Obinutuzumab in hematologic malignancies: Lessons learned to date

Abstract

The routine use of anti-CD20 monoclonal antibodies (mAbs) has improved patient outcomes in CD20-positive non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Despite the clinical success achieved with rituximab, relapses are still common with further improvements in anti-CD20 mAb efficacy required. Many novel anti-CD20 antibodies are in development, but obinutuzumab is currently the only type II glycoengineered anti-CD20 mAb in clinical testing. Obinutuzumab has increased antibody-dependent cell-mediated cytotoxicity, reduced complement-dependent cytotoxicity and enhanced direct non-apoptotic cell death. In preclinical models, obinutuzumab induced superior tumor remission compared with rituximab at the equivalent dose levels, and was active in rituximab-refractory tumors. Obinutuzumab exhibits encouraging efficacy as monotherapy in NHL, and combined with chemotherapy in relapsed/refractory NHL and treatment-naïve symptomatic CLL. In a recent randomized, phase III trial in patients with untreated comorbid CLL, overall response rate was significantly greater (78% vs. 65%, P<0.0001) and median progression-free survival was significantly prolonged (26.7 vs. 15.2months, P<0.0001) for obinutuzumab plus chlorambucil vs. rituximab plus chlorambucil. Obinutuzumab is a type II anti-CD20 antibody that utilizes distinct mechanisms of action relative to type I antibodies like rituximab and has led to significant clinical improvement over rituximab in a phase III trial in CLL. Further trials are ongoing to determine whether such improvements in outcome will be seen in CD20-positive B-cell malignancies.

Management of Epstein-Barr Virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation: Sixth European Conference on Infections in Leukemia (ECIL-6) guidelines

“…EBV-CTL can be isolated and expanded ex vivo from EBV-seropositive stem cell or third-party donors. Considering the recent success and safety profile of obinutuzumab in CD20-positive malignancies, 89,90 novel anti-CD20 monoclonal antibodies are possible candidates for future use in EBV-PTLD. The possibility of new and experimental therapies for EBV-PTLD has also recently emerged in the transplant setting, including brentuximab vedotin, anti-CD30 antibodies.…”

Reviving the guardian of the genome: Small molecule activators of p53

“…In addition to preclinical assessment of RG7338 as therapy for neuroblastoma (L. Chen et al, 2015; Lakoma et al, 2015), childhood sarcoma (Phelps et al, 2015), and ovarian carcinoma(Zanjirband, Edmondson, & Lunec, 2016), RG7338 is involved in five other phase I/II studies currently recruiting participants: in combination with obinutuzumab, a novel anti-CD20 mAB, for relapsed or refractory follicular lymphoma or diffuse large B-cell lymphoma (Illidge et al, 2015) (NCT02624986), in combination with Venetoclax, a novel BH3-mimetic/Bcl-2 inhibitor, for patients over 60 with relapsed or refractory AML who are ineligible for cytotoxic therapy (Woyach & Johnson, 2015) (NCT02670044), in combination with dexamethasone and ixazomib citrate, a novel proteasome inhibitor, for refractory multiple myeloma (P. G. Richardson et al, 2015) (NCT02633059), as a standalone drug for polycythemia vera and essential thrombocythemia (NCT02407080), and in a study designed to compare oral vs intravenous administration of RG7388 in terms of excretion balance, pharmacokinetics, metabolism, and bioavailability in patients with solid tumors (NCT02828930).…”

Targeted Therapy of CLL

“…Ofatumumab has a particularly high affinity and powerful CDC activity due to a distinct binding site at the CD20 transmembrane protein that is different to rituximab's binding region [8]. In contrast, obinutuzumab (GA101) is a type II antibody that mediates its cytotoxic activities mainly by increased binding and activation of natural killer cells particularly via its FCγIIIa fragment and ultimately by antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), rather than CDC (reviewed in [9]). These particular characteristics were achieved by modification of the Fc-attached glycan tree (‘glycoengineering') as well of the molecular structure of the antibody hinge region [10].…”