Enhancing the safety of antibody-based immunomodulatory cancer therapy without compromising therapeutic benefit: Can we have our cake and eat it too?
Enhancing the safety of antibody-based immunomodulatory cancer therapy without compromising therapeutic benefit: Can we have our cake and eat it too?
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DOI：
10.1517/14712598.2016.1152256
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发表时间：
2016
影响因子：
4.6
通讯作者：
Vella AT
中科院分区：
文献类型：
--
作者：
Ryan JM;Wasser JS;Adler AJ;Vella AT
靶向检查点抑制剂的单克隆抗体（mAb）已证明在治疗癌症患者方面具有临床益处，并为其他免疫调节mAb（如靶向共刺激受体的mAb）铺平了道路。然而，这些药物的全部临床效用受到治疗期间可能发生的免疫相关不良事件（irAE）的阻碍。我们首先提供了一个肿瘤免疫的一般概述，其次是两个主要类别的免疫调节单克隆抗体正在开发的癌症治疗：检查点抑制剂和共刺激受体激动剂的审查。然后我们讨论治疗相关的不良事件。最后，我们详细描述了驱动其治疗活性的机制，重点是抗体片段可结晶（Fc）结构域和Fc受体（FcR）之间的相互作用。鉴于Fc-FcR相互作用在促进免疫调节mAb引起治疗上有用的以及不良作用的能力方面似乎是至关重要的，可以有效地接合其靶标同时限制与FcR相互作用的mAb的工程化可能代表了开发具有增加的安全性和保留功效的下一代免疫增强杀肿瘤剂的有希望的未来途径。
Monoclonal antibodies (mAbs) targeting checkpoint inhibitors have demonstrated clinical benefit in treating patients with cancer and have paved the way for additional immune-modulating mAbs such as those targeting costimulatory receptors. The full clinical utility of these agents, however, is hampered by immune-related adverse events (irAEs) that can occur during therapy. We first provide a general overview of tumor immunity, followed by a review of the two major classes of immunomodulatory mAbs being developed as cancer therapeutics: checkpoint inhibitors and costimulatory receptor agonists. We then discuss therapy-associated adverse events. Finally, we describe in detail the mechanisms driving their therapeutic activity, with an emphasis on interactions between antibody fragment crystallizable (Fc) domains and Fc receptors (FcR). Given that Fc-FcR interactions appear critical in facilitating the ability of immunomodulatory mAbs to elicit both therapeutically useful as well as adverse effects, the engineering of mAbs that can effectively engage their targets while limiting interaction with FcRs might represent a promising future avenue for developing the next generation of immune-enhancing tumoricidal agents with increased safety and retention of efficacy.