Yan Li, Beckman Robert A
Hematology and Oncology, Clinical Research and Development, Centocor Research & Development, Inc, Wayne, PA 19087, USA.
Biotechniques. 2005 Oct;39(4):565-8.
Pharmacogenetics and pharmacogenomics are keys to the success of personalized medicine, prescribing drugs based on a patient's individual genetic and biological profile. In this review, we will focus on the application of pharmacogenetics and pharmacogenomics in developing monoclonal antibody (MAb) therapeutics in oncology. The significance of pharmacogenomics in MAb therapeutics is highlighted by the association between polymorphisms in Fc receptors and clinical response to anti-CD20 MAb rituximab (Rituxan) or anti-ganglioside GD2 MAb 3F8, as well as the potential link between polymorphisms in HER2 and cardiac toxicity in patients treated with the anti-HER2 MAb trastuzumab (Herceptin). The dependence on gene copy number or expression levels of HER2 and epidermal growth factor receptor (EGFR) for therapeutic efficacy of trastuzumab and cetuximab (Erbitux), respectively, supports the importance of selecting suitable patient populations based on their pharmacogenetic profile. In addition, a better understanding of target mutation status and biological consequences will benefit MAAb development and may guide clinical development and use of these innovative therapeutics. The application of pharmacogenetics and pharmacogenomics in developing MAb therapeutics will be largely dependent on the discovery of novel surrogate biomarkers and identification of disease- and therapeutics-relevant polymorphisms. Challenges and opportunities in biomarker discovery and validation, and in implementing clinical pharmacogenetics and pharmacogenomics in oncology MAb development and clinical practice will also be discussed.
药物遗传学和药物基因组学是个性化医疗成功的关键，即根据患者个体的基因和生物学特征来开药。在本综述中，我们将聚焦于药物遗传学和药物基因组学在肿瘤学单克隆抗体（MAb）治疗药物研发中的应用。Fc受体多态性与抗CD20单克隆抗体利妥昔单抗（美罗华）或抗神经节苷脂GD2单克隆抗体3F8的临床反应之间的关联，以及HER2多态性与接受抗HER2单克隆抗体曲妥珠单抗（赫赛汀）治疗患者心脏毒性之间的潜在联系，突显了药物基因组学在单克隆抗体治疗中的重要性。曲妥珠单抗和西妥昔单抗（爱必妥）的治疗效果分别依赖于HER2和表皮生长因子受体（EGFR）的基因拷贝数或表达水平，这支持了根据患者的药物遗传学特征选择合适患者群体的重要性。此外，更好地了解靶点突变状态及其生物学后果将有利于单克隆抗体的研发，并可能指导这些创新治疗药物的临床研发和应用。药物遗传学和药物基因组学在单克隆抗体治疗药物研发中的应用将在很大程度上依赖于新型替代生物标志物的发现以及与疾病和治疗相关的多态性的鉴定。还将讨论生物标志物发现与验证以及在肿瘤学单克隆抗体研发和临床实践中实施临床药物遗传学和药物基因组学所面临的挑战与机遇。
