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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Ibritumomab tiuxetan (ZevalinTM) is a murine anti-CD20 antibody linked to a chelating agent that can bind to the radioisotopes Yttrium-90 or Indium-111(Figure 7.40). Developed by Spectrum Pharmaceuticals, and approved in 2002, it is used to treat a specific type of non-Hodgkin’s lymphoma known as follicular lymphoma (a cancer of the B cells). From a practical standpoint, ibritumomab tiuxetan and the radioisotope are obtained separately and mixed together shortly before administration which reduces storage issues for the product. Structure of ibritumomab tiuxetan (ZevalinTM), showing the beta-emitting Yttrium-90 trapped by the DTPA chelating moiety which is covalently attached to the antibody (Figure from Hess C., Venetz D., and Neri D., Emerging classes of armed antibody therapeutics against cancer. Med. Chem. Commun., 2014, 5, 408. DOI: 10.1039/c3md00360d. Copyright © The Royal Society of Chemistry 2014).
Radioimmunotherapy of Hematological Malignancies
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
90Y-ibritumomab tiuxetan consists of a monoclonal IgG1K anti-CD20 mAb, the murine parent immunoglobulin of rituximab, covalently attached to a metal chelator molecule (tiuxetan, an isothiocyanatobenzyl derivative of the polyaminocarboxylic acid DTPA), which stabilizes the mAb-isotope complex for delivery to the lymphoma site (38). Biological half-life elimination of 90Y-ibritumomab tiuxetan is 30 hours. More than 90% of the β-radiation is absorbed within a 5-mm proximity (corresponding to a diameter of 100 to 200 cells) of the radiation source. This facilitates highly targeted delivery of radiation without the need for patient isolation or shielding (16). The tiuxetan chelator molecule provides a stable link between the mAb and the radioisotope, and, therefore, free isotope clearance rates are minimal and predictable with 7.3% ± 3.2% of the radiolabeled activity being excreted in the urine over seven days (39). Consequently 90Y-ibritumomab tiuxetan may be administered on an outpatient basis. Figure 1 outlines the 90Y-ibritumomab tiuxetan therapeutic regimen.
Mantle cell lymphoma: insights into therapeutic targets at the preclinical level
Published in Expert Opinion on Therapeutic Targets, 2020
MCL cells are generally considered radiosensitive. Compared to external radiotherapy, which has a limited role in the therapy of MCL, radioimmunotherapy (RIT) offers a targeted delivery of a radionuclide bound to the monoclonal antibody directly to the lymphoma cells that are subsequently eliminated predominantly by the emitted electrons and gamma rays, so called ‘cross-fire’ effect. There are two anti-CD20 RIT approved for the treatment of B-cell lymphoma: a combined beta- and gamma-emitter iodine-131 tositumomab with half-life approx. 8 days, and a pure beta-emitter yttrium-90 ibritumomab tiuxetan with half-life 2.7 days [185]. Ibritumomab demonstrated single-agent efficacy both in the therapy or R/R MCL and as consolidation after first and second-line therapy [186–188]. Because RIT delivers continuous radiation to MCL cells, its combination with DNA damage pathway inhibitors might be synthetically lethal [189].
Yttrium-90 ibritumomab tiuxetan consolidation versus rituximab maintenance therapy after induction chemotherapy in patients with indolent non-Hodgkin lymphoma: a single-institution experience
Published in Hematology, 2019
Masaki Iino, Yuma Sakamoto, Tomoya Sato
There are two approaches for post-remission treatment in iNHL, namely, maintenance therapy and consolidation therapy. Rituximab maintenance therapy is a well-established post-remission treatment for patients who responded to first-line chemotherapy. Two-year rituximab maintenance therapy improved PFS in randomized trials [2,3] and OS in a meta-analysis of randomized trials [4]. Therefore, rituximab maintenance therapy has been suggested as a standard of care for patients with iNHL. In contrast, consolidation is a short-term intensive treatment. The efficacy of consolidative radioimmunotherapy (RIT) using yttrium-90 ibritumomab tiuxetan (90Y-IT) was demonstrated in the First-Line Indolent Trial [5]. 90Y-IT comprises ibritumomab covalently linked to tiuxetan, which chelates yttrium-90. Ibritumomab is a murine monoclonal IgG1 antibody against CD20 and the parent of the genetically modified chimeric antibody rituximab. Following the results of early clinical trials [6–8], 90Y-IT was approved for treating recurrent or refractory iNHL in Japan. However, there has been only one retrospective study [9] and one preliminary result from a randomized phase II study comparing rituximab maintenance and RIT in patients with follicular lymphoma (FL) [10]. Therefore, we address the efficacy and safety of 90Y-IT consolidation compared with those of rituximab maintenance in patients with iNHL.
Treating relapsed follicular lymphoma
Published in Expert Review of Hematology, 2018
Thomas Erblich, Silvia Montoto
Monoclonal antibodies can be ‘spiked’ with a radioactive isotope. This enhances the killing capability of the antibody by exerting additional direct cytotoxicity once the antibody is taken up into the lymphoma cell after binding to the CD20 receptor. Long-term myelotoxicity and risk of MDS/AML remains a main concern with this treatment modality. 90-Yttrium Ibritumomab tiuxetan (90Y-IT) is an anti-CD20 antibody which was compared in a randomized controlled trial to ritxumab in rituximab-naïve patients with relapsed/refractory lymphoma [26]. The ORR was 80% for the RIT group vs. 56% for the rituximab group. CR rates were 34% and 20%. Reversible myelosuppression was the main toxicity with the RIT group. The data was updated two years later after a median follow-up of 44 months and showed a trend toward longer time-to-progression (TTP) with 15 vs. 10.2 months and a time to next therapy of 21.1 vs. 13.8 months in patients treated with (90)Y Ibritumomab tiuxetan compared with the rituximab control arm. In those patients who achieved a CR, the median TTP with RIT was 25 months vs. 13 months with rituximab alone.