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A Nonfucosylated Anti-HER2 Antibody Augments Antibody-Dependent Cellular Cytotoxicity in Breast Cancer Patients

Authors' Affiliations: ¹ Breast Group, Komagome Hospital, Tokyo Metropolitan Cancer and Infectious Diseases Center; ² Pharmaceutical Research Center, Kyowa Hakko Kogyo Co. Ltd.; and ³ Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tokyo, Japan

Requests for reprints: Masakazu Toi, Breast Group, Komagome Hospital, Tokyo Metropolitan Cancer and Infectious Diseases Center, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan. Phone: 81-3-3823-2101; Fax: 81-3-3824-1552; E-mail: maktoi77{at}wa2.so-net.ne.jp.

Purpose: Removal of fucose residues from the oligosaccharides of human antibody is a powerful approach to enhance antibody-dependent cellular cytotoxicity (ADCC), a potential important antitumor mechanism of therapeutic antibodies. To provide clinically relevant evidence of this mechanism, we investigated ADCC of a fucose-negative version of trastuzumab [anti–human epidermal growth factor receptor 2 (HER2) humanized antibody] using peripheral blood mononuclear cells (PBMC) from breast cancer patients as effector cells.

Experimental Design: Thirty volunteers, including 20 breast cancer patients and 10 normal healthy control donors, were recruited randomly, and aliquots of peripheral blood were collected. ADCC of commercial trastuzumab (fucosylated) and its fucose-negative version were measured using PBMCs drawn from the volunteers as effector cells and two breast cancer cell lines with different HER2 expression levels as target cells. Relationships between cytotoxicity and characteristics of the patients, such as content of natural killer cells in PBMCs, type of therapy, FCGR3A genotypes, etc. were also analyzed.

Results: ADCC was significantly enhanced with the fucose-negative antibody compared with the fucose-positive antibody using PBMCs from either normal donors or breast cancer patients. Enhancement of ADCC was observed irrespective of the various clinical backgrounds of the patients, even in the chemotherapy cohort that presented with a reduced number of natural killer cells and weaker ADCC.

Conclusions: This preliminary study suggests that the use of fucose-negative antibodies may improve the therapeutic effects of anti-HER2 therapy for patients independent of clinical backgrounds.

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