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Enhanced Natural Killer Cell Binding and Activation by Low-Fucose IgG1 Antibody Results in Potent Antibody-Dependent Cellular Cytotoxicity Induction at Lower Antigen Density

¹ Tokyo Research Laboratories, Kyowa Hakko Kogyo, Co., Ltd.; ² Department of Molecular Preventive Medicine, School of Medicine, University of Tokyo, Tokyo, Japan; and ³ Department of Internal Medicine and Molecular Science, Nagoya City University Graduate School of Medical Science, Nagoya, Japan

Requests for reprints: Kenya Shitara, Division of Immunology, Tokyo Research Laboratories, Kyowa Hakko Kogyo, Co., Ltd., 3-6-6 Asahi-machi, Machida-shi, Tokyo 194-8533, Japan. Phone: 81-42-725-0857; Fax: 81-42-725-2689; E-mail: kshitara{at}kyowa.co.jp.

Purpose: Recent studies have revealed that fucose removal from the oligosaccharides of human IgG1 antibodies results in a significant enhancement of antibody-dependent cellular cytotoxicity (ADCC) via improved IgG1 binding to FcRIIIa. In this report, we investigated the relationship between enhanced ADCC and antigen density on target cells using IgG1 antibodies with reduced fucose.

Experimental Design: Using EL4 cell-derived transfectants with differential expression levels of exogenous human CC chemokine receptor 4 or human CD20 as target cells, ADCC of fucose variants of chimeric IgG1 antibodies specific for these antigens were measured. We further investigated IgG1 binding to natural killer (NK) cells and NK cell activation during ADCC induction to elucidate the mechanism by which low-fucose IgG1 induces ADCC upon target cells with low antigen expression.

Results: Low-fucose IgG1s showed potent ADCC at low antigen densities at which their corresponding high-fucose counterparts could not induce measurable ADCC. The quantitative analysis revealed that fucose depletion could reduce the antigen amount on target cells required for constant degrees of ADCC induction by 10-fold for CC chemokine receptor 4 and 3-fold for CD20. IgG1 binding to NK cells was increased by ligating IgG1 with clustered antigen, especially for low-fucose IgG1. Up-regulation of an activation marker, CD69, on NK cells, particularly the CD56^dim subset, in the presence of both the antibody and target cells was much greater for the low-fucose antibodies.

Conclusions: Our data showed that fucose removal from IgG1 could reduce the antigen amount required for ADCC induction via efficient recruitment and activation of NK cells.

Key Words: Antibody immunotherapy • antibody effector function • leukemia/lymphoma

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