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Complement Activation Plays a Key Role in Antibody-Induced Infusion Toxicity in Monkeys and Rats

Tomonori Tawara^1,*,, Kazumasa Hasegawa^*, Yusuke Sugiura^*, Katsuhiko Harada, Toru Miura, Sunao Hayashi, Tomoyuki Tahara^*, Masaharu Ishikawa^*, Hideaki Yoshida^*, Kinya Kubo^*, Isao Ishida and Shiro Kataoka^*,

^* Discovery Research Laboratories, Development Research Laboratories, and Frontier Laboratory, Kirin Pharma, Gunma, Japan; and Department of Biological and Chemical Engineering, Faculty of Engineering, Gunma University, Gunma, Japan

Infusion reactions are a major side effect of the administration of therapeutic Abs and are the result of a complex immune reaction. In this study, we report that substitutions of Fc amino acids in the anti-HLA-DR Ab HD8 reduce its ability to induce infusion reactions in rats and monkeys. We first showed that i.v. administration of IgG1- and IgG2-subclass HD8 Abs induces severe infusion reactions in monkeys. These Abs express strong complement-dependent cytotoxicity (CDC), and in vivo depletion of complement in rats by pretreatment with cobra venom factor abrogated the lethal infusion reactions generated by HD8-IgG1. Thus, the infusion reactions appear to be largely driven by the complement system. To reduce the CDC function of HD8-IgG1, its Fc region was modified by two amino acid substitutions at Pro³³¹Ser and Lys³²²Ala. The modified Ab was incapable of expressing CDC in vitro and did not induce severe infusion reactions in rats and monkeys, even at extremely high doses. The modified Ab retained its Ab-dependent cellular cytotoxicity function as well as its antitumor activity in a tumor-bearing mouse model. In summary, complement appears to drive infusion reactions, and modifications that eliminate the CDC activity of an Ab also reduce its ability to induce infusion reactions.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint request to Dr. Tomonori Tawara, Discovery Research Laboratories, Kirin Pharma, Miyahara 3, Takasaki, Gunma, 370-1295, Japan. E-mail address: ttawara{at}kirin.co.jp

² Abbreviations used in this paper: ADCC, Ab-dependent cellular cytotoxicity; CDC, complement-dependent cytotoxicity; CVF, cobra venom factor.