Cryptophycin-55/52 based antibody-drug conjugates: Synthesis, efficacy, and mode of action studies
Cryptophycin-55/52 based antibody-drug conjugates: Synthesis, efficacy, and mode of action studies
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基于 Cryptophycin-55/52 的抗体-药物偶联物：合成、功效和作用方式研究
DOI：
10.1016/j.ejmech.2020.112364
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发表时间：
2020
影响因子：
6.7
通讯作者：
Yang Jinliang
中科院分区：
文献类型：
--
作者：
Lai Qinhuai;Wu Mengdan;Wang Ruixue;Lai Weirong;Tao Yiran;Lu Ying;Wang Yuxi;Yu Lin;Zhang Ruirui;Peng Yujia;Jiang Xiaohua;Fu Yuyin;Wang Xin;Zhang Zhixiong;Guo Cuiyu;Liao Wei;Zhang Yiwen;Kang Tairan;Chen Hao;Yao Yuqin;Gou Lantu;Yang Jinliang
Cryptophycin-52（CR 52）是一种微管蛋白抑制剂，在体外（皮摩尔水平）和小鼠异种移植模型中显示出有希望的抗肿瘤活性。然而，临床试验中狭窄的治疗窗口限制了其进一步发展。抗体-药物偶联物（Antibody-drug conjugate，ADC）是将细胞毒性化合物（payload）通过连接体与抗体偶联而形成的，能够通过抗体将药物靶向递送至肿瘤部位，增强治疗效果，降低毒副作用。本研究旨在探讨基于CR 52的ADC用于肿瘤靶向治疗的可能性。由于CR 52中缺乏偶联位点，合成了含有游离羟基的前药念珠藻素-55（CR 55），并通过基于Mc-NHS和Mc-Val的连接体与模型抗体曲妥珠单抗（FDA批准用于乳腺癌治疗的抗HER 2抗体药物）偶联。Cit-PAB-PNP。曲妥珠单抗-CR 55偶联物（命名为T-L1-CR 55、T-L2-CR 55和T-L3-CR 55）的平均药物-抗体比（DAR）分别为3.50、3.29和3.35。这些偶联物在HER 2阳性肿瘤细胞系中表现出强效细胞毒性，IC 50值为低纳摩尔水平（0.58-1.19 nM）。此外，在已建立的卵巢癌（SKOV 3）和胃癌（NCI-N87）异种移植模型中，10 mg/kg剂量下，它们显示出显著的抗肿瘤活性，无明显毒性。最后，药物释放进行了分析，结果表明，T-L3-CR 55能够有效地释放CR 55，并进一步环氧化为CR 52，这可能是负责其最好的抗肿瘤活性的性能。综上所述，我们的研究结果表明，这些缀合物具有肿瘤靶向治疗的潜力，这为进一步研究基于CR 55/CR 52的ADC用于肿瘤治疗提供了思路。
Cryptophycin-52 (CR52), a tubulin inhibitor, exhibits promising antitumor activityin vitro(picomolar level) and in mouse xenograft models. However, the narrow therapeutic window in clinical trials limits its further development. Antibody-drug conjugate (ADC), formed by coupling cytotoxic compound (payload) to an antibody via a linker, can deliver drug to tumor locations in a targeted manner by antibody, enhancing the therapeutic effects and reducing toxic and side effects. In this study, we aim to explore the possibility of CR52-based ADC for tumor targeted therapy. Due to the lack of a coupling site in CR52, its prodrug cryptophycin-55 (CR55) containing a free hydroxyl was synthesized and conjugated to the model antibody trastuzumab (anti-HER2 antibody drug approved by FDA for breast cancer therapy) via the linkers based on Mc-NHS and Mc-Val-Cit-PAB-PNP. The average drug-to-antibody ratios (DARs) of trastuzumab-CR55 conjugates (named T-L1-CR55, T-L2-CR55, and T-L3-CR55) were 3.50, 3.29, and 3.35, respectively. These conjugates exhibited potent cytotoxicity in HER2-positive tumor cell lines with IC50values at low nanomolar levels (0.58–1.19 nM). Further, they displayed significant antitumor activities at the doses of 10 mg/kg in established ovarian cancer (SKOV3) and gastric cancer (NCI–N87) xenograft models without overt toxicities. Finally, the drug releases were analyzed and the results indicated that T-L3-CR55 was able to effectively release CR55 and further epoxidized to CR52, which may be responsible for its best performance in antitumor activities. In conclusion, our results demonstrated that these conjugates have the potential for tumor targeted therapy, which provides insights to further research the CR55/CR52-based ADC for tumor therapy.