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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Obinutuzumab is a glycoengineered Type II anti-CD20 monoclonal antibody that has lower complement-dependent cytotoxicity (CDC) than rituximab but greater antibody-dependent cellular cytotoxicity (ADCC) and greater phagocytosis and direct B-cell killing effects. Obinutuzumab combined with chemotherapy has significant clinical activity in patients with chronic lymphocytic leukemia (CLL), previously treated indolent and aggressive non-Hodgkin’s lymphoma, and rituximab refractory indolent non-Hodgkin’s lymphoma.
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
Obinutuzumab is a humanized type II mAB with a glycol-engineered Fc region which binds a CD20 epitope overlapping that of rituximab, but in a different orientation and over a greater surface area [26]. Obinutuzumab has a modified elbow hinge region compared with rituximab, and this along with its different binding characteristics, are thought to be responsible for increased in vitro direct cell death which has been demonstrated in various tumor cell lines [17, 26, 27]. It does not engage in high rates of CDC like rituximab but induces cell death by a non-apoptotic, lysosome-mediated mechanism via homotypic aggregation [27, 28]. Obinutuzumab also exhibits greater ADCC and phagocytosis than rituximab [26]. Glycoengineering of the carbohydrate moiety of obinutuzumab resulted in a lower fructose content and resultant higher affinity for FcyRIII on immune effector cells. This has resulted in improved in vitro ADCC and ADCP compared with fully fucosylated antibodies such as rituximab and ofatumumab [29–31]. In addition, obinutuzumab displays more efficient activation of neutrophils and mediation of phagocytosis through FcyRIIIb than rituximab [28, 32].
Oncological effects on the central nervous system
Published in Anju Sahdev, Sarah J. Vinnicombe, Husband & Reznek's Imaging in Oncology, 2020
Monoclonal antibody therapy against the CD20 antibody (the best-known drug is rituximab) has been in use for some time now in the treatment of lymphoproliferative disorders, specifically follicular and diffuse large B-cell lymphoma, with improved survival. However, the association of this antibody therapy with an increased risk of PML is well-known. Obinutuzumab (used in CLL and some lymphomas) has also been implicated, as has mycophenolate, and there are now case reports with other monoclonal antibody therapies (e.g. pembrolizumab) (22).
Combination strategies for lupus nephritis: facts and controversies
Published in Expert Review of Clinical Immunology, 2023
A phase II RCT (NOBILITY) of 125 patients with active ISN/RPS class III/IV LN who received either obinutuzumab (1000 mg x 2 doses 2 weeks apart at baseline and week 24) or PBO in addition to background GC and MMF was recently published [52]. The duration of this study was much longer (104 weeks) than in the LUNAR study (52 weeks) [43]. The end points, CRR at week 52 and week 104, were achieved at higher rates in the obinutuzumab than PBO group of patients (35% vs 23%; p = 0.12; 41% vs 23%; p = 0.03). Obinutuzumab led to more improvement in SLE serologies, eGFR and proteinuria than PBO but was not associated with an increase in SAE, serious infections or mortality. The lower incidence of serious infections could be partly related to lower dose of oral prednisone (0.5 mg/kg/day) and MMF (2–2.5 g/day) adopted in the protocol. However, non-serious infusion-related reaction was more commonly reported with obinutuzumab. Thus, the newer generation anti-CD20 biologic agent appears to be promising in LN but the onset of clinical benefit may be slow. A phase III RCT (REGENCY) of obinutuzumab in LN is in progress (NCT04221477).
Acalabrutinib in chronic lymphocytic leukemia
Published in Expert Opinion on Pharmacotherapy, 2023
Enrica Antonia Martino, Antonella Bruzzese, Ernesto Vigna, Enrico Iaccino, Francesco Mendicino, Eugenio Lucia, Virginia Olivito, Gianfranco Filippelli, Antonino Neri, Fortunato Morabito, Massimo Gentile
ACA was studied in phase I/II trials evaluating its safety and efficacy in relapse-refractory (R/R) CLL. In the first trial, 61 R/R CLL patients received ACA at 100–400 mg once daily in the study’s dose-escalation (phase 1) portion and 100 mg twice daily in expansion phase 2. No dose-limiting toxic effects occurred during the dose-escalation phase. The most adverse events were of grade 1 or 2. The overall response rate was 95%; the optimal dosage was established at 100 mg twice daily [8]. In the phase 1b/2 study, 134 patients with R/R CLL received ACA 100 mg twice daily in monotherapy for a median of 41 months. The most adverse events (AEs) were mild or moderate, whereas grade ≥3 AEs occurred in ≥5% of patients. Atrial fibrillation (AF) and major bleeding AEs occurred in 7% and 5% of patients. The overall response rate (ORR) was 94%, regardless of the presence of del(11)(q22.3), del(17)(p13.1), complex karyotype, or IGHV mutation status. The median duration of response and progression-free survival (PFS) has not been reached; the estimated 45-month PFS was 62% [9]. The association with Obinutuzumab (Obi) was first investigated in a phase 1b/2 study, including treatment-naïve (TN) or R/R CLL patients. The ORR was 95% in TN and 92% in the R/R cohort. At 36 months, 94% of TN and 88% of R/R were, respectively, progression-free [10].
The future of antibody therapy in chronic lymphocytic leukemia
Published in Expert Opinion on Emerging Drugs, 2021
Jennifer L. Crombie, Jennifer R. Brown
Obinutuzumab is a next-generation anti-CD20 antibody that has become fundamental to the treatment of patients with CLL after demonstrating improved PFS compared to rituximab, when given in combination with chlorambucil[59]. Obinutuzumab is a fully humanized, afucosylated IgG1 monoclonal antibody against CD20. Unlike rituximab and ofatumumab, obinutuzumab is a type II antibody, which primarily acts through cell death induction and enhanced ADCC and ADCP (Figure 2) [10,41,60]. Obinutuzumab recognizes a unique epitope of CD20 (Figure 2) and has a modified amino acid sequence compared to type I agents, resulting in spatial alterations of the CD20-mAb assembly complex on B-cells[41]. As type II antibodies do not localize into lipid rafts, CDC is significantly reduced as compared to rituximab and ofatumumab. However, cell mediated killing is enhanced, as afucosylation of the Fc region results in enhancement in binding affinity to the FcγRIIIa receptor[61]. Direct cell killing can also occur, in which cell death is thought to rely on actin reorganization rather than BCL-2 dependent caspase activation, and is mediated by lysosomes[62]. Additionally, it has been shown that type II antibodies, such as obinutuzumab, are less predisposed to FcγRIIb mediated CD20 internalization that can result in resistance in type I antibodies[63].