Oral steroid-sparing agents can be stopped at initiation of rituximab therapy in MG. • Rituximab is an effective treatment across different myasthenia gravis serotypes. • Daily prednisone dosage is significantly decreased after rituximab dosing. Rituximab is a chimeric monoclonal antibody that binds CD20 and causes the depletion of B-cell subsets. Although initially designed to treat lymphoma, it has found wide use in the management of various autoimmune conditions, including myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction. Treated myasthenia patients are often on an oral steroid-sparing agent. To determine the safety of stopping oral steroid-sparing agents at the initiation of rituximab therapy and its effectiveness we reviewed the records of 27 MG patients with rituximab, including 13 with anti-MuSK+ MG, 10 with anti-AChR+ MG, and 4 double seronegative MG patients. All patients that were on an oral steroid-sparing agent (21 of 27) were able to stop it, and they did not require re-introduction of the medication. Also, the daily prednisone dosage was significantly decreased in 20/24 patients across all three serotype groups. MGFA post intervention status analysis also showed 15/27 of all patients achieved minimal manifestation status or remission across all groups. Antibody titers decreased dramatically and promptly in anti-MuSK+ MG patients. Our data suggests that stopping oral steroid-sparing agents at initiation of rituximab therapy is safe. Also, our data indicates that rituximab is highly effective in the management of seropositive MG patients. [ABSTRACT FROM AUTHOR]

Abstract: PAMAM dendrimer/reduced graphene oxide nanocomposite modified pencil graphite electrode (PAMAM/RGO/PGE) was used to fabricate an electrochemical DNA biosensor for determination of Rituxan (RTX) at low concentrations, for the first time. The fabricated biosensor was characterized with FE‐SEM, EIS, and CV techniques. The ds‐DNA/PAMAM/RGO/PGE was used as a working electrode to study the interaction between the RTX and salmon sperm ds‐DNA by DPV technique. Because of the interaction between the drug and DNA leads to a decrease in the guanine oxidation peak current, it was used as an indicator for the determination of the RTX. Under the optimized experimental conditions, a wide linear relationship between RTX concentration and guanine signal was obtained within the range of 7.0 to 60.0 μmol L−1 and 60.0 to 300.0 μmol L−1 with a low detection limit (0.56 μmol L−1). To clarify the interaction mechanism between the RTX and the ds‐DNA, DPV and UV‐Vis measurements were used. The reproducibility, stability, and performance of the constructed biosensor was examined by quantitative measuring RTX in pharmaceutical and human serum samples with good precision (RSD; 2.0–6.0 %) and acceptable recoveries (100.04–101.95 %). [ABSTRACT FROM AUTHOR]

Therapeutic monoclonal antibodies (TmAb) have emerged as effective treatments for a number of cancers and autoimmune diseases. However, large interpatient disparities in the pharmacokinetics of TmAb treatment requires close therapeutic drug monitoring (TDM) to optimise dosage for individual patients. Here we demonstrate an approach for achieving rapid, sensitive quantification of two monoclonal antibody therapies using a previously described enzyme switch sensor platform. The enzyme switch sensor consists of a β-lactamase – β-lactamase inhibitor protein (BLA-BLIP) complex with two anti-idiotype binding proteins (Affimer proteins) as recognition elements. The BLA-BLIP sensor was engineered to detect two TmAbs (trastuzumab and ipilimumab) by developing constructs incorporating novel synthetic binding reagents to each of these mAbs. Trastuzumab and ipilimumab were successfully monitored with sub nM sensitivity in up to 1% serum, thus covering the relevant therapeutic range. Despite the modular design, the BLA-BLIP sensor was unsuccessful in detecting two further TmAbs (rituximab and adalimumab), an explanation for which was explored. In conclusion, the BLA-BLIP sensors provide a rapid biosensor for TDM of trastuzumab and ipilimumab with the potential to improve therapy. The sensitivity of this platform alongside its rapid action would be suitable for bedside monitoring in a point-of-care (PoC) setting. [ABSTRACT FROM AUTHOR]

