Campos Maira P, Konecny Gottfried E
Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
Curr Opin Obstet Gynecol. 2018 Feb;30(1):44-50. doi: 10.1097/GCO.0000000000000432.
Antibody-drug conjugates (ADCs) represent a promising new class of cancer therapeutics. Currently more than 60 ADCs are in clinical development, however, only very few trials focus on gynecologic malignancies. In this review, we summarize the most recent advances in ADC drug development with an emphasis on how this progress relates to patients diagnosed with gynecologic malignancies and breast cancer.
The cytotoxic payloads of the majority of the ADCs that are currently in clinical trials for gynecologic malignancies or breast cancer are auristatins (MMAE, MMAF), maytansinoids (DM1, DM4), calicheamicin, pyrrolobenzodiazepines and SN-38. Both cleavable and noncleavable linkers are currently being investigated in clinical trials. A number of novel target antigens are currently being validated in ongoing clinical trials including folate receptor alpha, mesothelin, CA-125, NaPi2b, NOTCH3, protein tyrosine kinase-like 7, ephrin-A4, TROP2, CEACAM5, and LAMP1. For most ADCs currently in clinical development, dose-limiting toxicities appear to be unrelated to the targeted antigen but more tightly associated with the payload. Rational drug design involving optimization of the antibody, the linker and the conjugation chemistry is aimed at improving the therapeutic index of new ADCs.
Antibody-drug conjugates can increase the efficacy and decrease the toxicity of their payloads in comparison with traditional cyctotoxic agents. A better and quicker translation of recent scientific advances in the field of ADCs into rational clinical trials for patients diagnosed with ovarian, endometrial or cervical cancer could create real improvements in tumor response, survival and quality of life for our patients.
抗体药物偶联物（ADCs）是一类很有前景的新型癌症治疗药物。目前有60多种ADC正在进行临床开发，然而，仅有极少数试验聚焦于妇科恶性肿瘤。在本综述中，我们总结了ADC药物开发的最新进展，重点阐述了这一进展与被诊断为妇科恶性肿瘤和乳腺癌患者的相关性。
目前正在针对妇科恶性肿瘤或乳腺癌进行临床试验的大多数ADC的细胞毒性载荷为奥瑞他汀（MMAE、MMAF）、美登素类（DM1、DM4）、加利车霉素、吡咯并苯二氮卓类和SN-38。目前临床试验正在研究可裂解和不可裂解的连接子。目前正在进行的临床试验中验证了一些新型靶抗原，包括叶酸受体α、间皮素、CA-125、NaPi2b、NOTCH3、蛋白酪氨酸激酶样7、 Ephrin-A4、TROP2、CEACAM5和LAMP1。对于目前正在进行临床开发的大多数ADC，剂量限制性毒性似乎与靶向抗原无关，而与载荷更密切相关。涉及优化抗体、连接子和偶联化学的合理药物设计旨在提高新型ADC的治疗指数。
与传统细胞毒性药物相比，抗体药物偶联物可提高其载荷的疗效并降低毒性。将ADC领域的最新科学进展更好、更快地转化为针对被诊断为卵巢癌、子宫内膜癌或宫颈癌患者的合理临床试验，可能会切实改善我们患者的肿瘤反应、生存率和生活质量。
