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

• Published in: Clinical cancer research Vol. 11; no. 6; pp. 2327 - 2336
• Main Authors: NIWA, Rinpei, SAKURADA, Mikiko, KOBAYASHI, Yukari, UEHARA, Aya, MATSUSHIMA, Kouji, UEDA, Ryuzo, NAKAMURA, Kazuyasu, SHITARA, Kenya
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-03-2005
• Subjects: antibody effector function; Antibody immunotherapy; Antibody-Dependent Cell Cytotoxicity; Antigens, CD20 - metabolism; Antineoplastic agents; Biological and medical sciences; CD56 Antigen - metabolism; Fucose - immunology; Humans; Immunoglobulin G - metabolism; Killer Cells, Natural - immunology; leukemia/lymphoma; Lymphoma - metabolism; Lymphoma - pathology; Medical sciences; Pharmacology. Drug treatments; Protein Binding; Receptors, CCR4; Receptors, Chemokine - genetics; Receptors, Chemokine - metabolism; Tumor Cells, Cultured; Antigen; Natural killer cell; Antibody; Cytotoxicity; IgG1; Density; In vitro; Fucose
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-04-2263

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 FcγRIIIa. 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.