This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Iida, S. Articles by Satoh, M. Search for Related Content PubMed PubMed Citation Articles by Iida, S. Articles by Satoh, M.

Nonfucosylated Therapeutic IgG1 Antibody Can Evade the Inhibitory Effect of Serum Immunoglobulin G on Antibody-Dependent Cellular Cytotoxicity through its High Binding to FcRIIIa

Authors' Affiliation: Tokyo Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Machida-shi, Tokyo, Japan

Requests for reprints: Mitsuo Satoh, Senior Researcher, Tokyo Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., 3-6-6 Asahi-machi, Machida-shi, Tokyo 194-8533, Japan. Phone: 81-42-725-2556; Fax: 81-42-726-8330; E-mail: msatoh{at}kyowa.co.jp.

Purpose: Recent studies have revealed that fucosylated therapeutic IgG1s need high concentrations to compensate for FcRIIIa-competitive inhibition of antibody-dependent cellular cytotoxicity (ADCC) by endogenous human plasma IgG. Here, we investigated whether ADCC of nonfucosylated therapeutic IgG1 is also influenced by plasma IgG in the same way as fucosylated IgG1s.

Experimental Design: Ex vivo ADCC upon CD20⁺ human B cells was induced by incubation of human whole blood with nonfucosylated and/or fucosylated anti-CD20 IgG1s rituximab, and quantified by measuring the remaining CD19⁺ human B cells using flow cytometry.

Results: Nonfucosylated anti-CD20 showed markedly higher (over 100-fold based on EC₅₀) ex vivo B-cell depletion activity than its fucosylated counterpart in the presence of plasma IgG. The efficacy of fucosylated anti-CD20 was greatly diminished in plasma, resulting in the need for a high concentration (over 1.0 µg/mL) to achieve saturated efficacy. In contrast, nonfucosylated anti-CD20 reached saturated ADCC at lower concentrations (0.01-0.1 µg/mL) with much higher efficacy than fucosylated anti-CD20 in all nine donors through improved FcRIIIa binding. Noteworthy, the high efficacy of nonfucosylated anti-CD20 was inhibited by addition of fucosylated anti-CD20. Thus, the efficacy of a 1:9 mixture (10 µg/mL) of nonfucosylated and fucosylated anti-CD20s was inferior to that of a 1,000-fold dilution (0.01 µg/mL) of nonfucosylated anti-CD20 alone.

Conclusions: Our data showed that nonfucosylated IgG1, not including fucosylated counterparts, can evade the inhibitory effect of plasma IgG on ADCC through its high FcRIIIa binding. Hence, nonfucosylated IgG1 exhibits strong therapeutic potential through dramatically enhanced ADCC at low doses in humans in vivo.

This article has been cited by other articles:

				B. Li, S. Shi, W. Qian, L. Zhao, D. Zhang, S. Hou, L. Zheng, J. Dai, J. Zhao, H. Wang, et al. Development of Novel Tetravalent Anti-CD20 Antibodies with Potent Antitumor Activity Cancer Res., April 1, 2008; 68(7): 2400 - 2408. [Abstract] [Full Text] [PDF]

				S. Varchetta, N. Gibelli, B. Oliviero, E. Nardini, R. Gennari, G. Gatti, L. S. Silva, L. Villani, E. Tagliabue, S. Menard, et al. Elements Related to Heterogeneity of Antibody-Dependent Cell Cytotoxicity in Patients Under Trastuzumab Therapy for Primary Operable Breast Cancer Overexpressing Her2 Cancer Res., December 15, 2007; 67(24): 11991 - 11999. [Abstract] [Full Text] [PDF]

				Y. Kanda, T. Yamada, K. Mori, A. Okazaki, M. Inoue, K. Kitajima-Miyama, R. Kuni-Kamochi, R. Nakano, K. Yano, S. Kakita, et al. Comparison of biological activity among nonfucosylated therapeutic IgG1 antibodies with three different N-linked Fc oligosaccharides: the high-mannose, hybrid, and complex types Glycobiology, January 1, 2007; 17(1): 104 - 118. [Abstract] [Full Text] [PDF]