Schlereth Bernd, Kleindienst Petra, Fichtner Iduna, Lorenczewski Grit, Brischwein Klaus, Lippold Sandra, da Silva Antonio, Locher Mathias, Kischel Roman, Lutterbüse Ralf, Kufer Peter, Baeuerle Patrick A
Micromet AG, Staffelseestr 2, 81477 Munich, Germany.
Cancer Immunol Immunother. 2006 Jul;55(7):785-96. doi: 10.1007/s00262-005-0082-x. Epub 2005 Sep 27.
Bispecific single-chain antibody constructs specific for human CD3 have been extensively studied for antitumor activity in human xenograft models using severe combined immunodeficient mice supplemented with human T cells. High efficacy at low effector-to-target ratios, independence of T cell costimuli and a potent activation of previously unstimulated polyclonal T cells were identified as hallmarks of this class of bispecific antibodies. Here we studied a bispecific single-chain antibody construct (referred to as 'bispecific T cell engager', BiTE) in an immunocompetent mouse model. This was possible by the use of a murine CD3-specific BiTE, and a syngeneic melanoma cell line (B16F10) expressing the human Ep-CAM target. The murine CD3-specific BiTE, called 2C11x4-7 prevented in a dose-dependent fashion the outgrowth of subcutaneously growing B16/Ep-CAM tumors with daily i.v. injections of 5 or 50 microg BiTE which was most effective. Treatment with 2C11x4-7 was effective even when it was started 10 days after tumor cell inoculation but delayed treatments showed a reduction in the number of cured animals. 2C11x4-7 was also highly active in a lung tumor colony model. When treatment was started on the day of intravenous tumor cell injection, seven out of eight animals stayed free of lung tumors, and three out of eight animals when treatment was started on day 5. Our study shows that BiTEs also have a high antitumor activity in immunocompetent mice and that there is no obvious need for costimulation of T cells by secondary agents.
针对人CD3的双特异性单链抗体构建体已在使用补充人T细胞的严重联合免疫缺陷小鼠的人异种移植模型中广泛研究其抗肿瘤活性。低效应细胞与靶细胞比例下的高效性、T细胞共刺激的独立性以及对先前未刺激的多克隆T细胞的有效激活被确定为这类双特异性抗体的标志。在此，我们在免疫活性小鼠模型中研究了一种双特异性单链抗体构建体（称为“双特异性T细胞衔接器”，BiTE）。这通过使用鼠源CD3特异性BiTE和表达人Ep-CAM靶标的同基因黑色素瘤细胞系（B16F10）得以实现。名为2C11x4-7的鼠源CD3特异性BiTE以剂量依赖性方式阻止皮下生长的B16/Ep-CAM肿瘤的生长，每日静脉注射5或50μg最有效的BiTE。即使在肿瘤细胞接种后10天开始用2C11x4-7治疗也有效，但延迟治疗显示治愈动物数量减少。2C11x4-7在肺肿瘤集落模型中也具有高活性。当在静脉注射肿瘤细胞当天开始治疗时，八只动物中有七只没有肺肿瘤，在第5天开始治疗时，八只动物中有三只没有肺肿瘤。我们的研究表明，BiTE在免疫活性小鼠中也具有高抗肿瘤活性，并且没有明显需要二级试剂对T细胞进行共刺激。
