Ikeda Shunya, Hasegawa Kana, Kogue Yosuke, Arimori Takao, Kawamoto Ryuhei, Wibowo Tansri, Yaga Moto, Inada Yuri, Uehara Hirofumi, Matsubara Miwa, Tachikawa Mana, Suga Makiko, Kida Shuhei, Shibata Kumi, Tsutsumi Kazuhito, Fukushima Kentaro, Fujita Jiro, Ueda Tomoaki, Kusakabe Shinsuke, Hino Akihisa, Ichii Michiko, Hirose Asao, Nakamae Hirohisa, Hino Masayuki, Nakao Takafumi, Inoue Megumu, Yoshihara Kyoko, Yoshihara Satoshi, Ueda Shuji, Tachi Tetsuro, Kuroda Hideki, Murakami Koki, Kijima Noriyuki, Kishima Haruhiko, Igashira Eri, Murakami Mari, Takiuchi Tsuyoshi, Kimura Tadashi, Hiroshima Takashi, Kimura Toru, Shintani Yasushi, Imai Chihaya, Yusa Kosuke, Mori Ryota, Ogino Takayuki, Eguchi Hidetoshi, Takeda Kiyoshi, Oji Yusuke, Kumanogoh Atsushi, Takagi Junichi, Hosen Naoki
World Premier Interenational Immunology Frontier Research Center, Osaka University, Osaka, Japan.
Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
Nat Cancer. 2025 Apr;6(4):595-611. doi: 10.1038/s43018-025-00934-1. Epub 2025 Mar 24.
Acute myeloid leukemia (AML)-specific target antigens are difficult to identify. Here we demonstrate that HLA-DRB1 can serve as a leukemia-specific target of chimeric antigen receptor (CAR) T cells in patients with AML after allogeneic hematopoietic stem cell transplantation (allo-HCT). We identified KG2032 as a monoclonal antibody specifically bound to AML cells in about half of patients, but not to normal leukocytes other than B lymphocytes. KG2032 reacted with a subset of HLA-DRB1 molecules, specifically those in which the 86th amino acid was not aspartic acid. KG2032 reacted minimally with nonhematopoietic tissues. These results indicate that KG2032 reactivity is highly specific for AML cells in patients who carry KG2032-reactive HLA-DRB1 alleles and who received allo-HCT from a donor carrying KG2032-nonreactive HLA-DRB1 alleles. KG2032-derived CAR T or natural killer cells showed significant anti-leukemic activity in preclinical models in female mice, suggesting that they may cure patients with AML who are incurable with allo-HCT.
急性髓系白血病（AML）特异性靶抗原难以识别。在此我们证明，在异基因造血干细胞移植（allo-HCT）后，HLA-DRB1可作为AML患者嵌合抗原受体（CAR）T细胞的白血病特异性靶点。我们鉴定出KG2032为一种单克隆抗体，约半数患者的AML细胞可与之特异性结合，但除B淋巴细胞外，不与正常白细胞结合。KG2032与一部分HLA-DRB1分子发生反应，特别是第86位氨基酸不是天冬氨酸的那些分子。KG2032与非造血组织的反应极小。这些结果表明，对于携带KG2032反应性HLA-DRB1等位基因且接受来自携带KG2032非反应性HLA-DRB1等位基因供体的allo-HCT的患者，KG2032反应对AML细胞具有高度特异性。在雌性小鼠的临床前模型中，源自KG2032的CAR T细胞或自然杀伤细胞显示出显著的抗白血病活性，这表明它们可能治愈allo-HCT无法治愈的AML患者。
