A tale of two antibodies: obinutuzumab versus rituximab

Abstract

While rituximab has dramatically improved outcomes for patients with CD20 malignancies for two decades, responses are not universal and resistance can develop. Obinutuzumab was developed to potentiate activity and overcome resistance. Pre-clinical data suggests obinutuzumab is superior to rituximab at effecting B cell depletion; however recent phase III clinical trial results have been mixed. The decision of which antibody to employ will probably be further complicated by the approval of a subcutaneous preparation of rituximab and several anti-CD20 biosimilars. Clinicians are now challenged with deciding whether to switch to obinutuzumab in approved settings, accepting the potential for increased toxicity and probable increased cost. The benefit conferred by obinutuzumab over rituximab may be context-specific and vary based on histological subtype and immune integrity. This comprehensive review will explore the preclinical differences, investigate the proposed pathogenesis of rituximab resistance, compare the employed dosing strategies and interrogate available clinical results to help inform practice.

A global antiB cell strategy combining obinutuzumab and daratumumab in severe pediatric nephrotic syndrome

“…In detail, obinutuzumab is able to overcome the low affinity of certain polymorphisms of the FcGamma receptor 3A on effector cells, hence improving antibody-dependent cytotoxicity in a greater proportion of patients. Clinically, obinutuzumab induces more profound and lasting remission, with an almost twofold higher complete response rate in patients treated for indolent nonHodgkin lymphoma [ 15 ] and may also be more efficient than rituximab in autoimmune diseases [ 16 – 18 ].…”

Novel Therapies Potentially Available for Pediatric B-Cell Non-Hodgkin Lymphoma

“…A number of next-generation monoclonal antibodies have also been investigated but have had limited success in improving survival outcomes. Obinutuzumab, a type II monoclonal antibody with greater in vitro ADCC and direct cell death than rituximab, 36 did not improve outcomes in adults newly diagnosed with DLBCL randomized to receive either rituximab or obinutuzumab in conjunction with cyclophosphamide/ doxorubicin/vincristine/prednisone (CHOP). 37 A pediatric phase II trial combining obinutuzumab 1 ifosfamide/ carboplatin/etoposide (ICE) is ongoing (ClinicalTrials.gov identifier: NCT02393157).…”

A review of advances in the understanding of lupus nephritis pathogenesis as a basis for emerging therapies

“…Proposed explanations for this apparent paradox include the efficacy of background immunosuppression, suboptimal depletion of tissue-infiltrating B cells and plasma cells, increased BAFF secretion, and inadequate sensitivity of clinical efficacy endpoints. Lack of treatment efficacy could also be related to monoclonal antibody metabolism, reduced antibody binding due to FcγRIII polymorphism, complement depletion, increased expression of complement inhibitory molecules such as CD55 and CD59, abnormal lipid raft composition, or limited access to the parenchyma of solid organs 23 , 24 . In this regard, B cells are present in the tubulo-interstitium and contribute to local inflammation and kidney injury 25 .…”

“…Obinutuzumab is a glycoengineered, type II, humanized anti-CD20 antibody developed to treat lymphoproliferative disorders and to alleviate several mechanisms which could lead to treatment resistance. Obinutuzumab has no fucosylated sugars on the Fc portion and demonstrates enhanced binding affinity to the FcγRIII receptor on immune effector cells 24 . Obinutuzumab is more effective than rituximab in inducing direct B cell death and antibody-dependent cellular cytotoxicity and phagocytosis.…”