Monoclonal antibodies (mAbs) are a major targeted therapy for malignancies, infectious diseases, autoimmune diseases, transplant rejection and chronic inflammatory diseases due to their antigen specificity and longer half-life than conventional drugs. However, long-term systemic antigen neutralization by mAbs may cause severe adverse events. Improving the selectivity of mAbs to distinguish target antigens at the disease site from normal healthy tissue and reducing severe adverse events caused by the mechanisms-of-action of mAbs is still a pressing need. Development of pro-antibodies (pro-Abs) by installing a protease-cleavable Ab lock is a novel and advanced recombinant Ab-based strategy that efficiently masks the antigen binding ability of mAbs in the normal state and selectively “turns on” the mAb activity when the pro-Ab reaches the proteolytic protease-overexpressed diseased tissue. In this review, we discuss the design and advantages/disadvantages of different Ab lock strategies, focusing particularly on spatial-hindrance-based and affinity peptide-based approaches. We expect that the development of different masking strategies for mAbs will benefit the local reactivity of mAbs at the disease site, increase the therapeutic efficacy and safety of long-term treatment with mAbs in chronic diseases and even permit scientists to develop Ab drugs for formerly undruggable targets and satisfy the unmet medical needs of mAb therapy.

中文翻译：

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Ab 锁可提高抗体药物的选择性和安全性。


单克隆抗体（mAb）由于其抗原特异性和比传统药物更长的半衰期，成为恶性肿瘤、传染病、自身免疫性疾病、移植排斥和慢性炎症性疾病的主要靶向治疗药物。然而，单克隆抗体的长期全身性抗原中和可能会导致严重的不良事件。提高单克隆抗体的选择性以区分疾病部位的靶抗原和正常健康组织，并减少单克隆抗体作用机制引起的严重不良事件仍然是迫切需要的。通过安装蛋白酶可裂解的 Ab 锁来开发前抗体 (pro-Abs) 是一种新颖且先进的重组 Ab 策略，可有效掩盖正常状态下 mAb 的抗原结合能力，并选择性“开启”mAb 活性当抗体原到达蛋白水解酶过度表达的患病组织时。在这篇综述中，我们讨论了不同 Ab 锁定策略的设计和优点/缺点，特别关注基于空间阻碍和基于亲和肽的方法。我们期望开发不同的单克隆抗体掩蔽策略将有利于单克隆抗体在疾病部位的局部反应性，提高单克隆抗体长期治疗慢性疾病的疗效和安全性，甚至允许科学家开发针对以前无法成药的抗体药物目标并满足单克隆抗体治疗未满足的医疗需求。