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Non-Hodgkin Lymphoma
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
The enhanced understanding of the genetic events and immune microenvironment has facilitated a greater application of targeted and immunological therapies for patients with relapsed and rituximab refractory FL. In such patients, earlier studies with the BTK inhibitor, ibrutinib, resulted in a modest efficacy, possibly due to the presence of coexisting mutations, such as CARD11, which are now considered to confer resistance to ibrutinib. Several novel anti-CD20 monoclonal antibodies, such as veltuzumab, as monotherapy and in combination with the anti-CD74, milatuzumab and ocrartuzumab (AME-133) are ongoing. There appears to be greater promise for epigentically targeted therapies (such as tazemetostat, an EZH2 inhibitor) and vorinostat (a histone deactylase inhibitor). Studies are also testing the inclusion of immune checkpoint inhibitors and CAR T-cell specific for CD19, a differentiation antigen expressed in B-cells and B lineage malignancies. The next generation of novel antibody-based therapies, such as bispecific antibodies, which combine the specificity of two antibodies, so they can bind to different antigens. Bispecific T-cell engager (BiTE) binds CD3 on T-cells and an antigen on tumour cells to activate T-cells to kill the cancer cells. The first-in-class BiTE antibody, blinatumomab, which specifically targets CD19 on B-cells, was approved in 2014 for clinical use in patients with relapsed or refractory ALL and is now being tested in FL, and preliminary results when the drug is administered at very low doses are encouraging.
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
Efforts are underway to develop more effective anti-CD20 mABs as well as join them with other non-chemotherapeutic agents in novel combinations. In addition to ofatumumab, additional second-generation type I anti-CD20 mABs have been developed, including ocrelizumab and veltuzumab. Ocrelizumab is a humanized type I anti-CD20 mAB which has shown superior binding affinity for low-affinity variants of the FcyRIIIa receptor, which have been associated with inferior disease outcomes following single-agent rituximab treatment [112]. It also has increased ADCC and lower CDC activity compared to rituximab. In a phase I/II trial of patients with relapsed/refractory FL after prior rituximab therapy, ocrelizumab demonstrated efficacy and safety, with OR rate of 38% and median PFS of 11.4 months [113]. Veltuzumab is also a humanized type I anti-CD20 mAB which has exhibited more potent binding avidities and increased CDC compared with rituximab [114]. It has demonstrated potent anti-tumor activity in animal models and in patients with untreated and refractory/recurrent indolent lymphomas via subcutaneous administration [115–117]. Other third-generation anti-CD20 mABs are also under evaluation in preclinical and early phase studies. Ocaratuzumab is an Fc protein engineered humanized type I mAB which has demonstrated enhanced ADCC against CLL cells compared to rituximab, as well as increased binding affinity with CD20 and higher avidity to the low affinity variants of the FcyRIIIa receptor [118]. It is currently under investigation in a phase I/II dose escalation trial of patients with relapsed or refractory FL (clinicaltrials.gov identifier: NCT00354926).
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.
The latest developments with anti-CD20 monoclonal antibodies in chronic lymphocytic leukemia
Published in Expert Opinion on Biological Therapy, 2018
Mitchell Evers, Margot Jak, J. H. W. Leusen
Next to these approved antibodies, two novel antibodies directed against CD20 have entered clinical trials for CLL: veltuzumab and ublituximab. Veltuzumab is a humanized IgG1 antibody which varies only in 1 amino acid to the complementarity-determining regions of rituximab. However, the framework of veltuzumab differs considerably, granting lower off-rates and enhanced complement activation [34]. Data from a phase I clinical trial showed that low doses of subcutaneously injected veltuzumab are well-tolerated and decreased leukemic cells from the blood [35]. Follow-up efficacy studies in combination with small molecules targeting the BCR signaling pathway will give insights into whether veltuzumab is able to improve current therapy or not.
What is novel in the clinical management of pemphigus
Published in Expert Review of Clinical Pharmacology, 2019
After rituximab was shown to be successful in the treatment of pemphigus, researchers focused on designing other anti-CD20 monoclonal antibodies (mAbs). These novel anti-CD20 mAbs were developed to be less immunogenic but more effective and tolerable. Up till now, two agents have been introduced. Veltuzumab, a second-generation humanized anti-CD20 mAb, was shown to induce complete remission off therapy in a patient with resistant pemphigus [39]. It has received FDA orphan drug status for resistant pemphigus in 2015 [40]. The administration method is one subcutaneous injection of 325 mg veltuzumab repeated after 2 weeks [41].