Department of Radiation Oncology, University Hospital Freiburg, Freiburg, Germany. Faculty of Biology, University of Freiburg, Freiburg, Germany.
Department of Radiation Oncology, University Hospital Freiburg, Freiburg, Germany.
Cancer Res. 2015 Jun 1;75(11):2166-76. doi: 10.1158/0008-5472.CAN-14-2415. Epub 2015 Apr 3.
Cancer stem cells (CSC) drive tumorigenesis and contribute to genotoxic therapy resistance, diffuse infiltrative invasion, and immunosuppression, which are key factors for the incurability of glioblastoma multiforme (GBM). The AC133 epitope of CD133 is an important CSC marker for GBM and other tumor entities. Here, we report the development and preclinical evaluation of a recombinant AC133×CD3 bispecific antibody (bsAb) that redirects human polyclonal T cells to AC133(+) GBM stem cells (GBM-SC), inducing their strong targeted lysis. This novel bsAb prevented the outgrowth of AC133-positive subcutaneous GBM xenografts. Moreover, upon intracerebral infusion along with the local application of human CD8(+) T cells, it exhibited potent activity in prophylactic and treatment models of orthotopic GBM-SC-derived invasive brain tumors. In contrast, normal hematopoietic stem cells, some of which are AC133-positive, were virtually unaffected at bsAb concentrations effective against GBM-SCs and retained their colony-forming abilities. In conclusion, our data demonstrate the high activity of this new bsAb against patient-derived AC133-positive GBM-SCs in models of local therapy of highly invasive GBM.
癌症干细胞（CSC）驱动肿瘤发生，并导致对遗传毒性治疗的耐药性、弥漫浸润性侵袭和免疫抑制，这是多形性胶质母细胞瘤（GBM）不可治愈的关键因素。CD133 的 AC133 表位是 GBM 和其他肿瘤实体的重要 CSC 标志物。在这里，我们报告了一种重组 AC133×CD3 双特异性抗体（bsAb）的开发和临床前评估，该抗体将人多克隆 T 细胞重定向到 AC133（+）GBM 干细胞（GBM-SC），诱导其强烈的靶向裂解。这种新型 bsAb 阻止了 AC133 阳性皮下 GBM 异种移植物的生长。此外，在与局部应用人 CD8（+）T 细胞一起脑内输注时，它在原位 GBM-SC 衍生的侵袭性脑肿瘤的预防和治疗模型中表现出强大的活性。相比之下，正常造血干细胞中有一些是 AC133 阳性的，在对 GBM-SC 有效的 bsAb 浓度下几乎不受影响，并且保留了其集落形成能力。总之，我们的数据表明，这种新型 bsAb 在局部治疗高度侵袭性 GBM 的模型中对患者来源的 AC133 阳性 GBM-SC 具有高活性。
