Have we overestimated the benefit of human(ized) antibodies?
Have we overestimated the benefit of human(ized) antibodies?
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DOI：
10.4161/mabs.2.6.13601
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发表时间：
2010-11-01
期刊：
影响因子：
5.3
通讯作者：
Miller, Stephen D.
中科院分区：
文献类型：
--
作者：
Getts, Daniel R.;Getts, Meghann T.;Miller, Stephen D.
一段时间以来，已知动物源性抗体的输注会引发针对外源蛋白的抗体的产生以及包括细胞因子释放综合征在内的不良事件。这些免疫学现象推动了人源化和全人单克隆抗体的发展。产生人类抗体的能力既是一种祝福，也是一种诅咒。虽然已经实现了一些药剂的临床功效和安全性的增量增益，但尚未观察到所有人（化）抗体的积极作用。许多人（化）抗体引发抗药抗体应答和输注反应的发展。目前认为抗体需要是人源化的以具有增强的治疗效用，这可能会减缓用于临床适应症的新型动物源性单克隆抗体治疗剂的开发。在鼠抗体的情况下，大于20%诱导可耐受/可忽略的免疫原性，表明在这些情况下，人源化可能不会在治疗效用方面提供显著增益。此外，一些鼠抗体的人源化可能降低其临床有效性。现有数据表明，人源化抗体的效用需要根据具体情况进行评估，采用成本效益方法，同时考虑生物化学特征和靶向治疗适应症。
The infusion of animal-derived antibodies has been known for some time to trigger the generation of antibodies directed at the foreign protein as well as adverse events including cytokine release syndrome. These immunological phenomena drove the development of humanized and fully human monoclonal antibodies. The ability to generate human(ized) antibodies has been both a blessing and a curse. While incremental gains in the clinical efficacy and safety for some agents have been realized, a positive effect has not been observed for all human(ized) antibodies. Many human (ized) antibodies trigger the development of anti-drug antibody responses and infusion reactions. The current belief that antibodies need to be human (ized) to have enhanced therapeutic utility may slow the development of novel animal-derived monoclonal antibody therapeutics for use in clinical indications. In the case of murine antibodies, greater than 20% induce tolerable/negligible immunogenicity, suggesting that in these cases humanization may not offer significant gains in therapeutic utility. Furthermore, humanization of some murine antibodies may reduce their clinical effectiveness. The available data suggest that the utility of human(ized) antibodies needs to be evaluated on a case-by-case basis, taking a cost-benefit approach, taking both biochemical characteristics and the targeted therapeutic indication into account.