Abstract:

Monoclonal antibodies have been widely used in tumor therapy. However, the effects of monoclonal anti-tumor antibodies for treating tumor are still limited as tumor is a heterogeneous disease involving a variety of disease-mediated alterations in ligands and receptors as well as signaling cascades crosstalk. Therefore, it is difficult to suppress tumor progression by targeting single antigen or epitope. Blocking different pathological factors/pathways at the same time is thus becoming a promising strategy for tumor treatment to improve therapeutic efficacy. In recent years, bispecific antibody-based drugs have attracted increasing research attention as novel therapeutic strategies in liquid and solid tumors, thanks to the remarkable progress made in the synthetic biology, bioengineering and nanotechnology. Bispecific antibody is an artificially engineering-modified antibody capable of binding two distinct antigens/epitopes simultaneously to increase selectivity to tumors, and consequently induce a powerful anti-tumor immune response. Due to their low immunogenicity, good stability and easy preparation, a variety of bispecific antibody formats have been developed, mainly including full-length bispecific antibodies and derivatives that lack Ig domains, trifunctional bispecific antibodies, bispecific T cell engagers (BiTEs), dual affinity retargeting (DART) antibodies and bispecific nanoplatforms/nanobodies. Bispecific antibody-based drugs are of great significance to tumor immunotherapy in following aspects: 1) obtains stronger specific capacity of capturing tumor cells to reduce antigen-loss escape, 2) activate and recruit immune effector cells such as T lymphocytes and natural killer cells to enhance tumor cells killing, and 3) influence two different receptors or signaling pathways concurrently that display unique or overlapping functions in the pathogenetic process. At the same time, nanotechnologies are being largely involved into the development of multiple bispecific antibodies. This article briefly comments on the production of bispecific antibodies, and also highlights the progress of bispecific antibodies and their combination with nanotechnology-based delivery systems in the application of immunotherapy for hematological malignancies and solid tumors.

Key words: bispecific antibodies, immunotherapy, targeting, tumor, nanotechnology

摘要：

单克隆抗体已经广泛用于肿瘤的靶向治疗，但由于肿瘤属于异质性疾病，涉及介导疾病进展的多种配受体信号变化以及信号级联通路之间的交互作用。因此，针对单一抗原的治疗难以有效抑制疾病的进程，而阻断多种不同的病理因素和途径是有望提高治疗效果的重要途径。近年来，合成生物学、生物工程和纳米技术等在不断发展，利用这些技术来设计工程化的治疗性抗体或可为肿瘤靶向免疫治疗带来新的思路。双特异性抗体是一种具有两种抗体特异性的人工抗体，可以同时识别不同的抗原或表位，由此实现多种功能，例如可以将T细胞重定向至肿瘤细胞并同时阻断两条不同的或相互串扰的细胞信号传导通路；与此同时，备受关注的纳米载体技术则为双抗体药物的研发与应用提供了有利的新工具。本文首先对双特异性抗体的生产和制备做简要介绍，然后对双特异性抗体在恶性血液肿瘤（急性髓细胞白血病和B细胞恶性血液肿瘤）和实体瘤（乳腺癌、卵巢癌、肺癌和头颈癌等）免疫治疗中的应用进展做分类介绍，并进一步介绍了双特异性抗体与纳米技术相结合形成的递送系统在肿瘤免疫治疗中的研究进展；最后讨论了双特异性抗体在设计和医学应用中面临的问题，并展望了纳米技术介导的靶向治疗策略在肿瘤治疗中的应用前景，以及双特异性抗体与免疫检查点抑制剂或疫苗等其他疗法联合应用的可能。

关键词: 双特异性抗体, 免疫治疗, 靶向, 肿瘤, 纳米技术