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Impact of Obinutuzumab Alone and in Combination for Follicular Lymphoma

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Impact of Obinutuzumab Alone and in Combination for Follicular Lymphoma Journal name: Blood and Lymphatic Cancer: Targets and Therapy Article Designation: REVIEW Year: 2017 Volume: 7 Blood and Lymphatic Cancer: Targets and Therapy Dovepress Running head verso: Sarraf Yazdy and Cheson Running head recto: Obinutuzumab for follicular lymphoma open access to scientific and medical research DOI: http://dx.doi.org/10.2147/BLCTT.S114173 Open Access Full Text Article REVIEW Impact of obinutuzumab alone and in combination for follicular lymphoma Maryam Sarraf Yazdy Abstract: Although rituximab-based chemoimmunotherapy prolongs the survival of patients Bruce D Cheson with follicular lymphoma (FL), this disease is considered incurable in most patients. Thus, new therapies are needed not only for those in the relapsed/refractory setting, but also for Division of Hematology-Oncology, Georgetown University Hospital, initial treatment. Obinutuzumab (G, GA101) is a third-generation, fully humanized type II Lombardi Comprehensive Cancer glycoengineered, anti-CD20 monoclonal antibody that results in increased direct cell death and Center, Washington, DC, USA antibody-dependent, cell-mediated cytotoxicity/phagocytosis compared to rituximab. Obinu- tuzumab has significant antitumor activity when used alone or in combinations in untreated or relapsed refractory FL patients. Studies have demonstrated its ability to prolong progression-free survival and, in some cases, overall survival, and to eliminate minimal residual disease. Several For personal use only. ongoing trials are investigating combinations with chemotherapy, immunomodulators, targeted drugs, and immunotherapy agents. G is generally well tolerated, with associated adverse effects including infusion-related reactions, neutropenia, thrombocytopenia, and reactivation of hepatitis B virus. Future studies with this antibody should focus on identifying predictive markers and developing chemotherapy-free combinations that will improve the outcome of patients with FL. Keywords: obinutuzumab, follicular lymphoma, MRD, monoclonal antibody Introduction The improved survival of patients with follicular lymphoma (FL) has resulted from the incorporation of rituximab (Genentech, Inc., South San Francisco, CA, USA) into chemoimmunotherapy regimens. However, not all patients benefit from such approaches. Recent studies suggest that patients who fail to maintain a remission of 1 year, 2 years, or 30 months have a significantly inferior outcome to those who do not 1–3 Blood and Lymphatic Cancer: Targets Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 27-Dec-2018 experience an event. Twenty percent of patients with FL relapse within 2 years of treatment have an inferior 5-year overall survival (OS) of 50% compared to 90% for patients who did not relapse early. Nevertheless, the disease is considered incurable in most patients.4–7 Patients typically experience multiple relapses and eventually develop resistance to treatment, often including rituximab.8 Numerous mechanisms of rituximab resistance have been hypothesized, including decreased cellular penetration, impaired Correspondence: Bruce D Cheson rituximab binding (via FcγRIII polymorphisms), downregulation of CD20, increased Lombardi Comprehensive Cancer rituximab metabolism, resistance of tumor cells to rituximab-effector mechanisms, Center, MedStar Georgetown University impaired immune effector cell recruitment or function, and complement depletion and Hospital, 3800 Reservoir Road NW, Washington, DC 20007, USA downregulation of proapoptotic proteins.9–12 Tel +1 202 444 7932 The poor outcome of rituximab-refractory patients has led to a search for more Fax +1 202 444 1229 Email [email protected] effective agents to improve patient outcome, including monoclonal antibodies (mAbs). submit your manuscript | www.dovepress.com Blood and Lymphatic Cancer: Targets and Therapy 2017:7 73–83 73 Dovepress © 2017 Sarraf Yazdy and Cheson. