Institute of Immunology, Medical Faculty Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany.
J Immunol. 2012 Sep 15;189(6):3249-59. doi: 10.4049/jimmunol.1200341. Epub 2012 Aug 8.
Prostate cancer is the most common noncutaneous malignancy in men. The prostate stem cell Ag (PSCA) is a promising target for immunotherapy of advanced disease. Based on a novel mAb directed to PSCA, we established and compared a series of murine and humanized anti-CD3-anti-PSCA single-chain bispecific Abs. Their capability to redirect T cells for killing of tumor cells was analyzed. During these studies, we identified a novel bispecific humanized Ab that efficiently retargets T cells to tumor cells in a strictly Ag-dependent manner and at femtomolar concentrations. T cell activation, cytokine release, and lysis of target cells depend on a cross-linkage of redirected T cells with tumor cells, whereas binding of the anti-CD3 domain alone does not lead to an activation or cytokine release. Interestingly, both CD8+ and CD4+ T cells are activated in parallel and can efficiently mediate the lysis of tumor cells. However, the onset of killing via CD4+ T cells is delayed. Furthermore, redirecting T cells via the novel humanized bispecific Abs results in a delay of tumor growth in xenografted nude mice.
前列腺癌是男性最常见的非皮肤恶性肿瘤。前列腺干细胞抗原（PSCA）是晚期疾病免疫治疗的一个有前途的靶点。基于一种针对 PSCA 的新型单克隆抗体，我们建立并比较了一系列鼠源和人源化的抗-CD3-抗-PSCA 单链双特异性抗体。分析了它们将 T 细胞重新导向杀伤肿瘤细胞的能力。在这些研究中，我们鉴定了一种新型的人源化双特异性抗体，它能够以严格的抗原依赖性方式和皮摩尔浓度有效地将 T 细胞重新导向肿瘤细胞。T 细胞的激活、细胞因子的释放和靶细胞的裂解依赖于重新导向的 T 细胞与肿瘤细胞的交联，而单独结合抗-CD3 结构域不会导致激活或细胞因子释放。有趣的是，CD8+和 CD4+T 细胞都被平行激活，并能有效地介导肿瘤细胞的裂解。然而，通过 CD4+T 细胞进行杀伤的开始时间延迟。此外，通过新型人源化双特异性抗体重新定向 T 细胞可导致异种移植裸鼠肿瘤生长延迟。