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18F-FDG Positron Emission Tomography (PET) is used to monitor tumor response to 131I-therapy, but is confounded by prompt emissions (284, 364, 637, and 723 keV) from 131I, particularly in animal PET imaging. We propose a method for correcting this emission in 18F-FDG PET. The 131I prompt emission effect was assessed within various energy windows and various activities. We applied a single gamma correction method to a phantom and in vivo mouse model. The 131I prompt emission fraction was 12% when 300 µCi of 131I and 100 µCi of FDG were administered, and increased exponentially with escalating 131I activity for all energy windows. The difference in spill-over ratio was reduced to 131I prompt emission correction. In the mouse model, the standard uptake value (SUV) did not differ significantly between FDG PET only (gold standard) and FDG PET after 131I prompt emission-correction, whereas it was overestimated by 38% before correction. Contrast was improved by 18% after 131I prompt emission correction. We first found that count contamination on 18F-FDG follow-up scans due to 131I spilled-over count after 131I rituximab tumor targeted therapy. Our developed 131I prompt emission-correction method increased accuracy during measurement of standard uptake values on 18F-FDG PET.

The global incidence of multiple sclerosis (MS) appears to be increasing. Although it may not be associated with a high mortality rate, this disease has a high morbidity rate which affects the quality of life of patients and reduces their ability to do their activities of daily living. Thankfully, the development of novel disease modifying therapies continues to increase. Monoclonal antibodies (MABs) have become a mainstay of MS treatment and they are likely to continue to be developed for the treatment of this disease. Specifically, MABs have proven to be some of the most efficacious treatments at reducing relapses and the inflammation in MS patients, including the first treatment for primary progressive MS and are being explored as reparative/remyelinating agents as well. These relatively new treatments will be reviewed here to help evaluate their efficacy, adverse events, immunogenicity, and benefit-risk ratios in the treatment of the diverse spectrum of MS. The focus will be on MABs that are currently approved or may be approved in the near future.

Rituximab (MabThera®/Rituxan®), a chimeric murine/human monoclonal antibody that binds specifically to the transmembrane antigen CD20, was the first therapeutic antibody to enter clinical practice for the treatment of cancer. As monotherapy and in combination with chemotherapy, rituximab has been shown to prolong progression-free survival and, in some indications overall survival, in patients with various B-cell malignancies, while having a well-established and manageable safety profile and a wide therapeutic window. As a result, rituximab is considered to have revolutionized treatment practices for patients with B-cell malignancies. A subcutaneous (SC) formulation of rituximab has been developed, comprising the same monoclonal antibody as the originally marketed formulation [rituximab concentrate for solution for intravenous (IV) infusion], and has undergone a detailed, sequential clinical development program. This program demonstrated that, at fixed doses, rituximab SC achieves non-inferior serum trough concentrations in patients with non-Hodgkin lymphoma and chronic lymphocytic leukemia, with comparable efficacy and safety relative to the IV formulation. The added benefit of rituximab SC was demonstrated in dedicated studies showing that rituximab SC allows for simplified and shortened drug preparation and administration times resulting in a reduced treatment burden for patients as well as improved resource utilization (efficiency) at the treatment facility. The improved efficiency of delivering rituximab's benefit to patients may broaden patient access to rituximab therapy in areas with low levels of healthcare resources, including IV-chair capacity constraints. This article is a companion paper to G. Salles, et al., which is also published in this issue.Funding: F. Hoffmann-La Roche Ltd. [ABSTRACT FROM AUTHOR]

Two potential platform technologies for the oral delivery of protein therapeutics were synthesized and tested. pH-responsive poly(itaconic acid-co-N-vinyl-2-pyrrolidone) (P(IA-co-NVP)) hydrogel microparticles were tested in vitro with model proteins salmon calcitonin, urokinase, and rituximab to determine the effects of particle size, protein size, and crosslinking density on oral delivery capability. Particle size showed no significant effect on overall delivery potential but did improve percent release of encapsulated protein over the micro-scale particle size range studied. Protein size was shown to have a significant impact on the delivery capability of the P(IA-co-NVP) hydrogel. We show that when using P(IA-co-NVP) hydrogel microparticles with 3 mol% tetra(ethylene glycol) dimethacrylate crosslinker, a small polypeptide (salmon calcitonin) loads and releases up to 45 μg/mg hydrogel while the mid-sized protein urokinase and large monoclonal antibody rituximab load and release only 19 and 24 μg/mg hydrogel, respectively. We further demonstrate that crosslinking density offers a simple method for tuning hydrogel properties to variously sized proteins. Using 5 mol% TEGDMA crosslinker offers optimal performance for the small peptide, salmon calcitonin, whereas lower crosslinking density of 1 mol% offers optimal performance for the much larger protein rituximab. Finally, an enzymatically-degradable hydrogels of P(MAA-co-NVP) crosslinked with the peptide sequence MMRRRKK were synthesized and tested in simulated gastric and intestinal conditions. These hydrogels offer ideal loading and release behavior, showing no degradative release of encapsulated salmon calcitonin in gastric conditions while yielding rapid and complete release of encapsulated protein within 1 h in intestinal conditions. [ABSTRACT FROM AUTHOR]

