Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA.
Clinical Development and Regulatory, Sutro Biopharma, South San Francisco, CA.
Clin Lymphoma Myeloma Leuk. 2018 Jul;18(7):452-468.e4. doi: 10.1016/j.clml.2018.05.006. Epub 2018 May 10.
Antibody-drug conjugates (ADCs) are tripartite molecules consisting of a monoclonal antibody, a covalent linker, and a cytotoxic payload. ADC development has aimed to target the specificity inherent in antigen-antibody interactions to deliver potent cytotoxins preferentially to tumor cells and maximize antitumor activity and simultaneously minimize off-target toxicity. The earliest ADCs provided disappointing results in the clinic; however, the lessons learned regarding the need for human or humanized antibodies, more stable linkers, and greater potency payloads led to improved ADCs. Three ADCs, gemtuzumab ozogamicin, brentuximab vedotin (BV), and inotuzumab ozogamicin, have been approved for hematologic malignancies. Site-specific conjugation methods have now resulted in a new generation of more uniform, molecularly defined ADCs. These are expected to display improved in vivo properties and have recently entered the clinic. We reviewed investigational ADCs currently in clinical testing for the treatment of B-cell lineage malignancies, including leukemias, lymphomas, and multiple myeloma. The rationales for antigen targeting, data reported to date, current trial status, and preclinical results for several newer ADCs expected to enter first-in-human studies are presented. Owing to the large number of ongoing and reported BV clinical studies, only the studies of BV for diffuse large B-cell lymphoma and those combining BV with checkpoint inhibitors in B-lineage malignancies have been reviewed. With > 40 ongoing clinical trials and 7 investigational ADCs already having advanced to phase II studies, the role of ADCs in the armamentarium for the treatment of B-lineage malignancies continues to be elucidated.
抗体药物偶联物（ADCs）是由单克隆抗体、共价连接子和细胞毒性有效载荷组成的三部分分子。ADC 的开发旨在利用抗原抗体相互作用固有的特异性，将有效细胞毒素优先递送至肿瘤细胞，以最大化抗肿瘤活性，同时最小化脱靶毒性。最早的 ADC 在临床上的结果令人失望；然而，人们从中吸取的教训是需要使用人源化或人源抗体、更稳定的连接子和更高效的有效载荷，这导致了改进的 ADC 的出现。三种 ADC，即吉妥珠单抗奥佐米星、本妥昔单抗维达汀（BV）和奥滨尤妥珠单抗，已被批准用于血液系统恶性肿瘤。现在，基于位点的偶联方法已经产生了新一代更均匀、分子定义明确的 ADC。这些 ADC 有望显示出改进的体内特性，并已最近进入临床研究。我们回顾了目前正在临床研究中用于治疗 B 细胞谱系恶性肿瘤的研究性 ADC，包括白血病、淋巴瘤和多发性骨髓瘤。我们介绍了用于抗原靶向的原理、迄今为止报告的数据、当前的临床试验状况，以及几种预计将进入首次人体研究的新型 ADC 的临床前结果。由于正在进行和报告的 BV 临床研究数量众多，我们仅对用于弥漫性大 B 细胞淋巴瘤的 BV 研究，以及在 B 细胞恶性肿瘤中与检查点抑制剂联合使用的 BV 研究进行了综述。由于有 40 多项正在进行的临床试验和 7 种研究性 ADC 已经进入 II 期研究，ADC 在治疗 B 细胞谱系恶性肿瘤中的作用仍在不断阐明。
