Zhang Honglei, Sun Jiali, Zhang Yu, Zhang Zhenqian, Wang Xiaoshuang, Liu Zhilin, Zhang Xuefei, Tang Zhaohui, Chen Xuesi
Key Laboratory of Environmentally Friendly Chemistry and Applications of Ministry of Education and Key Laboratory of Polymeric Materials & Application Technology of Hunan Province, Xiangtan University, Xiangtan, 411105, PR China; Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China.
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China; School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, China.
Biomaterials. 2023 Oct;301:122285. doi: 10.1016/j.biomaterials.2023.122285. Epub 2023 Aug 17.
Antibody-drug conjugates (ADCs) are the most potent active tumor-targeting agents used clinically. However, the preparation of ADCs with high drug-to-antibody ratios (DARs) remains a major challenge. Herein, a Fab-nondestructive SN38-loaded antibody-polymeric-drug conjugate (APDC), aPDL1-NPLG-SN38, was prepared that had a DAR as high as 72 for the first time, by increased numbers of payload binding sites via the carboxyl groups of poly (l-glutamic acid) (PLG). The bonding of Fc-III-4C peptide with PLG-graft-mPEG/SN38 (Fc-NPLG-SN38) was achieved using a click reaction between azide and DBCO groups. The aPDL1-NPLG-SN38 conjugate was then synthesized by the high-affinity interaction between the Fc-III-4C peptide in Fc-NPLG-SN38 and the crystallizable fragment (Fc) of PDL1 monoclonal antibody (aPDL1). This approach avoided the potential deleterious effects on the Fab structure of the monoclonal antibody. The aqueous environment used in its preparation helped maintain monoclonal antibody recognition capability. Through the specific recognition by aPDL1 of PDL1 that is highly expressed on MC38 tumors, the accumulation of aPDL1-NPLG-SN38 in the tumors was 2.8-fold greater than achieved with IgG-NPLG-SN38 that had no active tumor-targeting capability. aPDL1-NPLG-SN38 exhibited excellent therapeutic properties in both medium-sized and large MC38 tumor animal models. The present study provides the details of a novel preparation strategy for SN38-loaded ADCs having a high DAR.
抗体药物偶联物（ADC）是临床上使用的最有效的主动肿瘤靶向药物。然而，制备高药物与抗体比率（DAR）的ADC仍然是一个重大挑战。在此，通过聚（L-谷氨酸）（PLG）羧基增加有效载荷结合位点，首次制备了一种Fab无损的负载SN38的抗体-聚合物药物偶联物（APDC），即aPDL1-NPLG-SN38，其DAR高达72。利用叠氮化物和DBCO基团之间的点击反应实现了Fc-III-4C肽与PLG-接枝-mPEG/SN38（Fc-NPLG-SN38）的结合。然后，通过Fc-NPLG-SN38中的Fc-III-4C肽与PDL1单克隆抗体（aPDL1）的可结晶片段（Fc）之间的高亲和力相互作用，合成了aPDL1-NPLG-SN38偶联物。这种方法避免了对单克隆抗体Fab结构的潜在有害影响。其制备过程中使用的水性环境有助于维持单克隆抗体的识别能力。通过aPDL1对MC38肿瘤上高表达的PDL1的特异性识别，aPDL1-NPLG-SN38在肿瘤中的蓄积量比没有主动肿瘤靶向能力的IgG-NPLG-SN38高2.8倍。aPDL1-NPLG-SN38在中型和大型MC38肿瘤动物模型中均表现出优异的治疗特性。本研究提供了一种制备高DAR的负载SN38的ADC的新策略的详细信息。
