Introduction

Monoclonal antibodies have been utilized in clinical and basic research for the treatment of various malignancies. Whilst all therapeutically approved monoclonal antibodies or fragments thereof are directed against cell-surface receptors or proteins of the human secretome, intracellular antigen targeting strategies still await translation into the clinic. This contradicts the notion of antibodies being the magic bullet concept as many cancer targets are out of reach.

Areas covered

This review provides a summary of intracellular translocation strategies that were successfully employed for antibody delivery in preclinical studies. Examples encompass a variety of different approaches such as polymeric and lipid-based nanoparticles (NP), biomimetics, bispecific antibody constructs, the use of cell-penetrating peptides, as well as various sophisticated combinations thereof. We will further discuss endosomal escape as the major bottleneck in functional intracellular transport and provide suggestions on how to overcome current challenges.

Expert opinion

Despite significant advances in protein delivery technologies, reports of highly efficient transport vehicles are sparse when systemically applied in vivo. Consequently, more detailed mechanistic studies are needed to identify and optimize the molecular ‘Achilles heel’ of individual methodologies. Ultimately, to target intracellular proteins that have been undruggable in the past, a combination of strategies may be required.

中文翻译：

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针对牢不可破：针对细胞内靶标的抗体递送中的新兴技术。

介绍

单克隆抗体已用于临床和基础研究中，以治疗各种恶性肿瘤。尽管所有经过治疗批准的单克隆抗体或其片段都针对人分泌蛋白的细胞表面受体或蛋白质，但细胞内抗原靶向策略仍在等待翻译成临床。由于许多癌症靶标无法触及，因此这与抗体这一神奇的概念相矛盾。

覆盖区域

这篇综述提供了在临床前研究中成功用于抗体递送的细胞内易位策略的总结。实例包括多种不同的方法，例如聚合和基于脂质的纳米颗粒（NP），仿生物，双特异性抗体构建体，细胞穿透肽的使用以及它们的各种复杂组合。我们将进一步讨论内体逃逸是功能性细胞内运输的主要瓶颈，并就如何克服当前的挑战提供建议。

专家意见

尽管蛋白质递送技术取得了重大进展，但当全身应用在体内时，关于高效运输工具的报道却很少。因此，需要进行更详细的机械研究，以识别和优化各个方法的分子“致命弱点”。最终，要靶向过去难以吸收的细胞内蛋白，可能需要多种策略的组合。