German Cancer Research Center DKFZ, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany,
BioDrugs. 2013 Feb;27(1):35-53. doi: 10.1007/s40259-012-0008-z.
Monoclonal anti-tumor antibodies (mAbs) that are clinically effective usually recruit, via their constant fragment (Fc) domain, Fc receptor (FcR)-positive accessory cells of the immune system and engage these additionally against the tumor. Since T cells are FcR negative, these important cells are not getting involved. In contrast to mAbs, bispecific antibodies (bsAbs) can be designed in such a way that they involve T cells. bsAbs are artificially designed molecules that bind simultaneously to two different antigens, one on the tumor cell, the other one on an immune effector cell such as CD3 on T cells. Such dual antibody constructs can cross-link tumor cells and T cells. Many such bsAb molecules at the surface of tumor cells can thus build a bridge to T cells and aggregate their CD3 molecules, thereby activating them for cytotoxic activity. BsAbs can also contain a third binding site, for instance a Fc domain or a cytokine that would bind to its respective cytokine receptor. The present review discusses the pros and cons for the use of the Fc fragment during the development of bsAbs using either cell-fusion or recombinant DNA technologies. The recombinant antibody technology allows the generation of very efficient bsAbs containing no Fc domain such as the bi-specific T-cell engager (BiTE). The strong antitumor activity of these molecules makes them very interesting new cancer therapeutics. Over the last decade, we have developed another concept, namely to combine bsAbs and multivalent immunocytokines with a tumor cell vaccine. The latter are patient-derived tumor cells modified by infection with a virus. The virus-Newcastle Disease Virus (NDV)-introduces, at the surface of the tumor cells, viral molecules that can serve as general anchors for the bsAbs. Our strategy aims at redirecting, in an Fc-independent fashion, activities of T cells and accessory cells against autologous tumor antigens. It creates very promising perspectives for a new generation of efficient and safe cancer therapeutics that should confer long-lasting anti-tumor immunity.
单克隆抗肿瘤抗体（mAbs）在临床上有效，通常通过其恒定区（Fc）域招募免疫系统中 Fc 受体（FcR）阳性辅助细胞，并使这些细胞与肿瘤结合。由于 T 细胞不具有 FcR，因此这些重要的细胞不会参与其中。与 mAbs 相反，双特异性抗体（bsAbs）可以设计成能够涉及 T 细胞的形式。bsAbs 是人工设计的分子，能够同时结合两种不同的抗原，一种在肿瘤细胞上，另一种在免疫效应细胞上，如 T 细胞上的 CD3。这种双抗体构建物可以交联肿瘤细胞和 T 细胞。因此，许多这样的 bsAb 分子在肿瘤细胞表面可以形成连接到 T 细胞的桥梁，并聚集其 CD3 分子，从而激活它们进行细胞毒性活性。bsAbs 还可以包含第三个结合位点，例如 Fc 结构域或细胞因子，其将与相应的细胞因子受体结合。本综述讨论了在使用细胞融合或重组 DNA 技术开发 bsAbs 时，Fc 片段的使用的优缺点。重组抗体技术允许生成非常有效的 bsAbs，其不包含 Fc 结构域，例如双特异性 T 细胞衔接子（BiTE）。这些分子的强大抗肿瘤活性使它们成为非常有前途的新型癌症治疗方法。在过去的十年中，我们开发了另一种概念，即将 bsAbs 和多价免疫细胞因子与肿瘤细胞疫苗结合使用。后者是通过感染病毒修饰的患者来源的肿瘤细胞。该病毒 - 新城疫病毒（NDV） - 在肿瘤细胞表面引入可以作为 bsAbs 的通用锚的病毒分子。我们的策略旨在以不依赖 Fc 的方式重新定向 T 细胞和辅助细胞针对自体肿瘤抗原的活性。它为新一代高效和安全的癌症治疗方法创造了非常有前途的前景，这些方法应赋予持久的抗肿瘤免疫。