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work http://dx.doi.org/10.2147/BLCTT.S114173 you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Powered by TCPDF (www.tcpdf.org) 1 / 1 Sarraf Yazdy and Cheson Dovepress For an antibody to establish a place in current strategies, it (two complete responses [CRs] and three partial responses should either be more active than rituximab, be effective in [PRs]). All patients had one or more adverse events (AEs) the setting of rituximab resistance, or prolong survival when including 40% IRR and at least one grade 3–4 AE reported given as maintenance. in 49% of patients. Multiple clinical trials with ublituximab MAbs against CD20 are divided into two classes: type alone or in combination with other agents are ongoing. I (i.e., rituximab, ofatumumab [Novartis Pharmaceuticals Anti-CD20s no longer in development include Veltu- Corporation, East Hanover, NJ, USA], veltuzumab [Immu- zumab which is a second-generation humanized anti-CD20 nomedics, Inc., Morris Plains, NJ, USA], and ublituximab mAb and, in vitro, functions similarly to rituximab; however, [TG Therapeutics, Inc., New York, NY, USA]) and type II it has a framework region that differs from rituximab.24 (i.e., obinutuzumab [Genentech, Inc.] and tositumomab Veltuzumab achieved an objective response rate of 44% [GlaxoSmithKline LLC., Wilmington, DE, USA]).13 Upon in 82 patients with relapsed, refractory FL.25 PRO131921 binding, type I antibodies induce a translocation of CD20 is a third-generation humanized anti-CD20 antibody with into large lipid rafts within the plasma membrane, which increased ADCC compared to rituximab.26 In a Phase I trial in does not occur in type II antibodies.14 This event boosts relapsed or refractory CD-20-positive indolent NHL (iNHL), complement activation and results in high complement- a 50% response rate was achieved in rituximab-refractory dependent cytotoxicity (CDC) in type I antibodies, whereas FL patients. AME-133v (Mentrik Biotech, LLC., Dallas, type II antibodies have low CDC induction.15 Internaliza- TX, USA), an engineered humanized IgG1 mAb against tion of CD20 antibody complex after binding of rituximab CD20, demonstrated increased preclinical ADCC activity results in decreased effector cell recruitment and antibody compared to rituximab.27 In a Phase I study of 23 previously half-life whereas type II mAbs demonstrate minimal CD20 treated patients with FL, there were CRs in two (9%) and internalization.16 Only half as many type II antibodies bind PRs in three (13%). per B-cell as type I mAbs.13 The biological implications of this finding are unknown. Obinutuzumab For personal use only. Multiple other second-generation anti-CD20-directed Mechanism of action mAbs have been developed. Ofatumumab is a type I mAb Obinutuzumab (G, GA101) is a third-generation, type II, with greater CDC compared with rituximab, and it detaches glycoengineered, humanized, anti-CD20 mAb of the IgG1 more slowly from CD20.17 It was first approved in patients isotope.28 Fc domains are engineered to improve its therapeu- with chronic lymphocytic leukemia (CLL) who were refrac- tic activity, specifically in patients who express low-affinity tory to alemtuzumab and fludarabine (Ben Venue Labora- Fc receptors on the immune cells.29 Many of the mechanisms tories, Bedford, OH, USA).18 Ofatumumab demonstrated of action of obinutuzumab appear distinct from those of minimal single-agent activity in rituximab-refractory FL.19 rituximab. The different elbow-hinge amino acid sequence In a randomized, multicenter Phase II study of ofatumumab, and 30° wider elbow angle of obinutuzumab compared to a Rosenbaum et al randomized 51 patients with untreated FL to type I mAb such as rituximab results in spatial alterations either 500 mg (n=15) or 1000 mg (n=36) four weekly doses of the CD20–mAb complex on B-cells.28,30 Furthermore, followed by an extended induction phase with four additional posttranslational glycoengineering of type II mAbs enhances 20 Blood and Lymphatic Cancer: Targets Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 27-Dec-2018 doses of ofatumumab every 8 weeks. The overall response binding affinity to the FcγRIII receptor on immune effector rate (ORR) was 86.7% and 60% in 1000 and 500 mg arms, cells and results in increased direct cell death and ADCC/ respectively, suggesting a dose–response effect.20 antibody-dependent, cell-mediated phagocytosis (ADCP).31 Given that ofatumumab appears to result in higher infu- Obinutuzumab binds CD20 in a different orientation than sion-related reactions (IRRs) and neutropenia compared to type I antibodies, despite identifying an overlapping epitope. rituximab, it has not been pursued extensively in this setting.21 It is hypothesized that the different binding topology of this Ublituximab is a type I, glycoengineered anti-CD20 class causes the two Fab arms to bind within one tetramer, recombinant mAb with significantly enhanced antibody- whereas type I mAbs bind different tetramers with each Fab dependent, cell-mediated cytotoxicity (ADCC) compared to arm. Per this hypothesis, this binding type
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