Mogamulizumab

Overview

Mogamulizumab (KW-0761) is a humanized deglycosylated IgG1 mAb that targets CC chemokine receptor 4 (CCR4). This antibody can enhance ADCC effect by removing fucose content on the Fc region of mogamulizumab IgG. Through this, the binding affinity of the FcγR on the surface of non-specific effector cells (such as killer (NK) cells and macrophages/monocytes) to the Fc region of the IgG molecule is enhanced, thereby eliminating tumor cells. This MOA not only increases activity of cytotoxic cells, but also promotes the release of cytoplasmic lyase, granzymes, perforin-containing particles and tumor necrosis factor (TNF) that induces antibody-targeted cell lysis.

ADCC Enhancement Technology for Mogamulizumab

Mogamulizumab is a novel type II glycosylation-engineered humanized anti-CCR4 monoclonal antibody developed to meet the needs for an agent with stronger effects on CCR4-positive cancers. The glycosylation process used to develop this agent is achieved by reducing the fucosylation in the Fc region of the mAb molecule, resulting in an increased binding affinity of the agent for the FcγRIIIa receptor on immune effector cells.

Fig.2 Glycoengineering by defucosylation of immunoglobulin G oligosaccharides in the Fc region of Mogamulizumab.

Mechanism of Action of Mogamulizumab

Mogamulizumab is a cell clone of a deglycosylated mAb produced using ADCC-enhanced technology, meaning that its complex type has no fucose in the constant (Fc) region on the carbohydrate structure of cells. Mogamulizumab has ADCC activity but does not exhibit any CDC activity or neutralizing ability to CCR4 ligand. Mogamulizumab has a complementarity determining region (CDR) CC-chemokine receptor 4 (CCR4) derived from mouse anti-human, which binds to CCR4 antigen on the surface of T cells and induces ADCC. The MoA of Mogamulizumab is established by three elements: CCR4 antigen on target cells, Mogamulizumab antibody, and gamma receptor IIIa (FcγRIIIa) interacting with Fc on natural killer (NK) effector cells. The MoA is depicted below.

Fig.3 Mechanisms of action of Mogamulizumab.

Glycan Analysis of Mogamulizumab

Glycan profiles of Mogamulizumab by hydrophilic interaction liquid chromatography (HILIC).

ADCC Activity

KW-0761 mediates effective in vitro ADCC activity against primary Adult T-Cell Leukemia Lymphoma (ATLL) cells in the autologous environment.

Antitumor Efficacy in Preclinical

• Mogamulizumab induces potent anti-tumor activity against EBV-positive NK cell lymphoma in a mouse xenograft model.

• Antitumor Activity of mogamulizumab in SCID Mouse Models

Clinical Applications

Mogamulizumab has obtained FDA approval for Cutaneous T-cell lymphoma (CTCL) and Adult T-Cell Leukemia Lymphoma (ATLL) based on the results confirmed by the third phase MAVORIC study.

• Clinical experience with mogamulizumab in patients with CTCL. The table below summarizes the safety comparison of mogamulizumab with other systemic treatment options for CTCL.

• Clinical experience with mogamulizumab in ATLL.

For more detailed information, please do not hesitate to contact us.

Reference

1. Tobinai K.; et al. A Review of Mogamulizumab (GA101), a Novel Type II Anti-CCR4 Monoclonal Antibody, for the Treatment of Patients with B-Cell Malignancies. Advances in Therapy. 2017, 34(2):324-356.