Ek O, Yanishevski Y, Zeren T, Waurzyniak B, Gunther R, Chelstrom L, Chandan-Langlie M, Schneider E, Myers D E, Evans W, Uckun F M
Wayne Hughes Institute, St. Paul, MN, USA.
Leuk Lymphoma. 1998 Jul;30(3-4):389-94. doi: 10.3109/10428199809057550.
B43(anti-CD19)-Genistein immunoconjugate targets genistein, a naturally occurring protein tyrosine kinase inhibitory isoflavone to the membrane-associated anti-apoptotic CD19-LYN complexes and triggers apoptotic cell death. In this preclinical study, the toxicity profiles of B43-Genistein as well as unconjugated genistein were evaluated in mice. B43-Genistein and genistein were administered either as single bolus injections or daily injections for 10 consecutive days via the intraperitoneal route to mice. Genistein was not toxic to mice at the highest dose of 40 mg/kg and no test article-related histopathological lesions were found in any of the 64 genistein-treated mice. B43-Genistein had a significantly longer elimination half-life and slower plasma and tissue clearance than unconjugated genistein. B43-Genistein was not toxic to mice at the highest single dose of 40 mg/kg or highest cumulative dose of 100 mg/kg and no test article-related histopathological lesions were found in any of the 108 mice treated with B43-genistein. To our knowledge, this is the first preclinical toxicity and pharmacokinetic study of a tyrosine kinase inhibitor-containing immunoconjugate.
B43（抗CD19）-染料木黄酮免疫偶联物将染料木黄酮（一种天然存在的蛋白酪氨酸激酶抑制性异黄酮）靶向与膜相关的抗凋亡CD19-LYN复合物，并触发细胞凋亡性死亡。在这项临床前研究中，对B43-染料木黄酮以及未偶联的染料木黄酮在小鼠中的毒性特征进行了评估。B43-染料木黄酮和染料木黄酮通过腹腔途径以单次推注或连续10天每日注射的方式给予小鼠。染料木黄酮在最高剂量40 mg/kg时对小鼠无毒，在64只接受染料木黄酮治疗的小鼠中均未发现与受试物相关的组织病理学损伤。B43-染料木黄酮的消除半衰期明显长于未偶联的染料木黄酮，其血浆和组织清除速度也较慢。B43-染料木黄酮在最高单次剂量40 mg/kg或最高累积剂量100 mg/kg时对小鼠无毒，在108只接受B43-染料木黄酮治疗的小鼠中均未发现与受试物相关的组织病理学损伤。据我们所知，这是第一项关于含酪氨酸激酶抑制剂免疫偶联物的临床前毒性和药代动力学研究。
