Obinutuzumab is a glycoengineered type II antibody that differs from type I anti-CD20 antibodies by being associated with actin reorganization and adhesion followed by direct cell death.1 Obinutuzumab has been glycoengineered by reduction in fucose content of the Fc region, which increases its affinity for Fcγ receptors in effector cells and confers greater antibody-dependent cellular cytotoxicity compared with nonglycoengineered antibodies.2 In preclinical studies, obinutuzumab has been shown to be superior to rituximab (Rituxan) in xenograft lymphoma models.2
Clinical Trials
Phase I clinical trials demonstrated the safety of obinutuzumab; however, higher doses appeared to be necessary to saturate the CD20 receptors.3 The two phase II studies recently reported in Journal of Clinical Oncology explored obinutuzumab treatment in relapsed/refractory indolent or aggressive non-Hodgkin lymphoma.
The study by Morschhauser et al included 40 patients with relapsed/refractory diffuse large B-cell or mantle cell lymphoma with dose-level randomizations. Responses were observed in 32% of the diffuse large B-cell lymphoma group and 27% of the mantle cell lymphoma group. Although these are modest response rates, there were a few patients with responses lasting longer than 2 years.
The trial by Salles et al examined obinutuzumab in patients with relapsed/refractory indolent lymphoma. The response rate was higher in the indolent lymphoma patients, with a best response rate of 64% and a median duration of response of 17.2 months (range, 0.8–31.3 months).
The toxicity in both trials was modest, with some infusion reactions and two episodes of tumor lysis syndrome. There were no treatment-related deaths in the studies.
Potential Therapeutic Improvement
These studies provide an excellent example of taking an engineered molecule that demonstrates possibly superior attributes in the lab and translating it to human clinical trials, with potential to improve upon our current therapies with other anti-CD20 monoclonal antibodies. Due to the mechanism of action including increased antibody-dependent cellular cytotoxicity, there was concern that obinutuzumab would have increased toxicity, including infusion reactions. However, the clinical trials to this point have not demonstrated such toxicities. Based upon these and other studies, an obinutuzumab dose of 1,000 mg for all cycles has been chosen and is being moved forward in current phase II and III trials.
Obinutuzumab is also now being tested in several combination trials with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) for front-line treatment of diffuse large B-cell lymphoma and with bendamustine (Treanda) for rituximab-refractory follicular lymphoma. Additionally, specific subtypes of lymphoma may respond better to different anti-CD20 antibodies based upon Fcγ receptors or other tumor biology characteristics. Only prospective randomized trials will be able to demonstrate superiority of obinutuzumab to rituximab in any of these clinical situations. ■
Disclosure: Dr. Vose reported no potential conflicts of interest.
Dr. Vose is the Neumann M. and Mildred E. Harris Professor and Chief of the Division of Hematology/Oncology at the University of Nebraska Medical Center, Omaha.
References
1. Alduaji W, Ivanov A, Honeychurch J, et al: Novel type II anti-CD20 monoclonal antibody (GA101) evokes homotypic adhesion and actin-dependent, lysosome-mediated cell death in B-cell malignancies. Blood 117:4519-4529, 2011.
2. Mossner E, Brunker P, Moser S, et al: Increasing the efficacy of CD20 antibody therapy through the engineered direct and immune effector cell-mediated B-cell cytotoxicity. Blood 115:4393-4402, 2010.
3. Menesses-Lorente G, Carlile D, Birkett J, et al: Pharmacokinetics of RO5072759 (GA101) in patients with relapsed/refractory CD20+ malignant diseases (phase I/II study BO20999). Blood 116:Abstract 1833, 2010.