Introduction Neuromyelitis optica is an inflammatory demyelinating disease of the central nervous system. To date, optimal therapeutic approaches for neuromyelitis optica have yet to be defined. Natalizumab is highly effective in relapsing-remitting multiple sclerosis and might be considered as an option. Case presentation Here, we describe a 67-year-old Caucasian man with definite neuromyelitis optica with detection of anti-aquaporin-4 antibodies over the course of the disease. After initially discussing the diagnosis of multiple sclerosis at an outside hospital, our patient received interferon beta 1a as well as repeated corticosteroid pulses without success. Under subsequent therapy with natalizumab, he continued to present relapses. It was not until discontinuation of natalizumab, repeated cycles of plasma exchanges and initiation of therapy with rituxan that the disease course started to stabilize. Although B cells were completely depleted, our patient experienced another severe myelitis relapse during further follow-up and an additional immunosuppressive therapy with cyclophosphamide was started. Under this regimen, no further relapses occurred over the next 24 months. Conclusions This case adds further evidence to the previously discussed notion that natalizumab, while highly effective in multiple sclerosis, may not work sufficiently in neuromyelitis optica. It further advocates for repetitive testing of anti-aquaporin-4 antibodies before and after treatment initiation. [ABSTRACT FROM AUTHOR]

Five patients with active disseminated vitiligo were given 1 g of a chimeric (murine/human) monoclonal antibody to CD20 in a single intravenous infusion and followed-up for 6 months. Three of the patients showed an overt clinical and histological improvement of the disease, one presented slight improvement and the remaining patient showed no changes. Improvement was neither associated with changes in laboratory parameters nor to a specific human leucocyte antigen D-related ( HLA- DR) phenotype. We believe that these preliminary results are encouraging, and further clinical trials should be undertaken. An important aim should be the finding of a marker with a good response to this therapeutic approach. [ABSTRACT FROM AUTHOR]

Rituximab (Rituxan®; iogen Idec, San Diego, CA, USA) is a human-mouse chimeric monoclonal antibody specific for CD20, a surface glycoprotein expressed on B lymphocytes. Administration of rituximab as a single agent to patients with chronic lymphocytic leukemia (CLL) has limited clinical activity, but generally does not eradicate leukemia from the marrow. However, when administered in combination with chemotherapy, rituximab can improve the survival of patients relative to those treated with chemotherapy alone. As a result of this, the US Food and Drug Administration approved the use of rituximab in previously untreated and previously treated CD20-positive CLL in combination with fludarabine monophosphate and cyclophosphamide. The results of clinical studies evaluating the activity of rituximab when used alone or in combination with other antileukemia agents for the treatment of this disease are reviewed here. [ABSTRACT FROM AUTHOR]

Patients with chronic lymphocytic leukemia (CLL) have benefited from the introduction of targeted therapy for leukemia. Rituximab (a chimeric murine-derived monoclonal antibody that targets CD20 on lymphocytes) was the first monoclonal antibody to affect the natural course of this disease. Several reports have shown modest single-agent activity in patients with CLL. However, the best results come from the combination of this agent with chemotherapy; a significant benefit has been seen with the use of fludarabine, cyclophosphamide, and rituximab (FCR). The addition of rituximab to chemotherapy boosted overall response rates, complete response rates and prolonged progression free survival. Recent data showed an overall survival benefit with FCR. Other combinations including bendamustine and rituximab appear more effective than bendamustine alone, while combining rituximab with other types of agents also appears to improve response rates. This type of relatively nontoxic regimen is being investigated in elderly patients who may not tolerate standard combination chemoimmunotherapies. [ABSTRACT FROM AUTHOR]

