PDF(Pubmed)
Abstract：
Recombinant antibodies (Abs) are an integral modality for the treatment of multiple tumour malignancies. Since the Food and Drug Administration (FDA) approval of rituximab as the first monoclonal antibody (mAb) for cancer treatment, several mAbs and antibody (Ab)-based therapies have been approved for the treatment of solid tumour malignancies and other cancers. These Abs function by either blocking oncogenic pathways or angiogenesis, modulating immune response, or by delivering a conjugated drug. The use of Ab-based therapy in cancer patients who could benefit from the treatment, however, is still limited by associated toxicity profiles which may stem from biological features and processes related to target binding, alongside biochemical and/or biophysical characteristics of the therapeutic Ab. A significant immune-related adverse event (irAE) associated with Ab-based therapies is cytokine release syndrome (CRS), characterized by the development of fever, rash and even marked, life-threatening hypotension, and acute inflammation with secondary to systemic uncontrolled increase in a range of pro-inflammatory cytokines. Here, we review irAEs associated with specific classes of approved, Ab-based novel cancer immunotherapeutics, namely immune checkpoint (IC)-targeting Abs, bispecific Abs (BsAbs) and Ab-drug-conjugates (ADCs), highlighting the significance of harmonization in preclinical assay development for safety assessment of Ab-based biotherapeutics as an approach to support and refine clinical translation.
摘要：
重组抗体(Ab)是用于治疗多种肿瘤恶性肿瘤的完整形式。自从美国食品和药物管理局（FDA）批准利妥昔单抗作为第一个用于癌症治疗的单克隆抗体（mAb）以来，几种基于单克隆抗体和抗体(Ab)的疗法已被批准用于治疗实体瘤恶性肿瘤和其他癌症。这些Abs通过阻断致癌途径或血管生成发挥功能，调节免疫反应，或通过递送共轭药物。在可以从治疗中受益的癌症患者中使用基于Ab的治疗，然而,仍然受到相关毒性谱的限制，这些毒性谱可能源于与靶标结合相关的生物学特征和过程，以及治疗性Ab的生化和/或生物物理特征。与基于Ab的治疗相关的显著免疫相关不良事件（irAE）是细胞因子释放综合征（CRS），以发烧为特征，皮疹，甚至标记，危及生命的低血压,和急性炎症，继发于全身不受控制的一系列促炎细胞因子的增加。这里,我们审查与特定类别的批准相关的IRAE，基于Ab的新型癌症免疫治疗剂，即免疫检查点(IC)靶向抗体，双特异性抗体（BsAb）和Ab-药物缀合物（ADC），强调协调在临床前试验开发中的重要性，用于基于Ab的生物治疗药物的安全性评估，作为支持和完善临床翻译的方法。
