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Anti-CD20 Monoclonal Antibody Treatment in Follicular Lymphoma and Chronic Lymphocytic Leukemia
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Several monoclonal antibodies have been developed to target tumor cells based on expression of the CD20 antigen given the characteristics making CD20 an effective target. The most clinically developed and well-established anti-CD20 mABs include rituximab, ofatumumab, and obinutuzumab. Other anti-CD20 mABs which have been investigated include ublituximab, veltuzumab, ocaratuzumab, and tositumomab. The various anti-CD20 mABs are categorized based on CD20 antigen binding features, capacity to induce complement-dependent cytotoxicity, and effects on immune effector cells [16–18]. Binding of type I anti-CD20 mABs leads to strong complement-mediated cytotoxicity which is mediated by translocation of the antibody-CD20 antigen complex into lipid rafts upon binding to CD20 [16, 18]. In contrast, type II mABs, such as obinutuzumab, induce a much greater degree of direct cell death upon binding to target cells but do not induce redistribution of CD20 into lipid rafts and are not potent effectors of complement-dependent cytotoxicity (CDC) [19]. Cell death elicited by type II mABs is thought to be a largely non-apoptotic lysosomal mode of cell death [20]. Both types of antibodies are effective in inducing antibody-dependent cell-mediated cell death (ADCC) and antibody-dependent cell phagocytosis (ADCP) through effector cell Fc y receptor ligation [21].
Ofatumumab subcutaneous injection for the treatment of relapsing forms of multiple sclerosis
Published in Expert Review of Clinical Immunology, 2022
G. Dalla Costa, L. Leocani, G. Comi
Ublituximab. More than 1,500 patients with B-cell malignancies have been treated with ublituximab in completed or ongoing phase II, 48-week, placebo-controlled, multicenter clinical trials showing a robust efficacy combined with acceptable safety and tolerability [41]. In a phase II, multicenter, placebo-controlled trial, different doses of ublituximab and varying infusion times were tested in 48 MS patients. No enhancing lesions were seen at weeks 24 and 48, and a 10.6% reduction in T2 lesion volume was seen in the active group vs. the placebo group [42]. Infusion of 450-mg ublituximab administered over times as rapid as one hour was generally well tolerated and this protocol is now being tested in the phase III ULTIMATE trials (ClinicalTrials.gov NCT03277261 and NCT03277248). As a chimeric mAb, the potential development of anti-ublituximab antibodies will need to be monitored.
The future of antibody therapy in chronic lymphocytic leukemia
Published in Expert Opinion on Emerging Drugs, 2021
Jennifer L. Crombie, Jennifer R. Brown
In addition to these anti-CD20 antibodies that are already FDA approved for the treatment of CLL, other novel antibodies remain in the therapeutic pipeline. Ublituximab is one such example, which first entered into clinical trials in 2017[66]. Ublituximab is a chimeric IgG1 monoclonal antibody that has low fucose content, enhances binding to the FcγRIIIa and increases ADCC (Figure 2)[67]. In addition, ublituximab recognizes a unique epitope on CD20 with high affinity[68]. A phase I/II trial of ublituximab in relapsed/refractory NHL or CLL patients previously treated with rituximab therapy demonstrated that ublituximab was well tolerated and efficacious in a heterogeneous pretreated patient population[67]. Registration for ublituximab is currently being pursued in combination with targeted agents, discussed in further detail below. Veltuzumab, similarly, is a humanized IgG1 antibody which differs in only one amino acid to the complementarity-determining regions of rituximab[66]. Differences in antibody framework, however, allow for lower off-rates and enhanced CDC[69]. A phase I trial of veltuzumab in CLL demonstrated that low doses of subcutaneously injected antibody were well tolerated and efficacious[70]. It remains unclear whether this drug will be further developed for patients with CLL.
Emerging drugs for the acute treatment of relapses in adult neuromyelitis optica spectrum disorder patients
Published in Expert Opinion on Emerging Drugs, 2022
Edgar Carnero Contentti, Pablo A. López, Juan I. Rojas
Ublituximab is a monoclonal antibody specifically binding to the trans-membrane antigen CD20 [37]. Its efficacy has been tested in an open-label phase 1b safety and proof-of-concept trial in 5 subjects with AQP4-Ab-positive NMOSD who presented with acute TM and/or ON [37]. In addition to treatment with 1 g of daily IVMP, patients received a single dose of 450 mg of ublituximab within 5 days of relapse onset. The primary outcome measure was safety, and the secondary efficacy measures included change in EDSS, durability of remission and B cell count. EDSS scores dropped from a median of 6.5 on admission to 4.0 at 90-day follow-up. Two subjects did not achieve total B cell depletion and relapsed within 3 months. Although the pharmacokinetics of ublituximab suggest that the time to exert its biological effect could take a bit longer (NCT02276963), a clinical difference was observed between patients that received the intervention vs. those who did not in the performed study. Ublituximab proved to be safe in all 5 NMOSD subjects, with no serious adverse events recorded. There were no opportunistic infections in any of the participants and only 1 subject experienced a transient leukopenia [37]. The mechanism by which ublituximab is expected to be effective is depletion of plasmablasts and plasma cells that produce antibodies (AQP4 antibodies mainly) that are directly involved in the disease process, as well as, depletion of B cells, that have a role as potent antigen presenting cells in the disease. Despite all the above, more studies should be done with an increased number of patients to confirm the potential role of anti-CD20 in improve outcomes acute treatment of relapses in NMOSD.