Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China.
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, China.
Adv Mater. 2023 Nov;35(46):e2300377. doi: 10.1002/adma.202300377. Epub 2023 Oct 15.
Antibody-drug conjugates (ADCs) have exciting possibilities in targeted tumor therapy. However, in the existing ADC preparation processes, the random attachment of the payloads to the antigen-binding fragments (Fab) greatly increases the risk of disrupting its antigen recognition ability, while the drug-antibody ratio (DAR) is low, leading to a cumbersome preparation process and low drug delivery efficiency. Herein, poly(glutamic acid) is used to expand the number of drug binding sites, based on the "click chemistry" of azide and DBCO, and the high affinity of Fc-III-4C peptide to the crystalline fragment (Fc) of the monoclonal antibodies. Various antibody-polymer-drug conjugates are obtained with ultrahigh DAR using this organic-solvent-free "Lego-like" modular construction. Among them, aHER2-P-MMAE with DAR of 41.6 achieves tumor growth inhibition (TGI) of 99.7% for both medium-sized and large SKOV-3 ovarian tumors, and aPDL1-P-MMAE (DAR = 40.7) achieves TGI of 98.5% for MC38 colon tumors. In summary, a universal platform is created to prepare Fab-nondestructive ADCs with ultrahigh DAR, which can be used to develop precision medicine for personalized anticancer therapy.
抗体药物偶联物（ADCs）在靶向肿瘤治疗方面具有令人兴奋的应用前景。然而，在现有的 ADC 制备过程中，由于有效载荷随机连接到抗原结合片段（Fab）上，这极大地增加了破坏其抗原识别能力的风险，同时药物抗体比（DAR）较低，导致繁琐的制备过程和较低的药物递送效率。在此，我们基于叠氮化物和 DBCO 的“点击化学”，以及 Fc-III-4C 肽与单克隆抗体的结晶片段（Fc）之间的高亲和力，使用聚（谷氨酸）来扩展药物结合位点的数量。使用这种无有机溶剂的“乐高式”模块化构建方法，得到了具有超高 DAR 的各种抗体-聚合物-药物偶联物。其中，DAR 为 41.6 的 aHER2-P-MMAE 对中等大小和大 SKOV-3 卵巢肿瘤的肿瘤生长抑制（TGI）达到 99.7%，而 DAR 为 40.7 的 aPDL1-P-MMAE 对 MC38 结肠肿瘤的 TGI 达到 98.5%。总之，我们创建了一个通用平台，用于制备 Fab 非破坏性的超高 DAR ADC，这可用于开发用于个性化抗癌治疗的精准医学。
