Obinutuzumab (GA101), a type II glycosylation-modified humanized anti-CD20 therapeutic antibody, was initially developed for use of novel immunotherapy involving patients with lymphocytic leukemia and B cell-derived lymphoma. Compared to type I anti-CD20 antibodies (e.g., rituximab), Obinutuzumab has a unique mode of action (MOA) that acts primarily by inducing cell death and antibody-dependent cell-mediated cytotoxicity (ADCC) directly to the target. Obinutuzumab working as monotherapy in patients with B-cell malignancies and invasive non-Hodgkin's lymphoma (NHL) has shown some promising results. Improved efficacy on combination therapy with rituximab-based monotherapy in Chronic lymphocytic leukemia (CLL) patients is also reported.
Obinutuzumab (GA101) is originally developed because the need for a new reagent that has higher activity than rituximab. The glycosylation process used to develop Obinutuzumab is achieved by reducing the fucosylation in the Fc region of that mAb, resulting in increased binding affinity of the agent for the FcγRIIIa receptor on immune effector cells.
Fig.1 Glycoengineering by defucosylation of immunoglobulin G oligosaccharides in the Fc region of obinutuzumab.
The MOA of type II obinutuzumab is enhancing direct cell death and ADCC / ADCP effect, while reducing CDC effect through glycoengineering. On the contrary, the classic type I anti-CD20 monoclonal antibody (such as rituximab) acts primarily through CDC and ADCC / ADCP, contributing much less to overall anti-tumor activity.
Fig.2 Mechanisms of action of obinutuzumab.
Obinutuzumab (GA101) was expressed in CHO cells. Glycan analysis using HILIC-HPLC showed that Obinutuzumab exhibited very low levels of fucose.
Obinutuzumab induces higher level of ADCC activity compared to Rituximab.
Obinutuzumab exhibits superior effects in vivo than rituximab used in human lymphoma xenograft models. In the staged invasive model, it was noted that the dose-dependent efficacy of Obinutuzumab is in the range of 1-30 mg/kg. A complete tumor regression was shown in all animals and 90% sustained tumor eradication at the highest dose of 30 mg/kg. In contrast, equivalent dosages of rituximab or orfarizumab did not show significant tumor regression.
Creative Biolabs provides luciferase-based ADCC assay. This Jurkat cell based assay is pioneered by Creative Biolabs, and the methodology is very well accepted by the field. See attached ADCC Reporter Assay Protocol for further details.
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