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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Until recently, 131I-tositumomab was developed to treat patients with relapsed follicular lymphoma and non-Hodgkin’s lymphoma. In the clinic it was administered sequentially with the unlabeled antibody (i.e., tositumomab alone). However, GSK withdrew this agent in 2014 on the grounds that there are now more beneficial treatments available for these cancer types.
Iodine is needed to maintain health
Published in Tatsuo Kaiho, Iodine Made Simple, 2017
Iodine 131 may be used both as diagnostic and therapeutic drugs. γ rays (364 keV) are used for diagnosis and β rays for treatment. Sodium iodide [131I] is a radioactive drug which has been used in treatments since ancient times. When administered orally, 30% of the radiation is accumulated in the thyroid gland. As a result, it is used in the treatment of hyperthyroidism and goiter. Tositumomab [131I], a monoclonal antibody with iodine 131 added, has raised the 10-year survival rate of malignant lymphoma by 50% [49a,b]. Hence, not all radioactive iodine should be considered bad.
Radioimmunotherapy of Hematological Malignancies
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
The contribution of targeted radiation to the overall responses seen in RIT has been addressed with two randomized studies comparing the radioimmunoconjugates 90Y-ibritumomab tiuxetan and 131I-tositumomab with the unlabeled mAbs (31,42). Both studies have shown greatly superior clinical responses of RIT over the unlabeled mAb. The 90Y-ibritumomab tiuxetan versus rituximab is described above and the second study compared treatment outcomes for unlabeled tositumomab (predose) and 131I-tositumomab to an equivalent total dose of unlabeled tositumomab involved 78 patients with refractory/relapsed low-grade NHL (31). The investigators reported an ORR of 55% versus 19% (p = 0.002) with a CR 33% versus 8% (p = 0.012) in 131I-tositumomab versus unlabeled tositumomab groups, respectively. The median duration of the ORR was not reached for 131I-tositumomab versus 28.1 months for unlabeled tositumomab. The median duration of CR was not reached in either arm, and the median TTP was 6.3 months versus 5.5 months (p = 0.031), respectively. Although hematological toxicity was more severe and nonhematological AEs were more frequent after 131I-tositumomab than after tositumomab alone, there were no serious infectious or bleeding complications. The frequency of developing HAMA was similar in the two arms of 27% (131I-tositumomab group) versus 19% (tositumomab-alone group), respectively. This study demonstrated that although unlabeled tositumomab showed single agent activity, the conjugation of 131I to tositumomab significantly enhanced the therapeutic efficacy (31).
Fc galactosylation follows consecutive reaction kinetics and enhances immunoglobulin G hexamerization for complement activation
Published in mAbs, 2021
Bingchuan Wei, Xuan Gao, Lance Cadang, Saeed Izadi, Peilu Liu, Hui-Min Zhang, Elizabeth Hecht, Jeongsup Shim, Gordon Magill, Juan Rincon Pabon, Lu Dai, Wilson Phung, Elaine Lin, Christopher Wang, Kevin Whang, Sean Sanchez, Jose Oropeza Jr, Julien Camperi, Jennifer Zhang, Wendy Sandoval, Yonghua Taylor Zhang, Guoying Jiang
CDC, an effector function of IgG from the classical complement pathway, plays a critical role in the MOA of several US Food and Drug Administration-approved mAb therapeutics, including rituximab, ofatumumab, and I-tositumomAb.18,19 When IgGs bind to the antigen on the surface of the target cell, the classical complement pathway is triggered by binding protein Complement component 1q (C1q) to the antibody, forming a membrane attack complex and leading to tumor cell lysis.18–20 Diebolder et al. discovered IgG1s hexamerize orderly through Fc interaction after antigen binding at the cell surface, and then bind to C1q, which leads to effective complement activation.21–23 The binding sites between IgG1 hexamer and C1q in the structure complex were identified recently.24 Van den Bremer et al. demonstrated charge variants at the C terminus, such as C-terminal lysine, may hinder hexamer formation.25 Wang et al. found the presence of asparagine (N)-linked glycans affect hexamerization, which implies the conformation of the Fc plays a key role in hexamerization.26 The post-translational modifications of IgG1s, especially the modifications on Fc, could affect the formation of IgG1 hexamerization, and hence affect C1q binding and CDC potency. As an important part of the Fc glycan, terminal galactose was found to affect protein conformation27 and promote the activation of the complement system by increasing C1q binding affinities.17,28,29 However, the structural and functional correlations between Fc galactosylation and CDC potency remain unclear.
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].
Obinutuzumab activates FcγRI more potently than other anti-CD20 antibodies in chronic lymphocytic leukemia (CLL)
Published in OncoImmunology, 2018
Shlomo Elias, Shira Kahlon, Rebecca Kotzur, Noah Kaynan, Ofer Mandelboim
In recent years, new antibodies against CD20 have been developed, notably ofatumumab and obinutuzumab.6 Both antibodies have been used for the treatment of CLL with possible clinical advantage of obinutuzumab over rituximab.7,8 Obinutuzumab was also recently approved for the treatment of relapsed/refractory follicular lymphoma.9 Two other anti-CD20 antibodies, ibritumomab and tositumomab, were conjugated to a radioactive substance to enhance their cytotoxic activity, and additional anti-CD20 antibodies are currently being studied in clinical trials.6 In this study, we focused on the three anti-CD20 antibodies which are in clinical use in CLL: rituximab, ofatumumab and obinutuzumab.