The pathogenic roles of B cells in autoimmune diseases occur through several mechanistic pathways that include autoantibodies, immune complexes, dendritic and T cell activation, cytokine synthesis, chemokine-mediated functions, and ectopic neolymphogenesis. Each of these pathways participate to different degrees in autoimmune diseases. The use of B cell-targeted and B cell subset-targeted therapies in humans is illuminating the mechanisms at work in a variety of human autoimmune diseases. In this review, we highlight some of these recent findings that provide insights into both murine models of autoimmunity and human autoimmune diseases. [ABSTRACT FROM AUTHOR]

Jordan SC, Vo AA, Tyan D, Nast CC, Toyoda M. Current approaches to treatment of antibody-mediated rejection.Pediatr Transplantation 2005: 9: 408–415.© 2005 Blackwell MunksgaardAntibody-mediated rejection (AMR) has recently been recognized as a significant and unique form of rejection that is not amenable to treatment with standard immunosuppressive medications aimed at modification of T-cell function. Recent interest in AMR and the role of B cells in rejection has been aided by the concomitant discovery that C4d staining of renal biopsy tissue is strongly associated with AMR and a poor prognosis, and the emergence of desensitization protocols for treatment of highly human leukocyte antigen (HLA)-sensitized patients. Treatment options include: (i) the use of high-dose intravenous immunoglobulin (IVIG) which works by blocking anti-HLA antibody activity and through complement inhibition, (ii) the use of Rituxan (anti-CD20 chimeric antibody) to deplete B cells and interfere with antigen-presenting cell (APC) activity of B cells subsequently decreasing T-cell activation, and (iii) the use of plasmapheresis (PE) + anti-cytomegalovirus (CMV) immunoglobulin G (IgG) or IVIG in lower doses. This protocol removes deleterious anti-HLA antibodies and may also allow complexing of anti-HLA with anti-idiotypes in the anti-CMV IgG. Although early, data support the efficacy of all three approaches. Many centers are now designing protocols that utilize a combination of all three agents. In summary, recent advances in the diagnosis and treatment of AMR has allowed for significant improvements in outcomes of a condition usually associated with rapid graft failure. However, much work needs to be done to better understand the immunologic processes leading to AMR and how current therapies can be best used to effectively prevent and treat it. [ABSTRACT FROM AUTHOR]

Rituxan, a chimeric anti-CD20 antibody, is the first antibody approved for immunotherapy in non-Hodgkin's B-cell lymphoma and other B-cell lymphoproliferative disorders. Additionally, efficacy of Rituxan treatment has been reported in nonmalignant autoimmune diseases such as rheumatoid arthritis. Crosslinking of CD20 molecules by Rituxan induces therapeutic B-cell depletion. CD20 is a B-lymphocyte specific integral membrane protein, proposed to function as a store-operated calcium channel, which is activated upon receptor-stimulated calcium depletion of intracellular stores. Crosslinking of CD20 by antibodies has been reported to induce a redistribution of CD20 molecules to specialized microdomains at the plasma membrane known as lipid rafts. Here, we report that in the absence of Rituxan, CD20 exhibits a low affinity to lipid rafts. However, binding of Rituxan significantly increases the affinity of CD20 for lipid rafts resulting in its redistribution to a fraction resistant to Triton X-100 solubilization. Furthermore, we demonstrate that disturbing the raft integrity by cholesterol extraction results in dissociation of CD20 from a Triton X-100 resistant fraction followed by complete inhibition of Rituxan-induced calcium entry and apoptosis. The integrity of lipid rafts seems to play a crucial role for CD20-induced caspase activation. These data show, for the first time, that Rituxan-induced translocation of CD20 to lipid rafts is important for increased intracellular Ca2+ levels and downstream apoptotic signalling. [ABSTRACT FROM AUTHOR]

