A Review of Obinutuzumab (GA101), a Novel Type II Anti-CD20 Monoclonal Antibody, for the Treatment of Patients with B-Cell Malignancies

Abstract

Obinutuzumab (GA101) is a novel, type II, glycoengineered, humanized anti-CD20 monoclonal antibody that has been developed to address the need for new therapeutics with improved efficacy in patients with lymphocytic leukemia and lymphoma of B-cell origin. Obinutuzumab has a distinct mode of action relative to type I anti-CD20 antibodies, such as rituximab, working primarily by inducing direct cell death and antibody-dependent cell-mediated cytotoxicity. Obinutuzumab is under investigation in a wide-ranging program of clinical trials in patients with B-cell malignancies. Efficacy as monotherapy has been reported in patients with relapsed/refractory indolent and aggressive non-Hodgkin lymphoma (NHL) and in chronic lymphocytic leukemia (CLL) of B-cell origin. Improved outcomes have also been noted when obinutuzumab is added to chemotherapy in patients with B-cell NHL, and superiority over rituximab has been reported with combination therapy in patients with CLL. Ongoing research is focusing on developing options for chemotherapy-free treatment and on new combinations of obinutuzumab with novel targeted agents.

Keywords: Antibody-dependent cell-mediated cytotoxicity; B-cell lymphoma; CD20; Chronic lymphocytic leukemia; Glycoengineering; Monoclonal antibody; Non-Hodgkin lymphoma; Obinutuzumab; Oncology; Rituximab.

Fig. 1

Structure and binding behavior of obinutuzumab. Glycoengineered structure and type II binding properties of obinutuzumab. a Glycoengineering by defucosylation of immunoglobulin G oligosaccharides in the Fc region of obinutuzumab. In Chinese hamster ovary producer cells, N-acetylglucosamine (NAG) is assembled into oligosaccharides, which sterically prevents the addition of fucose to the carbohydrate attached to asparagine (Asn) 297. b Hypothetical model of CD20 binding properties of type I and II antibodies. In contrast to inter-tetrameric CD20 binding of type I antibodies, intra-tetrameric binding of type II antibodies to CD20 does not lead to FcγRIIb-mediated internalization of CD20 in lipid rafts (reproduced from Goede et al. [38] with permission; copyright © 2015 Karger Publishers, Basel, Switzerland)

Fig. 2

Putative mechanisms of action of obinutuzumab. Please refer to the text for further information and supporting references. ADCC antibody-dependent cell-mediated cytotoxicity, ADCP antibody-dependent cellular phagocytosis, CDC complement-dependent cytotoxicity (adapted from Goede et al. [41] with permission)

Fig. 3

Percentage tumor growth inhibition (TGI) in combination studies of mouse Z138 MCL xenografts [69]. *Statistically significant (p < 0.001; Tukey-Kramer test) vs. single-agent treatments. **Statistically significant vs. G monotherapy and RIT + FLU. ***Statistically significant vs. RIT monotherapy. TGI was calculated from tumor volume (TV) [(length × width²)/2], calculated from staging until study termination, as follows: TGI (%) = $100-\frac{\text{Median}[\text{TV}{\left(\text{treated}\right)}_{\text{day}z}-\text{TV}{\left(\text{treated}\right)}_{\text{day}x}]}{\text{Median}[\text{TV}{\left(\text{respective}\text{control}\right)}_{\text{day}z}-\text{TV}{\left(\text{respective}\text{control}\right)}_{\text{day}x}]}\times 100.$ Each treatment group was compared with its respective vehicle control. TVday z represented TV for an individual animal at a defined study day (day z), and TVday x represented TV of an individual animal at the staging day (day x). Animals in control groups received 0.9% sodium chloride vehicle; randomization to treatments took place 9–27 days after tumor cell injection. Animals were killed at various time points from day 30 to day 66. BEN bendamustine, CHL chlorambucil, FLU fludarabine, G obinutuzumab (GA101), MCL mantle cell lymphoma, RIT rituximab, TGI tumor growth inhibition