Obinutuzumab

Overview

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.

ADCC Enhancement Technology for Obinutuzumab

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.

Glycoengineering by defucosylation of immunoglobulin G oligosaccharides in the Fc region of obinutuzumab. Fig.1 Glycoengineering by defucosylation of immunoglobulin G oligosaccharides in the Fc region of obinutuzumab.

Mechanism of Action 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.

Mechanisms of action of obinutuzumab. Fig.2 Mechanisms of action of obinutuzumab.

Glycan Analysis of Obinutuzumab

Obinutuzumab (GA101) was expressed in CHO cells. Glycan analysis using HILIC-HPLC showed that Obinutuzumab exhibited very low levels of fucose.

Obinutuzumab

ADCC Activity

Obinutuzumab induces higher level of ADCC activity compared to Rituximab.

Obinutuzumab

Antitumor Efficacy in Preclinical

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.

Obinutuzumab

Clinical Trials of Obinutuzumab

Obinutuzumab

Reference

  1. Tobinai K.; et al. A Review of Obinutuzumab (GA101), a Novel Type II Anti-CD20 Monoclonal Antibody, for the Treatment of Patients with B-Cell Malignancies. Advances in Therapy. 2017, 34(2):324-356.

RESOURCES

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. 

All products and services are for Research Use Only. Do Not use in humans.

CASE STUDY

ADCC Assay WT vs AfucoTM Mabs  Visit

Resource

Antibody Fc Engineering: Towards Better Therapeutics  Visit

ONLINE INQUIRY

Creative Biolabs has established a team of customer support scientists ready to discuss ADCC/CDC optimization strategies, antibody production, bioinformatics analysis and other molecular biology/biotechnology issues.

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