Traditional therapy for chronic lymphocytic leukemia (CLL) has consisted of alkylating agents, purine analogs, or a combination of these drugs. These agents are effective at producing remissions but are not curative.Thus, new drugs are still needed to improve the outcome of patients with CLL. The introduction of monoclonal antibodies, such as rituximab and alemtuzumab, provides a novel therapeutic modality.Rituximab is an active agent in CLL. Standard doses of rituximab result in higher response rates in previously untreated than in relapsed patients but low complete response (CR) rates. Rituximab is most effective in combination with chemotherapy, especially fludarabine-based regimens in the first-line and salvage setting. Rituximab is also useful in the treatment of complications of CLL, such as pure red cell aplasia, autoimmune thrombocytopenia, and autoimmune hemolytic anemia. Alemtuzumab has impressive activity in patients with refractory CLL and may play an important role in the consolidation treatment of CLL. Alemtuzumab is most efficacious at clearing disease in the peripheral blood and bone marrow. Bulky lymphadenopathy is less sensitive to therapy. Because of the significant lymphopenia associated with alemtuzumab, antibacterial and antiviral prophylaxis should always be used. [ABSTRACT FROM AUTHOR]

: BackgroundIn contrast to conventional cytotoxic chemotherapy and radiation therapy, a new method of targeted cancer therapeutics is being directed towards molecular pathways that underlie the malignant phenotype. These therapies target specific tumor cell receptors or signaling events that are critical to tumor progression while reducing toxicity to normal cells.: Data sourcesThe purpose of this review is to highlight several examples of novel targeted therapeutics that are currently approved by the FDA for treatment of patients with cancer. Rituxan is a humanized monoclonal antibody that binds to the CD20 antigen present on B cell lymphomas and is currently approved for the treatment of patients with relapsed or refractory low-grade CD20 positive follicular lymphoma. The humanized anti-HER-2/neu herceptin is approved for use in patients with metastatic breast cancer that demonstrates overexpression of HER-2/neu. Finally, Gleevec is a tyrosine kinase inhibitor that inhibits abl-specific phosphorylation and is approved for use in select patients with chronic myelogenous leukemia that is refractory to interferon therapy.: ConclusionsThe lessons learned from the use of these therapeutics will add to the growing knowledge of mechanistic approaches to the treatment of patients with cancer based upon targeted therapies, and herald a bright future that will improve the lives of patients with cancer. [Copyright &y& Elsevier]

Summary. Antibody-based approaches have become a novel treatment modality for lymphoma patients. Humanized 1D10 (Hu1D10; Remitogen) is among the antibodies that are currently under evaluation in phase II clinical trials in lymphoma patients. The 1D10 antibody is directed against a polymorphic epitope on the β-chain of human leucocyte antigen (HLA) class II. We found expression of the 1D10 epitope on B cells and monocytes from approximately 50% of healthy donors. Analyses of 1D10 expression on malignant cells revealed that approximately half of the HLA class II-positive haematological malignancies expressed the 1D10 epitope. In whole blood antibody-dependent cellular cytotoxicity (ADCC) assays, Hu1D10 was more effective than rituxan in killing malignant ARH-77 B cells. Interestingly, Hu1D10-mediated lymphoma cell lysis was significantly enhanced when blood from granulocyte colony-stimulating factor (G-CSF)-treated patients was compared with blood from healthy controls. Analyses of the relevant effector cell populations revealed that FcγRI (CD64)-positive polymorphonuclear cells were critical for enhanced Hu1D10-mediated lymphoma killing during G-CSF therapy, while the same effector cell population induced only marginal lysis with rituxan. Furthermore, Hu1D10 was highly effective in inducing apoptosis in primary lymphoma cells from B chronic lymphocytic leukaemia patients. These preclinical results form the basis for a phase I/II clinical trial of Hu1D10 in combination with G-CSF. [ABSTRACT FROM AUTHOR]

Summary. Rituximab has significant activity as a single agent in the treatment of follicular non-Hodgkin's lymphoma (NHL). Interleukin 2 (IL-2) is a lymphokine that increases effector cell number. In an effort to augment antibody-dependent cell-mediated cytotoxicity (ADCC) associated with rituximab therapy, low-dose IL-2 was added to a standard rituximab regimen and patients were evaluated for safety and efficacy. Twenty patients with relapsed or refractory follicular NHL were treated with IL-2 (1·2 MIU/m2 /d for 56 d subcutaneously) as outpatients. Rituximab (375 mg/m2 ) was given on d 15, 22, 29 and 36. The regimen was well tolerated and only three patients required dose adjustments in IL-2. Infusional toxicity associated with rituximab was not exacerbated by IL-2. Peripheral blood immunophenotyping demonstrated significant increases in circulating CD8+ and CD56+ lymphocytes in all evaluable patients (P = 0·0002). Increases in total eosinophil number were observed in all patients. Eleven patients responded to therapy, for an overall response rate of 55%. Four additional patients had stable disease. For these 15 patients, the median time to progression exceeded 13 months. We conclude concomitant cytokine therapy to enhance ADCC with monoclonal antibody therapy was well tolerated and did not exacerbate antibody-related infusional toxicity. Further studies of this rational combination are warranted and ongoing. [ABSTRACT FROM AUTHOR]

Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by the accumulation of proteinaceous material within the lungs. While typically managed with whole lung lavage (WLL), more recent PAP therapies aimed at reducing granulocyte-macrophage colony stimulating factor autoantibodies (anti-GM-CSF) have reduced symptoms and improved lung function. We present a patient with PAP refractory to WLL, exogenous GM-CSF and rituximab who underwent a novel plasmapheresis protocol as a therapeutic trial. While previously reported regimens have utilized plasmapheresis sessions distributed over months, our patient underwent five consecutive days of plasmapheresis, followed by rituximab. Anti-GM-CSF levels decreased from 24.8 to 2.7 mcg/mL post-plasmapheresis. This reduction of autoantibody correlated with reduction in WLL frequency, increase in diffusing capacity for carbon monoxide, and subjective improvement in dyspnea. Our case suggests that five consecutive days of plasmapharesis results in increased clearance of anti-GM-CSF and may be potentially efficacious in cases of refractory PAP. [ABSTRACT FROM AUTHOR]

Rituximab or Rituxan is a common drug used in the treatment of lymphomas. It is almost always used in conjunction with other chemotherapy regimens. Mechanism of action involves killing of the CD 20+ cells. Rituximab is implicated in precipitating tumor lysis syndrome (TLS) in patients with diffused large B cell lymphoma (DLBCL). The precise pathophysiological mechanism is not well known. Here, we present a case where the patient only received Rituxan for her newly diagnosed B-cell lymphoma which triggered a tumor lysis cascade. This in turn resulted in multiple electrolyte disturbances, multi-organ failure, and mortality. This report discusses the case presentation in addition to the different types of TLS and how this knowledge can be applied in the clinical setting for the future., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Iftikhar et al.)

18F-FDG Positron Emission Tomography (PET) is used to monitor tumor response to 131I-therapy, but is confounded by prompt emissions (284, 364, 637, and 723 keV) from 131I, particularly in animal PET imaging. We propose a method for correcting this emission in 18F-FDG PET. The 131I prompt emission effect was assessed within various energy windows and various activities. We applied a single gamma correction method to a phantom and in vivo mouse model. The 131I prompt emission fraction was 12% when 300 µCi of 131I and 100 µCi of FDG were administered, and increased exponentially with escalating 131I activity for all energy windows. The difference in spill-over ratio was reduced to <5% after 131I prompt emission correction. In the mouse model, the standard uptake value (SUV) did not differ significantly between FDG PET only (gold standard) and FDG PET after 131I prompt emission-correction, whereas it was overestimated by 38% before correction. Contrast was improved by 18% after 131I prompt emission correction. We first found that count contamination on 18F-FDG follow-up scans due to 131I spilled-over count after 131I rituximab tumor targeted therapy. Our developed 131I prompt emission-correction method increased accuracy during measurement of standard uptake values on 18F-FDG PET. [ABSTRACT FROM AUTHOR]

The global incidence of multiple sclerosis (MS) appears to be increasing. Although it may not be associated with a high mortality rate, this disease has a high morbidity rate which affects the quality of life of patients and reduces their ability to do their activities of daily living. Thankfully, the development of novel disease modifying therapies continues to increase. Monoclonal antibodies (MABs) have become a mainstay of MS treatment and they are likely to continue to be developed for the treatment of this disease. Specifically, MABs have proven to be some of the most efficacious treatments at reducing relapses and the inflammation in MS patients, including the first treatment for primary progressive MS and are being explored as reparative/remyelinating agents as well. These relatively new treatments will be reviewed here to help evaluate their efficacy, adverse events, immunogenicity, and benefit-risk ratios in the treatment of the diverse spectrum of MS. The focus will be on MABs that are currently approved or may be approved in the near future. [ABSTRACT FROM AUTHOR]