Development of in vivo cytotoxicity assay system using humanized mice maintaining human mature NK cells for long-term

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K18405
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Laboratory animal science
• Research Institution: Central Institute for Experimental Animals
• Principal Investigator: Katano Ikumi 公益財団法人実験動物中央研究所, 実験動物研究部, 研究員 (90442558)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: ヒト化マウス / NK細胞 / ヒト免疫 / ADCC

Outline of Final Research Achievements

We generated that a NOG-human IL-15 Tg mouse strain was useful for evaluating in vivo antibody-dependent cellular cytotoxicity (ADCC) mediated by human peripheral blood-derived NK cells in the presence of therapeutic antibody.
And, We generated immunoglobulin gamma Fc region receptor (FcRg)-deficient NOG-IL-15 Tg (NOG-FcRg KO IL-15 Tg) mice and investigated whether human NK cell-derived ADCC activity could be distinguished from mouse cell -mediated antibody-dependent cellular phagocytosis (ADCP). The Daudi-transplanted NOG-FcRg KO IL-15 Tg mice were intravenously transferred with in vitro expanded human NK cells and treated with rituximab. Only the group with human NK cells and rituximab treatment showed significant suppression of tumor growth in the kidney, while treatment with rituximab alone had minimum influence.
These data suggest that NOG-FcRg KO, IL-15 mice are more suitable for specifically detecting human NK cell mediated in vivo ADCC activity than NOG-IL-15 Tg mice.

Free Research Field

実験動物学

Academic Significance and Societal Importance of the Research Achievements

がんに対する分子標的抗体の創薬研究において、抗体の機能解析は試験管内での検証系が主流である。しかし、この結果は生体での反応を必ずしも反映するものではなく、臨床研究で予期しない副作用が観察されることが多い。従って、ヒトの細胞に対する反応性を生体内で検証し得る動物モデルが求められてきた。従来のモデルでは抗体の細胞傷害機能-ADCC活性-の検証はほぼ不可能であったが、ヒトNK細胞を生着させたNOG-IL-15 Tgマウスで検証が可能となった。さらにNOG-FcRg KO, IL-15 TgマウスではADCC活性の検出感度を飛躍的に高めることができた。この動物モデルは創薬の発展に貢献するものと考える。