Eda Yasuyuki, Murakami Toshio, Ami Yasushi, Nakasone Tadashi, Takizawa Mari, Someya Kenji, Kaizu Masahiko, Izumi Yasuyuki, Yoshino Naoto, Matsushita Shuzo, Higuchi Hirofumi, Matsui Hajime, Shinohara Katsuaki, Takeuchi Hiroaki, Koyanagi Yoshio, Yamamoto Naoki, Honda Mitsuo
AIDS Research Center, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo 162-8640, Japan.
J Virol. 2006 Jun;80(11):5563-70. doi: 10.1128/JVI.02095-05.
In an accompanying report (Y. Eda, M. Takizawa, T. Murakami, H. Maeda, K. Kimachi, H. Yonemura, S. Koyanagi, K. Shiosaki, H. Higuchi, K. Makizumi, T. Nakashima, K. Osatomi, S. Tokiyoshi, S. Matsushita, N. Yamamoto, and M. Honda, J. Virol. 80:5552-5562, 2006), we discuss our production of a high-affinity humanized monoclonal antibody, KD-247, by sequential immunization with V3 peptides derived from human immunodeficiency virus type 1 (HIV-1) clade B primary isolates. Epitope mapping revealed that KD-247 recognized the Pro-Gly-Arg V3 tip sequence conserved in HIV-1 clade B isolates. In this study, we further demonstrate that in vitro, KD-247 efficiently neutralizes CXCR4- and CCR5-tropic primary HIV-1 clade B and clade B' with matching neutralization sequence motifs but does not neutralize sequence-mismatched clade B and clade E isolates. Monkeys were provided sterile protection against heterologous simian/human immunodeficiency virus challenge by the passive transfer of a single high dose (45 mg per kg of body weight) of KD-247 and afforded partial protection by lower antibody doses (30 and 15 mg per kg). Protective neutralization endpoint titers in plasma at the time of virus challenge were 1:160 in animals passively transferred with a high dose of the antibody. The antiviral efficacy of the antibody was further confirmed by its suppression of the ex vivo generation of primary HIV-1 quasispecies in peripheral blood mononuclear cell cultures from HIV-infected individuals. Therefore, KD-247 promises to be a valuable tool not only as a passive immunization antibody for the prevention of HIV infection but also as an immunotherapy for the suppression of HIV in phenotype-matched HIV-infected individuals.
在一篇附带报告中（Y. 江田、M. 泷泽、T. 村上、H. 前田、K. 木町、H. 米村、S. 小柳、K. 塩崎、H. 樋口、K. 牧泉、T. 中岛、K. 小里富、S. 时吉、S. 松下、N. 山本和M. 本田，《病毒学杂志》80:5552 - 5562，2006年），我们讨论了通过用人免疫缺陷病毒1型（HIV - 1）B亚型原发性分离株衍生的V3肽进行序贯免疫来生产高亲和力人源化单克隆抗体KD - 247的情况。表位作图显示KD - 247识别HIV - 1 B亚型分离株中保守的Pro - Gly - Arg V3末端序列。在本研究中，我们进一步证明，在体外，KD - 247能有效中和具有匹配中和序列基序的CXCR4 - 和CCR5 - 嗜性原发性HIV - 1 B亚型和B'亚型，但不能中和序列不匹配的B亚型和E亚型分离株。通过被动转移单次高剂量（每千克体重45毫克）的KD - 247，猴子获得了针对异源猴/人免疫缺陷病毒攻击的无菌保护，较低剂量（每千克30毫克和15毫克）的抗体则提供了部分保护。在病毒攻击时，被动转移高剂量抗体的动物血浆中的保护性中和终点效价为1:160。该抗体的抗病毒功效还通过其抑制HIV感染个体外周血单核细胞培养物中原发性HIV - 1准种的体外产生得到进一步证实。因此，KD - 247有望成为一种有价值的工具，不仅可作为预防HIV感染的被动免疫抗体，还可作为在表型匹配的HIV感染个体中抑制HIV的免疫疗法。
