Zou Jian, Kinosada Haruka, Takayanagi Shin-Ichiro, Ishii Toshihiko, Amano Toru, Nihira Kaito, Kanie Shohei, Adachi Maiko, Tahara Harunobu, Sakoda Teppei, Kikushige Yoshikane, Akashi Koichi, Satou Hidetaka
Fuji Research Park, Biomedical Science Research Laboratories 2, Research Unit, Research Division, Kyowa Kirin Co., Ltd., Sunto-gun, Shizuoka, 411-8731, Japan.
Tokyo Research Park, Biomedical Science Research Laboratories 2, Research Unit, Research Division, Kyowa Kirin Co., Ltd., Machida, Tokyo, 194-8533, Japan.
Leukemia. 2025 May 22. doi: 10.1038/s41375-025-02642-2.
Acute myeloid leukemia (AML) is a common hematopoietic malignancy with high recurrence rates, and there is an urgent need for new therapeutic agents. T-cell immunoglobulin mucin-3 (TIM-3) is expressed on the surface of both LSCs and blasts in most AML patients, but not in normal hematopoietic stem cells (HSCs). We have developed KK2845, an antibody drug conjugate (ADC) that consists of an anti-TIM-3 fully human IgG1 antibody, a valine-alanine linker and a highly potent DNA cross-linking pyrrolobenzodiazepine (PBD) dimer SG3199. KK2845 exhibited potent cytotoxicity against AML cells both in vitro and in vivo. The cytotoxicity against AML cells was almost comparable between KK2845 and CD33-ADC, an anti-CD33 antibody conjugated with PBD dimer that has shown high remission rates in clinical studies. In addition to the cytotoxicity depending on PBD dimer, KK2845 also showed potent antibody-dependent cell cytotoxicity (ADCC) activity against AML cells. KK2845 showed less cytotoxicity against human normal bone marrow cells than CD33-ADC. The pharmacokinetics of KK2845 in cynomolgus monkey after intravenous infusion demonstrated a favorable profile. Taken together, these data suggest that KK2845 could be a novel ADC therapeutic in AML.
急性髓系白血病（AML）是一种常见的造血系统恶性肿瘤，复发率高，因此迫切需要新的治疗药物。在大多数AML患者中，T细胞免疫球蛋白粘蛋白-3（TIM-3）在白血病干细胞（LSC）和原始细胞表面均有表达，但在正常造血干细胞（HSC）中不表达。我们研发了KK2845，这是一种抗体药物偶联物（ADC），由抗TIM-3全人IgG1抗体、缬氨酸-丙氨酸连接子和一种高效的DNA交联吡咯并苯二氮䓬（PBD）二聚体SG3199组成。KK2845在体外和体内均对AML细胞表现出强大的细胞毒性。KK2845对AML细胞的细胞毒性与CD33-ADC几乎相当，CD33-ADC是一种与PBD二聚体偶联的抗CD33抗体，在临床研究中显示出高缓解率。除了依赖PBD二聚体的细胞毒性外，KK2845还对AML细胞表现出强大的抗体依赖性细胞毒性（ADCC）活性。与CD33-ADC相比，KK2845对人正常骨髓细胞的细胞毒性较小。静脉输注后，KK2845在食蟹猴体内的药代动力学表现良好。综上所述，这些数据表明KK2845可能是一种用于AML治疗的新型ADC药物。
